CA2249369A1 - N-(2 oxoacetyl or sulphonyl)-pyrrolidine/piperidine-2-carboxylic acid derivatives with improved multi-drug resistance activity - Google Patents
N-(2 oxoacetyl or sulphonyl)-pyrrolidine/piperidine-2-carboxylic acid derivatives with improved multi-drug resistance activity Download PDFInfo
- Publication number
- CA2249369A1 CA2249369A1 CA002249369A CA2249369A CA2249369A1 CA 2249369 A1 CA2249369 A1 CA 2249369A1 CA 002249369 A CA002249369 A CA 002249369A CA 2249369 A CA2249369 A CA 2249369A CA 2249369 A1 CA2249369 A1 CA 2249369A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- straight
- pyridyl
- methyl
- branched
- 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.)
- Abandoned
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- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
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- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
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- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 description 1
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/626,259 US5717092A (en) | 1996-03-29 | 1996-03-29 | Compounds with improved multi-drug resistance activity |
| US08/626,259 | 1996-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2249369A1 true CA2249369A1 (en) | 1997-10-09 |
Family
ID=24509627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002249369A Abandoned CA2249369A1 (en) | 1996-03-29 | 1997-03-24 | N-(2 oxoacetyl or sulphonyl)-pyrrolidine/piperidine-2-carboxylic acid derivatives with improved multi-drug resistance activity |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US5717092A (OSRAM) |
| EP (1) | EP0891331B1 (OSRAM) |
| JP (1) | JP4759762B2 (OSRAM) |
| AT (1) | ATE251140T1 (OSRAM) |
| AU (1) | AU2346597A (OSRAM) |
| CA (1) | CA2249369A1 (OSRAM) |
| DE (1) | DE69725293T2 (OSRAM) |
| DK (1) | DK0891331T3 (OSRAM) |
| ES (1) | ES2208890T3 (OSRAM) |
| PT (1) | PT891331E (OSRAM) |
| WO (1) | WO1997036869A1 (OSRAM) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6150527A (en) * | 1994-08-18 | 2000-11-21 | Ariad Pharmaceuticals, Inc. | Synthetic multimerizing agents |
| US6133456A (en) * | 1994-08-18 | 2000-10-17 | Ariad Gene Therapeutics, Inc. | Synthetic multimerizing agents |
| US20030036654A1 (en) * | 1994-08-18 | 2003-02-20 | Holt Dennis A. | Synthetic multimerizing agents |
| US5795877A (en) * | 1996-12-31 | 1998-08-18 | Guilford Pharmaceuticals Inc. | Inhibitors of NAALADase enzyme activity |
| US6218424B1 (en) * | 1996-09-25 | 2001-04-17 | Gpi Nil Holdings, Inc. | Heterocyclic ketone and thioester compounds and uses |
| US5786378A (en) * | 1996-09-25 | 1998-07-28 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters |
| US5801187A (en) | 1996-09-25 | 1998-09-01 | Gpi-Nil Holdings, Inc. | Heterocyclic esters and amides |
| SK57899A3 (en) | 1996-12-31 | 2000-05-16 | Guilford Pharm Inc | N-linked ureas and carbamates of heterocyclic thioesters |
| NZ335480A (en) * | 1996-12-31 | 2001-04-27 | Guilford Pharm Inc | Neurotrophic low molecular weight N-linked sulfonamides of heterocyclic thioesters and their use as inhibitors of immunophilin proteins |
| US5935989A (en) | 1996-12-31 | 1999-08-10 | Gpi Nil Holdings Inc. | N-linked ureas and carbamates of heterocyclic thioesters |
| US5874449A (en) * | 1996-12-31 | 1999-02-23 | Gpi Nil Holdings, Inc. | N-linked sulfonamides of heterocyclic thioesters |
| US6242468B1 (en) | 1997-02-27 | 2001-06-05 | Jia-He Li | Carbamate and urea compositions and neurotrophic uses |
| US5846979A (en) * | 1997-02-28 | 1998-12-08 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic esters, amides, thioesters, and ketones |
| US20010049381A1 (en) | 1997-06-04 | 2001-12-06 | Gpl Nil Holdings, Inc., | Pyrrolidine derivative hair growth compositions and uses |
| US5945441A (en) | 1997-06-04 | 1999-08-31 | Gpi Nil Holdings, Inc. | Pyrrolidine carboxylate hair revitalizing agents |
| US6852496B1 (en) * | 1997-08-12 | 2005-02-08 | Oregon Health And Science University | Methods of screening for agents that promote nerve cell growth |
| PL343313A1 (en) | 1998-04-08 | 2001-08-13 | Lilly Co Eli | Methods for inhibiting mrp1 |
| IL138391A0 (en) | 1998-04-08 | 2001-10-31 | Lilly Co Eli | Methods for inhibiting mrp1 |
| US6410041B1 (en) * | 1998-04-28 | 2002-06-25 | Trustees Of Tufts College | Culturing cells in presence of amphipathic weak bases and/or cations and multiple drug resistance inhibitor containing reserpine |
| US20020131972A1 (en) * | 1998-05-21 | 2002-09-19 | Daniel Sem | Multi-partite ligands and methods of identifying and using same |
| JP2002516857A (ja) * | 1998-06-02 | 2002-06-11 | ブリストルーマイヤーズ スクイブ カンパニー | 神経栄養性ジフルオロアミド剤 |
| US6331537B1 (en) | 1998-06-03 | 2001-12-18 | Gpi Nil Holdings, Inc. | Carboxylic acids and carboxylic acid isosteres of N-heterocyclic compounds |
| CN1295561A (zh) | 1998-06-03 | 2001-05-16 | Gpinil控股公司 | N－杂环羧酸或羧酸等排物的n－结合氨磺酰 |
| US6307049B1 (en) | 1998-09-30 | 2001-10-23 | The Procter & Gamble Co. | Heterocyclic 2-substituted ketoamides |
| AU6060099A (en) * | 1998-09-30 | 2000-04-17 | Procter & Gamble Company, The | 2-substituted ketoamides |
| US6300341B1 (en) | 1998-09-30 | 2001-10-09 | The Procter & Gamble Co. | 2-substituted heterocyclic sulfonamides |
| US6228872B1 (en) | 1998-11-12 | 2001-05-08 | Bristol-Myers Squibb Company | Neurotrophic diamide and carbamate agents |
| US6358531B1 (en) * | 1999-02-01 | 2002-03-19 | The Curators Of The University Of Missouri | Method for preparing porous shells or gels from glass particles |
| AU6387500A (en) * | 1999-08-05 | 2001-03-05 | Procter & Gamble Company, The | Multivalent exocyclic diketo compounds |
| AU7824900A (en) | 1999-10-07 | 2001-04-23 | Eli Lilly And Company | Compounds and methods for inhibiting mrp1 |
| US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
| US6417189B1 (en) | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
| US6818643B1 (en) | 1999-12-08 | 2004-11-16 | Bristol-Myers Squibb Company | Neurotrophic bicyclic diamides |
| CA2393466C (en) | 1999-12-21 | 2010-01-19 | Gpi Nil Holdings, Inc. | Hydantoin derivative compounds, pharmaceutical compositions, and methods of using same |
| US6376514B1 (en) | 2000-10-17 | 2002-04-23 | The Procter & Gamble Co. | Substituted six-membered heterocyclic compounds useful for treating multidrug resistance and compositions and methods thereof |
| US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
| US6593362B2 (en) | 2001-05-21 | 2003-07-15 | Guilford Pharmaceuticals Inc. | Non-peptidic cyclophilin binding compounds and their use |
| WO2002096420A2 (en) * | 2001-05-29 | 2002-12-05 | Guilford Pharmaceuticals Inc. | Method for treating nerve injury caused by surgery |
| US7653490B2 (en) * | 2001-09-10 | 2010-01-26 | Triad Liquidating Company LLC | Nuclear magnetic resonance assembly of chemical entities |
| US20030109448A1 (en) * | 2001-11-07 | 2003-06-12 | Crowley Kathleen S. | Methods of promoting uptake and nuclear accumulation of polyamides in eukaryotic cells |
| WO2003062773A1 (en) * | 2002-01-24 | 2003-07-31 | Pei Electronics, Inc. | Compact integrated infrared scene projector |
| US20030180797A1 (en) * | 2002-03-20 | 2003-09-25 | Lin Yu | Identification of ligands for a receptor family and related methods |
| WO2003080111A2 (en) * | 2002-03-25 | 2003-10-02 | Technologies Biolactis Inc. | Chemotherapeutic agents as anti-cancer vaccine adjuvants and therapeutic methods thereof |
| US7825136B2 (en) | 2003-07-10 | 2010-11-02 | Vertex Pharmaceuticals Incorporated | Potentiators of antibacterial activity |
| CN1281210C (zh) * | 2003-11-29 | 2006-10-25 | 胡汛 | 五味子乙素在制备治疗肿瘤药物中的应用 |
| US20060189551A1 (en) * | 2004-10-04 | 2006-08-24 | Duke University | Combination therapies for fungal pathogens |
| WO2006068905A2 (en) * | 2004-12-20 | 2006-06-29 | Wyeth | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
| HN2005035605A (es) * | 2004-12-20 | 2010-08-05 | Wyeth Corp | Analogos de rapamicina y los usos de los mismos en el tratamiento de trastornos neurologicos, proliferativos e inflamatorios |
| JP5767900B2 (ja) | 2011-08-24 | 2015-08-26 | 株式会社東芝 | 水中溶接装置及び方法 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4920218A (en) * | 1988-10-12 | 1990-04-24 | Merck & Co., Inc. | Novel hydroxide mediated FK-506 rearrangement process |
| DE4015255A1 (de) * | 1990-05-12 | 1991-11-14 | Hoechst Ag | Oxalyl-aminosaeurederivate, verfahren zu ihrer herstellung und ihrer verwendung als arzneimittel zur inhibierung der prolyl-hydroxylase |
| US5192773A (en) * | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| GB2247456A (en) * | 1990-09-03 | 1992-03-04 | Fujisawa Pharmaceutical Co | Tetrahydropyrane compounds, a process for their production and a pharmaceutical composition containing the same |
| KR100244372B1 (ko) * | 1991-05-09 | 2000-03-02 | 조슈아 에스.보저 | 신규한 면역 억제성 화합물 |
| US5620971A (en) * | 1991-05-09 | 1997-04-15 | Vertex Pharmaceuticals Incorporated | Biologically active acylated amino acid derivatives |
| US5250678A (en) * | 1991-05-13 | 1993-10-05 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
| AU2152092A (en) * | 1991-06-24 | 1993-01-25 | Erziehungsdirektion Of The Canton Zurich | Neurite growth regulatory factors |
| EP0660959A4 (en) * | 1992-09-07 | 1998-05-06 | Mikoh Technology Ltd | Diffraction surface data detector. |
| NZ314207A (en) * | 1992-09-28 | 2000-12-22 | Vertex Pharma | 1-(2-Oxoacetyl)-piperidine-2-carboxylic acid derivatives as multi drug resistant cancer cell sensitizers |
| JP4470226B2 (ja) * | 1994-08-18 | 2010-06-02 | アリアド・ファーマシューティカルズ・インコーポレイテッド | 新規な多量体化剤 |
| US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
-
1996
- 1996-03-29 US US08/626,259 patent/US5717092A/en not_active Expired - Lifetime
-
1997
- 1997-03-24 PT PT97916231T patent/PT891331E/pt unknown
- 1997-03-24 DE DE69725293T patent/DE69725293T2/de not_active Expired - Lifetime
- 1997-03-24 ES ES97916231T patent/ES2208890T3/es not_active Expired - Lifetime
- 1997-03-24 AU AU23465/97A patent/AU2346597A/en not_active Abandoned
- 1997-03-24 DK DK97916231T patent/DK0891331T3/da active
- 1997-03-24 AT AT97916231T patent/ATE251140T1/de not_active IP Right Cessation
- 1997-03-24 CA CA002249369A patent/CA2249369A1/en not_active Abandoned
- 1997-03-24 WO PCT/US1997/004916 patent/WO1997036869A1/en not_active Ceased
- 1997-03-24 EP EP97916231A patent/EP0891331B1/en not_active Expired - Lifetime
- 1997-03-24 JP JP53539597A patent/JP4759762B2/ja not_active Expired - Fee Related
- 1997-10-30 US US08/961,551 patent/US5935954A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| US5935954A (en) | 1999-08-10 |
| DK0891331T3 (da) | 2004-02-09 |
| JP4759762B2 (ja) | 2011-08-31 |
| DE69725293D1 (de) | 2003-11-06 |
| JP2000507578A (ja) | 2000-06-20 |
| PT891331E (pt) | 2004-02-27 |
| US5717092A (en) | 1998-02-10 |
| ES2208890T3 (es) | 2004-06-16 |
| DE69725293T2 (de) | 2004-07-15 |
| AU2346597A (en) | 1997-10-22 |
| WO1997036869A1 (en) | 1997-10-09 |
| EP0891331B1 (en) | 2003-10-01 |
| ATE251140T1 (de) | 2003-10-15 |
| EP0891331A1 (en) | 1999-01-20 |
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