Di-N-substituted piperazine or 1,4-di-substituted piperidine compounds in accordance with formula I (including all isomers, salts, esters, and solvates) ##STR1## wherein Q, n, R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.21, R.sup.27, R.sup.28, X, and Z are as defined herein are muscarinic antagonists useful for treating cognitive disorders such as Alzheimer's disease. Pharmaceutical compositions and methods of preparation are also disclosed. Also disclosed are synergistic combinations with acetyl-cholinesterase inhibitors of compounds capable of enhancing acetylcholine release and having the above formula.

FIELD OF THE INVENTION 
The present invention relates to di-N-substituted piperazines and 
1,4-di-substituted piperidines useful in the treatment of cognitive 
disorders, pharmaceutical compositions containing the compounds, methods 
of treatment using the compounds, and to the use of said compounds in 
combination with acetylcholinesterase inhibitors. 
BACKGROUND OF THE INVENTION 
Alzheimer's disease and other cognitive disorders have received much 
attention lately, yet treatments for these diseases have not been very 
successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 
3734-3737), compounds that selectively antagonize m2 muscarinic receptors, 
especially in relation to m1 muscarinic receptors, should possess activity 
against cognitive disorders. Baumgold et al. (Eur. J. Pharmacol., 251, 
(1994) 315-317) disclose 3-.alpha.-chloroimperialine as a highly selective 
m2 muscarinic antagonist. 
The present invention is predicated on the discovery of a class of 
di-N-substituted piperazines and 1,4-di-substituted piperidines. Logemann 
et al. (Brit. J. Pharmacol. (1961), 17, 286-296) describe certain 
di-N-substituted piperazines, but these are different from the inventive 
compounds of the present invention. Furthermore, the compounds of Logemann 
et al. are not disclosed to have activity against cognitive disorders. 
International Patent Publication Number WO93/08799 published May 13 1993 
(Smith-Kline Beecham) discloses inter alia indane derivatives that are 
endothelin receptor antagonists and are (in part) of the following 
formula: 
##STR2## 
wherein: R.sub.1 is --X(CH.sub.2).sub.n Ar or --X(CH.sub.2).sub.n R.sub.8 
; 
R.sub.2 is H or Ar; 
P.sub.1 is --X(CH.sub.2).sub.n R.sub.8 ; 
P.sub.2 is --X(CH.sub.2).sub.n R.sub.8 or --XR.sub.9 Y; 
R.sub.8 is H, alkyl, alkenyl, alkynyl, CO.sub.2 H, CO.sub.2 alkyl, or 
CO.sub.2 Ar; 
R.sub.9 is alkyl, alkenyl or phenyl; 
R.sub.10 is H, alkyl (which may be substituted with CO.sub.2 H, CO.sub.2 
alkyl or CO.sub.2 (CH.sub.2).sub.n Ar), alkenyl, phenyl, OH, alkoxy, 
S(O).sub.q alkyl, S(O).sub.q alkenyl, S(O).sub.q aryl, NH.sub.2, NHalkyl, 
N(alkyl).sub.2, F, Cl, Br, I, CF.sub.3, NHCHO, NHCOalkyl, 
--X(CH.sub.2).sub.n R.sub.8 or --XR.sub.9 Y; 
X is (CH.sub.2).sub.n, O, NH, Nalkyl, or S(O).sub.q ; 
Y is CH.sub.3 or X(CH.sub.2).sub.n Ar; 
Ar is a variety of substituted or unsubstituted heterocyclic and aromatic 
hydrocarbon groups, including piperidinyl and piperazinyl, which may carry 
substituents; 
Z.sub.1 and Z.sub.2 are independently H, alkyl, alkenyl, alkynyl, OH, 
alkoxy, S(O).sub.q alkyl, NH.sub.2, NHalkyl, N(alkyl).sub.2, F, Cl, Br, I, 
CF.sub.3, NHCHO, NHCOalkyl, --X(CH.sub.2).sub.n R.sub.8, phenyl, benzyl or 
cycloalkyl; 
Z.sub.3 is Z.sub.1 or --XR.sub.9 Y; 
n is 0 or an integer from 1 to 6, and q is 0, 1 or 2; 
and the groups designated as `alkyl`, `alkenyl`, `alkynyl` or `phenyl` can 
all be substituted. 
(The definitions of radicals as given in that patent do not in general 
pertain to the present invention, even though similar symbols may be 
used.) 
SUMMARY OF THE INVENTION 
The present invention relates to compounds according to the structural 
formula I, 
##STR3## 
including all stereoisomers and pharmaceutically acceptable salts, esters, 
and solvates thereof, wherein: 
Z is N, CH or C--alkyl; 
X is --O--, --S--, --SO--, --SO.sub.2 --, --CO--, --CH.sub.2 --, 
--CONR.sup.20 --, --NR.sup.20 --SO.sub.2 --, --NR.sup.20 CO--, or 
--SO.sub.2 --NR.sup.20 --; 
Q is --O--, --S--, --SO--, --SO.sub.2 --, or --CH.sub.2 --; 
R is 
##STR4## 
R.sup.1 and R.sup.21 are independently selected from the group consisting 
of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, 
cycloalkenylalkyl, phenylalkyl, and hydroxyalkyl; 
R.sup.2 is cycloalkyl, cycloalkyl substituted with 1 to 3 independently 
selected R.sup.3 groups, cycloalkenyl, cycloalkylalkyl, 
##STR5## 
(wherein R.sup.y is H, alkyl, alkenyl, SO.sub.2 R.sup.z or COR.sup.z 
wherein R.sup.Z is alkyl, alkenyl, aryl, heteroaryl, or cycloalkyl), with 
the proviso that R.sup.2 is R.sup.3 -substituted-1-piperidinyl only when Z 
is CH or C-alkyl; or, when Z is CH, R.sup.2 may also be alkoxycarbonyl, 
--N(R.sup.9)(hydroxyalkyl) wherein R.sup.9 is H, hydroxyalkyl, or alkyl, 
or --N(R.sup.9).sub.2 wherein the two R.sup.9 groups may be joined to form 
an alkylene group; 
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.22, R.sup.24, and R.sup.25 are 
independently selected from the group consisting of H, alkyl, halo, 
alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, 
polyhaloalkyl, nitro, sulfonyl, hydroxy, amino, alkylamino, formyl, 
alkylthio, acyloxy, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl, 
alkylsulfinyl, --OCONH.sub.2, --OCONH--alkyl, --OCON(alkyl).sub.2, 
--NHCOO--alkyl, --NHCO--alkyl, phenyl, hydroxyalkyl, and 1-morpholinyl; 
R.sup.8 is hydrogen, lower alkyl or cyclopropyl; 
R.sup.20 is H, phenyl or alkyl; 
R.sup.27 and R.sup.28 are independently selected from the group consisting 
of H, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, mercaptoalkyl, 
alkylthioalkyl, and carboxyalkyl, and additionally R.sup.27 and R.sup.28 
may be joined to form an alkylene group; and 
n is 0 or an integer from 1 to 3. 
Another aspect of the invention is a pharmaceutical composition which 
comprises a compound having structural formula I as defined above, 
including stereoisomers, pharmaceutically acceptable salts, esters, and 
solvates thereof, in combination with a pharmaceutically acceptable 
carrier. 
Another aspect of the invention is the use of a compound of formula I as 
defined above, including stereoisomers, pharmaceutically acceptable salts, 
esters, and solvates thereof, for the preparation of a pharmaceutical 
composition useful in the treatment of cognitive disorders and 
neurodegenerative diseases such as Alzheimer's disease. 
Yet another aspect of the invention comprises a method for making a 
pharmaceutical composition comprising mixing a compound of formula I as 
defined above, including stereoisomers, pharmaceutically acceptable salts, 
esters, and solvates thereof, with a pharmaceutically acceptable carrier. 
Another aspect of this invention is a method for treating a cognitive or 
neurodegenerative disease comprising administering to a patient suffering 
from said disease an effective amount of a compound of formula I as 
defined above, including stereoisomers, pharmaceutically acceptable salts, 
esters, and solvates thereof. 
Another aspect of this invention is a method for treating cognitive and 
neurodegenerative diseases, such as Alzheimer's disease, with a compound 
of formula I as defined above, including stereoisomers, pharmaceutically 
acceptable salts, esters, and solvates thereof, in combination with an 
acetylcholinesterase inhibitor. 
Another aspect of this invention is a method for treating a cognitive or 
neurodegenerative disease comprising administering to a patient suffering 
from said disease an effective amount of a combination of a compound of 
formula I as defined above, including stereoisomers, pharmaceutically 
acceptable salts, esters, and solvates thereof, said compound being 
capable of enhancing acetylcholine release (and being preferably an m2 or 
m4 selective muscarinic antagonist), together with an acetylcholinesterase 
inhibitor. 
Another aspect of this invention is a kit comprising in separate containers 
in a single package pharmaceutical compounds for use in combination to 
treat cognitive disorders, wherein 
one container contains a compound of formula I as defined above, including 
stereoisomers, pharmaceutically acceptable salts, esters, and solvates 
thereof, said compound being capable of enhancing acetylcholine release 
(and preferably being an m2 or m4 selective muscarinic antagonist) in a 
pharmaceutically acceptable carrier, and 
a second container contains an acetylcholinesterase inhibitor in a 
pharmaceutically acceptable carrier, 
the combined quantities being an effective amount. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In a particularly preferred group of compounds of the formula I, Z is N. In 
another preferred group, n is 1 or 2 or especially 0. 
In another preferred group of compounds, X is SO or especially O or 
SO.sub.2. 
In yet another preferred group of compounds, R.sup.8 is H or methyl. 
In another preferred group of compounds, R is 
##STR6## 
(wherein R.sup.5 and R.sup.6 are H, CH.sub.3, nitro, NH.sub.2, 
acetylamino, or methoxy), especially 4-methoxyphenyl; X is preferably O, 
SO or SO.sub.2, R.sup.3 and R.sup.4 are H, and R.sup.1 is H, cycloalkyl, 
cycloalkylalkyl or alkyl, and R.sup.21 is H. 
In another preferred group of compounds, R.sup.3 and R.sup.4 are H, and 
R.sup.1 is H, cycloalkyl or alkyl and R.sup.21 is H. R.sup.1 is preferably 
H, CH.sub.3 or cyclohexylmethyl, and R.sup.2 is cyclohexyl. 
In another preferred group of compounds, R.sup.3 and R.sup.4 are H, X is O, 
SO or SO.sub.2, and R.sup.1 is H, cycloalkyl or alkyl and R.sup.21 is H. 
R.sup.1 is preferably H or CH.sub.3. 
In another preferred group of compounds, at least one of R.sup.27 and 
R.sup.28 is alkyl. In particular, at least one of R.sup.27 and R.sup.28 is 
alkyl and the other is H or alkyl; more preferably, one of R.sup.27 and 
R.sup.28 is methyl and the other is hydrogen. 
In another preferred group of compounds, R is 4-methoxyphenyl. 
In a particularly preferred group of compounds of the formula I: 
R is a phenyl group, which may be substituted with nitro or especially with 
methoxy, where each of these groups is preferably in the 4-position, or in 
particular a 2-pyrimidinyl group; 
X is S, SO, or especially SO.sub.2 or O; 
Q is O or especially CH.sub.2 ; 
n is 1 or 2 or especially 0; 
R.sup.1 is H and R.sup.21 is cyclohexylmethyl; 
R.sup.27 and R.sup.28 are CH.sub.3 or especially H; 
Z is N; and 
R.sup.2 is cyclohexyl or 1-piperidinyl. 
Except where stated otherwise the following definitions apply throughout 
the present specification and claims. These definitions apply whether a 
term is used by itself or in combination with other terms. For example, 
the definition of "alkyl" applies not only to "alkyl" but also to the 
"alkyl" portions of "alkoxy", "polyhaloalkyl", etc. 
Alkyl represents a straight or branched saturated hydrocarbon chain having 
1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. A "lower alkyl" 
group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. 
Alkenyl represents a straight or branched hydrocarbon chain of from 3 to 15 
carbon atoms, more preferably 3 to 12 carbon atoms, having at least one 
carbon-to-carbon double bond but the free valency at least one carbon atom 
removed from the double bond. 
Cycloalkyl represents a saturated carbocyclic ring having 3 to 12 carbon 
atoms. 
Cycloalkenyl represents a carbocyclic ring having from 5 to 8 carbon atoms 
and at least one carbon-to-carbon double bond in the ring. 
Acyl represents a radical of a carboxylic acid and thus includes groups of 
the formula Alkyl--CO--, Aryl--CO--, Aralkyl--CO--, Cycloalkyl--CO--, 
wherein the various hydrocarbon radicals are as defined in this section. 
Halo represents fluoro, chloro, bromo or iodo. 
Aryl represents phenyl or naphthyl, each of which may be substituted with 
one to three groups R.sup.c selected from halo, alkyl, hydroxy, alkoxy, 
phenoxy, amino, alkylamino and dialkylamino groups. Preferred aryl groups 
are phenyl, substituted phenyl, 1-naphthyl, 2-naphthyl and indanyl groups. 
Heteroaryl represents a cyclic group having at least one O, S and/or N 
interrupting a carbocyclic ring structure and having a sufficient number 
of pi electrons to provide aromatic character. The aromatic heterocyclic 
group preferably has from 2 to 14, especially from 3 to 9 carbon atoms, 
e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 
5-thiazolyl, 2-, 4- or 5 4-, 5- or especially 2-pyrimidinyl, 2-pyrazinyl, 
3- or 4-pyridazinyl, 3-, 5- or 6-1,2,4-triazinyl!, 3- or 
5-1,2,4-thiadiazolyl!, 2-, 3-, 4-, 5-, 6- or 7-benzofuranyl, 2-, 3-, 4-, 
5-, 6- or 7-indolyl, 3-, 4- or 5-pyrazolyl, or 2-, 4- or 5-oxazolyl, etc. 
Preferred heteroaryl groups include 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- 
or 3-thienyl, 2-, 4- or 5-imidazolyl, and 7-indolyl. 
Polyhalo indicates substitution of at least 2 halo atoms in the group 
modified by the term "polyhalo". 
Sulfonyl represents a group of the formula --SO.sub.2 --. 
Sulfinyl represents a group of the formula --SO--. 
Alkylene represents a straight or branched saturated hydrocarbon chain 
having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, and two free 
valencies, which for the purpose of this invention are not on the same 
carbon atom when the alkylene group has 2 to 20 carbon atoms. Preferred 
alkylene groups are methylene or polymethylene groups of the formula 
--(CH.sub.2)(.sub.2-20)--. 
Each radical or group that appears more than once in a structural formula, 
for example R.sup.9 when R.sup.2 is --N(R.sup.9).sub.2, may be 
independently selected from the whole definition for that radical or 
group. 
Compounds of this invention may exist in at least two stereoisomeric 
configurations based on the asymmetrically substituted carbon atom to 
which the group 
##STR7## 
is attached. Further stereoisomerism may be present, for example when 
R.sup.1 and R.sup.21 are not identical, or when X is SO, or when at least 
one of R.sup.27 and R.sup.28 is not hydrogen. All possible stereoisomers 
of formula I are within the scope of the invention. 
Compounds of formula I can exist in unsolvated as well as solvated forms, 
including hydrated forms. In general, the forms that are solvated with 
pharmaceutically acceptable solvents such as water, ethanol and the like, 
are equivalent to the unsolvated forms for the purposes of this invention. 
A compound of formula I may form pharmaceutically acceptable salts with 
organic and inorganic acids. Examples of suitable acids for salt formation 
are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, 
salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and 
other mineral and carboxylic acids well known to those skilled in the art. 
A salt is prepared by contacting a free base form with a sufficient amount 
of the desired acid to produce a salt in the conventional manner. The free 
base form may be regenerated by treating the salt with a suitable dilute 
aqueous base such as dilute aqueous sodium hydroxide, potassium carbonate, 
ammonia or sodium bicarbonate. The free bases differ from the 
corresponding salts somewhat in certain physical properties, such as 
solubility in polar solvents, but the salts are otherwise equivalent to 
the corresponding free bases for purposes of the invention. 
Compounds of formula I and their salts can be prepared by standard methods. 
The methods of the following Schemes are preferred; the starting materials 
either are known or can be prepared by standard methods, and the radicals 
in the formulae (unless otherwise stated) have the meanings given for 
formula I, with the proviso that R.sup.2 can also be a nitrogen-protecting 
group that is replaced (e.g., at the end of the Scheme) with a group 
R.sup.2 according to formula I: 
##STR8## 
In Scheme A, Q can be --O--, --S--, or --CH.sub.2 --. In Step (a), L.sup.1 
and L.sup.2 are groups that can be eliminated during the reaction. L.sup.2 
is preferably a leaving group such as a halogen atom, especially bromine 
or fluorine, and L.sup.1 is preferably an alkali metal, e.g., sodium or 
potassium. The reaction is carried out in an inert organic solvent, which 
is preferably anhydrous, e.g., DMSO, DMF, or a polar ether such as 
dimethoxyethane. 
When X is O or S, the reactant contributing the group X can be prepared by 
reaction of the parent compound containing the group XH and an alkali 
metal hydride in situ in the inert organic solvent. 
Step (b) comprises the reduction of the carbonyl group to hydroxy methylene 
with a reducing agent such as an aluminum hydride, e.g., lithium aluminum 
hydride, or a borohydride, e.g., sodium borohydride, in an inert organic 
solvent. When an aluminum hydride is used, the solvent should be anhydrous 
and is preferably an ether solvent such as THF; when a borohydride is 
used, the solvent can be a lower alkanol, especially methanol or ethanol, 
or THF, DMF, or DMSO, all of which may be anhydrous or aqueous. Step (c) 
comprises the conversion of the hydroxy group into a leaving group 
L.sup.3, e.g., a sulfonate ester group such as a group SO.sub.3 --(lower 
alkyl) or with a halogen atom, especially bromine or iodine. This 
conversion can be carried out with a sulfonyl chloride, e.g., methane-, 
ethane- or 4-toluene-sulfonylchloride, and an organic base, e.g., a 
tertiary amine such a pyridine or triethylamine; or with a halogenating 
agent, e.g., SOCl.sub.2 or PBr.sub.3, if desired with displacement of the 
resulting bromide by iodide when an iodide is required. 
Step (d) comprises the amination of the reactive group L.sup.3, e.g. Cl, 
with a piperidine or piperazine to form the desired product of the formula 
I. This reaction can be carried out neat with the piperidine or piperazine 
or in an organic solvent, and an acid-binding agent can if desired be 
used. An excess of the piperidine or piperazine may serve both as 
acid-binding agent and as organic solvent. When a piperazine is used, its 
second nitrogen atom can bind the acid liberated in the reaction and no 
extra acid-binding agent may be necessary. 
Step (e) can be carried out by condensation of the reactants in the 
presence of a basic catalyst, e.g, an amine such as piperidine. Under 
these circumstances an excess of the catalyst can serve as solvent. 
Alternatively, the reaction can be effected in the presence of a strongly 
basic catalyst such as LDA (lithium diisopropylamide) or lithium HMDS 
(lithium hexamethyidisilazane), which preferably is added at a low 
temperature, e.g., -78.degree. C. to 0.degree. C., in an inert anhydrous 
organic solvent such as THF or diethyl ether. The reaction with the 
aldehyde may then be effected at a low temperature, at room temperature or 
at moderately elevated temperature, e.g., at -78 to +60.degree. C., 
preferably about 0 to +30.degree. C., and under an inert atmosphere, e.g., 
nitrogen. When the aldehyde R.sup.21A --CHO is used to introduce the group 
R.sup.21, then R.sup.21A has one carbon atom fewer than R.sup.21 such that 
R.sup.21A --CH.sub.2 is R.sup.21. The intermediate carbinol of the formula 
##STR9## 
can then be dehydrated (for example, direct with acid or, after conversion 
of the hydroxy group into a leaving group, e.g., a halide or sulfonate, 
with base), and the resulting compound with a double bond can be 
hydrogenated, e.g. with hydrogen and a catalyst such as Pd/C, to the 
compound of the formula A6. When the hydrogenation also reduces the 
carbonyl group, then the reduction of the following Step (f) can be 
obviated. 
Step (f) can then be carried out by the methods of Steps (b) (reduction) 
and (c) (conversion of the hydroxy group into a leaving group L.sup.3) 
above, and Step (g) by the method of Step (d) above. 
If it is desired to introduce a group R.sup.1 in addition to R.sup.21, then 
the process of Step (e) can be repeated before Steps (f) and (g) are 
carried out. 
An alternative method for preparing compounds of the formulae A5 and A7 in 
Scheme A comprises the condensation of a compound of the formula A2 or A6 
with a compound of the formula A4, followed by the reduction of the 
resulting condensation product, e.g., imine, preferably in the same step. 
The condensation can be effected in the presence of a compound or 
compounds serving as a mild Lewis acid (or a protic acid) and a 
dehydrating agent. The mild Lewis acid is conveniently a titanium 
tetra(lower alkoxide), especially Ti(O-2-Pr).sub.4, which is commercially 
available and gives good results. The resulting condensation product 
(e.g., imine) can then be reduced with a mild reducing agent, e.g., a 
sodium borohydride, but preferably one that is not reactive towards the 
Lewis acid or protic acid, especially sodium cyanoborohydride. 
Alternatively, the reaction can be effected with sodium 
triacetoxyborohydride as both Lewis acid and reducing agent, in the 
presence of acetic acid. 
The condensation and reduction is carried out in the presence of an inert 
organic solvent, preferably a chlorinated hydrocarbon, e.g., 
1,2-dichloroethane or especially methylene chloride. 
##STR10## 
In Scheme B, Q is --O-- or --S--. In Step (a) the compound of the formula 
B1 (wherein R.sup.A is R or preferably H) is reacted with a reactive 
derivative of an acid of the formula 
L.sup.4.(CH.sub.2).sub.n.CH.sub.2.CO.sub.2 H, or such an acid with a 
substituent R.sup.1 and/or R.sup.21 on the 2-carbon atom, wherein L.sup.4 
is a reactive group such as a chlorine or bromine atom. The reactive 
derivative is preferably the acid chloride, but may be the bromide or 
anhydride. The reaction is effected under Friedel-Crafts conditions with a 
catalyst and inert organic solvent; the catalyst is for example anhydrous 
aluminum chloride or boron trifluoride, and the solvent is preferably 
nitrobenzene. The reaction is typically started at low temperature, e.g., 
at 0-20.degree. C., and continued at moderately elevated temperature, 
e.g., 30-100.degree. C. 
A group R.sup.21 (where R.sup.21 is other than hydrogen) may be introduced 
in Step (b) as described under Scheme A above. When the group R.sup.A is 
hydrogen, the group R may be introduced in Step (c) by reaction of the 
starting material with a compound of the formula RL.sup.4, wherein L.sup.4 
is a leaving group, e.g., a sulfonate ester group but preferably a 
halogen, especially Cl or Br. The reaction is preferably carried out in an 
organic solvent in the presence of a strong inorganic base, e.g., sodium 
or potassium hydride or hydroxide, and an inert organic solvent, e.g. 
anhydrous DMSO, DMF, or a polar ether such as dimethoxyethane. Steps (d) 
and (e) may then be carried out as described under Scheme A above for 
Steps (b), (c) and (d) therein. 
##STR11## 
In Scheme C, Q is O or S. In Step (a), the group R is introduced by 
reaction of the starting material with a compound of the formula RL.sup.4, 
wherein L.sup.4 is a leaving group, as described under Step (c) of Scheme 
B above. The remaining steps (b) through (g) can then be effected 
according to the processes described above for steps (b) through (g) 
respectively of Scheme A. 
##STR12## 
The process of Step (a) (reductive amination) can be carried out according 
to the alternative condensation/reduction process of Scheme A (described 
above as an alternative method for preparing compounds of the formulae A5 
and A7). The group L.sup.5 is preferably a chlorine atom or especially a 
bromine or iodine atom. The product of the formula D.sup.2 can then be 
reacted with an alkyl-lithium reagent, e.g., n-BuLi or t-BuLi, in an inert 
anhydrous organic solvent, to replace the group L.sup.5 with Li, and the 
resulting organometallic compound can be reacted with the aldehyde RCHO to 
yield the compound of the formula D3. The benzylic hydroxy group in D3 can 
then be reduced, for example with a trialkylsilane, preferably Et.sub.3 
SiH, and a strong acid, preferably trifluoroacetic acid. If the product of 
the formula D4 is to contain a group R.sup.1 or R.sup.21, this group may 
be introduced into the compound of the formula D1. 
The group R.sup.2 in this process is preferably a nitrogen-protecting 
group, e.g., a benzyloxycarbonyl (CBZ) or especially a t-butyloxycarbonyl 
(BOC) group. Such a protecting group can be replaced with a group R.sup.2 
defined above under formula I. A protecting group such as an amidating 
group can be removed by hydrolysis; e.g., a protecting BOC group can be 
removed with trifluoroacetic acid or with HCl in EtOAc. The desired group 
R.sup.2 can then be introduced (in one or more steps); for example, a 
1-piperidinyl group or N-RY-1-piperidinyl group can be introduced by 
reductive condensation with a compound of the formula 
##STR13## 
followed by removal of the protecting BOC group by hydrolysis. Both the 
reductive condensation and the hydrolysis can be effected as described 
above. Any further substituent R.sup.y (wherein R.sup.y is as defined 
above) can then be introduced on to the newly liberated nitrogen atom. For 
example, an amide can be formed by condensation with the acid chloride 
(R.sup.y.Cl, when R.sup.y is an acyl group), if necessary in the presence 
of a base, or by condensation with the acid itself (R.sup.y.OH, when 
R.sup.y is an acyl group) in the presence of 1-hydroxy-benzotriazole, 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and N-methyl-morpholine. 
After the process of Scheme A, B, C or D has been carried out, a resulting 
compound of the formula I wherein Q represents S can be oxidized to a 
compound wherein Q represents SO or SO.sub.2 ; the oxidizing agent is 
preferably a peracid such as peracetic acid, 3-chloroperbenzoic acid, or 
perboric acid, in the presence of a strong acid used in excess, e.g., 
methanesulfonic acid. If the compound wherein Q is S is being oxidized to 
the sulfoxide (or the sulfoxide to the sulfone), then about one equivalent 
of oxidizing agent should be used; if the compound wherein Q is S is being 
oxidized to the sulfone, then about two equivalents (preferably at least 
two equivalents) of oxidizing agent should be used. 
PHARMACOLOGICAL ACTIVITY 
The compounds of formula I exhibit selective m2 and/or m4 muscarinic 
antagonizing activity, which has been correlated with pharmaceutical 
activity for treating cognitive disorders such as Alzheimer's disease and 
senile dementia. 
The compounds of formula I display pharmacological activity in test 
procedures designed to indicate m1, m2 and m4 muscarinic antagonist 
activity. The compounds are non-toxic at pharmaceutically therapeutic 
doses. Following are descriptions of the test procedures. 
MUSCARINIC BINDING ACTIVITY 
The compound of interest is tested for its ability to inhibit binding to 
the cloned human m1, m2, and m4 muscarinic receptor subtypes. The sources 
of receptors in these studies were membranes from stably transfected CHO 
cell lines which were expressing each of the receptor subtypes. Following 
growth, the cells were pelleted and subsequently homogenized using a 
Polytron in 50 volumes cold 10 mM Na/K phosphate buffer, pH 7.4 (Buffer 
B). The homogenates were centrifuged at 40,000.times.g for 20 minutes at 
4.degree. C. The resulting supernatants were discarded and the pellets 
were resuspended in Buffer B at a final concentration of 20 mg wet 
tissue/ml. These membranes were stored at -80.degree. C. until utilized in 
the binding assays described below. 
Binding to the cloned human muscarinic receptors was performed using .sup.3 
H-quinuclidinyl benzilate (QNB) (Watson et al., 1986). Briefly, membranes 
(approximately 8, 20, and 14 .mu.g of protein assay for the m1, m2, and 
m4-containing membranes, respectively) were incubated with .sup.3 H- QNB 
(final concentration of 100-200 pM) and increasing concentrations of 
unlabeled drug in a final volume of 2 ml at 25.degree. C. for 90 minutes. 
Non-specific binding was assayed in the presence of 1 .mu.M atropine. The 
incubations were terminated by vacuum filtration over GF/B glass fiber 
filters using a Skatron filtration apparatus, and the filters were washed 
with cold 10 mM Na/K phosphate buffer, pH 7.4. Scintillation cocktail was 
added to the filters, and the vials were incubated overnight. The bound 
radioligand was quantified in a liquid scintillation counter (50% 
efficiency). The resulting data were analyzed for IC.sub.50 values (i.e. 
the concentration of compound required to inhibit binding by 50%) using 
the EBDA computer program (McPherson, 1985). Affinity values (K.sub.i) 
were then determined using the following formula (Cheng and Prusoff, 
1973): 
##EQU1## 
Hence a lower value of K.sub.i indicates greater binding affinity. 
The above procedure is known in the art and has been the subject of 
detailed publications. 
To determine the degree of selectivity of a compound for binding the m2 
receptor, the K.sub.i value for m1 receptors was divided by the K.sub.i 
value for m2 receptors. A higher ratio indicates a greater selectivity for 
binding the m2 muscarinic receptor. 
MICRODIALYSIS METHODOLOGY 
The following procedure is used to show that a compound functions as an m2 
antagonist: 
Surgery: For these studies, male Sprague-Dawley Rats (250-350 g) were 
anesthetized with sodium pentobarbital (54 mg/kg, ip) and placed on a Kopf 
stereotaxic apparatus. The skull was exposed and drilled through to the 
dura at a point 0.2 mm anterior and 3.0 mm lateral to the bregma. At these 
coordinates, a guide cannula was positioned at the outer edge of the dura 
through the drilled opening, lowered perpendicularly to a depth of 2.5 mm, 
and permanently secured with dental cement to bone screws. Following the 
surgery, rats were given ampicillin (40 mg/kg, ip) and individually housed 
in modified cages. A recovery period of approximately 3 to 7 days was 
allowed before the microdialysis procedure was undertaken. 
Microdialysis: All of the equipment and instrumentation used to conduct in 
vivo microdialysis was obtained from Bioanalytical Systems, Inc. (BAS). 
The microdialysis procedure required the insertion through the guide 
cannula of a thin, needle-like perfusable probe (CMA/12.3 mm.times.0.5 mm) 
to a depth of 3 mm in striatum beyond the end of the guide. The probe was 
connected beforehand with tubing to a microinjection pump (CMA-/100). Rats 
were collared and tethered, and, following probe insertion, were placed in 
a large clear plexiglass bowl with litter material and access to food and 
water. The probe was perfused at 2 .mu.l/min with Ringer's buffer (NaCl 
147 mM; KCl 3.0 mM; CaCl.sub.2 1.2 mM; MgCl.sub.2 1.0 mM) containing 5.5 
mM glucose, 0.2 mM L-ascorbate, and 1 .mu.M neostigmine bromide at pH 7.4. 
To achieve stable baseline readings, microdialysis was allowed to proceed 
for 90 minutes prior to the collection of fractions. Fractions (20 .mu.l) 
were obtained at 10-minute intervals over a 3-hour period using a 
refrigerated collector (CMA170 or 200). Following the collection of four 
to five baseline fractions, the drug or combination of drugs to be tested 
was administered to the animal. Once collection was complete, each rat was 
autopsied to determine how accurately the probe was placed. 
Acetylcholine (ACh) analysis: The concentration of ACh in collected samples 
of microdialysate was determined using HPLC/electrochemical detection. 
Samples were auto-injected (Waters 712 Refrigerated Sample Processor) onto 
a polymeric analytical HPLC column (BAS, MF-6150) and eluted with 50 mM 
Na.sub.2 HPO.sub.4, pH 8.5. To prevent bacterial growth, Kathon CG reagent 
(0.005%) (BAS) was included in the mobile phase. Eluate from the 
analytical column, containing separated ACh and choline, was then 
immediately passed through an immobilized enzyme reactor cartridge (BAS, 
MF-6151) coupled to the column outlet. The reactor contained both 
acetylcholinesterase and choline oxidase covalently bound to a polymeric 
backbone. The action of these enzymes on ACh and choline resulted in 
stoichiometric yields of hydrogen peroxide, which was electrochemically 
detected using a Waters 460 detector equipped with a platinum electrode at 
a working potential of 500 mvolts. Data acquisition was carried out using 
an IBM Model 70 computer equipped with a microchannel IEEE board. 
Integration and quantification of peaks were accomplished using "Maxima" 
chromatography software (Waters Corporation). 
Total run time per sample was 11 minutes at a flow rate of 1 ml/min. 
Retention times for acetylcholine and choline were 6.5 and 7.8 minutes 
respectively. To monitor and correct for possible changes in detector 
sensitivity during chromatography, ACh standards were included at the 
beginning, middle and end of each sample queue. 
Increases in ACh levels are consistent with presynaptic m2 receptor 
antagonism. 
RESULTS OF THE TESTS 
The present invention also relates to achieving similar synergistic results 
by administering any compound capable of enhancing ACh release, such as a 
muscarinic antagonist, e.g., scopolamine or QNB, in combination with an 
acetylcholinesterase inhibitor. Preferably the ACh release-enhancing 
compound is either an m2 selective muscarinic antagonist, i.e. one having 
a ratio of (K.sub.i for m1)/(K.sub.i for m2) greater than 1, or an m4 
selective muscarinic antagonist, i.e. one having a ratio of (K.sub.i for 
m1)/(K.sub.i for m4) greater than 1. The m2 or m4 selective muscarinic 
antagonists for practicing this aspect of the invention include without 
limitation 3-.alpha.-chloroimperialine, AF-DX 116, AF-DX 384, BIBN 99 
(these last three compounds being available from Boehringer-Ingleheim), 
tripitramine, and himbacine. 
The tests reported in the following Table show that the compounds numbered 
5, 9, 10, 14 and 15 in particular have useful values of the m1/m2 and 
m4/m2 ratios and should have valuable properties for the treatment of 
cognitive disorders. 
TABLE 1 
__________________________________________________________________________ 
K.sub.i (nm); m1/m2 & m4/m2 
Compound m1 m4 
ACTIVITIES OF COMPOUNDS OF FORMULA I 
No. M.P. .degree. C. 
m1 m2 m2 m4 m2 
__________________________________________________________________________ 
##STR14## 
1 1 356 4.5 
79 106 1.3 
2 #STR15## 2 67-68 
42 1.5 
27 
3 #STR16## 3 219-221 
82 0.6 
130 37 0.3 
4 #STR17## 4 124-126 
223 1.0 
224 &gt;200 
&gt;0.9 
5 #STR18## 5 179-181, dimaleate 
160t 
7.5 
21 35 1.6 
6 #STR19## 6 205 (dec.) 
633 6.6 
96 77 0.8 
7 #STR20## 7 191-193, HCl salt 
105 4.0 
26 21 0.8 
8 #STR21## 8 191-193, HCl salt 
88 3.3 
27 23 0.9 
9 #STR22## 9 204-206, dimaleate 
265t 
7.7 
35 
0 #STR23## 10 183-184, HCl salt 
151 13.2 
11.5 
17 1.5 
1 #STR24## 11 181-182, HCl salt 
314 3.6 
88 
2 #STR25## 12 150-154, dimaleate 
173t 
1.9 
92 
3 #STR26## 13 67 4.0 
17 33 2.0 
4 #STR27## 14 (Isomer A) 
232, HCl salt 
112 18.4 
6.1 16 2.6 
5 #STR28## 15 (Isomer B) 
253-254, HCl salt 
1.23 
11.2 
0.11 
0.27 
2.5 
__________________________________________________________________________ 
3 TABLE 2 
- Effect of Compounds of the Invention on Release of Acetyl Choline 
(ACh) from Striatum of Conscious Rats following Peritoneal Administr 
ation 
Compound and results Compound and results 
##STR29## 
6 
##STR30## 
7 
Compound 14, Isomer A Compound 15, Isomer B 
Dose = 10 mg/kg; 3 rats Dose = 
10 mg/kg; 3 rats Sample Collection Mean % of 
Standard Mean % of Standard 
Time (Minutes) baseline error baseline error 
20 (1) 99.47 0.83 98.61 1.74 
30 (2) 100.85 4.62 93.87 0.13 
40 (3) 99.71 3.14 102.42 1.41 
50 (4) 99.20 1.59 103.86 3.90 
60 100.78 4.20 102.14 4.10 
70 86.66 6.26 175.31 6.60 
80 95.26 4.15 278.67 31.06 
90 95.90 1.66 266.94 17.84 
100 102.30 16.27 245.19 16.74 
110 108.24 13.56 217.34 9.29 
120 85.62 16.35 222.39 20.20 
130 103.94 13.20 205.69 12.36 
140 99.35 13.94 188.49 11.52 
150 91.47 11.51 189.79 13.56 
160 90.80 20.28 184.27 13.03 
170 89.0 12.35 189.27 23.70 
180 83.13 10.95 189.86 12.41 
Notes: 
(1) Control; gives first baseline. 
(2) Control; gives second baseline. 
(3) Control; gives third baseline. 
(4) Compounds were injected at 50 minutes. 
Particularly preferred compounds of the formula I include those of the 
following formulae, and their acid addition salts: 
##STR31## 
and also the compounds of the following formulae, and their acid addition 
salts: 
##STR32## 
in all of these compounds, the methyl group attached to the piperazine 
ring (where present) is in the (R)-conformation. 
Pharmaceutical compositions can be prepared from the compounds of formula 
I, which are capable of enhancing ACh release, by admixing them with 
pharmaceutically acceptable, inert carriers. Acetylcholinesterase 
inhibitors can be used as optional constituents of such pharmaceutical 
compositions to provide a better, frequently even synergistic, effect. The 
pharmaceutically acceptable carriers may be either solid or liquid. 
Preparations in solid form include powders, tablets, dispersible granules, 
capsules, cachets and suppositories. A solid carrier can be one or more 
substances which may also act as diluents, flavoring agents, solubilizers, 
lubricants, suspending agents, binders or tablet-disintegrating agents; it 
may also be an encapsulating material. 
Preparations in liquid form include solutions, suspensions and emulsions. 
As an example may be mentioned solutions in water or in water-propylene 
glycol for parenteral injection. 
Also included are preparations in solid form which are intended for 
conversion, shortly before use, to liquid form preparations for either 
oral or parenteral administration. Such liquid forms include solutions, 
suspensions and emulsions. The solid forms are most conveniently provided 
in unit dose form for this purpose and are used to provide a single liquid 
dosage unit. 
The invention also contemplates alternative delivery systems including, but 
not necessarily limited to, transdermal delivery. The transdermal 
compositions can take the form of creams, lotions and/or emulsions and can 
be included in transdermal patches of the matrix or reservoir type as are 
conventional in the art for this purpose. 
Preferably, the pharmaceutical preparation is in unit dosage form. In such 
form, the preparation is subdivided into unit doses containing appropriate 
quantities of the active components. The unit dosage form can be a 
packaged preparation, the package containing discrete quantities of 
preparation such as packeted tablets, capsules and powders in vials or 
ampoules. The unit dosage form can also be a capsule, cachet or tablet 
itself, or it may be the appropriate number of any of these in a packaged 
form. 
The quantity of active compound in a unit dose preparation may be varied or 
adjusted from 1 mg to 100 mg according to the particular application and 
the potency of the active ingredient and the intended treatment. This 
would correspond to a dose of about 0.001 to about 20 mg/kg, which may be 
divided over 1 to 3 administrations per day. The composition may, if 
desired, also contain other therapeutic agents. 
The dosages may be varied, depending on the requirement of the patient, the 
severity of the treated condition, and the particular compound 
administered. Determination of the proper dosage for a particular 
situation is within the skill of those in the medical art. For 
convenience, the total daily dosage may be divided and administered in 
portions throughout the day or by means providing continuous delivery. 
When a compound of formula I or a compound capable of enhancing ACh release 
is used in combination with an acetylcholinesterase inhibitor to treat 
cognitive disorders, these two active components may be co-administered 
simultaneously or sequentially. Alternatively, a single pharmaceutical 
composition comprising a compound of formula I or a compound capable of 
enhancing ACh release and an acetylcholinesterase inhibitor in a 
pharmaceutically acceptable carrier can be administered. The components of 
the combination can be administered individually or together in any 
conventional oral or parenteral dosage form, such as capsule, tablet, 
powder, cachet, suspension, solution, suppository, nasal spray, etc. The 
dosage of the acetylcholinesterase inhibitor may range from 0.001 to 100 
mg/kg body weight.

The invention disclosed herein is exemplified by the following Examples, 
which should not be construed to limit the scope of the disclosure. 
Alternative mechanistic pathways and analogous structures may be apparent 
to those skilled in the art. 
EXAMPLES 
Example 1 
Step A 
##STR33## 
4.2 g (29 mmoles) of 5-fluoroindanone and 5.05 g (31 mmoles) of sodium 
benzenesulfinate were combined in dry DMSO (20 mL). The mixture was heated 
to about 120.degree. C. for 48 hours, cooled to room temperature, and 
poured into ice water (300 mL). The precipitate that developed was 
filtered off and triturated with 100 mL dry ether, then filtered off again 
and dried in vacuo to give 1.57 g (20% yield) of the desired sulfone as a 
brown powder. This was used directly in the next reaction. 
Step B 
##STR34## 
1.07 g (3.9 mmoles) of 5-phenylsulfonylindanone was taken up in dry THF (20 
mL) at room temperature. A 1M solution of lithium aluminum hydride in THF 
(3.9 mL) was added slowly. The resulting mixture was stirred for one hour 
at room temperature, and quenched cautiously with 2M sodium hydroxide 
solution and then with water. Solid potassium carbonate was added, and the 
mixture was stirred until the salts formed a granular precipitate. This 
was filtered off and washed with ether, and the organic solvents were 
evaporated to give 0.998 g of the desired alcohol (92%), which was 
sufficiently pure for the next reaction. 
Step C 
##STR35## 
0.700 g (2.55 mL) of the starting indanyl alcohol were taken up in neat 
thionyl chloride (2 mL), and the resulting mixture was stirred at room 
temperature for one hour. The volatiles were removed on a rotary 
evaporator, and the crude chloride was taken up in DMF (5 mL) with 
N-hydroxyethyl piperazine (0.94 mL, 3 equiv.). This mixture was heated to 
about 60.degree. C. for 16 hours, cooled to room temperature, and poured 
into ice water (100 mL). The crude product was extracted with methylene 
chloride, the organic layers were dried and evaporated, and the residue 
was purified by column chromatography on silica gel. The column was eluted 
with ethyl acetate containing 5% methanol and then with ethyl acetate 
containing 5% methanol and 2% triethylamine to give the desired product. 
Example 2 
##STR36## 
6-Hydroxy-4-chromanone, 1: 
A solution of resorcinol (11.0 g) in nitrobenzene (120 mL) at 5.degree. C. 
was treated dropwise with .beta.chloropropionyl chloride (12.7 g) with 
stirring. Anhydrous AlCl.sub.3 (31 g) was added portionwise with stirring, 
and the temperature was kept below 15.degree. C. After 15 minutes the 
mixture was heated to 40-45.degree. C. and kept there with stirring for 3 
hours longer; it was then cooled to room temperature and allowed to stand 
overnight. The reaction mixture was poured with stirring into crushed ice 
(200 g) containing conc. HCl (10 mL). This was extracted with ether and 
the organic layer was extracted with 5% NaOH. The basic layer was made 
acidic with conc. HCl. A tar-like solid separated out and was 
recrystallized from hot water to yield a white solid, m.p. 138-142.degree. 
C. 
7-(4'-Nitrophenoxy)-4-chromanone, 2: 
A solution of 6-hydroxychromanone (1.64 g, 10 mmol) in DMF (10 mL) was 
treated with NaH (10 mmole, 60% in mineral oil) with stirring. After 30 
minutes it was treated with a solution of 4-fluoronitrobenzene in DMF (5 
ml) and stirred at 90.degree. C. for 6 hours. After cooling, it was 
diluted with ice water (75 mL) and then extracted with EtOAc (2.times.50 
mL). Evaporation of the dried organic layer gave a gum-like residue (1.9 
g). This crude product was used in the next step without further 
purification. 
1-Cyclohexyl-4-7-(4-nitrophenyl)oxy!-chroman-4-yl!-piperazine, 3: 
Crude 7-(4'-nitrophenyloxy)-4-chromanone (1.9 g) in EtOH (150 mL) was 
reduced with NaBH.sub.4 (250 mg) at room temperature overnight. The crude 
product was purified through a column of silica gel (EtOAc:CH.sub.2 
Cl.sub.2, 2:8) to give pure 7-(4'-nitrophenyloxy)-4-chromanol (550 mg). 
This compound (550 mg) was converted to the chloride with thionyl chloride 
(0.28 g) in CH.sub.2 Cl.sub.2 (30 mL) at 0.degree. C. for 1 hour and then 
at room temperature for 3 hours. Work-up yielded crude 
4-chloro-7-(4'-nitrophenyloxy)-chroman (500 mg). This was heated with 
N-cyclohexylpiperazine (0.9 g) at 130.degree. C. for one hour. The mixture 
was then diluted with water (35 mL), made basic with K.sub.2 CO.sub.3 and 
extracted with EtOAc. The residue from evaporation of the dried organic 
layer was purified through a column of TLC-grade silica gel (35 g). The 
desired product was recrystallized rom acetonitrile, m.p. 67-68.degree. C. 
Example 3 
##STR37## 
6-Hydroxytetralone, 4: 
A solution of 6-methoxytetralone (35 mmol), and AlBr.sub.3 (75 mmol) in 
toluene (250 mL) was heated on an oil bath at 100.degree. C. for 5 to 6 
hours. The solution was cooled to room temperature and then poured onto a 
mixture of 1N HCl (200 mL) and crushed ice (500 g). This was stirred with 
EtOAc (300 mL) and filtered through a sintered glass funnel. The filtrate 
was transferred to a separatory funnel and the aqueous layer was extracted 
with EtOAc (2.times.100 mL). The organic layers were combined and dried 
with MgSO.sub.4, filtered and evaporated to a solid, 6-hydroxytetralone, 
which was pure by NMR and TLC (1:1 hexane:EtOAc). 
6-(2-Pyrimidinyl)oxyl-tetralone, 5: 
6-Hydroxytetralone (31 mmol) was dissolved in dry DMF (50 mL), chilled in 
an ice/water bath and blanketed with a stream of nitrogen. NaH (60% in 
mineral oil, 31 mmol) was added slowly and in portions. Once gas evolution 
ceased, 2-chloropyrimidine (31 mmol) was added, the ice bath was removed 
and the solution heated at 100.degree. C. for 1.5 hours. It was then 
cooled to room temperature and the solvent was removed in vacuo. The 
residue was treated with water and CH.sub.2 Cl.sub.2 (200 mL each). 
Evaporation of the organic layer yielded crude material which was purified 
by flash chromatography (1:1 hexane:EtOAc) to afford 
6-(2-pyrimidinyl)oxyl-tetralone as a light yellow powder. 
4-Cyclohexyl-1-piperazinyl-6-(2-pyrimidinyl)oxy!!-1,2,3,4-tetrahydro-naph 
thalene, 6: 
6-(2-Pyrimidinyl)oxy!-tetralone (3.2 mmol), N-cyclohexylpiperazine (3.2 
mmol) and Ti(O-2-Pr).sub.4 (3.2 mmol) were dissolved in CH.sub.2 Cl.sub.2 
(10 mL). The solution was stirred at room temperature for 20 hours and 
then quenched with NaCNBH.sub.3 (6.4 mmol in 5 mL EtOH). Water (20 mL) was 
added, the resulting mixture was filtered through a pad of `Celite`, and 
the residue was rinsed with CH.sub.2 Cl.sub.2 (10 mL). The organic layer 
was dried with Na.sub.2 SO.sub.4 and evaporated to yield the crude product 
as an oil. Purification by column chromatography on TLC-grade silica gel 
and 100:3:1 CH.sub.2 Cl.sub.2 :EtOH:NH.sub.4 OH as eluant gave the pure 
product, 
4-cyclohexyl-1-piperazinyl-6-(2-pyrimidinyl)oxy!!-1,2,3,4-tetrahydro-nap 
hthalene. This was converted to the dimaleate salt, m.p. 179-181.5.degree. 
C., by dissolving in EtOAc and heating with 2 equivalents of maleic acid. 
Example 4 
##STR38## 
5-((2-Pyrimidinyl)oxy)indanone: 
5-Hydroxyindanone (3.2 g, 21.6 mmol) was dissolved in dry DMF (20 mL) in a 
3-neck flask fitted with an N.sub.2 inlet and reflux condenser. The system 
was blanketed with N.sub.2, and 60% NaH in mineral oil (860 mg) was added 
slowly and in portions at 0.degree. C. Then 2-chloropyrimidine (2.5 g) was 
added, the ice bath was replaced with an oil bath, and the solution was 
heated at 100.degree. C. for 3 hours. This was then cooled to room 
temperature before removal of DMF in vacuo. To the residue was added water 
(50 mL), the mixture was extracted with CH.sub.2 Cl.sub.2 (50 mL), and the 
aqueous layer extracted twice more with CH.sub.2 Cl.sub.2. The organic 
layer was extracted with 1N NaOH (50 mL) to remove unreacted phenol and 
then dried with Na.sub.2 SO.sub.4 and evaporated to a dark brown solid 
(3.6 g). The solid was extracted with EtOAc; filtration removed an 
insoluble precipitate. The filtrate was dried as before and evaporated to 
yield the product which was pure by NMR and TLC (1:1 hexane:EtOAc). 
2-(2-(Cyclohexylmethyl)-3H-1-oxo-inden-5-yl) pyrimidine. 8: 
To piperidine (0.25 mL) at 0.degree. C. was added acetic acid (0.2 mL) 
followed by cyclohexanecarboxaldehyde (918 mg, 8.2 mmol) and 
5-(2-pyrimidinyl)oxy!-indanone, 7 (1.85 g, 8.2 mmol) (synthesized by the 
same route as 5 above). The mixture was heated at 100.degree. C. for 25 
minutes. Methanol (20 mL) was added to the hot solution, which, after 
cooling, was concentrated in vacuo. The residue was treated with water and 
CH.sub.2 Cl.sub.2 (20 mL each), and the organic layer was dried with 
Na.sub.2 SO.sub.4. Evaporation of the solvent gave the crude material as a 
dark brown oil. Purification by flash chromatography with 1:1 hexane:ethyl 
acetate resulted in the pure enone, 8. 
2-(2-(Cyclohexylmethyl)-2,3-dihydro-1-oxo-indan-5-yl)pyrimidine: 
The enone was cleanly reduced to the saturated ketone with 10% Pd-C 
catalyst (100 mg) on a Parr apparatus for 45 minutes. The catalyst was 
filtered off to yield the saturated ketone. 
Alternative Reduction of Ketone (general procedure) 
The ketone (1 equivalent) is dissolved in EtOH and NaBH.sub.4 (0.75 
equivalent) is added. This is stirred at room temperature and monitored by 
TLC (1:1 Hexane:EtOAc) until all ketone has disappeared (about 2 to 4 
hours) and the reaction is complete. Then the EtOH is removed in vacuo and 
the residue treated with an equal amount of CH.sub.2 Cl.sub.2 and water. 
The organic layer is dried with Na.sub.2 SO.sub.4 and the solvent is 
evaporated off to yield the crude alcohol, which is used directly without 
purification. 
Conversion of Alcohol to Chloride (general procedure) 
The alcohol (1 equivalent) is dissolved in CH.sub.2 Cl.sub.2 and chilled in 
an ice water bath. Thionyl chloride (1.2 equivalents) is then added and 
the solution stirred under a CaSO.sub.4 drying tube and monitored by TLC 
(25% EtOAc in Hexane) until the alcohol has disappeared. An equivalent 
amount of water is added and the mixture is basified to pH 8 with solid 
NaHCO.sub.3. The aqueous layer is extracted with CH.sub.2 Cl.sub.2. The 
organic extracts are combined, dried and evaporated to provide the crude 
chloride, which is used without further purification. 
2-1-(4-Cyclohexyl-1-piperazinyl)-2-(cyclohexylmethyl)-2,3-dihydro-1H-inde 
n-5-yl!oxy!pyrimidine, 9: 
The chloride (1 equivalent) and cyclohexylpiperazine were dissolved in 
CH.sub.3 CN, refluxed for 2 hours, and then cooled to room temperature. 
Water was added and the mixture was extracted with EtOAc (4.times.). The 
organic extracts were dried and evaporated to yield the crude product 
which was purified by column chromatography using TLC-grade silica gel and 
EtOAc as eluant. 
2-1-(4-Cyclohexyl-1-piperazinyl)-2-(cyclohexylmethyl)-2,3-dihydro-1H-iden 
-5-yl!oxy!pyrimidine dimaleate was a mixture of diastereomers (proportions 
unknown), m.p. 150-154.degree. C. 
Example 5 
##STR39## 
The alcohol (0.4 g) was treated with thionyl chloride (20 mL) at ambient 
temperature for 3 hours. Thionyl chloride was removed under vacuum, the 
crude product was treated with piperidinopiperidine (1.22 g), and the 
reaction mixture heated overnight at 130.degree. C. At the end of this 
time the reaction mixture was cooled to ambient temperature, diluted with 
dichloromethane and washed with 10% sodium hydroxide solution. The crude 
product was purified on silica gel (triethylamine:ethyl acetate 1:20) to 
give the desired product (0.05 g). HRMS for C.sub.26 H.sub.35 N.sub.2 
O.sub.3 S: Calcd.: 455.2368; Found: 455.2373. 
Example 6 
2-1 -(4-Cyclohexyl-1-piperazinyl)-2-(cyclohexylmethyl)-2,3-dihydro-1 
H-inden-5-yl!oxy!pyrimidine, 9:x 
##STR40## 
The chloride (0.6 g, 2.0 mmol) (from the first crude product of the process 
of Example 5), DMF (10 mL), sodium iodide (1.8 g), triethylamine (0.21 g) 
and piperazine (0.38 g, 2.0 mmol) were heated overnight at 50.degree. C., 
and stirred for an additional 2 hours at 70.degree. C. The reaction 
mixture was then cooled to room temperature and diluted with ethyl 
acetate. The solution was washed with 10% Na.sub.2 CO.sub.3, water and 
brine, and then concentrated to yield a mixture of two diastereomers. 
Separation was carried out by chromatography on silica gel using ethyl 
acetate; diastereomer R.sub.f for Isomer A (compound 14, Table 1)=0.3, and 
for Isomer B (compound 15, Table 1)=0.4. 
Further compounds that are described in the Tables or listed by formula 
immediately after the Tables can be prepared by analogous methods. 
While a number of embodiments of this invention are described herein, it is 
apparent that the embodiments can be altered to provide other embodiments 
that utilize the compositions and processes of this invention. Therefore, 
it will be appreciated that the scope of this invention includes 
alternative embodiments and variations which are defined in the foregoing 
Specification; and the invention is not to be limited to the specific 
embodiments that have been presented herein by way of example.