CN102093261A - Salicylic acid metformin salt and preparation method and medical application thereof - Google Patents
Salicylic acid metformin salt and preparation method and medical application thereof Download PDFInfo
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- CN102093261A CN102093261A CN2009102628777A CN200910262877A CN102093261A CN 102093261 A CN102093261 A CN 102093261A CN 2009102628777 A CN2009102628777 A CN 2009102628777A CN 200910262877 A CN200910262877 A CN 200910262877A CN 102093261 A CN102093261 A CN 102093261A
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- ointment
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N CN(C)C(NC(N)=N)=N Chemical compound CN(C)C(NC(N)=N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N OC(c(cccc1)c1O)=O Chemical compound OC(c(cccc1)c1O)=O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a novel salicylic acid metformin salt. A salt compound can be applied to the preparation of a medicament for treating diabetes and complications of diabetes, a medicament for treating cerebral ischemia, a medicament for treating cardiovascular diseases, medicaments for treating thrombus and atherosclerosis or a medicament for treating metabolic syndrome. The invention also relates to a method for preparing the salt compound.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the novel Whitfield's ointment melbine salt of a class.Such salt compound can be used for preparing anti-diabetic and complication medicine, anti-cerebral ischemia drugs, anti-cardiovascular disease, antithrombotic reagent, Antiatherosclerosis medicine or treatment metabolic syndrome medicine.The invention still further relates to the preparation method of such salt compound.
Background technology
N1,N1-Dimethylbiguanide is the medicine of an oral administration diabetes B, and it is used for the treatment of diabetes B the history in more than 50 year, and it belongs to the biguanides antidiabetic drug, does not stimulate the beta Cell of islet excreting insulin.It is mainly used in the fat light-duty diabetic of non-insulin-depending type, and its general mechanism of action comprises: (1) increases the susceptibility of surrounding tissue to Regular Insulin; (2) suppress the liver starch heteroplasia, reduce the output of glycogen; (3) can suppress of the absorption of intestines parietal cell to glucose.At present, N1,N1-Dimethylbiguanide is extensive use of clinically with the form of its hydrochloride, adds that in addition it has much the price of advantage, more and more is subjected to the favor of doctor and patient.But also there are some side effects in N1,N1-Dimethylbiguanide, wherein intestines and stomach side reaction (diarrhoea, vomiting etc.) accounts for about 30%, and its reason to small part ascribes the high water-soluble of it to and the very poor absorptive character of intestines and stomach (only being absorbed at the duodenum position of small intestine).The absorption pattern of this medicine is subjected to the influence of its cationization trend, thereby tendency is adsorbed in electronegative small intestine endothelium.The absorption of N1,N1-Dimethylbiguanide has saturability, and very incomplete.Under common dosage and administering mode, Plasma Concentration reached stable state in 24-48 hour, and usually less than 1 mcg/ml.In the clinical experiment that contrast is arranged, even if under maximum dosage, the maximum plasma concentration of N1,N1-Dimethylbiguanide (Cmax) also is no more than 4 mcg/ml.Therefore, in order to reduce the gastrointestinal side effect of N1,N1-Dimethylbiguanide, there is following several scheme can supply to consider: 1) when taking N1,N1-Dimethylbiguanide, to take diarrhea medicine safely and effectively, as dioctahedral smectite; 2) the pharmaceutically acceptable fat-soluble salt of preparation N1,N1-Dimethylbiguanide to reduce the water-soluble of medicine, increases the gastrointestinal absorption of medicine, improves bioavailability of medicament, and then suppresses the gastrointestinal side effect of N1,N1-Dimethylbiguanide.
Whitfield's ointment is present in natural bark of willow, Gaultheria leaf and the sweet birch tree, can be obtained by the saligenin metabolism.It is widely used in the organic synthesis, also is a kind of plant hormone.It has outstanding exfoliation, the ability of Peppermint Extract, and is safe, and lower than tartaric acid to the stimulation of skin.The salicylate of high dosage or ester (4-10 gram/sky) comprise salicylic acid sodium salt and acetylsalicylic acid, are used to treatment as inflammation such as rheumatic fever and rheumatic arthritis, and the energy lowering blood glucose concentration that once was in the news.Its mechanism of action may be by suppressing the sub-I kappa b kinase ss of activation (IKK β) of nf κ B (NF-κ B) and its upstream.Recent study shows that suppressing IKK β path may be by influencing insulin resistant (Science, 2001,293 (31): 1673-1677) that insulin signaling improves diabetes B and obesity.In addition, ADA recommends the diabetes B patient should strict adhere to adopting secondary prevention (the International Journal of Diabetes in DevelopingCountries of acetylsalicylic acid as cardiovascular and cerebrovascular diseases, 2008,28 (2): 165-175).A clinical study result of up-to-date announcement shows: use low-dosage aspirin can significantly reduce type-II diabetes patient cardiovascular and cerebrovascular incident mortality ratio in primary prevention, and do not increase the hemorrhagic risk.And the Whitfield's ointment effective active matter that generates in vivo of acetylsalicylic acid (acetylsalicylic acid) just.
Summary of the invention
The present invention discloses novel Whitfield's ointment melbine salt, its preparation method and the medicinal use with pharmaceutical use shown in the formula I first, is included in the purposes of preparation anti-diabetic and complication medicine thereof, anti-cerebral ischemia drugs, anti-cardiovascular disease, antithrombotic reagent, Antiatherosclerosis medicine or treatment metabolic syndrome medicine aspect.Both can reduce the water-soluble of N1,N1-Dimethylbiguanide behind Whitfield's ointment and the N1,N1-Dimethylbiguanide salify, use the side effect that heavy dose of N1,N1-Dimethylbiguanide brought separately thereby reduce, can increase salicylic water-soluble again, and in the salicylic blood sugar reducing function of performance, bring into play the effect of its control diabetic subject's insulin resistant and cardiovascular and cerebrovascular complication.
The present invention relates to as shown in the formula the compound shown in the I:
In formula I, Whitfield's ointment exists as the anionic form of salt, and the carboxyl negative ion is provided, and N1,N1-Dimethylbiguanide exists as the cationic form of salt, and the ammonium positive ion is provided, and both are with the ionic linkage combination.
N represents the number of N1,N1-Dimethylbiguanide, n=1/4,1/3,1/2,1 or 2.
Shown in the above-mentioned formula I in the compound preferred compound be characterised in that:
N1,N1-Dimethylbiguanide and Whitfield's ointment salify, both ratios are 1/3,1/2,1 or 2.
More preferred compound shown in the formula I is characterised in that:
N1,N1-Dimethylbiguanide and Whitfield's ointment salify, both preferred ratios are 1/2 or 1.
Compound of the present invention can prepare with following method:
A, Whitfield's ointment and N1,N1-Dimethylbiguanide free alkali are carried out to reactant salt in solvent, temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 100 ℃.The solvent that is adopted can be methyl alcohol, ethanol, acetone, Virahol, the trimethyl carbinol, propyl carbinol, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether, water, dimethyl formamide, diethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, methylene dichloride, 1, the mixed solvent that 2-ethylene dichloride, normal butane, hexanaphthene, benzene, toluene or above-mentioned solvent are optional preferentially adopts methyl alcohol, ethanol or acetone as solvent.
B, with step a gained solution cooling crystallization, obtain the Whitfield's ointment melbine salt shown in the formula I.
The present invention also comprises pharmaceutical preparation, and said preparation comprises as the formula I compound of promoting agent or its pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and their not reverse and active compounds or patient have an effect.
The formulation of the present composition can be a formulation commonly used on the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in the pharmaceutical field.
The dosage of above promoting agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of the formula I compound of every kilogram of administration in per 24 hours is about 0.01-800mg, and preferred total amount is 0.1-100mg/kg.If necessary, with the form administration of single dose several times.
Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time and the interval of seriousness, preparation and administration.
Be part pharmacology test and result below:
Target compound is to the influence of glucose induced hyperglycemia mice blood sugar:
Method:
Get 40 of regular grade Kunming mouses, male and female half and half, body weight 18-22g, adaptability was fed 2 days.Mouse is divided into 4 groups at random, 10 every group.Segment bounds I compound is mixed with the 5mg/ml suspension with 0.5%CMC-Na solution, and N1,N1-Dimethylbiguanide is mixed with the 10mg/ml suspension.Gastric infusion (0.2ml/10g) behind the mouse fasting 12h, administration group are irritated stomach fraction I compound 100mg/kg,, the positive drug group is irritated stomach N1,N1-Dimethylbiguanide 200mg/kg.Negative control group and model group are irritated stomach isometric(al) 0.5%CMC-Na.Behind the gastric infusion 60min except that normal group each treated animal gavage glucose solution by 2g/kg (10% glucose solution, 0.2ml/10g), the normal group animal gavage water.Gavage glucose 30min posterior orbit and get blood, measure blood sugar by Reagent kit of glucose.Data are represented with mean ± standard deviation, adopt SSPS11.0 software to carry out statistical analysis.Test result (table 1) shows that the segment bounds I compound that is tried causes the mouse hyperglycemia model to glucose and has significant hypoglycemic activity.
Table 1, segment bounds I compound are to the influence of glucose induced hyperglycemia mice blood sugar
| Group | Dose (mg/kg) | Blood?glucose (mmol/L) |
| Control | - | 3.92±0.75 |
| Model | - | 8.4±1.14## |
| N1,N1-Dimethylbiguanide | 200 | 5.09±0.57** |
| Whitfield's ointment half melbine salt | 100 | 5.46±1.01** |
##P＜0.01?vs?Control，
**P＜0.01?vs?Model?Data?refer?to?mean±SD，n＝10.
Above pharmacology data shows that segment bounds I compound of the present invention has significant blood sugar reducing function, therefore can be used for preparing anti-diabetic and complication medicine thereof.
Embodiment:
Specify content of the present invention below by embodiment.In the present invention, the example of the following stated is in order better to set forth the present invention, is not to be used for limiting the scope of the invention.
Embodiment 1
Whitfield's ointment half melbine salt
(72.40mmol, 10eq) Whitfield's ointment is dissolved in the 35ml ethanol, adds 0.93g (7.24mmol) N1,N1-Dimethylbiguanide again, stirring at room with 10g.Be warming up to 90 ℃ of reactants dissolved, filter, the filtrate cooling crystallization, suction filtration, oven dry, getting the white solid product is Whitfield's ointment half melbine salt.M.p.136-140℃。
1H?NMR(DMSO-d
6，300MHz)δ2.93(s，3H)，6.56(s，2H)，6.89-6.95(m，2H)，7.18(s，1H)，7.47-7.53(m，1H)，7.77-7.80(dd，1H，J＝1.83Hz?and7.86Hz)。
Claims (10)
1. the Whitfield's ointment melbine salt shown in the general formula I:
In formula I, Whitfield's ointment exists as the anionic form of salt, and the carboxyl negative ion is provided, and N1,N1-Dimethylbiguanide exists as the cationic form of salt, and the ammonium positive ion is provided, and both are with the ionic linkage combination.
N represents the number of N1,N1-Dimethylbiguanide, n=1/4,1/3,1/2,1 or 2.
2. the compound of claim 1, it is characterized in that: N1,N1-Dimethylbiguanide and Whitfield's ointment salify, both ratios are 1/3,1/2,1 or 2.
3. the compound of claim 1, it is characterized in that: N1,N1-Dimethylbiguanide and Whitfield's ointment salify, both preferred ratios are 1/2 or 1.
4. the preparation method of the compound of claim 1 may further comprise the steps:
A. Whitfield's ointment and N1,N1-Dimethylbiguanide are carried out to reactant salt in solvent.
B. the solution with step a gained carries out crystallization, obtains corresponding Whitfield's ointment melbine salt.
5. the preparation method of claim 4, it is characterized in that: the solvent that salt-forming reaction is adopted can be methyl alcohol, ethanol, acetone, Virahol, the trimethyl carbinol, propyl carbinol, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether, water, dimethyl formamide, diethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, methylene dichloride, 1, the mixed solvent that 2-ethylene dichloride, normal butane, hexanaphthene, benzene, toluene or above-mentioned solvent are optional preferentially adopts methyl alcohol, ethanol or acetone as solvent.The temperature of salt-forming reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 100 ℃.
6. a pharmaceutical composition wherein contains the formula I compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
7. the compound of claim 1 is used for preventing and treat the purposes of the medicine of diabetes and complication, ischemic cardio cerebrovascular diseases, thrombus, atherosclerosis or metabolic syndrome in preparation.
8. the purposes of claim 7, it is characterized in that: diabetes are 1 type or diabetes B, and its complication comprises: diabetic nephropathy, diabetic foot, diabetic neuropathy or diabetes complicated cardiovascular and cerebrovascular diseases.
9. the purposes of claim 7, it is characterized in that: ischemic cardio cerebrovascular diseases is myocardial infarction, stenocardia, irregular pulse, coronary heart disease, cerebral ischemia, apoplexy, cerebral infarction or ischemia nerve degenerative diseases.
10. the purposes of claim 7 is characterized in that: the compound of claim 1 can be used for prevention and treatment thrombus, atherosclerosis or metabolic syndrome.
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| CN2009102628777A CN102093261A (en) | 2009-12-14 | 2009-12-14 | Salicylic acid metformin salt and preparation method and medical application thereof |
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| CN2009102628777A CN102093261A (en) | 2009-12-14 | 2009-12-14 | Salicylic acid metformin salt and preparation method and medical application thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262204A (en) * | 2014-09-22 | 2015-01-07 | 江苏天晟药业有限公司 | Preparation method of guanidine salicylate compound |
| CN105816373A (en) * | 2016-04-14 | 2016-08-03 | 广州丹奇日用化工厂有限公司 | Pore refining cleansing water and preparation method thereof |
| CN109096207A (en) * | 2018-08-28 | 2018-12-28 | 中国海洋大学 | A kind of salt, preparation method and the crystal structure of 5 FU 5 fluorouracil and melbine |
| WO2019120111A1 (en) * | 2017-12-18 | 2019-06-27 | 镇学初 | Use of metformin salt in treating cerebral infarction |
| CN110037998A (en) * | 2018-01-16 | 2019-07-23 | 镇学初 | Purposes of the melbine salt in treatment cerebral infarction |
| CN110604730A (en) * | 2018-06-15 | 2019-12-24 | 镇学初 | Application of metformin salt in treatment of cerebral infarction |
| CN112843033A (en) * | 2021-01-25 | 2021-05-28 | 中国人民解放军空军军医大学 | CHMP2B protein targeted inhibitor and application thereof in ischemic heart disease |
| CN113105367A (en) * | 2021-03-30 | 2021-07-13 | 广州大学 | Metformin salt and preparation method and application thereof |
| CN115073330A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Metformin cinnamate, preparation method, composition and application thereof |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104262204A (en) * | 2014-09-22 | 2015-01-07 | 江苏天晟药业有限公司 | Preparation method of guanidine salicylate compound |
| CN105816373A (en) * | 2016-04-14 | 2016-08-03 | 广州丹奇日用化工厂有限公司 | Pore refining cleansing water and preparation method thereof |
| WO2019120111A1 (en) * | 2017-12-18 | 2019-06-27 | 镇学初 | Use of metformin salt in treating cerebral infarction |
| US11497722B2 (en) * | 2017-12-18 | 2022-11-15 | Soochow University | Use of metformin salt in the treatment of cerebral infarction |
| CN110037998A (en) * | 2018-01-16 | 2019-07-23 | 镇学初 | Purposes of the melbine salt in treatment cerebral infarction |
| CN110604730A (en) * | 2018-06-15 | 2019-12-24 | 镇学初 | Application of metformin salt in treatment of cerebral infarction |
| CN109096207A (en) * | 2018-08-28 | 2018-12-28 | 中国海洋大学 | A kind of salt, preparation method and the crystal structure of 5 FU 5 fluorouracil and melbine |
| CN109096207B (en) * | 2018-08-28 | 2021-05-07 | 中国海洋大学 | Salt of 5-fluorouracil and metformin, preparation method and crystal structure thereof |
| CN112843033A (en) * | 2021-01-25 | 2021-05-28 | 中国人民解放军空军军医大学 | CHMP2B protein targeted inhibitor and application thereof in ischemic heart disease |
| CN115073330A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Metformin cinnamate, preparation method, composition and application thereof |
| CN115073331A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Metformin cinnamate monohydrate, preparation method, composition and application thereof |
| CN113105367A (en) * | 2021-03-30 | 2021-07-13 | 广州大学 | Metformin salt and preparation method and application thereof |
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Application publication date: 20110615 |