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WO1997016186A1 - Agonistes de la muscarine - Google Patents

Agonistes de la muscarine Download PDF

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Publication number
WO1997016186A1
WO1997016186A1 PCT/US1996/017213 US9617213W WO9716186A1 WO 1997016186 A1 WO1997016186 A1 WO 1997016186A1 US 9617213 W US9617213 W US 9617213W WO 9716186 A1 WO9716186 A1 WO 9716186A1
Authority
WO
WIPO (PCT)
Prior art keywords
ocular
receptors
effective
treatment
compound
Prior art date
Application number
PCT/US1996/017213
Other languages
English (en)
Inventor
Wayne J. Thompson
Richard W. Ransom
Pierre Mallorga
Ian M. Bell
Michael F. Sugrue
Peter M. Munson
Original Assignee
Merck & Co., 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
Priority claimed from GBGB9603849.2A external-priority patent/GB9603849D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU74783/96A priority Critical patent/AU7478396A/en
Publication of WO1997016186A1 publication Critical patent/WO1997016186A1/fr

Links

Classifications

    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • Glaucoma is an ocular disorder associated with elavated intraocular pressures which are too high for normal function and may result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest phase of glaucoma.
  • ⁇ -adrenergic blocking agents are effective in reducing intraocular pressure. While many of these agents are effective in reducing intraocular pressure, they also have other characteristics, e.g. membrane stabilizing activity, that are not acceptable for chronic ocular use.
  • Other agents which are used for treatment of glaucoma include carbonic anhydrase inhibitors and prostaglandins. Carbonic anydrase inhibitors work by blockade of inflow into the eye. Prostaglandins exert a reduction of scleral outflow. To date, only muscarinic agents work by directly increasing outflow. Since glaucoma is considered to be a result of decreased outflow from the eye, this approach provides greater therapeutic benefit by the nature of more direct action.
  • Cholinergic receptors are proteins embedded in the wall of a cell that respond to the chemical acetylcholine. Particularly, it is now known that the cholinergic receptors are subdivided into nicotinic and muscarinic receptors and that the muscarinic receptors are not all of the same type. Recent literature indicates that there are at least five types of cholinergic muscarinic receptors (types m 1 through m5). Receptors of type ml are those present in abundance and thought to be enriched in the brain neural tissue and neural ganglia. The other receptors are concentrated in other tissues such as the heart, smooth muscle tissue or glands.
  • pilocarpine Topical administration of muscarinic agonist, pilocarpine, lowers intraocular pressure by increasing outflow.
  • pilocarpine is a non-selective agonist, interacting with muscarinic receptors of several types.
  • the side effects associated with pilocarpine are miosis (decrease of pupil size) and systemic CNS effects which limit usefulness.
  • This invention is concerned with novel l-[cycloalkyl- pioeridin-4-yl]-2H benzimidazolones, their compositions and method of use.
  • the novel compounds are selective muscarinic agonists of the m2 subtype with low activity at the m3 subtype.
  • the compounds have good ocular penetration (bioavailability) when dosed at 0.1 % to 15% by weight of medicament, especially about 0.5 to 2% by weight of medicament and are effective for the treatment and/or prevention of glaucoma with fewer side effects than the pilocarpine therapy, due to lower activity at the m3 subclass of muscarinic receptors.
  • novel compounds of this invention are represented by the structural formula I:
  • Rl - R4 are independently H, alkyl, halo, alkoxy, OH, HOCH2-, aryl, 3-pyridyl, 5 -pyrimidinyl, amino, dialkylamino, alkene, thioalkyl, or alkylamino;
  • X is C or N
  • E is H, alkyl, alkylamino, dialkylamino, aryl, heteroaryl, heterocycle, alkoxy, alkoxyaryl, carbonyl heterocycle, alkoxyheteroaryl, alkoxyheterocycle, or does not exist; and Y is H, alkyl, halo, alkylamino, alkoxyamino, alkoxy, dialkylamino, or amino.
  • heterocycle or heterocyclic represents a stable 5- to 7- membered monocyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and including any bicyclic group in which any of the above defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic rings examples include pyridine, pyrazine, pyrimidine, pyridazine, triazine, imidazole, pyrazole, triazole, quinoline, isoquinoline, quinazoline, quinoxaline, phthalazine, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, oxadiazole, pyrrole, furan, thiophene, hydrogenated derivatives of these heterocyles such as piperidine, pyrrolidine, azetidine, tetrahydrofuran, and N-oxide derivatives of heterocyles containing basic nitrogen.
  • heterocyclic rings Any fused combinations of any of these above-defined heterocyclic rings is also a part of this definition. Attached to the heterocyclic ring can be substituents such as alkyls, amines, or halogens (F, Cl, Br, I).
  • alkyl is intended to include branched, cyclic and straight chain saturated aliphatic hydrocarbon groups having 1 to 15 carbon atoms, unless otherwise defined.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like.
  • Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
  • alkoxy represents an alkyl group of indicated carbon atoms attached through an oxygen linkage.
  • alkylamino represents an alkyl group of indicated carbon atoms attached through a nitrogen atom linkage.
  • dialkylamino represents two alkyl groups of indicated carbon r ms attached through a nitrogen atom linkage.
  • small alkyl is intended to indicate those alkyls with Cl to C6 carbon atoms, either branched or linear in connection.
  • halo represents fluoro, chloro, bromo or iodo.
  • aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like groups as well as rings which are fused e.g., naphthyl and the like.
  • Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
  • the preferred aryl groups are phenyl and naphthyl.
  • Aryl groups may likewise be substituted with 1 -3 groups such as alkyl, halo, carboxyalkyl, alkylamino, dialkylamino, alkoxy, alkoxyamino and the like.
  • heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, an in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
  • the heteroaryl group is optionally substituted with up to three groups. Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are pyrrol, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, e.g., thiadizaole.
  • R l -R4 are independently H, alkyl, or halo
  • E is H, alkyl, aryl, heteroaryl, heterocycle, alkylamino, or dialkylamino; and Y is H, alkyl, or halo.
  • the pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of formula I formed e.g. from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • Non-limiting examples of the novel compounds of this invention are as follows:
  • novel compounds of this invention are prepared by the following non-limiting procedures:
  • the reaction is carried out at room temperature (20-30°C) at a pH in the range of 2-7 (acidic) by the addition of glacial acetic acid or hydrochloric acid.
  • a suitably mono protected 1 ,4-cyclohexandione such as 1 ,4- cyclohexanedione mono-ethyleneketal can be used as an intermediate.
  • a suitably protected 4-piperidone such as A-E is C ⁇ 2Et, C ⁇ 2CH2Ph, or C ⁇ 2C(CH3)3 can be used as an intermediate.
  • Deprotection by known methods hydroogenation or acidic hydrolysis followed by basification
  • the selectivity of the compounds can be measured by radioligand displacement from ml-m5 receptors expressed in Chinese hamster ovary cells (CHO) as described in the Examples section.
  • the functional activity of the compounds can be assessed by measuring the agonist induced contractile response on muscle tissue from rabbit vas deferens (Ml), the guinea pig left atria (M2), or the guinea pig ileum (M3) as described in the Examples section.
  • the functional activity at the human muscarinic receptors can be assessed by measuring agonist induced phosphoinositide hydrolysis in CHO cells expressing the human ml and m3 receptors or agonist inhibition of foskolin-stimulated adenylate cyclase activity in CHO cells expressing the human m2 receptor as described in the Examples section.
  • the instant compounds of this invention are useful in treating and/or preventing the development of glaucoma.
  • Therapy to increase outflow can be administered by the use of the agent in eye drops. Indeed, in the vast majority of cases, treatment agents are administered to human eyes by the application of eye drops. Eye drops typically contain about 0.1 % to 15% by weight of medicament, especially about 0.5 to 2% by weight of medicament, the remainder being comprised of carriers and other excipients well known in the art. A pH of about 4.5 to about 7.5 is expected to be acceptable as an ophthalmic drop and practical in terms of known solubility and stability of piperidines. Phosphate buffering is also common for eye drops and is compatible with the instant muscarinic agonist. A common regimen for application of eye drops is one to four times a day spaced evenly throughout waking hours. More effective agents may require fewer applications or enable the use of more dilute solutions.
  • novel pharmaceutical formulations of this invention are also adapted for oral administration such as tablets, capsules and the like; for nasal administration, especially in the form of a spray; for injection, in the form of a sterile injectable liquid; or for topical ocular administration in the form of solutions, ointments, solid water soluble polymeric inserts, or gels.
  • Step 1 A mixture of 5 g of 1 ,4-cyclohexanedione mono-ethyleneketal, 4.3 g of l ,3-dihydro-l -(4-piperidinyl)-benzimidazol-2H-one, 75 mL of 1,2-dichloroethane, 1.2 mL of acetic acid and 5.45 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2C03 and the layers separated. The aqueous layer was extracted with 2 X 250 mL of chloroform and the combined organic layers dried over MgS ⁇ 4 and concentrated under reduced pressure.
  • Step 2 A mixture of 7.0 g of the ethylene ketal of l ,3-dihydro-l - ⁇ l-[4- oxocyclohex-l-yl]piperidin-4-yl ⁇ -2H-benzimidazol-2-one, 80 mL of glacial acetic acid, 80 mL of water and 20 mL of cone. HCl was heated under reflux for 2 h, then allowed to cool overnight. The mixture was concentrated under reduced pressure, diluted with 100 mL of saturated Na2C ⁇ 3 and extracted into 3 X 200 mL of CHCI3. The combined organic extracts were dried over MgS ⁇ 4 and concentrated under reduced pressure.
  • CHO cells When 80-100% confluent, CHO cells were harvested, and transferred to centrifuge tubes containing CHO buffer (20 mM HEPES at pH 7.4 containing 5mM MgCt ⁇ ). The cells were homogenized using a Brinkman Polytron homogenizer for 30 seconds at a setting of 5, on ice. The homogenate was centrifuged at 40,000 x g for 15 minutes at 4°C in a Beckman J2-21M centrifuge. The supernatant was discarded and the homogenization/centrifugation step repeated once.
  • Pelleted membranes were resuspended in CHO buffer to a concentration of one flask harvested (75 cm 2 ) per mL of buffer, mixed well and aliquoted in cryovials (lmL/vial). The vials were stored at -70°C until used in the assay.
  • the binding incubation was done in polypropylene macrowell tube strips in a final volume of 0.5 mL of HEPES buffer (20 mM; pH 7.4 containing 5 mM MgCt ⁇ ) containing 0.1 mL of cell membrane suspension, 3H-N-methylscopolamine (NEN Co ⁇ oration, NET-636, 70-87 /mmole) at a final concentration of approximately 0.2 nM and the competing drug in a varying range of concentrations or vehicle. After the addition of the cell homogenate the tubes were agitated on a vortex mixer and then placed in a water bath at 32°C.
  • Each atria is attached to platinum electrodes with 4-0 surgical silk and placed in a 10 mL jacketed tissue bath containing Krebs buffer at 37°C, bubbled with 5% CO2 / 95% O2.
  • the tissues are connected to a Statham-Gould force transducer; 0.75 gram of tension is applied and the tissues are electrically stimulated. [EFS parameters are 3 Hz; 4 ms duration; voltage is set to 5 V.]
  • the contractions are recorded on a Gould strip chart recorder.
  • the tissues are washed every 20 minutes and allowed to equilibrate.
  • a concentration response curve to the agonist is determined.
  • Tissues are washed every 20 minutes for 60 minutes.
  • the vehicle or compound is added to the bath and the tissues are incubated for 30 minutes.
  • Agonist EC50 values are determined for both vehicle and compound treated tissues before and after treatment. The compounds displayed EC50 values at M2 in the range of 5 to 100 nM.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention porte sur de nouveaux 1-[cycloalkylpioéridine-4-yl]-2H benzimidazolones, sur leurs compositions et leur mode d'utilisation. Ces nouveaux composés sont des agonistes muscariniques sélectifs du sous-type m2 et à faible action sur le sous-type m3. Ces composés se révèlent efficaces pour le traitement du glaucome avec moins d'effets secondaires qu'il n'en advient avec une thérapie avec de la pilocarpine.
PCT/US1996/017213 1995-10-31 1996-10-28 Agonistes de la muscarine WO1997016186A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74783/96A AU7478396A (en) 1995-10-31 1996-10-28 Muscarine agonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US709995P 1995-10-31 1995-10-31
US60/007,099 1995-10-31
GBGB9603849.2A GB9603849D0 (en) 1996-02-23 1996-02-23 Muscarine agonists
GB9603849.2 1996-02-23

Publications (1)

Publication Number Publication Date
WO1997016186A1 true WO1997016186A1 (fr) 1997-05-09

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WO (1) WO1997016186A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032481A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements
WO1999032479A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Derives de phtalamidepiperidine, de phtalamidepyrrolidine, et de phtalamide-azepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques
WO1999032445A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Derives d'oximinopiperidine, d'oximinopyrrolidine, et d'oximinoazepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques
WO1999036421A1 (fr) * 1998-01-19 1999-07-22 Pfizer Pharmaceuticals Inc. Composes de 4-(2-ceto-1-benzimidazolinyl)piperidine, utiles comme agonistes du recepteur orl1
WO2003105781A2 (fr) 2002-06-17 2003-12-24 Merck & Co., Inc. Compositions ophtalmiques destinees a traiter l'hypertension oculaire
US6951849B2 (en) 2001-10-02 2005-10-04 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7087593B2 (en) 2001-10-02 2006-08-08 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
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
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
WO2008119721A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés présentant une activité sur le récepteur m1 et utilisations de ceux-ci en médecine
WO2008119717A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2008119718A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2009037294A1 (fr) * 2007-09-20 2009-03-26 Glaxo Group Limited Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2009037296A1 (fr) * 2007-09-20 2009-03-26 Glaxo Group Limited Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2009124883A1 (fr) * 2008-04-09 2009-10-15 H. Lundbeck A/S Nouveaux 1,3-dihydro-benzoimidazol-2-ones utilisés en tant qu’agonistes m1
US8283364B2 (en) 2005-09-30 2012-10-09 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
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831043A (en) * 1987-02-13 1989-05-16 Roussel Uclaf Dopaminergic benzimidazol-2-ones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4831043A (en) * 1987-02-13 1989-05-16 Roussel Uclaf Dopaminergic benzimidazol-2-ones

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032479A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Derives de phtalamidepiperidine, de phtalamidepyrrolidine, et de phtalamide-azepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques
WO1999032445A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Derives d'oximinopiperidine, d'oximinopyrrolidine, et d'oximinoazepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques
WO1999032481A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements
WO1999036421A1 (fr) * 1998-01-19 1999-07-22 Pfizer Pharmaceuticals Inc. Composes de 4-(2-ceto-1-benzimidazolinyl)piperidine, utiles comme agonistes du recepteur orl1
US6423725B1 (en) 1998-01-19 2002-07-23 Pfizer Inc 4-(2-keto-1-benzimidazolinyl)piperidine compounds as ORL1-receptor agonists
US7291611B2 (en) 2001-10-02 2007-11-06 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US6951849B2 (en) 2001-10-02 2005-10-04 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7087593B2 (en) 2001-10-02 2006-08-08 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7273857B2 (en) 2001-10-02 2007-09-25 Acadia Pharmaceuticals Inc. Benzimidazolidinone derivatives as muscarinic agents
US7300928B2 (en) 2001-10-02 2007-11-27 Acadia Pharmaceuticals, Inc. Benzimidazolidinone derivatives as muscarinic agents
US7279490B2 (en) 2002-06-17 2007-10-09 Merck & Co, Inc. Ophthalmic compositions for treating ocular hypertension
WO2003105781A2 (fr) 2002-06-17 2003-12-24 Merck & Co., Inc. Compositions ophtalmiques destinees a traiter l'hypertension oculaire
US8283364B2 (en) 2005-09-30 2012-10-09 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
US8288412B2 (en) 2005-09-30 2012-10-16 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
CN103058990A (zh) * 2006-03-22 2013-04-24 葛兰素集团有限公司 对m1受体具有活性的苯并咪唑类化合物及其在药物中的应用
CN101448495B (zh) * 2006-03-22 2013-05-08 葛兰素集团有限公司 对m1受体具有活性的苯并咪唑类化合物及其在药物中的应用
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
US20120309789A1 (en) * 2006-03-22 2012-12-06 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
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
JP2009530347A (ja) * 2006-03-22 2009-08-27 グラクソ グループ リミテッド Ｍ１受容体において活性を有するベンズイミダゾールおよび薬剤におけるそれらの使用
JP2009530348A (ja) * 2006-03-22 2009-08-27 グラクソ グループ リミテッド Ｍ１受容体で活性を有するベンズイミダゾールおよび医薬におけるその使用
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
JP2010521414A (ja) * 2006-03-22 2010-06-24 グラクソ グループ リミテッド Ｍ１受容体で活性を有するベンズイミダゾールおよび医薬におけるその使用
WO2008119717A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2008119718A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2008119721A1 (fr) * 2007-03-29 2008-10-09 Glaxo Group Limited Composés présentant une activité sur le récepteur m1 et utilisations de ceux-ci en médecine
JP2010539218A (ja) * 2007-09-20 2010-12-16 グラクソ グループ リミテッド Ｍ１受容体にて活性を有する化合物および医薬としてのそれらの使用
US8278328B2 (en) 2007-09-20 2012-10-02 Glaxo Group Limited Compounds which have activity at M1 receptor and their uses in medicine
JP2010539217A (ja) * 2007-09-20 2010-12-16 グラクソ グループ リミテッド Ｍ１受容体にて活性を有する化合物および医薬としてのそれらの使用
WO2009037296A1 (fr) * 2007-09-20 2009-03-26 Glaxo Group Limited Composés qui ont une activité au niveau du récepteur m1 et leurs utilisations en médecine
US8299257B2 (en) 2007-09-20 2012-10-30 Glaxo Group Limited Compounds which have activity at M1receptor and their uses in medicine
WO2009037294A1 (fr) * 2007-09-20 2009-03-26 Glaxo Group Limited Composés présentant une activité au niveau du récepteur m1 et leurs utilisations en médecine
WO2009124883A1 (fr) * 2008-04-09 2009-10-15 H. Lundbeck A/S Nouveaux 1,3-dihydro-benzoimidazol-2-ones utilisés en tant qu’agonistes m1

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