WO2012146075A1 - 一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途 - Google Patents
一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途 Download PDFInfo
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- WO2012146075A1 WO2012146075A1 PCT/CN2012/071375 CN2012071375W WO2012146075A1 WO 2012146075 A1 WO2012146075 A1 WO 2012146075A1 CN 2012071375 W CN2012071375 W CN 2012071375W WO 2012146075 A1 WO2012146075 A1 WO 2012146075A1
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- 0 CCC(*)=CC=C(CC*c1ccc(*)cc1)[C@@]1O[C@](C*)C[C@](C)C1=C Chemical compound CCC(*)=CC=C(CC*c1ccc(*)cc1)[C@@]1O[C@](C*)C[C@](C)C1=C 0.000 description 2
- AMGPJZLHBPXKLJ-OBKDMQGPSA-N OC[C@H]([C@H]([C@@H]([C@H]1O)O)O)O[C@H]1c(cc1Cc(cc2)ccc2OCC(F)(F)F)ccc1Cl Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O)O[C@H]1c(cc1Cc(cc2)ccc2OCC(F)(F)F)ccc1Cl AMGPJZLHBPXKLJ-OBKDMQGPSA-N 0.000 description 1
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions
- the present invention relates to the field of medicine, and in particular to a novel compound having a sodium-dependent glucose transporter (SGLT2) inhibitor activity, a process for preparing the compound, a pharmaceutical composition comprising the compound, and the compound And use of the pharmaceutical composition in the preparation of a SGLT2 inhibitor drug and a treatment-related disease.
- SGLT2 sodium-dependent glucose transporter
- diabetes is a series of clinical syndromes caused by absolute or relative deficiency of insulin in the body.
- the World Health Organization divides diabetes into four types: type 1 diabetes, type 2 diabetes, continued diabetes, and gestational diabetes. Different types of diabetes can cause beta cells in the pancreas to not produce enough insulin to lower blood sugar levels, leading to hyperglycemia.
- Type 2 diabetes mellitus also known as non-insulin-dependent diabetes mellitus, is often found in adults, especially obese patients, accounting for more than 90% of diabetic patients.
- Early type 2 diabetes patients can be controlled by improving lifestyle (such as healthy diet, moderate exercise, etc.). Most patients need oral hypoglycemic drugs or insulin injections to help control blood sugar in the body, but the treatment and its therapeutic effects are limited.
- Type 2 diabetes is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance. Hyperglycemia is considered to be a major risk factor for the development of diabetic complications and may be directly associated with impaired insulin secretion seen in advanced NIDDM. Therefore, it is generally believed that normalization of blood glucose in patients with NIDDM will improve the effects of insulin and counteract the development of diabetic complications.
- SGLT sodium-glucose cotransporter
- inhibition of SGLT can further inhibit the reabsorption of sugar, thereby allowing the sugar to be excreted in the urine.
- SGLT2 inhibitors to diabetic model animals can improve insulin response to glycemia, increase insulin sensitivity, and delay the onset of kidney disease and neuropathy. Therefore, in patients with type 2 diabetes, selective inhibition of SGLT2 may increase glucose excretion in the urine, thereby normalizing plasma glucose, thereby increasing insulin sensitivity and delaying the development of diabetic complications.
- SGLT2 selective inhibitors of SGLT2 as a drug will help treat, ameliorate or prevent the onset and progression of diabetes and related diseases.
- Compounds that inhibit SGLT2 have been proposed as candidates for anti-diabetic drugs, and some C-aryl glucoside SGLT2 inhibitors have been developed, for example, with the following structure Dapagliflozin):
- Daglitazone (other part of the invention is referred to as "Compound 1") was jointly developed by Bristol-Myers Squibb and AstraZeneca and has been licensed and marketed by AstraZeneca. It is reported that dapagliflozin is more successful in maintaining lower blood glucose levels than the existing treatment drug glipizide. However, the current test results show that dapagliflozin still has certain defects in the half-life and absorption in vivo.
- the present invention structurally reforms existing C-aryl glucoside SGLT2 inhibitors to improve the half-life, absorption properties and pharmacological activities of such drugs, thereby obtaining useful compounds of useful value.
- the pharmacological research test of the present invention shows that the obtained novel compound can be used as a more efficient SGLT2 inhibitor, and has the advantages of longer half life, more absorption, and the like, and thus has broad application prospects.
- the method for synthesizing the compound of the present invention has the advantages of operating the cartridge, mild conditions, high yield, and the like, and is easier to industrially produce.
- an object of the present invention is to provide a sodium-dependent glucose transporter
- SGLT2 a novel compound of inhibitor activity, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, to address the deficiencies of current antidiabetic and related disease treatments.
- Another object of the present invention is to provide a process for the preparation of the compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof.
- a further object of the present invention is to provide pharmaceutical use of the compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof.
- Still another object of the present invention is to provide a pharmaceutical composition
- a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof as a main active ingredient.
- the invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph or enantiomer thereof,
- R1, and R2 are independently hydrogen, -OH, alkyl, -CF3, -OCHF 2, -OCF 3 , or halogen;
- R3 is cycloalkyl, -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH 2 CH 2 F, or -OCH 2 CH 3 ;
- R4 is hydrogen, -OH, -Oaryl, -OCH 2 aryl, alkyl, cycloalkyl, -CF3, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , OCH 2 CH 2 F, or halogen;
- R1 to R4 and A are as defined in claim 1; more preferably,
- R1, R3 and A are as defined in claim 1; most preferably, the compound of formula I is as shown in formula Id:
- Rl, R3 and A are as defined in claim 1.
- the group R3 in the compound of the formula I is -OCH 2 CF 3 , -OCH 2 CHF 2 , or -OCH 2 CH 2 F; further preferably, the R 3 is -OCH 2 CF 3 .
- a group in the compound of formula I ⁇ 2 can be hydrogen or F at the same time.
- the group R1 in the compound of the formula I is preferably a protein, further preferably C1; the group R2 is preferably hydrogen; and the group R4 is preferably hydrogen.
- the invention provides a process for the preparation of a compound of the above formula, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, which process comprises reacting a compound of formula IX with a step of reacting a compound of formula X,
- R1 to R4 and A are as defined above.
- the preparation method may include the following steps:
- R1 to R4 and A are as defined above.
- the compound of the formula III is reacted with trimethylphenyl phthalocyanine chloride in the presence of N-mercaptomorpholine.
- the carbonyl group of the compound of the formula VII can be sufficiently reduced in the step (4), for example, the carbonyl group can be sufficiently reduced by triethylsilylhydrogen, boron trifluoride-diethyl ether.
- the carbonyl group may be reacted to form a haloalkyl group, for example, the carbonyl group may be formed into a dithiolane group by the action of 1,2-ethanedithiol and boron trifluoride-2acetic acid. And then forming a haloalkyl group via a selective halogen reagent.
- the preparation method comprises the following steps:
- Step (6) -2
- the preparation method comprises the following steps:
- step 1 :
- the present invention provides the use of the above compound or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof for the preparation of a C-aryl glucoside SGLT2 inhibitor.
- the compounds provided by the present invention have the action of SGLT2 inhibitors, and thus can be prepared into corresponding SGLT2 inhibitor drugs for clinical treatment or research.
- the present invention provides the use of a compound of the above, or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, for the manufacture of a medicament for the treatment, prevention or delay of: diabetes , hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X, hypertriglyceridemia, atherosclerosis, hypertension, or diabetic complications;
- the diabetic complication is diabetic retinopathy, diabetic neuropathy, and/or diabetic nephropathy;
- the disease is diabetes, and type II diabetes is further preferred.
- the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer or racemic mixture thereof, and A pharmaceutically acceptable excipient.
- the pharmaceutical composition may be in any dosage form for clinical administration, such as tablets, suppositories, dispersible tablets, enteric coated tablets, chewable tablets, orally disintegrating tablets, capsules, dragees, granules, dry powders, oral solutions, injections. Use a small needle, a lyophilized powder for injection or a large infusion.
- the pharmaceutically acceptable excipients in the pharmaceutical composition may include one or more of the following depending on the particular dosage form and mode of administration: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders , fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, encapsulants, and pigments.
- the pharmaceutical composition may further comprise other therapeutic agents, such as one or more agents selected from the group consisting of antidiabetic agents, anti-obesity agents, antihypertensive agents, antiatherogenic agents, and lipid lowering agents.
- agents selected from the group consisting of antidiabetic agents, anti-obesity agents, antihypertensive agents, antiatherogenic agents, and lipid lowering agents.
- the pharmaceutical composition further comprises an anti-diabetic agent.
- the present invention provides a method for treating, preventing or delaying the following diseases: diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X, hypertriglyceridemia A atherosclerosis, hypertension, or diabetic complication, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt, solvate, polymorph, or pair thereof A mixture or racemic mixture or a pharmaceutical composition provided by the present invention.
- the compounds provided herein, or pharmaceutically acceptable salts, solvates, polymorphs, enantiomers or racemic mixtures thereof, or pharmaceutical compositions provided herein can be co-administered with other therapeutic or therapeutic agents.
- the dose of the compound or pharmaceutical composition required to effect a therapeutic, prophylactic or prolonged action will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, the route of administration and frequency, and the like, and The specific situation is judged.
- the dose may be from 1 to 100 mg/day, preferably from 2 to 50 mg/day, further preferably 10 mg/day; the dose may be divided into 1 to 1 per day. 3 administrations, preferably 1 time.
- the present invention provides a novel compound having the activity of a sodium-dependent glucose transporter (SGLT2) inhibitor.
- SGLT2 sodium-dependent glucose transporter
- Figure 1 is a pharmacokinetic curve of the compound of Example 3, wherein 1A is compound 1, 1B is compound 2, and 1C is compound 3;
- Figure 2 is the results of glucose tolerance test in Example 5, wherein 2A is the blood glucose level (mg/mL); 2B is the AAUC value (mg/dL* hr) of each group, wherein group 1 is a blank solution, group 2 is Compound 1, Group 3 is Compound 2, Group 4 is Compound 3;
- Figure 3 is the blood glucose test result in the glucose tolerance test in Example 6, which is the blood glucose level.
- Figure 4 is a blood glucose test result in the glucose tolerance test in Example 6, wherein 4A is ⁇ blood glucose level (mg/mL); 4B is AACC value (mg/dL* hr) of each group, wherein group 1 is a blank solution , Group 2 is Compound 1, Group 3 is Compound 2, Group 4 is Compound 3;
- Figure 5 is a graph showing the results of the urine glucose test in the glucose tolerance test in Example 6. The best way to implement the invention
- step 1 To (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxyindenyl)tetrahydro-2H-pyran-2-one (14.2 g) and at -7 °C To a solution of N-mercaptomorpholine (80 mL) in dry THF (EtOAc) (EtOAc)EtOAc. Phenylbenzene (160 mL) and 3 ⁇ 40 (300 mL) were poured into the mixture at 10 ° C, then the organic phase was washed with 3 ⁇ 40 (120 mL), 1M HCl (150 mL x 4) and brine (120 mL). .
- Step (4) -1
- Step (4) -2
- Step (6) -1
- Step (6) -2
- Step (2) Same as step (1) of the first embodiment. Step (2):
- Step (4) -1
- Step (4) -2
- Test compound Compound 1, Compound 2 and Compound 3;
- Control compound verapamil.
- Microsomes human liver microsomes (HMMC; PL050B) and male rat liver microsomes (RTMC;
- RT046 purchased from CellzDirect (Invitrogen); stored at - 80 °C before use.
- a mother liquid was prepared according to Table 1, and then a test compound or a control compound was added so that the final concentration of these compounds in the reaction system was 2 ⁇ M.
- the mixed solution was then preheated at 37 ° C for 2 minutes.
- NADPH was added to the mixed solution to a final concentration of 1 mM, and then the reaction system was placed at 37 °C. The same volume of ultrapure water was added to the blank control instead of NADPH.
- Mobile phase 0.1% aqueous solution of citric acid (B) and 0.1% citric acid-acetonitrile (A); elution procedure is 0 ⁇ 2min, mobile phase A is 5 ⁇ 100%, mobile phase B is 95% ⁇ 0%; 2 ⁇ 2.2min, mobile phase A is 100%, mobile phase B is 0%; 2.2 ⁇ 2.4min, mobile phase A is 100% ⁇ 5%, mobile phase B is 0% ⁇ 95%; 2.4 ⁇ 3min, mobile phase A At 5%, mobile phase B is 95%.
- Collision gas 6 L/min; Curtain gas: 30 L/min; Atomizing gas: 50 L/min; Auxiliary gas: 50 L/min; Temperature: 500 °C; Spray voltage: 4500 v
- Compound 1 Compound 2 and Compound 3 were each dissolved in a blank solution (5% 1-mercapto-2-pyrrolidone, 20% PEG-400 and 20 mM sodium diphosphate) at a concentration of 10 g/L.
- a blank solution 5% 1-mercapto-2-pyrrolidone, 20% PEG-400 and 20 mM sodium diphosphate
- the experimental animals were male SD rats, 6 to 8 weeks old, weighing 190-215 g, purchased from Beijing Weili Tonghua Experimental Animal Technology Co., Ltd.
- the SD rats were randomly divided into 7 groups of 3 animals each.
- Group 1 was a blank control group, and the above blank solution was intravenously administered.
- the doses and routes of administration of each group of rats are shown in Table 4.
- Group 7 Compound 3 10 SD rats were fasted for 16 hours prior to the pharmacokinetic test.
- a single dose of the compound or blank solution was then administered intravenously (1 mL/kg; 10 mg/kg) or orally (1 mL/kg; 10 mg/kg) as shown in Table 4.
- the jugular vein puncture method was used to collect 200 uL of blood at the time of administration, wherein for the intravenously administered animal group, 0, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 after administration. Blood was collected at an hour; for the group of animals orally administered, blood was collected at 0, 15 minutes, 30 minutes, 45 minutes, 75 minutes, 135 minutes, 4 hours, 8 hours, and 24 hours after administration.
- the blood sample was collected in a sample tube with EDTA, and the blood sample was immediately centrifuged at 4000 rpm for 5 minutes at 4 ° C, and then the plasma was transferred to another sample tube and stored at -20 ° C.
- Quantitative method internal standard method
- Compound 1, Compound 2 and Compound 3 were each dissolved in a blank solution (5% 1-mercapto-2-pyrrolidone, 20% PEG-400 and 20 mM sodium diphosphate) at a concentration of 1 Og/L.
- the experimental animals were male SD rats, 6 to 8 weeks old, weighing 190-215 g, purchased from Beijing Weili Tonghua Experimental Animal Technology Co., Ltd.
- the SD rats were randomly divided into 4 groups, 3 animals in each group.
- Group 1 was a blank control group, and the above blank solution was applied.
- the dosages and routes of administration of each group of rats are shown in Table 6.
- the rats Prior to the test, the rats were fasted for 16 hours and then orally administered a blank solution or compound. After 15 minutes of administration, blood glucose baseline levels were measured, and then rats of each group were orally administered with 50% aqueous glucose solution in an amount of 2 g/kg. The tails of each group were taken at 15 minutes, 60 minutes, 1 hour and 2 hours after oral glucose administration. Blood samples of the veins (1 drop) were measured for blood glucose levels by using the Accu-Chek Aviva system.
- This example examined the blood glucose and urine sugar levels of Oral Compound 2 and Compound 3 of the present invention and known Compound 1, thereby further verifying the in vivo efficacy of the compound.
- the rats Prior to the test, the rats were fasted for 16 hours and then orally administered a blank solution or compound. Blood glucose baseline levels were measured 8 hours after dosing. Subsequently, each group of rats was orally administered with a 50% aqueous solution of glucose in an amount of 2 g/kg. Blood samples (1 drop) from the tail vein of each group were taken at 15 minutes, 60 minutes, 1 hour, and 2 hours after oral glucose, and blood glucose levels were measured by using the Accu-Chek Aviva system.
- the urine of each group of rats was collected, and then the urine glucose level was analyzed by a TOSHIBA TBA-40FR automatic biochemical analyzer.
- the significance level was set to P ⁇ 0.05.
- the mean and standard deviation were calculated for all measurement parameters of the study design.
- One-way analysis of variance (ANOVA) after multiple comparisons between groups was performed using software GraphPad Prism 5.0.
- the experiment proves that the compound 2 of the present invention can inhibit the reabsorption of urine glucose and lower blood sugar, and its efficacy is equivalent to or superior to the existing drug of the type II diabetes, dapagliflozin (Compound 1). Meanwhile, the compound 2 of the present invention has a longer half-life in vivo and a higher oral absorption rate than the compound 1, and thus can be more advantageously prepared into various dosage forms for drug administration. Therefore, the compound 2 of the present invention is a potential drug having a superior effect and can be used for the treatment of diseases associated with SGLT2, particularly diabetes and related diseases.
- composition of the present invention wherein the "active ingredient" in each embodiment refers to a compound provided by the present invention or a pharmaceutically acceptable salt, solvate, polymorph, enantiomer thereof Or a racemic mixture.
- a single capsule contains: Active substance 10mg
- the active substance was dissolved in an appropriate amount of 0.01 N hydrochloric acid, added with NaCl to make isotonic, water was added to 2 ml, sterilized, and transferred to an ampoule to prepare an injection.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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JP2014506728A JP2014512399A (ja) | 2011-04-25 | 2012-02-20 | ナトリウム依存性グルコース輸送タンパク質阻害剤並びにその調製方法及び使用 |
KR1020137031105A KR101609859B1 (ko) | 2011-04-25 | 2012-02-20 | 소듐-의존적 포도당 운반 단백질의 억제제 및 이의 제조방법 및 용도 |
AU2012248061A AU2012248061C1 (en) | 2011-04-25 | 2012-02-20 | Inhibitor of sodium-dependent glucose transport protein and preparation method therefor and use thereof |
US14/114,197 US8957033B2 (en) | 2011-04-25 | 2012-02-20 | Inhibitor of sodium-dependent glucose transport protein and preparation method therefor and use thereof |
EP12775960.3A EP2703396B1 (en) | 2011-04-25 | 2012-02-20 | Inhibitor of sodium-dependent glucose transport protein and preparation method therefor and use thereof |
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US201161478796P | 2011-04-25 | 2011-04-25 | |
US61/478,796 | 2011-04-25 |
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US (1) | US8957033B2 (zh) |
EP (1) | EP2703396B1 (zh) |
JP (1) | JP2014512399A (zh) |
KR (1) | KR101609859B1 (zh) |
CN (1) | CN102757415B (zh) |
AU (1) | AU2012248061C1 (zh) |
WO (1) | WO2012146075A1 (zh) |
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EP2895490B1 (en) | 2013-09-27 | 2016-10-19 | Sunshine Lake Pharma Co., Ltd. | Glucopyranosyl derivatives and their uses in medicine |
CN105611920B (zh) * | 2013-10-12 | 2021-07-16 | 泰拉科斯萨普有限责任公司 | 羟基-二苯甲烷衍生物的制备 |
CN104529709B (zh) * | 2015-01-15 | 2016-02-24 | 佛山市赛维斯医药科技有限公司 | 苯基丙二醇衍生物、其制备方法和用途 |
CN104529720B (zh) * | 2015-01-15 | 2016-01-20 | 佛山市赛维斯医药科技有限公司 | 一类含三氟甲氧苯基丙二醇结构的衍生物、其制备方法和用途 |
CN104478665B (zh) * | 2015-01-15 | 2015-12-02 | 佛山市赛维斯医药科技有限公司 | 一类含三氟甲苯基丙二醇结构的衍生物、其制备方法和用途 |
CN104478673B (zh) * | 2015-01-15 | 2016-01-20 | 佛山市赛维斯医药科技有限公司 | 含烷氧苯基和苯基丙二醇衍生物、其制备方法和用途 |
CN104529719B (zh) * | 2015-01-15 | 2016-02-24 | 佛山市赛维斯医药科技有限公司 | 一类含烷氧苯基和三氟甲苯基丙二醇结构的衍生物和用途 |
CN104610017B (zh) * | 2015-01-15 | 2016-01-13 | 佛山市赛维斯医药科技有限公司 | 一类卤代苯基丙二醇衍生物、其制备方法和用途 |
CN104478672B (zh) * | 2015-01-15 | 2016-01-06 | 佛山市赛维斯医药科技有限公司 | 一类含烷氧苯基和卤代苯基丙二醇衍生物、其制备方法和用途 |
CN104592151A (zh) * | 2015-02-10 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | 一类含叔丁基脒结构sglt2/sglt1双靶点抑制剂及用途 |
CN104592149A (zh) * | 2015-02-10 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | 一类含叔丁基脒结构的烷氧苯基噻唑羧酸酰胺类双靶点抑制剂、其制备方法及用途 |
CN104592153A (zh) * | 2015-02-10 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | 一类sglt2/sglt1双靶点抑制剂、其制备方法及用途 |
CN104557765A (zh) * | 2015-02-10 | 2015-04-29 | 佛山市赛维斯医药科技有限公司 | 一类含脒结构的卤代苯基噻唑羧酸酰胺类双靶点抑制剂、其制备方法及用途 |
WO2020151621A1 (zh) * | 2019-01-24 | 2020-07-30 | 北京盈科瑞创新药物研究有限公司 | 化合物、其制备方法及医药用途 |
CN111471040B (zh) * | 2019-01-24 | 2023-06-02 | 北京盈科瑞创新药物研究有限公司 | 一种糖苷类衍生物的合成方法及其中间体和应用 |
CN114544850B (zh) * | 2022-02-22 | 2023-10-20 | 苏州正济医药研究有限公司 | 一种达格列净中间体及杂质的检测方法 |
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US6515117B2 (en) * | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
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DE102004048388A1 (de) * | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | D-Pyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
EP1828216B1 (en) * | 2004-12-16 | 2008-09-10 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
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- 2012-02-20 EP EP12775960.3A patent/EP2703396B1/en not_active Not-in-force
- 2012-02-20 AU AU2012248061A patent/AU2012248061C1/en not_active Ceased
- 2012-02-20 US US14/114,197 patent/US8957033B2/en not_active Expired - Fee Related
- 2012-02-20 KR KR1020137031105A patent/KR101609859B1/ko not_active IP Right Cessation
- 2012-02-20 CN CN201210040202.XA patent/CN102757415B/zh not_active Expired - Fee Related
- 2012-02-20 WO PCT/CN2012/071375 patent/WO2012146075A1/zh active Application Filing
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Also Published As
Publication number | Publication date |
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AU2012248061C1 (en) | 2016-07-14 |
AU2012248061A1 (en) | 2013-11-14 |
CN102757415A (zh) | 2012-10-31 |
AU2012248061B2 (en) | 2016-04-07 |
EP2703396A4 (en) | 2014-12-03 |
CN102757415B (zh) | 2015-07-29 |
US8957033B2 (en) | 2015-02-17 |
EP2703396B1 (en) | 2016-06-22 |
EP2703396A1 (en) | 2014-03-05 |
JP2014512399A (ja) | 2014-05-22 |
KR20140004783A (ko) | 2014-01-13 |
KR101609859B1 (ko) | 2016-04-07 |
US20140051648A1 (en) | 2014-02-20 |
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