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WO2017099969A1 - Modulateurs allostériques positifs du récepteur muscarinique m1 tétrahydroquinoxaline - Google Patents

Modulateurs allostériques positifs du récepteur muscarinique m1 tétrahydroquinoxaline Download PDF

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Publication number
WO2017099969A1
WO2017099969A1 PCT/US2016/062658 US2016062658W WO2017099969A1 WO 2017099969 A1 WO2017099969 A1 WO 2017099969A1 US 2016062658 W US2016062658 W US 2016062658W WO 2017099969 A1 WO2017099969 A1 WO 2017099969A1
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alkyl
compound
pharmaceutically acceptable
halogen
aryl
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Douglas C. Beshore
Wen-Lian Wu
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention is directed to a class of tetrahydroquinoxaline compounds, their salts, pharmaceutical compositions comprising them and their use in therapy of the human body.
  • the invention is directed to a class of tetrahydroquinoxaline compounds which are muscarinic Ml receptor positive allosteric modulators, and hence are useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
  • Alzheimer's Disease is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid ⁇ peptide ( ⁇ ).
  • ⁇ is a 39-43 amino acid produced in the brain by processing of the beta-amyloid precursor protein (APP) by the beta-amyloid protein cleaving enzyme ("beta secretase" or "BACE”) and gamma-secretase. The processing leads to accumulation of ⁇ in the brain.
  • APP beta-amyloid precursor protein
  • BACE beta-amyloid protein cleaving enzyme
  • Cholinergic neurotransmission involves the binding of acetylcholine either to the nicotinic acetylcholine receptor (nAChR) or to the muscarinic acetylcholine receptor (mAChR). It has been hypothesized that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from Alzheimer's Disease. Consequently, acetyl cholinesterase inhibitors, which inhibit acetylcholine hydrolysis, have been approved in the United States for use in the treatment of the cognitive impairments of Alzheimer's Disease patients. While acetyl cholinesterase inhibitors have provided some cognitive enhancement in Alzheimer's Disease patients, the therapy has not been shown to change the underlying disease pathology.
  • nAChR nicotinic acetylcholine receptor
  • mAChR muscarinic acetylcholine receptor
  • a second potential pharmacotherapeutic target to counteract cholinergic hypofunction is the activation of muscarinic receptors.
  • Muscarinic receptors are prevalent throughout the body. Five distinct muscarinic receptors (M1-M5) have been identified in mammals. In the central nervous system, muscarinic receptors are involved in cognitive, behavior, sensory, motor and autonomic functions. The muscarinic Ml receptor, which is prevalent in the cerebral cortex, hippocampus and striatum, has been found to have a major role in cognitive processing and is believed to have a role in the pathophysiology of Alzheimer's Disease. See Eglen et al, TRENDS in Pharmacological Sciences, 2001, 22:8, 409-414.
  • Ml agonists also have the potential to treat the underlying disease mechanism of Alzheimer's Disease.
  • the cholinergic hypothesis of Alzheimer's Disease is linked to both ⁇ -amyloid and hyperphosphorylated tau protein. Formation of ⁇ -amyloid may impair the coupling of the muscarinic receptor with G-proteins. Stimulation of the Ml muscarinic receptor has been shown to increase formation of the neuroprotective aAPPs fragment, thereby preventing the formation of the ⁇ peptide.
  • Ml agonists may alter APP processing and enhance aAPPs secretion. See Fisher, Jpn J Pharmacol, 2000, 84: 101-112.
  • Ml ligands which have been developed and studied for Alzheimer's Disease have produced side effects common to other muscarinic receptor ligands, such as sweating, nausea and diarrhea. See Spalding et al, Mol Pharmacol, 2002, 61 :6, 1297-1302. See also WO2005056552, WO2005030188 and WO2007067489.
  • the muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
  • the compounds of the invention which are muscarinic Ml receptor positive allosteric modulators, are believed to be useful in the treatment of Alzheimer's Disease and other diseases mediated by the muscarinic Ml receptor.
  • the present invention is directed to novel tetrahydroquinoxaline compounds of generic formula (I) described below, or pharmaceutically acceptable salts thereof, which are useful as an Ml receptor positive allosteric modulator.
  • the invention is further directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of general formula (I), or a
  • compositions which include an effective amount of a compound of formula (I), or a
  • the invention is directed to N-methyl tetrahydroquinoline compounds of general formula (I)
  • V is CH 2 , or
  • V is S, N, or O, and the others are CH 2 ;
  • X, Y, Q, and Z are each CR 3 , or one or two of X, Y, Q and Z is N and the others are CR ;
  • R 3 is hydrogen, halogen, -C1.4 alkyl, -S(Ci -6 alkyl), or hydroxy; R 1 is selected from
  • aryl, heteroaryl, alkyl, and alkenyl moiety is substituted with 0, 1, 2, or 3 groups selected from
  • each m is 0 or 1;
  • each n is 0, 1, or 2;
  • each R 2 is independently selected from
  • aryl, heteroaryl, alkyl, heterocycloalkyl, and alkenyl moiety is substituted with 0, 1, 2, or 3 groups selected from
  • R 4 and R 7 are each independently selected from
  • R 4 and R 7 the alkyl or aryl moiety is substituted with 0, 1, 2 or 3
  • R 5 and R 6 are each independently selected from
  • R 8 are each independently selected from
  • R 5 and R 6 are linked together with the nitrogen to which they are both attached to form a 3-6 membered ring.
  • Representative compounds of the instant invention include, but are not limited to, the following compounds or their pharmaceutically acceptable salts thereof:
  • w is 3, 4, 5, or 6. In variant of this embodiment, w is 4 or 5. In yet another embodiment of the invention, w is 2.
  • p is 0, 1, or 2. In another embodiment, p is 0 or 1. In a variant of this embodiment, p is 0. In another embodiment of the invention, n is 1 or 2. In another embodiment of the compounds of formula (I), n is 0.
  • One embodiment of the invention includes m is 0. Another embodiment of the compounds of formula (I) comprises m is 1.
  • V is CH 2 .
  • one or two of V is N and the other are CH 2 .
  • one or two of V is S, and the others are CH 2 .
  • one or two of V is O, and the others are CH 2 .
  • one V is S, another is O, and the others are CH 2 .
  • one V is N, another is O, and the others are CH 2 .
  • R 5 and R 6 are each independently selected from hydrogen, -C i-6 alkyl, and -C3.6 cycloalkyl. In a variant of this embodiment, R 5 and R 6 are each independently selected from hydrogen, -Ci-6 alkyl, and -C3-6 cycloalkyl.
  • R 4 and R 7 are each independently selected from hydrogen and -C ⁇ . 6 alkyl, and wherein said alkyl moiety is substituted with 0, 1, 2 or 3 halogen, cyano, -O-C i -6 alkyl, or -O-C i-6 haloalkyl.
  • R 4 and R 7 are each independently selected from hydrogen, methyl, ethyl, and propyl, and wherein said alkyl moiety is substituted with 0, 1, 2 or 3 halogen, cyano, -O-C i-6 alkyl, or -O-C i-6 haloalkyl.
  • each R 8 is independently selected from hydrogen and -Ci -6 alkyl, and wherein said alkyl moiety is substituted with 0, 1, 2 or 3 halogen, cyano, -O-C i-6 alkyl, or - O-C i-6 haloalkyl.
  • each R 8 is independently selected from hydrogen, methyl, ethyl, and propyl, and wherein said alkyl moiety is substituted with 0, 1, 2 or 3 halogen, cyano, -O-C i- 6 alkyl, or -O-C i-6 haloalkyl.
  • each R 2 is independently selected from halogen, hydroxy, -O-Ci -6 alkyl, -C i -6 alkyl, -C2-6 alkenyl, -CN, - R 5 R 6 , aryl, -S(C i _6 alkyl), heteroaryl, and heterocycloalkyl, wherein said aryl, heteroaryl, alkyl, and
  • heterocycloalkyl moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, -S(Ci _6 alkyl), -O-C i -6 alkyl, and -C i -6 alkyl.
  • each R 2 is independently selected from halogen, -0-C i .3 alkyl, -S(C i -6 alkyl), and -C i .3 alkyl, wherein said alkyl moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, -S(C i-6 alkyl), -O-C3-6 alkyl, and - Ci -6 alkyl.
  • each R 2 is independently selected from fluorine, chlorine, thiom ethyl, thioethyl, thiopropyl, methoxy, ethoxy, methyl, ethyl, and propyl.
  • R 1 is selected from aryl, heteroaryl, halogen, -O-C i -6 alkyl, -C i -6 alkyl, and -S(C i -6 alkyl), wherein said aryl, heteroaryl, and alkyl moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, -O-Ci-6 alkyl, -Ci-6 alkyl, - -S(Ci -6 alkyl), and oxo.
  • R 1 is selected from aryl and hetoroaryl, wherein said aryl and heteroaryl is substituted with 0, 1, 2 or 3 groups selected from halogen, hydroxy, -O-C i -6 alkyl, -Ci -6 alkyl,- -S(C i -6 alkyl), and oxo.
  • R 1 is selected from 5- to
  • 6- membered aryl, and 5- to 6-membered heteroaryl wherein said 5- to 6- membered aryl, and 5- to 6-membered heteroaryl are substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, methyl, ethyl, propyl, thiom ethyl, thioethyl, and thiopropyl.
  • R 1 is selected from 5- to 6- membered aryl, and 5- to 6-membered heteroaryl having 1 or 2 nitrogen atoms, wherein said 5- to 6- membered aryl and 5- to 6-membered heteroaryl is substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, methyl, ethyl, propyl, thiomethyl, thioethyl, and thiopropyl.
  • R 1 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, 2H-imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein R 1 is substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, methyl, ethyl, propyl, thiomethyl, thioethyl, and thiopropyl.
  • R 1 is -Ci-6 alkyl substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, thiomethyl, thioethyl, and thiopropyl.
  • R 1 is methyl, ethyl, propyl or butyl, substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, thiomethyl, thioethyl, and thiopropyl.
  • R 1 is methyl.
  • the invention is directed to N-methyl tetrahydroquinoline
  • X b , Y b , Q b , and Z b are each CR 3 ⁇ 4 , or one or two of X b , Y b , Q b , and Z b is N and the others are CR 3 ⁇ 4 ; p is 0, 1, 2, or 3;
  • R is hydrogen, fluorine, chlorine, -Ci-4 alkyl, -S(Ci-6 alkyl), or hydroxy;
  • R lb is selected from hydrogen, aryl, heteroaryl, and -Ci-6 alkyl, wherein said aryl, heteroaryl, and alkyl, moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy,
  • each R 2b is independently selected from halogen, hydroxy, -0-Ci .3 alkyl, -C1 -3 alkyl, and
  • -S(Ci-3 alkyl) wherein said alkyl moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, -S(Ci-3 alkyl), and-O-Ci-3 alkyl.
  • X b , Y b , Q b , and Z b are each CH; and R lb is selected from phenyl, heteroaryl, and -Ci-3 alkyl, wherein said phenyl, heteroaryl, and alkyl, moiety is substituted with 0, 1, 2, or 3 groups selected from halogen, hydroxy, -O-Ci -6 alkyl, -Ci -6 alkyl, and -S(Ci _6 alkyl).
  • R lb is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, 2H-imidazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, wherein R lb is substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, methyl, ethyl, propyl, thiom ethyl, thioethyl, and thiopropyl.
  • R is -Ci-6 alkyl substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, thiom ethyl, thioethyl, and thiopropyl.
  • R lb is methyl, ethyl, propyl or butyl, substituted with 0, 1, 2, or 3 groups selected from fluoro, chloro, hydroxy, methoxy, ethoxy, thiomethyl, thioethyl, and thiopropyl.
  • R lb is methyl.
  • the invention is also directed to methods of treating a patient (preferably a human) for diseases or disorders in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a patient preferably a human
  • diseases or disorders in which the Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders
  • the invention is also directed to the use of a compound of formula (I), for treating a disease or disorder in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders, by administering to the patient a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • a disease or disorder in which the Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders and sleep disorders
  • the invention is also directed to medicaments or pharmaceutical compositions for the treatment of diseases or disorders in a patient (preferably a human) in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • diseases or disorders in a patient (preferably a human) in which the Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, which comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention is also directed to a method for the manufacture of a medicament or a pharmaceutical composition for treating diseases in which Ml receptor is involved, such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • diseases in which Ml receptor is involved such as Alzheimer's Disease, cognitive impairment, schizophrenia, pain disorders, and sleep disorders, comprising combining a compound of formula (I), or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier.
  • variable e.g. aryl, heteroaryl, R1, R ⁇ , etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • the wavy line 'w x. indicates a point of attachment to the rest of the compound.
  • Lines drawn into the ring systems such as, for example: indicate that the indicated line (bond) may be attached to any of the substitutable ring carbon atoms.
  • alkyl refers to an aliphatic hydrocarbon group having one of its hydrogen atoms replaced with a bond.
  • An alkyl group may be straight or branched and contain from about 1 to about 10 carbon atoms.
  • an alkyl group contains from 1 to 6 carbon atoms (Ci- 6 alkyl) or from about 1 to about 3 carbon atoms (C 1 -3 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • an alkyl group is linear.
  • an alkyl group is branched. Unless otherwise indicated, an alkyl group is unsubstituted.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond.
  • An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n- pentenyl, octenyl and decenyl. Unless otherwise indicated, an alkenyl group is unsubstituted.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements examples include phenyl, naphthyl, tetrahydronaphthyl and indanyl.
  • an aryl group contains from about 6 to about 10 carbon atoms.
  • an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl.
  • Non- limiting examples of aryl groups include phenyl and naphthyl.
  • an aryl group is phenyl. Unless otherwise indicated, an aryl group is unsubstituted.
  • cycloalkyl means a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on.
  • 3 to 7-membered cycloalkyl refers to a cycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwise indicated, a cycloalkyl group is unsubstituted.
  • C i-6 includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms.
  • alkoxy refers to an -O-alkyl group, wherein an alkyl group is as defined above.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.
  • An alkoxy group is bonded via its oxygen atom.
  • halo or "halogen” as used herein, means -F, -CI, -Br or -I. In one embodiment, a halo group is -F or -CI. In another embodiment, a halo group is -F.
  • heteroaryl represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, wherein at least one ring is aromatic, and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Bicyclic heteroaryl ring systems include fused ring systems, where two rings share two atoms, and spiro ring systems, where two rings share one atom.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazoliny
  • benzothiazolyl benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetra-hydroquinoline and 3- oxo-3,4dihydro-2N-benzo[b][l,4]thiazine. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • heterocycloalkyl represents a non- aromatic cyclic or polycyclic group having from five to twelve ring atoms selected from C, O, N or S, at least one of which is O, N or S.
  • heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyranyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • heteroatom means O, S or N, selected on an independent basis.
  • a moiety that is substituted is one in which one or more hydrogens have been
  • substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2,4- difluoro-3-propylphenyl.
  • substituted n-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (- CH 2 -) substituted with oxygen to form carbonyl (-CO-).
  • thioalkyl means -Salkyl, -S(Ci-6 alkyl), wherein the alkyl group may be straight or branched and contain from about 1 to about 10 carbon atoms.
  • Celite® (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite”.
  • mammal “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
  • the present invention encompasses all stereoisomeric forms of the compounds of Formula I and Formula II. Centers of asymmetry that are present in the compounds of Formula I and Formula II can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of this invention.
  • a solid line, ⁇ m ,as a bond generally indicates a mixture of, or either of, the possible isomers, e.g., containing (R)- and (S)- stereochemistry.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as "stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral FIPLC
  • All stereoisomers (for example, optical isomers and the like) of the present compounds such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • positional isomers such as, for example, 4-pyridyl and 3-pyridyl.
  • keto-enol and imine-enamine forms of the compounds are included in the invention.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • stereomeric nomenclature includes “or”, for example, (S or R)-, the “or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • the compounds of the invention may be prepared according to the following reaction Schemes, in which variables are as defined before or are derived, using readily available starting materials, from reagents and conventional synthetic procedures. It is also possible to use variants which are themselves known to those of ordinary skill in organic synthesis art, but are not mentioned in greater detail.
  • the present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the invention.
  • the protecting groups may be removed at a convenient sequent stage using methods known from the art.
  • substantially pure means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.
  • muscarinic Ml receptor refers to one of the five subtypes of the muscarinic acetylcholine receptor, which is from the superfamily of G-protein coupled receptors.
  • the family of muscarinic receptors is described, for example, in Pharmacol Ther, 1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol, 2002, 61 : 1297- 1302.
  • the muscarinic receptors are known to contain one or more allosteric sites, which may alter the affinity with which muscarinic ligands bind to the primary binding or
  • positive allosteric modulator and “allosteric potentiator” are used interchangeably, and refer to a ligand which interacts with an allosteric site of a receptor to activate the primary binding site.
  • the compounds of the invention are positive allosteric modulators of the muscarinic Ml receptor.
  • potentiator may directly or indirectly augment the response produced by the endogenous ligand (such as acetylcholine or xanomeline) at the orthosteric site of the muscarinic Ml receptor in an animal, in particular, a human.
  • endogenous ligand such as acetylcholine or xanomeline
  • the actions of ligands at allosteric receptor sites may also be understood according to the "allosteric ternary complex model," as known by those skilled in the art.
  • the allosteric ternary complex model is described with respect to the family of muscarinic receptors in Birdsall et al, Life Sciences, 2001, 68:2517-2524.
  • Christopoulos Nature Reviews: Drug Discovery, 2002, 1 : 198- 210.
  • the compounds of the invention bind to an allosteric binding site that is distinct from the orthosteric acetylcholine site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand acetylcholine at the orthosteric site of the Ml receptor. It is also believed that the compounds of the invention bind to an allosteric site which is distinct from the xanomeline site of the muscarinic Ml receptor, thereby augmenting the response produced by the endogenous ligand xanomeline at the orthosteric site of the Ml receptor.
  • non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • the compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound.
  • Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethyl
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, trifluoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, /?ara-toluenesulfonic acid, and the like.
  • Suitable pharmaceutically acceptable salts include ammonium, sodium, potassium, hydrochloride, hydrobromide and fumarate.
  • the present invention is directed to the use of the compounds of formula (I) disclosed herein as Ml allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • Ml allosteric modulators in a patient or subject such as a mammal in need of such activity, comprising the administration of an effective amount of the compound.
  • a variety of other mammals can be treated according to the method of the present invention.
  • the compounds of the present invention have utility in treating or ameliorating
  • the compounds may also be useful in treating or ameliorating other diseases mediated by the muscarinic Ml receptor, such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment).
  • diseases mediated by the muscarinic Ml receptor such as schizophrenia, sleep disorders, pain disorders (including acute pain, inflammatory pain and neuropathic pain) and cognitive disorders (including mild cognitive impairment).
  • Parkinson's Disease pulmonary hypertension
  • chronic obstructive pulmonary disease COPD
  • asthma urinary incontinence
  • glaucoma schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld- Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.
  • the compounds of the invention are useful in treating
  • Alzheimer's Disease cognitive disorders, schizophrenia, pain disorders and sleep disorders.
  • the compounds may be useful for the prevention of dementia of the Alzheimer's type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer's type.
  • Potential schizophrenia conditions or disorders for which the compounds of the invention may be useful include one or more of the following conditions or diseases:
  • schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (phencyclidine, ketanine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, or illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson'
  • the present invention provides a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder.
  • DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders
  • the term "schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-IV-TR.
  • the skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress.
  • the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.
  • Potential sleep conditions or disorders for which the compounds of the invention may be useful include enhancing sleep quality; improving sleep quality; augmenting sleep maintenance; increasing the value which is calculated from the time that a subject sleeps divided by the time that a subject is attempting to sleep; decreasing sleep latency or onset (the time it takes to fall asleep); decreasing difficulties in falling asleep; increasing sleep continuity; decreasing the number of awakenings during sleep; decreasing nocturnal arousals; decreasing the time spent awake following the initial onset of sleep; increasing the total amount of sleep; reducing the fragmentation of sleep; altering the timing, frequency or duration of REM sleep bouts; altering the timing, frequency or duration of slow wave (i.e.
  • Pain disorders for which the compounds of the invention may be useful include neuropathic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root avulsions, painful diabetic neuropathy, painful traumatic pain (such as postherpetic neuralgia, nerve injury, the "dynias”, e.g., vulvodynia, phantom limb pain, root
  • central pain syndromes (potentially caused by virtually any lesion at any level of the nervous system); postsurgical pain syndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia); perioperative pain (general surgery, gynecological), chronic pain, dysmennorhea, as well as pain associated with angina, and inflammatory pain of varied origins (e.g.
  • osteoarthritis rheumatoid arthritis, rheumatic disease, teno- synovitis and gout
  • headache migraine and cluster headache, headache, primary hyperalgesia, secondary hyperalgesia, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
  • Compounds of the invention may also be used to treat or prevent dyskinesias.
  • compounds of the invention may be used to decrease tolerance and/or dependence to opioid treatment of pain, and for treatment of withdrawal syndrome of e.g., alcohol, opioids, and cocaine.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.
  • anti-Alzheimer's Disease agents for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSR180711 and MEM63908; ADAM 10 ligands or activators; gamma-secretase inhibitors, such as LY450139 and TAK 070; gamma secretase modulators; tau phosphorylation inhibitors; glycine transport inhibitors; LXR ⁇ agonists; ApoE4 conformational modulators; R2B antagonists; androgen receptor modulators; blockers of ⁇ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HTla antagonists, such as lecozotan; p25/CDK5 inhibitors; K1/NK3 receptor antagonists; COX-2 inhibitor
  • nitroflurbiprofen D-1251, VP-025, HT-0712 and EHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB-1 receptor inverse agonists, such as AVE1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such as memantine, neramexane and EVT101; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT-089; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP16795;
  • AMPA agonists or AMPA modulators such as CX-717, LY 451395, LY404187 and S-18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABAA inverse agonists; GSK3p inhibitors, including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective Ml agonists; HDAC inhibitors; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
  • PDE IV inhibitors including MEM1414, HT0712 and AVE8112
  • GABAA inverse agonists GSK3p inhibitors, including AZD1080, SAR502250 and CEP16805
  • neuronal nicotinic agonists including selective Ml agonists; HDAC
  • combinations of the compounds include combinations with agents for the treatment of schizophrenia, for example in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone,
  • the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, MDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperiden
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • a pharmaceutically acceptable salt for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent.
  • phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine,
  • Suitable examples of thioxanthenes include chlorprothixene and thiothixene.
  • An example of a dibenzazepine is clozapine.
  • An example of a butyrophenone is haloperidol.
  • An example of a diphenylbutylpiperidine is pimozide.
  • An example of an indolone is molindolone.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • neuroleptic agents when used in combination with the subject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride,
  • acetophenazine maleate fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride,
  • tetrabenazine frihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.
  • combinations of the compounds include combinations with agents for the treatment of pain, for example non-steroidal anti-inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (
  • AZD4282 potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED160; GABA-A receptor IO modulators (e.g., a GABA- A receptor agonist); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase B15 (“MAO- B") inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinic agonists, such as ABT894; MDA
  • the compounds of the present invention may be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GAB A agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT- 2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam
  • the subject or patient to whom the compounds of the present invention is administered is generally a human being, male or female, in whom Ml allosteric modulation is is desired, but may also encompass other mammals, such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys, chimpanzees or other apes or primates, for which treatment of the above noted disorders is desired.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active compound which is a compound of formula (I) is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • oral or parenteral including intravenous
  • compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in-water emulsion or as a water-in-oil liquid emulsion.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.
  • compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous
  • oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.
  • compositions can be in a form suitable for use in transdermal devices.
  • These formulations may be prepared via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administering a should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, EVI, or IP, and the like;
  • transdermal dosage forms including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.
  • a therapeutically effective amount refers to an amount of the compound of Formula (I) and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a disease or disorder mediated by the muscarinic Ml receptor.
  • a therapeutically effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • preventing refers to reducing the likelihood of the occurrence of the disease or condition.
  • treatment means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
  • the compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • unit dosage form is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person
  • unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.
  • compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material.
  • Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.
  • TBDMSC1 fert-butyldimethylsilyl chloride
  • DMEM Dulbecco's Modified Eagle Medium (High Glucose)
  • FBS fetal bovine serum
  • Step 2 1-benzyl 3-methyl 3,4-dihydroquinoxaline-l,3f2H)-dicarboxylate (1-c) To a stirred solution of methyl l,2,3,4-tetrahydroquinoxaline-2-carboxylate (1-b) (50 mg, 0.26 mmol) in acetonitrile (1 mL) under nitrogen at 0 °C was added K 2 C0 3 (54 mg, 0.39 mmol) followed by benzyl chloroformate (0.037 mL, 0.260 mmol). The resultant solution was stirred for 3 hours at room temperature and then diluted with water and extracted with
  • Step 3 l-benzyl-3-methyl-4-f2-chloroacetyl)-3,4-dihydroquinoxaline-l,3f2H)
  • Step 4 benzyl 3- ⁇ lS,2S)-2-hvdroxycvclohexyl)-l,4-dioxo-l,2,3.,4,4 ,5-hexahvdro-6H- pyrazino[l,2- lquinoxaline-6-carboxylate (1-e)
  • 1-benzyl 3-methyl 4-(2-chloroacetyl)-3,4-dihydroquinoxaline-l,3(2H)- dicarboxylate (1-d) (450 mg, 1.12 mmol) and (l ⁇ -aminocyclohexanol (193 mg, 1.67 mmol) in THF (30 mL) at 0 °C was added potassium carbonate (309 mg, 2.23 mmol).
  • Step 5 Benzyl 3-( ( lS S)-2-( ( fe ⁇ butyldimethylsilvDoxyfcvclohexyD- 1 ,4-dioxo- l,2,3.,4,4 ,5-hexahvdro-6H-pyrazino[l,2- lquinoxaline-6-carboxylate (1-f)
  • Step 6 3-faS,2S)-2- fe ⁇ -butyldimethylsilvnoxy)cvclohexyn-2,3,5,6-tetrahvdro-lH- Pyrazino[l,2- lquinoxaline-l,4f4 -H)-dione (1-g)
  • Pd/C 10 wt%, 120 mg, 1.128 mmol
  • Step 7 3-faS,2S)-2- fe ⁇ -butyldimethylsilvnoxy)cvclohexyn-6-q6-methylpyridin-3- yl)methyl)-2,3.,5,6-tetrahvdro-lH-pyrazino[l,2- lquinoxaline-l,4f4 -H)-dione
  • Step 8 3-( ( lS,2S)-2-hvdroxycvclohexyn-6-( ( 6-methylpyridin-3-vnmethvn-2,3,5,6- tetrahydro-lH-pyrazino[l,2-alquinoxaline-l,4f4 H)-dione (1-1)
  • the utility of the compounds as Ml receptor positive allosteric modulators may be demonstrated by methodology known in the art including by the assay described below.
  • the assay is designed to select compounds that possess modulator activity at the acetylcholine muscarinic Ml receptor or other muscarinic receptors expressed in CHOnfat cells by measuring the intracellular calcium with a FLIPR384 Fluorometric Imaging Plate Reader System.
  • the assay studies the effect of one or several concentrations of test compounds on basal or acetylcholine-stimulated Ca2+ levels using FLIPR.
  • the compound was prepared and subjected to a pre-incubation period of four minutes. Thereafter, a single EC20 concentration of acetylcholine was added to each well (3 nM final). The intracellular Ca2+ level of each sample was measured and compared to an acetylcholine control to determine any modulatory activity.
  • CHOnfat/hMl, hM2, hM3 or hM4 cells were plated 24 hours before the assay at a density of 18,000 cells/well (100 L) in a 384 well plate.
  • CHOnfat/hMl and CHOnfat/hM3 Growth Medium 90% DMEM (Hi Glucose); 10% HI FBS; 2 mM L-glutamine; 0.1 mM NEAA; Pen-Strep; and lmg/ml Geneticin, were added.
  • M2Gqi 5 CHOnfat and M4Gqi5CHOnfat cells an additional 600 ⁇ g/ml hygromycin was added.
  • Buffers Assay Buffer: Hanks Balanced Salt Solution, with 20 mM Hepes, 2.5 mM
  • Acetylcholine 10 ⁇ in water, working stock at both 20 ⁇ and 30 ⁇ in assay buffer, final concentration of 10 ⁇ . This was used to check the maximum stimulation of the CHOKl/hMl cells. 20 ⁇ (2x) acetylcholine was added in the preincubation part of the assay, and the 30 ⁇ (3x) stock is added in the second part. (EC20)Acetyl choline: 10 mM in water, working stock of 9 nM (3x), and final concentration in assay was 3 nM. This was used after the preincubation with test compounds. Addition of the EC20 Acetylcholine to each well with a test compound will ascertain any modulator activity. 24 wells contained 3nM Acetylcholine alone as a control.
  • Screening Plate Compounds were titrated in 96-well plates (columns 2-11), 100% DMSO, started at a concentration of 15 mM (150x stock concentration), and 3-fold serial dilutions using Genesis Freedom200 System.
  • Four 96-well plates were combined into a 384- well plate using Mosquito Nanolitre Pipetting System by transferring 1 ⁇ of serial diluted compounds to each well, and 1 mM acetylcholine (lOOx stock concentration) were added as a control.
  • Temo 49 ⁇ assay buffer was added to each well of the 384-well plate right before assay.
  • Acetylcholine (3x) is pipetted into wells corresponding to the screening compounds, and into control wells.
  • the 30 ⁇ acetylcholine control (3x) was added into control wells, and the 3x agonist plate was transferred into a 384 well plate.
  • the cells were washed three times with 100 ⁇ . of buffer, leaving 30 ⁇ . of buffer in each well.
  • the cell plate, screening plate, and agonist addition plates were placed on the platform in the FLIPR and the door closed. A signal test to check background fluorescence and basal fluorescence signal was performed. Laser intensity was adjusted if necessary.
  • IP inflection point

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Abstract

La présente invention concerne des composés tétrahydroquinoxaline de formule (I) qui sont des modulateurs allostériques positifs du récepteur M1 et qui sont utiles dans le cadre du traitement de maladies dans lesquelles est impliqué le récepteur M1, par exemple la maladie d'Alzheimer, la schizophrénie, la douleur ou les troubles du sommeil. L'invention concerne également des compositions pharmaceutiques qui comprennent les composés et l'utilisation des composés et des compositions dans le traitement de maladies médiées par le récepteur M1.
PCT/US2016/062658 2015-12-10 2016-11-18 Modulateurs allostériques positifs du récepteur muscarinique m1 tétrahydroquinoxaline Ceased WO2017099969A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120252808A1 (en) * 2009-12-17 2012-10-04 Kuduk Scott D Quinoline amide m1 receptor positive allosteric modulators
US20150065498A1 (en) * 2011-05-17 2015-03-05 Scott D. Kuduk N-linked lactam m1 receptor positive allosteric modulators

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120252808A1 (en) * 2009-12-17 2012-10-04 Kuduk Scott D Quinoline amide m1 receptor positive allosteric modulators
US20150065498A1 (en) * 2011-05-17 2015-03-05 Scott D. Kuduk N-linked lactam m1 receptor positive allosteric modulators

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11198699B2 (en) 2019-04-02 2021-12-14 Aligos Therapeutics, Inc. Compounds targeting PRMT5

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