BRPI0911208A2 - moduladores inflamatórios antioxidantes: ácido oleanólico derivados com saturação no c-anel. - Google Patents

moduladores inflamatórios antioxidantes: ácido oleanólico derivados com saturação no c-anel.

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Publication number
BRPI0911208A2
BRPI0911208A2 BRPI0911208-1A BRPI0911208A BRPI0911208A2 BR PI0911208 A2 BRPI0911208 A2 BR PI0911208A2 BR PI0911208 A BRPI0911208 A BR PI0911208A BR PI0911208 A2 BRPI0911208 A2 BR PI0911208A2
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BR
Brazil
Prior art keywords
acid derivatives
compounds
oleanolic acid
ring saturation
inflammatory modulators
Prior art date
Application number
BRPI0911208-1A
Other languages
English (en)
Inventor
Anderson Eric
Jiang Xin
Liu Xiaofeng
Visnick Melean
Original Assignee
Reata Pharmaceuticals, Inc.
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Publication date
Application filed by Reata Pharmaceuticals, Inc. filed Critical Reata Pharmaceuticals, Inc.
Publication of BRPI0911208A2 publication Critical patent/BRPI0911208A2/pt
Publication of BRPI0911208B1 publication Critical patent/BRPI0911208B1/pt

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    • C07JSTEROIDS
    • C07J63/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008Expansion of ring D by one atom, e.g. D homo steroids
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D261/00Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
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    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
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    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/757Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24Oxygen or sulfur atoms
    • C07D207/262-Pyrrolidones
    • C07D207/2632-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/272-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07ORGANIC CHEMISTRY
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    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings

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Abstract

compostos moduladores inflamatórios antioxidantes, composição farmacêutica, bem como seu uso a presente invenção refere-se, entre outros compostos, novos derivados do ácido oleanólico com a fórmula: em que as variáveis são definidas neste documento. também são previstas composições farmacêuticas, kits e artigos manufaturados contendo esses compostos, métodos e intermediários usados para produção dos compostos, e métodos de uso desses compostos e composições.
BRPI0911208-1A 2008-04-18 2009-04-20 Compostos moduladores inflamatórios antioxidantes, seu uso, e composição farmacêutica BRPI0911208B1 (pt)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US4633208P 2008-04-18 2008-04-18
US61/046,332 2008-04-18
US11133308P 2008-11-04 2008-11-04
US61/111,333 2008-11-04
PCT/US2009/041170 WO2009129545A1 (en) 2008-04-18 2009-04-20 Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the c-ring

Publications (2)

Publication Number Publication Date
BRPI0911208A2 true BRPI0911208A2 (pt) 2019-03-26
BRPI0911208B1 BRPI0911208B1 (pt) 2021-05-25

Family

ID=41726396

Family Applications (1)

Application Number Title Priority Date Filing Date
BRPI0911208-1A BRPI0911208B1 (pt) 2008-04-18 2009-04-20 Compostos moduladores inflamatórios antioxidantes, seu uso, e composição farmacêutica

Country Status (15)

Country Link
US (6) US7915402B2 (pt)
EP (1) EP2279197B1 (pt)
JP (1) JP5529850B2 (pt)
KR (1) KR101713140B1 (pt)
CN (1) CN102164941B (pt)
AU (1) AU2009237578C1 (pt)
BR (1) BRPI0911208B1 (pt)
CO (1) CO6311106A2 (pt)
EA (1) EA022588B1 (pt)
IL (1) IL208714A (pt)
MX (1) MX2010011437A (pt)
NZ (1) NZ588709A (pt)
TW (1) TWI442925B (pt)
WO (1) WO2009129545A1 (pt)
ZA (1) ZA201007590B (pt)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6326507B1 (en) 1998-06-19 2001-12-04 Trustees Of Dartmouth College Therapeutic compounds and methods of use
KR101313702B1 (ko) 2005-02-03 2013-10-04 와이어쓰 제피티니브 및/또는 에를로티니브 내성암 치료용 약제학적 조성물
EP1942937A1 (en) 2005-11-04 2008-07-16 Wyeth Antineoplastic combinations with mtor inhibitor, herceptin, and/or hki-272
US8022216B2 (en) 2007-10-17 2011-09-20 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
BRPI0907423A2 (pt) 2008-01-11 2020-10-27 Reata Pharmaceuticals, Inc. composto triterpenoide sintético para uso em um método de melhoria da função renal em um indivíduo, e uso do referido composto
JP5529851B2 (ja) 2008-04-18 2014-06-25 リアタ ファーマシューティカルズ インコーポレイテッド 抗酸化炎症モジュレーター:c−17においてアミノ改変およびその他の改変を加えたオレアノール酸誘導体
US8071632B2 (en) 2008-04-18 2011-12-06 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
MX2010011439A (es) 2008-04-18 2011-01-25 Reata Pharmaceuticals Inc Moduladores de inflamacion antioxidantes: derivados del acido oleanolico homologacion c-17.
KR101713140B1 (ko) 2008-04-18 2017-03-08 리타 파마슈티컬스 잉크. C-환에서 포화된 산화방지성 염증 조절제 올레아놀산 유도체
WO2009146218A2 (en) 2008-04-18 2009-12-03 Reata Pharmaceuticals, Inc. Compounds including an anti-inflammatory pharmacore and methods of use
BRPI0914790A2 (pt) 2008-06-17 2015-10-20 Wyeth Llc uso de um composto de vinorelbina e um composto de hki-272, composição farmacêutica e produto e kit para o tratamento de neoplasma
EP2309860B1 (en) 2008-07-22 2014-01-08 Trustees of Dartmouth College Monocyclic cyanoenones and methods of use thereof
US8669273B2 (en) 2008-08-04 2014-03-11 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
DK3000467T3 (da) 2009-04-06 2023-03-27 Wyeth Llc Behandling med neratinib mod brystkræft
US8759535B2 (en) 2010-02-18 2014-06-24 High Point Pharmaceuticals, Llc Substituted fused imidazole derivatives, pharmaceutical compositions, and methods of use thereof
DK2536285T3 (en) 2010-02-18 2018-07-16 Vtv Therapeutics Llc Substituted fused imidazole derivatives, pharmaceutical compositions and methods for their use
DK2558105T3 (da) 2010-04-12 2020-01-27 Reata Pharmaceuticals Inc Bardoxolonmethyl til behandling af fedme
WO2012057343A1 (ja) * 2010-10-28 2012-05-03 国立大学法人九州大学 Nad(p)hオキシダーゼ阻害剤、酸化ストレス疾患治療薬、酸化ストレス疾患治療方法及びスクリーニング方法
CN103596929B (zh) 2010-12-17 2016-10-19 里亚塔医药公司 作为抗氧化发炎调节剂的吡唑及嘧啶三环烯酮
MX348862B (es) * 2011-03-11 2017-07-03 Reata Pharmaceuticals Inc Derivados c4-monometil triterpenoides y sus metodos de uso.
WO2012162260A2 (en) 2011-05-21 2012-11-29 Kdt, Llc. Transgenic biosensors
CN102499925B (zh) * 2011-10-21 2015-11-11 上海中医药大学 一种中性粒细胞弹性蛋白酶抑制剂
JP6211527B2 (ja) * 2011-12-01 2017-10-11 ハンジョウ ベンシェン ファーマシューティカル シーオー., エルティーディー.Hangzhou Bensheng Pharmaceutical Co., Ltd. 2−置換オレアノール酸誘導体、その調製方法及びその用途
CN103945852B (zh) * 2011-12-01 2016-10-19 杭州本生药业有限公司 2-位取代的齐墩果酸衍生物、及其制备方法和应用
US9828326B2 (en) * 2011-12-27 2017-11-28 Northeast Ohio Medical University Amooranin compounds and analogs thereof and related methods of use
CN102532246B (zh) * 2012-02-27 2014-06-18 浙江大学 一种齐墩果酸衍生物及其制备方法和应用
CN102631351A (zh) * 2012-03-27 2012-08-15 上海中医药大学附属曙光医院 齐墩果酸在制药中的应用
TWI623548B (zh) 2012-04-27 2018-05-11 瑞塔醫藥有限責任公司 齊墩果酸(bardoxolone methyl)之2,2-二氟基丙醯胺衍生物、多晶型及其使用方法
WO2013169740A2 (en) * 2012-05-08 2013-11-14 Trustees Of Dartmouth College Synthetic triterpenoids and methods for modulating stem/progenitor cell gene expression
US8921419B2 (en) 2012-05-08 2014-12-30 Trustees Of Dartmouth College Triterpenoids and compositions containing the same
US8981144B2 (en) 2012-05-08 2015-03-17 Trustees Of Dartmouth College Method for synthesizing 2-cyano-3,12-dioxoolean-1, 9(11)-dien-28-oic acid methyl ester and derivatives thereof
WO2013188818A1 (en) 2012-06-15 2013-12-19 Reata Pharmaceuticals, Inc. A-ring epoxidized triterpenoid-based anti-inflammation modulators and methods of use thereof
US9512094B2 (en) 2012-09-10 2016-12-06 Reata Pharmaceuticals, Inc. C17-heteroaryl derivatives of oleanolic acid and methods of use thereof
SMT201700501T1 (it) * 2012-09-10 2017-11-15 Reata Pharmaceuticals Inc Derivati c17-eteroarilici dell'acido oleanolico e metodi d'uso degli stessi
JP6243428B2 (ja) * 2012-09-10 2017-12-06 リアタ ファーマシューティカルズ インコーポレイテッド オレアノール酸のc17−アルカンジイルおよびアルケンジイル誘導体ならびにその使用方法
WO2014040073A1 (en) 2012-09-10 2014-03-13 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
JP2015527407A (ja) * 2012-09-10 2015-09-17 アッヴィ・インコーポレイテッド グリチルレチン酸誘導体およびその使用方法
AR096046A1 (es) 2013-04-24 2015-12-02 Abbvie Inc Derivados de 2,2-difluoropropanamida de metil bardoxolona, formas polimórficas y métodos de uso
EP4736949A2 (en) 2013-08-23 2026-05-06 Reata Pharmaceuticals Holdings, LLC Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
CN103897011A (zh) * 2014-04-10 2014-07-02 中国药科大学 一类cddo咪唑衍生物、其制备方法和用途
WO2016022543A1 (en) * 2014-08-07 2016-02-11 Northeast Ohio Medical University Lipoprotein lipase activator for mitigation of atherosclerosis and methods of using same
WO2016033132A1 (en) 2014-08-26 2016-03-03 Trustees Of Dartmouth College Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole
US10189791B2 (en) 2014-08-26 2019-01-29 Trustees Of Dartmouth College Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole
US20170333450A1 (en) * 2014-10-31 2017-11-23 The Regents Of The University Of California Compositions and methods for treating hiv-associated cognitive dysfunction
WO2016089648A1 (en) 2014-12-01 2016-06-09 Vtv Therapeutics Llc Bach 1 inhibitors in combination with nrf2 activators and pharmaceutical compositions thereof
EP3256451B1 (en) 2015-02-12 2021-10-20 Reata Pharmaceuticals, Inc. Imidazolyl tricyclic enones as antioxidant inflammation modulators
JP7074674B2 (ja) 2015-09-23 2022-05-24 リアタ ファーマシューティカルズ インコーポレイテッド Il-17の阻害及び他の使用のためのc4修飾オレアノール酸誘導体
CN110198718B (zh) 2016-11-08 2023-01-10 里亚塔医药控股有限责任公司 使用甲基巴多索隆或其类似物治疗阿尔波特综合征的方法
TWI831738B (zh) 2016-12-16 2024-02-11 美商瑞塔醫藥有限責任公司 用於抑制RORγ及其他用途的嘧啶三環烯酮衍生物
CA3075729A1 (en) 2017-09-14 2019-03-21 Phoenix Biotechnology, Inc. Use of oleandrin to treatn viral infection
MX2020002884A (es) 2017-09-14 2020-10-05 Phoenix Biotechnology Inc Método y composición neuroprotectora mejorada para tratar afecciones neurológicas.
US9969768B1 (en) 2017-11-16 2018-05-15 King Saud University Oleanolic acid methyl ester derivatives
US11911504B2 (en) 2018-02-02 2024-02-27 Galen Therapeutics Llc Apparatus and method for protecting neurons and reducing inflammation and scarring
US10137138B1 (en) 2018-05-29 2018-11-27 King Saud University Sulfonylurea derivatives of oleanolic acid
US11993574B2 (en) 2018-06-15 2024-05-28 Reata Pharmaceuticals, Inc Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma
US12060340B2 (en) 2018-06-20 2024-08-13 Reata Pharmaceuticals, Inc Cysteine-dependent inverse agonists of nuclear receptors ROR-gamma/ROR-gamma-t and methods of treating diseases or disorders therewith
CN109678922B (zh) * 2018-11-12 2020-07-14 广州市香雪制药股份有限公司 降三萜类化合物及其制备方法、应用
CN111631187B (zh) * 2019-03-01 2022-04-22 广西中医药大学 快速诱导肝纤维化动物模型的方法
EP3999522B1 (en) * 2019-07-19 2025-09-03 Reata Pharmaceuticals, Inc. C17 polar-substituted heteroaromatic synthetic triterpenoids and methods of use thereof
RU2708400C1 (ru) * 2019-08-07 2019-12-06 Федеральное государственное бюджетное учреждение науки Новосибирский институт органической химии им. Н.Н. Ворожцова Сибирского отделения Российской академии наук (НИОХ СО РАН) (17S)-N-БЕНЗИЛ-5-((3β-АЦЕТОКСИ-28-НОР-УРС-12-ЕН)-17-ИЛ)-1,3,4-ОКСАДИАЗОЛ-2-АМИН, ОБЛАДАЮЩИЙ СЕЛЕКТИВНОЙ ЦИТОТОКСИЧНОСТЬЮ В ОТНОШЕНИИ КЛЕТОК РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ MCF-7
CA3159778A1 (en) * 2019-12-19 2021-06-24 Reata Pharmaceuticals, Inc. Synthetic triterpenoids with nitrogen-based substituents at c-17 and methods of use thereof
CN111205346B (zh) * 2020-02-10 2022-01-28 中国药科大学 齐墩果酸的衍生物及其医药用途
KR20220151038A (ko) 2020-03-31 2022-11-11 피닉스 바이오테크놀러지 인코포레이티드. 코로나바이러스 감염 예방를 위한 조성물
EP4295854A3 (en) 2020-03-31 2024-04-03 Phoenix Biotechnology, Inc. Method and compositions for treating coronavirus infection
BR112022022599A2 (pt) 2020-05-09 2023-03-21 Reata Pharmaceuticals Holdings Llc Métodos de tratamento de covid-19 usando bardoxolona metil ou análogos da mesma
CN111777657B (zh) * 2020-07-21 2021-08-10 丽水市中医院 一种皂苷化合物及其制备方法与应用
CN114617890A (zh) * 2020-12-08 2022-06-14 四川夏派森医药科技有限公司 DH404在治疗SARS-CoV-2感染中的应用
AU2021397631A1 (en) 2020-12-11 2023-07-20 Reata Pharmaceuticals Holdings, LLC Synthetic triterpenoids for use in therapy
MX2023008454A (es) * 2021-01-18 2023-08-07 Reata Pharmaceuticals Inc Derivados sintéticos de ácido ursólico y métodos de uso de estos.
CN121794280A (zh) 2023-07-28 2026-04-03 里亚塔医药控股有限责任公司 用于制备三萜类衍生物的方法
CN119868373B (zh) * 2025-03-27 2025-06-13 四川省医学科学院·四川省人民医院 一种小分子化合物在缺血性心脏病中的应用

Family Cites Families (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5555153Y2 (pt) 1975-03-19 1980-12-20
US4395423A (en) 1978-10-10 1983-07-26 Sterling Drug Inc. Polycyclic cyanoketones
NZ191586A (en) 1978-10-10 1981-10-19 Sterling Drug Inc Cyanoketones derived from glycyrrhetinic acid and pharmaceutical compositions
US4526988A (en) 1983-03-10 1985-07-02 Eli Lilly And Company Difluoro antivirals and intermediate therefor
EP0184365B1 (en) 1984-12-04 1993-08-04 Eli Lilly And Company Improvements in the treatment of tumors in mammals
US5013649A (en) 1986-07-01 1991-05-07 Genetics Institute, Inc. DNA sequences encoding osteoinductive products
PT86377B (pt) 1986-12-24 1990-11-20 Lilly Co Eli Processo para a preparacao de conjugados de imunoglobulinas com um difluoronucleosideo acilado
EP0329348B1 (en) 1988-02-16 1995-07-12 Eli Lilly And Company 2',3'-Dideoxy-2',2'-difluoronucleosides
US5064823A (en) 1988-08-24 1991-11-12 Research Triangle Institute Pentacyclic triterpenoid compounds as topoisomerase inhibitors or cell differentiation inducers
CA2004695C (en) 1988-12-12 1999-08-10 Rosanne Bonjouklian Phospholipid nucleosides
WO1991015498A2 (en) 1990-04-04 1991-10-17 Nycomed Imaging As Nucleoside derivatives
ATE164588T1 (de) 1991-01-29 1998-04-15 Shionogi & Co Triterpenderivat
SE502569C2 (sv) 1991-05-31 1995-11-13 British Tech Group Användning av en immunologiskt inert matris av en sterol och saponiner som kan bilda sfäriska nanopartiklar med snäv storleksfördelning som läkemedelsbärare, partiklar, komposition samt kit
UA41261C2 (uk) 1992-06-22 2001-09-17 Елі Ліллі Енд Компані Спосіб одержання збагачених бета-аномером нуклеозидів
US5426183A (en) 1992-06-22 1995-06-20 Eli Lilly And Company Catalytic stereoselective glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
YU43193A (sh) 1992-06-22 1997-01-08 Eli Lilly And Company 2'-deoksi-2',2'-difluoro(4-supstituisani)pirimidinski nukleozidi antivirusnog i antikancerogenog dejstva i međuproizvodi
US5606048A (en) 1992-06-22 1997-02-25 Eli Lilly And Company Stereoselective glycosylation process for preparing 2'-Deoxy-2', 2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
US5401838A (en) 1992-06-22 1995-03-28 Eli Lilly And Company Stereoselective fusion glycosylation process for preparing 2'-deoxy-2',2'-difluoronucleosides and 2'-deoxy-2'-fluoronucleosides
DE4308042C2 (de) 1993-03-13 2000-10-12 Alstom Energy Syst Gmbh Wälzmühle
US6025395A (en) 1994-04-15 2000-02-15 Duke University Method of preventing or delaying the onset and progression of Alzheimer's disease and related disorders
US5972703A (en) 1994-08-12 1999-10-26 The Regents Of The University Of Michigan Bone precursor cells: compositions and methods
US5521294A (en) 1995-01-18 1996-05-28 Eli Lilly And Company 2,2-difluoro-3-carbamoyl ribose sulfonate compounds and process for the preparation of beta nucleosides
PT909184E (pt) 1996-07-03 2004-02-27 Upjohn Co Libertacao de farmaco para um alvo utilizando derivados de sulfonamida
CA2278056C (en) 1997-01-24 2006-12-12 Norsk Hydro Asa Gemcitabine derivatives
US20050276836A1 (en) 1997-06-11 2005-12-15 Michelle Wilson Coated vaginal devices for vaginal delivery of therapeutically effective and/or health-promoting agents
US5965119A (en) 1997-12-30 1999-10-12 Enzon, Inc. Trialkyl-lock-facilitated polymeric prodrugs of amino-containing bioactive agents
US6326507B1 (en) * 1998-06-19 2001-12-04 Trustees Of Dartmouth College Therapeutic compounds and methods of use
US6369101B1 (en) 1999-02-26 2002-04-09 Regents Of The University Of Minnesota Therapeutic method to treat herpes virus infection
US6485756B1 (en) 1999-04-06 2002-11-26 Collaborative Technologies, Inc. Stable, homogeneous natural product extracts containing polar and apolar fractions
DE60043400D1 (de) 1999-05-14 2010-01-07 Nereus Pharmaceuticals Inc Interleukin-1 und Tumornekrosefaktor-alpha Modulatoren,Synthese dieser Modulatoren und Methoden zur Anwendung dieser Modulatoren
WO2001001135A1 (en) 1999-06-25 2001-01-04 Roche Diagnostics Corporation Enzyme inhibition immunoassay
US6649654B1 (en) 1999-11-23 2003-11-18 The Regents Of The University Of California Methods for identifying and using IKK inhibitors
JP2001240573A (ja) * 2000-03-01 2001-09-04 Meiji Seika Kaisha Ltd トリテルペン誘導体及び肝疾患治療剤
CN1331319A (zh) 2000-06-30 2002-01-16 上海博德基因开发有限公司 一种新的多肽——sr蛋白特异性丝氨酸激酶212.98和编码这种多肽的多核苷酸
WO2002003996A1 (en) 2000-07-12 2002-01-17 RAJKUMAR, Sujatha Use of dammarane-type tritepenoid saporins
US6951847B2 (en) 2000-09-29 2005-10-04 Regents Of The University Of Minnesota Methods of treating fungal infections using lupeol
US6689767B2 (en) 2000-09-29 2004-02-10 Regents Of The University Of Minnesota Triterpenes having antibacterial activity
AU2001294953A1 (en) 2000-09-29 2002-04-08 Regents Of The University Of Minnesota Triterpenes having fungicidal activity against yeast
US6878751B1 (en) 2000-10-19 2005-04-12 Imperial College Of Science Technology And Medicine Administration of resveratrol to treat inflammatory respiratory disorders
WO2002047611A2 (en) 2000-11-28 2002-06-20 Board Of Regents, The University Of Texas System Cddo-compounds and combination therapies thereof
US7435755B2 (en) 2000-11-28 2008-10-14 The Trustees Of Dartmouth College CDDO-compounds and combination therapies thereof
AU2002308701A1 (en) 2001-05-14 2002-11-25 University Of Maryland, Baltimore Novel alanine transaminase enzyme and methods of use
EP1492523A2 (en) 2001-11-23 2005-01-05 Chugai Seiyaku Kabushiki Kaisha Method for identification of tumor targeting enzymes
US7176237B2 (en) 2002-01-15 2007-02-13 The Trustees Of Dartmouth College Tricyclic-bis-enone derivatives and methods of use thereof
CA2473799A1 (en) 2002-01-18 2003-07-31 Regents Of The University Of Minnesota Triterpene quaternary salts as biologically active surfactants
JP2006515859A (ja) * 2002-05-13 2006-06-08 トラスティーズ オブ ダートマス カレッジ 阻害剤およびその使用法
WO2004041203A2 (en) 2002-11-04 2004-05-21 Xenoport, Inc. Gemcitabine prodrugs, pharmaceutical compositions and uses thereof
WO2004089357A2 (en) 2003-04-02 2004-10-21 Regents Of The University Of Minnesota Anti-fungal formulation of triterpene and essential oil
US20050208151A1 (en) 2003-10-30 2005-09-22 Entelos, Inc. Treatment of rheumatoid arthritis with FLIP antagonists
US8288439B2 (en) 2003-11-04 2012-10-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Methods and compositions for the inhibition of HIV-1 replication
US20060258752A1 (en) 2004-02-12 2006-11-16 Vander Jagt David L Method and compounds for cancer treatment utilizing NFkB as a direct or ultimate target for small molecule inhibitors
JP2005314381A (ja) 2004-03-30 2005-11-10 Anges Mg Inc 増殖性腎疾患の予防・治療・改善剤
JP5087400B2 (ja) 2004-09-07 2012-12-05 パシフィック アロー リミテッド アンゲロイル基を有する抗腫瘍化合物
JP2006175836A (ja) 2004-12-24 2006-07-06 Fuji Photo Film Co Ltd 感熱記録材料
JP2006347952A (ja) * 2005-06-16 2006-12-28 Yoshihiro Futamura リパーゼ活性化作用を呈するアントラキノン誘導体、それからなる抗肥満薬、食品製剤及び化粧品
AU2006265113A1 (en) 2005-07-01 2007-01-11 The Johns Hopkins University Compositions and methods for the treatment or prevention of disorders relating to oxidative stress
DE102005041613A1 (de) 2005-09-01 2007-03-08 Ergonex Pharma Gmbh Pharmazeutische Zusammensetzungen zur Behandlung von Karzinoid-Syndrom
DE102005041616B4 (de) 2005-09-01 2011-03-17 Johannes-Gutenberg-Universität Mainz Melanom-assoziierte MHC Klasse I assoziierte Oligopeptide und für diese kodierende Polynukleotide und deren Verwendungen
NZ569078A (en) 2005-12-12 2012-01-12 Mosamedix Bv Annexin derivatives suitable for pretargeting in therapy and diagnosis
US20070232577A1 (en) 2006-03-23 2007-10-04 Advanced Life Sciences, Inc. Synthetic pentacyclic triterpenoids and derivatives of betulinic acid and betulin
US20070249561A1 (en) 2006-04-25 2007-10-25 Taylor Bradley K Pharmacological method for treatment of neuropathic pain
WO2008000068A1 (en) 2006-06-27 2008-01-03 Wellington Laboratories Inc. Method for preparing 2-iodo triterpenoid compounds
JP2008016095A (ja) 2006-07-04 2008-01-24 Sharp Corp 通信システム、復号再生装置、記録装置、通信プログラム及び記録媒体
CN101117348B (zh) * 2006-08-01 2010-12-29 浙江海正药业股份有限公司 A环和c环多氧化取代的五环三萜及其制备方法和用途
JP2008110962A (ja) 2006-08-02 2008-05-15 Santen Pharmaceut Co Ltd Nrf2活性化物質を有効成分として含む角結膜障害の予防または治療剤
WO2008016095A1 (en) 2006-08-02 2008-02-07 Santen Pharmaceutical Co., Ltd. PREVENTIVE OR REMEDY FOR KERATOCONJUNCTIVAL DISORDERS CONTAINING Nrf2 ACTIVATOR AS THE ACTIVE INGREDIENT
EP2094651A1 (en) 2006-11-17 2009-09-02 Trustees Of Dartmouth College Synthesis and biological activities of new tricyclic-bis-enones (tbes)
US8299046B2 (en) 2006-11-17 2012-10-30 Trustees Of Dartmouth College Synthetic triterpenoids and tricyclic-bis-enones for use in stimulating bone and cartilage growth
EP2680010A1 (en) 2007-02-08 2014-01-01 Biogen Idec MA Inc. Nrf2 screening assays and related methods and compositions
WO2008111497A1 (ja) 2007-03-08 2008-09-18 Santen Pharmaceutical Co., Ltd. トリテルペノイドを有効成分として含有する酸化ストレスが関連する眼疾患の予防又は治療剤
WO2008136838A1 (en) 2007-05-04 2008-11-13 Trustees Of Dartmouth College Novel amide derivatives of cddo and methods of use thereof
US8088824B2 (en) 2007-08-15 2012-01-03 Reata Pharmaceuticals Inc. Forms of CDDO methyl ester
WO2009023845A2 (en) 2007-08-15 2009-02-19 The Board Of Regents Of The University Of Texas System Combination therapy with synthetic triterpenoids and gemcitabine
WO2009058849A1 (en) 2007-10-29 2009-05-07 University Of Rochester Use of electrophilic compounds for inducing platelet production or maintaining platelet function
BRPI0907423A2 (pt) 2008-01-11 2020-10-27 Reata Pharmaceuticals, Inc. composto triterpenoide sintético para uso em um método de melhoria da função renal em um indivíduo, e uso do referido composto
US8071632B2 (en) 2008-04-18 2011-12-06 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: novel derivatives of oleanolic acid
MX2010011439A (es) 2008-04-18 2011-01-25 Reata Pharmaceuticals Inc Moduladores de inflamacion antioxidantes: derivados del acido oleanolico homologacion c-17.
KR101713140B1 (ko) 2008-04-18 2017-03-08 리타 파마슈티컬스 잉크. C-환에서 포화된 산화방지성 염증 조절제 올레아놀산 유도체
WO2009146218A2 (en) 2008-04-18 2009-12-03 Reata Pharmaceuticals, Inc. Compounds including an anti-inflammatory pharmacore and methods of use
JP5529851B2 (ja) 2008-04-18 2014-06-25 リアタ ファーマシューティカルズ インコーポレイテッド 抗酸化炎症モジュレーター:c−17においてアミノ改変およびその他の改変を加えたオレアノール酸誘導体
EP2309860B1 (en) 2008-07-22 2014-01-08 Trustees of Dartmouth College Monocyclic cyanoenones and methods of use thereof
WO2010053817A1 (en) 2008-11-04 2010-05-14 Trustees Of Dartmouth College Betulinic acid derivatives and methods of use thereof
SI2395979T1 (sl) 2009-02-13 2017-12-29 Reata Pharmaceuticals, Inc. Peroralni farmacevtski sestavki, ki vsebujejo amorfni CDDO-Me, z zapoznelim sproščanjem
DK2558105T3 (da) 2010-04-12 2020-01-27 Reata Pharmaceuticals Inc Bardoxolonmethyl til behandling af fedme
WO2011140078A1 (en) 2010-05-04 2011-11-10 Concert Pharmaceuticals, Inc. Synthetic triterpenoid derivatives
CN102070697A (zh) 2010-12-09 2011-05-25 中国药科大学 一种齐墩果酸衍生物、其制备方法及用途
US8846647B2 (en) 2011-01-31 2014-09-30 Bristol-Myers Squibb Company C-17 and C-3 modified triterpenoids with HIV maturation inhibitory activity
MX348862B (es) 2011-03-11 2017-07-03 Reata Pharmaceuticals Inc Derivados c4-monometil triterpenoides y sus metodos de uso.

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