WO1999032481A1 - Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements - Google Patents

Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements Download PDF

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Publication number
WO1999032481A1
WO1999032481A1 PCT/US1998/027590 US9827590W WO9932481A1 WO 1999032481 A1 WO1999032481 A1 WO 1999032481A1 US 9827590 W US9827590 W US 9827590W WO 9932481 A1 WO9932481 A1 WO 9932481A1
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chc
compounds
mmol
independently
pharmaceutically acceptable
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PCT/US1998/027590
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English (en)
Inventor
Abdelmoula Namil
Andrew Hoffman
Mark R. Hellberg
Thomas R. Dean
Zixia Feng
Hwang-Hsing Chen
Najam Sharif
Anura Dantanarayana
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Alcon Laboratories, Inc.
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Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU23079/99A priority Critical patent/AU2307999A/en
Publication of WO1999032481A1 publication Critical patent/WO1999032481A1/fr

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    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to new compounds having muscarinic activity.
  • the compounds are useful in treating glaucoma, myopia, various other medical conditions that directly or indirectly involve muscarinic receptors within the human body.
  • the invention is particularly directed to the treatment of glaucoma by controlling the principal symptom of that disease, elevated intraocular pressure. More specifically, the invention relates to the use of particular muscarinic compounds to control intraocular pressure ("IOP") and thereby prevent or at least forestall progressive field of vision loss and other manifestations of glaucoma.
  • IOP intraocular pressure
  • Glaucoma is a progressive disease which leads to optic nerve damage (i.e., glaucomatous optic neuropathy), and ultimately, partial or total loss of vision.
  • optic nerve damage i.e., glaucomatous optic neuropathy
  • the loss of visual field is secondary to the degeneration of optic nerve fibers which comprise the optic nerve.
  • the causes of this disease have been the subject of extensive studies for many years, but are still not fully understood.
  • IOP Intra major risk factor for glaucomatous optic neuropathy
  • the usual reason for elevated IOP is an impairment of the outflow of fluid (i.e., aqueous humor) from the eye.
  • aqueous humor a fluid that is not considered to be a common factor for elevated IOP
  • the pressure may be reduced by inhibiting the production (i.e., inflow, secretion or formation) of aqueous humor by the ciliary processes of the eye.
  • Beta adrenoceptor blockers and carbonic anhydrase inhibitors are examples of drug classes that lower intraocular pressure by inhibiting the inflow of aqueous humor.
  • Other classes of drugs reduce IOP by increasing the outflow of aqueous humor from the eye.
  • Examples of these drug classes include miotics, such as pilocarpine and carbachol, and adrenergics or sympathomimetics, such as epinephrine. While the use of the drug classes stated above is common practice in the medical therapy of glaucoma, it is not without side effects. Each class suffers from causing a particular set of side effects, locally and/or systemically, that is related to the pharmacological actions of that class. For example, beta blockers, by blocking beta adrenoceptors in the heart, can cause bradycardia or slow heart rate, and by blocking beta adrenoceptors in the bronchi can cause bronchoconstriction.
  • miotics such as pilocarpine and carbachol
  • adrenergics or sympathomimetics such as epinephrine.
  • Muscarinic agents such as pilocarpine, may be used to reduce IOP by increasing the outflow of aqueous humor, but the use of these agents frequently produces side effects such as miosis, impaired accommodation and/or browache.
  • Miosis is caused by the contractile effect of the muscarinic agents on the iris sphincter. Muscarinic agents also have a contractile effect on the ciliary muscle. This effect is believed to be responsible for impairment of accommodation, as well as the browache experienced by some patients.
  • the agents used in glaucoma therapy show multiple pharmacological effects, some beneficial and some not. Since glaucoma medication must be taken over the patient's lifetime, it is advantageous to minimize the above-discussed side effects, so as to promote patients' compliance with the prescribed drug therapy, while maintaining the beneficial effect on intraocular pressure.
  • muscarinic receptors there are multiple subtypes of muscarinic receptors, and that these receptor subtypes may be localized in different tissues, or may otherwise mediate different pharmacological effects. While some non-selective muscarinic agents may interact with multiple receptors and cause multiple effects, other muscarinic agents may interact more selectively with one or a combination of muscarinic receptor subtypes such that the beneficial effects are increased while the detrimental side-effects are reduced.
  • PCT International Publication Number WO 97/16196 indicates that certain 1- [cycloalkylpiperidin-4-yl]-2H benzimidazolones are selective muscarinic agonists of the m2 subtype with low activity at the m3 subtype, and when utilized for glaucoma therapy have fewer side effects than pilocarpine therapy.
  • the present invention is based on the discovery of new muscarinic compounds and the use of these compounds to treat glaucoma, myopia and other medical conditions.
  • the following publications may be referred to for further background information regarding medical uses of compounds having at least some structural similarities to the compounds of the present invention:
  • PCT International Publication Number WO 97/24324 discloses 1-(1,2- disubstituted piperidinyl)-4-substituted piperidine derivatives as tachykinin receptor antagonists for treating pain;
  • PCT International Publication Number WO 97/16440 discloses 1-(1,2- disubstituted piperidinyl)-4-substituted piperazine derivatives as tachykinin receptor antagonists for treating pain;
  • PCT International Publication Number WO 97/16187 discloses 1 ,3-dihydro- l-[l-(l-heteroarylpiperazin-4-yl)cyclohex-4-yl]-2H-benzimidazol-ones as muscarinic antagonists for treating and/or preventing myopia; (4) United States Patent No.
  • 5,574,044 discloses l,3-dihydro-l- ⁇ l-[piperidin-4- yl]piperidin-4-y 1 ⁇ -2H-benzimidazol-2-ones and 1 ,3 -dihydro- 1 - ⁇ 4-amino- 1 -cyclohexyl ⁇ -2H- benzimidazol-2-ones as muscarinic antagonists for treating and/or preventing myopia;
  • United States Patent No. 5,691,323 discloses l,3-dihydro-l- ⁇ l-[piperidin-4- yl]piperidin-4-y 1 ⁇ -2H-benzimidazol-2-ones and 1 ,3 -dihydro- 1 - ⁇ 4-amino- 1 -cyclohexyl ⁇ -2H- benzimidazol-2-ones as muscarinic antagonists for treating and/or preventing myopia;
  • United States Patent No. 5,718,912 discloses the use of 1- l o [cycloalkylpioeridin-4-yl ]-2H benzimidazolones to treat glaucoma;
  • United States Patent No. 5,461,052 discloses the use of tricyclic compounds to prevent myopia
  • United States Patent No. 5,637,604 discloses the use of muscarinic antagonists in the treatment and control of ocular development.
  • the present invention is directed to a new group of compounds and to the use of these compounds to treat various conditions that directly or indirectly involve muscarinic receptors.
  • the compounds may also be used to treat the symptoms of other types of conditions or injuries, based on the action of the compounds on muscarinic receptors.
  • conditions that may be treated with the compounds of the present invention include glaucoma, myopia, dry eye and dry mouth (xerostoma).
  • the compounds may also be utilized to treat conditions of the central nervous system, such as psychosis and Alzheimer's disease.
  • the compounds have analgesic
  • the compounds of the present invention are particularly useful in the treatment of glaucoma, based on the ability of the compounds to regulate intraocular pressure or "IOP" .
  • IOP intraocular pressure
  • the compounds of the present invention are believed to control IOP via an action on muscarinic receptors. However, they are more potent than pilocarpine in lowering IOP, and, at a dose that causes an equal reduction in IOP, demonstrate a reduced level of miosis.
  • the production of miosis i.e., pupil constriction
  • the compounds of the present invention are also believed to be relatively free of the other major side effects associated with piloca ⁇ ine therapy, namely, impairment of accommodation and browache.
  • the compounds of the present invention have the following formula:
  • m and n are independently 0 or 1 ; o and p are independently 1 or 2; represents a double or single bond;
  • R is H, lower alkyl, arylalkyl, alkenyl, alkynyl or cycloalkyl;
  • R 1 , R 2 and R 3 are independently H, lower alkyl, halogen, lower alkoxyl, OH, HOCH 2 , aryl, arylalkyl, SR or N(R) 2 ;
  • A is selected from the group consisting of:
  • G and G' are independently H, lower alkyl, arylalkyl, alkynyl, alkenyl, cycloalkyl, aryl or heteroaryl;
  • Y is H, lower alkyl, halogen, lower alkoxyl, OH, HOCH 2 , SR, N(R) 2 , C(O)OR or OC(O)R; and
  • a, b, c and d are selected from the group consisting of CH and N such that no more than two of a, b, c and d are N, with the proviso that a,b,c and d are not
  • alkyl includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms (C, to C 15 ).
  • the alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxyl.
  • Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
  • cycloalkyl includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated.
  • the rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl.
  • Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
  • alkenyl includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms (C, to C 15 ) with at least one carbon-carbon double bond.
  • the chain hydrogens may be substituted with other groups, such as halogen.
  • Preferred straight or branched alkenyl groups include, allyl, 1-butenyl, l-methyl-2-propenyl and 4-pentenyl.
  • alkynyl includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms (C, to C 15 ) with at least one carbon-carbon triple bond.
  • the chain hydrogens may be substituted with other groups, such as halogen.
  • Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, l-methyl-2-propynyl and 2-pentynyl.
  • alkoxyl represents an alkyl group attached through an oxygen linkage.
  • lower alkyl represents alkyl groups containing 1 to 6 carbons (C, to C 6 ).
  • lower alkoxyl represents alkoxyl groups containing 1 to 6 carbons (C, to C 6 ).
  • halogen represents fluoro, chloro, bromo, or iodo.
  • aryl refers to carbon-based rings which are aromatic. Aromatic rings have alternating double and single bonds between an even number of atoms forming a system which is said to 'resonate'.
  • the rings may be isolated, such as phenyl, or fused, such as naphthyl.
  • the ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
  • heteroaryl refers to aromatic or semiaromatic hydrocarbon rings which contain at least one heteroatom, such as O, S, or N.
  • the heteroatoms are located in the ring adjacent to another C or N ring member.
  • Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms.
  • the heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryls include pyridine, indole, quinoline, furan, thiophene and pyrrole.
  • the most preferred compounds are those wherein m, n, o and p are 1;
  • R is H, lower alkyl; alkynyl, alkenyl, or cycloalkyl;
  • R 1 , R 2 and R 3 are H, lower alkyl, lower alkoxyl, OH or HOCH 2 ; and
  • A is
  • salts of the compounds formula (I) may also be utilized in the present invention.
  • examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, flimarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • Compound (3) is prepared by combining compounds (1), (2) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C and a pH in the range of 2-7.
  • a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride
  • the starting materials (1), and (2) are either commercially available or can be obtained by conventional procedures. The use of certain protecting groups and deprotecting steps may be necessary , as will be appreciated by those skilled in the art.
  • Compounds of the formula (3) may exist as mixtures of stereoisomers. The preparation of individual stereoisomers may be effected by the chromatographic separation of the stereoisomers or by the selective control of the reaction conditions.
  • the compounds of formula (I) are utilized to treat glaucoma, myopia and dry eye by topically applying a solution or other suitable ophthalmic composition containing the compound to the eye.
  • a solution or other suitable ophthalmic composition containing the compound to the eye.
  • the establishment of a specific dosage regimen for each individual patient is left to the discretion of clinicians.
  • the amount of the compound applied to the eye with each dose may vary, depending on the severity of the condition being treated, the drug release characteristics of the compositions in which the compound is contained, and various other factors familiar to those skilled in the art.
  • the amount of compound administered topically to the eye will generally be in the range of from about 0.3 to about 300 micrograms per dose, preferably from about 2 to about 100 micrograms per dose.
  • the compounds may be administered by topically applying one to two drops of a solution or comparable amount of a microemulsion, suspension, solid, or semi-solid dosage form to the affected eye(s) one to four times per day.
  • concentration of the compounds of formula (I) in such compositions will vary, depending on the type of composition utilized. For example, it may be possible to use a relatively lower concentration of the compound when compositions which provide for sustained release of the compounds or compositions which include a penetration enhancer are utilized.
  • the concentrations generally will be in the range of from about 0.001 to about 1 percent by weight, based on the total weight of the composition (" wt.%”), preferably from about 0.01 to about 0.3 wt.%.
  • the compounds of formula (I) may be included in various types of ophthalmic compositions. Since the compounds are relatively stable and soluble in water, the compositions will generally be aqueous in nature. Aqueous solutions are generally preferred, based on ease of formulation, as well as patients' ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the compounds may also be readily inco ⁇ orated into other types of aqueous compositions, such as viscous or semi- viscous gels or other types of solid or semi-solid compositions.
  • compositions of the present invention may also include one or more ancillary ingredients, such as preservatives, co-solvents and viscosity building agents.
  • Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium 1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001% to 1.0% by weight.
  • a surfactant or other appropriate co-solvent may be included in the compositions.
  • co-solvents include: polyethoxylated castor oils, such as those manufactured by BASF under the Cremophor® brand; Polysorbate 20, 60 and 80; nonionic surfactants, such as the following Pluronic® brand surfactants of BASF: Pluronic® F-68, F-84 and P-103; cyclodextrin; or other agents known to those skilled in the art.
  • co-solvents are typically employed at a level of from 0.01% to 2% by weight.
  • Viscosity greater than that of simple aqueous solutions may be desirable to increase ocular abso ⁇ tion of the compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation.
  • Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.
  • An appropriate buffer system e.g., sodium phosphate or sodium acetate or sodium borate
  • sodium phosphate or sodium acetate or sodium borate may be added to prevent pH drift under storage conditions.
  • the compounds of formula (I) may also be utilized to treat psychosis, Alzheimer's disease, dry mouth, pain and various other conditions.
  • the compounds may be administered by any convenient method, for example, by oral, parenteral, buccal, rectal or transdermal administration.
  • the compounds may be administered via conventional pharmaceutical compositions adapted for such administration.
  • the compositions are generally provided in unit dose form (e.g., tablets), comprising 0.5 - 100 mg of one or more compounds of formula (I) in a pharmaceutically acceptable carrier, per each unit dose.
  • the dosage of the compounds is 1 - 300 mg/day, preferably 10 - 100 mg/day, when administered to patients, e.g. humans, as a drug.
  • the compounds may be administered one to four times a day.
  • Step 4 Preparation of l,3-dihydro-4-phenyl-l-(l-ethoxycarbonylpiperidine-4-yl)piperidine-4-yl-4- imidazol-2-one hydrochloride.
  • Step 3 Preparation of l,3-dihydro-l-[l-[l-ethoxycarbonylpiperidin-3-yl]piperidin-4-yl]-2H-benz- imidazol-2-one.
  • Step l Preparation of 1 -benzyl-4-(2-methoxypheny l)aminopiperidine .
  • l-Benzyl-4-(2-methoxyphenyl)aminopiperidine (5 g, 16.85 mmol) was dissolved in HBr 47% (20 mL) and warmed at reflux for 4 h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. To the residue was added dichloromethane (100 mL), triethylamine (6.8 g, 67.4 mmol) and 4-nitrophenyl chloroformate (6.8 g, 33.7 mmol). The reaction mixture was stirred at room temperature for 3 h and then washed with IN NaOH (20 mL).
  • compositions of the present invention further illustrates the topical ophthalmic pharmaceutical compositions of the present invention.
  • compositions of the present invention particularly oral tablet compositions.

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

Abstract

L'invention concerne un nouveau groupe de composés présentant une activité muscarinique (I), m et n représentant indépendamment 0 ou 1; o et p représentent indépendamment 1 ou 2; ---- représentant un liaison simple ou double; X représentant C(R)2, O, S(O)q, NR, C(=O), CHOR, C=NOR, NC(=O)OR, NC(=O)N(R)2, NC(=O)R, CHC(=O)OR, CHC(=O)N(R)2, CHC(=O)R, NS(O)2C(R)3, (a) ou (b), q représentant 0, 1 ou 2; R représentant H, alkyle, alkoxyle, arylalkyle, alkynyle, alkényle, ou cycloalkyle inférieur; D représentant CH ou N; E représentant C=O,S(=O), S(=O)2, C=S ou C=NR; J représentant O, CR, C(R)2, NR ou NRC(=O); R?1, R2 et R3¿ représentant indépendamment H, alkyle inférieur, halogène, alkoxyle inférieur, OH, HOCH¿2?, aryle, aryalkyle, SR ou N(R)2, et A est choisi dans le groupe composé par (c), (d), (e) et (f). L'invention concerne également des composés et des sels pharmaceutiquement acceptables de ceux-ci, destinés à traiter le glaucome, la myopie, la psychose, et d'autres dysfonctionnements faisant intervenir des récepteurs muscariniques.
PCT/US1998/027590 1997-12-23 1998-12-22 Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements WO1999032481A1 (fr)

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AU23079/99A AU2307999A (en) 1997-12-23 1998-12-22 Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6876597P 1997-12-23 1997-12-23
US60/068,765 1997-12-23

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Cited By (35)

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WO2000044376A1 (fr) * 1999-01-28 2000-08-03 Bristol-Myers Squibb Company Composes antidepresseurs heterocycliques
WO2001002417A1 (fr) * 1999-07-05 2001-01-11 Dongbu Hannong Chemical Co., Ltd. Monomere nucleotidique contenant du sucre 'azar' en six branches et oligomeres antisens de ce monomere
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
EP1379246A1 (fr) * 2001-04-18 2004-01-14 Euro-Celtique S.A. Analogues de la nociceptine
WO2004089942A2 (fr) * 2001-10-02 2004-10-21 Acadia Pharmaceuticals Inc. Derives de benzimidazolidinone utilises en tant qu'agents muscariniques
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
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WO2007142583A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes des récepteurs muscariniques qui sont efficaces dans le traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
WO2007142585A1 (fr) * 2006-06-09 2007-12-13 Astrazeneca Ab Agonistes du récepteur muscarinique convenant au traitement de la douleur, de la maladie d'alzheimer et de la schizophrénie
JP2009510041A (ja) * 2005-09-30 2009-03-12 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におけるそれらの使用
JP2009510037A (ja) * 2005-09-30 2009-03-12 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ベンゾイミダゾロン類
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
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
WO2009037293A1 (fr) * 2007-09-20 2009-03-26 Glaxo Group Limited Composés ayant une activité au niveau du récepteur m1 et utilisations de ces derniers en médecine
JP2009512635A (ja) * 2005-09-30 2009-03-26 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におけるそれらの使用
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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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US8119661B2 (en) 2007-09-11 2012-02-21 Astrazeneca Ab Piperidine derivatives and their use as muscarinic receptor modulators
WO2013122107A1 (fr) * 2012-02-14 2013-08-22 大日本住友製薬株式会社 Nouveau dérivé de pyrrolidine cyclique fusionné
WO2014122474A1 (fr) 2013-02-07 2014-08-14 Takeda Pharmaceutical Company Limited Carboxylates de pipéridin-1-yle et d'azépin-1-yle à titre d'agonistes du récepteur muscarinique m4
US9090618B2 (en) 2012-12-27 2015-07-28 Purdue Pharma L.P. Substituted benzimidazole-type piperidine compounds and uses thereof
US10329289B2 (en) 2015-12-23 2019-06-25 Merck Sharp & Dohme Corp. 6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor
US10836775B2 (en) 2016-12-22 2020-11-17 Merck Sharp & Dohme Corp. 6,6-fused heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
US11319298B2 (en) 2016-12-22 2022-05-03 Merck Sharp & Dohme Corp. Heteroaryl piperidine ether allosteric modulators of the M4 muscarinic acetylcholine receptor
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US11834407B2 (en) 2016-10-14 2023-12-05 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
US11999745B2 (en) 2020-12-18 2024-06-04 Heptares Therapeutics Limited Pharmaceutical compounds
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists

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