CN104127424A - Glibenclamide derivative, preparation method and application thereof - Google Patents
Glibenclamide derivative, preparation method and application thereof Download PDFInfo
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- CN104127424A CN104127424A CN201410371316.1A CN201410371316A CN104127424A CN 104127424 A CN104127424 A CN 104127424A CN 201410371316 A CN201410371316 A CN 201410371316A CN 104127424 A CN104127424 A CN 104127424A
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Abstract
The invention belongs to the technical field of medicines, relates to a glibenclamide derivative, a preparation method and application thereof, and concretely relates to application of the glibenclamide derivative to prepare diabetes medicines. The glibenclamide derivative has the structure shown as a formula (I), and in the formula (I), R1, R2, R3 and R4 are respectively halogens or H, at least one group is halogens, and the halogens are fluorine, chlorine, bromine and iodine. The compound has obvious blood sugar reducing activity, and has the characteristics of high efficiency, low toxicity and relatively long action time.
Description
Technical field:
The invention belongs to medical technical field, relate to glibenclamide derivant and its preparation method and application, be specifically related to it in the application of preparing in diabetes medicament.
Background technology:
The sulfonylurea hypoglycemic drug of insulin secretion accelerating is applied decades clinically, and determined curative effect, untoward reaction are clear and definite, remain main clinically hypoglycemic drug.According to 2012 annual Remedies for diabetes market intelligences, sulfonylureas accounts for 33.8% of whole hypoglycemic drug market, and wherein the sulfonylurea hypoglycemic drug such as glibenclamide, glipizide and gliquidone enters first 15 of the Remedies for diabetes clinical application market share.
The structure activity relationship of sulfonylureas shows on the nitrogen-atoms of urea, there is a lipophilic substituent with certain space volume, and hypoglycemic activity is relatively good, and therefore, glipizide, gliquidone and glibenclamide structure common ground are all to contain cyclohexane extraction.Outside bibliographical information glipizide, gliquidone and the glibenclamide metabolic pathway apart from himself, (there are the metabolism such as the open loop of pyrazine ring, gliquidone demethylation as glipizide), these medicine internal metabolisms have common metabolic rule, i.e. all easy 4 and reactions of 3 generation oxidative metabolisms at cyclohexylamine, on cyclohexane ring, introduce the hydroxyl of polarity and inactivation (J Chromatography B:Analytical Technologies in the Biomedical and Life Sciences.2007,860 (1): 34-41; Arzneimittel-Forschung, 1975,25 (9): 1455-60; Radioisotopes, 1975,24 (3): 167-73.).The metabolic pathway of for example glibenclamide is mainly the metabolite that on hexamethylene ring, oxidation occurs and obtain 4, hexamethylene ring and 3, specific as follows:
The present invention adopts metabolism prevention method, at glibenclamide, cyclohexane extraction para-position or a position of easy metabolism replace with halogen, new analog has been synthesized in design, reduce to a certain extent these drug metabolism deactivation rates, meanwhile, increase its hypoglycemic activity by increasing substituent lipotropy on nitrogen-atoms.This series derivates has good hypoglycemic activity, can be for the preparation of hypoglycemic drug.
Summary of the invention:
The invention provides the long glibenclamide derivant with hypoglycemic activity of efficient a, low toxicity, action time,
Wherein R
1, R
2, R
3, R
4be respectively halogen or H, wherein have at least one to be halogen, halogen is fluorine, chlorine, bromine, iodine, is preferably fluorine.
Its synthetic reaction flow process is as follows:
Concrete steps are:
The cyclohexyl isocyanate of the chloro-2-methoxyl group-N-of 5-(4-sulfonamides phenethyl) Benzoylamide and halogen-containing replacement is in suitable solvent, and at 20-150 DEG C, reaction 3-24 hour, obtains target compound.
Described solvent is: toluene, dimethylbenzene, oxolane, 2-methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), DMF, N, the common solvent such as N-diethylformamide, ethyl acetate, butyl acetate.
Detailed description of the invention:
Embodiment 1:
With 4,4-difluoro substitutive derivative, FGBN synthesizes example, and under structural formula is shown in, this analog derivative specifically synthetic logical method is as follows:
Take the chloro-2-methoxyl group-N-of 5.53g (15.00mmol) 5-(4-sulfonamides phenethyl) Benzoylamide, be dissolved in 80mL DMF, after having dissolved, add 1.38g (34.50mmol) to grind superfine sodium hydroxide, after stirring, add 4.83g (30.00mmol) 4,4-difluoro cyclohexyl isocyanate, adds post-heating to 60 DEG C and stirs 20h.After having reacted, be poured in 300mL frozen water after reactant liquor is cooling, separate out solid, obtain glibenclamide derivant FGBN5.11g, productive rate 64%, fusing point 176-178 DEG C with dehydrated alcohol recrystallization after dry.ESI-MS(m/z)：530.1[M+H]
+，552.0[M+Na]
+；528.0[M-H]
-。
1HNMR(400MHz，DMSO-d
6)δ10.44(s，1H)，8.28(t，J＝5.6Hz，1H)，7.85(d，J＝8.3Hz，2H)，7.64(d，J＝2.8Hz，1H)，7.56-7.40(m，3H)，7.15(d，J＝8.9Hz，1H)，6.57(d，J＝7.5Hz，1H)，3.80(s，3H)，3.55(dd，J＝12.9，6.8Hz，2H)，3.49(d，J＝8.2Hz，1H)，2.93(t，J＝7.0Hz，2H)，2.14-1.55(m，6H)，1.50-0.95(m，2H)。
Biological activity test experimental section
The experiment of glibenclamide derivant blood sugar lowering
1. Experiment Introduction:
Rat gives STZ-citrate buffer solution according to 30mg/kg tail vein injection, after 3 weeks, carry out lumbar injection carbohydrate tolerance experiment (IPTT experiment), the rat that filters out impaired glucose tolerance gives high lipid food and gives tested medicine according to 10mg/kg gavage simultaneously.Found that derivant may be aided with due to high lipid food NIDDM rats to low dose of STZ inhibited, glibenclamide derivant may be aided with NIDDM rats inhibitory action due to high lipid food to low dose of STZ and be better than positive control medicine glibenclamide.
2. experiment purpose:
Coordinate high lipid food to bring out NIDDM rats by STZ, then give tested observed drug its blood sugar reducing function.
3. tested medicine and reagent
Tested medicine
Title: glibenclamide and derivant FGBN thereof (embodiment 1)
The unit of providing: provided by pharmaceutical chemistry teaching and research room of Shenyang Pharmaceutical University
Reagent:
Yolk powder, Beijing Suo Laibao Science and Technology Ltd. lot number: 20130106
Cholesterol, Chemical Reagent Co., Ltd., Sinopharm Group's lot number: 20120409
Sodium deoxycholate, Beijing Suo Laibao Science and Technology Ltd. lot number: 902C022
Sucrose, Tianjin great Mao chemical reagent factory lot number: 20130913
Streptozotocin, SIGMA company lot number: WXBB2432VP
Citric acid, Tianjin Bo Di Chemical Co., Ltd. lot number: 20081110
Sodium citrate, Tianjin great Mao chemical reagent factory lot number: 20000403
Normal saline
Carboxymethyl cellulose sodium, Tianjin Bo Di Chemical Co., Ltd., lot number: XK-13-011-00003
The preparation of reagent:
Streptozotocin injection (concentration is 3mg/mL):
Citric acid (FW:210.14) 2.1g adds and in normal saline 100mL, is made into A liquid.Sodium citrate (FW:294.10) 2.94g adds and in normal saline 100mL, is made into B liquid.A:B=1:1 regulates pH=4.2-4.5, is the citrate buffer solution of required configuration STZ.Wrap up in bottle with dry aluminium foil (or tinfoil paper) paper bag.Take two parts of 180mg of STZ, a 270mg in reagent bottle, tinfoil lucifuge, is placed in ice bath.In ice bath, add buffer to dissolve.Inject corresponding STZ by empty stomach body weight, in 30 minutes, inject complete.
1% Carboxymethyl cellulose sodium:
Take Carboxymethyl cellulose sodium 1g, measure 100mL distilled water and be placed in beaker, Carboxymethyl cellulose sodium is evenly sprinkling upon to distilled water surface, leave standstill 24h.
Glibenclamide suspension:
Analytical balance takes solid glibenclamide 0.1g, be placed in mortar, measure 1% Carboxymethyl cellulose sodium 5mL with 5mL syringe and inject mortar, fully being ground to aspirin powder is dispersed in 1% Carboxymethyl cellulose sodium, rinse mortar with 95mL1% base sodium cellulosate again, then move in reagent bottle for subsequent use.This liquid should stir before using, can gavage after making it evenly.
Glibenclamide derivant suspension compound method is identical.
4. laboratory animal
SD rat, SPF level, male, body weight 160～180g, is provided the quality certification by Shenyang Pharmaceutical University's animal center: SCXK (the Liao Dynasty) 2010-0001.
Raising condition: raising temperature, 18～26 DEG C; Raise humidity, 40～70%.Feedstuff and normal feedstuff are provided by Yuhong District, Shenyang City Qian Min animal feed factory, and test is prepared by experimenter with high lipid food (10% Adeps Sus domestica, 10% sucrose, 10% yolk powder, 2.5% cholesterol, 0.5% sodium deoxycholate, 67% normal feedstuff).
5. experimental technique
5.1. type Ⅱdiabetes mellitus Establishment of Rat Model and screening
50 of SD male rats, test room environmental (feeding environment: 18～25 DEG C of temperature) adaptability and raise 3 days.Be divided at random four groups, be respectively blank group, negative control group, glibenclamide group, glibenclamide derivant FGBN group, 15 every group.Divide and weigh, number.Before all zooperies, fasting be can't help water 12 hours, and blank group is left intact, and the STZ-citric acid buffer salt solution (3mg/mL) that other groups give by 30mg/kg intravenous injection is raised 2 weeks.After 2 weeks, before all zooperies the previous day, fasting be can't help water 12 hours, carries out lumbar injection glucose tolerance test (IPGTT).All rat tail blood taking methods are measured fasting glucose by blood glucose meter, then press 2g/kg body weight lumbar injection glucose (2g/mL).Then measure respectively injection rear 30min, 60min and 120min blood glucose value with method.Filter out the rat of fasting glucose >7.0, more again as stated above packet numbering computation time to area under curve (AUC).By the AUC value of negative control group and each administration group, the AUC value of blank group is carried out to t inspection respectively, t test value <0.05 thinks that modeling is successful.SPSS15.0for windows statistical software for data analysis.
5.2. administration and fasting plasma glucose and statistics
By every the type Ⅱdiabetes mellitus rat screening 5 cage sub-cage rearings, negative control group, glibenclamide group and glibenclamide derivant group give high lipid food, within first week after administration, measure respectively fasting glucose with second week.Concrete grammar is: except blank group, before all zooperies, fasting be can't help water 12 hours, and after last administration blood glucose meter negative control group, glibenclamide group and glibenclamide derivant group fasting glucose for 1h docking blood taking method.After input computer, organize fasting blood sugar with glibenclamide group and glibenclamide derivant FGBN negative control group is carried out to t inspection.SPSS15.0for windows statistical software for data analysis.
6. experimental result
6.1. type Ⅱdiabetes mellitus rat model screening experiment result
Table 1: the STZ of tail vein injection 30mg/kg is to rat impaired glucose tolerance result
* P<0.05 administration group Vs blank group
* P<0.01 administration group Vs blank group
As can be seen from Table 1, negative control group, glibenclamide group, glibenclamide derivant FGBN organize the utmost point significant difference of having compared with blank group AUC, illustrate and form type Ⅱdiabetes mellitus rat model.
The type Ⅱdiabetes mellitus rat fasting blood-glucose reducing effect that table 2 causes STZ
* P<0.05 administration group Vs negative control group * * P<0.01 administration group Vs negative control group
#P<0.05 positive control drug Vs is subject to reagent ##P<0.01 positive control drug Vs to be subject to reagent
Table 2 result shows that positive control drug glibenclamide (10mg/kg) has obvious blood sugar reducing function.Its derivant FGBN (10mg/kg) has obvious blood sugar reducing function.From first week to the 8th week, glibenclamide derivant FGBN blood sugar reducing function was stronger than positive control drug glibenclamide, and action time is longer.
Claims (6)
1. glibenclamide derivant, is characterised in that, structural formula is as shown in (I):
Wherein R
1, R
2, R
3, R
4be respectively halogen or H, wherein have at least one to be halogen.
2. glibenclamide derivant according to claim 1, is characterized in that, described halogen is fluorine, chlorine, bromine, iodine, is preferably fluorine.
3. a pharmaceutical composition, comprises glibenclamide derivant and pharmaceutically acceptable carrier described in claim 1 or 2.
4. the glibenclamide derivant described in claim 1 or 2 or compositions claimed in claim 3 are in the application of preparing in hypoglycemic drug.
5. a preparation method for glibenclamide derivant as claimed in claim 1, is characterized in that:
Synthetic reaction flow process is as follows:
Concrete steps are:
The chloro-2-methoxyl group of 5--
nthe cyclohexyl isocyanate of-(4-sulfonamides phenethyl) Benzoylamide and halogen-containing replacement is in suitable solvent, and at 20-150 DEG C, reaction 3-24 hour, to obtain final product.
6. preparation method as claimed in claim 5, it is characterized in that, described solvent is: toluene, dimethylbenzene, oxolane, 2-methyltetrahydrofuran, methyl tertiary butyl ether(MTBE), DMF, N, the common solvent such as N-diethylformamide, ethyl acetate, butyl acetate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237445A (en) * | 2015-10-20 | 2016-01-13 | 大连九信生物化工科技有限公司 | Synthetic process of 4-[2-(5-chloro-2-methoxy benzamide)ethyl]benzsulfamide |
| CN108078999A (en) * | 2017-12-22 | 2018-05-29 | 沈阳药科大学 | Pharmaceutical composition for preventing cerebral arterial thrombosis and its preparation method and application |
| EP4183774A4 (en) * | 2020-07-17 | 2024-02-21 | Shanghai Senhui Medicine Co., Ltd. | Sulfonylurea derivative and medical uses thereof |
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| CN1395560A (en) * | 2000-01-14 | 2003-02-05 | 布里斯托尔-迈尔斯斯奎布公司 | Glyburide composition |
| CN1413107A (en) * | 1999-12-23 | 2003-04-23 | 诺瓦提斯公司 | Use of hypoglycemic agent for treating impaired clucose metabolism |
| EP1435240A2 (en) * | 1998-07-15 | 2004-07-07 | Merck Sante | Solid oral dosage form comprising a combination of methformin and glibenclamide |
| CN1895250A (en) * | 2005-07-15 | 2007-01-17 | 天津药物研究院 | Gliquilone slow-releasing preparation |
-
2014
- 2014-07-30 CN CN201410371316.1A patent/CN104127424A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1435240A2 (en) * | 1998-07-15 | 2004-07-07 | Merck Sante | Solid oral dosage form comprising a combination of methformin and glibenclamide |
| CN1413107A (en) * | 1999-12-23 | 2003-04-23 | 诺瓦提斯公司 | Use of hypoglycemic agent for treating impaired clucose metabolism |
| CN1395560A (en) * | 2000-01-14 | 2003-02-05 | 布里斯托尔-迈尔斯斯奎布公司 | Glyburide composition |
| CN1895250A (en) * | 2005-07-15 | 2007-01-17 | 天津药物研究院 | Gliquilone slow-releasing preparation |
Non-Patent Citations (1)
| Title |
|---|
| 王晓林等: "格列喹酮合成工艺研究", 《吉林化工学院学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237445A (en) * | 2015-10-20 | 2016-01-13 | 大连九信生物化工科技有限公司 | Synthetic process of 4-[2-(5-chloro-2-methoxy benzamide)ethyl]benzsulfamide |
| CN108078999A (en) * | 2017-12-22 | 2018-05-29 | 沈阳药科大学 | Pharmaceutical composition for preventing cerebral arterial thrombosis and its preparation method and application |
| EP4183774A4 (en) * | 2020-07-17 | 2024-02-21 | Shanghai Senhui Medicine Co., Ltd. | Sulfonylurea derivative and medical uses thereof |
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