CN103626722B - Nitric oxide donator type Hypoglycemics, Preparation Method And The Use - Google Patents

Nitric oxide donator type Hypoglycemics, Preparation Method And The Use Download PDF

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CN103626722B
CN103626722B CN201210306949.5A CN201210306949A CN103626722B CN 103626722 B CN103626722 B CN 103626722B CN 201210306949 A CN201210306949 A CN 201210306949A CN 103626722 B CN103626722 B CN 103626722B
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compound
acceptable salt
pharmacy acceptable
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CN103626722A (en
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刘登科
刘颖
解晓帅
祁浩飞
张大帅
魏巍
邹美香
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Tianjin Institute of Pharmaceutical Research Co Ltd
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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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to ofhypoglycemic medicine technical field, it is provided that there is Nitric oxidedonating compounds and the pharmacy acceptable salt thereof of formula I structure, wherein R1, R2, R3Definition with the specification above. The present invention also relates to the preparation method of above-claimed cpd, and also discloses using this compound or its pharmacy acceptable salt as the pharmaceutical composition of active effective constituent, and they are preparing the application in ofhypoglycemic medicine.

Description

Nitric oxide donator type Hypoglycemics, Preparation Method And The Use
Technical field
The invention belongs to medical art, more properly say, relate to a class there is hypoglycemic compound and its preparation method, containing their pharmaceutical composition with prepare the purposes of ofhypoglycemic medicine.
Background technology
Over nearly 20 years, China's onset diabetes rate continues to rise, and China has become the whole world second largest state of diabetic subject's number, is only second to India. 2009, country's manpower and social security portion is up-to-date discloses " basic medical insurance, work-related injury insurance and birth insurance Drug catalogue ", the Regular Insulin recorded and medicine affect blood sugar growth reached 18 kinds. Wherein: have 13 oral blood glucose regulation medicines, cover the main kind of the sulfonylurea of domestic listing, biguanides, alpha-glucosidase inhibitor, thiazolidinediones and novel Drugs Promoting Insulin Secretion (meglitinide), ensure the medication of curing the disease of numerous people. But it is exactly hypoglycemia that a lot of medicine exists maximum side effect, also has poor resistance, drug interaction in addition, take gastrointestinal injury big for a long time, easily cause maldigestion.
To be that a class is novel fall sugar compounds to nitrogen protoxide (NO) compound donator of the present invention. NO is messenger molecule important in organism and effector molecule, participates in the adjustment of different physiological roles, has the effect of protection stomach mucous membrane in gastrointestinal system. Patient causes insulin resistant because nitricoxide synthase (eNOS) defect makes NO generation minimizing, NO donor medicine also can reduce insulin resistant (document: the CookS caused therefrom, ScherrerU.FundamClinPharmacol, 2002,16:441-453). NO donor comprises nitric ether (R-ONO2), nitrous acid ester (R-ONO), nitrous acid mercaptan (R-SNO) etc., wherein the most frequently used is exactly nitric ether. It is a class nitric ether that the present invention has the compound of formula I, has good researching value.
Summary of the invention
It is an object of the present invention to, disclose 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 oxidedonating compounds and pharmaceutical salts thereof.
Another object of the present invention is, open taking a class Nitric oxidedonating compounds and pharmaceutical salts thereof as the pharmaceutical composition of main active ingredient.
A further object of the invention is, discloses the application as ofhypoglycemic medicine aspect of a class Nitric oxidedonating compounds and pharmaceutical salts thereof, particularly for the preparation of the purposes in 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:
R1��R2For: hydrogen, halogen, alkoxyl group, halogenated alkoxy;
R3For :-CH2CH2-,
Preferred following compound and pharmacy acceptable salt thereof:
I-1.2-(3-(3-(piperidines-1-ylmethyl) phenoxy group) propyl group amino)-2-oxygen acetyl nitrate ester
I-2.2-(3-(2-methoxyl group-5-(piperidines-1-ylmethyl) phenoxy group) propyl group amino)-2-oxygen acetyl nitrate ester
I-3.2-(3-(2-(difluoro-methoxy)-5-(piperidines-1-ylmethyl) phenoxy group) propyl group amino)-2-oxygen acetyl nitrate ester
I-4.2-(3-(3-(piperidines-1-ylmethyl) phenoxy group) propyl group amino) acetyl nitrate ester
I-5.2-(3-(2-methoxyl group-5-(piperidines-1-ylmethyl) phenoxy group) propyl group amino) acetyl nitrate ester
I-6.2-(3-(2-(difluoro-methoxy)-5-(piperidines-1-ylmethyl) phenoxy group) propyl group amino) acetyl nitrate ester
Type I compound pharmacy acceptable salt refers to: salt formed by compound and 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: TarpanovV, VlahovR, PenkovM, etal.ANewSynthesisofRoxatidineAcetate [J] .SyntheticCommunications, 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 type I compound is as follows:
Wherein X is Cl, Br; R1��R2��R3Definition is as previously mentioned.
Replacing 3-hydroxy benzaldehyde compound (II), in formic acid solvent, 50 ~ 120 DEG C are obtained by reacting key intermediate III with piperidines. Intermediate III and 3-halogen for propylamine under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, taking methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene as solvent, 0��110 DEG C 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, taking ethyl acetate, methylene dichloride, trichloromethane or toluene etc. as solvent ,-10 ~ 30 DEG C of obtained intermediates V of reaction. Intermediate V and Silver Nitrate are solvent at methylene dichloride, trichloromethane, acetonitrile or toluene, 30 ~ 120 DEG C of final obtained chemical compounds Is of lucifuge reaction. In addition, by intermediate IV with 2-haloalkane alcohol under the acid binding agents such as triethylamine, pyridine, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide exist, taking methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene etc. as solvent, 0 ~ 120 DEG C of obtained intermediate VI of reaction, then intermediate VI and nitrosonitric acid, aceticanhydride are solvent at methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF) or toluene ,-25 ~ 30 DEG C of final obtained chemical compounds Is of reaction.
The obtained various compound of reaction or be dissolved in DMF, acetone, methyl alcohol, ethanol, ether or DMSO dripping products therefrom add mineral acid, organic acid make pharmacy acceptable salt.
Specifically products therefrom is dissolved in DMF, acetone, methyl alcohol, ethanol, ether or DMSO, drips and add acidic alcohol to pH2, make hydrochloride. Or products therefrom is dissolved in DMF, acetone, methyl alcohol or ethanol, 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 adding the vitriol oil, adjust pH2-3, its vitriol obtained, etc.
This compounds is effective for human treatment's hyperglycemia. Although the compound of the present invention can without the direct administration of any preparation, but described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (such 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 arbitrarily on technology of pharmaceutics acceptable auxiliary and vehicle 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 such as injection, pulvis etc.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form can according to the situation of the state of an illness of patient, diagnosis specific be applied, the amount of compound used or concentration regulate in a wider scope. Usually, the weight range of active compound is 0.5��90%(weight of composition), another preferred scope is 0.5��70%.
The compound with structure shown in formula I of the present invention or its pharmacy acceptable salt, have obvious restraining effect to hyperglycemia.
The hypoglycemic activity of the compounds of this invention is described further below by pharmacodynamic experiment.
A. external insulin-sensitizing activity test
By 3T3-L1 cell cultures in containing in the DMEM nutrient solution of 10%NBS, within every 3 days, go down to posterity once. Cell is placed in 24 well culture plates, with 0.5mmol/LIBMX and 1 ��m of ol/LDEX and 1.0 ��m of ol/L Regular Insulin process 48h after covering with, add the test-compound of various dose (0.01,0.1 and 1 ��m of ol/L) simultaneously, continue to be cultured to experiment and terminate. Collecting cell, with the triglyceride level in colorimetric method for determining cell and protein content, calculates the increasing amount of intracellular triglyceride after administration. Positive controls selects rosiglitazone. Blank group is the nutrient solution containing 0.1% dimethyl sulfoxide (DMSO). Experimental result is in table 1.
Table 1 target compound stimulates PECTORAL LIMB SKELETON to be divided into the activity of adipocyte
B. mouse oral sugar tolerance model (oralglucosetolerancetest, OGTT) measures
Sample is mixed with 5mg.mL with 1% Xylo-Mucine-1The suspension of concentration, administration amount is every 20g body weight 0.4mL, is equivalent to 100mg kg-1Dosage.
Healthy ICR mouse, male and female half and half, body weight 20g��24g, meets primary standard. Animal fasting 16h, note 2g kg in 15min abdominal cavity after medicine-1The glucosamine salt aqueous solution [after positive control drug sitagliptin (sitagliptin) medicine 1.5h injectable dextrose monohydrate], 0.50h after modeling, 1.00h, 1.50h, 2.00h, 2.50h, 3.00h, 3.50h and 4.00h timing kapillary gets blood 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 (inhibitoryrate, IR%), the results are shown in Table 2.
IR%={1-[AUC (7a-7u)/AUC (model)] } �� 100%, wherein, AUC is the area under curve (areaundercarve) of " blood sugar concentration-time " curve.
Table 2 is to mouse blood sugar restraining effect
From above pharmacological evaluation, hyperglycemia is had obvious inhibition by the compound of the present invention.
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 detects through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC). Such as infrared spectra (IR) can be adopted subsequently, nuclear magnetic resonance spectrum (1HNMR,13CNMR), mass spectrum (MS) etc. further confirm its structure.
Reference example 1
Intermediate III-1
The reaction flask that stirring, condenser, thermometer are housed adds 2.4g3-hydroxy benzaldehyde, is dissolved with 40mL formic acid, stir, at 60 DEG C, add 4.2g piperidines, add post-heating to 110 DEG C continuation reaction 2h(TLC display and react completely). With the dilution of 150mL water after being cooled to 15 DEG C, adding 0.1g activated carbon decolorizing, filter, solution adjusts pH8.5 with 12% ammonia solution, in 10 DEG C of crystallizations, filters out crystal, and washing obtains intermediate III-1, yellow crystals 3.0g, product rate 78% after dry. 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
The reaction flask that stirring, condenser, thermometer are housed adds 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 DEG C of reaction 2h. Naturally cool to 15 DEG C, filter, in filtrate, add potassium acetate (0.24g), vacuum distilling goes out about 25mlDMF, adds the dilution of 50ml water in residue, and pH4.6 adjusted by acetic acid, dichloromethane extraction, water layer is adjusted after pH9.5 with 12% ammonia solution, then with dichloromethane extraction (50ml �� 2), anhydrous sodium sulfate drying, steam solvent, obtain yellow oily (2.8g, receipts rate 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
The reaction flask that stirring, condenser, thermometer are housed adds intermediate IV-1 (2.5g, 0.01mol), dissolve with methylene dichloride (10ml), add Anhydrous potassium carbonate (1.8g, 0.018mol), in the bath control of ice salt, temperature is slowly dripped lower than 3 DEG C and is added chloroacetyl chloride (1.5g, 0.013mol), drips Bi Jixu stirring reaction 1h. Adding frozen water (10ml), stratification, organic phase is with saturated common salt water washing (10ml �� 2), and anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed except solvent, obtains white wax-like intermediate V-1 (3.0g, receipts rate 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
The reaction flask that stirring, condenser, thermometer are housed adds intermediate IV-1 (2.5g, 0.01mol), dissolve with methylene dichloride (10ml), add Anhydrous potassium carbonate (1.8g, 0.018mol), slowly drip under room temperature and add ethylene chlorhydrin (1.1g, 0.013mol), drip Bi Jixu stirring reaction 1h. Adding frozen water (10ml), stratification, organic phase is with saturated common salt water washing (10ml �� 2), and anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed except solvent, obtains white solid intermediate VI-1 (2.6g, receipts rate 92%). MS (m/z): 292.
With reference to the method for reference example 4, synthesising target compound VI-2��VI-3 can be obtained.
Embodiment 1
2-(3-(3-(piperidines-1-ylmethyl) phenoxy group) propyl group amino)-2-oxygen acetyl nitrate ester (chemical compounds I-1)
The reaction flask that stirring, condenser, thermometer are housed adds intermediate V-1 (3.2g, 0.01mol), anhydrous acetonitrile (20m1) dissolves, add Silver Nitrate (2.0g, anhydrous acetonitrile (10m1) 0.012mol), lucifuge refluxes under stirring after 5h, TLC display reacts completely and is cooled to room temperature, evaporated under reduced pressure solvent. Residuum adds methylene dichloride (20ml), stirs 10min, filter, filtrate decompression solvent evaporated. Adding dehydrated alcohol (30ml), evaporated under reduced pressure after activated carbon decolorizing, reduced pressure at room temperature is spent the night, and obtains faint yellow clear oil thing I-1 (3.1g, receipts rate 90%), purity 98.2% (HPLC method). MS (m/z): 351.
With reference to the method for embodiment 1, synthesising target compound I-2��I-3 can be obtained.
Embodiment 2
2-(3-(3-(piperidines-1-ylmethyl) phenoxy group) propyl group amino) acetyl nitrate ester (chemical compounds I-4)
By 6.5ml nitrosonitric acid, the mixing of 19.5ml aceticanhydride in the reaction flask that stirring, condenser, thermometer are housed, control temperature is at-15 DEG C, drip wherein and add intermediate VI-1(2.9g, tetrahydrofuran solution 100mL 0.01mol), drip and finish, slowly rising to room temperature, reaction 4h, drips with 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 over anhydrous dried over mgso. Concentrating under reduced pressure, crude product is through column chromatography (v(sherwood oil): v(ethyl acetate)=1:1] purifying, obtain yellow oil 1.9g, receipts rate 58%, purity 99.1%. MS (m/z): 337.
With reference to the method for embodiment 1, synthesising target compound I-5��I-6 can be obtained.
Embodiment 3
Chemical compounds I-2 hydrochloric acid salt: get chemical compounds I-2 yellow oil 1.5g, be dissolved in 10mL dehydrated alcohol. Ice-water bath is cooled to 5 DEG C, drips and adds 11.1% ethanol solution hydrochloride is 2 to pH, continues at stir about 1h under ice-water bath. Filtering, vacuum-drying, obtains yellow solid.
Embodiment 4
Chemical compounds I-4 becomes taurate: gets chemical compounds I-4 yellow oil 2.0g, is dissolved in 10ml acetone. Add after being heated to backflow and wait mole taurine, continue at backflow time stirring reaction and be about 1.5h. React complete, in left at room temperature 24h. Precipitate out yellow crystal, filter, vacuum-drying.
Embodiment 5
Chemical compounds I-5 becomes vitriol: gets chemical compounds I-6 product as light yellow solid 1.2g, is dissolved in 15ml methyl alcohol. Ice-water bath is cooled to 0 DEG C, drips and adds 10% sulfuric acid methanol solution is 3 to pH, continues at stir about 1h under ice-water bath. Filter, obtain faint yellow solid.
In order to the pharmaceutical composition of the Nitric oxidedonating compounds of the present invention is described more fully, provide following example of formulations below, described embodiment only for illustration of, instead of for limiting the scope of the invention. Described preparation can use any active compound in the compounds of this invention and salt thereof, it is preferred to use the compound described in embodiment 1-5.
Embodiment 6
Hard gelatin capsule is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 order sieves for subsequent use. After mentioned component being mixed by recipe quantity, it is packed in hard gelatin capsule.
Embodiment 7
Tablet is prepared by following compositions:
Preparation technology: supplementary material is dry in advance, crosses 100 order sieves for subsequent use. First the auxiliary material of recipe quantity is fully mixed even. By bulk drug, to increase progressively, dilution method is added in auxiliary material, and each added-time fully mixes even 2-3 time, ensures that medicine and auxiliary material fully mix even, crossing 20 order sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry particle is crossed 16 orders and is sieved whole grain, measure intermediates 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 dissolving polysorbate and propylene glycol, adds medicinal basic adjust ph to 4 ~ 8 and makes it dissolve. Add gac, whip attachment 30min, carbon removal, essence 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, makes it dissolve by medicinal basic adjust ph to 4-8. Adding N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate carries out packing, adopts freeze-drying, and obtained loose block, sealing, to obtain final product.

Claims (10)

1. there is compound and the pharmacy acceptable salt thereof of structure shown in formula I:
Wherein:
R1��R2For: hydrogen, bromine, iodine;
R3For :-CH2CH2-,
2. compound and a pharmacy acceptable salt thereof, is selected from:
3. compound as claimed in claim 1 or 2 and pharmacy acceptable salt thereof, pharmacy acceptable salt refers to: compound becomes salt with mineral acid, organic acid.
4. compound as claimed in claim 3 and pharmacy acceptable salt thereof, 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 type I compound in claim 1, it is characterised in that: intermediate III and 3-halogen for propylamine under acid binding agent exists, taking methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF), DMF or toluene as solvent, 0��110 DEG C of reaction; The intermediate IV generated and halogen acyl halide are under acid binding agent exists, and taking ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent ,-10��30 DEG C of reactions obtain intermediates V; Intermediate V and Silver Nitrate are taking methylene dichloride, trichloromethane, acetonitrile or toluene as solvent, and 30��120 DEG C of lucifuge reactions obtain chemical compounds Is;
Wherein X is Cl, Br; R1��R2��R3Definition is as claimed in claim 1.
6. the preparation method of type I compound in claim 1, it is characterized in that: intermediate IV and 2-chlorine alkanol are under acid binding agent exists, taking methyl alcohol, ethanol, ethyl acetate, methylene dichloride, trichloromethane or toluene as solvent, 0��120 DEG C of obtained intermediate VI of reaction; Intermediate VI and nitrosonitric acid, aceticanhydride are in methylene dichloride, trichloromethane, acetonitrile, tetrahydrofuran (THF) or toluene solvant, and-25��30 DEG C of reactions obtain chemical compounds Is;
Wherein X is Cl, Br; R1��R2��R3Definition is as claimed in claim 1.
7. preparation method as described in item as arbitrary in claim 5��6, it is characterised 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, comprises the compound described in the arbitrary item of claim 1��2 or its pharmacy acceptable salt and one or more pharmaceutical carriers for the treatment of significant quantity.
9. compound described in the arbitrary item of claim 1��2 and pharmacy acceptable salt thereof are for the preparation of the application in hypoglycemic drug.
10. apply as claimed in claim 9, for the preparation of the purposes in treatment hyperglycemia medicine.
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Publication number Priority date Publication date Assignee Title
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
CN111548482B (en) * 2020-04-02 2022-09-13 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

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039088A1 (en) * 1998-12-23 2000-07-06 Novo Nordisk A/S Glucagon antagonists/inverse agonists
CN101134745A (en) * 2007-09-29 2008-03-05 中国药科大学 Nitric oxide donator type telmisartan derivant, preparation method and medical uses thereof
CN101337891A (en) * 2008-05-19 2009-01-07 中国药科大学 Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use
CN101863900A (en) * 2010-06-29 2010-10-20 天津药物研究院 Novel nitric oxide donating thienopyridine derivative and preparation method and application thereof
WO2012064150A2 (en) * 2010-11-11 2012-05-18 한국생명공학연구원 Composition comprising benproperine derivatives as active ingredients for preventing and treating angiogenesis-related diseases
CN102498091A (en) * 2009-09-16 2012-06-13 安斯泰来制药株式会社 Glycine compound

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039088A1 (en) * 1998-12-23 2000-07-06 Novo Nordisk A/S Glucagon antagonists/inverse agonists
CN101134745A (en) * 2007-09-29 2008-03-05 中国药科大学 Nitric oxide donator type telmisartan derivant, preparation method and medical uses thereof
CN101337891A (en) * 2008-05-19 2009-01-07 中国药科大学 Nitric oxide donor type 3-butylphthalide derivates, method for preparing same and pharmaceutical use
CN102498091A (en) * 2009-09-16 2012-06-13 安斯泰来制药株式会社 Glycine compound
CN101863900A (en) * 2010-06-29 2010-10-20 天津药物研究院 Novel nitric oxide donating thienopyridine derivative and preparation method and application thereof
WO2012064150A2 (en) * 2010-11-11 2012-05-18 한국생명공학연구원 Composition comprising benproperine derivatives as active ingredients for preventing and treating angiogenesis-related diseases

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes;D.C.Henstridge，等;《Diabetologia》;20051105;第48卷;第2602-2608页 *
一氧化氮供体修饰非甾体类抗炎药研究进展;刘志军，等;《国际药学研究杂志》;20071231;第34卷(第6期);第414-417页 *
呋咱氮氧化物类一氧化氮供体型药物的研究进展;孟飞，等;《药学进展》;20120331;第36卷(第3期);第97-102页 *

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