ZA200005149B - Compounds with activity on muscarinic receptors. - Google Patents

Compounds with activity on muscarinic receptors. Download PDF

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ZA200005149B
ZA200005149B ZA200005149A ZA200005149A ZA200005149B ZA 200005149 B ZA200005149 B ZA 200005149B ZA 200005149 A ZA200005149 A ZA 200005149A ZA 200005149 A ZA200005149 A ZA 200005149A ZA 200005149 B ZA200005149 B ZA 200005149B
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alkyl
compound
alkoxy
substance
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ZA200005149A
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Mark Robert Brann
Erika Anne Currier
Mikael Friberg
Tracy Spalding
Terri Messier
Katharan Lauri Duggento
Niels Skjaerbaek
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Acadia Pharm Inc
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • A—HUMAN NECESSITIES
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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

Description

i WO 99/50247 PCT/US99/07057
COMPOUNDS WITH ACTIVITY ON 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 receptors 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 mi-m3) (cf. T.I. Bonner et al, Science 237, 1987, pp. 527- 532; T.1. Bonner et al., Neuron 1, 1988, pp. 403-410). It has been found that m1 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 heart 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. 1145-1152) have shown that muscarinic compounds have a profound effect on cognitive functions, ¢.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 the presence of muscarinic receptor subtypes in various tissues, it would appear that the m1 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. Levey, Proc. Natl. Acad. Sci. USA 93, 1996, pp. 13541- 13546). It has been proposed that the m1 (and possibly m4) subtype plays a major role
SUBSTITUTE SHEET (RULE 26)
as a postsynaptic muscarinic receptor (located on cholinoceptive neurons in the neocortex and hippocampus) in various cognitive and motor functions and is likely to be a major contributor to the m1 responses measured in these regions of the brain.
It has previously been found that conditions associated with cognitive impairment, such as Alzheimer’s disease, are 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 innervate areas of the association cortex and hippocampus involved in higher processes (cf. 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 acetylcholine esterase (AChE) inhibitors such as 9-amino-1,2.3.4- 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 (cf. Kasa 1s et al, supra). On the other hand, tacrine has been found to have cholinergic side effects due to the peripheral 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 been 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, 9" Ed., 1996, pp. 161-176). The adverse effects of tacrine have severely limited its clinical utility. Another AChE inhibitor, (R,S)-1-benzyl-4-[5,6- dimethoxy-1-indanon-2yljmethylpiperidine HC! (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 elevated parasympathetic tone. :
It has previously been suggested that, since the muscarinic m1 receptors in the prefrontal cortex and hippocampus appear to be intact, it may be possible to remedy : or at least ameliorate the loss of acetylcholine in Alzheimer’s disease patients by administration of drugs acting as agonists on those muscarinic receptors (cf. J.H.
Brown and P. Taylor, “Muscarinic Receptor Agonists and Antagonists”, Chapter 7 in -2- ) Substitute Sheet (Rule 26)
. © WO 99/50247 PCT/US99/07057
Goodman and Gilman: The Pharmacological Basis of Therapeutics, ot Ed., 1996, P.
Tne muscarinic agonists {pe.evad ic Te ml selective) nitheric suggested for The treatment of Alzheimer’s disease, such as arecoline, have not shown greater efficacy in clinical trials than AChE inhibitors (cf. S.V.P. Jones et al., supra). In one study (cf.
T.Samderland et 2! Prodv Pon Pow 72 108K ne 371.220 grennline wae found +n have not so much cognitive enhancing 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 subtypes (H. Briuner-Osbome 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 activity is believed to account for the adverse gastrointestinal effects of the agonists. 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 26 selectivity and low potency of the currently 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.
Ed : 30 -3.
Substitute Sheet (Rule 26)
Summary of the Invention
The present invention provides compounds with muscarinic agonist activity of the general formula (I): i x Ry,
Xo + (XQ), ) TOA (Ry), CX, oN L—— (CH,), TY I
X, — wherein
Xi, Xa, Xa, Xs and X; are selected from C, N and O; kisOori; tis 0. I or 2;
Ry 1s straight or branched-chain C4 alkyl, Cis alkenyl. C,4 alkynyl, Cs alkylidene, Cz alkoxy, Cs heteroalkyl, C4 aminoalkyl, C,s haloalkyl, C;; alkoxycarbonyl, C;.3 hydroxyalkoxy, C.g hydroxyalkyl, -SH, C,.¢ alkylthio, -O-CH,-
Cs.s aryl, -C(0)-Cs.¢ aryl substituted with C,; alkyl or halo; Cs. aryl or Cs. cycloalkyl optionally comprising I or more heteroatoms selected from N. S and O; -C(O)NR3R,, -NR3Rs, -NR3C(O)NR4Rs, -CR3Rs4, -OC(O)R3, -(O)(CH,)NR3R4 or -(CH;)NR3R4; where Rj,
R4 and Rs are the same or different, each independently being selected from H. Cis alkyl; Cs. aryl optionally comprising 1 or more heteroatoms selected from N, O and
S, and optionally substituted with halo or C4 alkyl; Cs. cycloalkyl; or R; and Ry together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8;
A is Cs aryl or Cs. cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O;
R, is H, amino, hydroxyl, halo, or straight or branched-chain C,. alkyl, Cy ' alkenyl, Cy. alkynyl, C,.¢ alkoxy, C,. heteroalkyl, C;.¢ aminoalkyl, C,¢ haloalkyl,
Ce alkylthio, Cj. alkoxycarbonyl, -CN, -CF;, -ORs, -COR;, NO,, -NHR;, - :
NHC(O)R;, -C(O)NR3Rs, -NRjRs, -NR3C(O)NR4Rs, -OC(O)R;, -C(O)R3R4, -O(CH;)(NR3, -CNR3R, or -(CHy)(NR3R4; where q is an integer from 1 to 6; nis 0, 1,2, 3 or 4, the groups Ry, when n> 1, being the same or different; p is 0 or an integer from 1 to 5; -4- ) Substitute Sheet (Rule 26)
Y is O, S, CHOH, -NHC(O)-, -C(O)NH-, -C(0)-, -OC(0)-, NR; or -CH=N-, and
Ry is H or C4 alkyl; or absent; and .
Zz CReRs wherein Rg and Rs ers Independenty seiected from H, and straight or branched chain C;.g alkyl; or a pharmaceutically acceptable salt, ester or prodmg thereof.
The present invention firther wrovide shgeeongsinct soe soiet ons CompTIing an effective amount of a compound of formula (1).
Further provided are methods of treating the symptoms of a disease or condition associated with reduced levels of acetylcholine, said method comprising administering a therapeutically 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 0.
Brief Description of the Drawings
Figure 1 is a graph showing 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 compound 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
P 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 ; 30 while avoiding the adverse affects of the drugs hitherto suggested for this purpose.
Compounds exhibiting this property have surprisingly been isolated by screening against m1-m5 receptor subtypes.
According to one embodiment, the present invention provides compounds of formula (I), wherein -5-
Substitute Sheet (Rule 26)
Xi, Xa, X3, Xs and Xs are C: or one of X,, X;, X;, X4 or Xs 1s O or N and the others are C; kisOor I; tis 1; s R; is straight or branched-chain C4 alkyl, Cyq alkenyl, Cy alkynyl, C4 alkylidene. Cj4 alkoxy, Cs aminoalkyl, Cg haloalkyl, C4 alkoxycarbonyl, -C(O)NR3R4. -NR3R4, -NR3C(O)NR4Rs, -OC(O)R;, or -(CH,)NR;3Ry: where R;, Ry and Rs are the same or different, each independently being selected from H and C,4 alkyl; and s is an integer from 1 to 8; nis 1,2 or 3; and
A is phenyl or naphthyl; where R; is straight or branched-chain C4 alkyl. Co alkenyl, Co. alkynyl, C4 alkoxy, C¢ aminoalkyl, C,.¢ haloalkyl, C4 alkoxycarbonyl, -CN, -CF;, -OH, -COR3. -NHR3, -NHC(O)R;, -C(O)NR;3R4, -NR3R,, -NR;C(O)NR4Rs, -OC(O)R;, or -CH,)¢NRsRs; where q is an integer from 1 to 6; or
A is aryl comprising 1 or more heteroatoms selected from N, S and O:
Rj is H, halo, straight or branched-chain C, alkyl, Cy. alkenyl, C,.4 alkynyl, C, alkoxy, Cy heteroalkyl, C,.¢ aminoalkyl, C,.¢ haloalkyl, C,. alkoxycarbonyl, -CN, -
CF3, OH, -COR3, -NHR3, -NHC(O)R;, -C(O)NR3Rs, -NR3R., -NR3C(O)NRy4R;, -
OC(O)R3 or -(CHy){NR3Ry; or a pharmaceutically acceptable salt. ester or prodrug thereof.
In one preferred embodiment, the compound is of the formula (II):
Ro, pm RD
X{ N—(CH)-Y— II
NJ NE
Preferred subgeneric embodiments of compounds of formula (II) include . compounds of formulas (Ila) and (IIb): -6-
Substitute Sheet (Rule 26)
N * WO 99/50247 PCT/US99/07057
Rp “ uo : x Ne (CHyy— 7 — - fia
NL
®) Rs 0 ne (CHY—Y—, IT
According to one preferred series of embodiments of compounds of formulas I, II, lla and IIb, tis 1 and Y is -C(O)-, -NHC(O)~, S, O or -OC(O)-. In another, Xs is C.
Preferably, R, is alkyl, where preferably R; is alkyl, aminoalkyl, alkoxy or hydroxyl.
Inone embodiment, pis 3. In another, R; is Cy alkyl and R; is methyl, hydroxyl or alkoxy.
In one embodiment, nis 1 or 2; Y is -C(O)- or O and t is 1. Preferably, R; is halo.
According to other embodiments, t is 0; or R, is alkoxy, benzyl or phenyl.
X3 may also be N, where according to one embodiment, R; is alkyl or alkoxy; or
Rj is benzyl or phenyl; where R; is alkyl or alkoxy.
According to another embodiment, X; is O, where t may be, for example, 0.
Preferably, R; is alkyl or alkoxy; or Ry is halo.
Particular embodiments of the invention include: 4-Methoxy-1-[4-(2-methylphenyl)-4-oxo-1-butyl piperidine: 4-Ethoxy-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Propoxy-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Butoxy-1-[4-(2-methylphenyl)-4-oxo-1-butylpiperidine; 4-Methoxymethyl-1-[4-(2-methylpheny!)-4-oxo-1-butyl]piperidine; 4-Ethoxymethyl-1-|4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; - 20 4-Propoxymethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl piperidine; 4-(2-Methoxyethyl)-1-[4-(2-methylphenyl)-4-o0xo-1-butyl piperidine; - 4-(2-Ethoxyethyl)-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Methoxy-4-methyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Methoxy-4-ethyl-1-[4-(2-methylphenyl)-4-oxo- 1 -butyl piperidine; 4-Methoxy-4-propyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine; -7-
Substitute Sheet (Rule 26)
4-Methoxy-4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl] piperidine; 4-Ethoxy-4-methyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl piperidine: } 4-Ethoxy-4-ethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Ethoxy-4-propyl-1-[4-(2-methylphenyl)-4-oxo-1 -butyl]piperidine; 4-Ethoxy-4-n-butyl-1-[4-(2-methylpheny!)-4-0x0-1 -butyl]piperidine; 4-Propoxy-4-methyl-1-[4-(2-methylphenyl)-4-ox0- 1 -butyl]piperidine; 4-Propoxy-4-ethyl-1-[{4-(2-methylphenyl)-4-oxo-1-butyl piperidine; 4-Propoxy-4-propyl-1-[4-(2-methylphenyl)-4-o0xo- 1 -butyl]piperidine; 4-Propoxy-4-n-butyl-1-[{4-(2-methylphenyl)-4-0x0-1 -butyl]piperidine; 4-n-Butoxy-4-methyl-1-[4-(2-methylphenyl)-4-oxo-1 -butyl]piperidine; 4-n-Butoxy-4-ethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine: 4-n-Butoxy-4-propyl-1-[4-(2-methylphenyl)-4-oxo-1 -butyl]piperidinc; 4-n-Butoxy-4-n-butyl-1-{4-(2-methylphenyl)-4-oxo-1-butyl piperidine; 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)-o-tolyl-amine;
N-(4-(4-n-Butylpiperidine)- -o-tolyl-butyl)-hydroxylamine; 4-n-Butyl-1-[4-(2-chlorophenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2-bromophenyl)-4-oxo- 1 -butyl]piperidine; 4-n-Butyl-1-[4-(2-fluorophenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2-mercaptophenyl)-4-oxo-1-butyl]piperidine: 4-n-Butyl-1-[4-(2-sulfanylmethylphenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(2-sulfanylethylphenyl)-4-oxo-1 -butyljpiperidine; 4-n-Butyl-1-[4-(2-aminophenyl)-4-oxo- 1-butyl|piperidine; 4-n-Butyl-1-[4-(2-methylaminopheny!)-4-oxo-1 -butyl]piperidine; 4-n-Butyl-1-{4-(2-ethylaminophenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(2-dimethylaminophenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2-diethylaminopheny!)-4-oxo- 1-butyl]piperidine; 4-n-Butyl-1-[4-(1-H-imidazol-2-yl)-4-0xo- 1-butyl]piperidine; 4-n-Butyl-1-[4-(1-imidazol-1-yl)-4-oxo- 1 -butyl]piperidine; 4-n-Buty!-1-[4-(1-thiazol-2-y1)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-([1,2,3]triazol- 1-yl)-4-oxo-1-butyl piperidine; -8-
Substitute Sheet (Rule 26)
R * WO 99/50247 PCT/US99/07057 2-[4-n-butyl-piperidine-1-ethyl]-8-methyl-3,4-dihydro-2 H-naphthalen-1 -one; 2-[4-n-butyl-piperidine-1-ethyl]-7-methyl-indan- -one; - 3-l4-n-putyl-piperidine- | -sthyl -chroman-4-one, 2-[4-n-butyl-piperidine-1-ethyl]-1 H-benzoimidazole; 4-n-Butyl-1-[4-(4-fluoro-2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-p-Buryl. 1.14. (7 hudrovimhenyN A pvo 1 host l nines dina. 4-n-Butyl-1-[4-(2-methoxyphenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(1-thiophen-2-yl)-4-oxo- 1 -butyl]piperidine; 4-n-Butyl-1-[4-(2-ethylphenyl}-4-oxc-1-butyl piperidine; 4-n-Butyl-1-[4-(2-ethoxyphenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2,4-dimethylphenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4~(2,3-dimethylphenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(3-methoxyphenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl piperidine; 4-n-Butyl-1-[4-(4-methylphenyl)-4-oxo-1-butyl]piperidine; 4-n-Butyl-N-phenyl-butyramide; 4-Methyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl|piperidine; 4-n-Butyl-1-[4-(naphthalen-1-yl1)-4-oxc-1-butyllpiperidine; 4-Benzyl-1-[4-(2-methylphenyl)-4-oxo- 1 -butyl]piperidine; 1-[4-(2-methylphenyl)-4-oxo-1-butyl]pyrrolidine; 4-Benzyl-1-[4-(2-methylphenyl)-4-oxo- 1-butyl]piperazine; 2-Propyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 2-Ethyl-1-{4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-n-Propyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl piperazine; 3,5-Dimethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperidine; 4-Methyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperazine; 4-n-Hexyl-1-{4-(2-methylphenyl)-4-oxo-1-butyl] piperazine; - 4-Hydroxyethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl piperazine; 4-Ethyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]| piperazine; 4-Benzyl-1-[4-(4-fluorophenyl)-4-oxo-1-butyl piperidine; 4-Benzyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl piperidine; 4-Phenyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl)piperazine; 3-Hydroxymethyl-1-{4-(2-methylphenyl)-4-oxo- 1-butyl]piperidine; 4-Methyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl]piperidine; -9-
Substitute Sheet (Rule 26)
1-[4-(2-methylphenyl)-4-oxo0-1-butyl]piperidine: 2-Hydroxymethyl-1-[4-(2-methylphenyl)-4-oxo-1-buty] piperidine; 4-Benzyl-1-[4-(2-methylphenyl)-4-oxo- 1 -pentyl piperazine; 4-n-Hexyl-1-[4-(2-methylphenyl)-4-oxo-1 -pentyl]piperazine; 4-(Piperidine-1-yl)-1-[4-(2-methylphenyl)-4-oxo-1 -butyl piperidine; 1-[4-(2-methylphenyl)-4-oxo-1 -butyl]-2,3-dihydro- 1 H-indole: 4-Benzyl-1-[5-(2-methylphenyl)-5-oxo-1-pentyl piperidine; 4-n-Butyl-1-[5-(2-methylphenyl)-5-oxo-1 -pentyl]piperidine; 4-n-Butyl-1-[4-(2,6-dimethylphenyl)-4-oxo-1 -butyl piperidine; 4-n-Butyl-1-[4-(2-methoxymethylphenyl)-4-oxo-1 -butyl]piperidine; 1-(2-Methylphenyl)-2-(4-benzylpiperazin-1 ~yl)-ethanone; 3,5-Dimethyl-1-[5-(2-methylphenyl)-5-oxo-1-pentyl]piperidine:; 3,5-Dimethyl -1-[4-(4-fluorophenyl)-4-0xo0- -butyl]piperidine; 1-[4-(4-Fluorophenyl)-4-oxo-1-butyl]pyrrolidine; 4-Benzyl-1-[6-(2-methylphenyl)-6-0xo0-1 -hexyl]piperazine; 3,5-Dimethyl -1-[6-(2-methylphenyl)-6-0xo-1 -butyl piperidine; 4-Benzyl-1-[5-(2-methoxyphenyl)-5-oxo-1 -pentyl]piperazine; 4-Benzyl-1-[3-phenyl-3-0x0-1-propyl piperazine: 4-n-Butyl-1-[5-(2-methoxyphenyl)-5-oxo-1-pentyl]piperidine: 3,5-Dimethyl-1-[4-(4-fluoro-2-methylphenyl)-4-oxo-1 -butyl]piperidine; 3-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]azetidine; 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo0-2-methyl-1 -butyl]piperidine; 4-n-Butyl-1 -[4-(2-methylphenyl)-4-o0x0-2,2-dimethyl-1 -butyl]piperidine; 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-2-ethyl-1-butyl piperidine; 4-n-Butyl-1-[4-(2-methylphenyl)-4-0x0-2-propyl-1 -butyl]piperidine; and 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-2,2-diethyl- 1-butyl]piperidine.
Compounds per se specifically excluded from the scope of formula I are 4-n-
Butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo- ; 1-butyl] piperazine; 2-[3-(3-n-Butylpiperidine)propanesulfanyljtoluene; and 4-
Propyloxy-1-[4-(4-fluorophenyl)-4-oxo-1-butyl piperidine (i.e., compounds where - : (CH2)p-Y- is «(CH,)3-C(O)- or -(CHy)3-S-; and X; through Xs are C; such that -A- (R2)s and R; are not together: o-methyl-phenyl and n-butyl, respectively; phenyl and n-butyl, respectively; or p-fluoro-phenyl and -O-(CH,),CHj, respectively). -10-
Substitute Sheet (Rule 26)
} ~ WO 99/50247 PCT/US99/07057
The present invention further provides a method of agonizing a muscarinic receptor comprising contacting the receptor with an effective amount of a compound of formule 0, Inclusive of 20 compounds within the eoope oF Soomule Ca, including 4-n-Butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine; 4-n-Butyl-1-[4-(2- methylphenyl)-4-oxo-1-butyl] piperazine; 2-[3-(3-n-Butylpiperidine)propanesulfanyl] toluene; and 4-Pronvioxy-1-74-(4-fluoronhenyl)-4-oxo-1-butyl piperidine).
The present further provides 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-Butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine; 4-n-Butyl- 1-[4-(2-methylphenyl)-4-oxo-1-butyl]piperazine; 2-[3-(3-n-
Butylpiperidine)propanesuifanyl] toluene; and 4-Propyloxy-1-[4-(4-fluorophenyl)-4- oxo-1-butyl]piperidine).
The present invention further also provides methods of treating the symptoms of a disease or condition associated 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 thc volume of the aqueous 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 m1 receptor. Such an agonist is defined as a compound that increases the . activity of the ml muscarinic receptor when it contacts the receptor. Selectivity is defined as a property of a muscarinic ml agonist whereby an amount of agonist ) 30 effective to increase the activity of the m1 receptor causes little or no increase in the activity of the m3 and mS subtypes, and preferably the m2 and m4 subtypes.
As used herein, the term “alkyl” means a straight or branched-chain alkane group with 1-6 carbon atoms in the chain, for instance methyl, ethyl, propyl, isopropyl, n- 11 -
Substitute Sheet (Rule 26)
butyl, sec-butyl, tert-butyl, etc. 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: the term “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 carbon 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. pyridyl, piperidinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxadiazolyl, thiadiazolyl, imidazolinyl, imidazolidiny! and the like. The ring may be substituted by one or more of the groups included in the definition of R; above. It is understood that the substituents Ci¢ alkyl, Cj alkenyl,
Ci alkynyl, Cy. alkoxy, C4 heteroalkyl, C. aminoalkyl, Ci. haloalkyl or C,. alkoxycarbonyl may, if present, be substituted by one or more of hydroxyl, C4 alkoxy, halogen, cyano, amino or nitro.
As used herein, the term “halogen” or “halo” includes chlorine, fluorine, iodine and bromine.
It is understood that the ring represented by the structure
Xy %s. (Xs xX, X; N may be both saturated and 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. ) -12-
Substitute Sheet (Rule 26)
“Nw + aHe—C Hy ——v—L 7] > re
X) i (Xi) (H] 1 (Ry) — (Ran
I Yer >" (XX)
The starting compound having formula (X) may be prepared by genera! 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.
O., et al, J. Pharm. Sci. 68:591-595 (1979); Bossier, J. R. et al, Chem. Abstr. 66:46195h and 67:21527a (1967); 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 al., Neuropharmacoiogy 14:739-746 (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. Cromatog. 407:1-18 (1987), the disclosures of which are incorporated by reference herein in their entirety. The radiolabelled derivatives having formula (XX) may bc prepared by, for example, using a tritiated reducing agent to form the reductive amination or by utilizing a '*C-labelled starting material.
Alternatively, where the starting compound comprises a carbonyl group, the compound having the formula (XXII) may be reduced with, for cxample, Alt;, diborane:methyl sulfide or other standard carbonyl reducing reagents to produce the ; ligand having the formula (XXX). -13 -
Substitute Sheet (Rule 26)
(Ri) (R2) ~~ Q =
NS N—C——(C or (XXH) (Ri) (Ran —\ —_—
RY {a> N—(C aii 5 (XXX)
The receptor ligands having formula (XXXII) may be prepared by nucleophilic displacement of an electrophile (E) by the amino derivative (XXXI). Examples of electrophiles which may be used for this purpose include halides such as I. Cl, Br. tosylate or mesylate. (Ri) (R2) —\ —
NS NH + E——~(C ia 5 (XXX) (Rik (R2)n
I \ —
SE yer (XXXII)
When Y in formula (XXXII) is ~C(0)-, this compound may be prepared from oxidation of an sec. alcohol with for example pyridinium chlorocromate or N- - chlorosuccinimide or CrO3-H,SOj or nickel peroxide or metal (Al, K) or DCC-
DMSO.
When Y in formula (XXXII) 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 athiol with arylhalides under for example Cu catalysis. -14-
Substitute Sheet (Rule 26)
. ~ WO 99/50247 PCT/US99/07057
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
NaBhy or 5y the use of LiAlfs.
Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the nomponnd zecaording #0 the inmvartian uith oo olin. oF chemmzoeutice ll 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 pharmaceutically 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 pharmaceutically 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, triethiodide and valerate salt.
The present invention includes 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 i 30 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 -15-
Substitute Sheet (Rule 26)
solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also included in the scope of this 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 or 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 regeneration 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
Is invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. JF.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wats,
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 present 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 liquid 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 -16-
Substitute Sheet (Rule 26)
accepted practices such as those disclosed in Remington's Pharmaceutical Sciences.
Gennaro, Ed., Mack Publishing Co., Easton PA, 1990. Alternatively, the compositions may Se in sustamned-release form suitable for once-weekly or once-monthiy 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 imjec¥on. The present lovantion luo contzmplater oeoiding solani Mor formulations for administration to, 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, lubricants, 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 pharmaceutical excipient. e.g. such as the ones described above. and other pharmaceutical diluents, 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 0.1 tc 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 containing the active compound and an outer layer as a coating surrounding the core. The outer coating may be a enteric layer which serves to resist disintegration in the stomach and permits the inner core to pass intact into the -17 -
Substitute Sheet (Rule 26)
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 parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are 1s employed when intravenous administration is desired. The compositions can also be formulated as an ophthalmic 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 tachycardia 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 of : 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. ~-18 -
Substitute Sheet (Rule 26)
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 fo other auman 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 fragteams on omalinestineg of 0 mamber of dincosen god Aioomdens Cale foci 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 16 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, or 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, cr 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 dosage 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 . 30 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. -19 -
Substitute Sheet (Rule 26)
The daily dosage of the products may be varied over a wide range from 0.01 to 100 mg per adult human per 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 treated. 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 about 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 testing in order to obtain optimal pharmacological effect
On a muscarinic receptor, in particular the muscarinic ml receptor subtype, while
IS minimizing any potential toxic or otherwise unwanted effects. In addition, co-administration or sequential 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 using recombinant receptor subtypes, preferably of the human receptors if these are available, e.g. conventional second messenger or binding assays. A particularly convenient 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 different muscarinic subtypes, to amplify in the presence of a ligand of the receptor. Cell amplification 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. : -20-
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. + WO 99/50247 PCT/US99/07057
Exampies
Example I - 4-n-Butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyljpiperidine (5)
I-Benzyl-4-n-butvlideneniperidine 72) A 500 ml. necked flack fired with z 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 aslurry of butyltriphenylphosphonium bromide (26.6 g, 67 mmol) in DMSO (70 mL).
The red mixture was stirred for 15 min at rt. 1-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. H,O (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). 'H
NMR (CDCl3) 0.90-0.95 (t, 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), 2.50 (s, 2H), 5.17 (t, 1H), 7.20-7.42 (m, 5H). 4-n-Butylpiperidine (3). In a 500 mL flask fitted with a stirrer was added a slurry 0f2 (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 hydrogen was added via a reaction flask. A total of 2.5 dm’ of hydrogen was consumed. The reaction mixture was filtered and evaporated and the residue was dissolved in H,O (40 mL) and NaOH (20 mL, 2 M) followed by extraction with ethyl acetate (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%). "HNMR (CDCl) 0.85 (1, 3H), 1.0-1.38 (m, 9H), 1.65 (dd, 2). 2.38 (s, 1H), 2.55 (dt, 2H), 3.04 (dt, 2H). 4-(4-n-Butylpiperidin-1-yl)butanenirrile (4). In a 100 mL flask with a magnetic stirrer was placed 3 (2.3 g, 16.4 mmol), 4-bromobutyronitrile (2.4 g, 16.4 mmol), potassium carbonate powder (2.5 g, 18 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at rt for 5 h followed by addition of H,O (15 mL). The mixture was extracted with ethyl acetate (3 x 30 mL) and the combined organic phases were -21-
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evaporated to dryness to produce 3.9 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 (CDCls) 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-1-[4-(2-methylphenyl)-4-oxo- 1 -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 Et;O (4 mL) and the reaction mixture was ailowed to stand at rt for 1 hour. Compound 4 (720 mg, 3.4 mmol) dissolved in Et,0 (4 mL) was added and the mixture was refluxed over-night. 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 were evaporated to dryness to produce 1.2 g of crude 5. The crude product was subjected to CC [eluent: CH,Cl,:CH;0H (99:1)] to give pure 5 (0.42 g, 26%). 'H NMR (CDCl;) 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 (1, 1H), 7.65 (d, 1H).
Example II - 3-Hydroxymethyl-{4-(2-methylphenyl)-4-oxo-1-butyl[piperidine (7) 4-(3-Hydroxymethyl-piperidin-1-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 H;O (20 mL) was followed by extraction with ethyl acetate (3 x 20 mL) and the combined organic phases were dried (MgSO,) 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-1-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 under vacuum, followed by addition of anhydrous THF (7 mL). i
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 CuBr (23 mg, 0.16 mmol, 2 mol %) and the reaction mixture -22-
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was stirred at rt overnight. The reaction mixture was quenched by addition of H,SO4 (20 mL, 2 M) and stirred at rt for 2 hours followed by addition of NaOH (8 mL, 2 M).
Aiditicn of THF (15 ml) was followed by extraction with CH,Chy (3 x 20 mL), and the organic phases were dried (MgSOs) 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- 8004 CULON 2 0 10LTT AT oo condos Go anal tice pt sample of compound 7. LC-MS [M+ HJ" 275 (cald. 275.2).
Example III - 2-Propyl-[4-(2-methylphenyl)-4-oxo-1-butyljpiperidine (9) 4-(2-propyl-piperidin-1-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 saturated brine (25 mL). The reaction mixture was extracted with ethyl acetate (3 x 25 mL) and the combined organic phases were dried (MgSOy) and evaporated to dryness to produce crude 8. The crude product was subjected to CC [eluent: CH;Cl, : MeOH (99:1)] to give pure 8 (0.48 g, 83 %); LC-
MS [M+ HJ" 194 (cald. 194.2). 2-Propyl-[4-(2-methylphenyl)-4-oxo-I1-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-icdotoluene (380 1, 2.8 mmol) in Et;0 (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 CH,Cl, (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight.
The reaction mixture was quenched by addition of H,SO4 (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 cthyl acetate (3 x 50 mL) and the combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), dried . (MgSO) and evaporated to 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% ) 30. CHsCN + 0.1%TFA] to produce an analytically pure sample of compound 9; LC-MS [M +H] 287 (cald. 287.2). -23-
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Example IV - 1-[4-(2-methylphenyl)-4-oxo-1-butyljpiperidine (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 Et;0 (3 mL) and the reaction mixture was allowed to reflux for 1 hours. A suspension of 4-piperidin-1-yl- butanenitrile 10 (Dahlbom et. al. Acta. Chem. Scand. 1951, 5, 690-697) (0.305 mg, 2.0 mmol) in CHCl, (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H,SO, (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 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 dried (MgSQ4) and evaporated 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% CH3;CN + 0.1%TFA] to produce an analytically pure sample of compound 11; LC-MS [M —~ HJ" 245 (cald. 245.2).
Example V - 4-methyl-1-[4-(4-bromophenyl)-4-oxo-1-butyl]piperidine (12)
In a 10 mL dried flask was added 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 H,O (10 mL).
The reaction mixture was extracted with Et,0 (3 x 15 mL) and the combined organic phases are dried (MgSO) 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 + 0.1%TFA] to produce an analytical pure sample of compound 12; LC-MS [M + HJ" 322 (cald. 323.1).
Example VI - I-[4-(2-methylphenyl)4-oxo-1-butyijpyrrolidine (13) )
In a 10 mL oven-dried flask was charged Mg turnings (30 mg, 1.2 mmol) which were activated under vacuum by the use of a heat-gun. Under inert atmosphere was : added a solution of 2-iodotoluene (0.22 g, 1.0 mmol) in Et,O (2 mL) and the reaction mixture was allowed to reflux for 1 hour. A mixture of 4-pyrrolidin-1-yl-butyronitrile (Burckhalter et. al. J. Org. Chem. 1961, 26, 4070-4076) (0.14 g, 1.0 mmol) in CH,Cl, (2 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. -24-
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The reaction mixture was quenched by addition of H,SO4 (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 foiiowec oy extraction with etnyi acetate (3 x 20 mi), and the organic phases were dried (MgSQ,) and evaporated to dryness to produce 0.12 g of crude 13. The crude product was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA;
Buffer D. @noL TILOM + DI3TTL] to pinluli en anaiyLis. pul samnpie of compound 13. LC-MS [M +H] 231 (cald. 231.3).
Example VII - 4-Methyi-1-[4-(2-meihyiphenyl)4-oxo-1-butyl]piperazine (15) 4-(4-Methyl-piperazin-1-yl)-butyronitrile (14). In a 25 mL flask was placed 1- methyl-piperazine (0.52 g, 5.1 mmol), 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 it for 4 h., followed by addition of H,O (20 mL) and extraction with ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO,) and evaporated to dryness to produce 0.72 g of crude 14 which was used without further purification in the synthesis of compound 15. 4-Methyl-1-[4-(2-methylphenyl)4-oxo-1-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. Under inert atmosphere was added a mixture of 2- iodotoluene (0.65 g, 3.0 mmol) in Et;0 (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 CH,Cl; (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H;SOy4 (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 CHCl, (3 x 20 mL). The organic phases were dried (MgSO) and evaporated to dryness to produce 0.26 g of crude 15. The crude product - was subjected to preparative HPLC [eluent: Buffer A: 0.1% TFA, Buffer B: 80%
CH3;CN + 0.1%TFA] to produce an analytically pure sample of compound 15. LC-MS } 30 [M+ H] 260 (cald. 260.4). -25 -
Substitute Sheet (Rule 26)
Example VIII - 4-n-Butyl-1-{4-(2-methylphenyl)4-oxo-1-butyljpiperazine (17) 4-(4-Butyl-piperazin-1-yl)-buryronitrile (16). In a 25 mL flask was placed 1-butyl- piperazine (712 mg, 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 H,0O (20 mL) and extraction with ethyl acetate (3 x 25 mL). The combined organic phases were washed with brine (25 mL), dried (MgSO,) and evaporated to dryness to produce 0.89 g of crude 16 which was used without further purification in the synthesis of compound 17. 4-n-Butyl-1-[4-(2-methylphenyl)4-oxo-1-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 mmol) in Et,O (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
CHyCl; (3 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H,SO4 (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 CH,Cl; (3 x 20 mL), and the organic phases were dried (MgSOQ,) and evaporated 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% CH3;CN + 0.1%TFA] to produce an analytical pure sample of compound 17. LC-MS [M + HJ" 302 (cald. 302.5).
Example IX - 4-n-Butyl-1-[4-(2-ethoxyphenyl)-4-oxo-1-butyl]piperidine (18) [na 10 mL oven-dried flask was added Mg turnings (94 mg, 3.8 mmol) which was activated by the use of a heat-gun under vacuum. Under inert atmosphere was added a suspension of 1-ethoxy-2-iodobenzene (0.71 g, 2.9 mmol) in Et;0 (3 mL) and the reaction mixture was allowed to reflux for 3 hours. Compound 4 (0.40 g, 1.9 mmol) : dissolved in CHCl, (3 mL) was added and the mixture was stirred at 40°C for additional 3 hours. The reaction mixture was quenched by addition of H,SO4 (10 mL, 2 M) and left stirring overnight at room temperature, followed by addition of NaOH (20 mL, 2 M) until basic conditions. 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), and the combined organic phases were dried (MgSO4) and -26-
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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+ Hr 331 {caid. 331.50.
Example X - 4-n-Butyi-1-[4-(2,3-dimethyiphenyl)-4-oxo-1 -butyl]piperidine (19)
Ime 120ml cvemdried foc added Moving: (34 ng, 3.5 SLTLL wil was activated under vacuum by the use of a heat-gun. Under inert atmosphere was added a suspension of 1-iodo-2,3-dimethylbenzene (0.69 g, 3.0 mmol) in Et,O (5 mL) under spontancously reflux, and the reaction mixiure was allowed to reflux for 4 hours. A suspension of compound 4 (0.41 g, 2.0 mmol) in CH,Cl; (2 mL) was added to the reaction mixture and left at rt overnight. The reaction mixture was quenched by addition of H,SO4 (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 combined organic phases are washed with brine (10 mL) and NaOH (10 mL, 2 M), and the organic phases were dried (MgSO,) and evaporated to dryness to produce 0.69 g of crude 19. The crude product was subjected to CC [eluent: CH,Cl, : MeOH (99:1)] to give pure 19 (0.40 g, 64 %); LC-MS [M +
HI" 315 (cald. 315.5).
Example XI - 4-n-Butyl-1-[4-(2,4-dimethylphenyl)-4-oxo-1-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 1-iodo-2,4-dimethylbenzene (0.69 g, 2.9 mmol) in Et,0 (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 CHCl, (2 mL) was added under inert atmosphere to the reaction mixture and left stirring at rt overnight. The reaction mixture was quenched by addition of H,SO4 (8 mL, 2 M) and stirred at rt for 4 hours, - then the reaction mixture was basified 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 (MgSO4) and evaporated to dryness to produce 0.61 g of crude 20. The crude product was subjected to CC [eluent: CH,Cl, : MeOH (99:1)] to give pure 20 (0.21 g, 35 %); LC-MS [M+ HJ" 315 (cald. 315.5). -27-
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Example XII - 4-n-Butyl-1-[4-(2-methoxyphenyvl)-4-oxo-1 -butylfpiperidine (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 I-bromo-2-ethylbenzene (0.66 g, 3.6 mmol) in Et,O (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 CH;Cl; (2 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H,SO, (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 (MgS0O4) and evaporated to dryness to produce 0.75 g of crude 21. The crude product was subjected to CC [eluent: CHCl, : MeOH (99:1)] to give pure 21 (0.68 g, 90 %); LC-MS [M +
HJ" 315 (cald. 315.5).
Example XIII - 4-n-Butyl-1-{4-(2,4-dimethylphenyl)-4-oxo-1 -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 1-lodo-2-methoxymethylbenzene (0.67 g, 2.7 mmol) in Et,0 (4 mL) and the reaction mixture was allowed to reflux for I hours. A suspension of compound 8 (0.38 g, 1.8 mmol) in CH;Cl; (4 mL) was added via a syringe and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched by addition of H,SO4 (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 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 (MgSO) and evaporated to dryness to produce 0.51 g of crude 22. The crude product was subjected to CC [eluent: CH,Cl; : MeOH (99:1)] to give pure 22 (0.14 g, 23 %); LC-MS [M+
HJ" 331 (cald. 331.5).
Example XIV - 4-n-Butyl-1-[4-(2-pyridinyl)-4-oxo-1-butyl [piperidine (24) 4-(4-Butyl-piperidin-1-yl)butyric 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 -28-
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CH3;CN (10 mL). The reaction mixture was stirred over-night at rt followed by filtration and evaporation to dryness. Addition of H,0 (50 mL) was followed by extraction with etny. acetate {3 x 100 mL). The combined organic phases were dried (MgSO4} and evaporated to dryness, to produce 2.84 g of crude 23. The crude product was subjected to CC [eluent: CH,Cl, : MeOH (99:1)] to give pure 23 (1.93 g, 75%).
TOMS TAL TTF NAT (az1d 241 DY 4-n-Butyl-1-[4-(2-pyridinyl)-4-oxo-1-butyl [piperidine (24). To a dry 25 mL reaction flask was added 2-bromopyridine (200 mg, 1.3 mmol) dissolved in CH,CL (3 mL) and the temperature was adjusted 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 CH,Cl, (2 mL) was added. The reaction mixture was left to warm to rt over-night before being quenched with H;SO4 (5 mL, I M). The reaction mixture was extracted with ethyl acetate (6 x 25 ml) and the combined organic phases were dried (MgSO) and evaporated to dryness, to 15s produce 0.31 g of crude 24. The crude product was subjected to CC [eluent: CH,Cl, :
MeOH (10:1)] to give pure 24 (75 mg, 12%). LC-MS [M + H]" 288 (cald. 288.2).
Example XV - 4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxo-1-butyl]piperidine (27)
I-Benzyloxy-2-iodo-benzene (25). In a 25 mL ovendried flask 2-iodophenol (1.03 20g, 4.7 mmel) 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 H,0 (50 mL) followed by extraction with ethyl acetate (3 x 50 mL) and the combined organic phases were dried (MgSO,) and evaporated to dryness, to produce 1.7 g of crude 25.
The crude product was subjected to CC [eluent: Heptane : EtOAc (9:1)] to give pure 25(1.2 g, 81%). LC-MS [M + H]" 310 (caid. 310.0). 4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1-butyl Jpiperidine (26). In a 25 mL oven-dried flask was added Mg turnings (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) (1.18 g, 3.8 mmol) in Et;0 (10 mL) and the reaction mixture was allowed to reflux for 3.5 hours. A solution of 4-(4-n- butylpiperidin-1-yl)butanenitrile 4 (0.53 g, 2.5 mmol) dissolved in CH,Cl, (3 mL) was added and the reaction mixture and was stirred at 40°C over-night. The reaction mixture was quenched by addition of HaSO4 (10 mL, 2 M) and left stirring for | hour, -29 -
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followed by addition of NaOH (20 mL. 2 M) until basic conditions. 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), and the combined organic phases were dried (MgSO) and evaporated to dryness to produce 1.28 g of crude 26. The crude product was subjected to CC [eluent: Tol : EtOAc (1:1)] to give pure 26 (0.51 g, 51 %); LC-MS [M + H]™ 393 (cald. 393.7). 4-n-Butyl-1-[4-(2-hydroxyphenyl)-4-oxo-1-butyl piperidine (27). To a 25 mL reaction flask was added a solution of 4-n-Butyl-1-[4-(2-benzyloxyphenyl)-4-oxo-1- butyl]piperidine (26) (49 mg, 1.2 mmol) dissolved in dry EtOH (10 mL) and conc.
HCI (0.1 mL) followed by addition of palladium on charcoal (40 mg). The reaction flask was then charged with H, by the use of balloon technique and left stirring at rt over-night under H, 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 (MgSO,) and evaporated to dryness to produce 0.42 g of crude 27. The crude product was subjected to CC [eluent: : CH,Cl, : MeOH (99:1)] to give pure 27 (0.21 g, 58 %):; LC-MS [AM + HJ" 303 (cald. 303.2).
Example XVI - Screening of test compounds in an assay using muscarinic receptor subtypes mil, m2, m3, m4 and m5
Transfection of cells with muscarinic receptor DNAs (general procedure) NIH 3T3 cells (available from the American Type Culture Collection as ATCC CRL 1658) were grown at 37°C in a humidified atmosphere (5% CO,) incubator in Dulbecco's modified Eagle’s medium (DMEM) supplemented with 4.5 g/l glucose. 4 mM glutamine, 50 units/ml penicillin, 50 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 2x10° per 15 cm dish in 20 ml of DMEM containing 10% calf serum.
The m1-m5 muscarinic receptor subtypes were cloned substantially as described by Bonneret al, Science 237, 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 Gg-i5 construct is described by Conklin et al., Nature 363, 1993, p.274). -30-
Substitute Sheet (Rule 26)
. 0 t WO099/50247 PCT/US99/07057
On day one, the cells were transfected using the Superfect transfection reagent (available from Qiagen, Valencia, CA) in accordance with the manufacturer's
Instructions. Receptor UNA, p-gal UNA {pSi-S-griactosidase avaliable Irom
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 or DNA wype added mew =Tare Deine az oddieo. «0 do —Toenn £0 wl
Superfect was added to the DNA and mixed thoroughly by pipetting up and down several times. The mixture was incubated at room temperature for 10-15 minutes. The media were aspirated, and 12 ml 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 evenly over the surface. The cells were incubated overnight at 37°C and 5% CO,.
After incubation, the media were 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 transfected with muscarinic receptor subtypes (general procedure) DMEM containing 2% 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 in DMEM to 8x the final concentration. 50 ul of the
DMEM containing 2% Cyto-SF3 was added to each well of 96-well microtiter plates under sterile conditions. Then, 16 pl of compound solutions were added to the top wells of the plates, and dilution of the solutions was performed by taking 16 pl of the compound solutions from the top wells and pipetting them into the next row of wells.
This procedure was repeated with each subscquent row of wells, cxcept that 50 pl 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. -31-
Substitute Sheet (Rule 26)
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 1 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 carefully aspirated so as not to dislodge the cells. The cell pellet was suspended in 1600 pl 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 pl 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% COs.
After incubation, the medium was removed by inverting the microtiter plates and shaking them gently, after which they were blotted on absorbent paper. 100 nl chromogenic substrate (3.5 mM o-nitrophenyl-B-D-galactopyranoside, 0.5% Nonidet
NP-40, in phosphate buffered saline) 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. -32-
Substitute Sheet (Rule 26)
, «+ “WO 99/50247 PCT/US99/07057
Results Using the general procedure described above, NIH 3T3 cells were co- transfected with DNAs encoding the m1, m3 and m5 receptor subtypes. A compound “brary containing approximately 35,000 small organic compounds Der ‘well; was screened against the receptors by the procedures described above. Fig. 1 illustrates data from one 96-well plate from the screen. On this plate, two compounds were active at ane or more of the transfected recemtors Tn tha total eorsan fave ralated 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 m1 receptor subtype, at which it was a potent partial agonist, inducing a lower maximal response than the reference compound carbachol.
In further experiments, the four 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 tested 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 a-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 responses induced by the muscarinic agonist carbachol.
Example XVII - R-SAT Assay
R-SAT assays (see U.S. patent no. 5,707,798, incorporated herein by reference) were carried out where cells transfected with m1, m3 or m5 receptors were exposed to ‘ seven compounds at 1.5 uM concentration. Cellular response is expressed as a percentage of the maximum response of the cells (defined as response to 10 uM : 30 carbachol). The results arc presented in the following table. -33-
Substitute Sheet (Rule 26)
Compound Receptor and Concentration ism ism 15 M
A TT | To 3 (Example I)
B L776 Hl | 7419 I -6|+/-|10 (Example IX) | | Cl
J C 91 +/-19 | 41+/-]9 0]+/-112 (Example XV)
D Ei 9 13 i | 2+ 15 (Example X) | | IE (Example XI) | | !
F She | TT | ai (Example XII)
I a acd ad *4-n-Butyl-1-[4-phenyl-4-oxo-1-butyl]piperidine
As indicated above, the compounds are selective agonists of the m1 receptor.
The invention described and 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 herein, the disclosures of which are incorporated by reference in their entireties. 34.
Substitute Sheet (Rule 26)

Claims (1)

  1. PCT/USS9/07057
    1. A compound of formula (I): XOX, A Ra (R) Xi Tz (HY —i : wherein Xi, X32, X3, X4 and Xs are selected from C, N and O; kisQor i; tis 0, lor 2; Rj is straight or branched-chain Cy.g alkyl, Cp.galkenyl, Cig alkynyl, Cig alkylidene,
    C1.g alkoxy, C,.g heteroalkyl, C,.g aminoalkyl, C,.g haloalkyl, Ci.g alkoxycarbonyl, Cig hydroxyalkoxy, C.g hydroxyalkyl, ~SH, C;.g alkylthio, -O-CH,-Cs.s aryl, -C(0)-Cs.¢ aryl substituted with Ci.3 alkyl or halo; Css aryl or Cs cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O; -C(O)NR;3R,, -NR3Ry, -NR3C(O)NRRs, - CR3R4, -OC(O)R3, ~(O)(CH2)sNR3R4 or -(CH)sNR3Ry; where Rs, Rs and Rs are the same or different, each independently being selected from H, C;¢ alkyl; Cs. aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or Ci.g alkyl; C36 cycloalkyl, or R3 and Ra together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8; A is Cs.15 aryl or Cs; cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O; R; is H, amino, hydroxyl, halo, or straight or branched-chain Ci. alkyl, Cs. alkenyl, Ca alkynyl, Ci alkoxy, Ci heteroalkyl, C,¢ aminoalkyl, Ci haloalkyl, Cy. alkoxycarbonyl, Cy. alkylthio, -CN, -CFj3, -OR3, -COR3, NO», -NHR3, -NHC(O)R3, - C(O)NR;3R4, -NR;3R4, -NR3C(O)NR4Rs, -OC(O)R;, -C(O)R3Ry, -O(CH1)¢NR3, -CNR3R; or -(CH3){NR3Ry; where q is an integer from 1 to 6; AMENDED SHEET
    PCT/USS9/07057 =i8C,,72,2 crt, re grouns Ry, when n> 1, being the seme or erent; p is 0 or an integer from 1 to 5; Y is 0, S, CHOH, -NHC(O)-, -C(O)NH-, -C(O)-, -OC(0)-, NR; or -CH=N-, and Ry is Hor Cia alkyl: or zbsent: Z is CRgRo wherein Rg and Rg are independently selected from H, and straight or branched-chain Cg alkyl; provided where (CHy)p-Y- is (CH2)3-C(O)- or ~-(CH2)3-S-; and X| through Xs are C; that -A-(Ry)n and R; are not together: o-methyl-phenyl and n-butyl, respectively; phenyl and n-butyl, respectively; or p-fluoro-phenyi and -O-(CH;),CHj, respectively; or a pharmaceutically acceptable salt, ester or prodrug thereof.
    2. The compound of claim 1, wherein: Xy, Xs, X3, X4 and Xs are C; or one of Xj, Xp, Xs, X4 or Xs is O or N and the others are C; kisQor i; “is 1; Rj is straight or branched-chain C,; g alkyl, C, galkenyl, Cs alkynyl, C,_g alkylidene, Cig alkoxy, Cy.g aninoalkyl, Cig haloalkyl, Cig alkosycatbouyl, -C(O)NR;3Ry, -NR3R4, -NR3C(O)NR4Rs, -OC(O)R3, or -(CH;)sNR3R4; where Rj, Ry and Rs are the same or different, each independently being selected from H and C,.¢ alkyl; and s is an integer from 1 to 8; nis, 2 or3; and A is phenyl! or naphthyl; where R, is straight or branched-chain Ci. alkyl, Cy alkenyl, C6 alkynyl, Ci alkoxy, C1.¢ aminoalkyl, Ci. haloalkyl, Ci alkoxycarbonyl, -CN, -CF3, -OH, -COR3, -NHR3, -NHC(O)R3, -C(O)NR3R4, -NR3R4, -NR3C(O)NR4Rs, -OC(O)R3, or -CH,)gNR3R4; where q 1s an integer from 1 to 6; or A is aryl comprising 1 or more heteroatoms selected from N, S and O; R, is H, halo, straight or branched-chain C,.¢ alkyl, Cy alkenyl, Cog alkynyl, Ci alkoxy, Ci heteroalkyl, Ci aminoalkyl, Cy. haloalkyl, Cy. alkoxycarbonyl, -CN, -CFs, 36 AMENDED SHEET
    PCT/US99/07057 C=, CCRs, -NERs, N=ZCOR;, -CICINR3 Ry, -NR3Ry, -NR3C(CINRLRs, -CC{C)R; or -(CH3)qNR3Ry; or a pharmaceutically acceptable salt, ester or prodrug thereof.
    3. Acomnound ofclaim 1 or 2, wherein nis 3.
    4. A compound of claim 1 or 2, wherein k is 0.
    5. The compound of claim I: Rh Ne Ron X N— (CH,);—Y 2 It 3 2/p __/
    6. The compound of claim 5: R, Ry FN (CH, —~Y lla 3 2/p __/
    7. A compound of claim 6, wherein tis | and Y 1s -C(O)-, -NHC(O)-, §, G or -OC(O)-.
    8. The compound of claim 7, whercin Xs is C.
    9. The compound of claim 8, wherein R; is alkyl.
    10. The compound of claim 9, wherein Rj is alkyl, aminoalkyl, alkoxy or hydroxyl.
    11. A compound of claim 10, wherein p is 3.
    12. A compound of claim 11, wherein R; is Cy alkyl and R; is methyl, hydroxy! or alkoxy.
    13. A compound of claim 12, wherein Y is -C(O)- or O.
    14. The compound of claim 9, wherein R; is halo.
    15. The compound of claim 6, wherein t is 0.
    16. The compound of claim 8, wherein R; is alkoxy.
    17. The compound of claim 8, wherein R; is benzyl or phenyl.
    18. The compound of claim 7, wherein Xj; is N.
    19. The compound of claim 18, wherein R; is alkyl or alkoxy. 37 AMENDED SHEET
    PCT/US99/07057
    20. Thecompourndclezim [FE wherein Rls emmy or sheny..
    21. The compound of claim 19, wherein R; is alkyl or alkoxy.
    22. The compound of claim 20, wherein R; is alkyl or alkoxy. 23 The namnound of claim 7. wherein X3 is O.
    24. The compound cof claim 23, wherein Ry is alkyl.
    25. The compound of claim 24, wherein R; is alkyl or alkoxy.
    26. The compound of claim 24, wherein R, is halo.
    217. The compound of claim 5: RD, Rs
    28. A compound of claim 27, wherein Y is -C{O}-, -NHC(O}-, S, O or -OC(O)-.
    29. The compound of claim 28, wherein Xj; is C.
    30. The compound of claim 29, wherein R; is alkyl.
    31. The compound of claim 30, wherein R; is alkyl, aminoalkyl, alkoxy or hydroxyl.
    32. A compound of claim 31, wherein p is 3.
    33. A compound of claim 32, wherein R, is Coz alkyl and R» is methyl, hydroxyl or alkoxy.
    34. A compound of claim 33, wherein Y is -C(O)- or O.
    35. The compound of claim 30, wherein R, is halo.
    36. The compound of claim 27, wherein t is 0.
    37. The compound of claim 29, wherein R; is alkoxy.
    38. The compound of claim 29, wherein R, is benzyl or phenyl.
    39. The compound of claim 28, wherein Xs is N.
    40. The compound of claim 39, wherein R; is alkyl or alkoxy.
    41. The compound of claim 39, wherein R; is benzyl or phenyl.
    42. The compound of claim 40, wherein R; is alkyl or alkoxy.
    43. The compound of claim 41, wherein R; is alkyl or alkoxy. 44, The compound of claim 28, wherein X3 is O. 38 AMENDED SHEET
    PCT/US99/07057 45, The ocmnound oficial 44 wherein Ry ls 2lkyl.
    46. The compound of claim 45, wherein R; is alkyl or alkoxy.
    47. The compound of claim 45, wherein Rj is halo. AR A method of apnnizing 2 muscarinic recentor comorising contacting said receptor with an effective amount of 2 compound of formula (I): xX Xx, Cy (Rog Rk TX ~N z2— CH Y¥Y———(— ji xX, wherein Xi, Xa, X3, X4 and Xs are selected from C, N and O; kisCorl; tisQor I; R; is straight or branched-chain Cs alkyl, Cs.g alkenyl, Cs alkynyl, Ci. alkylidene, Cis alkoxy, Cig heteroalkyl, Cy.g aminoalkyl, C;_g haloalkyl, C;.g alkoxycarbonyl, Cig hydroxyalkoxy, Cg hydroxyalkyl, -SH, C;.g thicalkyl, -O-CH)-Cs¢ aryl, -C(0)-Cs. aryl substituted with C,.3 alkyl or halo; Cs. aryl or Cs. cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O (89620); -C(O)INR3Ry, - NR3R4, -NR3C(O)NR4Rs, -CR3Ry, -OC(O)R3, -C(O)(CH2)sNR;R4 or -(CH3)sNR3Ry; where Rs, Ry and Rs are the same or different, each independently being selected from H,
    Ci. alkyl; Cs aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or Cy. alkyl; Cs. cycloalkyl; or R3 and Ry together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to 8; Ais Cs.1z aryl or Cs; cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, S and O; R, is H, amino, hydroxyl, halo, or straight or branched-chain Cy alkyl, Cs.¢ alkenyl, Cy alkynyl, Ci.¢ alkoxy, Cy. heteroalkyl, Cis aminoalkyl, Ci. haloalkyl, C1. alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, NO;, -NHR 3, -NHC(O)R3, 39 AMENDED SHEET
    PCT/US99/07057 -CIONZR Ry, NER, NZTENR Rs, CCC Rs, CORR, ~O(CHy)¢NR3, -CNR3R4 or ~(CH:)qNR3R4; where q is an integer from 1 to 6; nis 0, 1, 2, 3 or 4, the groups R,, when n > 1, being the same or different; nie for or integer from 1 40 5: Vis CQ, §, CHOH, -NHC(Q)-, -C(O)NH., -C(O)-, -OC(0)-, NR; or -CH=N-, and Ry is H or C4 alkyl; or absent; and Z is CRgRo wherein Ry and Ry are independently selected from H, and straight or branched chain Cg alkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof.
    45. A method of claim 48: Rok Ry), Seem 11
    50. A method of claim 49, wherein tis 1 and Y is -C(O)-, -NHC(O)-, S, O or -OC(0)-.
    51. The method of claim 50, wherein X3 is C
    52. The method of claim 51, wherein R; is alkyl.
    53. The method of claim 52, wherein R; is alkyl, aminoalkyl, alkoxy or hydroxyl. 54, A method of claim 53, wherein p is 3.
    55. A method of claim 54, wherein R; is Cg alkyl and Rj is methyl, hydroxyl or alkoxy.
    56. A method of claim 55, wherein Y is -C(O)- or O.
    57. The method of claim 52, wherein R» is halo.
    58. The method of claim 49, wherein t is 0.
    59. The method of claim 51, wherein R; is alkoxy.
    60. The method of claim 51, wherein R; is benzyl! or phenyl.
    61. The method of claim 52, wherein X;3 is N.
    62. The method of claim 61, wherein R; is alkyl or alkoxy.
    63. The method of claim 61, wherein R; is benzyl or phenyl. 40 AMENDED SHEET
    PCT/US99/07057
    S&. Themethod ofcleim £7, vwinereln Rp ls allyl or glkexy.
    65. The method of claim 63, wherein Rj is alkyl or alkoxy.
    56. The method of claim 50, wherein X3 is O. £7 Tha mathad of claim 86 wherein Ry is alkyl,
    68. The method of claim 67, wherein R; is alkyl! or alkoxy.
    69. The method of claim 67, wherein R; is halo.
    70. A pharmaceutical composition comprising an effective amount of 2 compound of formula (I): X Ran xe xo, } [ax Rp EIN FE NY. I % wherein Xi, Xa, X3, X4 and Xs are selected from C, N and O; kisOQor 1; tisGori; R; is straight or branched-chain Cg alkyl, Cs galkenyl, Cag alkynyl, C,5 alkylidene,
    C,.g alkoxy, Cg heteroalkyl, Cg aminoalkyl, C;_g haloalkyl, C,_g alkoxycarbonyi,
    C..g hydroxyalkoxy, C; g hydroxyalkyl, -SH, Cg thioalkyl, -O-CH,-Cs.¢ aryl, -C(0)-Cs. aryl substituted with Cy.3 alkyl or halo; Cs. aryl or Cs.¢ cycloalkyl optionally comprising 1 or more heteroatoms selected from N, S and O; -C(O)NR;3R4, -NR3Ry, ~ NR;3;C(O)NR4Rs, -CR3R4, -OC(O)R3, -C(O)(CH2)sNR3R4 or -(CH2)sNR3R4; where Rs, Ry and Rs are the same or different, each independently being selected from H, C4 alkyl;
    Cs. aryl optionally comprising 1 or more heteroatoms selected from N, O and S, and optionally substituted with halo or Cy. alkyl; Cs. cycloalkyl; or R3 and Ry together with the N atom, when present, form a cyclic ring structure comprising 5-6 atoms selected from C, N, S and O; and s is an integer from 0 to §; A is Cs.15 aryl or Cs; cycloalkyl, each optionally comprising 1 or more heteroatoms selected from N, §S and O; 41 AMENDED SHEET
    PCT/UJS99/07057 Rp is =, amine, mydroxy., nec, or gtreight or srenohed-cheln Cig 2’kyl, Cog 2lkenyl, Ca alkynyl, C, alkoxy, Ci heteroalkyl, C,.¢ aminoaikyl, C; haloalkyl, C6 alkoxycarbonyl, -CN, -CF3, -OR3, -COR3, NO,, -NHR3, -NHC(O)R3, CIONRLR. NR,R, NR.CIOWRLRs, -OCIOIR;. ~C(OR3R. -O(CHa)gNR3, -CNR;3R; or -{CH3){NR3Ry; where g is an integer from 1 to 6; nis 0, 1, 2, 3 or 4, the groups Ro, when n > 1, being the same or different; pis § or an integer from 1 to 5; Y is 0, §, CHOH, -NHC(O)-, -C(O)NH-, -C(O)-, -OC(0)-, NR or -CH=N-, and Ry is H or C4 alkyl; or absent; Z is CRgRg wherein Rg and Ry are independently selected from H, and straight or branched chain Cy g alkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof; and a pharmaceutically acceptable carrier.
    71. A composition of claim 70 compromising: Ra) GON OC amy f II J : \
    72. A composition of claim 71, wherein t is 1 and Y is -C(O)-, -NHC(O)-, S, O or -0OC(O)-.
    73. The composition of claim 72, wherein X3 is C.
    74. The composition of claim 73, wherein R; is alkyl.
    75. The composition of claim 74, wherein R; is alkyl, aminoalkyl, alkoxy or hydroxyl.
    76. A composition of claim 75, wherein p is 3.
    71. A composition of claim 75, wherein R; is Cug alkyl and Rj is methyl, hydroxy! or alkoxy.
    78. A composition of claim 77, wherein Y is -C(O)- or O.
    79. The composition of claim 74, wherein Ry; is halo.
    80. The composition of claim 71, wherein t is 0. 42 AMENDED SHEET
    PCT/US99/07057
    8. Theccmpositionofclaim 73, wherein Rs 2lkoxy.
    82. The composition of claim 73, wherein R; is benzyl or phenyl.
    83. The composition of claim 74, wherein X; is N. 24 The nomnagition of claim 82. wherein R, is alkyl or alkoxy.
    85. The composition of claim 82, wherein R, is benzyl or phenyl.
    86. The composition of claim 83, wherein R; is alkyl or alkoxy.
    87. The composition of claim 84, wherein R; is alkyl or alkoxy.
    88. The composition of claim 72, wherein Xj is O.
    89. The composition of claim 88, wherein R, is alkyl.
    90. The composition of claim 89, wherein R; is alkyl or alkoxy.
    91. The composition of claim 87, wherein R; is hale.
    92. Use of one or more compounds of claim 1 in the manufacture of a preparation for treating the symptoms of a disease or condition associated with reduced levels of acetylcholine.
    93. Use of claim 92, wherein said disease or condition is neurogenerative disease, cognitive impairment, age-related cognitive decline or dementia.
    94. Use of a composition of claim 70 in the manufacture of a preparation for treating the symptoms of a disease or condition associated with reduced levels of acetyicholine.
    9s. Use of claim 94, wherein said disease or condition is neurcgenerative disease, cognitive impairment, age-related cognitive decline or dementia.
    96. Use of a muscarinic receptor agonist treating the symptoms of a disease or condition associated with increased intraocular pressure.
    97. Use of claim 96, wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
    98. Use of claim 96, wherein said muscarinic receptor agonist is m1 selective.
    99. Use of a muscarinic receptor agonist in the manufacture of a preparation for use with one or more compounds of claim 1 in the treatment of the symptoms of a disease or condition associated with increased intraocular pressure.
    100. Use of claim 99 wherein said muscarinic receptor agonist is m1 selective.
    101. Use of claim 96, wherein said disease is glaucoma. 43 AMENDED SHEET
    PCT/USS9/07057
    182. Use cfz composition comprising 2 muscarinic recestor egonist In the manufacture of a preparation for treating the symptoms of a disease or condition associated with increased intraocular pressure. 03 Tee ~fnloiem 107 wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
    104. Use of claim 102, wherein said muscarinic receptor agonist is m1 selective.
    105. Use of a composition comprising a muscarinic receptor agonist in the manufacture of a preparation for use with one or more compounds of claim 70, in the treatment of the symptoms of a disease or condition associated with increased intraocular pressure.
    106. Use of claim 105, wherein said muscarinic receptor agonist is m1 selective.
    107. Use of claim 102, wherein said disease is glaucoma.
    108. A method of identifying agents capable of reducing intraocular pressure, said method comprising: contacting a putative agent with an m1 muscarinic receptor subtype; contacting the putative agent with an m3 muscarinic receptor subtype; comparing the increase in activity of each receptor subtype; and identifying agents selective for the m1 muscarinic receptor subtype; thereby identifying agents capable of reducing intraocular pressure.
    109. Use of a compound of formula (I) as defined in claim 48, or a pharmaceutically acceptable salt, ester or prodrug thereof, in the manufacture of a preparation for agonizing a muscarinic receptor by contacting said receptor with an effective amount of said preparation.
    110. Use of claim 109: (Rp (R ) % _ \ — A M2/n X N-— (CHy),— — [1
    111. Useofclaim 110, whereintis I and Y is -C(O)-, -NHC(O)-, S, O or ~-0C(0)-. 44 AMENDED SHEET
    PCT/USS9/07057 32, Jsscfolglm 111, uwimerein X3is C.
    113. Use of claim 112, wherein R; is alkyl.
    114. Use of claim 113, wherein R» is alkyl, aminoalkyl, alkoxy or hydroxyl. 115 Tee ofclaim 114 wherein nis 3.
    116. Use of claim 115, wherein R; is Cpg 2lkyl and R;, is methyl, hydroxy! or alkoxy.
    117. Use of claim 116, wherein Y is -C(O)- or O.
    118. Use of claim 113, wherein R; is hale.
    119. Use of claim 110, wherein t is 0.
    120. Use of claim 112, wherein R; is alkoxy.
    121. Use of claim 112, wherein R; is benzy! or phenyl.
    122. Use of claim 113, wherein X35 is N.
    123. Use of claim 122, wherein R; is alkyl or alkoxy.
    124. Use of claim 122, wherein R is benzy! or phenyl.
    125. Use of claim 123, wherein R; is alkyl or alkoxy.
    126. Use of claim 124, wherein R; is alkyl or alkoxy.
    127. Use ofclaim 111, wherein X35 is O.
    128. Use ofclaim 127, wherein R; is alkyl.
    129. Use of claim 128, wherein R; is alkyl or alkoxy.
    130. Use of claim 128, wherein Ry is halo.
    131. A substance or composition for use in a method of agonizing a muscarinic receptor, said substance or composition comprising a compound of formula (I) as defined in claim 48, or a pharmaceutically acceptable salt, ester or prodrug thereof, and said method comprising contacting said receptor with an effective amount of said substance or composition.
    132. A method of claim 133: Ry), | ®,). hNS Wem (CH,) —( II _/ P NY 45 AMENDED SHEET
    PCT/USS9/07057
    “33. A substance oroomzosition oruse ing method cltreetment cfciein 122) wherein tis 1 and Y is ~C(O)-, -NHC(O)-, S, O or -OC(O)-.
    134. A substance or composition for use in a method of treatment of claim 133, wherein X, is C.
    135. A substance or composition for use in a method of treatment of claim 134, wherein R; is alkyl.
    136. A substance or compesiticn for use in a method of treatment cf claim 135, wherein R; is alkyl, aminoalkyl, alkoxy or hydroxyl.
    137. A substance or composition for use in a method of treatment of claim 136, wherein p is 3.
    138. A substance or composition for use in a method of treatment of claim 137, wherein R; is Cys alkyl and R; is methyl, hydroxyl or alkoxy.
    139. A substance or composition for use in a method of treatment of claim 138, wherein Y is -C(O)- or O.
    140. A substance or composition for use in a method of treatment of claim 135, wherein R, is halo. 141, A substance or composition for use in a method of treatment of claim 132, wherein t is 0.
    142. A substance or composiilon {or use in a method of ireaiment of claim 134, wherein R; is alkoxy.
    143. A substance or composition for use in a method of treatment of claim 134, wherein R; is benzyl or phenyl.
    144. A substance or composition for use in a method of treatment of claim 135, wherein Xs is N.
    145. A substance or composition for use in a method of treatment of claim 144, wherein R; is alkyl or alkoxy.
    146. A substance or composition for use in a method of treatment of claim 144, wherein R; is benzyl or phenyl.
    147. A substance or composition for use in a method of treatment of claim 145, wherein R, is alkyl or alkoxy. 46 AMENDED SHEET
    - PCT/USS9/07057 14%, A sutstemce orcomzositicon for use ing method of restment ol clei TLE wherein R; is alkyl! or alkoxy.
    149. A substance or composition for use in a method of treatment of claim 133, wherein X, is O
    150. A substance or composition for use in a method of treatment of claim 149, wherein R; is alkyl.
    151. A substance or composition for use in a method of treatment of claim 150, wherein R; is alkyl or alkoxy.
    152. A substance or composition for use in a method of treatment of claim 150, wherein R, is halo.
    153. A substance or composition for use in a method of treating the symptoms of a disease or condition associated with reduced levels of acetylchlorine, said substance or composition comprising one or more compounds of claim 1, and said method comprising and said method comprising administering a therapeutically effective amount of said substance or composition. 154, A substance or composition for use in a method of treatment of claim 153, wherein said disease or condition is neurogenerative disease, cognitive impairment, age- related cognitive decline or dementia.
    155. A substance or composition for use in a method of treating the symptoms of a disease or condition associated with reduced levels of acetylchlorine, said substance or composition comprising a composition of claim 70, and said method comprising and said method comprising administering a therapeutically effective amount of said substance or composition.
    156. A substance or composition for use in 2 method of treatment of claim 155, wherein said disease or condition is neurogenerative disease, cognitive impairment, age- related cognitive decline or dementia.
    157. A substance or composition for use in a method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said substance or composition comprising a muscarinic receptor agonist, and said method comprising administering a therapeutically effective amount of said substance or composition. 47 AMENDED SHEET
    “ PCT/US9%/07057
    258. A sutstzmee croomzosition for use in oz method oftresiment of clain 157, wherein said muscurinic receptor agonist comprises m1 receptor agonist activity.
    158. A substance or composition for use in a method of treatment of claim 157, wherein said muscarinic recentor agonist is m1 selective.
    160. A substance or composition for use with one or more compounds of claim I, ina method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said substance or compositicn comprising a muscarinic receptor agonist, and said method comprising administering a therapeutically effective amount of said substance or composition and administering a therapeutically effective amount of said one or more compounds.
    161. A substance or composition for use with one or more compounds of claim 16C, wherein said muscarinic receptor agonist is m1 selective.
    162. A substance or composition for use in a method of treatment of claim 157, wherein said disease is glaucoma.
    163. A substance or composition for use in a method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said substance or composition comprising a composition comprising a muscarinic receptor agonist, and said method comprising administering a therapeutically effective amount of said substance or composition.
    164. A substance or composition for use in a method of treatment of claim 163, wherein said muscarinic receptor agonist comprises m1 receptor agonist activity.
    165. A substance or composition for use in a method of treatment of claim 163, wherein said muscarinic receptor agonist is m1 selective.
    166. A substance or composition for use with a composition of claim 70, in a method of treating the symptoms of a disease or condition associated with increased intraocular pressure, said substance or composition comprising a muscarinic receptor agonist, and said method comprising administering a therapeutically effective amount of said substance or composition and administering a therapeutically effective amount of said composition of claim 70.
    167. A substance or composition for use in a method of treatment of claim 166, wherein said muscarinic receptor agonist is m1 selective. 48 AMENDED SHEET
    -
    . We PCT/US99/07057
    “C8. Astbstence ocrcoompesiticn foruse ing method of trestment cl gleim 188, wherein said disease is glaucoma.
    169. A compound according to any one of claims 1 to 47, substantially as herein dagarihed ord floetrotad
    170. A method according tc any one of claims 48 to 69, substantially as herein described and illustrated.
    171. A composition according to any one of claims 70 tc 91, substantially as herein described and illustrated.
    172. Use according to any one of claims 92 tc 107 or 109 tc 130, substantially as herein described and illustrated.
    173. A method according to claim 108, substantially as herein described and illustrated.
    174. A substance or composition for use in a method of treatment according to any one of claims 131 to 168, substantially as herein described and illustrated.
    175. A new compound, a new non-therapeutic method of treatment, a new composition, a new use of a compound as claimed in claim 1 or of a composition as claimed in claim 70, a new method of identifying agents, or a substance or composition for a new use in a method of treatment, substantially as herein described. 49 AMENDED SHEET
ZA200005149A 1998-03-31 2000-09-26 Compounds with activity on muscarinic receptors. ZA200005149B (en)

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