Title of Invention	COMPOUNDS WITH SELECTIVE ACTIVITY ON M1 MUSCARINIC RECEPTORS
Abstract	Compounds' and methods art provided for the alleviation or treatment of diseases or conditions in which modification of muscarinic m1 receptor activity has a beneficial effect. In he. method, a therapeutically effective amount of a selective muscarinic m1 agonist compound is administered to a patient in need of such treartment.

Full Text

COMPOUNDS WITH SELECTTVE ACTIVITY ON M, MUSCARINIC RECEPTORS Field of the Invention The present invention relates to novel compounds which are selective for muscarinic acetylcholine receptor subtypes, as well as to methods for activating muscarinic receptors and for treating or alleviating diseases in which modification of muscarinic receptor activity is beneficial. Background of the Invention Muscarinic acetylcholine rescepters play a central role in the central nervous system for higher cognitive functions, as well as in the peripheral parasympathetic nervous system. Cloning has established the presence of five distinct muscarinic receptor subtypes (termed ml-m5) (cf. T.I. Bonner et al. Science 237, 1987, pp. 527- 532; T.I. Bonner et al., Neuron 1 1988, pp. 403-410). It has been found that ml is the predominant subtype in the cerebral cortex and is believed to be involved in the control of cognitive functions. m2 is predominant in heart and is believed to be involved in the control of hear rate, m3 is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation. m4 is present in brain, and m5 is present in brain and may be involved certain functions of the central nervous system associated with the dopaminergic system. Animal studies of various muscarinic ligands (S. Iversen, Life Sciences 60 (Nos. 13/14), 1997, pp. 1145-1151) have shown that muscarinic compounds have a profound effect on cognitive functions, e.g. learning and memory. This would suggest a potential utility of muscarinic agonists in the improvement of cognitive functions in diseases characterized by cognitive impairment, both age-related (such as Alzheimer's disease or other dementias) and not age-related (such as attention deficit hyperactivity disorder). Based on me presence of r luscarinic receptor subtypes in various tissues, it would appear that the ml receptor subtype is the more abundant one in the cerebral cortex, basal ganglia and hippocampus where it accounts for 35-60% of all muscarinic receptor binding sites (cf. A. Bevey, Proc. Natl. Acad. ScL USA 93, 1996, pp. 13541- 13546). It has been proposed that the ml (and possibly m4) subtype plays a major role as a postsynaptic muscarinic receptor (located on cholinoceptive neurons in the neocortex and hippocampus) ir various cognitive and motor functions and is likely to be a major contributor to the m responses measured in these regions of the brain. It has previously been foun i that conditions associated with cognitive impairment, such as Alzheimer's disease 0are accompanied by selective loss of acetylcholine in the brain. This is believed to be the result of degeneration of cholinergic neurons in the basal forebrain which innervi .te areas of the association cortex and hippocampus involved in higher processes (of. S. Iversen, supra). This finding would suggest that such conditions may be treated or at least ameliorated with drugs that augment the cholinergic function in the affected areas of the brain. Treatment with acetylchol ne esterase (AChE) inhibitors such as 9-amino-l,2,3,4- tetrahydroacridine (tacrine) results in an increase of acetylcholine in the brain which indirectly causes stimulation of muscarinic receptors. Tacrine treatment has resulted in a moderate and temporary cognitive improvement in Alzheimer's patients (of. Kasa et al., supra). On the other hand, tacrine has been found to have cholinergic side effects due to the periphera acetylcholine stimulation. These include abdominal cramps, nausea, vomiting, diarrhea, anorexia, weight loss, myopathy and depression. Gastrointestinal side effects have been observed in about a third of the patients treated. Tacrine has also beer found to cause significant hepatotoxicity, elevated liver transaminases having been observed in about 30% of the patients (cf. P. Taylor, "Anticholinergic Agents". Chapter 8 in Goodman and Gilman: The Pharmacological Basis of Therapeutics. 9th Ed . 1996, pp. 161-176). The adverse effects of tacrine have severely limited its clinical utility. Another AChE inhibitor, (R,S)-l-benzyl-4-[5,6- dimethoxy-l-indanon-2yl]methylpiperidine.HCl (donepezil), has recently been approved for the treatment of symptoms of mild to moderate Alzheimer's disease (cf. P. Kasa et al, supra). No hepatic damage has been observed for this compound but it has gastrointestinal effects similar to those of tacrine, probably due to stimulation of the m3 receptor caused by el evated parasympathetic tone. It has previously been suggested that, since the muscarinic ml receptors in the prefrontal cortex and hippocampus appear to be intact, it may be possible to remedy or at least ameliorate the oss of acetylcholine in Alzheimer's disease patients by administration of drugs ac ing as agonists on those muscarinic receptors (cf. J.H. Brown and P. Taylor, "Mu carinic Receptor Agonists and Antagonists", Chapter 7 in Goodman and Gilman: The Pharmc cological Basis of Therapeutics, 9th Ed., 1996, p. 147). The muscarinic agonists (believed to be ml selective) hitherto suggested for the treatment of Alzheimer's disease such as arecoline, have not shown greater efficacy in clinical trials than AChE inhibito s (cf. S.V.P. Jones et al., supra). In one study (cf. T. Sunderland et al.. Brain Res. Rey. 13. 1988, pp. 371-389), arecoline was found to have not so much cognitive enhanc ng effects as effects on behavioral changes often observed in Alzheimer's disease patients, such as a significant increase in motor activity, significant uplifting of mood, and significant decrease in anergia. However, presumed ml agonists have later been found to be weak partial agonists selective for the m2 and/or m3 receptor subtype s (H. Bräuner-Osborne et al., J. Med. Chem. 38, 1995, pp. 2188-2195). As indicated above, m2 subtype selectivity is presumed to be responsible for the cardiovascular effects observed for these agonists, e.g. tachycardia and bradycardia, and m3 activ ty is believed to account for the adverse gastrointestinal effects of the agonits. m2 and/or m3 activity is therefore a significant drawback for the muscarinic agonists proposed until now for the treatment of Alzheimer's disease, severely limiting the doses of the drugs which it has been possible to administer to patients who may therefore have received sub-optimal doses. Furthermore, the lack of subtype selectivity and low potency of the :urrently tested cholinergic compounds appear to favor the negative peripheral side effects and have limited cognitive effects because of weak and/or opposing actions in the brain. It would therefore be of great advantage to develop compounds which have an improved selectivity for the ml subtype, but which have little or no activity on the m2 and m3 subtypes. Summary of the Invention The present invention provides compounds with nuscarinic agonist activity of the general formula (I): wherein R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 heteroalkyl, C1-8 aminoalkyl, C1-8 haloalky C1-8 alkoxycarbonyl, C1-8 hydroxyalkoxy, C1-8 hydroxya kyl. -SH, C1-8 thioalkyl, or -O-CH2-C5-6 aryl; A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected rom O, N or S; when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hycdroxyl, halo, or straight or branched-chain C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C1- alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, -CN. -CF3, -OR3, -COR3, NO2, -NHR3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NGC(O)NR4R5, -OC(O)R3, or -(CH2)qNR3R4 where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl; C5-6aryl optionaly comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; or when A is phenyl, R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 a kynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkox/carbonyl, -CN, -CF3 -OR3, -COR3, NO2, -NHR3, -NHC (0)R3, -C(O)NR3R4, -NR3R4. -NR3C(O)NR4R5, -OC(O)R3, or -(CH2)qNR3R4, where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl; C5-6aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optio Nally substituted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5 -6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; n is 1, 2, 3 or 4, the groups R2, when n > 1, being the same or different; p is 0 or an integer from 1 0 5; Y is -NHC(O)- or -C(O)-; ind Z is a bond or CR8R9 whe enR8 and R9 are independently selected from H, and straight or branched chain C1-8 alk '1 provided where -(CH2)p-Y- is (CH2)3-C(O)-, that -A-(R2)n and R1 are not together: o-methyl-phenyl and n-butyl, 1 espectively; or a pharmaceutically accey table salt, ester or prodrug thereof, such as herein described. The expression "bond", used throughout the description and claims, refers to "single bond". The present invention furtrei provides pharmaceutical compositions comprising an effective amount of a compound of formula (I). Further provided are method is. of treating the symptoms of a disease or condition associated with reduced levels of acetylcholine, said method comprising administering a therapeuticall' effective amount of a composition comprising a compound of formula (I). In yet a further embodiment, the present invention provides a method of treating the symptoms of a disease or condition associated with increased intraocular pressure. such as, for example, glaucoma, where the method comprises administering a therapeutically effective amount of a composition comprising a compound of formula Brief description of the Accompanying Drawings Figure 1 is a graph shoving raw data from one 96-well microtiter plate of screening of 35,000 small organic molecules in the assay described in Example XVI. Figure 2 is a graph showing data comparing the profile of the reference antagonist atropine with ml muscarinic receptor transfected cells stimulated with either carbachol (open triangles) or compund A (Example I) (closed triangles). Detailed Description of the Invention The present invention provides compounds preferably showing a relatively high selectivity towards the ml receptor subtype relative to other muscarinic subtypes which may have a beneficial effect in the treatment of cognitive impairment such as Alzheimer's disease or other conditions associated with age-related cognitive decline while avoiding the adverse af iects of the drugs hitherto suggested for this purpose. Compounds exhibiting this property have surprisingly been isolated by screening against ml-m5 receptor subtypes. Preferred embodiments of (he compound of Formula (I) are represented by compounds of Formula II, IIa and IIb (shown below), wherein R1, R2, Y, p and n are as defined hereinbefore. Particular embodimer is of the invention include: 4-Methoxy-1 -[4-(2-methy Iphenyl)-4-oxo-l -butyl]piperidine: 4-Ethoxy-1 -[4-(2-methylpehenyl)-4-oxo-1 ~butyl]piperidine: 4-Propoxy-l-[4-(2-methylphenyl)-4-oxo-l-butyl]piperidine: 4-Butoxy-1 -[4-(2-methylphenyl)-4-oxo-1 -buryl]piperidine; 4-Methoxymethyl-l-[4-( 2-methylphenyl)-4-oxo-l-butyl]piperidine; 4-Ethoxymethyl-1 -[4-(2- •nethylphenyl)-4-oxo-l-butyl]piperidine; 4-Propoxymethyl-l-[4-(2-rnethyJphenyJ)-4-oxo-l-buty]]piperidine; 4-(2-Methoxyethy 1)-1 -[4 -(2-methylphenyl)-4-oxo-1 -butyl]piperidine; 4-(2-EthoxyethyI)-l -[4-( 2-methylphenyl)-4-oxo-l-butyl]piperidine; 4-Methoxy-4-methyl-l-|4-(2-methyIphenyI)-4-oxo-l-butyI]piperidine; 4-Methoxy-4-ethyl-l-[4 (2-mnethylphenyl)-4-oxo-l-butyl]piperidine; 4-Methoxy-4-propyl-l -[ 4-(2-methylphenyl)-4-oxo-l-butyl]piperidine; 4-Methoxy-4-n-butyl-1 -[4-(2-methylphenyl)-4-oxo-1 -butyl]pipcridine; 4-Ethoxy-4-methyl-I -[4-(2-methy phenyl)-4-oxo-1 -butyl]piperidine; 4-Ethoxy-4-ethyl-l -[4-(2-methylphenyl)-4-oxo-l -butyl] piperidine; 4-Ethoxy-4-propyl-l -[4-(2-methy phenyl)-4-oxo-1 -butyl]piperidine; 4-Ethoxy-4-n-butyl-1 -[4-(2-meth lphenyl)-4-oxo-1 -butyl]piperidine; 4-Propoxy-4-methyl-1 -[4-(2-metlyphenyl)-4-oxo-1 -butyl]piperidine: 4-Propoxy-4-ethyl-1 -[4-(2-methlylphenyl)-4-oxo-1 -butyl]piperidine; 4-Propoxy-4-propyl-l-[4-(2-methlylphenyl)-4-oxo-l-butyljpiperidine; 4-Propoxy-4-n-butyl-1 -[4-(2-methlyphcnyl)-4-oxo-1 -butyl]piperidine; 4-n-Butoxy-4-methyl-1 -[4-(2-methlylpheny l)-4-oxo-1 -butyljpiperidine; 4-/i-Butoxy-4-ethyl-1 -[4-(2-methyl iphenyI)-4-oxo-1 -butyljptperidtne; 4-/j-Butoxy-4-propyl-l -[4-(2-methylphenyl)-4-oxo-l-butyljpiperidine; 4-«-Butoxy-4-M-butyl-1 -[4-(2-methylphenyl)-4-oxo-1 -butyljpiperidine; 2-[3-(4-n-Butylpiperidine)propoxy]toluene; 2-[3-(4-n-Butylpiperidine)propanesulfanyl}toluene; 2-[3-(4-n-Butylpiperidine)propanesulfinyl]toluene; 3-(4-n-Butylpiperidine)-o-tolyl butane-1 -thione; 3-(4-n-Butylpiperidinopropyl)-)-tolyl-amine; N-(4-(4-n-Butylpiperidine)l -o -tolyl-butyO-hydroxylamine; 4-n-Buty 1-1 -[4-(2-chloropheny I) -4-oxo-1 -butyljpiperidine; 4-n-Butyl-1 -[4-(2-bromophen) l)-4-oxo-1 -butyljpiperidine; 4-n-Buty 1-1 -[4-(2-fluoropheny l)-4-oxo-1 -butyljpiperidine; 4-n-Buty 1-1 -[4-(2-mercaptoph tny 1 )-4-oxo-1 -butyljpiperidine; 4-n-Butyl-1 -[4-(2-sulfanyimet iviphenyl)-4-oxo-butyljpiperidine; 4-n-Butyl-l -[4-(2-sulfanyleth: -lphenyl)-4-oxo-l -butyljpiperidine; 4-n-Butyl-1 -[4-(2-aminopheny1 )-4-oxo-1 -butyljpiperidine; 4-n-Butyl-1 -[4-(2-methylaminiophenyl)-4-oxo-1 -butyljpiperidine; 4-n-Butyl-l -[4-{2-ethylamino phenyl)-4-oxo-l -butyljpiperidine; 4-n-Butyl-1 -[4-(2-dimethylar unophenyl)-4-oxo-1 -butyljpiperidine; 4-n-Buty 1-1 -[4-(2-diethy lami lopheny l)-4-oxo-1 -butyljpiperidine; 4--Buty 1-1 -[4-( 1 -tf-imidazo 1- 2-yl)-4-oxo-1 -butyljpiperidine; 4-n-Buty 1-1 -[4-( 1 -imidazol-1 -yl)-4-oxo-1 -butyljpiperidine; 4-n-Butyl-1 -[4-( 1 -thiazol-2- y I )-4-oxo-1 -butyljpiperidine; 4-n-Butyl-l-[4-([l,2,3]triazc-l-yl)-4-oxo-l-butyl]piperidine; 2-[4-n-butyl-piperidine-1 -ethyl]- 3-methyl-3,4-dihydro-2H-naphthalen-1 -one: 2-[4-n-butyl-piperidine-1 -ethyl]- 7-methyl-indan-1 -one; 3-[4-n-butyl-piperidine-1 -ethyl]- chroman-4-one; 2-[4-n-butyl-piperidine-l-ethyl] 1 H-benzoimidazole; 4-n-Buty 1-1 -[4-(4-fluoro-2-metf y iphenyl)-4-oxo-1 -butyl]piperidine; 4-n-Butyl- l-[4-(2-hydroxyphenyl )-4-oxo-1 -butyl]piperidine; 4-n-Butyl-1 -[4-(2-methoxypher yl)-4-oxo- l-butyl]piperidine; 4-n-Buty 1-1 -[4-( 1 -thiophen-2-y )-4-oxo-1 -butyl]piperidine; 4-n-Buty 1-1-[4-(2-ethylpheny 1)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1 -[4-(2-ethoxypheny l)-4-oxo-1 -butyl]piperidine; 4-n-Butyl-l -[4-(2,4-dimethylpnenyl)-4-oxo-l-butyl]piperidine; 4-n-Butyl-l-[4-(2,3-dimethylpnenyl)-4-oxo-l-butyl]piperidine; 4-n-Butyl-1 -[4-(3-methoxyphe ny 1 )-4-oxo-1 -butyl]piperidine: 4-n-Butyl-1 -[4-(2-benzyloxypheny l)-4-oxo- l-butyl]piperidine; 4-n-Butyl-l-[4-(4-methylpheryl)-4-oxo-l-butyl]piperidine; 4-n-Butyl-N-phenyl-butyramide; 4-Methyl-l-[4-(2-methylpheryl)-4-oxo-l-butyl]piperidine; 4-n-Butyl-l-[4-(naphthalenphenyl)-4-oxo-l-butyl]piperidine; 4-Benzy 1-1 -[4-(2-methy Iphenyl)-4-oxo-1 -butyljpiperidine; 1 -[4-(2-methylphenyl)-4-oxc-1 -butyl]pyrrolidine; 4-Benzy 1-1 -[4-(2-methy Iphe iyl)-4-oxo-1 -butyl]piperazine; 2-Propyl-1 -[4-(2-methylphenyl)-4-oxo- l-butyl]piperidine; 2-Ethyl-l-[4-(2-methylphenyl)-4-oxo-l-butyI]piperidine; 4-n-Propyl-l-[4-(2-methyIpheenyl)-4-oxo-l-butyl]piperazine; 3,5-Dimethyl-1 -[4-(2-methylpheny l)-4-oxo-1 -butyl]piperidine; 4-Methy I-1 -[4-(2-methylphenyl )-4-oxo-1 -butyl]piperazine; 4-n-Hexyl-l-[4-(2-methylpienyl)-4-oxo-l-butyl]piperazine; 4-Hydroxyethyl-l-[4-(2-mithylphenyl)-4-oxo-l-butyl]pipera2ine; 4-Ethyl-1 -[4-(2-methylphenyl)-4-oxo-1 -butyl]piperazine; 4-Benzy 1-1 -[4-(4-fluorophenyl)-4-oxo-l -butyl]piperidine; 4-Benzyl-l-[4-(4-bromopl,enyl)-4-oxo-l-butyljpiperidine; 4-Phenyl-1 -[4-(2-methylp] leny l)-4-oxo-1 -butyljpiperazine; 3-Hydroxymethy 1-1 -[4-(2 methylphenyl)-4-oxo-1 -butyl]piperidine; 4-Methyl-1 -[4-(4-bromop ienyl)-4-oxo-1 -butyl]piperidine: 1 -[4-(2-methylphenyl)-4-oxo-1 -| .utyljpiperidine; 2-Hydroxymethyl-1 -[4-(2-methj lphenyl)-4-oxo-1 -butyljpiperidine: 4-Benzyl-1-[4-(2-methyIpheny 1 -4-oxo-1-pentyl]pipcrazine; 4-M-Hexyl-1 -{4-(2-methylpheny l)-4-ox°-l -pentyljpiperazine; 4-(Piperidine-1 -yl)-1 -[4-(2-met iylphenyl)-4-oxo-1 -butyljpiperidine: l-[4-(2-methylphenyl)-4-oxo-l butylJ-2,3-dihydro-l//-indole; 4-Benzyl-l-[5-(2-methylpheny )-5-oxo-l-pentyl]pipcridine; 4-n-Butyl-1 -[5-(2-methylphenyl)-5-oxo-1 -pentyl]piperidine; 4-n-Buty I-1 -[4-(2,6-dimethylpnenyl)-4-oxo-1 -butyljpiperidine; 4-n-Butyl-1 -[4-(2-methoxymehylphenyl)-4-oxo-1 -butyl]piperidine; 1 -(2-Methylpheny l)-2-(4-ben2 /Ipiperazin-1 -yI)-ethanone; 3,5-Dimethyl-1 -[5-(2-methylF henyl)-5-oxo-l-pentyljpiperidine; 3.5-Dimethy 1 -1 -[4-(4-fluorop heny l)-4-oxo-1 -butyljpiperidine; l-[4-(4-Fluorophenyl)-4-oxo-1 -butyl]pyrrolidine; 4-Benzyl-1 -[6-(2-methy Ipher yl )-6-oxo-l -hexyl]piperazine; 3,5-Dimethyl -l-[6-(2-methy pnenyl)-6-oxo-l -butyljpiperidine; 4-Benzyl-1 -[5-(2-methoxyph tnyI)-5-oxo-1 -pentyl]piperazine; 4-BenzyI-l-[3-phenyI-3-oxo-1 -propyl]piperazine; 4-n-Butyl-1 -[5-(2-methoxyp leny l)-5-oxo-1 -pentyl]piperidine; 3.5-Dimethyl-1 -[4-(4-fluoro 2-methylphenyl)-4-oxo-l-butyl]piperidine; 3-n-Butyl-1 -{4-(2-methylphi :nyl)-4-oxo-l -butyl]azetidine; 4-n-Buty 1-1 -[4-(2-methylph myl )-4-oxo-2-methyl-1 -butyl}piperidine; 4-n-Butyl-1 -[4-(2-methylpb myl)-4-oxo-2,2-dimethyl-l -butyl]piperidine; 4-n-Butyl-1 -[4-(2-methylph eny l)-4-oxo-2-ethyl-1 -butyl]piperidine; 4-n-Butyl-l-[4-(2-methylpr enyl)-4-oxo-2-propyl-l-butyl]piperidine; and 4-n-Buty 1-1 -[4-(2-methylpl ,eny l)-4-oxo-2,2-diethyl-1 -butyl]piperidine. Compounds per se specifically excluded from the scope of formula I are 4-n- Butyl-l-[4-phenyl-4-oxo-l •butyljpiperidine; 4-n-Butyl-l-[4-(2-methylphenyl)-4-oxo- 1-butyl J piperazine; 2-3-(3-n-Butylpiperidine)propanesulfanyI]toluene; and 4- Propyloxy-l-[4-(4-fluoropienyl)-4-oxo-l-butyl]piperidine (i.e., compounds where - (CH2)P-Y- is -(CH2)3-C(C)- or -(CH2)3-S-; and X, through X5 are C; such that -A- (R2)n and Ri are not togc her. o-methyl-phenyl and n-butyl, respectively; phenyl and n-butyl, respectively; or p fluoro-phenyl and -O-(CH2)2CH3. respectively). The present invention fun her provides a method of agonizing a muscarinic receptor comprising contacting the receptor with an effective amount of a compound of formula (I), inclusive of all compounds within the scope of formula (I)(i.e., including 4-n-Butyl-l-[4-pnenyl-4-oxo-l-butyl]piperidine; 4-M-Butyl-l-[4-(2- methylphenyl)-4-oxo-1 -butyl] nperazine; 2-[3-(3-n-Butylpiperidine)propanesulfanyl] toluene; and 4-Propyloxy-l-[4- (4-fluorophenyl)-4-oxo-l-butyl]piperidine). The present further provide s pharmaceutical compositions comprising an effective amount of a compound of formula (I), inclusive of all compounds within the scope of formula (I)(i.e., including -n- 3utyl-l-[4-phenyl-4-oxo-l-butyl]piperidine; 4-n-Butyl- 1-[4-(2-methylphenyl)-4-oxo- -butyljpiperazine; 2-[3-(3-n- Butylpiperidine)propanesulfaryl] toluene; and 4-Propyloxy-I-[4-(4-fluorophenyl)-4- oxo-1 -butyl]piperidine). The present invention further also provides methods of treating the symptoms of a disease or condition associa.ed with reduced levels of acetylcholine, the method comprising administering a therapeutically effective amount of a composition described herein. Exemplary diseases or conditions include neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia. The compounds of the present invention have also demonstrated the ability to reduce intraocular pressure, and therefore can be used in treatment of such diseases as glaucoma. Glaucoma is a disease in which an abnormality is observed in the circulation-control mechanism of the aqueous humor filling up the anterior chamber, i.e., the space formed between the cornea and the lens. This leads to an increase in the volume of the aquecus humor and an increase in intraocular pressure, consequently leading to the visual field defect and even to loss of eyesight due to the compulsion and contraction of the papillae of the optic nerve. The compounds of the present invention preferably show selective agonist activity towards the ml receptor. S ich an agonist is defined as a compound that increases the activity of the ml muscarine receptor when it contacts the receptor. Selectivity is defined as a property of a muscarinic ml agonist whereby an amount of agonist effective to increase the ac ivity of the ml receptor causes little or no increase in the activity of the m3 and m5 s abtypes, and preferably the m2 and m4 subtypes. As used herein, the ten a "alkyl" means a straight or branched-chain alkane group witb 1-6 carbon atoms in be chain, for instance methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, tert-butyl, et;. The term "heteroalkyl" is intended to indicate an alkane group containing 1 or 2 heteroatoms selected from O, S or N. As used herein, the term "alkenyl" means a straight or branched-chain alkene group with 2-6 carbon atoms in the chain; theterm "alkynyl" is intended to indicate a straight or branched-chain alkyne group with 2-6 carbon atoms in the chain. As used herein, the terms "aryl" and "cycloalkyl" preferably refer to mono- and bicyclic ring structures comprising 5 to 12 carbon atoms, more preferably monocyclic rings comprising 5 to 6 carlon atoms. Where such rings comprise one or more heteroatoms, selected from N. S and O, (i.e., heterocyclic rings) such rings comprise a total of 5 to 12 atoms, more preferably 5 to 6 atoms. Heterocyclic rings include, but are not limited to, furyl, pyrrolyl, pyrazolyl, thienyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyricy., piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxadiazolyl, thiadiazolyl. imidazolinyl, imidazolidinyl and the like. The ring may be substituted by one or more of the groups included in the definition of R2 above. It is inderstood that the substituents C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl or C1-6 alkoxycarbonyl may, if present. be substituted by one or more of hydroxyl, C1-4 alkoxy, halogen, cyano, amir o or nitro. As used herein, the tern "halogen" or "halo" includes chlorine, fluorine, iodine and bromine. It is understood that the ring represented by the structure may be both saturated ar d unsaturated. Compounds of the present invention may be prepared by methods analogous to the methods disclosed in GB 1,142,143 and US 3,816,433. Ways of modifying those methods to include other reagents etc. will be apparent to those skilled in the art. Thus, for instance, compounds of formula I may be prepared as shown in the following reaction scheme. The starting compound having formula (X) may be prepared by general methods of organic synthesis. For general methods of preparing compounds of formula (X), reference is made to Fuller. R. W. et al., J. Med. Chem. 14:322-325 (1971); Foye, W. 0., et al.. J. Pharm.Sci. 68 591-595 (1979); Bossier, J. R. et al.. Chem. Abstr. 66:46195h and 67:21527a (967); Aldous. F. A. B., J. Med. Chem. 17:1100-1111 (1974); Fuller, R. W. et_al., J Pharm. Pharmacol. 25:828-829 (1973); Fuller, R. W. et a]., Neuropharmacology 14:39-746 (1975); Conde, S. et al.. J. Med. Chem. 21:978- 981 (1978); Lukovits. I. et aL Int. J. Quantum Chem. 20:429-438 (1981); and Law. B., J. Cromatoe. 407:1-18 (1987), the disclosures of which are incorporated by reference herein in their ent rety. The radiolabelled derivatives having formula (XX) may be prepared by, for example, using a tritiated reducing agent to form the reductive amination or by utilizing a14C-labelled starting material. Alternatively, where the starting compound comprises a carbonyl group, the compound having the formula (XXII) may be reduced with, for example. AIH3, diborane:methyl sulfide or other standard carbonyl reducing reagents to produce the ligand having the formula (XXX). The receptor ligands having formula (XXXII) may be prepared by nucleophilic displacement of an electrophila E) by the amino derivative (XXXI). Examples of electrophiles which may be used for this purpose include halides such as I, CI, Br. tosylate or mesylate. When Y in formula (XXXII) is -C(O)- this compound may be prepared from oxidation of an sec. alcohol with for example pyridinium chlorocromate or N- chlorosuccinimide or CrO3-H 2SO4 or nickel peroxide or metal (Al, K) or DCC- DMSO. When Y in formula (XXX1I) is -O-, this compound may be prepared by alkylation of an alcohol with arylhalides under for example Cu catalysis. When Y in formula (XXXII) is -S-, this compound may be prepared by alkylation of a thiol with arylhalides under for example Cu catalysis. When Y in formula (XXXII) is -CHOH-, this compound may be prepared by reduction of the corresponding ketone by catalytic hydrogenation or by the use of NaBH4 or by the use of LiAH4 Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts whica may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharma ceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands. e.g. quarternary ammonium salts. Examples of Dharmaceutically acceptable salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate. borate, bromide, calcium, carbonate, chloride clavulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate. lactate, lactobionate, laurate, maleate, mandelate. mesylate, methylbromide, methylnitrate, methylsulfate, nitrate. N-methylglucamine ammonium salt, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannate, tartrate, tosylate, triethidide and valerate salt. The present invention inluces within its scope prodrugs of the compounds of this invention. In general, such prodrugs are inactive derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu. Where the compounds according to the invention have at least one chiral center, they may exist as a racemate or as enantiomers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of' the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also included in the scope of th is invention. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic form. or individual enantiomers may be prepared either by stereoselective synthesis o by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and egeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the processes for preparation of the compounds of the present invention, it may be necessarv and/or desirable to protect sensitive or reactive groups on any of the molecules comcemed. This may be achieved by means of conventional protecting groups, such as those described in Protective groups in Organic Chemistry, ed. J.F.W. McOmie, Plenun Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Compounds of the presert invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific pharmacological modification of the activity of muscarinic receptors is required. The present invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient. Preferably such compositions are in unit dosage forms such as tablets, pills, capsules (including sustained-release or delayed-release formulations) powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or iquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral (e.g. intravenous, intramuscular or subcutaneous), intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation, and may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington's Pharmaceutical Sciences. Gennaro, Ed., Mack Publishing Co.. Easton PA, 1990. Alternatively, the compositions may be in sustained-release form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. The present invention also contemplates providing suitable topical formulations for administration t.o. e.g. eye or skin or mucosa. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, ubricants. disintegrating agents, flavoring agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite. xanthan gum and the like. For preparing solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutic a. excipient, e.g. such as the ones described above, and other pharmaceutical diluent., e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. By the term "homogeneous" is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition may then be subdivided into unit dosage forms of the type described above containing from 0J to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner core contuining the active compound and an outer layer as a coating surrounding the core. The ofter coating may be an enteric layer which serves to resist disintegration in the stomach and permits the inner core to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with, conventional materials such as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the present compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil. coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin. methylcellulose or polyvinyl-pyrrolidone. Other. dispersing agents which may be employed include glycerin and the like. For pa enteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compositions can also be formulated as an ophthalmi: solution or suspension formation, i.e., eye drops, for ocular administration Consequently, the present invention also relates to a method of alleviating or treating a disease or condition in which modification of muscarinic receptor activity, in particular ml receptor activity, has a beneficial effect by administering a therapeutically effective amount of a compound of the present invention to a subject in need of such treatment. Such diseases or conditions may, for instance arise from inadequate stimulation or activation of muscarinic receptors. It is anticipated that by using compounds which are selective for a particular muscarinic receptor subtype, in particular ml, the problems with adverse side effects observed with the known muscarinic drugs, such as achycardia or bradycardia or gastrointestinal effects, may substantially be avoided. The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The term "therapeutically effective amount" as used herein means that amount or active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Preferably, compounds of general formula I exhibit subtype selectivity for the muscarinic ml receptor subtype Likewise, the compounds exhibit selectivity for the muscarinic ml receptor subtype compared to other human G-protein coupled receptors tested including serotonin, histamine, dopamine or adrenergic receptors. One important implication of this selectivity is that these compounds may be effective in the treatment or amelioration of a number of diseases and disorders of the central nervous system without the undesirable side effects previously observed with non- selective compounds. The ability of the compounds of the present invention to demonstrate muscarinic ml receptor subtype selectivity makes them potentially very useful in treating a number of diseases and disorders characterized by cognitive impairment such as attention deficit disorder, 01 neurodegenerative diseases, e.g. Alzheimer's disease, other forms of age-related cognitive decline, e.g. senile dementia, or dementia-related symptoms such as decreased motor activity, mood changes, anergia. apathy, restlessness and aggressive behavior. It is currently believed that the muscarinic ml receptor may also be involved in control of intraocular pressure, and that muscarinic ml agonists may therefore be used to treat or alleviate ocular diseases such as glaucoma. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses two. three or four times daily. Furthermore, compounds for the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to persons skilled in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the iosage regimen. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder which is being treated. The daily dosage of the products may be varied over a wide range from 0.01 to 100 mg per adult human pe: day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0. 10.0, 15.0, 25.0 or 50.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be reated. A unit dose typically contains from about 0.001 mg to about 50 mg of the active ingredient, preferably from about 1 mg to about 10 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, the range is from aoout 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. Compounds according to the present invention may be used alone at appropriate dosages defined by routine tt sting in order to obtain optimal pharmacological effect on a muscarinic receptor, in particular the muscarinic ml receptor subtype, while minimizing any potential toxic or otherwise unwanted effects. In addition, co-administration or sequent ial administration of other agents which improve the effect of the compound may, in some cases, be desirable. The pharmacological properties and the selectivity of the compounds of this invention for specific muscarinic receptor subtypes may be demonstrated by a number of different assay methods ising recombinant receptor subtypes, preferably of the human receptors if these are ivailable, e.g. conventional second messenger or binding assays. A particularly converiem functional assay system is the receptor selection and amplification assay disclosed in US 5,707.798 describing a method of screening for bioactive compounds by utilizing the ability of cells transfected with receptor DNA, e.g. coding for the differeni muscarinic subtypes, to amplify in the presence of a ligand of the receptor. Cell unplification is detected as increased levels of a marker also expressed by the cells. The invention is disclosed in further detail in the following examples which are not in any way intended to limit the scope of the invention as claimed. Examples Example I - 4-n-Butyl-l-f4-(2-methylphenyl)-4-oxo-l-butylJpiperidine (5) l-Benzyl-4-n-butylidenepipendine (2). A 500 mL 3-necked flask fitted with a stirrer, was charged with sodium hydride (1.61 g, 67 mmol) and DMSO (40 mL). The resulting suspension was heated to 90°C for 30 min, until the evolution of hydrogen ceased. The suspension was cooled on an ice-bath for 20 min followed by addition of a slurry of butyltriphenylphospnomum bromide (26.6 g, 67 mmol) in DMSO (70 mL). The red mixture was stirred for 15 min at rt. l-Benzyl-4-piperidone 1 (14.0 g, 74 mmol) was slowly added over 30 min. and the mixture was stirred at room temperature over night. H2O (200 mL) was added to the reaction mixture followed by extraction with heptane (4 x 100 mL) and ethyl acetate (2 x 100 mL). The combined organic phases were dried and evaporated to dryness, producing 38.1 g of a yellow oil. The oil was distilled to give 14.9 g (88 %) of 2, bp 101-105°C (0.1 mm Hg). 1H NMR (CDC13) 0.90-0.95 (1, 3H), 1.25-1.41 (m, 2H), 1.90-2.20 (m, 2H), 2.18-2.30 (m, 4H), 2.40-2.45 (m, 4H), :.50 (s, 2H), 5.17 (t, 1H), 7.20-7.42 (m, 5H). 4-n-Butylpiperidine (3). It a 500 mL flask fitted with a stirrer was added a slurry of 2 (13.2 g, 58 mmol) and 10% palladium on charcoal (1.2 g) in ethanol (70 mL), followed by addition of concentrated hydrochloric acid (1.5 mL). The reaction flask was evacuated and hydroget was added via a reaction flask. A total of 2.5 dm3 of hydrogen was consumed. The reaction mixture was filtered and evaporated and the residue was dissolved in H20 (40 mL) and NaOH (20 mL, 2 M) followed by extraction with ethyl acetae (3 x 100 mL). The combined organic phases were washed with brine (30 mL) and evaporated to dryness to produce 7.1 g of crude 3. The crude product was subjected to CC [eluent: heptane : EtOAc (4:1)] to give pure 3 (2.7 g, 33%). 1H NMR (CD3l3) 0.85 (t, 3H), 1.0-1.38 (m, 9H), 1.65 (dd, 2H). 2.38 (s. 1H), 2.55 (dt, 2H), 3.04 dt, 2H). 4-(4-n-Butylpiperidin-l ytybutanenitrile (4). In a 100 mL flask with a magnetic stirrer was placed 3 (2.3g 16.4 mmol), 4-bromobutyronitrile (2.4 g, 16.4 mmol), potassium carbonate powder 25 g, 18 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 5 h followed by addition of H2o5 mL). The mixture was extracted with ethyl a:etate (3 x 30 mL) and the combined organic phases were evaporated to dryness to product 19 of crude 4. The crude product was subjected to CC [eluent: heptane : EtOAc (1:1)] to give pure 4 (2.3 g, 87%). 'H NMR (CDC13) 0.82 (t, 3H), 1.19-1.37 (m, 9H), 1.64-1.75 (d, 2H), 1.84-2.01 (m, 4H), 2.39-2.54 (m. 4H), 2.89-2.97 (d, 2H). 4-n-Butyl-l-[4-(2-methylphenyl)-4-oxo-l-butyl]piperidine (5). In a 25 mL oven- dried flask was charged Mg turnings (125 mg, 5.2 mmol) which were activated by the use of a heat-gun. Under inert atmosphere was added a suspension of 2-iodoanisole (1.13 g, 5.2 mmol) in Et20 (4 mL) and the reaction mixture was allowed to stand at rt for 1 hour. Compound 4 (720 mg, 3.4 mmol) dissolved in Et20 (4 mL) was added and the mixture was refluxed over-light. THF (15 mL) and sulfuric acid (4 mL, 2 M) was added and the reaction mixture was stirred for 4 h, followed by addition of NaOH (6 mL, 2 M). The reaction mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases wen evaporated to dryness to produce 1.2 g of crude S. The crude product was subjected to CC [eluent: CH2C12:CH30H (99:1)] to give pure 5 (0.42 g, 26%). 'H NMR (CDCI3) 0.83 (t, 3H), 1.20-1.42 (m, 9H), 1.65-1.73 (d, 2H), 1.96-2.20 (m, 4H), 2.53 (t, 2H), 3.02-3.17 (m, 4H), 3.89 (s, 3H), 6.95-7.01 (m, 2H), 7.44 (t, 1H), 7.65 (d,lH). Example II - 3-Hydroxymetnyl-l4-(2-methylphenyl)-4~oxo-l-butyl]piperidine (7) 4-(3-Hydroxymethyl-pipendm-l-yl)-butyronitrile (6). In an oven-dried 25 mL flask was placed piperidine- 3-yl-methanol (1.12 g, 10 mmol) in acetonitrile (10 mL), followed by addition of potassium carbonate (1.38 g, 10 mmol) and 4- bromobutyronitrile (0.90 ml., 9 mmol). The reaction mixture was stirred at rt. for 12 h. The mixture was filtered and evaporated to dryness. Addition of H2O (20 mL) was followed by extraction with ethyl acetate (3 x 20 mL) and the combined organic phases were dried (MgSO4 and evaporated to dryness to produce 1.50 g of crude 6 which was used without further purification in the synthesis of compound 7. 3-Hydroxymethyl-[4-(2' methylphenyl)-4-oxo-l~butyl]piperidine (7). In a 50 mL oven-dried flask was added Mg turnings (780 mg, 32 mmol), which were activated by the use of a heat-gun unde - vacuum, followed by addition of anhydrous THF (7 mL). Under inert atmosphere was added a suspension of 2-iodotoluene (5.3 g, 24 mmol) in THF (10 mL) and the reaction mixture was allowed to reflux for 4 hours. A suspension of compound 6. (1.50 g, 8 mmol) in THF (5 mL) was added via a syringe followed by addition of CaBr (23 mg, 0.16 mmol. 2 mol %) and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (20 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaQH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraction with CH2CI2 (3 x 20 mL), and the organic phases were dried (MgSO4) and evaporated to dryness to produce 0.41 g of crude 7. The crude product was subjected to preparative HPLC CC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH2CN + 0.1%TFA] to produce an analytical pure sample of compound 7. LC-MS [N'+ H]+ 275 (cald. 275.2). Example III - 2-Propyl-l4~(2'meihylphenyl)-4-oxo-l'butyl]piperidine (9) 4-(2-propyt-piperidin-l-yl)-butyronitrile (8). A mixture of 2-propylpiperidine (550 mg, 4.3 mmol), 4-bromobutyronitrile (430 mg, 3.0 mmol) and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (5 mL) was stirred at rt for 12 h.. followed by addition of a satarated brine (25 mL). The reaction mixture was extracted with ethyl acetate (3 x 25 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce crude 8. The crude product was subjected to CC [eluent: CH2C13 : MeOH (99:1)] to give pure 8 (0.48 g, 83 %); LC- MS (M + H) 194 (cald. 194.2'. 2-Propyl-{4-(2-methylphetyl)-4-oxo-I-butyl]piperidine (9). In a 10 mL oven- dried flask was added Mg turnings (97 mg, 4.1 mmol) which were activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 2-iodotoluene (380 1, 2.8 mmol) in Et20 (3 mL) and the reaction mixture was allowed to reflux for 1 hour. A mixture of compound 8 (0.43 g, 2.2 mmol) in CH2cl2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 12 hours followed by addition of NaOH (10 mL, 2 M). Addition of THF (15 mL) was followed by extraction with ethyl acetate (3 x 50 mL) and the combined organic phases are washec with brine (10 mL) and NaOH (10 mL, 2 M), dried (MgSCM and evaporated tc dryness to produce 0.43 g of crude 9. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN + 0.1%TFA] to produce an analytically pure sample of compound 9; LC-MS [M+H]+ 287 (cald. 287.2) Example IV - l-[4-(2-methylphenyl)-4-oxo-l-butyl]piperidine (11) In a 10 mL oven-dried flask was added Mg turnings (97 mg, 4.1 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 2-iodo-toluene (380 L, 3.0 mmol) in Et20 (3 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of 4-piperidin-l-yl- butanenitrile 10 (Dahlbom et. al. Acta. Chem. Scand. 1951, 5, 690-697) (0.305 mg, 2.0 mmol) in CH2G2 (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL, 2 M) and stirred at rt for 12 hours followed by addition of NaOH (12 mL, 2 M). Addition of THF (15 mL) was fo lowed by extraction with ethyl acetate (3 x 50 mL), and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and dried (MgSO4) and e\aporated to dryness to produce 0.21 g of crude 11. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN + 0.1°/TFA] to produce an analytically pure sample of compound 11; LC-MS [A/+ H]+ 145 (cald. 245.2). Example V - 4-methyl-l-[4-(4-bromophenyl)-4-oxo-l-butyl]piperidine (12) In a 10 mL dried flask was acded 4-methylpiperidine (719 L, 6 mmol), dioxane (5 mL) followed by addition of potassium carbonate (0.30 g, 2.18 mmol), potassium iodide (10 mg) and 4-bromo-4 chlorobutyrophenone (785 mg, 2.76 mmol). The reaction mixture was left at 110°C for 12 h., followed by dilution with H2O (10 mL). The reaction mixture was extracted with Et2O (3x15 mL) and the combined organic phases are dried (MgSCo4) and evaporated to dryness to produce 0.50 g of crude 12. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN + 0.10/oTFA] to produce an analytical pure sample of compound 12; LC-MS [M+ H]+ .' 22 (cald. 323.1). Example VI - l-l4-(2~methylphenyl)4-oxo-l-butyljpyrrolidine (13) In a 10 mL oven-dried flask .vas charged Mg turnings (30 mg, 1.2 mmol) which were activated under vacuum by tne use of a heat-gun. Under inert atmosphere was added a solution of 2-iodotoluene (0.22 g, 1.0 mmol) in Et20 (2 mL) and the reaction mixture was allowed to reflux for hour. A mixture of 4-pyrrolidin-l-yl-butyronitrile (Burckhalter et. al. J. Org. Chem. 1961, 26, 4070-4076) (0.14 g, 1.0 mmol) in CH2C12 (2 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (10 mL. 2 M) and stirred at rt for 2 hours followed by addition of NaOH (10 mL, 2 M). Addition of THF (15 mL) was followed by extraction witi ethyl acetate (3 x 20 mL), and the organic phases were dried (MgS04) and evapoiated to dryness to produce 0.12 g of crude 13. The crude product was subjected tc preparative HPLC [eluent: Buffer A: 0.1% TFA: Buffer B: 80% CH3CN + O.l'/cTFA] to produce an analytical pure sample of compound 13. LC-MS [A/+ H]* :'.31 (cald. 231.3). Example VII - 4-Methyl-l-{4-(2-methylphenyl)4-oxo-l-butyljpiperazine (15) 4'(4-Methyl-piperazin-]-yl)-butyronitrile (14). In a 25 mL flask was placed 1- methyl-piperazine (0.52 g, 5.1 mnol), 4-bromobutyronitrile (0.78 g, 5.3 mmol) and potassium carbonate (0.71 g, 5.3 mmol) suspended in acetonitrile (5 mL). The reaction mixture was stirred at rt or 4 h.. followed by addition of H2O (20 mL) and extraction with ethyl acetate (3x25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO crude 14 which was used without further purification in the synthesis of compound 15. 4-Methyl-]-[4-(2-methylphenyl,4'Oxo-l-butyl]piperazine (15). In a 10 mL oven- dried flask was added Mg turnings (116 mg, 4.0 mmol) which were activated under vacuum by the use of a heat-gun. I Jnder inert atmosphere was added a mixture of 2- iodotoluene (0.65 g, 3.0 mmol) in I'x^O (3 mL) and the reaction mixture was allowed to reflux for 1 hour. A solution of compound 14 (0.33 g. 2.0 mmol) in CH2CI2 (3 mL) was added via a syringe arid the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (6 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraction with CH2C 2 (3 x 20 mL). The organic phases were dried (MgSO«) and evaporated to dryness tc produce 0.26 g of crude 15. The crude product was subjected to preparative HPLC feluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN + 0.1%TFA] to produce an analytically pure sample of compound 15. LC-MS [M+H]* 260 (cald. 260.4). Example VIII - 4-n-Butyl-l-[4-(2- 4-(4-Butyl-piperazin-l-yl)-buryronitrile (16). In a 25 mL flask was placed 1-butyl- piperazine (712 nig, 5.0 mmol), 4-bromobutyronitrile (779 mg, 5.3 mmol) and potassium carbonate (687 mg, 5.0 mmol) suspended in acetonitrile (5 mL), The reaction mixture was stirred at rt for 12 h., followed by addition of H2O (20 mL) and extraction with ethyl acetate (3x25 mL). The combined organic phases were washed with brine (25 mL). dried (MgSC4) and evaporated to dryness to produce 0.89 g of crude 16 which was used withoui further purification in the synthesis of compound 17. 4-n-Butyl-l-[4-(2-methylphenyl)4-oxo-l-butyl]piperazine (17). In a 10 mL oven- dried flask charged with Mg turnings (100 mg, 4.0 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 2-iodotoluene (0.66 g, 3.0 mmcT in Et20 (3 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of compound 16 (0.43 g, 2.0 mmol) in CH2CI2 (3 mL) was added via * syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO4 (6 mL, 2 M) and stirred at rt for 2 hours followed oy addition of NaOH (8 mL, 2 M). Addition of THF (15 mL) was followed by extraciion with CH2CI2 (3 x 20 mL), and the organic phases were dried (MgSO«) and evapoiated to dryness to produce 0.50 g of crude 17. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA; Buffer B: 80% CH3CN + 0. %TFA] to produce an analytical pure sample of compound 17. LC-MS [M+ H]* 302 (cald. 302.5). Example IX - 4-n-Butyl-l-l4-(J.-ethoxyphenyl)-4-oxo-l-butyl]piperidine (IS) In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated by the use of a heat-g .in under vacuum. Under inert atmosphere was added a suspension of l-ethoxy-2-iodo benzene (0.71 g, 2.9 mmol) in Et20 (3 mL) and the reaction mixture was allowed ' 0 reflux for 3 hours. Compound 4 (0.40 g, 1.9 mmol) dissolved in CH2CI2 (3 mL) was added and the mixture was stirred at 40°C for additional 3 hours. The reaction mixture was quenched by addition of H2SO4 (10 mL. 2 M) and left stirring overnight at room temperature, followed by addition of NaOH (20 mL, 2 M) until basic coiiditions. The reaction mixture was extrated with ethyl acetate (3 x 50 mL)) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL. 2 M). anc the combined organic phases were dried (MgS04) and evaporated to dryness to produce 0 60 g of crude 18. The crude product was subjected to CC [eluent: Tol : EtOAc (1:1)] to give pure 18 (0.32 g, 34 %); LC-MS [M + Hf 331 (cald. 331.5). Example X - 4-n-Butyl-I-f4-(2,3-c'imethylphenyl)-4-oxo-l-butyl]piperidine (19) In a 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of l-iodo-2.3-dimethylbenzene (0.69 g, 3.0 mmol) in Et2O (5 mL) under spontaneously reflux, and the reac :ion mixture was allowed to reflux for 4 hours. A suspension of compound 4 (0.41 g„ 2.0 mmol) in CH2CI2 (2 mL) was added to the reaction mixture and left at rt ovimight. The reaction mixture was quenched by addition of H2SO4 (7 mL, 2 M) and stirred at rt for 3 hours, followed by addition of NaOH (20 mL, 2 M) until basic conditions. The reaction mixture was extracted with ethyl acetate (3 x 50 mL) and the CDmbined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), iind the organic phases were dried (MgS04) and evaporated to dryness to produce 0 69 g of crude 19. The crude product was subjected to CC [eluent: CH2C12 : MeOH (94>:l)] to give pure 19 (0.40 g, 64 %); LC-MS [M + H]+315 (cald. 315.5). Example XI - 4-n-Butyl-l-[4-(2,4-dimethylphenyl)-4-oxo-l-butyl]piperidine (20) In a 10 mL oven-dried flask charged with Mg turnings (95 mg, 3.9 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of l-iodo-2,4~iimethyIbenzene (0.69 g, 2.9 mmol) in Et20 (4.5 mL) under spontaneously reflux, and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.41 g, 2.0 mmol) dissolved in CH2CI2 (2 mL) was added under inert atmosphere to the reaction mixture and left stirring at rt overnight. The reaction mixture was quenched by addition af H2SO4 (8 mL, 2 M) and stirred at rt for 4 hours, then the reaction mixture was basilied by addition of NaOH (20 mL, 2 M). Addition of THF (20 mL) was followed by extraction with ethyl acetate (3 x 50 mL) and the 1 combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M). and the organic phases were dried (MgS04) and evaporated to dryness to produce 0.61 g of crude 20. The crude prociuct was subjected to CC [eluent: CH2CI2 : MeOH (99:1)] to give pure 20 (0.21 g, 35 %); LC-MS [M+ Hf 315 (cald. 315.5). Example XII - 4-n-Butyl-l-f4(2-methoxyphenyl)-4-oxo-I-buiyl/piperidine (21). In a 10 mL oven-dried flask charged with Mg turnings (0.12 g, 4.9 mmol) which was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of l-brom.>-2-ethylbenzene (0.66 g, 3.6 mmol) in Et20 (2 mL) and the reaction mixture was allowed to reflux for 2 hours. A suspension of compound 4 (0.50 g, 2.4 mmol) in CH2CI2 (2 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H2SO« (14 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (20 mL. 2 M). Addition of THF (20 mL) was followed by extraction with ethyl acetate (3 x 50 mL) and the: combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M) and the organic phases were dried (MgS04) and evaporated to dryness to produce 0.75 g of crude 21. The crude product was subjected to CC [eluent: CH2C12 : MeOH (99:1)] to give pure 21 (0.68 g, 90 %); LC-MS [M + H]* 315 (cald. 315.5). Example XIII - 4~n-Butyl'l-[4-(*',4-dimethylphenyl)-4*>xo-l-butylJpiperidine (22) A 10 mL oven-dried flask was charged with Mg turnings (88 mg, 3.6 mmol) andweactivated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of l-Iodo-2-m<:thoxymethylbenzene g mmol in et20> mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of compound 8 (0.38 g, 1.8 mmol) ii CH2C12 (4 mL) was added via a syringe and the reaction mixture was stirred at rt Dvemight. The reaction mixture was quenched by addition of H2S04 (10 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (10 mL. 2 M). Addition cf THF (15 mL) was followed by extraction with ethyl acetate (3 x 50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL. 2 M), and the organic phases were dried (MgS04) and evaporated to dryness to produce 0.51 g of crude 22. The crude product was subjected to CC [eluent: CH2C12: MeOH (99:1)] to give pure 22 (0.14 g, 23 %); LC-MS [M + Hf331 (cald. 331.5). Example XIV - 4-n-Butyl-l-/4-(2~pyridinyl)-4-oxo-l-butyI]piperidine (24) 4-(4-Butyl-piperidin-l~yl)butyrh acid methyl ester (23). To a 25 mL reaction flask was added 4-bromo-butyric acid methyl ester (2.04 g, 11.2 mmol), compound 3 (1.51 g, 10.8 mmol) and potassium carbonate (1.63 g, 11.8 mmol) suspended in CH3CN (10 mL). The reaction mixture was stirred over-night at rt followed by filtration and evaporation to drynejs. Addition of H2O. (50 mL) was followed by extraction with ethyl acetate (3 x 1 (MgSO*) and evaporated to dryness to produce 2.84 g of crude 23. The crude product was subjected to CC [eluent: CH2C 2 : MeOH (99:1)] to give pure 23 (1.93 g, 75%). LC-MS [M+ Hf 241 (cald. 241.2). 4-n-Butyl-l-[4-(2-pyridinyl)-4-oto-l-butyl]piperidine (24). To a dry 25 mL reaction flask was added 2-bromopyridine (200 mg, 1.3 mmol) dissolved in CH2CI2 (3 mL) and the temperature was adjisted to -78°C. After being stirred for 20 min, addition of n-BuLi (0.84 mL, 1.4 mmol) was conducted under inert atmosphere. After additional 30 min, a solution of 23 dissolved in CH2O2 (2 mL) was added. The reaction mixture was left to warm to rt over-night before being quenched with H2SO4 (5 mL. 1 M). The reaction mixture was extracted with ethyl acetate (6 x 25 mL) and the combined organic phases wen: dried (MgSC^) and evaporated to dryness, to produce 0.31 g of crude 24. The crude product was subjected to CC [eluent: CH2CI2: MeOH (10:1)] to give pure 24 (75 mg, 12%). LC-MS [M+ Hf 288 (cald. 288.2). Example XV - 4-n-Butyl-l-[4-(2-h_>droxyphenyl)-4-oxo-l-butylJpiperidine (27) l-Benzyloxy-2-iodo-benzene (25). In a 25 mL ovendried flask 2-iodophenol (1.03 g, 4.7 mmol) and potassium carbonate (0.71 g, 5.2 mmol) were dissolved in dry acetone (10 mL). The mixture was stirred for 15 min followed by addition of benzylbromide (0.61 mL, 5.2 mmol) and left over-night at rt. Addition of H2O (50 mL) followed by extraction with etiiyl acetate (3 x 50 mL) and the combined organic phases were dried (MgSCu) and eviporated to dryness, to produce 1.7 g of crude 25. The crude product was subjected tc CC [eluent: Heptane : EtOAc (9:1)] to give pure 25 (1.2 g, 81%). LC-MS [M+ H]+ I-10 (cald. 310.0). 4-n-Butyl-l-[4-(2-benzyloxypheiyl)-4-oxo-l-butyl]piperidine (26). In a 25 mL oven-dried flask was added Mg tunings (123 mg, 5.1 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a solution of l-benzyloxy-2-iodo-benzene (25) (.18 g, 3.8 mmol) in Et20 (10 mL) and the reaction mixture was allowed to reflux for 3.5 hours. A solution of 4-(4-n- butylpiperidin-l-yl)butanenitrile 4 (0.53 g, 2.5 mmol) dissolved in CH2CI2 (3 mL) was added and the reaction mixtur; and was stirred at 40°C over-night. The reaction mixture was quenched by addition M'HiSCu (10 mL. 2 M) and left stirring for 1 hour. followed by addition of NaOH (20 mL. 2 M) until basic conditions. The reaction mixture was extrated with ethy acetate (3 x 50 mL) ) and the combined organic phases are washed with brine (\1 mL) and NaOH (10 mL, 2 M), and the combined organic phases were dried (MgSD crude 26. The crude product was subjected to CC [eluent: Tol : EtOAc (1:1)) to give pure 26 (0.51 g, 51 %); LC-MS [//+ Hf 393 (cald. 393.7). 4-n-Butyl-l-[4-(2-hydroxyphe>ryl)-4-oxo-]-butyl]pipehdine (27). To a 25 mL reaction flask was added a solution of 4-n-ButyI-l-[4-(2-benzyloxyphenyl)-4-oxo-]- butyl]piperidine (26) (49 mg. 1.2 mmol) dissolved in dry EtOH (10 mL) and cone. HC1 (0.1 mL) followed by addition of palladium on charcoal (40 mg). The reaction flask was then charged with Hj by the use of balloon technique and left stirring at rt over-night under H2 atmosphere. The reaction mixture was basified by addition of NaOH (2 mL, 2.0 M) and filtered through celite. The aqueous phase was extracted with ethyl acetate (3 x 50 mL) and the combined organic phases were washed with brine (10 mL) and NaOH (10 mL, 2 M), dried (MgS04) and evaporated to dryness to produce 0.42 g of crude 27. The crade product was subjected to CC (eluent:: CH2Ch : MeOH (99:1)] to give pure 27 (0-1 g, 58 %); LC-MS [M + H]+ 303 (cald. 303.2). Example XVI - Screening of test compounds in an assay using muscarinic receptor subtypes ml, ml, mi, m4 and mS Transfection of cells -with muscarinic receptor DNAs (general procedure) NIH 3T3 cells (available from the Amercan Type Culture Collection as ATCC CRL 1658) were grown at 37°C in a humidified atmosphere (5% C02) incubator in Dulbeccos modified Eagle's medium (DMEvf) supplemented with 4.5 g/1 glucose, 4 raM glutamine, 50 units/ml penicillin, 5D units/ml streptomycin (available from Advanced Biotechnologies, Inc., Gaithersburg, MD) and 10% calf serum (available from Sigma, St. Louis, MI). The cells were treated with trypsin-EDTA, spun down and plated at 2xl06 per 15 cm dish in 20 mi of D vIEM containing 10% calf serum. The ml-m5 muscarinic receptor subtypes were cloned substantially as described by Bonner et al., Science 257,1987 p. 527, and Bonner et al., Neuron 1,1988. p. 403. For the m2 and m4 receptors, the cells were co-transfected with DNA encoding a chimera between the Gq protein and the five carboxy-terminal amino acids of the Gi protein (the Gq-i5 construct is described by Conklin et al., Nature 363,1993, p.274). On day one. the cells were transfected using the Superfect transfection reagent (available from Qiagen, Valen:ia, CA) in accordance with the manufacturer's instructions. Receptor DNA, 3-gal DNA (pSI-P-galactosidase available from Promega, Madison , WI), chimeric Gq-i5 DNA for the m2 and m4 receptor subtype assays, and salmon sperm DNA (available from Sigma, St. Louis, MI) as filler to a total of 20 ug DNA was addec per plate. Prior to addition to the plates, 60 ul Superfect was added to the DNA and mixed thoroughly by pipetting up and down several times. The mixture was intubated at room temperature for 10-15 minutes. The media were aspirated, and 12 m fresh DMEM containing 10% calf serum and 50 units/ml penicillin/streptomycin was added to the plates. The DNA-Superfect solution was mixed once more with a pipette and added to the plate which was swirled to distribute the DNA mixture, evthly over the surface. The cells were incubated overnight at 37°C and 5% C02. After incubation, the media wt:re aspirated and the plates were rinsed once with a 15 ml volume of Hank's Buffered Saline. The plates were swirled to ensure thorough rinsing. 20 ml fresh DMEM supplemented with 10% calf serum and 50 units/ml penicillin/streptomycin was added to the plates. The cells were incubated for 24-48 hours until the plates were 100% confluent. Assay of NIH 3T3 cells transacted with muscarinic receptor subtypes (general procedure) DMEM containing 2Vo Cyto-SF3 was heated at 37°C in a water bath under sterile conditions. Sterile working stock solutions of test compounds to be assayed were prepared by diluting the compounds in DMEM to 8x the final concentration for testing. The compound (carbachol) to be included in the assay as a positive control was also diluted ir DMEM to 8x the final concentration. 50 ^1 of the DMEM containing 2% Cyto-SF3 was added to each well of 96-well microtiter plates under sterile conditions. Then, 16 fj.1 of compound solutions were added to the top wells of the plates, and dilution of the solutions was performed by taking 16 ul of the compound solutions from the top v/ells and pipetting them into the next row of wells. This procedure was repeated with each subsequent row of wells, except that 50 ul medium alone was added to the baseline control wells (the wells that contain medium and cells, but not test compounds) and plate control wells (wells containing medium, but not test compounds and cells). The plates were then placed in an incubator at 37°C to equilibrate temperature and pH. When the cell cultures had reached 100% confluence, the medium was aspirated and each plate was rinsed with 15 ml Hank's Buffered Saline (HBS), The cells were left in the incubator for about 10-15 minutes until the HBS had turned slightly yellow. The HBS was then aspirated and ml trypsin was added to each plate and swirled so as to completely cover the plates. The edges of the plates were gently rapped several times to loosen the cells. After the cells had been dislodged from the surface, 8 ml DMEM containing 10% calf serum and 50 units/ml penicillin and 50 units/ml streptomycin was added to inhibit the trypsin. The plates were rinsed with this medium, and the cells were pipetted into a tube. The cells were centrifuged at 1000 rpm for 5-10 min. in an IEC Centra CL2 centrifuge (produced by Sorvall). Afterwards, the medium was caref ally aspirated so as not to dislodge the cells. The cell pellet was suspended in 1600 ul DMEM containing 10% calf serum and 50 units/ml penicillin and 50 units, ml streptomycin, after which 20 ml DMEM supplemented with 2% Cyto-SF3 was added. 50 μ1 aliquots of this cell suspension was added to the wells of the 96-well microtiter plates prepared above (except for the plate control wells). The plates were then incubated for 4 days at 37°C and 5% CO2. After incubation, the medium was removed by inverting the microtiter plates and shaking them gently, after which they were blotted on absorbent paper. 100 ul chromogenic substrate (3.5 mM o-nitrophenyl-β-D-gaiactopyranoside, 0.5% Nonidet NP-40, in phosphate buffered salinei was added to each well, and the plates were incubated at 30°C until the optimum absorbance at 405 nm was obtained. The asborbance of the baseline and plate control wells were subtracted from all values. Results Using the general procedure described above, NIH 3T3 cells were co- transfected with DNAs encoding the ml, m3 and m5 receptor subtypes. A compound library containing approximately 15,000 small organic compounds (1 per well) was screened against the receptors by the procedures described above. Fig. \ illustrates data from one 96-well plate from the screen. On this plate, two compounds were active at one or more of the traisfected receptors. In the total screen, four related compounds were identified that showed activity. To determine which of the receptors were activated in the screen, the compounds were tested as described above against each of the receptors transfected into separate cell cultures. Compound A only activated the ml receptor subtype, at which it was a potent partial agonist, inducing a lower maximal response than the reference compound carbachol. In further experiments, the our compounds were found to selectively activate the ml receptor with no significant activity at the m2. m3, m4 or m5 muscarinic receptors. The most active compound, compound A, was not an antagonist of carbachol-induced responses of the five muscarinic receptor subtypes. Compound A was further lested for agonist activity against several other receptors at the a-adrenergic receptor subtypes 1D, 1B, 1A, 2A, 2B and 2C, the histamine H1 and the serotonin 5-HT1A and 5-HT2A subtypes. The compound showed no significant activity in these assays. In antagonist experiments, compound A did not inhibit responses of the α-adrenergic receptor subtypes 2A, 2B or 2C, or the serotonin receptor subtypes 5-HT1A or 5-HT2A. As illustrated in Figure 2. the responses induced by compound A were blocked by the muscarinic antagonist atropine with the same potency as were resporses induced by the muscarinic agonist carbachol. Example XVII - RSATAssay R-SAT assays (see U.S patent no. 5,707,798. incorporated herein by reference) were carried out where cells transfected with ml, m3 or m5 receptors were exposed to seven compounds at 1.5 )μM concentration. Cellular response is expressed as a percentage of the maximum response of the cells (defined as response to 10 μM carbachol). The results are presented in the following table. As indicated above, the compunds are selective agonists of the ml receptor. The invention described anc claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Various references are cited nerein, the disclosures of which are incorporated by reference in their entireties. I. A compound of formula (I): wherein R1 is straight or branched-chain C2-8 alkyl, C2-8alkenyl, C2-8 alkynyl, C1-8 alkylidcne. C1-8 alkoxy, C1-8heteroalkyl, C1-8amino ikyl, C1-8haloalkyl, C1-8alkoxycarbonyl, C1-8hydroxyalkoxy, C1-8hydroxyallyl, -SH, C1-8thioalkyJ, or -O-CH2-C5-6 aryl; A is C5-7 cycloalkyl, phenyl, naphthyl or G3-l2 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S; when A is C5-7 cycloalkyl, naphthyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxyl, halo, or straight or branched-chain C1-6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, C1-6 akoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, -CN, -CF3:, -OR3, -COR3, NO:, -NHR3, -NHC(0)R3, -C(O)NR3R4, -NR3R4, -NR3C(O))NR4R5, -OC(O)R3, or -(CH2)qNR3.R4 where R3, R4 and R5 are the same or different, each independently being selected from H3, C1-6 alkyl; C5-6aryl optionally comprising I or more heteroatoms selected from N, O and S, and optionally subst tuted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from I to 6; or when A is phenyl, R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C1-6 alkenyl, C2-6 alkyny , C1-6 alkoxy, C1-6 heteroalkyl, c-6 aminoalkyl, G.s haloalkyl, Cr, alkoxycarbonyl, -CN, -CF3, -OR3, -COR,, N02, -NHR3, -NHC (0)R3, -C(0)NR3R4, -NR3R4, -SR3C(0)NR4R5, -OC(0)R3, or -(CH2)(|NR3R4; where R3. R4 and R5 are the saint; or different, each independently being selected from H, C1-6 alkyl; C5-6 aryl opt onally comprising I or more heteroatoms selected from N, O and S, and optic nally substituted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; n is 1, 2, 3 or 4, the groups R2, when n > 1, being the same or different; p is 0 or an integer from I 10 5; Y is -NHC(O)- or -C(O)- and Z is a bondor CR8R9 wherein Rg and R9 are independently selected from H, and straight or branched chain C1-8 alkyI; provided where -(CH2)P-Y- is -. C H2)3-C(O)-, that -A-(R2)n and R1 are not together: o-methyl-phenyl and n-butyl, respectively; or a pharmaceutically acceptable salt, ester or prodrug thereof, such as herein described. 2. The compound as claimed i 1 claim 1, wherein Ri is straight or branched-chian C2-8 alkyl, C2-8alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy, C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl; n is 1,2 or 3, A is phenyl and R2 is chloro, bromo, straighi or branched-chain G.« alkyl, C2.6 alkenyl, C2.6 alkynyl, C1-6 alkoxy, C1-6 heteroalk; I: C1-6 aminoalkyl, C1-6haloalkyl, C1-6alkoxycarbonyl, -CN, -CF3, -COR3, -NHR3, -NHC(O)R3, -C(0)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O) R3. or -0(CH2)qNR3 or A is thienyl; and R2 is H, halo, straigh: or branched-chain G-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 alkoxy, C1-6he eroalkyl; C1-6aminoalkyl, C1-6 haloalkyl,C1-6 alkoxycarbonyl, -CN, -CF3, -COR3, -NHR3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3, or -O(CH2)qNR3. or a pharmaceutically acceptab e salt, ester or prodrug thereof, such as herein described. 3. The compound as claimed in claim 1 or claim 2, wherein p is 3. 15. The compound as claimed in claim 14, wherein R2 is alkyl, aminoalkyl, alkoxy or hydroxy I. 16. A compound as claimed in 1claim 15, wherein p is 3. 17. The compound as claimed n claim 16, wherein R2 is methyl, hydroxyl or alkoxy. 18. The compound as claimed n claim 17, wherein Y is-C(O)-. 19. The compound as claimed in claim 14, wherein R2 is chloro or bromo. 20. The compound as claimed in claim 6, wherein R1 is alkoxy. 21. The compound as claimed-n claim 1, wherein Y is -NHC(O)-; p is 2; and Z is a bond. 22. The compound as claimed n claim 1. wherein Y is -C(O)-; p is 3; and Z is a bond. 23. The compound as claimed in claim 21, wherein n is 1 or 2. 24. The compound as claimed in claim 2, wherein A is thienyl. 25. The compound as claimed in claim 24, wherein Y is -C(O)-. 26. The compound as claimed in any one of claims 24 or 25, wherein R2 is halo, C1-6 alkyl, orC1-6 alkoxy. 27. The compound as claimed in claim 24, wherein Y is -NHC(O)-. 28. The compound as claimed in claim 5, [and] wherein R2 is halo, C1-6 alkyl, or C1-6 alkoxy. 29. The compound as claimed in claim 25, wherein p is 3. 30. The compound as claimec in claim 25, wherein Z is a bond. 31. The compound as claimec in claim 29, wherein Z is a bond. 32. The compound as claimec in claim 27, wherein p is 2. 33. The compound as claimed in claim 27, wherein Z is a bond. 34. The compound as claimed in claim 32, wherein Z is a bond. 35. A compound of formula (1la): R1 is alkoxy; R2 is amino, hydroxy!, chloro, bromo, or straight or branched-chain C1-6 alkyl, C1-6 alkenyl, C1-6alkynyl, Cw alkoxy, C1-6heteroalkyl, C1-6 aminoalkyl, C1-6haloalkyl, C1-6 alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, N02, -NHR3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4R5, -OC(O)R3, or -(CH2)qNR3R4; where R3, R4 and R5 are the same or different, each independently teing selected from H, Cw alkyl; C5-6aryl optionally comprising I or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6alkyl; C1-6 cycloulkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from I to 6; p is 0 or an integer from :o 5; Yis -NHC(O)-or -C(O1-6or a pharmaceutically acceptable salt, ester or prodrug thereof, such as herein described. 36. A compound of formula (1 lb): wherein R1 is alkoxy; R2 is amino, hydroxyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-6alkoxy, C1-6 heteroalkyl, C1-6 aminoalkyl, C1-6 haloalkyl, C1-6 alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, N02, -NHR3, -NHC(0)R3, -C(0)NR3R4, -NR3R4, -NR3C(0)NR4R5, -OC (0)R3, or -(CH2)qNR3R4; where R3, R4 and R5 are the same or different, each independent y being selected from H, C1-6 alkyl; C1-6aryl optionally comprising 1 or more heteroaloms selected from N, O.and S, and optionally substituted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; p is 0 or an integer from 1 to 5; Y is -NHC(O)- or -C(O)-; 01 a pharmaceutically acceptable salt, ester or prodrug thereof, such as herein described. 37. A compound of formula (I): wherein R1 is straight or branched-chain C2-8 alkyl, C2-8alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8alkoxy, C1-8 heteroalky , C1-8 aminoalkyi C1-8 haloalkyl, C1-8 alkoxycarbonyl, C1-8hydroxyalkoxy, C1-8 hydroxyalkyl, -SH, C1-8 thioalkyl, or -O-CH2-G-6 aryl; A is C5-7 cycloalkyl, phenyl, naphthyl or C5-12 heteroaryl, wherein said heteroaryl contains one heteroatom selected from O, N or S; when A is C5-7 cycloalkyl, naph :hyl or C5-12 heteroaryl as defined above, R2 is H, amino, hydroxy I, halo, or straight or branched-chainC1-6 alkyl, G- 6 alkenyl,C1-6 alkynyl, C1-6 alko , C1-6 heteroalkyl, C1-6 aminoalkyi, C1-6 haloalkyl, C1-6alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, N02, -NHR3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(0)NR.,R5, -OC(0)R3, or -(CH2)qNR3R4; where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6 alkyl; C1-6 aryl optionally co uprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or G-6 alkyl; G-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected f-om C, N, S and O; and q is an integer from 1 to 6; or when A is phenyl, R2 is amino, hydrc xyl, chloro, bromo, or straight or branched-chain C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkoxy, C2-6heteroalkyl, C2-6 aminoalkyl, C2-6haloalkyl, C2-6alkoxjcarbonyl, -CN, -CF3, -OR3, -COR3, N02, -NHR3, -NHC (0)R3, -C(0)NR3R4, -NR3R4, -NR3C(O)NR4R5. -OC(O)R3, or -(CH2)qNR3R4; where R3, R4 and R5 are he same or different, each independently being selected from H, C1-6 alkyl; C5-6yl optionally comprising I or more heteroatoms selected from N. O and S. and optionally substituted with halo or C1-6 alkyl; C3-6 cycloallcyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprisir g 5-6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; n is t, 2, 3 or 4, the groups R2, when n > I, being the same or different; p is 2; Yis -NHC(O)-; and Z is a bond; or a pharmaceutically acceptable salt, ester or prodrug thereof, such as herein described. 38. A compound as claimed in claim 37, wherein n is 1 or 2. 39. A compound of formula (I): wherein R1 is straight or branched-chain C2-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C1-8 alkoxy. C1-8 aminoalkyl, C1-8 haloalkyl, C1-8 alkoxycarbonyl; n is 1, 2 or 3, the g roups R2, when n > I, being the same or different; A is thienyl; and R2 is H, halo, straight or branched-chain C2-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C2-6 alkoxy, C2-6heteroalkyl; C2-6 aminoalkyl, C2-6 haloalkyl, C2-6alkoxycarbonyl, -CN, -CF3, -COR,, -NHR, -NHC(O)R3, -C(O)NR,R4, -NR3R4, -NR3C(O)NR4R5, -OC (0)R3, or -0(CH2)qNR3; where R3, R4 and R5 are the same or different, each independently being selected from H, C1-6alkyl; C5-6aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or C1-6 alkyl; C3-6 cycloalkyl; or R3 and R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms ;.elected from C, N, S and O; and q is an integer from 1 to 6; or R4 together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and q is an integer from 1 to 6; p is 0 or an integer from :o 5; Y is -NHC(O)- or -C(0; - ; and Z is a bond or CR8R9 whe rein R8 and R9 are independently selected from H, and straight or branched chain C1-8 alkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof, such as herein described. 40. A compound as claimed in 41. A compound as claimed in ; ny one of claims 39 or 40 wherein R2 is halo, C1-6 alkyl or C1-6alkoxy. 42. A compound as claimed in claim 39, wherein Y is-NHC(O)-. 43. A compound as claimed in claim 40, wherein p is 3. 44. A compound as claimed in c aim 40, wherein Z is a bond. 45. A compound as claimed in c aim 43, wherein Z is a bond. 46. A compound as claimed in c aim 42, wherein p is 2. 47. A compound as claimed in claim 42, wherein Z is a bond. 48. A compound as claimed in claim 46, wherein Z is a bond. Compounds' and methods art provided for the alleviation or treatment of diseases or conditions in which modification of muscarinic m1 receptor activity has a beneficial effect. In he. method, a therapeutically effective amount of a selective muscarinic m1 agonist compound is administered to a patient in need of such treartment.

Documents:

in-pct-2000-423-kol-granted-abstract.pdf

in-pct-2000-423-kol-granted-assignment.pdf

in-pct-2000-423-kol-granted-claims.pdf

in-pct-2000-423-kol-granted-correspondence.pdf

in-pct-2000-423-kol-granted-description (complete).pdf

in-pct-2000-423-kol-granted-examination report.pdf

in-pct-2000-423-kol-granted-form 1.pdf

in-pct-2000-423-kol-granted-form 18.pdf

in-pct-2000-423-kol-granted-form 3.pdf

in-pct-2000-423-kol-granted-form 5.pdf

in-pct-2000-423-kol-granted-gpa.pdf

in-pct-2000-423-kol-granted-reply to examination report.pdf

in-pct-2000-423-kol-granted-specification.pdf

in-pct-2000-423-kol-granted-translated copy of priority document.pdf