CN104127423A - Gliquidone derivative, preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, relates to a gliquidone derivative, a preparation method and application thereof, and concretely relates to application of the gliquidone derivative to prepare diabetes medicines. The gliquidone 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

Gliquidone derivant and its preparation method and application

Technical field:

The invention belongs to medical technical field, relate to gliquidone derivant and its preparation method and application, be specifically related to its application in preparing 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, (as glipizide, there are the metabolism such as the open loop of pyrazine ring, gliquidone demethylation), 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.).For example the metabolic pathway of gliquidone is mainly that the metabolite that oxidation obtains 4, hexamethylene ring and 3 occurs on hexamethylene ring, specific as follows:

The present invention adopts metabolism prevention method, at gliquidone, 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, by increasing substituent lipotropy on nitrogen-atoms, increase its hypoglycemic activity.This series derivates has good hypoglycemic activity, can be for the preparation of hypoglycemic drug.

Summary of the invention:

The invention provides the long gliquidone derivant with hypoglycemic activity of efficient a, low toxicity, action time,

R wherein ₁, R ₂, R ₃, R ₄be respectively halogen or H, wherein have at least one to be halogen.Described halogen is fluorine, chlorine, bromine, iodine, is preferably fluorine.

Its synthetic reaction flow process is as follows:

Concrete steps are:

4-(2-(7-methoxyl group-4,4-dimethyl-1,3-dioxo-3,4-dihydro-isoquinoline-2 (1H)-yl) ethyl) cyclohexyl isocyanate of benzsulfamide and halogen-containing replacement is in suitable solvent, at 20-150 ℃, 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.

The specific embodiment:

Embodiment 1:

With 4,4-difluoro substitutive derivative, FGKT synthesizes example, and under its structural formula is shown in, the concrete synthetic method of this analog derivative is as follows:

Take 6.04g (15.00mmol) 4-(2-(7-methoxyl group-4,4-dimethyl-1,3-dioxo-3,4-dihydro-isoquinoline-2 (1H)-yl) ethyl) benzsulfamide, 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 ℃ and stirs 20h.After having reacted, be poured in 300mL frozen water after reactant liquor is cooling, separate out solid, with dehydrated alcohol recrystallization, obtain gliquidone derivant FGKT 6.11g, productive rate 72%, fusing point 206-208 ℃ after dry.ESI-MS(m/z)：564.1[M+H] ⁺，602.1[M+K] ⁺；562.1[M-H] ^-。 ¹HNMR(400MHz，DMSO-d ₆)δ7.64(d，J＝8.0Hz，2H)，7.61(d，J＝8.7Hz，1H)，7.54(d，J＝2.7Hz，1H)，7.30(dd，J＝8.6，2.6Hz，1H)，7.19(d，J＝8.0Hz，2H)，5.85(s，1H)，4.13-4.06(m，2H)，3.84(s，3H)，3.37(s，1H)，2.89-2.78(m，2H)，1.92(s，2H)，1.73，(dd，J＝39.6，17.0Hz，4H)，1.46(d，J＝5.9Hz，6H)，1.34(dd，J＝21.7，11.0Hz，2H)。

Biological activity test experimental section

The experiment of gliquidone derivant blood sugar lowering

1. Experiment Introduction:

Rat gives STZ-citrate buffer solution according to 30mg/kg tail vein injection, carries out lumbar injection carbohydrate tolerance experiment (IPTT experiment) after 3 weeks, and the rat that filters out impaired glucose tolerance gives high lipid food and according to 10mg/kg gavage, gives tested medicine simultaneously.Found that derivant may be aided with due to high lipid food NIDDM rats to low dose of STZ inhibited, gliquidone derivant FGKT 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 gliquidone.

2. experiment purpose:

By STZ, coordinate high lipid food to bring out NIDDM rats, then give tested observed drug its blood sugar reducing function.

3. tested medicine and reagent

Tested medicine

Title: gliquidone and derivant FGKT 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.With dry aluminium foil (or tinfoil paper) paper bag, wrap up in bottle.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.By empty stomach body weight, inject corresponding STZ, 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, standing 24h.

Gliquidone suspension:

Analytical balance takes solid gliquidone 0.1g, be placed in mortar, with 5mL syringe, measure 1% Carboxymethyl cellulose sodium 5mL and inject mortar, fully being ground to aspirin powder is dispersed in 1% Carboxymethyl cellulose sodium, with 95mL1% base sodium cellulosate, rinse mortar again, then move in reagent bottle standby.This liquid should stir before using, can gavage after making it evenly.

Gliquidone 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 ℃; 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 ℃ of temperature) adaptability is raised 3 days.Be divided at random four groups, be respectively blank group, negative control group, gliquidone group, gliquidone derivant FGKT 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 with method, measure respectively injection rear 30min, 60min and 120min blood glucose value.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 check respectively, t test value <0.05 thinks that modeling is successful.SPSS 15.0 for windows statistical softwares for data analysis.

5.2. administration and fasting plasma glucose and statistics

By every 5 the cage sub-cage rearings of the type Ⅱdiabetes mellitus rat screening, negative control group, gliquidone group and gliquidone 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, gliquidone group and gliquidone derivant group fasting glucose for 1h docking blood taking method.After input computer, with gliquidone group and gliquidone derivant FGKT group fasting blood sugar, negative control group is carried out to t check.SPSS 15.0 for windows statistical softwares 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 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, gliquidone group, gliquidone derivant FGKT 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 couple STZ causes ( ) n=15

* P<0.05 administration group Vs negative control group * * P<0.01 administration group Vs negative control group

Table 2 result shows that positive control drug gliquidone (10mg/kg) has obvious blood sugar reducing function.Its derivant FGKT (10mg/kg) has obvious blood sugar reducing function.

Claims (6)

1. gliquidone derivant is characterised in that, structural formula is as (I):

R wherein ₁, R ₂, R ₃, R ₄be respectively halogen or H, wherein have at least one to be halogen.

2. gliquidone derivant according to claim 1, is characterized in that, described halogen is fluorine, chlorine, bromine, iodine, is preferably fluorine.

3. a pharmaceutical composition, comprises gliquidone derivant and pharmaceutically acceptable carrier described in claim 1 or 2.

4. the gliquidone derivant described in claim 1 or 2 or the application of compositions claimed in claim 3 in preparing hypoglycemic drug.

5. a preparation method for gliquidone derivant as claimed in claim 1, is characterized in that:

Synthetic reaction flow process is as follows:

Concrete steps are:

4-(2-(7-methoxyl group-4,4-dimethyl-1,3-dioxo-3,4-dihydro-isoquinoline-2 (1H)-yl) ethyl) cyclohexyl isocyanate of benzsulfamide and halogen-containing replacement is in suitable solvent, at 20-150 ℃, reaction 3-24 hour, obtains target compound.

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.