CN1733773A - Double(2-ethyl -3-hydroxyl-4-pyranone)copper(II)complex and its uses in treating diabetes - Google Patents
Double(2-ethyl -3-hydroxyl-4-pyranone)copper(II)complex and its uses in treating diabetes Download PDFInfo
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- CN1733773A CN1733773A CN 200510010956 CN200510010956A CN1733773A CN 1733773 A CN1733773 A CN 1733773A CN 200510010956 CN200510010956 CN 200510010956 CN 200510010956 A CN200510010956 A CN 200510010956A CN 1733773 A CN1733773 A CN 1733773A
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- copper
- hydroxyl
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- pyrokomane
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Abstract
Disclosed is a bis(2-ethyl-3hydroxy-4-pyranone) copper(II) complex and its use in treating diabetes, which relates to heterocyclic compound having oxygen atoms, especially a copper central ionic 2-ethyl-3-hydroxy-4-pyranone chelate and its use. The copper complex has a molecular formula of C14H14CuO6, and a formula weight of FW=341.5. The compound can be made into oral administration medicines against diabetes.
Description
Affiliated technical field
The present invention relates to contain the heterogeneous ring compound of Sauerstoffatom, particularly is the 2-ethyl-3-hydroxyl-pyrokomane inner complex and the application thereof of central ion with copper.
Background technology
Diabetes be one group because defect of insulin secretion and and the biological action obstacle causes is the metabolic disease of feature with the hyperglycemia, it can cause a series of complication, harm people's health.Modern study shows that Cu is the trace element of needed by human, active centre for many redox protein enzymes, in the metabolic process of glucose, play an important role [Yankee enemy chief editor. trace element is with healthy. Science Press. first version .2003, p91-106].Epidemiology survey shows shortage and the insufficient problem that has copper in diabetic subject's body, copper bearing compound can make the animal diabetes model demonstrate lowering blood glucose, improve activity [the JRJ Sorenson.Progress in Medicinal Chemistry of sugar tolerance, 1989,26,510-513].The hypoglycemic copper compound of research both at home and abroad and report is mainly CuSO at present
4, Cupric salicylate Cu (salicylate)
2, copper gluconate, Cu (gluconate)
2, voitol copper Cu (maltolate)
2, but theirs is fat-soluble poor, causes the low and hypoglycemic activity undesirable [SE Gandy, MG Buse.Diabetologia, 1983,24,437] [KH.Thompson, JH McNeil, COrvig.J Inorg Chem, 2004,98,683-690] of bioavailability.Therefore, the scientific worker is seeking and is testing the active high hypoglycemic copper complex of synthesizing new both at home and abroad.
Summary of the invention
The object of the invention provides a kind of new copper title complex that activity is high, toxic side effect is low that has.
Another object of the present invention provides the medicine of above-mentioned title complex as the treatment diabetes.
Copper complex of the present invention, chemistry two (2-ethyl-3-hydroxyl-pyrokomane) by name closes copper (II), its molecular formula C
14H
14CuO
6, molecular weight FW=341.5, chemical structural formula is:
Copper complex of the present invention is mixed with oral pharmaceutical or the injection of suspension as the treatment diabetes with 0.5% Xylo-Mucine.
The preparation method of copper complex of the present invention is:
With CuSO
4Or CuCl
2Be raw material, with the reaction of 2-ethyl-3-hydroxyl-pyrokomane, it is neutral regulating PH with NaOH in water, promptly separate out green two (2-ethyl-3-hydroxyl-pyrokomane) and close copper (II), after the filtering separation in water the chemical heavy crystallization obtain pure product.
The another kind of preparation method of copper compound of the present invention is:
2-ethyl-3-hydroxyl-pyrokomane elder generation and NaHCO
3In the quantitative neutralization reaction of the medium mole of water, add CuSO then
4Or CuCl
2The aqueous solution is promptly separated out green two (2-ethyl-3-hydroxyl-pyrokomane) and is closed copper (II), after the filtering separation in water the chemical heavy crystallization obtain pure product.
Compound of the present invention have fat-soluble good, hypoglycemic activity is high, toxic side effect is little, easy synthetic advantage, can be made into oral antidiabetic medicine or injection.
3-hydroxyl-pyrokomane is the widely used foodstuff additive of a class, also is the good ligand of cupric ion simultaneously.The present invention is a ligand with 3-hydroxyl-pyrokomane, synthesize a novel lipophilic copper complex, have the effect that promotes insulin secretion, lowering blood glucose, have also simultaneously that toxicity is little, chemical property stable, the synthetic advantage that is easy to, have the excellent development application prospect.
Embodiment
(1) preparation of The compounds of this invention
Get the CuSO of 5.3g
45H
2O, be dissolved in the 50ml water, add 50ml, 5.9g2-ethyl-3-hydroxyl-pyrokomane aqueous solution, regulating PH with 0.1mol/LNaOH is 7.0, stirring reaction 3 hours, separate out green two (2-ethyl-3-hydroxyl-pyrokomane) and close copper (II), filter to collect, after water, the washing with alcohol in 60-70 ℃ of following vacuum-drying 4 hours, chemical heavy crystallization in water then, obtain the pure product of 6.5g, productive rate 91%.
Get 2-ethyl-3-hydroxyl-pyrokomane 5g, be dissolved in the water of 50ml, add the NaHCO of equimolar amount
3(3.0g), obtain 2-ethyl-3-hydroxyl-pyrokomane sodium salt, add CuCl then
22H
2O solution (3.1g), stirring reaction 3 hours is separated out green two (2-ethyl-3-hydroxyl-pyrokomane) and is closed copper (II), filter to collect, after water, the washing with alcohol in 60-70 ℃ of following vacuum-drying 4 hours, chemical heavy crystallization in water then, obtain the pure product of 5.4g, productive rate 88%.
The feature structure parameter that two (2-ethyls-3-hydroxyl-pyrokomane) close copper (II) is:
(1) ultimate analysis C49.1%; H4.15%; Cu18.4% is with theoretical value C49.2%; H4.10%; The Cu18.6% unanimity.
(2) MS-FAB
+M/e=342 (M
+, 97%), 141 (2-ethyls-3-hydroxyl-pyrokomane
+, 23%)
(3)IR(cm
-1，KBr)1601(s，VC＝O)、1564 1473(s，VC＝C)、1189(m，VC-O)、541(m，VCu-O)
(4)λmax(H
2O)710nm(Cu
2+d-d)
(5) EPR (solid, room temperature) 3250G (Cu
2+d
9)
These parameters meet the chemical structure of institute's invention compound.
(2) hypoglycemic activity of The compounds of this invention
Tried diabetic mice and be divided into control group (DM) and copper compound administration group at random.Copper compound is mixed with suspension with 0.5% Xylo-Mucine, gastric infusion, and every day, 10mg/kg dosage gave at twice, and each 0.1ml/10gBW in 2 weeks of successive administration, observes glucose level weekly.Got after the last administration that blood is surveyed postprandial blood sugar or fasting plasma glucose was surveyed in fasting in 6 hours in 1 hour from the tail vein.Statistical analysis: data are represented with mean ± standard deviation, adopt statistical analysis between Students ' t-check row group.
The result shows the constant normal level that maintains of normal control treated animal blood glucose value; Diabetic model group blood sugar then maintains higher level, and comparing difference with the normal control group has significance.C
14H
14CuO
6Obviously reduce postprandial blood sugar and fasting plasma glucose (table 1,2), hypoglycemic activity is higher than Cu (maltolate)
2
Table 1. copper complex gastric infusion is to the influence of alloxan diabetes mouse postprandial blood sugar
| Group | Dosage (mg/kg/d) | The example number | 1 all 2 weeks of administration of administration before blood sugar (mmol/L) administration | ||
| Normally | Deng appearance CMC-Na | 10 | 7.96± 0.61 | 5.42± 0.68 | 4.95±0.54 |
| DM | Deng appearance CMC-Na | 10 | 17.47±3.37 | 21.36±5.55 | 21.30±4.06 |
| C 14H 14CuO 6 | 10 | 10 | 17.33±3.39 | 17.68± 5.60 * | 16.38±5.63 * |
| Cu(maltolate) 2 | 10 | 10 | 17.45±1.84 | 20.56±6.42 | 19.51±2.29 |
Annotate:
*P＜0.05 is compared with the diabetes control group (t-test check).
Table 2. copper complex is irritated and is emitted the influence of administration to alloxan diabetes mouse fasting plasma glucose
| Group | Dosage (mg/kg/d) | The example number | 1 all 2 weeks of administration of blood sugar (mmol/L) administration | |
| Normally | Deng appearance CMC-Na | 10 | 5.09±1.05 | 5.18±1.01 |
| DM | Deng appearance CMC-Na | 10 | 16.52±2.82 | 8.49±3.12 |
| C 14H 14CuO 6 | 10 | 10 | 12.27±5.41 * | 3.76±0.90 * |
| Cu(maltolate) 2 | 10 | 10 | 11.20±4.89 * | 6.28±3.39 |
Annotate: * P＜0.05, compare with the diabetes control group (t-test check).
(3) dose-effect relationship of the hypoglycemic activity of Fa Ming compound and mechanism
Tried mouse by the blood sugar random packet, normal control group, diabetes model control group (DM), senior middle school's low dose group are irritated stomach successively and are given equal-volume solvent (0.5%CMC-Na), C
14H
14CuO
65.0,10.0 and 20.0mg/kg.d, give every day at twice, each 0.1ml/10gBW, administration 1-2 days, 2 weeks of successive administration, observe glucose level weekly, measure amount of drinking water and food-intake every day; Got after the last administration that blood is surveyed postprandial blood sugar or fasting plasma glucose was surveyed in fasting in 6 hours in 1 hour from the tail vein; The eye socket vein was got blood when experiment finished, and-20 ℃ of refrigerators are preserved serum and surveyed Regular Insulin fully, and it is an amount of to get liver simultaneously ,-20 ℃ of frozen liver starch of surveying fully of refrigerator.
The result shows The compounds of this invention C
14H
14CuO
6Dose-dependently ground reduces postprandial blood sugar and fasting plasma glucose (table 3,4).Experiment also shows C
14H
14CuO
6Gastric infusion can obviously increase the diabetic mice serum insulin level, P＜0.05 or 0.01 after 2 weeks; But the influence to liver starch is not obvious, compares with diabetic model group, and difference does not have significance, P＞0.05 (table 5).
Table 3.C
14H
14CuO
6Gastric infusion is to the influence of alloxan diabetes mouse postprandial blood sugar
| Group | Dosage (mg/kg/d) | The example number | 1 all 2 weeks of administration of administration before blood sugar (mmol/L) administration | ||
| Normally | Deng appearance CMC-Na | 10 | 5.66±0.91 | 4.21±1.49 | 6.47±0.55 |
| DM | Deng appearance CMC-Na | 10 | 22.11±4.92 ▲▲ | 20.97±4.20 ▲▲ | 21.20±4.06 ▲▲ |
| C 14H 14CuO 6 | 5 10 20 | 11 11 11 | 22.80±3.89 ▲▲ 22.22±3.84 ▲▲ 22.27±2.87 ▲▲ | 19.52±3.39 ▲▲ 16.50±2.83 *▲▲ 16.78±0.99 *▲▲ | 20.66±3.67 ▲▲ 16.91±2.95 *▲▲ 17.21±1.43 *▲▲ |
Annotate:
*P＜0.05,
*P＜0.01 is compared with the diabetes control group;
▲ ▲(t-test tests) compared with the normal control group in P＜0.01.
Table 4.C
14H
14CuO
6Gastric infusion is to the influence of alloxan diabetes mouse fasting plasma glucose
| Group | Dosage (mg/kg/d) | The example number | 1 all 2 weeks of administration of blood sugar (mmol/L) administration | |
| Normally | Deng appearance CMC-Na | 10 | 3.09±0.35 | 3.27±0.79 |
| DM | Deng appearance CMC-Na | 10 | 13.11±2.42 ▲▲ | 13.74±3.38 ▲▲ |
| C 14H 14CuO 6 | 5 10 20 | 11 11 11 | 8.72±4.68 *▲▲ 7.95±3.35 **▲▲ 8.14±2.90 **▲▲ | 13.54±4.60 ▲▲ 8.01±4.68 *▲▲ 7.73±3.00 **▲▲ |
Annotate:
*P＞0.05,
*P＞0.01 is compared with the diabetes control group;
▲ ▲(t-t check) compared in P＜0.01 with the normal control group.
Table 5.C
14H
14CuO
6Gastric infusion is to the influence of alloxan diabetes mouse fasting plasma glucose
| Group | Dosage (mg/kg/d) | The example number | Serum insulin (mU/L) | Liver starch (mg/g weight in wet base) |
| Normally | Deng appearance CMC-Na | 10 | 11.03±0.60 | 3.63±0.83 |
| DM | Deng appearance CMC-Na | 10 | 7.83±3.22 | 3.71±1.83 |
| C 14H 14CuO 6 | 5 10 20 | 11 11 11 | 9.03±4.52 12.23±3.33 ** 13.58±4.19 ** | 4.94±1.58 5.72±4.61 4.31±4.31 |
Annotate:
*P＜0.05,
*(t-test check) compared in P＜0.05 with the diabetes control group.
(4) toxicity of The compounds of this invention
Select 50 of healthy ICR mouse, male female each half, body weight is divided into 5 groups at random at 18-22g, 10 every, the animal fasting is about 8 hours before the administration, The compounds of this invention C
14H
14CuO
6Be mixed with suspension with 0.5% Xylo-Mucine, carry out the disposable gastric infusion of mouse, observe toxic reaction and the death condition of 14 days animals after the administration continuously by the 20ml/kg body weight.
Calculate the Lethal Dose 50 LD of medicine
50, in the 0.5h, not seeing that abnormal response appears in animal behind the gastric infusion, death appears in animal behind the 1h, and part animal gastrointestinal tract flatulence is found in postmortem, and other internal organs are not seen macroscopic pathological change, record the LD of the disposable gastric infusion of The compounds of this invention
50=855.9mg/kg and fiducial interval confidence level are 95%.
Claims (2)
1, two (2-ethyls-3-hydroxyl-pyrokomane) close copper (II) title complex, it is characterized in that this complex molecule formula is C
14H
14Cu
O6, its molecular weight FW=341.5, chemical structural formula is:
2, two (2-ethyls-3-hydroxyl-pyrokomane) close the application of copper (II) title complex on the treatment diabetes, it is characterized in that with the oral pharmaceutical of this title complex as the treatment diabetes.
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|---|---|---|---|
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188103A (en) * | 2016-07-14 | 2016-12-07 | 河南中医学院 | A kind of azacyclo-transition metal copper complex containing multiple coordination sites, preparation method and application |
| WO2018152614A1 (en) * | 2017-02-21 | 2018-08-30 | Fine Cotton Factory Inc. | Articles for treating concussion and other disorders |
-
2005
- 2005-08-10 CN CNB2005100109560A patent/CN1307184C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188103A (en) * | 2016-07-14 | 2016-12-07 | 河南中医学院 | A kind of azacyclo-transition metal copper complex containing multiple coordination sites, preparation method and application |
| WO2018152614A1 (en) * | 2017-02-21 | 2018-08-30 | Fine Cotton Factory Inc. | Articles for treating concussion and other disorders |
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|---|---|
| CN1307184C (en) | 2007-03-28 |
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