CN102397275B - Aromatization enzyme inhibitor - Google Patents
Aromatization enzyme inhibitor Download PDFInfo
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- CN102397275B CN102397275B CN201110290620.XA CN201110290620A CN102397275B CN 102397275 B CN102397275 B CN 102397275B CN 201110290620 A CN201110290620 A CN 201110290620A CN 102397275 B CN102397275 B CN 102397275B
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Abstract
The invention relates to a series of aromatization enzyme inhibitors. In a structural formula, R1, R2 and R3 can be selected from -H, CH3-, CH3CH2-, CH3CH2CH2-, -Cl, -Br, -F, -OH, HOCH2CH2-, -COOH or ester of -COOH respectively; R4 is -H or alkyl; and n is 1, 2, 3, 4 or 5 and 1-benzyl carbazole. A series of ortho-methyl phenyl carboxylic acid compounds and derivatives thereof are synthesized by changing certain terminal structures of an ortho-methyl phenyl carboxylic acid compound, and a benzyl 1-benzyl carbazole compound is synthesized by taking carbazole as a raw material. These compounds have good inhibiting effects on aromatization enzymes. As proved by testing, the highest aromatization enzyme inhibiting activity of the inhibitor is 0.7 mug/mL, which is higher than that of aminoglutethimide (7.7 mug/mL) serving as a first generation aromatization enzyme inhibitor.
Description
Technical field
The invention belongs to the enzyme inhibitor field, especially a kind of arimedex.
Background technology
1, the structure of aromatase and function
Aromatase (Aromatase, CYP19) belong to the Cytochrome P450 superfamily, it is a kind of pheron that is formed by 503 aminoacid, extensively be present in the normal structure organs such as ovary, Placenta Hominis, testis, brain, fat, bone, be expressed in the endocytoplasmic reticulum film, and be combined with film close, at Placenta Hominis and stratum granulosum folliculi ovarici vesiculosi cell high expressed, between subcutaneous fat, muscle, liver, brain, normal breast, in the non-gland tissues such as matter and breast carcinoma low expression level is arranged also.In the Postmenopausal Breast Cancer patient's that 80 percent estrogen receptor (ER) the is positive tumor tissues activity of aromatizing enzyme is arranged.The active center of aromatase also has the porphyrin ring (haemachrome prothetic group) of an iron content, and it plays decisive role to the catalytic activity of enzyme, and wherein the iron atom at haemachrome prothetic group center 4 pyrroles's nitrogen-atoms on porphyrin ring are combined with coordinate bond.
Aromatase claims again the estrogen synthesis enzyme, and the synthetic estrone of catalysis androstenedione and testosterone and estradiol can make androgen change estrogen into, are the rate-limiting enzymes that androgen is converted into the estrogen process.In pre-menopausal women, the main transovarial aromatase of estrogen produces, androgen changes estrogenic process into and is subjected to the follicule-stimulating hormone (FSH) of hypophysis and the regulation and control of luteotropic hormone, under normal feedback loop regulation and control, can promote estrogenic secretion by the pituitary promoting sexual gland hormone, with to antiestrogenic minimizing, therefore, to premenopausal patient with breast cancer use separately arimedex (Aromatase inhibitors, AIs) can not establishment male, estrogenic transformation.Postmenopausal women's ovary no longer produces estrogen, estrogen is mainly derived from the peripheral tissues such as fat, muscle and liver, this process is not regulated and control by hypophysis, androgen becomes estrogen via aromatase on every side, owing to do not have feedback loop antagonism arimedex produce an effect, so postclimacteric patient with breast cancer can reduce hero, estrogenic conversion rates after taking arimedex greatly.
2, expression and the meaning of aromatase in breast carcinoma
Breast carcinoma is a kind of WomanHealth even life-threatening commonly encountered diseases and frequently-occurring disease of having a strong impact on, and wherein is estrogen-dependent type more than 1/3rd.Aromatase (Aromatase) is member in the cytochrome P 450 enzymes family, and in vivo take testosterone, androstenedione and 16-α-hydroxyandrostenedione as the physiology substrate, effect changes into estrone and estradiol through aromatization.Clinical research is found, estrogen level in postmenopausal women's peripheral circulation obviously descends, but the mammary gland tissue at the aromatase high expressed, estrogenic level is 10 times of periphery, the substrate androstenedione is 8 times of periphery, therefore the estrogen environment that has high concentration in the breast cancer tissue promotes recurrence and the transfer of breast carcinoma.Therefore, suppress activity of aromatizing enzyme, can suppress recurrence and the transfer of breast carcinoma.
Experimental studies have found that the activity of blocking-up aromatase can suppress the propagation of MCF-7 cell, but not obvious to normal breast epithelium function of organization; Zoopery finds that also the mammary gland tissue of the transgenic mice of high expressed aromatase presents the state of precancerous lesion.(the Brodie A such as Brodie, Lu Q, LiuY, et al.Preclinical studies using the intratumoral aromatase model for postmenopausal breast cancer[J] .Oncology (Huntingt), 1998,12 (35): 361-372) reported that the activity of aromatase and breast carcinoma propagation index PCNA have dependency, the above results has shown that all the estrogen level of the aromatase of high expressed in the breast carcinoma and breast cancer tissue's middle and high concentration is closely related, and this just provides theoretical foundation for using clinically arimedex treatment breast carcinoma.
3, the mechanism of action of arimedex
The mechanism of action of arimedex is to comprise the aromatase in the breast cancer tissue by inhibition adrenal gland, liver, fat, stop it to utilize androstenedione and testosterone to produce estrogen, thereby estrogen level in the reduction blood suppresses the estrogen dependent cancer Growth of Cells.Most of aromatase in breast carcinoma tissues have in the tumor active, this activity is directly relevant with tumor inner estrogen level, arimedex has significant inhibitory action to it, and the activity of aromatizing enzyme in the inhibition tumor cell helps the growth of inhibition tumor cell, found afterwards, Pre-menopausal Women is used arimedex owing to weakened the negative feedback inhibition of estrogen to hypothalamus and hypophysis, cause gonadotrophin secretion to be strengthened, visible ovary weight increases in some animal models, therefore, arimedex is substantially invalid to the normal Pre-menopausal Women of ovarian function.Because adrenal gland and fatty tissue also can produce estrogen, and be the estrogenic main source of postmenopausal women's peripheral blood, so can be with arimedex as the postmenopausal women, the another direction of estrogen-dependent patient with breast cancer's endocrine therapy particularly, and as far back as eighties of last century seventies, people with the arimedex clinical practice in the treatment of breast carcinoma.
Meanwhile, consider from physiological function and the construction features thereof of aromatase, the mechanism of action of arimedex is divided into two kinds: a kind of is to have similar structure to the natural substrate of enzyme, can compete the binding site of aromatase, and this type of inhibitor mostly is the analog of androstenedione; Another is to have hetero atom (such as S, O, N etc.) in the structure, these hetero atoms can with haemachrome in the iron atom combination.In addition, also have some inhibitor by suppressing the expression of corresponding gene, indirectly suppress the activity of aromatase; Some natural products also have the aromatase inhibitory action, also can be used as the competitive inhibitor of aromatase.
4, the clinical development of arimedex
Sequential by clinical development, arimedex can be divided into 3 generation (LEZEM, BORGNEM, PINSONP, et al.Synthes is and biologica evaluation of 5-[(aryl) (1H-imida-zol-1-yl) methyl]-1H-indoles:potent and selective aromatae inhibitors[J] .Bioorg Med Chem Lett, 2006,16 (5): 1134-1137): the amino that comprises 1st generation is led dormancy, the Arensm of 2nd generation, the Anastrozole in Rogletimide (Rogletimide) and the 3rd generation, letrozole, vorozole (Vorozole).
1st generation arimedex amino is led dormancy (Aminoglutethimide) and is used for clinical as antiepileptic at first, be used to hormone-dependent type breast carcinoma in late period the sixties in 20th century, but the selectivity of finding this medicine is too poor, when suppressing aromatase, also extensively affect other steroid hormone metabolic processes, the metabolism of adrenocortical hormone also is affected, and must replenish glucocorticoid during with this medicine.
2nd generation arimedex Lentaron (Lentaron) is the intramuscular injection dosage form, this medicine selectivity is better, do not affect the metabolism of other steroid hormones in the body, do not need to replenish glucocorticoid during use, but its curative effect is not better than tamoxifen, and be intramuscular injectable formulations, use inconvenient.Arensm (Fadrozole) reduces aldosterone level, has limited its application dose and can only reach 90% inhibition and render a service, the clinical practice that do not go through of other 2nd generation arimedexs.
The 3rd generation arimedex mainly comprise the Anastrozole of triazole type and letrozole and steroidal compounds letrozole (Letrozole), Anastrozole (Anastrozole), exemestane (Exemestane).Compare with the 1st, 2 generations, the 3rd generation its effectiveness that suppresses whole body activity of aromatizing enzyme and estrogen level of arimedex reach more than 97%, substantially reached Utopian requirement, metabolism to other steroid hormones does not produce interference, selectivity is higher, specificity is stronger, toleration is better, and without cross resistance, on the almost not impact of metabolism of hydrocortisone or aldosterone, the toleration of elderly patient and some organ function impaired patients is also fine.And be oral formulations, taking convenience, few side effects.
It is different to press simultaneously mechanism of action, can be divided into amphitypy by arimedex: the I type is the steroidal analog of androstenedione, belong to steroid aromatase deactivator, irreversibly be incorporated into the androstenedione site of aromatase, play the enzyme-deactivating effect, mainly comprise Formestane and the exemestane in the 3rd generation of 2nd generation; The II type is the non-steroidal inhibitor, belongs to nonsteroidal arimedex, can reversibly be combined with the heme of aromatase by a basic nitrogen-atoms, hinders NADPH dehydrogenation oxidation process, thereby suppresses the activity of aromatase.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art part, a kind of arimedex is provided, this inhibitor can reversibly be combined with the heme of aromatase by a basic nitrogen-atoms, hinder NADPH dehydrogenation oxidation process, thereby the activity that suppresses aromatase can effectively reduce estrogen content in the body, can be used for treatment or Breast Cancer Prevention.
The objective of the invention is to be achieved through the following technical solutions:
A kind of arimedex, its general structure is as follows:
Wherein, R
1, R
2, R
3Be selected from respectively-H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-,
-Cl ,-Br ,-F ,-OH, HOCH
2CH
2-,-COOH or-ester of COOH;
R
4For-H or alkyl, n is 0,1,2,3,4 or 5.
And described alkyl is CH
3-, CH
3CH
2-, CH
3CH
2CH
2-,
CH
3CH
2CH
2CH
2-,
And, described R
1, R
2, R
3Be selected from respectively-H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-,
-Cl ,-Br ,-F ,-OH, HOCH
2CH
2-or-a kind of among the COOH.
And the ester of described-COOH is-methyl ester, ethyl ester, n-propyl, isopropyl ester, ring propyl ester, the positive butyl ester of 1-or the positive butyl ester of 2-of COOH.
And described arimedex is adjacent (2-ethyl-4-methylimidazole-1-methyl) phenylacetic acid or 1-(2-methoxy carbonyl methyl) benzyl imidazole-4-Ethyl formate.
The application of above-mentioned arimedex in suppressing the aromatase medicine.
The application of above-mentioned arimedex in the treatment breast cancer medicines.
A kind of arimedex is characterized in that: structural formula is:
Advantage of the present invention and good effect are as follows:
1, the present invention is by changing some end structure of adjacent imidazoles aminomethyl phenyl carboxylic acid compound, synthesize a series of adjacent imidazoles aminomethyl phenyl carboxylic acid compounds and derivant thereof, and synthesize 1-benzyl carbazole compound take carbazole as raw material, these chemical compounds have preferably inhibitory action to aromatase, through verification experimental verification, this inhibitor suppresses the IC of aromatase
50Be up to 40ug/mL.
2, a series of arimedex provided by the invention can suppress androgen and changes estrogen into, for a kind of in the non-steroidal inhibitor, belong to nonsteroidal arimedex, can reversibly be combined with the heme of aromatase by a basic nitrogen-atoms, hinder NADPH dehydrogenation oxidation process, thereby the activity that suppresses aromatase can effectively reduce estrogen content in the body, can be used for treatment or Breast Cancer Prevention.
Description of drawings
Fig. 1 is the HNMR analysis chart of 2-chloromethylbenzene methyl acetate of the present invention;
Fig. 2 is the HNMR analysis chart of adjacent (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate of the present invention;
Fig. 3 is the HNMR analysis chart of adjacent (2-ethyl-4-methylimidazole-1-methyl) phenylacetic acid of the present invention;
Fig. 4 is the HNMR analysis chart of adjacent (the 4-Ethyl formate imidazoles-1-methyl) methyl phenylacetate of the present invention;
Fig. 5 is the HNMR analysis chart of adjacent (2-ethyl-4-methylimidazole-1-methyl) phenyl acetamide of the present invention;
Fig. 6 is the HNMR analysis chart of adjacent (glyoxal ethyline-1-methyl) methyl phenylacetate of the present invention;
Fig. 7 is the HNMR analysis chart of adjacent (glyoxal ethyline-1-methyl) phenyl acetamide of the present invention;
Fig. 8 is the HNMR analysis chart of adjacent (glyoxal ethyline-1-methyl) benzene acetonitrile of the present invention;
Fig. 9 is the HNMR analysis chart of adjacent (imidazoles-1-methyl) methyl phenylacetate of the present invention;
Figure 10 is the HNMR analysis chart of 1-benzyl carbazole of the present invention.
The specific embodiment
Below in conjunction with embodiment, the present invention is further described, and following embodiment is illustrative, is not determinate, can not limit protection scope of the present invention with following embodiment.
The general structure I of arimedex provided by the invention is as follows:
Wherein, R
1, R
2, R
3Can select arbitrarily at following group, these groups are :-H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-,
-Cl ,-Br ,-F ,-OH, HOCH
2CH
2-,-COOH or-ester of COOH, wherein ester group can be methyl ester, ethyl ester, n-propyl, isopropyl ester, ring propyl ester, the positive butyl ester of 1-, the positive butyl ester of 2-;
R
4Can be-H, CH
3-, CH
3CH
2-, CH
3CH
2CH
2-,
CH
3CH
2CH
2CH
2-,
In any one;
N is 0,1,2,3,4 or 5.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate
(1) 2-chloromethylbenzene methyl acetate preparation
Press United States Patent (USP) 6048998 preparations, get heterochromatic ketone (15g, 0.099mol) and be dissolved in (30.2g, 0.9mol) methanol solution, reaction bulb is put into ice-water bath, at-5 ℃-0 ℃ lower thionyl chloride (25g, 0.21mol) that drips; After dropwising, be warmed up to stirring at room two hours; After reaction finishes, solution of potassium carbonate with 10% is regulated pH＞6, with methanol extraction organic layer (75ml * 3 time), and with distilled water separatory (100ml * 3 time), anhydrous magnesium sulfate drying spends the night, and Rotary Evaporators is concentrated, get colourless oil liquid, product 2-chloromethylbenzene methyl acetate 16.9g, yield is 85%, reaction equation is as follows:
Its HNMR analysis chart is seen Fig. 1, wherein: 1H NMR (CDCl
3, ppm, relative to TMS, 400MHz): δ 3.689 (s, 3H), δ 3.800 (s, 2H), δ 4.667 (s, 2H), δ 7.365 (m, 2H), δ 7.279 (m, 2H).
(2) adjacent (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate preparation
Get 2-ethyl-4-methylimidazole (5g, 45.39mmol) and be dissolved in the 150ml chloroform, stir the lower 2-chloromethylbenzene methyl acetate (12g, 60.41mmol) that adds, behind the stirring 30min, heating direct is to refluxing 3h; Be cooled to room temperature, in the impouring distilled water, add the 100ml ethyl acetate, separatory and extract organic layer (2 times * 100ml); Anhydrous magnesium sulfate drying spends the night, and concentrated; Column chromatography purification (column chromatography silica gel, 100-200 order), ethyl acetate/petroleum ether (100: 300) eluting obtains neighbour's (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate, is faint yellow oily product, productive rate 64%.
Reaction equation:
Its HNMR analysis chart is seen Fig. 2: its nuclear-magnetism figure is: 1H NMR (CDCl
3, ppm, relative to TMS, 400MHz) and δ 1.27 (t, 3H), (2.20 s, 3H), 2.60 (m, 2H), (3.63 s, 3H), 3.69 (s, 2H), (5.06 s, 2H), 6.41 (s, 1H), (6.75 s, 1H), 6.77 (s, 1H), (7.23 s, 1H), 7.28 (s, 1H).
(3) aromatic enzyme-tion suppressioning activity of adjacent (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate is measured
(1) measuring principle
Under NADPH circular regeneration condition, but aromatase catalysis diphenyl fluorescein (dibenzylfluorescein, DBF) hydrolysis produces fluorescein (fluorescein).Catalytic mechanism changes estrogen into aromatase catalysis androgen.Therefore, can estimate according to the fluorescence intensity of fluorescein the catalytic activity of aromatase.Under the arimedex existence condition, can estimate the repressed situation of aromatase catalytic activity by control experiment.Experiment IF
0Aromatase catalysis DBF produces the amount of fluorescein during expression unrestraint agent, uses IF
iAromatase catalysis DBF produces the amount of fluorescein behind the expression adding inhibitor, and BLANK represents the system background value, then 100%-(IF
0-BLANK)/(IF
1-BLANK) * 100% be the tolerance that chemical compound suppresses the aromatase ability.
(2) reagent
1. NADPH circular regeneration system (C/SD liquid):
2.6mM?NADP
+，
7.6mM?glucose-6-phosphate，
0.8U/mL?glucose-6-phosphate?dehydrogenase，
13.9mM?MgCl
2，
1mg/mL?albumin，
Be dissolved in the buffer solution of potassium phosphate of 50mM (K-P Buffer, pH 7.4).
2. enzyme-substrate system (E/S liquid):
0.8μM?DBF，
40pmol/mL?of?aromatase，
4mg/mL?albumin，
Be dissolved in the buffer solution of potassium phosphate of 50mM (K-P Buffer, pH 7.4).
All samples is dissolved among the DMSO, and working concentration is 5 μ M.
(3) experimental procedure
Get 90 μ L C/SD liquid in 96 orifice plates, add each sample 10 μ L, mix 30s, hatch 10min under 37 ℃; Get rapidly 100 μ L the E/S liquid of preheating 3min in each hole, mix 30s, 37 ℃ of lower reaction 30min; In each hole, add the 2M NaOH solution of 75 μ L with the carrying out of cessation reaction; Then continue to hatch 2h under 37 ℃, treat signal stabilization, measure with fluorescence microplate reader, excitation wavelength is 485nm, and the mensuration wavelength is 535nm.Negative control adds 10 μ L DMSO, and solvent blank adds first and adding E/S liquid after NaOH solution stops.Suppressing the capacity calculation formula is: 100%-(IF
0-BLANK)/(IF
i-BLANK) * 100%.
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 1.6 μ g/mL.
(1) adjacent (2-ethyl-4-methylimidazole-1-methyl) phenylacetic acid preparation
Get neighbour's (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate 2.7g (10mmol) of preparation in the 100ml flask, add 10ml ethanol and 20ml 5%NaOH aqueous solution under stirring condition behind the backflow 10h, be neutralized to slant acidity with 6M hydrochloric acid, pressure reducing and steaming water is to doing, after the cooling with methanol extraction 2 times, merge methanol solution, pressure reducing and steaming methanol gets faint yellow oily thing, get faint yellow crystallization after the cooling and be neighbour's (2-ethyl-4-methylimidazole-1-methyl) phenylacetic acid, reaction equation is as follows:
Its HNMR analyzes and sees Fig. 3, wherein 1H NMR (CDCl
3, ppm, 400MHz) and δ 1.20 (t, 3H), 2.07 (s, 3H), (2.53 m, 2H), 3.30 (s, 3H), 3.50 (s, 2H), (5.02 s, 2H), 6.60 (s, 1H), 7.22 (m, 4H) MS:m/z=259.31 (M+H)
+, elementary analysis: C 69.25; H 7.12; N 10.91.
(2) adjacent (2-ethyl-4-methylimidazole-1-methyl) phenylacetic acid aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 17.3 μ g/mL.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (4-Ethyl formate imidazoles-1-methyl) methyl phenylacetate
(1) adjacent (4-Ethyl formate imidazoles-1-methyl) methyl phenylacetate is synthetic
Get imidazoles-4-Ethyl formate (5g, 35.68mmol) and be dissolved in the 150ml chloroform, stir the lower 2-chloroethyl methyl phenylacetate (8.0g, 40.27mmol) that adds, behind the stirring 30min, heating direct is to the 3h that refluxes.Be cooled to room temperature, in the impouring distilled water, add the 100ml ethyl acetate, separatory also extracts organic layer (2 * 100ml).Anhydrous magnesium sulfate drying spends the night, and concentrated.Column chromatography purification, ethyl acetate/petroleum ether (1: 3) eluting obtains neighbour's (4-Ethyl formate imidazoles-1-methyl) methyl phenylacetate, is white oily product, productive rate 73%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 4, wherein,
1H NMR (CDCl
3, ppm, relative to TMS, 400MHz) and δ 1.36 (t, 3H), 3.67 (s, 3H), 3.71 (s, 2H), 4.28 (m, 2H), 5.58 (s, 2H), 7.00 (s, 1H), (7.29 m, 2H), 7.49 (m, 2H), 7.81 (s, 1H) .MS:m/z=303.50 (M+H)
+, elementary analysis: C 63.27; H 6.24; N 9.21
(2) 1-(2-methoxy carbonyl methyl) benzyl imidazole-4-Ethyl formate aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 7.8 μ g/mL.
1, the synthetic and aromatic enzyme-tion suppressioning activity of adjacent (2-ethyl-4-methylimidazole-1-methyl) phenyl acetamide
(1) adjacent (2-ethyl-4-methylimidazole-1-methyl) phenyl acetamide is synthetic
Get neighbour's (2-ethyl-4-methylimidazole-1-methyl) methyl phenylacetate (3g, 11.02mmol) and be dissolved in the 10ml dehydrated alcohol, stir the lower 100ml of adding ammonia, stirring at room 3 days; The adularescent product is separated out in the solution, sucking filtration, and 35 ℃ of vacuum drying 12h obtain the white powder product, and yield is 36.4%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 5, wherein 1H NMR (CDCl
3, ppm, relative to TMS, 400MHz) and δ 1.106 (t, 3H), δ 2.058 (s, 3H), δ 2.504 (m, 2H), δ 3.497 (s, 2H), δ 5.164 (s, 2H), δ 5.505 (d, 1H), δ 6.643 (s, 1H), δ 6.985 (s, 1H), δ 7.234 (m, 3H), δ 7.538 (s, 1H) elementary analysis: N:16.47H:69.78H:7.455
(2) adjacent (2-ethyl-4-methylimidazole-1-methyl) phenyl acetamide aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be＞40 μ g/mL.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (glyoxal ethyline-1-methyl) methyl phenylacetate
(1) adjacent (glyoxal ethyline-1-methyl) methyl phenylacetate is synthetic
Get glyoxal ethyline (4.13g, 50.34mmol) and be dissolved in the 150ml chloroform, stir the lower K of adding
2CO
3(13.91,100.68mmol), stirring at room 30min; Stir the lower 2-chloroethyl methyl phenylacetate (5g, 25.17mmol) that drips, behind the stirring 30min, heating direct is to the 3h that refluxes.Be cooled to room temperature, in the impouring distilled water, add the 100ml ethyl acetate, separatory also extracts organic layer (3 * 75ml).Anhydrous magnesium sulfate drying spends the night, and concentrated.Column chromatography purification, ethyl acetate/petroleum ether (100: 100) eluting, adjacent (glyoxal ethyline-1-methyl) methyl phenylacetate, product is the pale yellow oily liquid body, productive rate 84.3%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 6: wherein,
1H NMR (DMSO, ppm, 400MHz): δ 2.169 (s, 3H), δ 3.627 (s, 3H), δ 3.824 (s, 2H), δ 5.176 (s, 2H), δ 6.560 (d, 1H), δ 6.813 (d, 1H), δ 6.982 (d, 1H), δ 7.247 (m, 3H)
(2) adjacent (glyoxal ethyline-1-methyl) methyl phenylacetate aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 1.7 μ g/mL.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (glyoxal ethyline-1-methyl) phenyl acetamide
(1) adjacent (glyoxal ethyline-1-methyl) phenyl acetamide is synthetic
Get neighbour's (glyoxal ethyline-1-methyl) methyl phenylacetate (3g, 12.28mmol) and be dissolved in the 10ml dehydrated alcohol, stir the lower 100ml of adding ammonia, stirring at room 3 days; The adularescent product is separated out in the solution, sucking filtration, and 35 ℃ of vacuum drying 12h obtain the white powder product, and yield is 43.7%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 7, wherein
1H NMR (DMSO, ppm, 400MHz): δ 2.177 (s, 3H), δ 3.516 (s, 2H), δ 5.241 (s, 2H), δ 6.483 (d, 1H), δ 6.804 (d, 1H), δ 6.993 (d, 2H), δ 7.231 (m, 3H), δ 7.543 (s, 1H)
(2) adjacent (glyoxal ethyline-1-methyl) phenyl acetamide aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 2.4 μ g/mL.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (glyoxal ethyline-1-methyl) benzene acetonitrile
(1) adjacent (glyoxal ethyline-1-methyl) benzene acetonitrile is synthetic
Get neighbour's (glyoxal ethyline-1-methyl) phenyl acetamide (1.5g, 6.54mmol) and be dissolved in 10ml POCl
3, 90 ℃ of back flow reaction 12 hours; Reaction is cooled to room temperature after finishing, and in the product impouring frozen water, it is neutral that 20% sodium carbonate liquor is regulated pH value, and 3 times (3 * 75ml), concentrated organic facies adds anhydrous magnesium sulfate drying and spends the night with ethyl acetate extraction.Product is through column chromatography purification (200-300 order column chromatography silica gel), chloroform/methanol (150: 10) eluting, and obtaining product is white crystal, yield is 62.1%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 8, wherein,
1H NMR (DMSO, ppm, 400MHz): δ 2.10 (s, 3H), δ 4.170 (s, 2H), δ 5.271 (s, 2H), δ 6.548 (d, 1H), δ 6.887 (s, 1H), δ 7.067 (s, 1H), δ 7.321 (m, 2H), δ 7.475 (d, 1H)
(2) adjacent (glyoxal ethyline-1-methyl) benzene acetonitrile aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be＞40 μ g/mL.
Synthetic and the aromatic enzyme-tion suppressioning activity of adjacent (imidazoles-1-methyl) methyl phenylacetate
(1) adjacent (imidazoles-1-methyl) methyl phenylacetate is synthetic
Get imidazoles (2g, 29.38mmol) and be dissolved in the 75ml chloroform, stir the lower potassium carbonate (10.15g that adds, 73.45mmol), stirring at normal temperature 15min stirs the lower 2-of dropping chloromethylbenzene methyl acetate (2.92g, 14.69mmol), behind the stirring 30min, heating direct is to the 10h that refluxes; Be cooled to room temperature, in the impouring distilled water, add the 100ml ethyl acetate, separatory and extract organic layer (2 times * 100ml); Anhydrous magnesium sulfate drying spends the night, and concentrated; Column chromatography purification (200-300 order column chromatography silica gel), ethyl acetate/petroleum ether (100: 300) eluting obtains neighbour's (imidazoles-1-methyl) methyl phenylacetate, is faint yellow oily product, productive rate 83.7%.Reaction equation is as follows:
Its HNMR analyzes and sees Fig. 9, wherein, and 1H NMR (CDCl
3, ppm, relative to TMS, 400MHz) and δ 3.621 (s, 2H), δ 3.675 (s, 3H), δ 5.206 (s, 2H), δ 6.864 (s, 1H), δ 7.013 (d, 1H), δ 7.083 (s, 1H), δ 7.292 (m, 3H), δ 7.491 (s, 1H).
(2) adjacent (imidazoles-1-methyl) methyl phenylacetate aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be＞40 μ g/mL.
Embodiment 9
(1) the synthetic and aromatic enzyme-tion suppressioning activity of 1-benzyl carbazole
Get carbazole (0.25g, 1.5mmol) be dissolved in the 75ml chloroform, stir the lower potassium carbonate (0.826g that adds, 5.98mmol), stirring at normal temperature 15min is dissolved in benzyl chloride (0.189g, 1.50mmol) in the 20ml chloroform and is configured to solution, slowly joined in the reactor by constant pressure funnel under the restir, under 40 ℃, react 8h after being added dropwise to complete.Import in the frozen water, have a large amount of white precipitates to generate.Leave standstill filtration, for several times until pH is neutral, the white powder of sucking filtration is out product with cold water washing.Use ethyl alcohol recrystallization, white crystal, productive rate is 56.3%.
Reaction equation is as follows:
Its HNMR analyzes and sees Figure 10, wherein, and 1H NMR (CDCl
3, ppm, relative to TMS, 400MHz) and δ 5.557 (s, 2H), δ 7.188 (d, 2H), δ 7.291 (m, 5H), δ 7.404 (d, 2H), δ 7.469 (m, 2H), δ 8.175 (d, 2H).
(2) 1-benzyl carbazole aromatic enzyme-tion suppressioning activity is measured
Press among the embodiment 1 arimedex activity determination method described in the step 3 and measure, must this chemical compound suppress the IC of aromatase
50Be 0.7 μ g/mL.
Claims (1)
1. arimedex, it is characterized in that: its general structure is as follows:
Wherein n is 1, R
1For-H, CH
3-, CH
3CH
2-, R
2For-H, CH
3-,-ester of COOH; R
3For-H, R
4Be CH
3-.
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Non-Patent Citations (6)
| Title |
|---|
| Imidazolylmethylbenzophenones as Highly Potent Aromatase Inhibitors;Silvia Gobbi,et al;《J.Med.Chem》;20070622;第50卷;第3420-3422页 * |
| Silvia Gobbi,et al.Imidazolylmethylbenzophenones as Highly Potent Aromatase Inhibitors.《J.Med.Chem》.2007,第50卷第3420-3422页. |
| 崔中立等.芳香化酶抑制剂的研究进展.《中国药物化学杂志》.2010,第20卷(第1期),第70-76页. |
| 张艳华等.芳香化酶抑制剂治疗乳腺癌的研究进展及临床评价.《中国医院用药评价与分析》.2004,第4卷(第01期),第9-11页. |
| 芳香化酶抑制剂治疗乳腺癌的研究进展及临床评价;张艳华等;《中国医院用药评价与分析》;20041231;第4卷(第01期);第9-11页 * |
| 芳香化酶抑制剂的研究进展;崔中立等;《中国药物化学杂志》;20101231;第20卷(第1期);第70-76页 * |
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