CN101445528A - Sulpho-glucosan derivative and preparation method and application thereof - Google Patents
Sulpho-glucosan derivative and preparation method and application thereof Download PDFInfo
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- CN101445528A CN101445528A CNA200810154445XA CN200810154445A CN101445528A CN 101445528 A CN101445528 A CN 101445528A CN A200810154445X A CNA200810154445X A CN A200810154445XA CN 200810154445 A CN200810154445 A CN 200810154445A CN 101445528 A CN101445528 A CN 101445528A
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Abstract
The invention relates to the field of diabetes related medicine, in particular to a depressor for a Na-glucose transporter II containing a structure of sulpho-glucose (SGLT2) and a preparation method thereof, and a pharmaceutical composition containing SGLT2 and an application thereof in the preparation of diabetes drugs, wherein, a radical group is defined in the specification.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to medicative 2 type sodium glucose transporter (SGLT2) inhibitor that contain sulfo-glucose structure of diabetes and preparation method thereof, and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject is at present nearly about 1.7 hundred million, wherein about most II type (being non-insulin-depending type) diabetic subjects that are.Antidiabetic medicine in clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea and trypsin class medicine at present, thiazolidinediones medicine, alpha-glucosidase inhibitor and the dipeptidyl peptidase-iv inhibitor etc. in addition of listing in recent years.These medicines have good therapeutic action, but there is safety issue in long-term treatment, as: problems such as liver toxicity and weight increase.
2 type sodium glucose transporters (SGLT2) are the novel targets of the treatment diabetes of discovered in recent years.The protein target spot of SGLT2 is distributed in kidney, its effect is the glucose that absorbs in the urine, and it is turned back in the blood, the protein target spot that therefore suppresses SGLT2 just can reduce glucose concn in the blood, and this method has reduced glucose level from different in the past approach.When the SGLT2 function is obstructed, will secrete more glucose in the urine, this will help the diabetic subject to keep correct glucose level.Because the SGLT2 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The invention discloses the New type of S GLT2 inhibitor that reduces plasma glucose levels effectively, these inhibitor lay the foundation for the medicine that further can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound and the pharmacy acceptable salt thereof of general formula I.
Another object of the present invention provides the method that preparation has the compound and the pharmacy acceptable salt thereof of general formula I.
A further object of the present invention provide contain general formula I compound as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Wherein,
R=H, F, Cl, Br, I, C
1-C
5Alkyl, OH, OR
1, NO
2, NH
2, CN or NR
2R
3, and they two replace or trisubstituted combination, wherein R
1Be selected from C
1-C
5Alkyl, R
2And R
3Be selected from H and C
1-C
5Alkyl
N=0 or 1
X=O or S
Preferred following compound of Formula I or its pharmacy acceptable salt,
Wherein,
R=H, F, Cl, C
1-C
3Alkyl, OR
1, NO
2, CN or NR
2R
3, or their dibasic combination, wherein R
1Be selected from C
1-C
3Alkyl, R
2And R
3Be selected from H and C
1-C
3Alkyl.
N=0 or 1
X=O or S
It is as shown in the table that preferred the present invention has the compound of general formula I:
| Compound number | The compound title |
| I-1 | 5-(Phenoxymethyl)-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-2 | The 5-[(4-ethoxy phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-3 | 5-[(4-chloro-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-4 | 5-[(4-amino-3-cyano group-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-5 | The 5-[(3-ethoxy phenoxy) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| I-6 | 5-[(3-ethyl phenoxy group) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| I-7 | 5-benzyl-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-8 | The 5-[(2-chloro-phenyl-) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| I-9 | The 5-[(3-p-methoxy-phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| I-10 | 5-[(4-chloro-2-aminomethyl phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
Compound of Formula I of the present invention is synthetic by following steps:
The reaction of Compound I I and compound III, obtain Compound I ', Compound I ' under the sodium methylate effect, obtain I.Wherein, compound III according to literature method preparation (Jia Yonglin, Li Bin, Bing Baichun, 2,3,4,6-four-O-ethanoyl-1-sulfydryl Glucopyranose synthetic, chemistry with bind 2007,29 (3): 189-192), Compound I I is synthetic by following route.
Compound IV and hydrazine hydrate reaction through the hydrazinolysis reaction, obtain compound V.
Compound V in the presence of KOH with CS
2Effect obtains compound VI.
Compound VI is handled through the vitriol oil, obtains Compound I I-a.Wherein, Compound I I-a is that general formula is a series in the compound of II, this moment X=S, R's is described as defined above.
Compound VI is handled through KOH, obtains Compound I I-b.Wherein, Compound I I-b is that general formula is a series in the compound of II, this moment X=O, R's is described as defined above.
The pharmacy acceptable salt of formula I compound of the present invention comprises, but be not limited to and various mineral acids, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc., or organic acid, for example pharmacy acceptable salt that generated such as formic acid, acetate, citric acid, oxalic acid, fumaric acid, toxilic acid, amino acid.
Formula I compound of the present invention or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention or its salt have the restraining effect of SGLT2 enzyme, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
Benzene oxygen acethydrazide (V-1)
Add 18.0g (0.1mol) compound IV-1 and 250mL dehydrated alcohol in the round-bottomed flask of 500mL, add 85% hydrazine hydrate 30g (0.51mol) under the stirring at room.Then the reaction mixture temperature rising reflux is 1 hour.Behind the cool to room temperature, reaction system is concentrated to original half on Rotary Evaporators, then stirs 1 hour under the room temperature, and suction filtration is collected crystal, obtains compound V-1 after the drying.Clear crystal, 14.8g, productive rate 89%.
Compound IV-1 and V-1 have general formula I V and have in the compound of general formula I V one.
Embodiment 2-10
With the operation of embodiment 1, replace compound IV-1 among the embodiment 1 with the compound IV-2 in the following table to IV-10, all the other are operated with embodiment 1, obtain in the following table listed compound V-2 to V-5.
Compound IV-2 belongs to two compounds that have general formula I V and have general formula V respectively to IV-10 and compound V-2 to V-10.
| The embodiment sequence number | Productive rate (%) | IV | V |
| 2 | 89 | The IV-2:(4-phenoxy ethoxy) ethyl acetate | The V-2:(4-phenoxy ethoxy) acethydrazide |
| 3 | 90 | IV-3:(4-chloro-2-oil of mirbane oxygen) ethyl acetate | V-3:(4-chloro-2-oil of mirbane oxygen) acethydrazide |
| 4 | 92 | IV-4:(4-amino-3-cyano group-2-oil of mirbane oxygen) ethyl acetate | V-4:(4-amino-3-cyano group-2-oil of mirbane oxygen) acethydrazide |
| 5 | 88 | The IV-5:(3-phenoxy ethoxy) ethyl acetate | The V-5:(3-phenoxy ethoxy) acethydrazide |
| 6 | 94 | IV-6:(3-ethylbenzene oxygen) ethyl acetate | V-6:(3-ethylbenzene oxygen) acethydrazide |
| 7 | 92 | IV-7: phenylacetic acid ethyl ester | V-7: phenyl acethydrazide |
| 8 | 90 | The IV-8:(2-chloro-phenyl-) ethyl acetate | The V-8:(2-chloro-phenyl-) acethydrazide |
| 9 | 93 | The IV-9:(3-p-methoxy-phenyl) ethyl acetate | The V-9:(3-p-methoxy-phenyl) acethydrazide |
| 10 | 90 | IV-10:(4-chloro-2-aminomethyl phenyl) ethyl acetate | V-10:(4-chloro-2-aminomethyl phenyl) acethydrazide |
Embodiment 11
2-sulfydryl-5-(Phenoxymethyl)-1,3,4-thiadiazoles (II-a-1)
Add 4.98g (30mmol) compound V-1 and 100mL dehydrated alcohol in the round-bottomed flask of 250mL, add 2.24g (40mmol) solid KOH under the stirring at room, stirred 10 minutes under the room temperature, then drip the exsiccant CS that 3.80g (50mmol) is dissolved in the 10mL dehydrated alcohol
2, stir under the afterreaction system that the finishes room temperature and spend the night.Suction filtration obtains a yellow solid, and drying obtains compound VI-1, yellow solid.Being dissolved in the 20mL vitriol oil under the compound VI that obtains-1 room temperature, then stirring under the room temperature and spend the night.Reaction system is poured in the 200mL frozen water, stirred 10 minutes, and suction filtration, filter cake washes with water, and drying obtains Compound I I-a-1.5.44g, productive rate 81%.IR(KBr)，3030，1498，1588，1200cm
-1.
Compound VI-1 and Compound I I-a-1 are respectively one that has in the compound of general formula VI and II-a.
Embodiment 12-16
Operation with embodiment 11, respectively with the compound V-1 among compound V-2, V-3 in the following table, V-4, V-7 and the V-8 replacement embodiment 11, all the other operations obtain listed Compound I I-a-2, II-a-3, II-a-4, II-a-7 and II-a-8 in the following table with embodiment 11.
Compound V-2, V-3, V-4, V-7 and V-8 and Compound I I-a-2, II-a-3, II-a-4, II-a-7 and II-a-8 belong to two compounds that have general formula V and have general formula I I-a respectively.
| The embodiment sequence number | Productive rate (%) | V | II-a |
| 12 | 76 | The V-2:(4-phenoxy ethoxy) acethydrazide | The II-a-2:5-[(4-phenoxy ethoxy) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles |
| 13 | 78 | V-3:(4-chloro-2-oil of mirbane oxygen) acethydrazide | II-a-3:5-[(4-chloro-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles |
| 14 | 69 | V-4:(4-amino-3-cyano group-2-oil of mirbane oxygen) acethydrazide | II-a-4:5-[(4-amino-3-cyano group-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles |
| 15 | 78 | V-7: phenyl acethydrazide | II-a-7:5-benzyl-2-sulfydryl-1,3, the 4-thiadiazoles |
| 16 | 82 | The V-8:(2-chloro-phenyl-) acethydrazide | The II-a-8:5-[(2-chloro-phenyl-) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles |
The characterization data of listed compound in the last table.
The II-a-2:5-[(4-phenoxy ethoxy) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles
Clear crystal.IR(KBr)，3031，1499，1591，1204cm
-1。
II-a-3:5-[(4-chloro-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles
Clear crystal.IR(KBr)，3030，1503，1594，1527，1324，1202cm
-1。
II-a-4:5-[(4-amino-3-cyano group-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles
Clear crystal.IR(KBr)，3224，3030，2219，1500，1578，1523，1325，1198cm
-1。
II-a-7:5-benzyl-2-sulfydryl-1,3, the 4-thiadiazoles
Clear crystal.IR(KBr)，3031，1495，1593cm
-1。
The II-a-8:5-[(2-chloro-phenyl-) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles
Clear crystal.IR(KBr)，3032，1498，1594cm
-1。
Embodiment 17
The 5-[(3-ethoxy phenoxy) methyl]-2-sulfydryl-1,3,4-oxadiazole (II-b-5)
Add 2.56g (15.4mmol) compound V-5 and 100mL dehydrated alcohol in the round-bottomed flask of 250mL, add 1.12g (20mmol) solid KOH under the stirring at room, stirred 10 minutes under the room temperature, then drip the exsiccant CS that 1.90g (25mmol) is dissolved in the 10mL dehydrated alcohol
2, stir under the afterreaction system that the finishes room temperature and spend the night.Suction filtration obtains a yellow solid, and drying obtains compound VI-5, yellow solid.Add above-claimed cpd VI-5 and 1.0g (17.9mmol) solid KOH in the 100mL round-bottomed flask, then add pyridine 50mL dissolving.Reaction mixture temperature rising reflux 3 hours.The cooling back is concentrated to about 10mL on Rotary Evaporators, then be poured in the 200mL water, is acidified to pH3-4 with concentrated hydrochloric acid, and ice-water bath stirred 10 minutes down, solid collected by filtration, and filter cake washs with frozen water, obtains Compound I I-b-5 after the drying.3.26g, productive rate 84%.IR(KBr)，3032，1598，1504，1203cm
-1。
Compound VI-5 and Compound I I-b-5 are respectively one that has in the compound of general formula VI and II-b.
Embodiment 18-20
With the operation of embodiment 17, with the compound V-5 among compound V-6, V-9 in the following table and the V-10 replacement embodiment 17, all the other are operated with embodiment 17, obtain listed Compound I I-b-6, II-b-9 and II-b-10 in the following table respectively.
Compound VI-6, VI-9 and VI-10 and Compound I I-b-6, II-b-9 and II-b-10 belong to two compounds that have general formula V and have general formula I I-b respectively.
| The embodiment sequence number | Productive rate (%) | V | II-b |
| 18 | 85 | V-6:(3-ethylbenzene oxygen) acethydrazide | II-b-6:5-[(3-ethyl phenoxy group) methyl]-2-sulfydryl-1,3, the 4-oxadiazole |
| 19 | 80 | The V-9:(3-p-methoxy-phenyl) acethydrazide | The II-b-9:5-[(3-p-methoxy-phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole |
| 20 | 78 | V-10:(4-chloro-2-aminomethyl phenyl) acethydrazide | II-b-10:5-[(4-chloro-2-aminomethyl phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole |
The characterization data of listed compound in the last table.
II-b-6:5-[(3-ethyl phenoxy group) methyl]-2-sulfydryl-1,3, the 4-oxadiazole
Clear crystal.IR(KBr)，3030，1502，1589，1201cm
-1。
The II-b-9:5-[(3-p-methoxy-phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole
Clear crystal.IR(KBr)，3032，1496，1592，1202cm
-1。
II-b-10:5-[(4-chloro-2-aminomethyl phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole
Clear crystal.IR(KBr)，3030，1492，1595，1205cm
-1。
Embodiment 21
5-(Phenoxymethyl)-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside (I-1)
Add 2.24g (10mmol) Compound I I-a-1 in the round-bottomed flask of a 100mL, the 20mL chloroform, 20mL water, 0.50g (12.5mmol) solid NaOH and 8.22g (20mmol) compound III, stir under the mixture room temperature, then add benzyl triethyl ammonium bromide (PTC).Gained reaction mixture at room temperature vigorous stirring spends the night.Reaction mixture with the water washing of 50mL * 3, is used anhydrous Na with the dilution of 200mL chloroform
2SO
4Drying boils off solvent on Rotary Evaporators, the resistates that obtains obtains Compound I '-1 through column chromatography purification.The Compound I that obtains '-1 is dissolved in the 100mL anhydrous methanol that is dissolved with 0.10g (1.85mmol) solid MeONa in advance, stirred 1 hour under the room temperature, then add 5g exsiccant 732 type storng-acid cation exchange resins, stirred 3 hours under the room temperature.Suction filtration is removed resin, and the filtrate evaporate to dryness obtains a white solid, and drying obtains Compound I-1.Clear crystal, 3.47g, productive rate 90%.IR(KBr)，3423，3030，1596，1502，1203cm
-1。
Wherein, Compound I '-1st, have general formula I ' compound in one.
Embodiment 22-30
With the operation of embodiment 21, with the Compound I I-a-1 among the replacement of the Compound I I in the following table embodiment 21, all the other are operated with embodiment 21, obtain listed Compound I in the following table respectively.
Compound I '-2 belong to I '-10 have general formula I ' compound.
| The embodiment sequence number | Productive rate (%) | II | I |
| 22 | 90 | The II-a-2:5-[(4-phenoxy ethoxy) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles | The I-2:5-[(4-ethoxy phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| 23 | 92 | II-a-3:5-[(4-chloro-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles | I-3:5-[(4-chloro-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| 24 | 88 | II-a-4:5-[(4-amino-3-cyano group-2-oil of mirbane oxygen) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles | I-4:5-[(4-amino-3-cyano group-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| 25 | 83 | The II-b-5:5-[(3-ethoxy phenoxy) methyl]-2-sulfydryl-1,3, the 4-oxadiazole | The I-5:5-[(3-ethoxy phenoxy) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| 26 | 86 | II-b-6:5-[(3-ethyl phenoxy group) methyl]-2-sulfydryl-1,3, the 4-oxadiazole | I-6:5-[(3-ethyl phenoxy group) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| 27 | 90 | II-a-7:5-benzyl-2-sulfydryl-1,3, the 4-thiadiazoles | I-7:5-benzyl-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| 28 | 91 | The II-a-8:5-[(2-chloro-phenyl-) methyl]-2-sulfydryl-1,3, the 4-thiadiazoles | The I-8:5-[(2-chloro-phenyl-) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside |
| 29 | 90 | The II-b-9:5-[(3-p-methoxy-phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole | The I-9:5-[(3-p-methoxy-phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
| 30 | 85 | II-b-10:5-[(4-chloro-2-aminomethyl phenyl) methyl]-2-sulfydryl-1,3, the 4-oxadiazole | I-10:5-[(4-chloro-2-aminomethyl phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside |
The characterization data of listed compound in the last table.
The I-2:5-[(4-ethoxy phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3434，3031，1591，1500，1204cm
-1。
I-3:5-[(4-chloro-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3432，3030，1589，1532，1498，1324，1200cm
-1。
I-4:5-[(4-amino-3-cyano group-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3445，3225，3030，2223，1593，1512，1212cm
-1。
The I-5:5-[(3-ethoxy phenoxy) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3439，3031，1593，1495，1202cm
-1。
I-6:5-[(3-ethyl phenoxy group) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3431，3031，1594，1512，1201cm
-1。
I-7:5-benzyl-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3441，3030，1595，1500，1207cm
-1。
The I-8:5-[(2-chloro-phenyl-) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3438，3032，1593，1503，1200cm
-1。
The I-9:5-[(3-p-methoxy-phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3445，3030，1591，1510，1200cm
-1。
I-10:5-[(4-chloro-2-aminomethyl phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
Clear crystal.IR(KBr)，3442，3029，1592，1501，1200cm
-1。
Embodiment 31
Consumption/sheet
Embodiment 21 samples (I-1) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 32
Consumption/sheet
Embodiment 22 samples (I-2) 100mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 33
Consumption/grain
Embodiment 25 samples (I-5) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 34
Consumption/grain
Embodiment 26 samples (I-6) 50mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 35
Consumption/50mL
Embodiment 27 samples (I-7) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 36
Consumption/50mL
Embodiment 28 samples (I-8) 50mg
Citric acid 100mg
NaOH an amount of (transferring pH4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 37
Embodiment 29 samples (I-9) 3.0g
Poloxamer 1.0g
Sodium hydroxide 0.2g
Citric Acid QS
N.F,USP MANNITOL 26.0g
Lactose 23.0g
Water for injection 100ml
Preparation technology: get water for injection 80ml, add main ingredient, N.F,USP MANNITOL, lactose, poloxamer stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100ml.Add the 0.5g gac, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal promptly.
Embodiment 38
100 bags of granules
Embodiment 30 samples (I-10) 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
The sweet 0.05g of A Siba
Essence 0.05g
2% hypromellose (pure water preparation) QS
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 39
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g meets primary standard.Animal fasting 16 hours, the dextrose in saline solution of 2h abdominal injection 2g/kg behind the medicine (1.5h injectable dextrose monohydrate behind the diamicron medicine), 0.5h, 1h, 2h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling, centrifugation serum is with each time point serum glucose level of determination of glucose oxidase.The results are shown in following table:
Above result shows that each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.
Claims (10)
1. has pharmaceutically acceptable salt of the compound of general formula I structure or its
Wherein,
R=H, F, Cl, Br, I, C
1-C
5Alkyl, OH, OR
1, NO
2, NH
2, CN or NR
2R
3, and they two replace or trisubstituted combination, wherein R
1Be selected from C
1-C
5Alkyl, R
2And R
3Be selected from H and C
1-C
5Alkyl
N=0 or 1
X=O or S.
2. the defined compound with general formula I of claim 1 or its acceptable salt pharmaceutically,
Wherein,
R=H, F, Cl, C
1-C
3Alkyl, OR
1, NO
2, CN or NR
2R
3, or their dibasic combination, wherein R
1Be selected from C
1-C
3Alkyl, R
2And R
3Be selected from H and C
1-C
3Alkyl.
N=0 or 1
X=O or S.
3. the defined compound of Formula I of claim 2 or its pharmacy acceptable salt are selected from:
5-(Phenoxymethyl)-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
The 5-[(4-ethoxy phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
5-[(4-chloro-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
5-[(4-amino-3-cyano group-2-nitro-phenoxy) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
The 5-[(3-ethoxy phenoxy) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
5-[(3-ethyl phenoxy group) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
5-benzyl-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
The 5-[(2-chloro-phenyl-) methyl]-1,3,4-thiadiazoles-2-base 1-sulfo--β-D-glucopyranoside
The 5-[(3-p-methoxy-phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside
5-[(4-chloro-2-aminomethyl phenyl) methyl]-1,3,4-oxadiazole-2-base 1-sulfo--β-D-glucopyranoside.
4. synthesize the method for the defined compound of Formula I of claim 1-3, may further comprise the steps:
(1) Compound I I and compound III the reaction, obtain Compound I '.
(2) Compound I ' under the sodium methylate effect, obtain I.
5. general formula I I as claimed in claim 4, can be synthetic by following route:
(1) compound IV and hydrazine hydrate reaction through the hydrazinolysis reaction, obtains compound V.
(2) compound V in the presence of KOH with CS
2Effect obtains compound VI.
(3) compound VI is handled through the vitriol oil, obtains Compound I I-a.Wherein, Compound I I-a is that general formula is a series in the compound of II, this moment X=S, R's is described as defined above.
(4) compound VI is handled through KOH, obtains Compound I I-b.Wherein, Compound I I-b is that general formula is a series in the compound of II, this moment X=O, R's is described as defined above.
6. the defined compound of Formula I of claim 1-3 or its pharmacy acceptable salt are as the application of 2 type sodium glucose transporter inhibitor.
7. the defined compound of Formula I of claim 6 or its pharmacy acceptable salt application aspect preparation treatment diabetes medicament.
8. pharmaceutical composition contains compound of Formula I or its pharmacy acceptable salt of one of claim 1-3 and appropriate carriers or vehicle.
9. the described pharmaceutical composition of claim 8, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
10. comprise according to described solid of claim 9 and liquid oral medicine: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2733146A1 (en) | 2012-11-20 | 2014-05-21 | KTB Tumorforschungsgesellschaft mbH | Thioether derivatives as protein kinase inhibitors |
| WO2014079545A1 (en) | 2012-11-20 | 2014-05-30 | Ktb Tumorforschungsgesellschaft Mbh | Thioether derivatives as protein kinase inhibitors |
| CN113563281A (en) * | 2021-07-06 | 2021-10-29 | 贵州大学 | Benzophenone compound containing 1,3, 4-thiadiazole thioether structure and application thereof |
| CN114933619A (en) * | 2022-05-18 | 2022-08-23 | 上海科利生物医药有限公司 | Thioglycoside analogs, and preparation method and application thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2382480C (en) * | 1999-08-31 | 2008-09-30 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| DE60115623T2 (en) * | 2000-03-17 | 2006-07-06 | Kissei Pharmaceutical Co., Ltd., Matsumoto | GLUCOPYRANOSYLOXY-BENZYL BENZEN DERIVATIVES, MEDICAL COMPOSITION AND INTERMEDIATE PRODUCTS FOR THE PREPARATION OF THE DERIVATIVES |
| EP1432720A1 (en) * | 2001-09-05 | 2004-06-30 | Bristol-Myers Squibb Company | O-pyrazole glucoside sglt2 inhibitors and method of use |
| JPWO2004089966A1 (en) * | 2003-04-01 | 2006-07-06 | 大正製薬株式会社 | Process for selective production of heteroaryl 5-thio-β-D-aldohexopyranoside |
| ES2377741T3 (en) * | 2003-06-20 | 2012-03-30 | Kissei Pharmaceutical Co., Ltd. | Pyrazole derivatives, pharmacological composition that contains them and production intermediates thereof |
| US7371732B2 (en) * | 2003-12-22 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture |
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2008
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2733146A1 (en) | 2012-11-20 | 2014-05-21 | KTB Tumorforschungsgesellschaft mbH | Thioether derivatives as protein kinase inhibitors |
| WO2014079545A1 (en) | 2012-11-20 | 2014-05-30 | Ktb Tumorforschungsgesellschaft Mbh | Thioether derivatives as protein kinase inhibitors |
| CN113563281A (en) * | 2021-07-06 | 2021-10-29 | 贵州大学 | Benzophenone compound containing 1,3, 4-thiadiazole thioether structure and application thereof |
| CN113563281B (en) * | 2021-07-06 | 2023-11-24 | 贵州大学 | Benzophenone compound containing 1,3, 4-thiadiazole thioether structure and application thereof |
| CN114933619A (en) * | 2022-05-18 | 2022-08-23 | 上海科利生物医药有限公司 | Thioglycoside analogs, and preparation method and application thereof |
| CN114933619B (en) * | 2022-05-18 | 2024-03-01 | 上海科利生物医药有限公司 | Thioglycoside column-like analogues and preparation method and application thereof |
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| CN101445528B (en) | 2011-06-15 |
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