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WO2006108040A1 - Indoles substitues et leur utilisation en tant qu'antagonistes de l'integrine - Google Patents

Indoles substitues et leur utilisation en tant qu'antagonistes de l'integrine Download PDF

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Publication number
WO2006108040A1
WO2006108040A1 PCT/US2006/012666 US2006012666W WO2006108040A1 WO 2006108040 A1 WO2006108040 A1 WO 2006108040A1 US 2006012666 W US2006012666 W US 2006012666W WO 2006108040 A1 WO2006108040 A1 WO 2006108040A1
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WO
WIPO (PCT)
Prior art keywords
arh
compounds
indol
alkyl
mmol
Prior art date
Application number
PCT/US2006/012666
Other languages
English (en)
Inventor
Pierre Roboisson
Juan Jose Marugan Sanchez
Original Assignee
Janssen Pharmaceutica, N.V.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica, N.V. filed Critical Janssen Pharmaceutica, N.V.
Publication of WO2006108040A1 publication Critical patent/WO2006108040A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to substituted indoles having Formula I (below). Also provided is a process for preparing compounds of Formula I.
  • the novel compounds of the present invention exhibit inhibition of ⁇ v ⁇ 3 and ⁇ v ⁇ 5 integrin receptor binding.
  • a method of treating ⁇ v ⁇ 3 integrin- and ⁇ v ⁇ 5 integrin-mediated pathological conditions such as tumor growth, metastasis, osteoporosis, restenosis, inflammation, macular degeneration, diabetic retinopathy, sickle cell anemia, CNS disorders and rheumatoid arthritis in a mammal in need of such treatment comprising administering to said mammal an effective amount of a compound of Formula I.
  • a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers or diluents.
  • R 19 and R 20 are independently hydrogen, halogen or alkyl
  • R 24 is hydrogen; and o and p are independently 0, 1 or 2; and
  • the COOH group on Formula I is shown as a carboxylic acid.
  • the structures of Formula I also include derivatives of carboxylic acids, such as a pharmaceutically acceptable ester or salt, hydrate, solvate or a functionality that acts as a prodrug (i.e., converts to the active species by an endogenous biological process such as an esterase, lipase, or other hydrolase), such as alkyl, aryl, aralkyl, dialkylaminoalkyl, 1- morpholinoalkyl, 1-piperidinylalkyl, pyridinylalkyl, alkoxy(alkoxy) alkoxyalkyl, or (alkoxycarbonyl)oxyethyl .
  • carboxylic acids such as a pharmaceutically acceptable ester or salt, hydrate, solvate or a functionality that acts as a prodrug (i.e., converts to the active species by an endogenous biological process such as an esterase, lipase, or other hydrolase
  • the present invention is considered to include stereoisomers as well as optical isomers, e.g. mixtures of enantiomers as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in selected compounds of the present series.
  • alkenyl is used herein to mean a straight or branched chain radical of 2-20 carbon atoms, unless the chain length is limited thereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, and the like.
  • the alkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms in length most preferably from 2 to 4 carbon atoms in length.
  • the compounds of the present invention are also useful in the treatment of central nervous system (CNS) related disorders.
  • CNS related disorders includes, but is not limited to: treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia, and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, and Parkinson's disease, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, as well as treating schizophrenia, anxiety, convulsions, chronic pain, psychosis, including anesthesia, and preventing opiate tolerance.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne de nouveaux composés de formule (I): où W est représenté par la formule (II) et la formule (III); X-Y représente -CH2-O-; CH2-NH- ou -CH2-CH2-; R16 représente hydrogène, alkyle, haloalkyle ou halogène; R19 et R20 représentent indépendamment hydrogène, halogène ou alkyle; R27 et R28 représentent indépendamment hydrogène, halogène, alkyle, alcoxy ou aryle; R24 représente hydrogène; R représente phényle ou pyridyle; et un ester ou sel, un hydrate ou des solvates pharmaceutiquement acceptables de ceux-ci. Ces composés peuvent être utilisés dans le traitement de pathologies médiées par les intégrines avß3 et avß5, notamment les pathologies, telles que la croissance tumorale, la métastase, la resténose, l'ostéoporose, l'inflammation, la dégénérescence maculaire, la rétinopathie diabétique et la polyarthrite rhumatoïde.
PCT/US2006/012666 2005-04-05 2006-04-05 Indoles substitues et leur utilisation en tant qu'antagonistes de l'integrine WO2006108040A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US66833305P 2005-04-05 2005-04-05
US60/668,333 2005-04-05

Publications (1)

Publication Number Publication Date
WO2006108040A1 true WO2006108040A1 (fr) 2006-10-12

Family

ID=36678642

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/012666 WO2006108040A1 (fr) 2005-04-05 2006-04-05 Indoles substitues et leur utilisation en tant qu'antagonistes de l'integrine

Country Status (1)

Country Link
WO (1) WO2006108040A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018089357A1 (fr) * 2016-11-08 2018-05-17 Bristol-Myers Squibb Company DÉRIVÉS D'INDAZOLE EN TANT QU'ANTAGONISTES DE L'INTÉGRINE αV
US10717736B2 (en) 2016-11-08 2020-07-21 Bristol-Myers Squibb Company Pyrrole amides as alpha V integrin inhibitors
US10851098B2 (en) 2016-11-08 2020-12-01 Bristol-Myers Squibb Company Azole amides and amines as alpha v integrin inhibitors
US10968219B2 (en) 2016-11-08 2021-04-06 Bristol-Myers Squibb Company 3-substituted propionic acids as αV integrin inhibitors
US11014922B2 (en) 2016-11-08 2021-05-25 Bristol-Myers Squibb Company Cyclobutane- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors
US11292802B2 (en) 2017-11-07 2022-04-05 Bristol-Myers Squibb Company Substituted tetrahydropyrrolo[1,2-a]pyrazines as alpha v integrin inhibitors
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060438A1 (fr) * 2001-01-29 2002-08-08 3-Dimensional Pharmaceuticals, Inc. Indoles substitues et utilisation de ceux-ci comme antagonistes d'integrine
US20040138284A1 (en) * 2000-02-11 2004-07-15 Matthias Wiesner Indol-3-yl derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040138284A1 (en) * 2000-02-11 2004-07-15 Matthias Wiesner Indol-3-yl derivatives
WO2002060438A1 (fr) * 2001-01-29 2002-08-08 3-Dimensional Pharmaceuticals, Inc. Indoles substitues et utilisation de ceux-ci comme antagonistes d'integrine

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11426473B2 (en) 2013-09-24 2022-08-30 Fujifilm Corporation Nitrogen-containing compound or salt thereof, or metal complex thereof
US11014922B2 (en) 2016-11-08 2021-05-25 Bristol-Myers Squibb Company Cyclobutane- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors
KR20190076033A (ko) * 2016-11-08 2019-07-01 브리스톨-마이어스 스큅 컴퍼니 αV 인테그린 길항제로서의 인다졸 유도체
JP2019536768A (ja) * 2016-11-08 2019-12-19 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ αＶインテグリンアンタゴニストとしてのインダゾール誘導体
US10717736B2 (en) 2016-11-08 2020-07-21 Bristol-Myers Squibb Company Pyrrole amides as alpha V integrin inhibitors
US10745384B2 (en) 2016-11-08 2020-08-18 Bristol-Myers Squibb Company Indazole derivatives as αv integrin antagonists
US10851098B2 (en) 2016-11-08 2020-12-01 Bristol-Myers Squibb Company Azole amides and amines as alpha v integrin inhibitors
CN110214137A (zh) * 2016-11-08 2019-09-06 百时美施贵宝公司 作为αv整联蛋白拮抗剂的吲唑衍生物
US11028071B2 (en) 2016-11-08 2021-06-08 Bristol-Myers Squibb Company Indazole derivatives as alpha v integrin antagonists
US10968219B2 (en) 2016-11-08 2021-04-06 Bristol-Myers Squibb Company 3-substituted propionic acids as αV integrin inhibitors
US11884661B2 (en) 2016-11-08 2024-01-30 Bristol-Myers Squibb Company 3-substituted propionic acids as αV integrin inhibitors
WO2018089357A1 (fr) * 2016-11-08 2018-05-17 Bristol-Myers Squibb Company DÉRIVÉS D'INDAZOLE EN TANT QU'ANTAGONISTES DE L'INTÉGRINE αV
JP7213804B2 (ja) 2016-11-08 2023-01-27 ブリストル－マイヤーズ スクイブ カンパニー αＶインテグリンアンタゴニストとしてのインダゾール誘導体
KR102506327B1 (ko) * 2016-11-08 2023-03-03 브리스톨-마이어스 스큅 컴퍼니 αV 인테그린 길항제로서의 인다졸 유도체
US11639353B2 (en) 2016-11-08 2023-05-02 Bristol-Myers Squibb Company Cyclobutanes- and azetidine-containing mono and spirocyclic compounds as αV integrin inhibitors
US11292802B2 (en) 2017-11-07 2022-04-05 Bristol-Myers Squibb Company Substituted tetrahydropyrrolo[1,2-a]pyrazines as alpha v integrin inhibitors

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