JP2018131450A5 - - Google Patents
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- JP2018131450A5 JP2018131450A5 JP2018083792A JP2018083792A JP2018131450A5 JP 2018131450 A5 JP2018131450 A5 JP 2018131450A5 JP 2018083792 A JP2018083792 A JP 2018083792A JP 2018083792 A JP2018083792 A JP 2018083792A JP 2018131450 A5 JP2018131450 A5 JP 2018131450A5
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- sulfonylurea
- methyl
- composition according
- metformin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000008194 pharmaceutical composition Substances 0.000 claims 37
- 229940100389 Sulfonylurea Drugs 0.000 claims 27
- 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 claims 25
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims 23
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims 16
- 229960003105 metformin Drugs 0.000 claims 16
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 claims 12
- 239000003814 drug Substances 0.000 claims 12
- 102000004877 Insulin Human genes 0.000 claims 11
- 108090001061 Insulin Proteins 0.000 claims 11
- 229940125396 insulin Drugs 0.000 claims 11
- 229940079593 drug Drugs 0.000 claims 10
- -1 4-methyl-quinazolin-2-yl Chemical group 0.000 claims 9
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims 8
- 229940123464 Thiazolidinedione Drugs 0.000 claims 7
- 206010012601 diabetes mellitus Diseases 0.000 claims 7
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims 6
- 230000002641 glycemic effect Effects 0.000 claims 6
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims 5
- 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 claims 5
- 230000002058 anti-hyperglycaemic effect Effects 0.000 claims 5
- 239000008103 glucose Substances 0.000 claims 5
- 208000030159 metabolic disease Diseases 0.000 claims 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 5
- 230000002265 prevention Effects 0.000 claims 5
- 102100024295 Maltase-glucoamylase Human genes 0.000 claims 4
- 108010028144 alpha-Glucosidases Proteins 0.000 claims 4
- 239000003472 antidiabetic agent Substances 0.000 claims 4
- 239000008280 blood Substances 0.000 claims 4
- 210000004369 blood Anatomy 0.000 claims 4
- 238000002648 combination therapy Methods 0.000 claims 4
- 229960005095 pioglitazone Drugs 0.000 claims 4
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 3
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 claims 2
- 230000003914 insulin secretion Effects 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 150000001467 thiazolidinediones Chemical class 0.000 claims 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims 2
- 208000013016 Hypoglycemia Diseases 0.000 claims 1
- 206010062237 Renal impairment Diseases 0.000 claims 1
- 230000006978 adaptation Effects 0.000 claims 1
- 229940127003 anti-diabetic drug Drugs 0.000 claims 1
- 230000003178 anti-diabetic effect Effects 0.000 claims 1
- 229940125708 antidiabetic agent Drugs 0.000 claims 1
- 210000000941 bile Anatomy 0.000 claims 1
- 208000016097 disease of metabolism Diseases 0.000 claims 1
- 230000009977 dual effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 229960004580 glibenclamide Drugs 0.000 claims 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 claims 1
- 229960004346 glimepiride Drugs 0.000 claims 1
- 229960001381 glipizide Drugs 0.000 claims 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 claims 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 claims 1
- 230000002218 hypoglycaemic effect Effects 0.000 claims 1
- 239000004026 insulin derivative Substances 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 239000002207 metabolite Substances 0.000 claims 1
- 229940111334 metformin / pioglitazone Drugs 0.000 claims 1
- 229940127017 oral antidiabetic Drugs 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 238000011295 triple combination therapy Methods 0.000 claims 1
- 230000004584 weight gain Effects 0.000 claims 1
- 235000019786 weight gain Nutrition 0.000 claims 1
- 229940075420 xanthine Drugs 0.000 claims 1
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10591908P | 2008-10-16 | 2008-10-16 | |
| EP08166829 | 2008-10-16 | ||
| EP08166829.5 | 2008-10-16 | ||
| US61/105,919 | 2008-10-16 | ||
| EP09167304 | 2009-08-05 | ||
| EP09167304.6 | 2009-08-05 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2016046077A Division JP2016164161A (ja) | 2008-10-16 | 2016-03-09 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2020128354A Division JP7174020B2 (ja) | 2008-10-16 | 2020-07-29 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2018131450A JP2018131450A (ja) | 2018-08-23 |
| JP2018131450A5 true JP2018131450A5 (cg-RX-API-DMAC7.html) | 2018-10-04 |
| JP6811203B2 JP6811203B2 (ja) | 2021-01-13 |
Family
ID=41426834
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011531494A Pending JP2012505859A (ja) | 2008-10-16 | 2009-10-15 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2014039772A Active JP6262023B2 (ja) | 2008-10-16 | 2014-02-28 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2016046077A Pending JP2016164161A (ja) | 2008-10-16 | 2016-03-09 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2018083792A Active JP6811203B2 (ja) | 2008-10-16 | 2018-04-25 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2022111237A Pending JP2022125360A (ja) | 2008-10-16 | 2022-07-11 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2024208369A Pending JP2025029032A (ja) | 2008-10-16 | 2024-11-29 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011531494A Pending JP2012505859A (ja) | 2008-10-16 | 2009-10-15 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2014039772A Active JP6262023B2 (ja) | 2008-10-16 | 2014-02-28 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2016046077A Pending JP2016164161A (ja) | 2008-10-16 | 2016-03-09 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2022111237A Pending JP2022125360A (ja) | 2008-10-16 | 2022-07-11 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
| JP2024208369A Pending JP2025029032A (ja) | 2008-10-16 | 2024-11-29 | 経口又は非経口抗糖尿病薬による治療にもかかわらず不十分な血糖調節の患者の糖尿病の治療 |
Country Status (20)
Families Citing this family (40)
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|---|---|---|---|---|
| US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
| US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
| DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
| DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
| NZ600394A (en) | 2006-05-04 | 2014-04-30 | Boehringer Ingelheim Int | Polymorphs of a dpp-iv enzyme inhibitor |
| PE20080251A1 (es) | 2006-05-04 | 2008-04-25 | Boehringer Ingelheim Int | Usos de inhibidores de dpp iv |
| EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
| CL2008002427A1 (es) | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2. |
| CA2719272C (en) | 2008-03-26 | 2020-08-18 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| AR071175A1 (es) | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante |
| UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
| KR20190016601A (ko) | 2008-08-06 | 2019-02-18 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
| MX2011002558A (es) | 2008-09-10 | 2011-04-26 | Boehringer Ingelheim Int | Terapia de combinacion para el tratamiento de diabetes y estados relacionados. |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| CA2745037C (en) | 2008-12-23 | 2020-06-23 | Boehringer Ingelheim International Gmbh | Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8(3-(r)-amino-piperidin-1-yl)-xanthine |
| AR074990A1 (es) | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
| AU2010212867B2 (en) | 2009-02-13 | 2013-05-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a SGLT2 inhibitor, a DPP-IV inhibitor and optionally a further antidiabetic agent and uses thereof |
| CN117547538A (zh) * | 2009-02-13 | 2024-02-13 | 勃林格殷格翰国际有限公司 | 包含dpp-4抑制剂(利格列汀)任选地组合其它抗糖尿病药的抗糖尿病药物 |
| EP2427195B1 (en) | 2009-05-07 | 2019-05-01 | Intellikine, LLC | Heterocyclic compounds and uses thereof |
| CN102753161A (zh) | 2009-11-27 | 2012-10-24 | 贝林格尔.英格海姆国际有限公司 | 基因型糖尿病患者利用dpp-iv抑制剂例如利拉利汀的治疗 |
| KR20130069615A (ko) * | 2010-05-05 | 2013-06-26 | 베링거 인겔하임 인터내셔날 게엠베하 | 피오글리타존 및 리나글립틴을 포함하는 약제학적 제형 |
| CN107961377B (zh) | 2010-05-05 | 2022-11-22 | 勃林格殷格翰国际有限公司 | 组合疗法 |
| MX2012014247A (es) * | 2010-06-24 | 2013-01-18 | Boehringer Ingelheim Int | Terapia para la diabetes. |
| JP2013545749A (ja) | 2010-11-10 | 2013-12-26 | インフィニティー ファーマシューティカルズ， インコーポレイテッド | 複素環化合物及びその使用 |
| AU2016202261B2 (en) * | 2010-11-15 | 2017-11-30 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
| AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
| UY33937A (es) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | Composiciones farmacéuticas que contienen inhibidores de dpp-4 y/o sglt-2 y metformina |
| PL2731947T3 (pl) | 2011-07-15 | 2019-07-31 | Boehringer Ingelheim International Gmbh | Podstawiona dimeryczna pochodna chinazoliny, sposób jej wytwarzania i jej zastosowanie w kompozycjach farmaceutycznych do leczenia cukrzycy typu I i II |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| US20130303462A1 (en) | 2012-05-14 | 2013-11-14 | Boehringer Ingelheim International Gmbh | Use of a dpp-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
| US20130303554A1 (en) * | 2012-05-14 | 2013-11-14 | Boehringer Ingelheim International Gmbh | Use of a dpp-4 inhibitor in sirs and/or sepsis |
| EP2854812A1 (en) * | 2012-05-24 | 2015-04-08 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
| WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
| EP2941267B1 (en) | 2013-01-03 | 2022-11-16 | Oramed Ltd. | Compositions for use in treating nafld |
| EP4364796A3 (en) * | 2013-03-15 | 2024-07-24 | Boehringer Ingelheim International GmbH | Use of linagliptin in cardio- and renoprotective antidiabetic therapy |
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| AU2017278261A1 (en) | 2016-06-05 | 2019-01-31 | Berg Llc | Systems and methods for patient stratification and identification of potential biomarkers |
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| DE60331236D1 (de) * | 2003-07-24 | 2010-03-25 | Eswaran Krishnan Iyer | Orale zusammensetzungen zur behandlung von diabetes |
| CA2540741A1 (en) * | 2003-10-03 | 2005-04-14 | Takeda Pharmaceutical Company Limited | Agent for treating diabetes |
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| EP1966215A1 (en) * | 2005-12-23 | 2008-09-10 | Novartis AG | Condensed heterocyclic compounds useful as dpp-iv inhibitors |
| EP2057160A1 (en) * | 2006-08-08 | 2009-05-13 | Boehringer Ingelheim International GmbH | Pyrrolo [3, 2 -d]pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
| CL2008002427A1 (es) * | 2007-08-16 | 2009-09-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende 1-cloro-4-(b-d-glucopiranos-1-il)-2-[4-((s)-tetrahidrofurano-3-iloxi)bencil]-benceno combinado con 1-[(4-metilquinazolin-2-il)metil]-3-metil-7-(2-butin-1-il)-8-(3-(r)-aminopiperidin-1-il)xantina; y su uso para tratar diabetes mellitus tipo 2. |
| PE20090597A1 (es) * | 2007-08-16 | 2009-06-06 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de pirazol-o-glucosido |
| GB2465132B (en) * | 2007-09-21 | 2012-06-06 | Lupin Ltd | Compounds as dipeptidyl peptidase IV (DPP IV) inhibitors |
| BRPI0920699A2 (pt) * | 2008-10-16 | 2020-09-01 | Boehringer Ingelheim International Gmbh | uso de um inibidor de dpp-4 no tratamento de diabetes em pacientes com controle insuficiente da glicemia apesar de terapia com um fármaco antidiabético oral ou não-oral |
| CN102753161A (zh) * | 2009-11-27 | 2012-10-24 | 贝林格尔.英格海姆国际有限公司 | 基因型糖尿病患者利用dpp-iv抑制剂例如利拉利汀的治疗 |
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- 2009-10-15 KR KR1020187009095A patent/KR20180035948A/ko not_active Ceased
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2014
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