WO2008119717A1 - Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine - Google Patents

Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine Download PDF

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Publication number
WO2008119717A1
WO2008119717A1 PCT/EP2008/053596 EP2008053596W WO2008119717A1 WO 2008119717 A1 WO2008119717 A1 WO 2008119717A1 EP 2008053596 W EP2008053596 W EP 2008053596W WO 2008119717 A1 WO2008119717 A1 WO 2008119717A1
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WO
WIPO (PCT)
Prior art keywords
group
compound
disorder
compounds
formula
Prior art date
Application number
PCT/EP2008/053596
Other languages
English (en)
Inventor
David Gwyn Cooper
Ian Thomson Forbes
Vincenzo Garzya
Graham Walker
Paul Adrian Wyman
Original Assignee
Glaxo Group Limited
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 Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2008119717A1 publication Critical patent/WO2008119717A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • M 1 receptor agonists have been sought for the symptomatic treatment of cognitive decline. More recently, a number of groups have shown that muscarinic receptor agonists display an atypical antipsychotic-like profile in a range of pre-clinical paradigms.
  • the muscarinic agonist, xanomeline reverses a number of dopamine driven behaviours, including amphetamine induced locomotion in rats, apomorphine induced climbing in mice, dopamine agonist driven turning in unilateral 6-OH-DA lesioned rats and amphetamine-induced motor unrest in monkeys (without EPS liability).
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • C 1-2 alkyl means a straight or branched alkyl containing at least 1 , and at most
  • R 5 is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.
  • salts of formula (I) should be pharmaceutically acceptable.
  • Suitable salts will be apparent to those skilled in the art and include for example mono- or di- basic salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, sulfamic phosphoric, hydroiodic, phosphoric or metaphosphoric acid; and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (
  • Possible prodrugs for some compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • Each dosage unit for oral administration contains, for example, from 1 to 250 mg (and for parenteral administration contains, for example, from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
  • the example compounds below were tested in both of the above assays, and were each found to have an average pEC 50 value of > 6.0 at the muscarinic M 1 receptor, and intrinsic activity of greater than or equal to 0.3.
  • FLIPR experiments on M 2-5 receptor to determine receptor subtype selectivity To determine selectivity of compounds of the invention against other muscarinic receptor subtypes, compounds were characterized in FLIPR experiments in CHO cells with stable expression of human muscarinic receptors, M 2 , M 3 , M 4 or M 5 . In the case of M 2 and M 4 receptors, chimeric G-protein Gqi5 was also co-expressed to couple receptors to the calcium signaling pathway.

Abstract

L'invention concerne des composés représentés par la formule (I), ou un sel de ces derniers. Dans ladite formule, R4, R5, R6, Q et R1 sont tels que définis dans la description. L'invention concerne également des utilisations des composés en tant que médicaments ainsi que dans la préparation de médicaments destinés au traitement de troubles psychotiques et de troubles cognitifs. L'invention concerne en outre des compositions pharmaceutiques comprenant lesdits composés.
PCT/EP2008/053596 2007-03-29 2008-03-27 Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine WO2008119717A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0706187.2A GB0706187D0 (en) 2007-03-29 2007-03-29 Compounds
GB0706187.2 2007-03-29

Publications (1)

Publication Number Publication Date
WO2008119717A1 true WO2008119717A1 (fr) 2008-10-09

Family

ID=38050503

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/053596 WO2008119717A1 (fr) 2007-03-29 2008-03-27 Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine

Country Status (2)

Country Link
GB (1) GB0706187D0 (fr)
WO (1) WO2008119717A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
CN115745765A (zh) * 2022-11-22 2023-03-07 浙大宁波理工学院 一种对溴烷基环己酮类化合物的制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013262A1 (fr) * 1994-10-27 1996-05-09 Merck & Co., Inc. Antagonistes de muscarine
WO1997016186A1 (fr) * 1995-10-31 1997-05-09 Merck & Co., Inc. Agonistes de la muscarine
EP1221443A1 (fr) * 1999-10-13 2002-07-10 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
WO2003105781A2 (fr) * 2002-06-17 2003-12-24 Merck & Co., Inc. Compositions ophtalmiques destinees a traiter l'hypertension oculaire
WO2007107565A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107567A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107566A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996013262A1 (fr) * 1994-10-27 1996-05-09 Merck & Co., Inc. Antagonistes de muscarine
WO1997016186A1 (fr) * 1995-10-31 1997-05-09 Merck & Co., Inc. Agonistes de la muscarine
EP1221443A1 (fr) * 1999-10-13 2002-07-10 Banyu Pharmaceutical Co., Ltd. Derives d'imidazolidinone a substitution
WO2003105781A2 (fr) * 2002-06-17 2003-12-24 Merck & Co., Inc. Compositions ophtalmiques destinees a traiter l'hypertension oculaire
WO2007107565A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107567A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2007107566A1 (fr) * 2006-03-22 2007-09-27 Glaxo Group Limited Benzimidazoles présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8283364B2 (en) 2005-09-30 2012-10-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8288413B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Benzimidazolones which have activity at M1 receptor
US8481566B2 (en) 2005-09-30 2013-07-09 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
US8344000B2 (en) 2007-09-20 2013-01-01 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
CN115745765A (zh) * 2022-11-22 2023-03-07 浙大宁波理工学院 一种对溴烷基环己酮类化合物的制备方法

Also Published As

Publication number Publication date
GB0706187D0 (en) 2007-05-09

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