CN106727453B - A kind of application of compound in preparation treatment hypothyroidism drug - Google Patents
A kind of application of compound in preparation treatment hypothyroidism drug Download PDFInfo
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Abstract
The invention discloses a kind of bromine phenolic compound 3-bromo-4- [3-bromo-4,5-dihydroxybenzyl] -5- (ethoxymethyl) benzene-1, the new application of 2-diol, the Diagnostic Value of Fasting Serum thyroid hormone (T3, T4, FT3, FT4) that the compound can be improved hypothyroidism animal pattern is horizontal, thyrotropic hormone (TSH) level in serum is reduced, can be used for preparing treatment hypothyroidism drug.
Description
Technical field
The invention belongs to a kind of bromine phenolic compound (compound names: 3-bromo-4- [3-bromo-4,5-
Dihydroxybenzyl] -5- (ethoxymethyl) benzene-1,2-diol (English name), the bromo- 4- of 3- [3- bromo- 4,
5- dihydroxy benzyl] -5- (ethoxymethyl) -1,2- benzenediol (Chinese), hereinafter referred to as: compound A) new application, especially
It is related to application of the compound A in preparation treatment hypothyroidism drug.
Background technique
Hypothyroidism (hypothyroidism, hereinafter referred to as: first subtracts) is a kind of serious harm people's body
The common endocrine system disease of health, clinical with serum thyroid hormones level (T3, T4, FT3, FT4) reduction, thyroid swashs
It is its main feature that plain (TSH), which is increased, with the low basal metabolic rate syndrome even myxedema such as fatigue and weakness, chilly be cold
It is mainly showed for it.
Recently as constantly increasing for thyroid disease disease incidence, the disease incidence that first subtracts also has the tendency that obviously increasing,
And often can simultaneously with or the multisystems multi viscera such as lead to angiocarpy, the cerebrovascular, digestion, breathing, adrenal gland, sexual gland damage
Evil, state of an illness severe one can occur first and subtract serious complication or even the threat to life such as crisis, cardiorenal function failure and lead to death.
Since the pathogenesis to this disease is not yet completely understood, modern medicine clinically subtracts treatment to first and mainly takes first shape
The anti-disease of effecting a permanent cure of glandular hormone preparation alternative medicine, this alternative medicine is palliative, need to often rely on medication throughout one's life, and many patients are past
Toward interrupting treatment because not being resistant to, and this alternative medicine side effect is also larger, while dividing caused by subtracting to first in other
It is unobvious to secrete Organ Dysfunction's curative effect, it is seen that ideal effect has not yet been reached to the treatment of this disease in present clinical commonly used drug,
Therefore the active drug for finding anti-disease of effecting a permanent cure is that clinical first subtracts disease and has one of important topic to be solved.
Compound A is that inventor is isolated from marine red alga Marine Red Alga Polysiphonia Urceolata (Polysiphonia urceolata)
A kind of compound, the doctoral thesis of inventor describe structure (Liu Quanwen, the trident rosetangle, Marine Red Alga Polysiphonia Urceolata and smelly of compound A for the first time
Peppery tree chemical component and bioactivity research, Postgraduate School, Chinese Academy of Sciences Ph.D. Dissertation, 2005), and as first
Author publishes structure and its free-radical scavenging activity (Liu Quanwen, Xu Hui, Li Guihua, the willow of compound A on publication
It is lined, Zhang Ting, Zou Ning, the identification and its free radical scavenging activity Food Science of new brominated phenol in Zhang Xin Marine Red Alga Polysiphonia Urceolata, 2009,
30(17): 127-129.).
In existing report, compound A plays the role of hypoglycemic weight-reducing (patent CN2004100875067), ties with compound A
The similar compound of structure can be used for treating cardiovascular and cerebrovascular disease (patent caused by the various ischemics as thrombotic
CN200710014327.4), still, free-radical scavenging activity, the effect of hypoglycemic weight-reducing and antithrombotic use can not be right
The present invention provides any enlightenment, there are no report of the compound A in treatment hypothyroidism in the prior art,
There is no relevant pharmacological evaluation and molecular biology experiment report.
Summary of the invention
It can be used in preparing the compound A for treating and preventing hypothyroidism it is an object of the present invention to provide a kind of,
Show the pharmacological action subtracted with good prevention and treatment first through animal pharmacological test, compound A can be used for preparing prevention and treatment first
The drug of shape hypoadenia disease, molecular structure are shown in formula 1.
1 compound A molecular structural formula of formula
Compound A's the preparation method comprises the following steps: document (Liu Quanwen, Xu Hui, Li Guihua, the Liu Cheng published with reference to inventor
Shade, Zhang Ting, Zou Ning, the identification and its free radical scavenging activity Food Science of new brominated phenol in Zhang Xin Marine Red Alga Polysiphonia Urceolata, 2009,30
(17): 127-129. the method recorded in).
The present invention has the advantage that compound A is easily prepared and industrial applications, compound A can be improved thyroid gland
Diagnostic Value of Fasting Serum T3, T4, FT3, FT4 of hypofunction disease animal pattern are horizontal, and reducing TSH level, compound A in serum can use
In treatment hypothyroidism.
Specific embodiment
Embodiment 1
The preparation of compound A is implemented through the following steps: the document published with reference to inventor (Liu Quanwen, Xu Hui,
The identification of new brominated phenol and its free radical scavenging activity food in Li Guihua, Liu Chengyin, Zhang Ting, Zou Ning, Zhang Xin Marine Red Alga Polysiphonia Urceolata
Science, 2009,30(17): the method recorded in 127-129.).
Detailed step is as follows: acquisition Marine Red Alga Polysiphonia Urceolata (Polysiphonia urceolata), cool place air-dries, and 50Kg is taken, with 90-
95% ethyl alcohol extracts 3 times at room temperature, uses 200 liters of ethyl alcohol every time, is then combined with alcohol extract, depressurizes back in temperature≤45 DEG C
Ethyl alcohol is received to no ethanol flavor, appropriate distilled water is added and is allowed to be suspended, is successively respectively extracted 4-6 times with chloroform and ethyl acetate respectively,
Under the conditions of temperature≤45 DEG C, chloroform and ethyl acetate are recovered under reduced pressure respectively, merges chloroform and acetic acid ethyl acetate extract, recycles molten
After agent sepia medicinal extract 750g, by silicagel column on 750g medicinal extract, using chloroform: acetone different volumes ratio as eluant, eluent (100:
0,50:1,20:1,10:1,5:1,2:1,0:100) eluted, Fractional Collections eluent, and with lamellae be unfolded into
Row detection (ferric trichloride test solution is color developing agent) simultaneously merges, and is divided into 8 rough segmentation positions (1-8), takes silica gel on the 3rd position
Column, with chloroform: acetone (9:1) be eluant, eluent, be divided into 3 flow points (3-1,3-2,3-3), take flow point 3-2(about 20g) on silica gel
Column, with chloroform: methanol (20:1) is that eluant, eluent obtains compound A, and purifies (being eluted with methanol) with gel column Sephadex-LH20
Pure compound A is obtained, through Spectrum Analysis, compound A identification are as follows: 3-bromo-4- [3-bromo-4,5-dihydroxybenzyl]-
5- (ethoxymethyl) benzene-1,2-diol (English name), the Chinese of compound A are as follows: the bromo- 4- [3- of 3-
Bromo- 4,5- dihydroxy benzyl] -5- (ethoxymethyl) -1,2- benzenediol.
Compound A has following physicochemical characteristics:Compound A structure formula are as follows: C16H16Br2O5,Its physical state is without fixed
Type powder；Ultraviolet spectrum data UV (MeOH) λmax(log ε) 289.50 (3.76), 207.50 (4.76) nm；Ir data IR (KBr) vmax 3388, 2924, 2870, 1662, 1608, 1583, 1490, 1427,
1348, 1284, 1095, 981, 754 cm-1；Nuclear magnetic resonance spectroscopy (1H-NMR, 400MHz,d H) data (solvent: deuterated
Acetone): 6.97(s, H6), 4.08(s, H7) and, 4.32(s, H8), 3.43(q,J=7.2 Hz, H9), 1.10 (t,J=7.2
Hz, H10), 6.73 (d, J=2.4 Hz, H2 ') (note:JIndicate coupling constant,sIndicate unimodal,dIndicate bimodal,tIndicate triple
Peak,qIndicate quartet);Carbon-13 nmr spectra (13C- NMR, 100MHz,d C) data: 144.2(C1), 142.9 (C2),
114.5 (C3), 129.7 (C4), 130.5(C5), 115.8 (C6), 36.1 (C7), 70.9 (C8), 65.7 (C9), 15.1
(C10), 133.1(C1 '), 123.2(C2 '), 109.6(C3 ') and, 141.4(C4 '), 146.1(C5 ')；Mass spectrometric data EIMSm/z 450, 448, 446 [M]+ (1.5, 3, 1.5), 404 (43), 402 (86), 400 (43), 387 (20),
385 (40), 383 (20), 323 (52), 221 (52), 277 (18), 275 (18), 242 (100), 213
(18), 139 (10), 121 (18), 57 (11)。
The pharmacological experiment study that 2 Compound A treatment first of embodiment subtracts.
Experiment purpose: by animal experiment study, observation and verifying compound A are to hypothyroidism (abbreviation: first
Subtract) preventive and therapeutic effect of animal pattern.
Experimental material and drug: experimental animal is purebred healthy new zealand white rabbit, and at 3 monthly ages, weight 1.80~2.00Kg is female
Male fifty-fifty, the Shandong animal certificate number SCXK() 20090009, it is purchased from Shandong Luye Pharmaceutical Co., Ltd., meets conventional animals
Standard；Compound A is voluntarily separated preparation by inventor, through efficient liquid phase chromatographic analysis, purity >=98%；Thyroxin tablet, on
Extra large Great Wall biochemical-pharmaceutical factory production, lot number 20160603；Serum TSH, T3, T4, FT3, FT radioimmunoassay kit, are purchased
From Shanghai Jing Ma Biotechnology Co., Ltd.
Drug is prepared: compound A powder is configured to 1 mg/ml concentration with dimethyl sulfoxide；After thyroxin tablet is ground
1 mg/ml concentration is configured to distilled water.
Experimental method
Bibliography (make by Xu Min, Ou Ming, Qiu Heming, Zhang Xicheng, Zhang Xiaohui Hypothyroidism deficiency of yang rabbit model
Type research, Journal of Traditional Chinese Medicine 1990, (6): 45-49.) method, selection rabbit is experimental animal, using the side of thyroid gland time resection
Method modeling.
3 monthly ages purebred new zealand white rabbit 50 is taken, quantity half male and half female chooses each rabbit weight in 1.80~2.20Kg
Between, 50 rabbits are randomly divided into 5 groups, every group of 10 rabbits, it may be assumed that fill after thyroid gland time excision group (model group), thyroid gland time excision
Compound A small dose group (compound A is gavaged after taking time excision of compound A large dosage group (compound A large dosage group), thyroid gland
Small dose group), thyroid gland gavages thyroxin tablet group (Western medicine group) after time cutting, thyroid gland does not cut off group (normal group).
Preceding 4 groups of rabbit parathyroid tissues are extractd 3/4ths under sterile, anesthesia, normally organize not excising thyroid group
It knits, is implementing perioperatively to detect serum calcium levels, it was demonstrated that parathyroid gland function is without damage, the 4th after thyroid gland time resection
It starts to give each group rabbit perfusion, and perfusion mode is that every rabbit is primary through the daily perfusion of stomach tube, and wherein compound A large dosage group is every
Secondary dosage is 5ml/kg weight, and each dosage of compound A small dose group is 2ml/kg weight；The each dosage of Western medicine group is
6ml/kg weight；Experimental rabbit gavages 5ml/kg weight physiology salt in identical perfusion method once a day in model group and normal group
Water.
Continue stomach-filling 20 days, then to each group experimental rabbit from abdominal aortic blood, every rabbit takes blood 5ml, gives rabbit before blood sampling
Prohibit water, fasting 12 hours, is centrifuged with blood sample of 3000 revs/min of the revolving speed to acquisition, takes serum to test, rabbit anteserum
Thyroid hormone and thyrotropic hormone normal range (NR) estimated value are acquired by the testing result average value for normally organizing 10 experimental rabbits.
Experimental result and analysis.
(1) compound A subtracts model rabbits Diagnostic Value of Fasting Serum thyroid hormone (T to first3、T4、FT3、FT4) and influence.
Experimental result:Thyroid Hormones In Serum T3 is horizontal (unit: ng/dl): model group is 57.10 ± 9.47, is changed
Conjunction object A large dosage group 96.85 ± 10.84, compound A small dose group 82.32 ± 9.98, Western medicine group 71.85 ± 9.84, normal group
102.08±14.35；Thyroid Hormones In Serum T4 is horizontal (unit: μ g/dl): model group is 14.25 ± 4.53, chemical combination
Object A large dosage group 23.93 ± 6.27, compound A small dose group 19.98 ± 4.58, Western medicine group 18.21 ± 4.27, normal group
25.37±5.98;Thyroid Hormones In Serum FT3 is horizontal (unit: pmol/ml): model group is 1.85 ± 0.84, chemical combination
Object A large dosage group 3.49 ± 1.53, compound A small dose group 2.87 ± 1.29, Western medicine group 2.57 ± 0.76, normally organize 4.11 ±
1.56；Thyroid Hormones In Serum FT4 is horizontal (unit: pmol/ml): model group is 1.28 ± 0.58 compound A large dosages
Group 2.44 ± 0.52,2.14 ± 0.68 Western medicine group 1.91 ± 0.46 of compound A small dose group normally organize 3.01 ± 0.78.
Experimental result data analysis: after 1. cutting art to rabbit modeling with thyroid gland, with normal group each hormonal readiness of rabbit anteserum
It makes comparisons, rabbit thyroid hormones level can be made to be substantially reduced, form first and subtract model rabbits, model group Diagnostic Value of Fasting Serum T3、T4、FT3、FT4
It is substantially reduced, there is significant differences (P < 0.01) compared with normal group, illustrate to cut the method for art to rabbit using thyroid gland
Modeling is successful；2. compound A group, after with Compound A treatment, the large and small dosage of compound A is respectively compared with model group, rabbit
Diagnostic Value of Fasting Serum T3、T4、FT3、FT4Apparent increase has significant difference (P < 0.01) as a result through statistical test；Western medicine group through with
After thyroxin tablet treatment, compared with model group, Diagnostic Value of Fasting Serum T3、T4、FT3、FT4Apparent increase, through statistical test, as a result
There is significant difference (P < 0.05), illustrating compound A and thyroxin tablet has raising T3、T4、FT3、FT4Effect；3. chemical combination
Object A large dosage group, small dose group are compared with Western medicine group, Diagnostic Value of Fasting Serum T3、T4、FT3、FT4Significantly raised value is apparently higher than Western medicine
As a result group has significant difference (P < 0.05) through statistical test, compound A is prompted to increase T3、T4、FT3、FT4Effect it is excellent
Thyreoidine plain piece；4. comparing between the large and small dosage group of compound A, Diagnostic Value of Fasting Serum T3、T4、FT3、FT4Lift-off value has conspicuousness
Difference (P > 0.05) illustrates that compound A increases T3、T4、FT3、FT4Effect have obvious dose-effect dependence.
Experimental result illustrates that compound A subtracts first and has preferable preventive and therapeutic effect, is better than Western medicine group, and have dose dependent.
(2) compound A subtracts the influence of model rabbits TSH to first
In serum thyrotropic hormone TSH level (unit: pmol/ml) laboratory test results: model group be 25.48 ±
3.56, compound A large dosage group 15.24 ± 1.94, compound A small dose group 17.52 ± 1.97, Western medicine group 20.85 ±
1.75, normally organize 14.92 ± 1.84.
Experimental result data analysis shows that: 1. compound A large dosage group, small dose group after with Compound A treatment, respectively
Compared with model group, it is statistically analyzed significant difference (P < 0.01), Western medicine group with thyroxin tablet after being treated, with mould
Type group compares, and has significant difference (P < 0.05), and illustrating compound A and thyroxin tablet plays the role of reducing TSH；2. chemical combination
Object A large dosage group, small dose group have significant difference (P < 0.05) compared with Western medicine group, and compound A is prompted to reduce TSH's
Effect is better than thyroxin tablet；3. comparing between the large and small dosage group of compound A, there is significant difference (P > 0.05), illustrate chemical combination
Object A reduces the effect of TSH without obvious dose-effect dependence, and prompting compound A to subtract first has preferable preventive and therapeutic effect.
Conclusion: can be seen that compound A from above-mentioned experimental studies results and subtract disease rabbit model to first has good therapeutic effect
And there is dose dependent.
Application examples 1
0.50 gram of compound A of the preparation of Example 1, is added 29.50 grams of excipient medical starch, is uniformly mixed, system
Grain, whole grain tabletting, obtained 100, tablet, every 5 milligrams of A containing compound.
Application examples 2
A2 grams of compound of the preparation of Example 1, is added to 1998 grams of distilled water, and solubilizer, corrigent and anti-corrosion is added
Appropriate agent, is made oral solution, and every milliliter A1 containing compound milligrams.
Claims (1)
1. a kind of application of bromine phenolic compound in preparation treatment hypothyroidism drug, which is characterized in that the bromine
Phenolic compounds are as follows: the bromo- 4- of 3- [the bromo- 4,5- dihydroxy benzyl of 3-] -5- (ethoxymethyl) -1,2- benzenediol；The compound has
Diagnostic Value of Fasting Serum thyroid hormone T3, T4, FT3, the FT4 for improving hypothyroidism animal pattern are horizontal, reduce in serum
The effect of thyrotropic hormone TSH level.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101426488A (en) * | 2006-03-28 | 2009-05-06 | 卡罗生物股份公司 | Stable oral pharmaceutical composition containing thyroid hormone receptor agonists |
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- 2017-01-13 CN CN201710024332.7A patent/CN106727453B/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101426488A (en) * | 2006-03-28 | 2009-05-06 | 卡罗生物股份公司 | Stable oral pharmaceutical composition containing thyroid hormone receptor agonists |
Non-Patent Citations (1)
| Title |
|---|
| 多管藻中新溴代酚的鉴定及其自由基清除活性;柳全文等;《食品科学》;20091231;第30卷(第17期);第129页最后一段 |
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