CN103304504A - Anti-diabetic compound, as well as preparation method and application thereof - Google Patents
Anti-diabetic compound, as well as preparation method and application thereof Download PDFInfo
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- CN103304504A CN103304504A CN2013102214405A CN201310221440A CN103304504A CN 103304504 A CN103304504 A CN 103304504A CN 2013102214405 A CN2013102214405 A CN 2013102214405A CN 201310221440 A CN201310221440 A CN 201310221440A CN 103304504 A CN103304504 A CN 103304504A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000003178 anti-diabetic effect Effects 0.000 title description 3
- 239000003472 antidiabetic agent Substances 0.000 title description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 229940126033 PPAR agonist Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 15
- 238000000605 extraction Methods 0.000 description 12
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- 238000001035 drying Methods 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 108010016731 PPAR gamma Proteins 0.000 description 8
- 102000000536 PPAR gamma Human genes 0.000 description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- 108010028924 PPAR alpha Proteins 0.000 description 6
- 102000023984 PPAR alpha Human genes 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 229940122355 Insulin sensitizer Drugs 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000037356 lipid metabolism Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000003614 peroxisome proliferator Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- JUNAPQMUUHSYOV-UHFFFAOYSA-N 2-(2h-tetrazol-5-yl)acetic acid Chemical class OC(=O)CC=1N=NNN=1 JUNAPQMUUHSYOV-UHFFFAOYSA-N 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 108010015181 PPAR delta Proteins 0.000 description 1
- 108010044210 PPAR-beta Proteins 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- 229940080774 Peroxisome proliferator-activated receptor gamma agonist Drugs 0.000 description 1
- 206010068676 Pneumoretroperitoneum Diseases 0.000 description 1
- 208000005727 Retropneumoperitoneum Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010612 desalination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- -1 glitazone compound Chemical class 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
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- 102000006255 nuclear receptors Human genes 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
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- 238000012549 training Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of medicines which are related to diabetes. Specifically, the invention relates to a compound which has the structure as shown in a formula I and can be used as a peroxisome proliferator-activated receptor (PPAR) agonist, as well as a preparation method and an application in the aspect of treating the diabetes.
Description
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to the medicative a kind of peroxisome proliferator-activated property acceptors of diabetes (PPAR) agonist, Its Preparation Method And Use.
Background technology
Diabetes are that the patient controls the impaired disease of blood sugar ability, and the patient has lost the ability of insulin action being made appropriate reaction to some extent.Major part is type ii diabetes (being non insulin dependent diabetes) in the diabetes, account for 80%-90%, research finds, the insulin resistant of peripheral tissues's (comprising skeletal muscle, liver and fatty tissue etc.) plays a part very important in the generation of type ii diabetes, development.Introduced at present a class and made the patient recover a responsive class medicine to self Regular Insulin, i.e. insulin sensitizers is so that Regular Insulin and triglyceride level return to normally.Peroxisome proliferator-activated property acceptor (PPARs) becomes desirable target in the treatment of research diabetes, it is one of nuclear receptor superfamily member, can regulate and control simultaneously several genes and express, participate in the physiological processs such as Adipocyte Differentiation, lipid metabolism adjusting and increase insulin sensitivity.There is three types in PPAR family: PPAR α, PPAR β (also being PPAR δ) and PPAR γ.PPAR α relates to the β-oxidation that stimulates lipid acid, also relate to control HDL cholesterol levels, in the liver lipid metabolism, play an important role, and PPAR γ acceptor relates to the Adipocyte Differentiation program and must activate, and can improve insulin resistant and improve insulin sensitivity (Yang Jun, Zou Xiulan, PPAR α/γ double excitations machine and diabetes B, Medical review, 2008,14 (16): 2492-2496).PPAR γ is considered to the main molecules target of glitazone insulin sensitizers, although the glitazone compound is the active drug for the treatment of type ii diabetes, but the side effect of this compounds is very obvious, for example serious toxin for liver type, body weight increase and anaemia, this mainly is that glitazone is main or full agonist (the N A Jie of PPAR γ, sieve D is thorough, her Feng of S, CN101098865A).Therefore, the dual agonists of PPAR α and PPAR γ just can alleviate even eliminate the side effect of glitazone PPAR gamma agonist, except making blood sugar and Regular Insulin normalizing, also has the effect of blood fat reducing and inhibition cardiovascular complication.
The invention discloses an adamantane-like tetrazoleacetic acid compounds as the dual agonists of PPAR α and PPAR γ, these inhibitor can be for the preparation of the medicine of the medicine, particularly non insulin dependent diabetes for the treatment of 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 compound and the pharmacy acceptable salt thereof of formula I.
Another object of the present invention provides the method that preparation has compound and the pharmacy acceptable salt thereof of formula I.
A further object of the present invention provide the compound that contains formula I and pharmaceutically acceptable salt 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 in conjunction with purpose of the present invention content of the present invention is specifically described.
The present invention has the compound of formula I structure:
The method of synthetic compound of formula i may further comprise the steps:
Compd A and B are at NaBH
3There is lower reaction in CN, obtains Compound C; Compound C is processed with bromide reagent and is obtained Compound D, and D and E react in the presence of alkali and obtain compound I.
Formula I compound of the present invention has the double excitations effect of PPAR α and PPAR γ, and can be used as effective constituent for the preparation of the medicine of diabetes aspect and losing weight increases and inhibition cardiovascular complication disease.The activity of formula I compound of the present invention is by hypoglycemic in the body and fall blood cholesterol levels and the triglyceride level model is verified.
Formula I compound of the present invention is effective in quite wide dosage range.The dosage of for example taking every day is divided into once or for several times administration in 20mg-400mg/ people's scope.The actual dosage of taking formula I compound of the present invention can be decided according to relevant situation by the doctor.These situations comprise: the person's of being treated 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, following embodiment only is for explanation, and is not for restriction 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.
Comparative Examples 1
In order to further specify the pharmacological characteristic of the compounds of this invention I, the present invention has introduced not yet disclosed, has equally the following formula: compound I-0 of anti-diabetic activity, as a comparison case:
Compound I-0 is got by the present patent application people research, and is a few days ago not yet open in the present patent application.
Comparative Examples 2
The preparation method of compound I-0
Reaction initial feed: commercially available.
1.81g (10mmol) compd A and 1.36g (10mmol) compd B is dissolved among the 20mLEtOH, reaction adds 1.89g (30mmol) NaBH after 3 hours again under the room temperature
3CN then continues to stir to spend the night.In the reaction mixture impouring 100mL frozen water, stir, regulate pH=6 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing once, anhydrous sodium sulfate drying boils off solvent at Rotary Evaporators and obtains a resistates, column chromatography purification then, obtain the sterling of C, ESI-MS, m/z=320 ([M+NH
4]
+).
2.11g (7mmol) Compound C is dissolved in the toluene of 10mL drying, the ice-water bath cooling is lower slowly stirs, and slowly drips 2.71g (10mmol) PBr
3Be dissolved in the solution that the methylene dichloride of 2mL drying is made, dropwise the afterreaction mixture and at room temperature stir after half an hour in the impouring 100mL frozen water, stir, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing once, anhydrous sodium sulfate drying boils off solvent at Rotary Evaporators and obtains a resistates, column chromatography purification then, obtain the sterling of D, ESI-MS, m/z=364 and 366 ([M+H]
+).
1.82g (5mmol) Compound D and 0.64g (5mmol) E is dissolved among the 10mL DMF, stirs, and adds 2.07g (15mmol) K
2CO
3, 100 ℃ of lower continuation stir until raw material consumption complete (12 hours).In the reaction mixture impouring 100mL frozen water, stir, regulate pH=2 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing is once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates, column chromatography purification then obtains the sterling of I, white solid, 207 ℃ of fusing points, ESI-MS, m/z=410 ([M-H]
-).
Embodiment 1
Reaction initial feed: commercially available.
1.81g (10mmol) compd A and 1.81g (10mmol) compd B is dissolved among the 20mL EtOH, reaction adds 1.89g (30mmol) NaBH after 3 hours again under the room temperature
3CN then continues to stir to spend the night.In the reaction mixture impouring 100mL frozen water, stir, regulate pH=6 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing is once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates, column chromatography purification then obtains the sterling of C, desalination look solid, 189 ℃ of fusing points, ESI-MS, m/z=364 ([M+NH
4]
+).
2.42g (7mmol) Compound C is dissolved in the toluene of 10mL drying, the ice-water bath cooling is lower slowly stirs, and slowly drips 2.71g (10mmol) PBr
3Be dissolved in the solution that the methylene dichloride of 2mL drying is made, dropwise the afterreaction mixture and at room temperature stir after half an hour in the impouring 100mL frozen water, stir, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing once, anhydrous sodium sulfate drying boils off solvent at Rotary Evaporators and obtains a resistates, column chromatography purification then, obtain the sterling of D, ESI-MS, m/z=410 ([M+H]
+).
2.05g (5mmol) Compound D and 0.64g (5mmol) E is dissolved among the 10mL DMF, stirs, and adds 2.07g (15mmol) K
2CO
3, 100 ℃ of lower continuation stir until raw material consumption complete (12 hours).In the reaction mixture impouring 100mL frozen water, stir, regulate pH=2 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL * 3, merge extraction phase, the salt water washing is once, anhydrous sodium sulfate drying, boil off solvent at Rotary Evaporators and obtain a resistates, column chromatography purification then obtains the sterling of I, white solid, 164 ℃ of fusing points, ESI-MS, m/z=455 ([M-H]
-).
Embodiment 2
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, the administration volume 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, gavage gives the dextrose in saline solution of testing compound pneumoretroperitoneum injection in 15 minutes 2g/kg, 0.5h, 1h, 1.5h and 2h 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.Blank mouse neither gives glucose and does not also give testing compound, and model mice only gives glucose and do not give testing compound.
Data can be found out from upper form, and compound I can significantly strengthen the mouse blood sugar dosis tolerata that glucose causes.
Embodiment 3
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, the administration capacity is the 0.4mL/20g body weight, is equivalent to 100mg/kg dosage.
Healthy Wister rat, male and female half and half about body weight 300g, meet primary standard.Animal was fed 30 days with high lipid food, measure cholesterol in serum and content of triglyceride, take cholesterol and content of triglyceride as the standard random packet, continuous gavage gave testing compound 7 days after the animal grouping, fasting is 12 hours before the last administration, 1h gets blood with kapillary from rat ball rear vein beard behind the medicine, and centrifugation serum is measured serum cholesterol and content of triglyceride with cholesterol and Triglyceride Reagent box.Shown in below test result is seen.
Cholesterol level (g/dl)
Content of triglyceride (g/dl)
The data declaration of above-mentioned two tables, compound of the present invention is reducing cholesterol and triglyceride level effectively.
Claims (3)
1. the compound of formula I structure:
2. synthesize the method for claim 1 formula I compound, may further comprise the steps:
Compd A and B are at NaBH
3There is lower reaction in CN, obtains Compound C; Compound C is processed with bromide reagent and is obtained Compound D, and D and E react in the presence of alkali and obtain compound I.
3. the purposes of the described compound of claim 1 aspect preparation treatment diabetes medicament.
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| CN201310221440.5A CN103304504B (en) | 2013-06-02 | 2013-06-02 | Anti-diabetic compound, as well as preparation method and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478860A (en) * | 2015-01-13 | 2015-04-01 | 佛山市赛维斯医药科技有限公司 | Adamantane tetrazole derivative and preparation method and application thereof |
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2013
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|---|---|---|---|---|
| CN1379766A (en) * | 1999-08-18 | 2002-11-13 | 阿斯特拉曾尼卡有限公司 | Benzoic acid derivatives for treatment of diabetes mellitus |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104478860A (en) * | 2015-01-13 | 2015-04-01 | 佛山市赛维斯医药科技有限公司 | Adamantane tetrazole derivative and preparation method and application thereof |
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| CN103304504B (en) | 2015-03-04 |
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