WO2005019182A1 - Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt - Google Patents

Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt Download PDF

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Publication number
WO2005019182A1
WO2005019182A1 PCT/EP2004/009172 EP2004009172W WO2005019182A1 WO 2005019182 A1 WO2005019182 A1 WO 2005019182A1 EP 2004009172 W EP2004009172 W EP 2004009172W WO 2005019182 A1 WO2005019182 A1 WO 2005019182A1
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WO
WIPO (PCT)
Prior art keywords
optionally substituted
halogen
mono
tri
amino
Prior art date
Application number
PCT/EP2004/009172
Other languages
English (en)
Inventor
Arnel Concepcion
Tadashi Inoue
Yuki Mochizuki
Aiko Muramatsu
Florian Gantner
Kosuke Nakashima
Klaus Urbahns
Kevin B. Bacon
Original Assignee
Bayer Healthcare Ag
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 Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Publication of WO2005019182A1 publication Critical patent/WO2005019182A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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

Definitions

  • Purinergic receptors are cell surface ATP receptors which can be divided into two major families, the metabotropic receptor family (the P2Y/P2U receptor family) and the ionotropic receptor family (the P2X receptor family). Whereas metabotropic receptor family members are G-protein coupled receptors, ionotropic receptor family members are ligand-gated channels mediating fast permeability changes to mono- and divalent cations (Na + , K + , Ca 2+ ).
  • P2X7 receptor antagonists can therefore be useful for the treatment of a wide variety of diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
  • diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative
  • the alkenyl per se represent a linear or branched alkenyl radical having generally 2 to 6, preferably 2 to 4 and particularly preferably 3 to 4 carbon atoms, representing illustratively ethenyl, propenyl, and butenyl.
  • the compounds of the present invention surprisingly show excellent P2X7 receptor antagonistic activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat diseases related to P2X7 receptor activity. More specifically, since the pyrazolylmethylbenzamide derivatives of the present invention inhibit P2X7 receptor activity, they are useful for treatment and prophylaxis of diseases as follows:
  • R 1 represents phenyl optionally substituted at a substitutable position with one or two substituents selected from the group consisting of halogen, amino, nitro, hydroxy, carbamoyl, C ⁇ . 6 alkylamino, di(C ⁇ -6 )alkylamino, N-(C ⁇ . 6 alkanoyl)amino, C ]-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and C 1-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, pyridiyl or quinolinyl optionally having one or two substituents selected from the group consisting of halogen, amino, carbamoyl, C ⁇ .
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0 ⁇ C to 200°C and preferably about 20°C to 100°C.
  • the reaction may be conducted for, usually, 10 minutes to 48 hours and preferably 30minutes to 24 hours.
  • the compound of formula (X) (wherein R 2 and R 3 are the same as defined above and Y is protecting group such as C ⁇ -6 alkyl, benzyl , 4-methoxybenzyl and 3,4-dimethoxybenzyl) can be prepared by the reaction of the compound of formula (V) (wherein R 2 and R 3 are the same as defined above) with the compound of formula (DC) (wherein L is a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, or C 6 . ⁇ o arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and C alkylsulfonyloxy group such as trifluoro- methanesulfonyloxy and methanesulfonyloxy and Y is the same as defined above).
  • DC wherein L is a leaving group including, for instance, halogen
  • the reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • a suitable organic solvent for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
  • Examplel-1 Melting point: ⁇ 70 °C Molecular weight: 441.53 Mass spectrometry: 442 (M + H) + In vitro activity class: A In a similar method according to the Examplel-1 above, the compounds in Example 1-2 to 1-21 were synthesized.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à de nouveaux dérivés de pyrazolylméthylbenzamide représentés par la formule (I), à des procédés pour préparer ces dérivés et à des préparations pharmaceutiques contenant ces dérivés. Ces dérivés de pyrazolylméthylbenzamide possèdent un pouvoir antagoniste accru contre le récepteur P2X7 et ils peuvent être utilisés dans la prophylaxie et le traitement des maladies associées à l'activité du récepteur P2X7. Ces dérivés de pyrazolylméthylbenzamide sont plus spécifiquement utiles dans le traitement et la prophylaxie des maladies suivantes: polyarthrite rhumatoïde, ostéo-arthrite, psoriasis, dermatite allergique, asthme, maladie respiratoire obstructive chronique (COPD), hypersensibilité des voies respiratoires, chocs sceptiques, glomérulonéphrite, colon irritable, maladie de Crohn, colite ulcéreuse, athérosclérose, croissance et métastases de cellules malignes, leucémie des myoblastes, diabète, maladie d'Alzheimer, méningite, ostéoporose, lésion du type brûlure, maladie cardiaque ischémique, ictus et veines variqueuses.
PCT/EP2004/009172 2003-08-20 2004-08-16 Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt WO2005019182A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP03018629 2003-08-20
EP03018629.0 2003-08-20

Publications (1)

Publication Number Publication Date
WO2005019182A1 true WO2005019182A1 (fr) 2005-03-03

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/009172 WO2005019182A1 (fr) 2003-08-20 2004-08-16 Derives de pyrazolylmethylbenzamide utilises comme antagonistes du recepteur p2xt

Country Status (1)

Country Link
WO (1) WO2005019182A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056091A2 (fr) * 2005-11-09 2007-05-18 Abbott Laboratories Antagonistes des recepteurs p2x7 et utilisations associees
WO2007141267A1 (fr) * 2006-06-06 2007-12-13 Glaxo Group Limited Dérivés de n- (phénylméthyl) -2- (1h-pyraz0l-4-yl) acétamide utilisés comme antagonistes fp2x7 pour le traitement de la douleur, de l'inflammation et de la neurodégénérescence
WO2008011611A3 (fr) * 2006-07-21 2008-05-02 Irm Llc Composés et compositions utilisés en tant qu'inhibiteurs de l'itpkb
WO2008125600A2 (fr) * 2007-04-11 2008-10-23 Glaxo Group Limited Dérivés de pyrazole utilisés comme modulateurs de p2x7
WO2008138876A1 (fr) * 2007-05-10 2008-11-20 Glaxo Group Limited Dérivés du pyrazole utilisés comme modulateurs de p2x7
EP2105164A1 (fr) 2008-03-25 2009-09-30 Affectis Pharmaceuticals AG Nouveaux antagonistes P2X7R et leur utilisation
WO2010118921A1 (fr) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
US20110190572A1 (en) * 2009-12-08 2011-08-04 Vanderbilt University Methods and Compositions for Vein Harvest and Autografting
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
EP2386541A1 (fr) 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Nouveaux procédés de préparation d'antagonistes de P2X7R
US8178526B2 (en) 2007-06-15 2012-05-15 Irm Llc Compounds and compositions as ITPKb inhibitors
WO2012110190A1 (fr) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Nouveaux antagonistes p2x7r et leur utilisation
WO2012114268A1 (fr) 2011-02-22 2012-08-30 Actelion Pharmaceuticals Ltd Dérivés de benzamide en tant qu'antagonistes du récepteur p2x7
WO2012163456A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2012163792A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2013155422A1 (fr) * 2012-04-12 2013-10-17 Ironwood Pharmaceuticals, Inc. Procédés permettant de traiter l'alopécie et l'acné
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003042191A1 (fr) * 2001-11-12 2003-05-22 Pfizer Products Inc. Benzamide et heteroarylamide utilises comme antagonistes du recepteur p2x7

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003042191A1 (fr) * 2001-11-12 2003-05-22 Pfizer Products Inc. Benzamide et heteroarylamide utilises comme antagonistes du recepteur p2x7

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007056091A3 (fr) * 2005-11-09 2007-07-12 Abbott Lab Antagonistes des recepteurs p2x7 et utilisations associees
WO2007056091A2 (fr) * 2005-11-09 2007-05-18 Abbott Laboratories Antagonistes des recepteurs p2x7 et utilisations associees
WO2007141267A1 (fr) * 2006-06-06 2007-12-13 Glaxo Group Limited Dérivés de n- (phénylméthyl) -2- (1h-pyraz0l-4-yl) acétamide utilisés comme antagonistes fp2x7 pour le traitement de la douleur, de l'inflammation et de la neurodégénérescence
WO2008011611A3 (fr) * 2006-07-21 2008-05-02 Irm Llc Composés et compositions utilisés en tant qu'inhibiteurs de l'itpkb
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
WO2008125600A2 (fr) * 2007-04-11 2008-10-23 Glaxo Group Limited Dérivés de pyrazole utilisés comme modulateurs de p2x7
WO2008125600A3 (fr) * 2007-04-11 2009-01-22 Glaxo Group Ltd Dérivés de pyrazole utilisés comme modulateurs de p2x7
WO2008138876A1 (fr) * 2007-05-10 2008-11-20 Glaxo Group Limited Dérivés du pyrazole utilisés comme modulateurs de p2x7
US8178526B2 (en) 2007-06-15 2012-05-15 Irm Llc Compounds and compositions as ITPKb inhibitors
EP2105164A1 (fr) 2008-03-25 2009-09-30 Affectis Pharmaceuticals AG Nouveaux antagonistes P2X7R et leur utilisation
WO2010118921A1 (fr) 2009-04-14 2010-10-21 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
JP2013512968A (ja) * 2009-12-08 2013-04-18 バンダービルト ユニバーシティ 静脈摘出および自家移植のための改善された方法および組成物
US8691556B2 (en) * 2009-12-08 2014-04-08 Vanderbilt University Methods and compositions for vein harvest and autografting
US10531654B2 (en) 2009-12-08 2020-01-14 Vanderbilt University Methods and compositions for vein harvest and autografting
US10149470B2 (en) 2009-12-08 2018-12-11 Vanderbilt University Methods and compositions for vein harvest and autografting
JP2016094386A (ja) * 2009-12-08 2016-05-26 バンダービルト ユニバーシティ 静脈摘出および自家移植のための改善された方法および組成物
US20110190572A1 (en) * 2009-12-08 2011-08-04 Vanderbilt University Methods and Compositions for Vein Harvest and Autografting
WO2011109833A2 (fr) 2010-03-05 2011-09-09 President And Fellows Of Harvard College Compositions de cellules dendritiques induites et utilisations associées
WO2011141194A1 (fr) 2010-05-14 2011-11-17 Affectis Pharmaceuticals Ag Nouveaux procédés de préparation d'antagonistes du p2x7r
EP2386541A1 (fr) 2010-05-14 2011-11-16 Affectis Pharmaceuticals AG Nouveaux procédés de préparation d'antagonistes de P2X7R
WO2012110190A1 (fr) 2011-02-17 2012-08-23 Affectis Pharmaceuticals Ag Nouveaux antagonistes p2x7r et leur utilisation
WO2012114268A1 (fr) 2011-02-22 2012-08-30 Actelion Pharmaceuticals Ltd Dérivés de benzamide en tant qu'antagonistes du récepteur p2x7
WO2012163792A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2012163456A1 (fr) 2011-05-27 2012-12-06 Affectis Pharmaceuticals Ag Nouveaux antagonistes de p2x7r et leur utilisation
WO2013155422A1 (fr) * 2012-04-12 2013-10-17 Ironwood Pharmaceuticals, Inc. Procédés permettant de traiter l'alopécie et l'acné

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