WO2009106534A1 - Nouveaux carboxamides hétérocycliques comme agonistes de m1 - Google Patents

Nouveaux carboxamides hétérocycliques comme agonistes de m1 Download PDF

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WO2009106534A1
WO2009106534A1 PCT/EP2009/052205 EP2009052205W WO2009106534A1 WO 2009106534 A1 WO2009106534 A1 WO 2009106534A1 EP 2009052205 W EP2009052205 W EP 2009052205W WO 2009106534 A1 WO2009106534 A1 WO 2009106534A1
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propyl
oxo
piperidin
dihydro
disorder
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PCT/EP2009/052205
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Benny Bang-Andersen
Anette Graven Sams
Krestian Larsen
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H. Lundbeck A/S
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D471/08—Bridged systems

Definitions

  • the present invention provides compounds that are Ml agonists or partial agonists and as such are useful to treat cognitive impairment associated inter alia with schizophrenia and other diseases and disorders mediated by the muscarinic Ml receptor.
  • the present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating said disorders and diseases using the compounds of the invention.
  • Muscarinic acetyl choline receptors are members of the G protein coupled receptor super family which mediate the action of the neurotransmitter acetylcholine in both the central and peripheral nervous system.
  • Five muscarinic receptor subtypes (M1-M5) have been cloned.
  • the muscarinic Ml receptor is predominantly expressed in the cerebral cortex and hippocampus, although it is also expressed in the periphery e.g. in exocrine glands.
  • Muscarinic receptors in the central nervous system especially Ml, play a critical role in mediating higher cognitive processing.
  • muscarinic agonists may improve the symptoms of schizophrenia by acting directly at postsynaptic muscarinic receptors in cortical areas (Friedman et al, Biol Psychiatry 1999, 45:1-16). Recently, polymorphism of the Ml muscarinic receptor gene was shown to be associated with a poor cognitive function in subjects with schizophrenia (Liao et al, Neuropsychobiology 2003, 48, 72-76). Data from postmortem studies show a decrease in Ml receptor protein and mRNA levels in prefrontal cortices in human subjects with schizophrenia, which is confirmed by an in vivo brain imaging study in unmedicated subjects with schizophrenia.
  • Cholinergic replacement therapy has largely been based on the use of acetylcholine esterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to side effects resulting from stimulation of peripheral muscarinic receptors including disturbed gastrointestinal motility and nausea.
  • cognitive impairment can be experienced in several patients groups, e.g. depressive or psychotic patients and patients with attention deficit hyperactivity disorder (ADHD), psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania, Parkinson's disease, mild cognitive impairment (MCI), dementia, anxiety, age associated memory impairment, or post-traumatic stress disorder and patients taking benzodiazepines or tricyclic antidepressants and in a range of neurodegenerative diseases in addition to Parkinson's Disease and Alzheimer's Disease.
  • ADHD attention deficit hyperactivity disorder
  • psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania, Parkinson's disease, mild cognitive impairment (MCI), dementia, anxiety, age associated memory impairment, or post-traumatic stress disorder
  • MCI mild cognitive impairment
  • dementia anxiety, age associated memory impairment
  • post-traumatic stress disorder e.g., benzodiazepines or tricyclic antidepressants and in a range of neurodegenerative diseases in addition to Parkinson's Disease and Alzheimer's Disease.
  • Ml receptor agonists or partial agonists could potentially improve cognitive function in patients suffering from these disorders.
  • Ml receptor agonists may also be suitable for use in combination with typical and atypical antipsychotics and other drugs for the treatment of disorders or diseases in the central nervous system such as mood stabilisers, antidepressants, anxiolytics, drugs for extrapyrimidal side effects and cognitive enhancers, to provide improved treatment of psychotic disorders.
  • the muscarinic family of receptors is furthermore the target for a number of pharmacological agents used for various other diseases, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.
  • Di- and tri-substituted piperidine and piperazine derivatives are disclosed as compounds with activity on muscarinergic receptors in WO 99/50247, WO 2001/05763 and US Patent 6,528,529.
  • WO 2003/057672, WO 2006/068904, US 11,019,556 and US 10,329,455 disclose tetrahydroquinoline derivatives with activity on Ml and M4 receptors.
  • WO 2004/1089942 and WO 2003/028650 disclose benzimidazolidinone derivatives, which increase acetylcholine signaling or effect in the brain, and which are highly selective muscarinic Ml and/or M4 receptor agonists. Neither of these references discloses the heterocyclic carboxamides of the present invention.
  • the compounds of the invention which are muscarinic Ml receptor agonists, are believed to be useful in the treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.
  • the present invention relates to novel heterocyclic carboxamides, which the inventors have found to be highly active Ml agonists, and as such likely to be effective in the treatment of cognitive impairment and other diseases mediated by the muscarinic Ml receptor.
  • the objective of the present invention is to provide novel compounds, which are agonists at the Ml receptor.
  • the present invention is further directed to the use of a compound, alone or in combination with other antipsychotic agents or other drugs, for the treatment of disorders or diseases in the central nervous system, for treating or preventing psychosis, such as a schizophrenic disorder or psychosis in Alzheimer's disease or bipolar disorder, for treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.
  • the present invention further provides a pharmaceutical composition for treating or preventing said disorders and diseases.
  • the present invention is directed to a method for the treatment, control, amelioration or reduction of risk of a disease or disorder where abnormal oscillatory activity occurs in the brain, including depression, migraine, Parkinson's disease, psychosis and schizophrenia, as well as a disease or disorder where there is abnormal coupling of activity, particularly through the thalamus and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma or pain, including acute pain, chronic pain and neuropathic pain states.
  • a disease or disorder where abnormal oscillatory activity occurs in the brain including depression, migraine, Parkinson's disease, psychosis and schizophrenia
  • a disease or disorder where there is abnormal coupling of activity particularly through the thalamus and with other diseases mediated by muscarinic receptors, such as Chronic Obstructive Pulmonary Disease, asthma, urinary incontinence, glaucoma or pain, including acute pain, chronic pain and neuropathic pain states.
  • G is a mono- or bicyclic heterocyclic group selected from:
  • Rl is Ci_6 alkyl, C3_5 cycloalkyl, Ci_6 alkyl-C3_7 cycloalkyl wherein each Ci_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with Ci_6 alkyl-C ⁇ -io aryl, C 6- I 0 aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-C ⁇ -io aryl, C 6-10 aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, may be optionally substituted with a halogen, OH, Ci_ 6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or
  • Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy
  • -L- is CH 2 CH 2 or CH 2 CH 2 CH 2 or absent
  • R2 is independently selected from halogen and Ci_6 alkoxy
  • n is an integer selected from 0, 1 and 2
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci -6 alkyl and NRl 3CH 2 ,
  • R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF3, Ci_6 alkyl and Ci_6 alkoxy,
  • Rl 3 is H or Ci _ 6 alkyl
  • the invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament.
  • the invention relates to compounds of formula I for the treatment of disorders associated with muscarinic receptors, such as cognitive impairment.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and one or more pharmaceutically acceptable carriers, diluents and excipients.
  • the invention provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, alone or in combination with one or more neuroleptic agents, for the treatment of schizophrenia.
  • the invention further provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of a disorder associated with muscarinic receptors, such as cognitive impairment.
  • the invention further provides a method of treating a disorder selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia, and chemotherapy- induced cognitive impairment), ADHD, mood disorders (including depression, mania and bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain such as neuropathic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (
  • the present invention thus provides the use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition thereof, for the treatment of a disorder associated with muscarinic receptors, such as cognitive impairment.
  • the compound is selected among the specific compounds disclosed in the Experimental Section.
  • Ci_6 alkyl refers to a straight- chained or branched saturated hydrocarbon radical having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1 -propyl, 2- propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l -butyl and n-hexyl.
  • Ci_6 alkoxy refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2- propoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.
  • C 3 - 5 cycloalkyl typically refers to cyclopropyl, cyclobutyl and cyclopentyl.
  • C3-7 cycloalkyl typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Ci_6 alkyl-C3-7 cycloalkyl refers to a C3-7 cycloalkyl group as defined above, bearing a Ci_6 alkyl group substitutent as defined above.
  • C 6-10 aryl refers to a mono- or polycyclic aromatic group, which contains from 6 to 10 ring carbon atoms, and partially saturated variants thereof. Typical examples, which should not be considered limiting, include phenyl, indenyl, indanyl, naphthyl and tetrahydronaphthy 1.
  • Ci_6 alkyl-C 6 - 10 aryl refers to a C 6 - 10 aryl group as defined above, bearing a Ci_6 alkyl group substituent as defined above.
  • heteroaryl group refers to a mono- or polycyclic aromatic group which contains up to 14 ring atoms, of which 1 to 5 are selected from N, O or S, and the remaining atoms are carbon, and wherein the ring atoms selected from N, O or S may be placed in one or more rings, and partially saturated variants thereof.
  • Typical examples comprise pyridyl, thienyl, furyl, indolyl, pyranyl, benzofuranyl, benzothienyl, quinoline, isoquinoline, naphthyridyl, dihydroquinolinyl, chromenyl, thiochromenyl, benzoquinolinyl and acridinyl.
  • Ci_6 alkyl-heteroaryl refers to a heteroaryl group as defined above, bearing a Ci_6 alkyl group substituent as defined above.
  • G is a mono- or bicyclic heterocyclic group selected from:
  • G is a bicyclic heterocyclic group selected from:
  • G is a bicyclic heterocyclic group selected from:
  • G is a monocyclic heterocyclic group:
  • the asterisk * in the above embodiments denotes the attachment point of the group G
  • the compounds of the present invention may have one or more asymmetric centre, and it is intended that any optical isomers (i.e. enantiomers or diastereomers), in the form of separated, pure or partially purified optical isomers and any mixtures thereof, including racemic mixtures, are included within the scope of the invention.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization.
  • the optically active acids suitable for this purpose may include, but are not limited to d- or 1-tartaric, mandelic or camphorsulfonic acids.
  • Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix.
  • the compounds of the present invention may also be resolved by the formation and separation, e.g.
  • Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.
  • Some of the compounds of the present invention may exist in different polymorphic forms and it is intended that any polymorphic forms that the compounds are able to form are included within the scope of the present invention.
  • cognition refers to difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). These can include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or difficulty in integrating thoughts, feelings and behaviour and extinction of irrelevant thoughts as well as attention and vigilance, verbal learning and memory, visual learning and memory, speed of processing and social cognition.
  • treatment in connection with a disease or disorder such as cognitive impairment, also includes prevention as the case may be.
  • therapeutically effective amount denotes an amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, that will elicit the biological or medical response of a mammal that is being sought by a researcher or clinician.
  • the therapeutically effective amount will depend on the condition to be treated, the route and duration of administration, the physical attributes of the mammal, including body weight and on whether anyother medications are being administered concurrently, and may be determined according to methods well known to those skilled in the art in light of the present disclosure.
  • the mammal treated in the present methods is preferably a human, male or female, in whom activation of muscarinic Ml receptor activity is desired.
  • the subject mammal is a human.
  • the present invention is applicable to both old and young people, in certain aspects such as in treating cognitive impairment, it would typically find greater application in elderly people.
  • the present invention includes within its scope the use of a compound of formula I, alone or in combination with other agents, for the treatment of diseases mediated by the muscarinic Ml receptor, such as cognitive impairment and neuropathic pain in a mammal.
  • the preferred mammal for purposes of this invention is human.
  • leaving group refers to a group that is displaced in a substitution or elimination reaction.
  • Typical leaving groups include, but are not limited to, the chloride ion (Cl " ), bromide ion (Br " ) and methanesulfonate ion (CH3SO3 ).
  • the orientation of the biradical A which is a selected from O, OCH 2 , S, N-Ci -6 alkyl, N(RD)CH 2 , CH 2 CH 2 , CH 2 , SCH 2 , and SOCH 2 , wherein Rl 3 is selected from hydrogen and Ci_6 alkyl, such as methyl, is as shown below:
  • substantially pure enantiomer refers to a substance that has preferably between about 95% and 100% of one form (either R or S) and between about 5% and 0% of the other form, more preferably between about 99% and 100% of one form (either R or S) and between about 1% and 0% of the other form, and, most preferably, between about 99.9% and 100% of one form (either R or S) and about 0.1% and 0% of the other form.
  • substantially pure diastereomer refers to a substance that has preferably between about 95% and 100% of one diastereomeric form and between about 5% and 0% of the other form, more preferably between about 99% and 100% of one form and between about 1% and 0% of the other form, and, most preferably, between about 99.9% and 100% of one diastereomeric form and about 0.1% and 0% of the other form.
  • rac means a racemic mixture of enantiomers.
  • the present invention relates to compounds of formula I:
  • G is a mono- or bicyclic heterocyclic group selected from:
  • Rl is Ci_6 alkyl, C3-5 cycloalkyl, Ci_6 alkyl-C3-7 cycloalkyl wherein each Ci_6 alkyl, C3-5 cycloalkyl and C3-7 cycloalkyl may be optionally substituted with Ci_6 alkyl-C ⁇ -io aryl, C ⁇ -io aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-C ⁇ -io aryl, C ⁇ -io aryl, Ci_6 alkyl-heteroaryl, or heteroaryl, may be optionally substituted with a halogen, OH, Ci_ 6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy,
  • L is CH 2 CH 2 or CH 2 CH 2 CH 2 or absent
  • R2 is independently selected from halogen and Ci_6 alkyl
  • n is an integer selected from 0, 1 and 2
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci -6 alkyl, and NRl 3CH 2 ,
  • R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF3, Ci_6 alkyl and Ci_6 alkoxy,
  • R13 is H, Ci -6 alkyl
  • G is a bicyclic heterocyclic group selected from:
  • Rl is selected from Ci_ 6 alkyl, C 3 _ 5 cycloalkyl and Ci_6 alkyl-C3_7 cycloalkyl, wherein each Ci_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with Ci_6 alkyl-C ⁇ -io aryl, C 6-10 aryl, Ci_6 alkyl- heteroaryl, or heteroaryl, and wherein each Ci_6 alkyl-C ⁇ -io aryl, C 6-10 aryl, Ci_6 alkyl-heteroaryl and heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy;
  • Rl is Ci_ 6 alkyl substituted with halogen or Ci_6 alkoxy
  • R2 is independently selected from halogen and Ci_6 alkyl
  • n is an integer selected from 0, 1 and 2
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, C i_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci -6 alkyl, and NRl 3CH 2 ,
  • R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF 3 , Ci_ 6 alkyl and Ci_6 alkoxy, and wherein R13 is selected from H and Ci_6 alkyl.
  • G is a bicyclic heterocyclic group selected from:
  • Rl is selected from Ci_6 alkyl, C3_5 cycloalkyl and Ci_6 alkyl-C3-7 cycloalkyl, wherein each Ci_6 alkyl, C3-5 cycloalkyl and C 3 _ 7 cycloalkyl may be optionally substituted with Ci_6 alkyl-C 6-10 aryl, C 6-10 aryl, Ci_ 6 alkyl-heteroaryl or heteroaryl, and wherein each Ci_6 alkyl-C 6-10 aryl, C 6-10 aryl, Ci_6 alkyl-heteroaryl or heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy;
  • Rl is Ci_ 6 alkyl substituted with halogen and Ci_6 alkoxy
  • R2 is independently selected from halogen and Ci_6 alkyl
  • n is an integer selected from 0, 1 and 2
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, C i_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci_ 6 alkyl and NRl 3CH 2 ,
  • R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF 3 , Ci_ 6 alkyl and Ci_6 alkoxy,
  • R13 is selected from H and Ci_6 alkyl.
  • G is a monocyclic heterocyclic group:
  • Rl is selected from Ci_6 alkyl (preferably ethyl, 1-propyl and 2-propyl), C3-5 cycloalkyl and Ci_6 alkyl-C3-7 cycloalkyl, wherein each Ci_ 6 alkyl, C 3 _ 5 cycloalkyl and C 3 _ 7 cycloalkyl may be optionally substituted with C 6 -10 aryl (preferably 3-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4-
  • each C 6-10 aryl, or heteroaryl may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci-6 alkoxy;
  • Rl is Ci_6 alkyl substituted with halogen or Ci_6 alkoxy
  • R2 is independently selected from halogen and Ci_6 alkyl
  • n is an integer selected from 0, 1 and 2, preferably 0
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, C i_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci -6 alkyl, and NRl 3CH 2 , preferably OCH 2 , CH 2 CH 2 , SCH 2 ;
  • R9, RlO, RI l and R12 are independently selected from H, halogen, CN, CF 3 , Ci -6 alkyl, Ci_6 alkoxy; R9 and RlO are preferably both hydrogen; RI l is preferably selected from hydrogen and Ci_6 alkoxy such as methoxy, or from halogen such as F; R12 is preferably selected from hydrogen and halogen such as F;
  • R13 is selected from H and Ci_6 alkyl, preferably methyl.
  • Rl is Ci_ 6 alkyl, such as methyl, 2-propyl, 2-butyl, 2-methyl-2- propyl, 2-methyl-l -butyl and n-hexyl.
  • Rl is C 3 - 5 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl.
  • Rl is Ci_ 6 alkyl-C 3 _ 7 cycloalkyl, such as cyclohexylmethyl or cyclopentylmethyl
  • Rl is Ci_6 alkyl-C ⁇ -io aryl, such as benzyl, 3-chlorobenzyl, 4-chloro- benzyl, 3,4-dichlorobenzyl, 3,4-dimethoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl or 3,4- (methylenedioxy)benzyl.
  • Rl is Ci_ 6 alkyl-heteroaryl, such as 2-methyl-thiophene, 2-methyl- pyridine, 3-methyl-pyridine or 4-methyl-pyridine.
  • Rl is methyl. In another embodiment, Rl is Ethyl. In another embodiment, Rl is 1 -Propyl. In another embodiment, Rl is 2-Propyl. In another embodiment, Rl is 2-Butyl. In another embodiment, Rl is 3-Pentyl. In another embodiment, Rl is cyclobutyl.
  • Rl is cyclopropyl. In another embodiment, Rl is cyclohexylmethyl. In another embodiment, Rl is cyclopentylmethyl. In another embodiment, Rl is 2-Thienyl- methyl. In another embodiment, Rl is Benzyl. In another embodiment, Rl is 3- Methoxybenzyl.
  • Rl is 4-Methoxybenzyl. In another embodiment, Rl is 3,4- dimethoxybenzyl. In another embodiment, Rl is 3,4-(methylendioxy)benzyl. In another embodiment, Rl is 3-chlorobenzyl. In another embodiment, Rl is 4-chlorobenzyl. In another embodiment, Rl is 3,4-dichlor-Benzyl.
  • -L-is absent. In another embodiment, -L-is CH 2 CH 2 . In another embodiment, -L-is CH 2 CH 2 CH 2 .
  • n is 0. In another embodiment, n is 1. In another embodiment, n is 2.
  • R3, R4, R5, R6, R7 and R8 are all hydrogen.
  • A is O. In another embodiment, A is S. In another embodiment, A is OCH 2 . In another embodiment, A is CH 2 CH 2 . In another embodiment, A is N-C 1-6 alkyl such as N(CH 3 ). In another embodiment, A is N(R13)CH 2 such as N(CH 3 )-CH 2 . In another embodiment, A is NH-CH 2. In another embodiment, A is SCH 2 . In another embodiment, A is SOCH 2 .
  • R9 is H. In another embodiment, R9 is F.
  • RlO is CH 3 O. In another embodiment, RlO is CH 3 . In another embodiment, RlO is Cl. In another embodiment, RlO is F. In another embodiment, RlO is hydrogen.
  • Rl 1 is CH 3 O. In another embodiment, Rl 1 is Cl. In another embodiment, Rl 1 is H. In another embodiment, Rl 1 is F.
  • R12 is H. In another embodiment, R12 is F.
  • R9, RlO, Rl 1 and Rl 2 are all hydrogen.
  • At least one of R9, RlO, Rl 1 and R12 is not hydrogen.
  • At least one of R9, RlO, Rl 1 and R12 is halogen. In another embodiment, at least one of R9, RlO, Rl 1 and R12 is Ci_6 alkoxy, such as methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.
  • Rl is selected from Ci_6 alkyl, such as ethyl, 1-propyl, 2-propyl or from Ci_6 alkyl-C ⁇ -io aryl, such as 3,4-dimethoxybenzyl, 3,4-(methylenedioxy)benzyl or 4- chlorobenzyl; -L-is absent; n is 0; R3, R4, R5, R6, R7 and R8 are all hydrogen; A is selected from OCH 2 , CH 2 CH 2 and SCH 2 ; RlO is selected from hydrogen andCi_6 alkyl, such as methyl, or from Ci_6 alkoxy, such as methoxy, or from halogen, such as F or Cl; R9 and RlO are both hydrogen; RI l is selected from hydrogen and Ci_6 alkoxy, such as methoxy, or from halogen, such as F; R12 is selected from hydrogen and halogen, such as F.
  • Ci_6 alkyl such as ethyl, 1-propyl
  • Rl is selected from Ci_ 6 alkyl such as methyl, ethyl, 1-propyl or 2- propyl, or from C3_5 cycloalkyl such as cyclopropyl, or from Ci_6 alky 1-C 6 -I o aryl, such as 3,4- dichlorobenzyl, benzyl, 3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4- (methylenedioxy)benzyl or 4-chlorobenzyl, or from Ci_ 6 alkyl-heteroaryl, such as thiophene- 2-methyl; -L-is absent; n is 0; R3, R4, R5, R6, R7 and R8 are all hydrogen; A is selected from OCH 2 , CH 2 CH 2 and SCH 2 ,O; R9 is hydrogen; RlO is selected from hydrogen and Ci -6 alkyl, such as methyl, or from Ci_6 alkoxy, such as me
  • Rl 1 and RlO are both F, so that the compound according formula I, as described above, can be represented by formula Ib, wherein
  • G is a mono- or bicyclic heterocyclic group selected from:
  • R1-R9 and R12 and 13 may be defined as,
  • Rl is Ci alkyl, C 4-6 alkyl, C3_5 cycloalkyl, Ci_6 alkyl-C3_7 cycloalkyl wherein each Ci alkyl, C4_6 alkyl, C3_5 cycloalkyl and C3_7 cycloalkyl may be optionally substituted with C ⁇ -io aryl or heteroaryl, and wherein each C ⁇ -io aryl or heteroaryl, may be optionally substituted with halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl or Ci_6 alkoxy; or
  • Ci alkyl or C 4-6 alkyl are substituted with halogen or Ci_6 alkoxy
  • L is CH 2 CH 2 or CH 2 CH 2 CH 2 or absent
  • R2 is independently selected from halogen and Ci_6 alkyl, n is an integer selected from O, 1 and 2,
  • R3, R4, R5, R6, R7 and R8 are independently selected from hydrogen, halogen, OH, Ci_6 thioalkoxy, CN, Ci_6 alkyl and Ci_6 alkoxy;
  • A is a biradical selected from: O, CH 2 , S, OCH 2 , CH 2 CH 2 , SCH 2 , SOCH 2 , N-Ci -6 alkyl and NRl 3CH 2 ,
  • R9 and R12 are independently selected from H, halogen, CN, CF3, Ci_6 alkyl and
  • R13 is H or Ci -6 alkyl
  • the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 1 ⁇ M or less as evaluated by the Muscarinic FLIPR 384 assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 500 nM or less as evaluated by the Muscarinic FLIPR 384 assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 100 nM or less as evaluated by the Muscarinic FLIPR 384 assay.
  • the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 50 nM or less as evaluated by the Muscarinic FLIPR 384 assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 10 nM or less as evaluated by the Muscarinic FLIPR 384 assay. In a separate embodiment, of the invention, the compound of formula I and/or Ib is a substantially pure enantiomer. In another embodiment, the compound of formula I and/or Ib is a substantially pure diastereomer.
  • the compounds of formula I and/or Ib are selected among the following specific compounds, either as the free base, a tautomer thereof or as a pharmaceutically acceptable acid addition salt thereof:
  • compositions of formula I and/or Ib typically, pharmaceutically acceptable salts.
  • Such salts include pharmaceutically acceptable acid addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-tol
  • the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
  • the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and/or Ib and a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section and a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses.
  • compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington:
  • compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the mammal to be treated, the nature of the condition to be treated and the active ingredient.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules.
  • compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.
  • Typical oral dosages of a compound of formula I and/or formula Ib range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the mammal treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg of a compound of formula I and/or formula Ib.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and/or formula Ib and at least one pharmaceutically acceptable carrier or diluent.
  • the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.
  • the compounds of this invention are generally utilized as the free base or as a pharmaceutically acceptable salt thereof.
  • Such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I and/or formula Ib with a molar equivalent of a pharmaceutically acceptable acid.
  • suitable organic and inorganic acids are described above.
  • solutions of the compounds of formula I and/or Ib in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the compounds of formula I and/or Ib may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the compounds of formula I and/or Ib and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient.
  • the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil- in- water or water-in-oil liquid emulsion.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • compositions of the invention may be prepared by conventional methods in the art.
  • tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets.
  • adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like.
  • any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.
  • the compounds of formula I and/or Ib are agonists at the Ml receptor and as such are useful for treating or reducing the severity of a Ml muscarinic receptor mediated diseases such as cognitive impairment and neuropathic pain.
  • treating or reducing the severity of a Ml muscarinic receptor mediated disease refers both to treatments for diseases that are directly caused by muscarinic activities and alleviation of symptoms of diseases not directly caused by muscarinic activities.
  • diseases whose symptoms may be affected by muscarinic activity include, but are not limited to, CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes such as neuropathic pain, Huntington's Chorea, Friederich's ataxia, Gilles de Ia Tourette's Syndrome, Downs Syndrome, Pick disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intraocular pressure in Glaucoma and treatment of dry eyes and dry mouth (xerostomia) including Sjogren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances and wound healing
  • the present invention thus provides a method of treating a mammal suffering from cognitive impairment, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or formula Ib.
  • This invention also provides a method of treating a mammal suffering from cognitive impairment associated with a psychiatric disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib.
  • psychiatric disorders include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • the present invention provides a method of treating a mammal suffering from cognitive impairment associated with a cognition disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib.
  • cognition disorders include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and age-related cognitive decline.
  • ADHD attention-deficit/hyperactivity disorder
  • the compounds of formula I and/or Ib or pharmaceutically acceptable salts thereof 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.
  • 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 therefore, contemporaneously or sequentially with the compounds of the present invention.
  • 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.
  • the compounds of formula I and/or Ib, or pharmaceutically acceptable salts thereof may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or atypical antipsychotic agent) to provide improved treatment of schizophrenia.
  • neuroleptic agent which may be a typical or atypical antipsychotic agent
  • the combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to other known treatments.
  • the present invention thus provides a method of treating a mammal suffering from schizophrenia, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I and/or Ib, either alone or as combination therapy with at least one neuroleptic agent.
  • neuroleptic agent refers to drugs, which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.
  • neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenyl- butylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), sertindole, o
  • Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.
  • combinations of the compounds of formula I and/or Ib include combinations with anti-Alzheimer's Disease agents, for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSRl 80711 and MEM63908; gamma-secretase inhibitors, such as LY450139 and TAK 070; tau phosphorylation inhibitors; blockers of A ⁇ 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-HT1 a antagonists, such as lecozotan; p25/CDK5 inhibitors; NKl /NK3 receptor antagonists; COX-2 inhibitors; HMG- CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-a
  • combinations of the compounds of formula I and/or Ib 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-I antagonists, such as AMG517, 705498, 782443, PAC20030, Vl 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240612 and NVPSAA 164; sodium channel blockers and antagonists, such as VX409 and SPI860
  • the compounds of the invention may also 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, GABA 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, all
  • the compounds of the invention may also be administered 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 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 (optionally as its hydrochloride or lac
  • adjunctive administration is meant the concurrent or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices.
  • This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as addon therapeutic administration.
  • the invention provides a method of treatment of schizophrenia by adjunctive therapeutic administration of a compound of formula I and/or Ib, or a pharmaceutically acceptable salt thereof, to a mammal receiving therapeutic administration of at least one neuroleptic agent.
  • the present invention provides methods of treating disorders selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment, cognitive impairment associated with schizophrenia, and chemotherapy-induced cognitive impairment), ADHD, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (including Crohn's disease), comprising: administering to a mammal an effective amount of a compound of the present invention. That is, the present invention provides for the use of a compound of the present invention or pharmaceutical composition thereof for the treatment disorders associated with muscarinic receptors.
  • cognitive disorders including
  • disorders to be treated according to the present invention a number are particularly preferred. Particularly preferred disorders include the treatment of cognitive disorders (particularly mild cognitive impairment and cognitive impairment associated with schizophrenia), Alzheimer's disease, and psychosis, including schizophrenia.
  • cognitive disorders particularly mild cognitive impairment and cognitive impairment associated with schizophrenia
  • Alzheimer's disease and psychosis, including schizophrenia.
  • LC-MS general: Solvent system: A is water/TFA (100:0.05) and B is water/acetonitrile/TFA (5:95:0.035) (TFA is trifluoroacetic acid). Retention times (RT) are expressed in minutes. MS instruments are from PESciex (API), equipped with APPI-source and operated in positive ion mode.
  • Method A API 150EX and Shimadzu LC8/SLC-10A LC system. Column: 30 x 4.6 mm Waters Symmetry Cl 8 with 3.5 ⁇ m particles operated at 60 °C. Linear Gradient elution with 10% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min.
  • Method B API 150EX and Shimadzu LCIOAD/SLC-IOA LC system. Column: 30 x 4.6 mm Waters Atlantis dC18 with 3 ⁇ m particles operated at 40 °C. Linear Gradient elution with 2% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min.
  • Method C API 300 and Shimadzu LC10ADvp/SLC-10Avp LC system.
  • the compounds of the invention may be prepared by the following general methods:
  • a and R3 - Rl 2 are as previously described, and where E is a leaving group such as chloride, bromide or methylsulphonate.
  • the reaction of compounds with formula II with compounds with formula IHa, IHb, or IHc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula II and compounds with formula IHa, IHb, or IHc in a suitable solvent such as DMF, in the presence of a suitable base such as diisopropyl-ethyl amine, at a suitable temperature such as 0-60°C.
  • a suitable base such as diisopropyl-ethyl amine
  • the base may be immobilized on a solid support such as polystyrene beads.
  • reaction of compounds with formula IV with compounds with formula IHa, IHb or IHc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula IV and compounds with formula IHa, IHb or IHc in a suitable solvent such as 1 ,2-dichloroethane or THF in the presence of a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride at a suitable temperature such as 20-40°C, in the presence or absence of a suitable acid such as acetic acid.
  • a suitable solvent such as 1 ,2-dichloroethane or THF
  • a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • a suitable temperature such as 20-40°C
  • A, n, -L-and R2 - Rl 2 are as described above, with a carboxylic acid chloride RlCOCl or a carboxylic acid RlCOOH, wherein Rl is as defined above.
  • the reaction of compounds with formula Va, Vb, or Vc with a carboxylic acid chloride RlCOCl may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula Va, Vb, or Vc and compounds RlCOCl in a suitable solvent such as acetonitrile or 1,2-di-chloroethane at a suitable temperature such as O- 60 °C, in the presence of a suitable base such as diisopropyl-ethyl amine. The base may be immobilized on a solid support such as polystyrene beads.
  • reaction of compounds of formula Va, Vb, or Vc with carboxylic acids is performed by methods known to the skilled chemist, such as reaction in the presence of a carbodiimide coupling reagent such as diisopropyl carbodiimide in the presence of a suitable base such as triethylamine, and in the presence or absence of an additive such as 1-hydroxy-benzotriazole, in a suitable solvent such as 1 ,2-dichloroethane at a suitable temperature such as 0-60 °C;
  • a carbodiimide coupling reagent such as diisopropyl carbodiimide
  • a suitable base such as triethylamine
  • an additive such as 1-hydroxy-benzotriazole
  • R3 - R8 are as described above, and E' and E are leaving groups such as chloride or bromide, and where E' and E may be the same or different, under basic conditions.
  • R3 - R8 are as described above, and E' is a leaving group such as chloride or bromide, and PG is a suitable protecting group, such as the trimethylsilyl group ((CE ⁇ Si-) under basic conditions.
  • protecting groups in synthesis see Greene and Wutts: Protecting groups in organic synthesis. 3 rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0-471-16019-9.
  • the alcohol can be transformed into a suitable leaving group such as the methanesulfonate (CH3SO3 ) group, by reaction with methanesulfonyl chloride in the presence of a suitable base such as triethyl amine, in a suitable solvent such as THF, at a suitable temperature such as 0-25 °C.
  • a suitable leaving group such as the methanesulfonate (CH3SO3 ) group
  • Oxidation of a compound with formula VII may be performed by standard procedures including reaction with a suitable oxidant such as IBX, in a suitable solvent such as THF or acetone, at a suitable temperature, such as reflux, or in DMSO at a suitable temperature, such as room temperature.
  • a suitable oxidant such as IBX
  • a suitable solvent such as THF or acetone
  • a suitable temperature such as reflux
  • DMSO a suitable temperature
  • R5 - R8 are as described above, and E' is a leaving group such as chloride or bromide, and PG is a suitable protecting group, such as the trimethylsilyl group ((CH 3 ) 3 Si-), under basic conditions.
  • n, R2 and -L-are as described above, and PG is a protecting group such as the
  • reaction with a carboxylic acid chloride may be performed by standard procedures known to a person skilled in the art. This includes mixing compounds with formula IXa, IXb, or IXc and carboxylic acid chlorides RlCOCl in a suitable solvent such as acetonitrile or 1 ,2-di-chloroethane at a suitable temperature such as 0-60 °C, in the presence of a suitable base such as diisopropyl- ethyl amine.
  • the base may be immobilized on a solid support such as polystyrene beads.
  • reaction of compounds of formula IXa, IXb, or IXc with carboxylic acids is performed by methods known to the skilled chemist, such as reaction in the presence of a carbodiimide coupling reagent such as diisopropyl carbodiimide in the presence of a suitable base such as triethylamine, and in the presence or absence of an additive such as 1-hydroxy-benzotriazole, in a suitable solvent such as 1 ,2-dichloroethane at a suitable temperature such as 0-60 °C.
  • a carbodiimide coupling reagent such as diisopropyl carbodiimide
  • a suitable base such as triethylamine
  • an additive such as 1-hydroxy-benzotriazole
  • IXa where n is 0 and -L-is CH2CH2 is prepared by amination of commercially available JV-Boc-nortropinone by methods described in: Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • IXb where n is 0 and -L-is CH2CH2 is prepared from 3-benzyl-3-aza- bicyclo[3.2.1]octan-8-one, obtained as described in Lowe, J. A. et al.: J. Med. Chem. 1994, p.2831-2840; followed by in situ de-benzylation and introduction of the Boc protecting group as described in WO06108127; followed by animation by methods described in: Machetti, F. et al: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • IXc where n is 0 and -L-is CH2CH2 is prepared from 5-oxo-2-aza- bicyclo[2.2.2]octane-2-carboxylic acid tert-bvXy ⁇ ester, obtained as described in Gong,L. et al. Biorg. Med. Chem. Lett. 2003, 3597-3540; followed by amination by methods described in: Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • IXa where -L-is absent, R2 is Me and n is 1 is prepared by the following procedures: from commercially available JV-BOC piperidone by silyl-enolization as described in van Niel, M.B. et al: J. Med. Chem., 1999, p. 2087-2104; followed by reaction with methyl iodide or another source of an electrophilic methyl group; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935; or from 2-methyl-4-oxo- piperidine-1-carboxylic acid benzyl ester obtained as described in Richards, S.
  • IXa where -L-is absent, R2 is Me and n is 2, is prepared from 3,3-dimethyl-4- oxo-piperidine-1-carboxylic acid tert-butyl ester obtained as described in WO 2005040120; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • IXa where -L-is absent, R2 is Me and n is 2, is prepared from 2,6- dimethyl-4-oxo-piperidine-l-carboxylic acid benzyl ester obtained as described in Richards, S. et al.: Bioorg. Med. Chem. Lett. 2006, p. 6241-6245; followed by in situ de- benzylcarbamoylation and introduction of the Boc protecting group by methods described in WO06108127; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • An example of IXa where -L-is absent, R2 is halogen and n is 1 is prepared by the following procedures: from commercially available JV-BOC piperidone by silyl-enolization as described in van Niel,
  • IXa where -L-is CH2CH2, R2 is chlorine and n is 1 is prepared from commercially available JV-Boc-nortropinone by methods described in Armstrong, A. et al. J. Org. Chem. 2002, p.8610-8617; followed by amination by methods described in Machetti, F. et al.: Eur. J. Org. Chem., 2004, p. 2928-2935.
  • Deprotection may be performed according to procedures known to the skilled person. For a general reference see Greene and Wutts: Protecting groups in organic synthesis. 3 rd Edition, 1999. John Wiley and Sons, Inc., 605 Third Avenue, New York, NY. ISBN 0-471-16019-9.
  • n, R2 and -L-are as described above, and PG is a protecting group such as the Boc group.
  • reaction of compounds with formula II with a compound with formula XIa, XIb, or XIc may be performed by standard procedures known to chemists skilled in the art. This includes mixing compounds with formula II and compound with formula XIa, XIb, or XIc in a suitable solvent such as acetonitrile or 2-butanone at a suitable temperature such as 20-80 °C, in the presence of a suitable base such as potassium carbonate or diisopropyl-ethyl amine.
  • a suitable solvent such as acetonitrile or 2-butanone
  • a suitable base such as potassium carbonate or diisopropyl-ethyl amine.
  • reaction of compounds with formula IV with a compound with formula XIa, XIb, or XIc may be performed by standard procedures known to chemists skilled in the art. This includes reacting compounds with formula IV and compound with formula XIa, XIb, or XIc with a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as dichloromethane at a suitable temperature such as 15-30 °C, in the presence or absence of a suitable acid such as acetic acid.
  • a suitable reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • H 2 O was added.
  • the mixture was cooled to 5 °C on an ice-water bath, then H 2 O 2 (30% aq.)
  • TBD-methyl polystyrene (0.33 mmol) was added to 1 ml of a stock solution of 4-amino-piperidine-l-carboxylic acid tert-bvXy ⁇ ester (0.1 mmol/mL) in 1,2-dichloroethane.
  • Isobutyryl chloride (0.11 mmol) was added to the reactors and the reactions were shaken over night at room temperature.
  • Tris-(2-aminoethyl)amine polystyrene (0.33 mmol) was added to the reactors, and the reactions were shaken for 120 min. The reaction mixtures were filtered into a deep well plate. TFA (2.5 mmol) was added and the reactions were shaken for 120 min at room temperature.
  • the intermediate was purified by SCX (The SCX-column was preconditioned with a 10% solution of AcOH in MeOH, the sample directly loaded, the loaded columns were washed with MeOH and acetonitrile, and the intermediate was then eluted with 4 M NH3 in MeOH).
  • TFA trifluoroacetic acid
  • DIEA/DIPEA N,JV-diisopropyl-JV-ethyl amine
  • HOBt 1-hydroxybenzotriazole
  • NCS JV-Chloro succinimide
  • EDC HCl l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • AcOH acetic acid
  • Boc te/t-butylcarbonyloxy Reagents used for the preparation of compounds Ia - 4b
  • Ml-mAChR human muscarinic Ml receptor
  • the cell line was grown in F- 12 Kaighn's medium with L- Glutamine (Gibco), 10% FetalClone I serum (HyClone), 1% penicillin and streptavidine, and 0.5 ⁇ g/ml G418 (Gibco).
  • CHO-Kl cells stably expressing human Ml-mAChR receptor were plated in growth medium at a density of 18.000 cells/well in clear-bottomed, cell-culture coated 96-well plates (Corning, Costar #3904) and grown for 48 hrs at 37°C in the presence of 5% CO 2 . Before assay, the cells were washed with 2x100 ⁇ l of assay buffer (Hanks' balanced salt solution with Ca 2+ and Mg 2+ (Gibco) containing 20 mM HEPES, pH 7.4.
  • assay buffer Hors' balanced salt solution with Ca 2+ and Mg 2+ (Gibco) containing 20 mM HEPES, pH 7.4.
  • the cells were incubated with a calcium-sensitive fluorescent dye, Calcium assay kit R8033 (100 ⁇ l /well, half concentration relative to manufacturers instruction, Molecular Devices Inc) with 2.5 mM Probenecid (Sigma) for 50 minutes at 37°C and followed by 10 min at room temperature. Calcium flux was measured using a FLIPR 384 fluorometric imaging plate reader (Molecular Devices Inc).
  • the cells are periodically excited by 488 nm light and emitted fluorescent light passed through a 510-570 nm filter and detected by a cooled CCD camera (Sullivan et al., 1999).
  • the FLIPR 384 apparatus allows multiple liquid additions by computer-controlled liquid-handling hardware.
  • Test compounds were diluted from 2 mM stock solutions in 100% DMSO in assay buffer, and then added to cells (25 ⁇ l to 100 ⁇ l in well). 10 different concentrations were tested for each compound. Fluorescence readout was measured for 5 minutes starting just prior to compound addition. C. Data analysis
  • the fluorescence readout was calculated as max-min response, i.e. maximum fluorescence reading after and before liquid addition.
  • the fluorescence max-min data were normalized to yield responses for no stimulation (buffer) and full stimulation (1 ⁇ M acetylcholine) of 0% and 100% stimulation, respectively. Data were collected from at least three independent experiments. Concentration-response data were fitted to the four-parameter logistic equation to estimate compound potency (EC50) and efficacy (E max ) (Motulsky and Christopoulos, 2004). In this assay, common muscarinic agonists yielded potency/efficacy of:

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Abstract

La présente invention concerne de composés agonistes de M1 de formule (I) et leur utilisation dans le traitement de troubles cognitifs associés i.a. avec la schizophrénie et dans le traitement d’autres maladies médiées par le récepteur muscarinique M1.
PCT/EP2009/052205 2008-02-26 2009-02-25 Nouveaux carboxamides hétérocycliques comme agonistes de m1 WO2009106534A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011112825A2 (fr) * 2010-03-10 2011-09-15 Vanderbilt University Analogues d'hétérocyclyl-azabicyclo[3.2.1]octane comme agonistes sélectifs de m1 et leurs procédés de fabrication et d'utilisation
US8697691B2 (en) 2009-12-21 2014-04-15 Vanderbilt University Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective M1 agonists and methods of making and using same
KR20190068946A (ko) 2017-12-11 2019-06-19 씨제이헬스케어 주식회사 광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법
KR20190120112A (ko) 2019-10-08 2019-10-23 씨제이헬스케어 주식회사 광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법
WO2023114224A1 (fr) 2021-12-13 2023-06-22 Sage Therapeutics, Inc. Combinaison de modulateurs positifs du récepteur muscarinique et de modulateurs allostériques positifs de nmda
JP7382406B2 (ja) 2018-12-07 2023-11-16 ヘプタレス セラピューティクス リミテッド ムスカリンｍ１および／またはｍ４受容体アゴニストとしてのキノリノンおよびベンゾオキサジン誘導体
WO2024012554A1 (fr) * 2022-07-14 2024-01-18 上海日馨医药科技股份有限公司 Agoniste de tpk et procédé de traitement de maladies neurodégénératives l'utilisant

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0934932A1 (fr) * 1996-08-22 1999-08-11 Meiji Seika Kabushiki Kaisha Derives quinoleine et agent psychotrope
WO2002044154A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Nouveaux composés
WO2006068904A1 (fr) * 2004-12-21 2006-06-29 Acadia Pharmaceuticals Inc. Analogues de tetrahydroquinoline en tant qu'agonistes muscariniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0934932A1 (fr) * 1996-08-22 1999-08-11 Meiji Seika Kabushiki Kaisha Derives quinoleine et agent psychotrope
WO2002044154A1 (fr) * 2000-11-28 2002-06-06 Glaxosmithkline Spa Nouveaux composés
WO2006068904A1 (fr) * 2004-12-21 2006-06-29 Acadia Pharmaceuticals Inc. Analogues de tetrahydroquinoline en tant qu'agonistes muscariniques

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697691B2 (en) 2009-12-21 2014-04-15 Vanderbilt University Alkyl 3-((2-amidoethyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate analogs as selective M1 agonists and methods of making and using same
WO2011112825A2 (fr) * 2010-03-10 2011-09-15 Vanderbilt University Analogues d'hétérocyclyl-azabicyclo[3.2.1]octane comme agonistes sélectifs de m1 et leurs procédés de fabrication et d'utilisation
WO2011112825A3 (fr) * 2010-03-10 2011-12-22 Vanderbilt University Analogues d'hétérocyclyl-azabicyclo[3.2.1]octane comme agonistes sélectifs de m1 et leurs procédés de fabrication et d'utilisation
KR20190068946A (ko) 2017-12-11 2019-06-19 씨제이헬스케어 주식회사 광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법
JP7382406B2 (ja) 2018-12-07 2023-11-16 ヘプタレス セラピューティクス リミテッド ムスカリンｍ１および／またはｍ４受容体アゴニストとしてのキノリノンおよびベンゾオキサジン誘導体
KR20190120112A (ko) 2019-10-08 2019-10-23 씨제이헬스케어 주식회사 광학활성을 갖는 피페리딘 유도체의 중간체 및 이의 제조방법
WO2023114224A1 (fr) 2021-12-13 2023-06-22 Sage Therapeutics, Inc. Combinaison de modulateurs positifs du récepteur muscarinique et de modulateurs allostériques positifs de nmda
WO2024012554A1 (fr) * 2022-07-14 2024-01-18 上海日馨医药科技股份有限公司 Agoniste de tpk et procédé de traitement de maladies neurodégénératives l'utilisant

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