WO1999032479A1 - Derives de phtalamidepiperidine, de phtalamidepyrrolidine, et de phtalamide-azepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques - Google Patents

Derives de phtalamidepiperidine, de phtalamidepyrrolidine, et de phtalamide-azepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques Download PDF

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Publication number
WO1999032479A1
WO1999032479A1 PCT/US1998/027585 US9827585W WO9932479A1 WO 1999032479 A1 WO1999032479 A1 WO 1999032479A1 US 9827585 W US9827585 W US 9827585W WO 9932479 A1 WO9932479 A1 WO 9932479A1
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Prior art keywords
compounds
independently
pharmaceutically acceptable
chc
arylalkyl
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PCT/US1998/027585
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English (en)
Inventor
Anura Dantanarayana
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Alcon Laboratories, Inc.
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Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU20950/99A priority Critical patent/AU2095099A/en
Publication of WO1999032479A1 publication Critical patent/WO1999032479A1/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
    • C07D401/02—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
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new compounds having muscarinic activity.
  • the invention is .also directed to the treatment of glaucoma by controlling the principal symptom of that disease, elevated intraocul-ar pressure. More specifically, the invention relates to the use of particul.ar musc.arinic 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 intraocul.ar pressure by mhibiting 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 sympamomimetics, such as epmephrine. While the use ot 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.
  • 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.
  • 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 remedii-al .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 mamlaining the remedii-al effect on intraocul.ar pressure.
  • the compounds of this invention have niinimal effects on pupil dilation and therefore offer .an advantage over atropine or other compounds having muscarinic activity that have been suggested as therapeutics for myopia.
  • Studies of muscarinic receptors have shown that 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 th.an 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 97/16440 discloses 1-(1,2- disubstituted piperidinyl)-4-substituted piperazine derivatives as tachyldnin receptor antagonists for treating pain;
  • PCT International Publication Number WO 97/16187 discloses 1,3-dihydro- l-[l-(l-heteroarylpiperazm-4-yl)cyclohex- -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-[pi ⁇ eridin-4- yl]piperidin-4-yl ⁇ -2H-benzirnidazol-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- [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. 5,122,522 discloses the use of pirenzepine .and other muscarinic antagonists in the treatment of 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. Examples of 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 properties, and my therefore be used to treat various types of pain.
  • the compounds of the present invention are p-articularly useful in the treatment of glaucoma, based on the ability of the compounds to regulate ⁇ ntraocul.ar pressure or "IOP".
  • IOP ⁇ ntraocul.ar pressure
  • the compounds of the present invention .are believed to control IOP via an action on muscarinic receptors. However, they .are more potent th ⁇ m 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) h ⁇ been a very troublesome side effect of piloc-arpine therapy.
  • the compounds of the present invention .are also believed to be relatively free of the other major side effects associated with pilocarpine therapy, namely, impairment of accommodation and browache.
  • the compounds of the present invention have the following formula:
  • R is H, lower alkyl, alkoxyl, arylalkyl, alkynyl; alkenyl or cycloalkyl;
  • D is CH orN
  • a, b, c and d are independently CH or N, with the proviso that no more than two of a, b, c, d are N;
  • R 4 is H, lower alkyl, halogen, lower alkoxyl, OH, HOCH 2 , aryl, arylalkyl, SR orN(R) 2 .
  • alkyl includes str-aight 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 str-aight 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 str ght or branched chain hydrocarbon groups having 1 to
  • the chain hydrogens may be substituted with other groups, such as halogen.
  • Preferred str ght 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
  • lower alkynyl represents alkynyl groups containing 1 to 6 carbons (C, to C 6 ).
  • lower alkenyl represents alkenyl 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.
  • the most preferred compounds are those wherein R 1 , R 2 , R 3 and R 4 are H and R is lower alkyl, lower alkynyl or lower alkenyl.
  • the compounds of the present invention may be prepared by the method illustrated below:
  • Amine 1 is reacted with the appropriate phthalic anhydride derivative 2 in an inert solvent such as tetr-ahydrofuran or toluene at a temperature from 25° C to 125° C.
  • the resulting phth ⁇ imide derivative 3 is deprotected by treating with sodium hydroxide or potassium hydroxide in a solvent such as methanol, ethanol or ethylene glycol at a temperature from 25° C to 125° C.
  • Compound 6 is prep-ared by combining 4, 5 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.
  • the starting materials 1 and 5 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 formula 6 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.
  • salts of the compounds of 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, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutic ly acceptable inorganic or organic acid addition salts.
  • the compounds of formula (I) are utilized to treat glaucoma, myopia and dry eye by topically applying a solution or other suitable ophth.almic composition containing the compound to the eye.
  • a solution or other suitable ophth.almic 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 1 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 incorporated into other types of aqueous compositions, such as viscous or semi- viscous gels or other types of solid or semi-solid compositions. In addition to the compounds of formula (I) and the .aqueous vehicles described above, the compositions of the present invention may also include one or more ancillary ingredients, such as preservatives, co-solvents and viscosity building agents.
  • ancillary ingredients such as preservatives, co-solvents and viscosity building agents.
  • Ophth-almic 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 absorption 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 ophth-almic 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
  • 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 adrriinistration.
  • 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.
  • compositions of the present invention are further illustrated by the following example, wherein the term "Compound” in Examples 1 and 2 are intended to represent a compound selected from the compounds of formula (I) or a pharmaceutically acceptable salt thereof.
  • compositions of the present invention further illustrates the topical ophthalmic pharmaceutical compositions of the present invention.
  • compositions resent invention particularly oral tablet compositions.

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

Abstract

Les composés de la présente invention ont la formule (I) dans laquelle m et n représentent indépendamment 0 ou 1; o et p représentent indépendamment 1 ou 2; X représente 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)2R, (1) ou (2), 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; et J représentant O, CR, C(R)2, NR ou NRC(=O); R?1, R2, et R3¿ représentent indépendamment H, alkyle inférieur, halogène, alkoxyle inférieur, OH, HOCH¿2?, aryle, arylalkyle, SR ou N(R)2; et A est (3), a, b, c, et d représentant indépendamment CH ou N, à condition que pas plus de deux éléments parmi a, b, c, et d représentent N; et R?4¿ représentant H, alkyle inférieur, halogène, alkoxyle inférieur, OH, HOCH¿2?, aryle, arylalkyle, SR ou N(R)2. L'invention concerne également l'utilisation de ces composés, et des sels pharmaceutiquement acceptables de ceux-ci, pour traiter le glaucome, la myopie, la psychose, et d'autres dysfonctionnement faisant intervenir des récepteurs muscariniques.
PCT/US1998/027585 1997-12-23 1998-12-22 Derives de phtalamidepiperidine, de phtalamidepyrrolidine, et de phtalamide-azepine, leur preparation, et leur utilisation comme agonistes(antagonistes) des recepteurs muscariniques WO1999032479A1 (fr)

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AU20950/99A AU2095099A (en) 1997-12-23 1998-12-22 Phthalimide-piperidine, -pyrrolidine and -azepine derivatives, their preparationand their use as muscarinic receptor (ant-)agonists

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US6862797P 1997-12-23 1997-12-23
US60/068,627 1997-12-23

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030892A1 (fr) * 2001-10-11 2003-04-17 Alcon, Inc. Methodes de traitement de l'oeil sec
US8440689B2 (en) 2009-12-23 2013-05-14 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones
WO2013072705A1 (fr) * 2011-11-18 2013-05-23 Heptares Therapeutics Limited Agonistes du récepteur muscarinique m1
WO2014045031A1 (fr) * 2012-09-18 2014-03-27 Heptares Therapeutics Limited Composés aza bicycliques utilisés comme agonistes du récepteur muscarinique m1
GB2519470A (en) * 2013-09-18 2015-04-22 Heptares Therapeutics Ltd Bicyclic aza compounds as muscarinic M1 receptor agonists
US9056873B2 (en) 2011-06-22 2015-06-16 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
RU2678835C2 (ru) * 2014-03-19 2019-02-04 Хептерс Терапьютикс Лимитед Агонисты мускариновых рецепторов
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
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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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
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US3316276A (en) * 1965-10-06 1967-04-25 Robins Co Inc A H N-(3-pyrrolidinyl)-phthalimide derivatives
GB1486104A (en) * 1975-01-23 1977-09-21 Wyeth John & Brother Ltd Phthalimidopiperidine derivatives
WO1996013262A1 (fr) * 1994-10-27 1996-05-09 Merck & Co., Inc. Antagonistes de muscarine
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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003030892A1 (fr) * 2001-10-11 2003-04-17 Alcon, Inc. Methodes de traitement de l'oeil sec
US8440689B2 (en) 2009-12-23 2013-05-14 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones
US9181255B2 (en) 2009-12-23 2015-11-10 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones as SYK inhibitors
US9108970B2 (en) 2009-12-23 2015-08-18 Takeda Pharmaceutical Company Limited Fused heteroaromatic pyrrolidinones
US9056873B2 (en) 2011-06-22 2015-06-16 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
US9663514B2 (en) 2011-06-22 2017-05-30 Takeda Pharmaceutical Company Limited Substituted 6-aza-isoindolin-1-one derivatives
CN106831541A (zh) * 2011-11-18 2017-06-13 赫普泰雅治疗有限公司 毒蕈碱性m1受体激动剂
WO2013072705A1 (fr) * 2011-11-18 2013-05-23 Heptares Therapeutics Limited Agonistes du récepteur muscarinique m1
US11793817B2 (en) 2011-11-18 2023-10-24 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
GB2511685A (en) * 2011-11-18 2014-09-10 Heptares Therapeutics Ltd Muscarinic m1 receptor agonists
US9187451B2 (en) 2011-11-18 2015-11-17 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US10973832B2 (en) 2011-11-18 2021-04-13 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US9573929B2 (en) 2011-11-18 2017-02-21 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US10413553B2 (en) 2011-11-18 2019-09-17 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US9907805B2 (en) 2011-11-18 2018-03-06 Heptares Therapeutics Limited Muscarinic M1 receptor agonists
US9266857B2 (en) 2012-09-18 2016-02-23 Heptares Therapeutics Limited Bicyclic AZA compounds as muscarinic M1 receptor agonists
US9669013B2 (en) 2012-09-18 2017-06-06 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 receptor agonists
CN107098899A (zh) * 2012-09-18 2017-08-29 赫普泰雅治疗有限公司 作为毒蕈碱的m1受体激动剂的二环氮杂化合物
JP2018021057A (ja) * 2012-09-18 2018-02-08 ヘプタレス セラピューティックス リミテッド ムスカリンｍ１受容体作動薬としての二環式アザ化合物
CN104640851B (zh) * 2012-09-18 2017-05-31 赫普泰雅治疗有限公司 作为毒蕈碱的m1受体激动剂的二环氮杂化合物
US9975890B2 (en) 2012-09-18 2018-05-22 Heptares Therapeutics Limited Bicyclic AZA compounds as muscarinic M1 receptor antagonists
CN104640851A (zh) * 2012-09-18 2015-05-20 赫普泰雅治疗有限公司 作为毒蕈碱的m1受体激动剂的二环氮杂化合物
US10259802B2 (en) 2012-09-18 2019-04-16 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 receptor antagonists
CN107098899B (zh) * 2012-09-18 2019-09-06 赫普泰雅治疗有限公司 作为毒蕈碱的m1受体激动剂的二环氮杂化合物
WO2014045031A1 (fr) * 2012-09-18 2014-03-27 Heptares Therapeutics Limited Composés aza bicycliques utilisés comme agonistes du récepteur muscarinique m1
GB2519470A (en) * 2013-09-18 2015-04-22 Heptares Therapeutics Ltd Bicyclic aza compounds as muscarinic M1 receptor agonists
RU2678835C2 (ru) * 2014-03-19 2019-02-04 Хептерс Терапьютикс Лимитед Агонисты мускариновых рецепторов
US11034704B2 (en) 2014-03-19 2021-06-15 Heptares Therapeutics Limited Muscarinic receptor agonists
US10428088B2 (en) 2014-03-19 2019-10-01 Heptares Therapeutics Limited Muscarinic receptor agonists
US12024499B2 (en) 2015-08-03 2024-07-02 Heptares Therapeutics Limited Muscarinic agonists
US11834407B2 (en) 2016-10-14 2023-12-05 Heptares Therapeutics Limited Substituted cyclohexanes as muscarinic M1 receptor and/or M4 receptor agonists
US11773090B2 (en) 2018-06-22 2023-10-03 Heptares Therapeutics Limited Pharmaceutical compounds
US11945801B2 (en) 2018-12-07 2024-04-02 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 and/or M4 receptor agonists
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5
US11999745B2 (en) 2020-12-18 2024-06-04 Heptares Therapeutics Limited Pharmaceutical compounds

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