CA2379875A1 - New effectors of dipeptidyl peptidase iv for topical use - Google Patents
New effectors of dipeptidyl peptidase iv for topical use Download PDFInfo
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- CA2379875A1 CA2379875A1 CA002379875A CA2379875A CA2379875A1 CA 2379875 A1 CA2379875 A1 CA 2379875A1 CA 002379875 A CA002379875 A CA 002379875A CA 2379875 A CA2379875 A CA 2379875A CA 2379875 A1 CA2379875 A1 CA 2379875A1
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- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19940130.6 | 1999-08-24 | ||
| DE19940130A DE19940130A1 (de) | 1999-08-24 | 1999-08-24 | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
| PCT/EP2000/008118 WO2001014318A2 (de) | 1999-08-24 | 2000-08-20 | Neue effektoren der dipeptidyl peptidase iv zur topischen anwendung |
Publications (1)
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| CA2379875A1 true CA2379875A1 (en) | 2001-03-01 |
Family
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|---|---|---|---|
| CA002379875A Abandoned CA2379875A1 (en) | 1999-08-24 | 2000-08-20 | New effectors of dipeptidyl peptidase iv for topical use |
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| WO (1) | WO2001014318A2 (enExample) |
| ZA (1) | ZA200200794B (enExample) |
Families Citing this family (54)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE04029691T1 (de) | 1998-02-02 | 2007-11-08 | Trustees Of Tufts College, Medford | Verwendung von Dipetidylpeptidasehemmer zur Regulierung des Glukosemetabolismus |
| US6979697B1 (en) | 1998-08-21 | 2005-12-27 | Point Therapeutics, Inc. | Regulation of substrate activity |
| GB0010183D0 (en) | 2000-04-26 | 2000-06-14 | Ferring Bv | Inhibitors of dipeptidyl peptidase IV |
| US7368421B2 (en) * | 2001-06-27 | 2008-05-06 | Probiodrug Ag | Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis |
| US7196201B2 (en) | 2001-06-27 | 2007-03-27 | Smithkline Beecham Corporation | Pyrrolidines as dipeptidyl peptidase inhibitors |
| US7183290B2 (en) | 2001-06-27 | 2007-02-27 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
| ES2296979T3 (es) | 2001-06-27 | 2008-05-01 | Smithkline Beecham Corporation | Fluoropirrolidinas como inhibidores de dipeptidil peptidasa. |
| AU2002357767C1 (en) | 2001-11-26 | 2009-03-19 | Trustees Of Tufts College | Peptidomimetic inhibitors of post-proline cleaving enzymes |
| JP2005511636A (ja) | 2001-11-26 | 2005-04-28 | トラスティーズ オブ タフツ カレッジ | 自己免疫疾患の治療方法及びそれに関する試薬 |
| KR20050122220A (ko) | 2003-03-25 | 2005-12-28 | 다케다 샌디에고, 인코포레이티드 | 디펩티딜 펩티다제 억제제 |
| WO2004098591A2 (en) | 2003-05-05 | 2004-11-18 | Probiodrug Ag | Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases |
| WO2004099134A2 (en) * | 2003-05-05 | 2004-11-18 | Prosidion Ltd. | Glutaminyl based dp iv-inhibitors |
| EP1625122A1 (en) | 2003-05-14 | 2006-02-15 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| US7678909B1 (en) | 2003-08-13 | 2010-03-16 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| KR20060041309A (ko) | 2003-08-13 | 2006-05-11 | 다케다 야쿠힌 고교 가부시키가이샤 | ４-피리미돈 유도체 및 펩티딜 펩티다제 저해제로서의 그의용도 |
| US7169926B1 (en) | 2003-08-13 | 2007-01-30 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| EP1697342A2 (en) * | 2003-09-08 | 2006-09-06 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US7790734B2 (en) | 2003-09-08 | 2010-09-07 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US7732446B1 (en) | 2004-03-11 | 2010-06-08 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| EA013427B1 (ru) | 2004-03-15 | 2010-04-30 | Такеда Фармасьютикал Компани Лимитед | Ингибиторы дипептидилпептидазы |
| JP2008501714A (ja) | 2004-06-04 | 2008-01-24 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼインヒビター |
| WO2006019965A2 (en) | 2004-07-16 | 2006-02-23 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| EP1794120B1 (en) | 2004-07-23 | 2012-04-11 | Nuada, LLC | Peptidase inhibitors |
| EP1828192B1 (en) | 2004-12-21 | 2014-12-03 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| DOP2006000008A (es) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
| JP4568361B2 (ja) | 2005-04-22 | 2010-10-27 | アラントス・ファーマシューティカルズ・ホールディング・インコーポレーテッド | ジペプチジルペプチダーゼ−ｉｖ阻害剤 |
| GEP20135791B (en) * | 2005-09-14 | 2013-03-25 | Takeda Pharmaceutical | Use of dipeptidyl peptidase inhibitors |
| PE20070622A1 (es) * | 2005-09-14 | 2007-08-22 | Takeda Pharmaceutical | Administracion de inhibidores de dipeptidil peptidasa |
| PT1942898E (pt) * | 2005-09-14 | 2011-12-20 | Takeda Pharmaceutical | Inibidores da dipeptidilpeptidase para o tratamento da diabetes |
| CN101360723A (zh) | 2005-09-16 | 2009-02-04 | 武田药品工业株式会社 | 制备嘧啶二酮衍生物的方法 |
| TW200745080A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor |
| TW200745079A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| EP1999108A1 (en) * | 2006-03-28 | 2008-12-10 | Takeda Pharmaceutical Company Limited | Preparation of (r)-3-aminopiperidine dihydrochloride |
| WO2007112347A1 (en) | 2006-03-28 | 2007-10-04 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
| AU2007238805B2 (en) | 2006-04-11 | 2012-04-05 | Arena Pharmaceuticals, Inc. | Methods of using GPR119 receptor to identify compounds useful for increasing bone mass in an individual |
| US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
| BRPI0716971A2 (pt) * | 2006-09-13 | 2013-10-15 | Takeda Pharmaceutical | Uso de 2-6(3-amino-piperini-l-il)-3-metil-2,4-dioxo-3,4-dihidro-2 h-pirimidin-1ilmetil-4-fluoro-benxonitrila |
| EP2089383B1 (en) | 2006-11-09 | 2015-09-16 | Probiodrug AG | 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases |
| TW200838536A (en) * | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| US9126987B2 (en) | 2006-11-30 | 2015-09-08 | Probiodrug Ag | Inhibitors of glutaminyl cyclase |
| US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
| CN101279955B (zh) * | 2007-04-03 | 2012-11-28 | 北京摩力克科技有限公司 | 作为二肽肽激酶-iv抑制剂的n-取代硫吗啉衍生物及其医药用途 |
| WO2008128985A1 (en) | 2007-04-18 | 2008-10-30 | Probiodrug Ag | Thiourea derivatives as glutaminyl cyclase inhibitors |
| EP2108960A1 (en) | 2008-04-07 | 2009-10-14 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditons modulated by PYY |
| CA2772488C (en) | 2009-09-11 | 2018-04-17 | Probiodrug Ag | Heterocyclic derivatives as inhibitors of glutaminyl cyclase |
| JP6026284B2 (ja) | 2010-03-03 | 2016-11-16 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤 |
| NZ602312A (en) | 2010-03-10 | 2014-02-28 | Probiodrug Ag | Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5) |
| JP5945532B2 (ja) | 2010-04-21 | 2016-07-05 | プロビオドルグ エージー | グルタミニルシクラーゼの阻害剤としてのベンゾイミダゾール誘導体 |
| EP2686313B1 (en) | 2011-03-16 | 2016-02-03 | Probiodrug AG | Benzimidazole derivatives as inhibitors of glutaminyl cyclase |
| MX386778B (es) | 2015-03-09 | 2025-03-19 | Intekrin Therapeutics Inc | Métodos para el tratamiento de enfermedad de hígado graso no alcohólico y/o lipodistrofia. |
| CA3058806A1 (en) | 2017-04-03 | 2018-10-11 | Coherus Biosciences Inc. | Ppar.gamma. agonist for treatment of progressive supranuclear palsy |
| ES2812698T3 (es) | 2017-09-29 | 2021-03-18 | Probiodrug Ag | Inhibidores de glutaminil ciclasa |
| CN110607336B (zh) * | 2019-10-17 | 2024-01-26 | 江南大学 | 酶催化制备半胱氨酸寡肽及其膜敷料的制备方法 |
Family Cites Families (71)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE296075C (enExample) | ||||
| US2961377A (en) * | 1957-08-05 | 1960-11-22 | Us Vitamin Pharm Corp | Oral anti-diabetic compositions and methods |
| US3174901A (en) * | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| US3879541A (en) * | 1970-03-03 | 1975-04-22 | Bayer Ag | Antihyperglycemic methods and compositions |
| US3960949A (en) * | 1971-04-02 | 1976-06-01 | Schering Aktiengesellschaft | 1,2-Biguanides |
| CH602612A5 (enExample) * | 1974-10-11 | 1978-07-31 | Hoffmann La Roche | |
| US4935493A (en) * | 1987-10-06 | 1990-06-19 | E. I. Du Pont De Nemours And Company | Protease inhibitors |
| US5433955A (en) * | 1989-01-23 | 1995-07-18 | Akzo N.V. | Site specific in vivo activation of therapeutic drugs |
| EP0512042B1 (en) | 1990-01-24 | 1998-04-08 | BUCKLEY, Douglas I. | Glp-1 analogs useful for diabetes treatment |
| DK0528858T3 (da) | 1990-04-14 | 1997-07-28 | Univ Tufts Med | Inhibitorer af dipeptidyl-aminopeptidase type IV |
| US5462928A (en) * | 1990-04-14 | 1995-10-31 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type IV |
| US6517824B1 (en) * | 1990-05-14 | 2003-02-11 | University Of Medicine & Denistry Of New Jersey | Polymer compositions comprising antifibrotic agents, and methods of treatment, pharmaceutical compositions, and methods of preparation therefor |
| WO1991017767A1 (en) | 1990-05-21 | 1991-11-28 | New England Medical Center Hospitals, Inc. | Method of treating inhibition of dipeptidyl aminopeptidase type iv |
| JPH0819154B2 (ja) | 1991-03-14 | 1996-02-28 | 江崎グリコ株式会社 | ジペプチジルカルボキシペプチダーゼを阻害するペプチド |
| JPH04334357A (ja) | 1991-05-02 | 1992-11-20 | Fujirebio Inc | 酵素阻害作用を有するアシル誘導体 |
| GB9115740D0 (en) | 1991-07-20 | 1991-09-04 | Smithkline Beecham Plc | Medicaments |
| EP1050540B1 (en) | 1991-10-22 | 2006-12-27 | New England Medical Center Hospitals, Inc. | Inhibitors of dipeptidyl-aminopeptidase type IV |
| WO1993020061A1 (en) | 1992-04-01 | 1993-10-14 | The University Of Toledo | 4-[4'-piperidinyl or 3'-pirrolidinyl] substituted imidazoles as h3-receptor antagonists and therapeutic uses thereof |
| IL106998A0 (en) * | 1992-09-17 | 1993-12-28 | Univ Florida | Brain-enhanced delivery of neuroactive peptides by sequential metabolism |
| WO1995011689A1 (en) | 1993-10-29 | 1995-05-04 | Trustees Of Tufts College | Use of inhibitors of dipeptidyl-aminopeptidase to block entry of hiv into cells |
| IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
| US5705483A (en) * | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
| CA2137206A1 (en) | 1993-12-09 | 1995-06-10 | John A. Galloway | Glucagon-like insulinotropic peptides, compositions and methods |
| WO1995022327A1 (en) | 1994-02-22 | 1995-08-24 | Knoll Ag | Use of 1-(arylalkylaminoalkyl) imidazoles for treating neurological damage |
| US5543396A (en) * | 1994-04-28 | 1996-08-06 | Georgia Tech Research Corp. | Proline phosphonate derivatives |
| US5552426A (en) | 1994-04-29 | 1996-09-03 | Eli Lilly And Company | Methods for treating a physiological disorder associated with β-amyloid peptide |
| AU2790895A (en) * | 1994-06-10 | 1996-01-05 | Universitaire Instelling Antwerpen | Purification of serine protease and synthetic inhibitors thereof |
| US5512549A (en) * | 1994-10-18 | 1996-04-30 | Eli Lilly And Company | Glucagon-like insulinotropic peptide analogs, compositions, and methods of use |
| US5614379A (en) * | 1995-04-26 | 1997-03-25 | Eli Lilly And Company | Process for preparing anti-obesity protein |
| US6448282B1 (en) | 1995-05-30 | 2002-09-10 | Gliatech, Inc. | 1H-4(5)-substituted imidazole derivatives |
| DE122010000020I1 (de) | 1996-04-25 | 2010-07-08 | Prosidion Ltd | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
| EP0914123A4 (en) | 1996-05-29 | 2000-10-11 | Prototek Inc | THALIDOMIDE PRODUCTS AND METHODS OF USING SAID PRODUCTS AS T CELL MODIFIERS |
| US6006753A (en) * | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
| US5827898A (en) * | 1996-10-07 | 1998-10-27 | Shaman Pharmaceuticals, Inc. | Use of bisphenolic compounds to treat type II diabetes |
| US6011155A (en) * | 1996-11-07 | 2000-01-04 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| TW492957B (en) | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
| AR016751A1 (es) | 1996-11-22 | 2001-08-01 | Athena Neurosciences Inc | Metodo para inhibir la liberacion del peptido beta-amiloide en una celula, composicion farmaceutica y compuestos utiles en dicho metodo |
| DE59907545D1 (de) | 1998-02-13 | 2003-12-04 | Schwabe Willmar Gmbh & Co | Stabile hyperforin-salze, verfahren zu ihrer herstellung und verwendung zur therapie der alzheimerschen krankheit |
| US5994379A (en) | 1998-02-13 | 1999-11-30 | Merck Frosst Canada, Inc. | Bisaryl COX-2 inhibiting compounds, compositions and methods of use |
| EP1062222A1 (en) | 1998-03-09 | 2000-12-27 | Fondatech Benelux N.V. | Serine peptidase modulators |
| DE19823831A1 (de) * | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
| JP2002517401A (ja) | 1998-06-05 | 2002-06-18 | ポイント セラピューティクス， インコーポレイテッド | 環状ボロプロリン化合物 |
| DE19826972A1 (de) * | 1998-06-18 | 1999-12-23 | Univ Magdeburg Tech | Verwendung von Enzyminhibitoren und pharmazeutische Zubereitung zur Therapie von dermatologischen Erkrankungen mit follikulären und epidermalen Hyperkeratosen und einer verstärkten Keratinozytenproliferation |
| AU4854999A (en) | 1998-07-02 | 2000-01-24 | Invitro Diagnostics, Inc. | Methods, compositions and apparatus for making nucleic acid molecules having a selected affinity to a target molecule |
| DE19834591A1 (de) * | 1998-07-31 | 2000-02-03 | Probiodrug Ges Fuer Arzneim | Verfahren zur Steigerung des Blutglukosespiegels in Säugern |
| DE19834610A1 (de) | 1998-07-31 | 2000-02-24 | Probiodrug Ges Fuer Arzneim | Mechanismus-orientierte Inhibitoren der Dipeptidyl Peptidase I |
| WO2000010549A1 (en) | 1998-08-21 | 2000-03-02 | Point Therapeutics, Inc. | Regulation of substrate activity |
| CO5150173A1 (es) * | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
| AU3960400A (en) | 1999-03-05 | 2000-09-28 | Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. | Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv |
| US6211182B1 (en) | 1999-03-08 | 2001-04-03 | Schering Corporation | Imidazole compounds substituted with a six or seven membered heterocyclic ring containing two nitrogen atoms |
| DE60012721D1 (de) | 1999-03-29 | 2004-09-09 | Uutech Ltd | Analoge des magensaft inhibierenden peptides und ihre verwendung für die behandlung von diabetes |
| US6110949A (en) * | 1999-06-24 | 2000-08-29 | Novartis Ag | N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| US6172081B1 (en) * | 1999-06-24 | 2001-01-09 | Novartis Ag | Tetrahydroisoquinoline 3-carboxamide derivatives |
| US6107317A (en) * | 1999-06-24 | 2000-08-22 | Novartis Ag | N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
| GB9917909D0 (en) | 1999-07-31 | 1999-09-29 | Synphar Lab Inc | Cysteine protease inhibitors |
| KR20080065707A (ko) | 1999-11-03 | 2008-07-14 | 에이엠알 테크놀로지, 인크. | 4-페닐-치환 테트라히드로이소퀴놀린, 및 노르에피네프린과도파민과 세로토닌의 재흡수를 차단하기 위한 이의 용도 |
| AU1916401A (en) | 1999-11-12 | 2001-06-06 | Guilford Pharmaceuticals Inc. | Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors |
| AU2001233622A1 (en) | 2000-02-25 | 2001-09-03 | Novo-Nordisk A/S | Inhibition of beta cell degeneration |
| US7064145B2 (en) * | 2000-02-25 | 2006-06-20 | Novo Nordisk A/S | Inhibition of beta cell degeneration |
| DE60042585D1 (de) | 2000-02-29 | 2009-09-03 | Univ Firenze | 3-Aza-6,8-dioxabicycloÄ3.2.1Üoctane und Analoga sowie diese enthaltende kombinatorische Bibliotheken |
| CZ20023234A3 (cs) * | 2000-03-31 | 2003-01-15 | Probiodrug Ag | Léčivo proti diabetu |
| US6605589B1 (en) | 2000-03-31 | 2003-08-12 | Parker Hughes Institute | Cathepsin inhibitors in cancer treatment |
| US6573096B1 (en) | 2000-04-01 | 2003-06-03 | The Research Foundation At State University Of New York | Compositions and methods for inhibition of cancer invasion and angiogenesis |
| DE10025464A1 (de) | 2000-05-23 | 2001-12-06 | Inst Medizintechnologie Magdeb | Kombinierte Verwendung von Enzyminhibitoren zur Therapie von Autoimmunerkrankungen, bei Transplantationen und Tumorerkrankungen sowie Kombinationen von Enzyminhibitoren umfassende pharmazeutische Zubereitungen |
| US6841685B2 (en) | 2000-06-07 | 2005-01-11 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Methods for making bis-heterocyclic alkaloids |
| GB0014969D0 (en) | 2000-06-19 | 2000-08-09 | Smithkline Beecham Plc | Novel method of treatment |
| US20020042400A1 (en) | 2000-08-17 | 2002-04-11 | Yajing Rong | Novel alicyclic imidazoles as H3 agents |
| CN1484709A (zh) | 2000-09-09 | 2004-03-24 | ŦԼ������ѧ�о������ | 分离转移性癌细胞的方法与组合物,及其在检测癌转移性上的应用 |
| EP1417220A2 (en) | 2001-08-13 | 2004-05-12 | Probiodrug AG | Irreversible cysteine protease inhibitors of legumain |
| CA2476681A1 (en) | 2002-02-19 | 2003-08-28 | Bruce N. Rogers | Fused bicyclic-n-bridged-heteroaromatic carboxamides for the treatment of disease |
| CA2521907A1 (en) | 2003-04-10 | 2004-10-21 | Pfizer Inc. | Bicyclic compounds as nr2b receptor antagonists |
-
1999
- 1999-08-24 DE DE19940130A patent/DE19940130A1/de not_active Withdrawn
-
2000
- 2000-08-20 EP EP00953186A patent/EP1206485B1/de not_active Expired - Lifetime
- 2000-08-20 AT AT00953186T patent/ATE357455T1/de not_active IP Right Cessation
- 2000-08-20 PT PT00953186T patent/PT1206485E/pt unknown
- 2000-08-20 DE DE50014187T patent/DE50014187D1/de not_active Expired - Fee Related
- 2000-08-20 WO PCT/EP2000/008118 patent/WO2001014318A2/de not_active Ceased
- 2000-08-20 KR KR1020027002338A patent/KR20020040787A/ko not_active Withdrawn
- 2000-08-20 JP JP2001518409A patent/JP2003519099A/ja not_active Withdrawn
- 2000-08-20 CA CA002379875A patent/CA2379875A1/en not_active Abandoned
- 2000-08-20 EP EP07104464A patent/EP1792910A2/de not_active Withdrawn
- 2000-08-20 MX MXPA02001800A patent/MXPA02001800A/es unknown
- 2000-08-20 BR BR0013577-1A patent/BR0013577A/pt not_active Application Discontinuation
- 2000-08-20 IL IL14817000A patent/IL148170A0/xx unknown
- 2000-08-20 NZ NZ528770A patent/NZ528770A/en unknown
- 2000-08-20 ES ES00953186T patent/ES2282130T3/es not_active Expired - Lifetime
- 2000-08-20 AU AU65721/00A patent/AU769404B2/en not_active Ceased
- 2000-08-20 CN CN00811936A patent/CN1370181A/zh active Pending
-
2002
- 2002-01-29 ZA ZA200200794A patent/ZA200200794B/en unknown
- 2002-02-22 NO NO20020858A patent/NO20020858L/no not_active Application Discontinuation
- 2002-02-22 US US10/082,001 patent/US6949515B2/en not_active Expired - Fee Related
-
2005
- 2005-03-01 US US11/069,926 patent/US7335645B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU769404B2 (en) | 2004-01-29 |
| ES2282130T3 (es) | 2007-10-16 |
| US7335645B2 (en) | 2008-02-26 |
| NZ528770A (en) | 2005-02-25 |
| DE19940130A1 (de) | 2001-03-01 |
| ATE357455T1 (de) | 2007-04-15 |
| KR20020040787A (ko) | 2002-05-30 |
| NO20020858D0 (no) | 2002-02-22 |
| US20020165164A1 (en) | 2002-11-07 |
| WO2001014318A3 (de) | 2001-11-01 |
| JP2003519099A (ja) | 2003-06-17 |
| AU6572100A (en) | 2001-03-19 |
| US20050209159A1 (en) | 2005-09-22 |
| EP1206485A2 (de) | 2002-05-22 |
| MXPA02001800A (es) | 2003-09-25 |
| BR0013577A (pt) | 2002-04-30 |
| ZA200200794B (en) | 2003-03-26 |
| EP1792910A2 (de) | 2007-06-06 |
| DE50014187D1 (de) | 2007-05-03 |
| WO2001014318A2 (de) | 2001-03-01 |
| US6949515B2 (en) | 2005-09-27 |
| PT1206485E (pt) | 2007-05-31 |
| IL148170A0 (en) | 2002-09-12 |
| CN1370181A (zh) | 2002-09-18 |
| EP1206485B1 (de) | 2007-03-21 |
| NO20020858L (no) | 2002-02-22 |
| US20030092630A2 (en) | 2003-05-15 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Discontinued |