WO2009123623A1 - Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase - Google Patents

Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase Download PDF

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Publication number
WO2009123623A1
WO2009123623A1 PCT/US2008/059025 US2008059025W WO2009123623A1 WO 2009123623 A1 WO2009123623 A1 WO 2009123623A1 US 2008059025 W US2008059025 W US 2008059025W WO 2009123623 A1 WO2009123623 A1 WO 2009123623A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
haloalkyl
optionally substituted
cycloalkyl
amino
Prior art date
Application number
PCT/US2008/059025
Other languages
English (en)
Inventor
John O. Link
Craig J. Mossman
Jie Liu
Soon Hyung Woo
Original Assignee
Virobay, Inc.
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 Virobay, Inc. filed Critical Virobay, Inc.
Priority to EP08744863A priority Critical patent/EP2262370A4/fr
Priority to JP2011502915A priority patent/JP5497732B2/ja
Priority to CN200880128989.7A priority patent/CN102014635B/zh
Priority to BRPI0822420-0A2A priority patent/BRPI0822420A2/pt
Priority to PCT/US2008/059025 priority patent/WO2009123623A1/fr
Publication of WO2009123623A1 publication Critical patent/WO2009123623A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • R >2 i •s hydrogen, alkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cyano, or -alkylene-X-R 9 (where X is -O-, -NR 10 -, -CONR 1 '-,
  • cycloalkylene optionally substituted with one or two R b independently selected from alkyl, halo, alkylamino, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl;
  • R 6 is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or -alkylene-X 2 -R 25 (where X 2 is -NR 26 -, -O-, -S(O) 114 -, -CO-, -COO-, -OCO-, - NR 26 CO-, -CONR 26 -, -NR 26 SO 2 -, -SO 2 NR 26 -, -NR 26 COO-, -OCONR 26 -NR 26 CONR 27 -, or - NR 26 SO 2 NR 27 -, where R 26 and R 27 are independently hydrogen, alkyl, or acyl, n4 is 0-2, and R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl
  • Aryl refers to a monocyclic or fused bicyclic ring assembly containing 6 to 10 ring carbon atoms wherein each ring is aromatic, e.g., phenyl, naphthyl, and the like.
  • “Pharmaceutically acceptable salts” means salts of compounds of Formula (I) which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity.
  • Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxy-ethanesulfonic acid,
  • Suitable esters of compounds of Formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-/>-toluoyltartrates, methylsulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • the invention is directed to a compound of Formula (I) wherein:
  • R 8 is hydrogen, alkyl, alkoxyalkyl or haloalkyl
  • Y is -alkylene- or -alkylene-O-, wherein the alkylene group is optionally substituted with one to six fluoro atoms;
  • the invention is directed to a compound of Formula (I) wherein:
  • reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, N,N- dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • halogenated organic solvents e.g., methylene chloride, chloroform, and the like
  • acetonitrile e.g., N,N- dimethylformamide
  • ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • a compound of Formula (I) where R 6 is an aromatic ring substituted with halo can be reacted with approp ⁇ ate boronic acid-under-palladium catalyzed Suzuki coupling reaction conditions to provide a corresponding compound of Formula (I) where R 6 is further substituted with an aryl or heteroaryl ring.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur des composés qui sont des inhibiteurs de cystéine protéases, et, en particulier, des cathepsines B, K, L, F et S, et qui sont par conséquent utiles pour traiter des maladies ayant pour médiateur ces protéases. La présente invention porte également sur des compositions pharmaceutiques comprenant ces composés et sur des procédés pour les préparer.
PCT/US2008/059025 2008-04-01 2008-04-01 Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase WO2009123623A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP08744863A EP2262370A4 (fr) 2008-04-01 2008-04-01 Composés contenant un di-fluoro en tant qu inhibiteurs de cystéine protéase
JP2011502915A JP5497732B2 (ja) 2008-04-01 2008-04-01 システインプロテアーゼ阻害剤としてのジフルオロ含有化合物
CN200880128989.7A CN102014635B (zh) 2008-04-01 2008-04-01 作为半胱氨酸蛋白酶抑制剂的含二氟化合物
BRPI0822420-0A2A BRPI0822420A2 (pt) 2008-04-01 2008-04-01 Composto, composição farmaceutica, e, métodos para tratar uma doença em uma animal e para tratar um paciente que passa por uma tarepia.
PCT/US2008/059025 WO2009123623A1 (fr) 2008-04-01 2008-04-01 Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/059025 WO2009123623A1 (fr) 2008-04-01 2008-04-01 Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase

Publications (1)

Publication Number Publication Date
WO2009123623A1 true WO2009123623A1 (fr) 2009-10-08

Family

ID=41135860

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/059025 WO2009123623A1 (fr) 2008-04-01 2008-04-01 Composés contenant un di-fluoro en tant qu’inhibiteurs de cystéine protéase

Country Status (5)

Country Link
EP (1) EP2262370A4 (fr)
JP (1) JP5497732B2 (fr)
CN (1) CN102014635B (fr)
BR (1) BRPI0822420A2 (fr)
WO (1) WO2009123623A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014518218A (ja) * 2011-06-17 2014-07-28 ビロベイ，インコーポレイティド 中枢神経系におけるミクログリア媒介ニューロン消失を処置するためのカテプシン阻害剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050240023A1 (en) * 2002-03-05 2005-10-27 Bayly Christopher I Cathepsin cysteine protease inhibitors

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021487A1 (fr) * 2003-08-27 2005-03-10 Merck Frosst Canada Ltd. Inhibiteurs de la cathepsine
MXPA05012129A (es) * 2003-09-18 2006-02-08 Axys Pharm Inc Haloalquilo que contiene compuestos como inhibidores de la proteasa de cisteina.
CA2547591C (fr) * 2003-10-24 2010-08-17 Aventis Pharmaceuticals Inc. Nouveaux derives de ceto-oxadiazole comme inhibiteurs de la cathepsine
WO2008042968A2 (fr) * 2006-10-04 2008-04-10 Virobay, Inc. Composés contenant un di-fluoro en tant qu'inhibiteurs de cystéine-protéase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050240023A1 (en) * 2002-03-05 2005-10-27 Bayly Christopher I Cathepsin cysteine protease inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2262370A4 *

Also Published As

Publication number Publication date
CN102014635B (zh) 2015-12-16
BRPI0822420A2 (pt) 2014-10-07
CN102014635A (zh) 2011-04-13
EP2262370A1 (fr) 2010-12-22
EP2262370A4 (fr) 2011-08-31
JP5497732B2 (ja) 2014-05-21
JP2011521893A (ja) 2011-07-28

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