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WO1999032489A1 - 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
WO1999032489A1
WO1999032489A1 PCT/US1998/027588 US9827588W WO9932489A1 WO 1999032489 A1 WO1999032489 A1 WO 1999032489A1 US 9827588 W US9827588 W US 9827588W WO 9932489 A1 WO9932489 A1 WO 9932489A1
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WIPO (PCT)
Prior art keywords
compounds
pharmaceutically acceptable
compound
myopia
chc
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PCT/US1998/027588
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English (en)
Inventor
Abdelmoula Namil
Hwang-Hsing Chen
Andrew Hoffman
Original Assignee
Alcon Laboratories, 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
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU22066/99A priority Critical patent/AU2206699A/en
Publication of WO1999032489A1 publication Critical patent/WO1999032489A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

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 hum.an body.
  • the invention is also 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 imp-airment 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 th.an pilocarpine therapy.
  • the present invention is b-ased 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 piper-azine derivatives as tachykinin receptor antagonists for treating pain;
  • PCT International Publication Number WO 97/16187 discloses 1,3-dihydro- l-[l-(l-hetero ⁇ lpiper ⁇ in-4-yl)cyclohex-4-yl]-2H-benzimid ⁇ ol-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-yl ⁇ -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- y l]piperidin-4-yl ⁇ -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- [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 musc-arinic -antagonists in the treatment of myopia
  • United States Patent No. 5,637,604 discloses the use of musc-arinic .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 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
  • h-as been a very troublesome side effect of pilocarpine 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 or N
  • 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
  • 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 preferred compounds of formula (I) are those wherein: o and p are 1; R 1 , R 2 and
  • 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 pharmaceutically acceptable inorganic or organic acid addition salts.
  • the compounds of the present invention may be prepared by means of the methods illustrated in Schemes 1-3 below:
  • Compound (3) is prepared by combining (1), (2) and a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature of 20° C to 40° C at a pH in the range of 2 to 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 nitrogen of compound (4) can be alkylated using the appropriate halide (alkyl halide, or alkynylalkyl halide for example) or sulfonate (alkyl methanesulfonate, alkeneylalkyl toluenesulfonate, for example) in the presence of a base such as sodium hydride, or potassium carbonate, in an solvent such as dimethylformamide, or acetonitrile at a temperature of -20° C to 120° C.
  • a base such as sodium hydride, or potassium carbonate
  • an solvent such as dimethylformamide, or acetonitrile
  • compound (4) is reacted with triethyl orthoformate at a temperature of 110° C to 160° C to form the diethyl acetal protected compound.
  • Compound (5) was converted to compound (6) by bis alkylation with 2-bromoethoxy-tert-butyldimethyl silane in the presence of a base such as sodium hydride at a temperature of -20° C to 60° C in a solvent such as dimethylformamide or tetr.ahydrofur.an.
  • the tert-butyldimethyl silyl (TBDMSi) protecting group can then be removed by treating the bis-alkylated compound (6) with a reagent such as tert-butyl ammonium fluoride in a solvent such as tetrahydrofur.an.
  • a reagent such as tert-butyl ammonium fluoride in a solvent such as tetrahydrofur.an.
  • the result.ant diol (7) is converted in to the bts-meth.anesulfonate by adding methanesulfonic anhydride in a solvent such as tetrahydrofuran containing triethylamine.
  • the bis- meth.anesulfonate can be reacted directly with the primary amine (8) in a solvent such as dimethylformamide at a temperature of 10° C to 100° C to provide compound (9).
  • the starting materials (4) and (8) 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 ait.
  • Compounds of the formula (9) 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.
  • Compound (12) is prep-ared by combining compounds (10), (11) .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 ketal protecting group of compound (12) is removed by warming the compound in .an acidic (hydrochloric acid, sulfuric acid, or trifluoroacetic acid ) aqueous solution at a temperature r-anging from 20° C to 100° C for 1 to 12 hours (“h").
  • An organic co-solvent such as methanol or tetrahydrofuran may be added to aid in the solubilization of the reaction components.
  • the resulting ketone (13) is converted to the 1,3,8- triazaspiro[4,5]decane-2,4-dione (14) by treating the compound with a mixture of sodium cyanide .and .ammonium carbonate in an ethanol/water solvent mixture, at a temperature of 20° C to 100° C.
  • Reaction of (14) with the appropriate alcohol in a solvent such as tetrahydrofuran in the presence of diisopropyl azodicarboxylate or diethyl azodicarboxylate and triphenylphosine or trimethyl phosphine at a temperature of -30° C to 40° C provides the N- substituted derivative (15).
  • 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 r.ange 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 ex.ample, 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 r-ange 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 ophth-almic 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.
  • Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimeros , 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 ait.
  • 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 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 a t. 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 ex-ample, 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 1
  • Step 2 Preparation of 3-dihydro-3-di-(ethan-2-ol)-2-oxo-l-indolecarbaldehyde diethyl acetal.
  • Step 3 Preparation of l-(l-ethoxycarbonylpiperidine-4-yl)-spiropyrolidine[4,3]indol-2'-one hydro- chloride.
  • the aqueous phase was washed with ether (50 ml X 6) and the aqueous layer was basified with potassium carbonate (to pH 10). The aqueous layer was extracted with dichloromethane (100 ml X 3). The combined organic layers were dried over magnesium sulfate and evaporated to a yellow oil, 19.25 g.
  • 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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau groupe de composés présentant une activité muscarinique. 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/US1998/027588 1997-12-23 1998-12-22 Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements WO1999032489A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU22066/99A AU2206699A (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
US6862897P 1997-12-23 1997-12-23
US60/068,628 1997-12-23

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WO1999032489A1 true WO1999032489A1 (fr) 1999-07-01

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Cited By (29)

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JP2003505371A (ja) * 1999-07-15 2003-02-12 サノフイ−サンテラボ スピロ［（４−シクロヘキサノン）−［３ｈ］インドル］−２’［１’ｈ］−オン誘導体の新規製造方法
JP2006507220A (ja) * 2002-04-26 2006-03-02 シェーリング　コーポレイション ムスカリン性アンタゴニスト
WO2006023852A3 (fr) * 2004-08-19 2006-08-31 Vertex Pharma Modulateurs des recepteurs muscariniques
WO2007076070A3 (fr) * 2005-12-22 2007-10-25 Vertex Pharma Modulateurs de recepteurs muscariniques
WO2007047146A3 (fr) * 2005-10-11 2007-11-01 Intermune Inc Inhibiteurs de réplication virale
JP2009518408A (ja) * 2005-12-05 2009-05-07 インサイト・コーポレイション ラクタム化合物およびそれを用いる方法
JP2009527569A (ja) * 2006-02-22 2009-07-30 バーテックス ファーマシューティカルズ インコーポレイテッド ムスカリン受容体の調節剤
US7612056B2 (en) 2004-04-06 2009-11-03 Jenssen Pharmaceutica N.V. Substituted diaza-spiro-[4.5]-decane derivatives and their use as neurokinin antagonists
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7786141B2 (en) 2004-08-19 2010-08-31 Vertex Pharmaceuticals Incorporated Dihydrospiroindene modulators of muscarinic receptors
US7786107B2 (en) 2006-08-18 2010-08-31 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7863449B2 (en) 2004-11-29 2011-01-04 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7973162B2 (en) 2007-10-03 2011-07-05 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8003660B2 (en) 2006-02-22 2011-08-23 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
WO2015140559A1 (fr) * 2014-03-19 2015-09-24 Heptares Therapeutics Limited Agonistes du récepteur muscarinique
JP2018508562A (ja) * 2015-03-19 2018-03-29 ヘプタレス セラピューティクス リミテッドＨｅｐｔａｒｅｓ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｌｉｍｉｔｅｄ ムスカリンｍ１受容体及び／またはｍ４受容体のアゴニストとしてのスピロ環状化合物
US10196380B2 (en) 2014-02-06 2019-02-05 Heptares Therapeutics Limited Bicyclic aza compounds as muscarinic M1 receptor and/or M4 receptor agonists
US10501483B2 (en) 2017-10-24 2019-12-10 Allergan, Inc. Enamines and diastereo-selective reduction of enamines
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
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
US12215099B2 (en) 2018-12-07 2025-02-04 Nxera Pharma Uk Limited Quinolinone and benzoxazine derivatives as muscarinic M1 and/or M4 receptor agonists
US12291512B2 (en) 2015-11-02 2025-05-06 Nxera Pharma Uk Limited Oxime compounds as agonists of the muscarinic M1 and/or M4 receptor

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Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003505371A (ja) * 1999-07-15 2003-02-12 サノフイ−サンテラボ スピロ［（４−シクロヘキサノン）−［３ｈ］インドル］−２’［１’ｈ］−オン誘導体の新規製造方法
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