CN103626722A - Hypoglycemic compound of nitric oxide donor type, preparation method and purpose thereof - Google Patents
Hypoglycemic compound of nitric oxide donor type, preparation method and purpose thereof Download PDFInfo
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- CN103626722A CN103626722A CN201210306949.5A CN201210306949A CN103626722A CN 103626722 A CN103626722 A CN 103626722A CN 201210306949 A CN201210306949 A CN 201210306949A CN 103626722 A CN103626722 A CN 103626722A
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- VQSXCZMVUMSITD-UHFFFAOYSA-N NCCCOc1cccc(CN2CCCCC2)c1 Chemical compound NCCCOc1cccc(CN2CCCCC2)c1 VQSXCZMVUMSITD-UHFFFAOYSA-N 0.000 description 1
- ORGBERFQYFWYGX-UHFFFAOYSA-N Oc1cccc(CN2CCCCC2)c1 Chemical compound Oc1cccc(CN2CCCCC2)c1 ORGBERFQYFWYGX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
The invention belongs to the technical field of hypoglycemic drugs and provides a nitric oxide donor compound with the general formula I and a pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are defined as in the specifications. The invention also relates to a preparation of the compound and discloses a medicine composition using the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and purpose thereof in the preparation of hypoglycemic drugs.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to the class pharmaceutical composition that there is hypoglycemic compound and preparation method thereof, contains them and the purposes of preparing ofhypoglycemic medicine.
Background technology
Over nearly 20 years, diabetes mellitus in China sickness rate continues to rise, and China has become global diabetic subject's number the second big country, is only second to India.2009, up-to-date < < basic medical insurance, work-related injury insurance and the birth insurance medicine catalogue > > of having announced of Department of Human Resources and Social Security of country, the Regular Insulin recording has reached 18 kinds with the medicine that affects blood sugar growth.Wherein: have 13 oral blood glucose regulation medicines, the principal item that has covered sulfonylurea, biguanides, alpha-glucosidase inhibitor, thiazolidinediones and the novel Drugs Promoting Insulin Secretion (meglitinide) of domestic listing, has ensured the medication of curing the disease of numerous people.But it is exactly hypoglycemia that a lot of medicines exist maximum side effect, also have in addition that tolerance is poor, drug interaction, long-term taking is large to gastrointestinal injury, easily causes maldigestion.
Nitrogen protoxide of the present invention (NO) compound donator is the novel hypoglycemic compound of a class.NO is important messenger molecule and effector molecule in organism, participates in the adjusting of different physiological roles, has the effect of protection stomach mucous membrane in gastrointestinal system.Patient reduces and causes insulin resistant because nitricoxide synthase (eNOS) defect generates NO, NO donor medicine also can reduce the insulin resistant (document: Cook S causing therefrom, Scherrer U.Fundam Clin Pharmacol, 2002,16:441-453).NO donor comprises nitric ether (R-ONO
2), nitrous acid ester (R-ONO), nitrous acid mercaptan (R-SNO) etc., wherein the most frequently used is exactly nitric ether.The compound that the present invention has formula I is a class nitric ether, has good researching value.
Summary of the invention
One object of the present invention is, discloses class novel nitric oxide donating compound and a pharmaceutical salts thereof.
Another object of the present invention is, discloses the preparation method of a class nitric oxide donors compound and pharmaceutical salts thereof.
A further object of the present invention is, openly take the pharmaceutical composition that a class nitric oxide donors compound and pharmaceutical salts thereof be main active ingredient.
A further object of the invention is, discloses a class nitric oxide donors compound and pharmaceutical salts thereof as the application of ofhypoglycemic medicine aspect, particularly in the purposes aspect prevention or treatment diabetes.
Now, in conjunction with the object of the invention, content of the present invention is described in detail.
The present invention is specifically related to compound and the pharmacy acceptable salt thereof of formula I structure:
Wherein:
R
1, R
2for: hydrogen, halogen, alkoxyl group, halogenated alkoxy;
R
3for :-CH
2cH
2-,
Preferred following compound and pharmacy acceptable salt thereof:
I-1.2-(3-(3-(piperidin-1-yl methyl) phenoxy group) propyl group is amino)-2-oxygen ethyl nitric ether
I-2.2-(3-(2-methoxyl group-5-(piperidin-1-yl methyl) phenoxy group) propyl group is amino)-2-oxygen ethyl nitric ether
I-3.2-(3-(2-(difluoro-methoxy)-5-(piperidin-1-yl methyl) phenoxy group) propyl group is amino)-2-oxygen ethyl nitric ether
I-4.2-(3-(3-(piperidin-1-yl methyl) phenoxy group) propyl group is amino) ethyl nitric ether
I-5.2-(3-(2-methoxyl group-5-(piperidin-1-yl methyl) phenoxy group) propyl group is amino) ethyl nitric ether
I-6.2-(3-(2-(difluoro-methoxy)-5-(piperidin-1-yl methyl) phenoxy group) propyl group is amino) ethyl nitric ether
Formula I compound pharmacy acceptable salt refers to: the salt that compound becomes with mineral acid, organic acid.Wherein preferred: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate; tosilate; maleate, benzoate, succinate; tartrate; Citrate trianion, fumarate, taurate; gluconate, amino acid salts.
Persons skilled in the art reference: Tarpanov V, Vlahov R, Penkov M, et al. A New Synthesis of Roxatidine Acetate[J] .Synthetic Communications, 1999,29 (1): 15-20, and patent PCT/EP93/03193, CN200710133478.1, CN201010212471.0 can conveniently synthesize intermediate (II) ~ (VI) and target compound I.
The syntheti c route of formula I compound is as follows:
Wherein X is Cl, Br; R
1, R
2, R
3definition as previously mentioned.
Replace 3-hydroxy benzaldehyde compound (II), in formic acid solvent, 50 ~ 120 ℃ are reacted with piperidines and obtain key intermediate III.Intermediate III and 3-halo propylamine are under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, take methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene as solvent, 0～110 ℃ of reaction, generates intermediate IV.Intermediate IV and halogen acyl halide are under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, take ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, and-10 ~ 30 ℃ of reactions make intermediate V.Intermediate V and Silver Nitrate are solvent at methylene dichloride, trichloromethane, acetonitrile or toluene, and 30 ~ 120 ℃ of lucifuge reactions finally make chemical compounds I.In addition, by intermediate IV and 2-halo alkanol under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. is solvent, 0 ~ 120 ℃ of reaction makes intermediate VI, then intermediate VI and nitrosonitric acid, aceticanhydride are solvent at methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF) or toluene, and-25 ~ 30 ℃ of reactions finally make chemical compounds I.
Reaction make various compounds or products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, ether or DMSO drip mineral acid, organic acid is made pharmacy acceptable salt.
Specifically products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, ether or DMSO, drips acidic alcohol to pH2, make hydrochloride.Or products therefrom is dissolved in to DMF, acetone, methyl alcohol or ethanol, and mole taurine such as add, obtain its taurate.Also this compound can be dissolved in DMF, acetone, methyl alcohol, ethanol or DMSO, drip the methanol solution of the vitriol oil, adjust pH2-3, make its vitriol, etc.
This compounds is effective for human treatment's hyperglycemia.Although compound of the present invention can be without the direct administration of any preparation, described various compounds are preferably used with the form of pharmaceutical preparation, and route of administration can be parenteral route (as vein, muscle administration) and oral administration.
The pharmaceutical composition of the compounds of this invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.Solid carrier can be at least one material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances such as methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis etc.
The amount of the active ingredient containing in pharmaceutical composition and unit dosage form (the compounds of this invention) can specifically be applied according to the situation of patient's the state of an illness, diagnosis, and the amount of compound used or concentration regulate in a wider scope.Conventionally, 0.5～90%(weight that the weight range of active compound is composition), another preferred scope is 0.5～70%.
Compound or its pharmacy acceptable salt with formula I structure of the present invention, has obvious restraining effect to hyperglycemia.
Below by pharmacodynamic experiment, further illustrate the hypoglycemic activity of the compounds of this invention.
A. external insulin-sensitizing activity test
3T3-L1 cell cultures, in containing in the DMEM nutrient solution of 10% NBS, is gone down to posterity once for every 3 days.Cell is placed in 24 well culture plates, covers with the rear 0.5mmol/L IBMX of using and 1 μ mol/L DEX and 1.0 μ mol/L Regular Insulin and processes 48h, adds the test-compound of various dose (0.01,0.1 and 1 μ mol/L) simultaneously, continues to be cultured to experiment and finishes.Collecting cell, with triglyceride level and the protein content in colorimetric method for determining cell, calculates after administration the increasing amount of triglyceride level in cell.Positive controls is selected rosiglitazone.Blank group is the nutrient solution containing 0.1% dimethyl sulfoxide (DMSO).Experimental result is in Table 1.
The activity of Adipocyte Differentiation lipoblast before table 1 target compound stimulates
B. the oral sugar tolerance model of mouse (oral glucose tolerance test, OGTT) is measured
Sample is mixed with 5mg.mL with 1% Xylo-Mucine
-1the suspension of concentration, dosage is every 20g body weight 0.4mL, is equivalent to 100mgkg
-1dosage.
Healthy ICR mouse, male and female half and half, body weight 20g～24g, meets primary standard.Animal fasting 16h, after medicine, 2gkg is noted in 15min abdominal cavity
-1dextrose in saline solution [1.5h injectable dextrose monohydrate after positive control drug sitagliptin (sitagliptin) medicine], respectively at 0.50h after modeling, 1.00h, 1.50h, 2.00h, 2.50h, 3.00h, 3.50h and 4.00h regularly get blood with kapillary from mouse ball rear vein beard, for the first time 2h injectable dextrose monohydrate again after injectable dextrose monohydrate, centrifugation serum, with each time point serum glucose level of determination of glucose oxidase.
The hypoglycemic activity of compound is weighed by inhibiting rate (inhibitory rate, IR%), the results are shown in Table 2.
IR%={1-[AUC (7a-7u)/AUC (model)] } * 100%, wherein, AUC is the area under curve (area under carve) of " blood sugar concentration-time " curve.
Table 2 pair mouse blood sugar restraining effect
From above pharmacological evaluation, compound of the present invention has obvious inhibition to hyperglycemia.
Embodiment
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.Described compound is through high performance liquid chromatography (HPLC), and thin-layer chromatography (TLC) detects.Can adopt subsequently such as infrared spectra (IR), nuclear magnetic resonance spectrum (
1h NMR,
13c NMR), mass spectrum (MS) etc. is further confirmed its structure.
Reference example 1
Intermediate III-1
In the reaction flask that stirring, condenser, thermometer are housed, add 2.4g 3-hydroxy benzaldehyde, with 40mL formic acid, dissolved, stir, at 60 ℃, add 4.2g piperidines, add post-heating to a 110 ℃ continuation reaction 2h(TLC demonstration and react completely).After being cooled to 15 ℃, use the dilution of 150mL water, add 0.1g activated carbon decolorizing, filter, 12% ammonia solution tune pH8.5 for solution, in 10 ℃ of crystallizations, leaches crystal, and washing, obtains intermediate III-1, yellow crystals 3.0g, productive rate 78% after being dried.MS（m/z）：191。
With reference to the method for reference example 1, can synthetic intermediate III-2～III-3.
Reference example 2
Intermediate IV-1
In the reaction flask that stirring, condenser, thermometer are housed, add intermediate III-1 (2.4g, 0.01mol), 3-chlorine propylamine (2.1g, 0.016mol) and sodium hydroxide (7.2g, 0.18mol), DMF(30ml) dissolve, 90 ℃ of reaction 2h.Naturally cool to 15 ℃, filter, in filtrate, add potassium acetate (0.24g), vacuum distilling goes out about 25ml DMF, adds the dilution of 50ml water in residue, and acetic acid is adjusted pH4.6, dichloromethane extraction, water layer is adjusted after pH9.5 with 12% ammonia solution, then uses dichloromethane extraction (50ml * 2), anhydrous sodium sulfate drying, steam solvent, obtain yellow oily (2.8g, yield 92%), MS (m/z): 248.
With reference to the method for reference example 2, can synthetic intermediate IV-2～IV-3.
Reference example 3
Intermediate V-1
In the reaction flask that stirring, condenser, thermometer are housed, add intermediate IV-1 (2.5g, 0.01mol), with methylene dichloride (10ml), dissolve, add Anhydrous potassium carbonate (1.8g, 0.018mol), cryosel is warm in bathing and controlling slowly drips chloroacetyl chloride (1.5g, 0.013mol), a Bi Jixu stirring reaction 1h lower than 3 ℃.Add frozen water (10ml), stratification, saturated common salt water washing (10ml * 2) for organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed and is desolventized, and obtains white wax-like intermediate V-1 (3.0g, yield 94%).MS(m/z)：324。
With reference to the method for reference example 3, can synthetic intermediate V-2～V-3.
Reference example 4
Intermediate VI-1
In the reaction flask that stirring, condenser, thermometer are housed, add intermediate IV-1 (2.5g, 0.01mol), with methylene dichloride (10ml), dissolve, add Anhydrous potassium carbonate (1.8g, 0.018mol), under room temperature, slowly drip ethylene chlorhydrin (1.1g, 0.013mol), drip Bi Jixu stirring reaction 1h.Add frozen water (10ml), stratification, saturated common salt water washing (10ml * 2) for organic phase, anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed and is desolventized, and obtains white solid intermediate VI-1 (2.6g, yield 92%).MS(m/z)：292。
With reference to the method for reference example 4, can obtain synthesising target compound VI-2～VI-3.
embodiment 1
2-(3-(3-(piperidin-1-yl methyl) phenoxy group) propyl group is amino)-2-oxygen ethyl nitric ether (chemical compounds I-1)
In the reaction flask that stirring, condenser, thermometer are housed, add intermediate V-1 (3.2g, 0.01mol), anhydrous acetonitrile (20m1) dissolves, add Silver Nitrate (2.0g, anhydrous acetonitrile 0.012mol) (10m1), lucifuge stirs lower backflow 5h, after TLC demonstration reacts completely, is cooled to room temperature, evaporated under reduced pressure solvent.In residuum, add methylene dichloride (20ml), stir 10min, filter filtrate decompression solvent evaporated.Add dehydrated alcohol (30ml), evaporated under reduced pressure after activated carbon decolorizing, reduced pressure at room temperature is spent the night, and obtains faint yellow transparent oily matter I-1 (3.1g, yield 90%), purity 98.2% (HPLC method).MS(m/z)：351。
With reference to the method for embodiment 1, can obtain synthesising target compound I-2～I-3.
embodiment 2
2-(3-(3-(piperidin-1-yl methyl) phenoxy group) propyl group is amino) ethyl nitric ether (chemical compounds I-4)
In the reaction flask that stirring, condenser, thermometer are housed, 6.5ml nitrosonitric acid, 19.5ml aceticanhydride are mixed, control temperature at-15 ℃, drip wherein intermediate VI-1(2.9g, tetrahydrofuran solution 100mL 0.01mol), drip and finish, slowly rise to room temperature, reaction 4h, drips frozen water stopped reaction.Reaction mixture 200ml acetic acid ethyl dissolution, washes with 200ml water, 200ml saturated sodium bicarbonate solution successively, then washes with 200ml water, 200ml saturated nacl aqueous solution.Organic layer anhydrous magnesium sulfate drying.Concentrating under reduced pressure, crude product is through column chromatography (v(sherwood oil): v(ethyl acetate)=1:1] purifying, obtain yellow oil 1.9g, yield 58%, purity 99.1%.MS(m/z)：337。
With reference to the method for embodiment 1, can obtain synthesising target compound I-5～I-6.
embodiment 3
Chemical compounds I-2 one-tenth hydrochloride: get chemical compounds I-2 yellow oil 1.5g, be dissolved in 10mL dehydrated alcohol.Ice-water bath is cooled to 5 ℃, drip 11.1% ethanol solution hydrochloride to pH be 2, continue at stir about 1h under ice-water bath.Filter, vacuum-drying, obtains yellow solid.
embodiment 4
Chemical compounds I-4 one-tenth taurate: get chemical compounds I-4 yellow oil 2.0g, be dissolved in 10ml acetone.After being heated to reflux, add and wait mole taurine, continue at time about 1.5h of stirring reaction that refluxes.React complete, standing 24h under room temperature.Separate out yellow crystal, filter vacuum-drying.
embodiment 5
Chemical compounds I-5 one-tenth vitriol: get chemical compounds I-6 light yellow solid product 1.2g, be dissolved in 15ml methyl alcohol.Ice-water bath is cooled to 0 ℃, drip 10% sulfuric acid methanol solution to pH be 3, continue at stir about 1h under ice-water bath.Filter, obtain faint yellow solid.
For the pharmaceutical composition of nitric oxide donors compound of the present invention is described more fully, following FORMULATION EXAMPLE is provided below, described embodiment is only for explanation, rather than for limiting the scope of the invention.Described preparation can be used any active compound and the salt thereof in the compounds of this invention, preferably uses the compound described in embodiment 1-5.
embodiment 6
By following compositions, prepare hard gelatin capsule:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.Press recipe quantity by after mentioned component mixing, be packed in hard gelatin capsule.
embodiment 7
By following compositions, prepare tablet:
Preparation technology: supplementary material is dry in advance, cross 100 mesh sieves standby.First the auxiliary material of recipe quantity is fully mixed.Bulk drug is added in auxiliary material to increase progressively dilution method, and each added-time fully mixes 2-3 time, guarantees that medicine and auxiliary material fully mix, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dry particle is crossed the whole grain of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
embodiment 8
The preparation of injection liquid:
Preparation method: get activeconstituents and join in the water for injection that dissolves polysorbate and propylene glycol, add medicinal basic to regulate pH value to 4 ~ 8 to make its dissolving.Add gac, whip attachment 30min, carbon removal, smart filter, embedding, sterilizing.
embodiment 9
The preparation of injection lyophilized powder:
The taurate 50mg of chemical compounds I-4
Medicinal basic 0.1-7.0%
N.F,USP MANNITOL 55-85%
Preparation method: get activeconstituents and add water for injection, regulate pH value to make its dissolving to 4-8 with medicinal basic.Add N.F,USP MANNITOL again, by the requirement of injection, carry out autoclaving, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, and sealing, obtains.
Claims (10)
1. compound and the pharmacy acceptable salt thereof with formula I structure:
Wherein:
R
1, R
2for: hydrogen, bromine, iodine, alkoxyl group, fluoroalkyl;
R
3for :-CH
2cH
2-,
2. compound and the pharmacy acceptable salt thereof with formula I structure as claimed in claim 1, its Chinese style I compound is:
3. compound and the pharmacy acceptable salt thereof with formula I structure as claimed in claim 1, pharmacy acceptable salt refers to: compound and mineral acid, organic acid salify.
4. compound and the pharmacy acceptable salt thereof with formula I structure as claimed in claim 3, pharmacy acceptable salt refers to: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, Citrate trianion, fumarate, taurate, gluconate.
5. the preparation method of claim 1 Chinese style I compound, is characterized in that: intermediate III and 3-halo propylamine, under acid binding agent exists, be take methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene as solvent, 0～110 ℃ of reaction; The intermediate IV generating and halogen acyl halide, under acid binding agent exists, be take ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent, and-10 ~ 30 ℃ of reactions make intermediate V; Intermediate V and Silver Nitrate be take methylene dichloride, trichloromethane, acetonitrile or toluene as solvent, and 30 ~ 120 ℃ of lucifuge reactions make chemical compounds I;
Wherein X is Cl, Br; R
1, R
2, R
3definition as claimed in claim 1.
6. the preparation method of claim 1 Chinese style I compound, is characterized in that: intermediate IV and 2-chlorine alkanol, under acid binding agent exists, be take methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent, and 0 ~ 120 ℃ of reaction makes intermediate VI; Intermediate VI and nitrosonitric acid, aceticanhydride are in methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF) or toluene solvant, and-25 ~ 30 ℃ of reactions make chemical compounds I;
Wherein X is Cl, Br; R
1, R
2, R
3definition as claimed in claim 1.
7. the preparation method as described in claim 5 ~ 6 any one, is characterized in that, described acid binding agent comprises triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide.
8. a hypoglycemic pharmaceutical composition, the compound or its pharmacy acceptable salt and one or more pharmaceutical carriers that comprise the formula I structure described in claim 1～2 any one for the treatment of significant quantity.
9. the compound of the formula I structure described in claim 1 ~ 2 any one and pharmacy acceptable salt thereof are in the application aspect hypoglycemic drug.
10. application as claimed in claim 9, in the purposes aspect treatment hyperglycemia medicine.
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| CN111548482A (en) * | 2020-04-02 | 2020-08-18 | 复旦大学 | Nitric oxide donor modified copolymer, sustained-release preparation containing nitric oxide donor modified copolymer, and preparation method and application of nitric oxide donor modified copolymer |
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| CN107721874A (en) * | 2017-11-20 | 2018-02-23 | 南京工业大学 | Method for preparing nitrate compounds by adopting micro-flow field reaction technology |
| CN107721874B (en) * | 2017-11-20 | 2020-05-19 | 南京工业大学 | Method for preparing nitrate compounds by adopting micro-flow field reaction technology |
| CN111548482A (en) * | 2020-04-02 | 2020-08-18 | 复旦大学 | Nitric oxide donor modified copolymer, sustained-release preparation containing nitric oxide donor modified copolymer, and preparation method and application of nitric oxide donor modified copolymer |
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