Thiophene and pyridine antipsychotic agents

Compounds of the general formula I ##STR1## wherein A is N; Ar is aryl, substituted aryl or benzofuranyl, wherein the substituents are selected from C.sub.1 -C.sub.8 alkoxy; B is CO or CH.sub.2 and HET is selected from any of piperizine, piperidine, hexahydroazepine, morpholine, thiomorpholine or pyrrolidine, which may be substituted with one of more oxo groups are disclosed as novel antipsychotic agents. Pharmaceutical compositions and methods of treating convulsions employing such compounds of formula I are also disclosed.

BACKGROUND OF THE INVENTION 
Antipsychotic drugs are known to alleviate the symptoms of mental illnesses 
such as schizophrenia. Examples of such drugs include phenothiazine 
derivatives such as promazine, chlorpromazine, fluphenazine, thioridazine 
and promethazine, thioxanthenes such as chlorprothixene and butyrophenones 
such as haloperidol and clozapine. While these agents may be effective in 
treating schizophrenia, virtually all except clozapine produce 
extrapyramidal side effects, such as facial tics or tardive dyskinesia. 
Since antipsychotics may be administered for years or decades to a 
patient, such pronounced side effects may complicate recovery and further 
isolate the individual from society. 
The present invention describes novel compounds that combine antipsychotic 
effects with minimal or reduced side effects such as extrapyramidal 
symptomology, and increased acid stability relative to some of the 
compounds known in the art. 
SUMMARY OF THE INVENTION 
Compounds of the general formula I 
##STR2## 
wherein Ar, A, B, W and HET are as defined hereinafter, are potent 
antipsychotic agents useful in the treatment of psychotic conditions such 
as schizophrenia in mammals including humans. The compounds of the present 
invention may also be useful in the treatment of other disorders of the 
central nervous system such as anxiety and aggression. The present 
invention is also directed to pharmaceutical compositions containing the 
compounds of formula I and methods of treating psychotic conditions 
employing such compounds.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention is directed to compounds of the general formula I: 
##STR3## 
wherein 
A is N or CH, but preferably N. 
Ar is aryl or substituted aryl or heteroaryl. The aryl group may be 
independently substituted with one or more of C.sub.1 -C.sub.8 alkyl, 
C.sub.3 -C.sub.10 cycloalkyl, C.sub.1 -C.sub.8 hydroxyalkyl, C.sub.1 
-C.sub.8 alkoxy, aryloxy, hydroxyl, trifluoromethyl, trifluoromethoxy, 
cyano, C.sub.1 -C.sub.8 alkylthio, halogen, nitro, C.sub.1 -C.sub.8 
haloalkyl, amino or C.sub.1 -C.sub.8 mono- or di-alkylamino. More 
preferably Ar is substituted phenyl or heteroaryl. When Ar is heteroaryl, 
the more preferred heteroaryl radical is benzofuranyl. The more preferred 
aryl substituents are selected from any of C.sub.1 -C.sub.8 alkoxy. Most 
preferably, the substituent is isopropoxy. The preferred site of 
substitution is the 2-position on the phenyl ring. 
W is a thiophene or pyridine ring. The thiophene ring is preferably 
attached to the CH.sub.2 link (at the CH.sub.2 that is connected to the 
piperidine or piperazine) at the 5 position on the thiophene ring and the 
pyridine ring is attached to the same CH.sub.2 group at the 6 position on 
the ring. 
B is CO or CH.sub.2 forming a carbon chain link between the thienyl or 
pyridine ring and the HET ring, provided, however, that when W is pyridine 
B is CH.sub.2. 
HET is a 5-8 membered substituted or unsubstituted, saturated ring 
containing 1 or 2 hetero atoms selected from any of N, S or O, provided 
that at least one hetero atom is nitrogen selected from wherein the point 
of attachment of the ring to the remainder of the molecule is at a 
nitrogen. More preferably, the ring contains 6-7 members. Even more 
preferably, HET is selected from any of piperazine, piperidine, 
hexahydroazepine, morpholine, thiomorpholine, pyrrolidine, or 
heptamethyleneimine. Most preferably, HET is selected from either of 
piperidine or hexahydroazepine. 
The HET ring may be independently substituted with one or more oxo 
substituents. The preferred substituent is a single oxo adjacent to the 
nitrogen which nitrogen is the point of ring attachment. 
The HET ring is preferably attached to the thiophene ring via the carbon 
link at either the 2 or 3 position on the thiophene ring and attached to 
the pyridine ring via the carbon link at the 2 position on the pyridine 
ring. The HET ring is always attached to the carbon link via a ring 
nitrogen. 
As used herein unless otherwise noted alkyl and alkoxy whether used alone 
or as part of a substituent group, include straight and branched chains. 
For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, 
n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 2-methylbutyl, 
neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl. Alkoxy radicals are oxygen 
ethers formed from the previously described straight or branched chain 
alkyl groups. Of course, if the alkyl or alkoxy substituent is branched 
there must be at least 3 carbons. 
The term "aryl" as used herein alone or in combination with other terms 
indicates aromatic hydrocarbon groups such as phenyl or naphthyl. The term 
heteroaryl means aromatic hydrocarbon groups containing 1 or 2 hetero 
atoms selected from any of S, O or N. With reference to substituents, the 
term independently means that when more than one of such substituent is 
possible such substituents may be the same or different from each other. 
Examples of particularly preferred compounds include: 
1-[[5-[[1-[-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thienyl]carbony 
l]piperidine; 
Hexahydro-1-[[5-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thie 
nyl]carbonyl]-1H-azepine; 
1-[[5-[[1-[2-(1-Methylethoxy)phenyl-4-piperazinyl]methyl]-2-thienyl]methyl] 
-2-piperidinone; 
1-[[5-[[1-(7-Benzofuranyl)-4-piperazinyl]methyl]-2-thienyl]methyl]-2-piperi 
dinone; 
1-[[5-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-2-thienyl]carbon 
yl]piperidine; 
Hexahydro-1-[[5-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-2-thie 
nyl]carbonyl]-1H-azepine; and 
1-[[6-[[1-[2-(Methylethoxy)phenyl]-4-piperazinyl]methyl]pyridinyl]-methyl]- 
2-piperidinone. 
Within the scope of the invention are compounds of the invention in the 
form of hydrates and other solvate forms. 
Representative salts of the compounds of formula 1 which may be used 
include those made with acids such as hydrochloric, hydrobromic, 
hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, 
glycolic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, 
tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, 
ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, 
cyclohexanesulfamic, salicyclic, p-aminosalicyclic, 2-phenoxybenzoic, 
2-acetoxybenzoic or a salt made with saccharin. Such salts can be made by 
reacting the free base of formula I with the acid and recovering the salt. 
The compounds of formula I may be prepared according to the following three 
reaction schemes. 
##STR4## 
Reaction Scheme 1 displays the route to certain thiophene compounds of the 
invention (e.g. 1). Thiophene carboxaldehyde 2 is prepared by treating 
5-bromomethyl-2-thiophenecarboxylic acid with a heterocylic moiety (4) 
such as a lactam in the presence of a suitable base (e.g. NaH) in a 
solvent such as toluene, followed by the reduction of the carboxylic acid 
5 in ethanol or other suitable solvent using a reducing agent such as 
NaBH.sub.4. Thereafter, the alcohol 6 is oxidized in methylene chlodde or 
other suitable solvent using a suitable oxidizing agent such as MnO.sub.2 
to produce the thiophene carboxaldehyde 2. Compound 2 is then reacted in 
methanol or other suitable solvent with an amine of formula 3 in the 
presence of a reducing agent such as NaCNBH.sub.3 to produce the desired 
compound 1. 
The 5-bromomethyl-2-thiophenecarboxylic acid, and the lactams as would be 
used for 4 are commercially available materials. Compounds 3 are either 
commercially available or may be made by known methods such as disclosed 
by Martin et. al. J. Med. Chem., 1989, 32, 1052. 
##STR5## 
In Reaction Scheme 2, compounds of formula 6 are prepared by reacting a 
4-bromothiophene of formula 8 with a heterocyclic amine of formula 4 (such 
as pyrrolidine or pyridine) in the presence carbon monoxide and a suitable 
catalyst such as bis(triphenylphosphine)palladium dichloride. Compounds of 
formula 8 are prepared from the reductive amination of 
4-bromo-2-thiophenecarboxaldehyde with compounds of formula 3 in 
1,2-dichloroethane or other suitable catalyst in the presence of glacial 
acetic acid using a reducing agent such as NaBH(OAc).sub.3. 
##STR6## 
In Reaction Scheme 3, compounds of formula 9 are prepared by treating 
compounds of formula 8 with a metal salt, the metal being chosen from 
sodium, lithium, potassium and the like, of a suitable lactam 
(HET=lactam), using THF or another suitable solvent. Compounds of formula 
8 are obtained from the reaction of 2,6-dichloromethylpyridine (Baker, et 
al, J. Chem. Soc., 1958, 3594) and compounds of formula 3 in THF or other 
suitable solvent. 
The antipsychotic activity of the compounds of the invention may be 
determined by the Block of Conditioned Avoidance Responding (Rat) test 
(CAR), the references being Cook, L. and E. Weidley in Ann. N.Y. Acad. 
Sci., 1957, 6, 740-752, and Davidson, A. B. and E. Weidley in Life Sci., 
1976, 18, 1279-1284. Modulation of the dopamine-2(D-2) receptor is 
generally recognized to be beneficial in the treatment of schizophrenia 
(G. P. Reynolds Trends Pharmacol. Sci. 1992, 13, 116). Therefore, the 
affinity of the compounds of this invention were measured for the D-2 
receptor. The CAR and D-2 binding tests were performed for compounds 
disclosed in this invention, and the data are listed in Table 1. 
Block of Conditioned Avoidance Responding (Rat) 
Apparatus: Rat operant chambers, housed within sound attenuated booths, 
both from Capden Instruments Ltd., were used in this test. The test 
chamber (8" H.times.903/8" W.times.9" D) is constructed of aluminum and 
plexiglass with floor grid bars of stainless-steel (1/8" O.D.) spaced 
9/16" apart. A stainless-steel operation level 11/2" wide projects 3/4" 
into the chamber and is positioned 2-2/8" above the grid floor. The shock 
stimulus is delivered via the grid floor by a Coulbourn Instruments solid 
state module. The parameters of the test and the collection of data are 
controlled automatically. 
Training: Male, Fischer 344 rats obtained from Charles River (Kingston, 
N.Y.) weighing more than 200 g, are individually housed with chow and 
water provided ad libitum. The rats are trained for two weeks to approach 
criterion levels in the avoidance test (90% avoidance rate). One-hour 
training sessions are run at about the same time each day for four or five 
days a week. The training session consists of 120 tdals, with the 
conditioned stimuli presented every 30 sec. A trial begins with 
presentation of the conditioned stimuli (a light and a tone). If the rat 
responds by depressing the operant lever during the 15-second presentation 
of the conditioned stimuli, the trial is terminated .and the animal is 
credited with a CAR. Failure to respond during the conditioned stimuli 
causes the presentation of the unconditioned stimulus (UCS), a 0.7 mA 
shock which is accompanied by a light and tone for five seconds. If the 
rat depressed the lever within the ten-second period, the shock and trial 
are terminated and an escape response recorded. If the rat fails to 
depress the lever during the UCS (shock), the trial is terminated after 
ten seconds of shock and the absence of a response is scored as a failure 
to escape. Intertrial level presses have no effect. If a rat performs at 
the 90% CAR level for two weeks, it is then run twice a week on the test 
schedule (see below) until baseline performance stabilized. Before any 
drug is administered, two weeks of CAR at a rate of 90% or better is 
required. 
Determination of ED.sub.50 Values 
Trained rats are run in a one-hour session on two consecutive days at the 
same time and in the same test chamber each day. The sessions consist of 
60 trials, one every minute. The conditioned stimuli are presented for 15 
sec (maximum) and the unconditioned stimuli five sec (maximum). On Day 1, 
a vehicle solution is administered to the rats at a time preceding the 
trial run corresponding to the pretreatment time for the test compound. 
The route of administration and the volume of vehicle are also matched to 
that of the test compound. Only animals that exhibited greater than 90% 
CAR on Day 1 are given the test compound on Day 2. 
Statistical Computations: ED50 values (that dose required to reduce the 
mean number of CARS to 50% of the control mean) are determined in the 
following manner. The percent change in CAR on the drug treatment day 
compared to vehicle pretreatment day is the key measure. The percent 
change (% change) in CAR is determined using the following formula: 
EQU % change CAR=((Day 2% CAR/Day 1% CAR).times.100)-100 
A negative number indicates a blockade of CAR, whereas a positive number 
would indicate increased CAR. The test results are reported as the mean % 
change for the group of rats. A reading of -20% is generally taken to 
represent a minimum value for a compound to be designated as active at a 
given dose in the CAR test. Failure to escape was calculated for each 
animal as follows: 
EQU % Failures=# of Failures to Escape/# of trials 
The % failures, viz., loss of escape, is also reported as a group mean. 
Failures to escape are monitored closely and a session is terminated if 
ten failures occurred. ED.sub.50 values and 95% confidence limits are 
calculated using linear regression analysis. The results of the CAR tests 
is shown in Tables 1. 
Receptor Binding Assay 
The dopamine D.sub.2 binding activity of compounds was determined using a 
P.sub.2 fraction (synaptosomal membranes) prepared from male, Wistar rats. 
The D.sub.2 assay employed a P.sub.2 fraction from the striatum, the 
ligand .sup.3 H-spiperone at a concentration of 0.05 nM, and 1 mM 
haloperidol as a blank determinant. Incubation was in 3 mM potassium 
phosphate buffer for 45 min at 37.degree. C. Under these conditions, 
specific binding constituted 75% of total binding, and the K.sub.l values 
for some known drugs were: 0.37 nM for haloperidol and 82 nM for 
clozapine. 
The data from this assay were analyzed by calculating the percent 
inhibition of the binding of the tritiated ligands by given concentrations 
of the test compound. K.sub.l values, where given, were obtained from the 
logit analysis of concentration-inhibition curves. A value of 1000 or less 
is generally taken to represent the value for a compound to be designated 
as active in this screen. If a compound is active in this screen, but not 
in the CAR screen, it is still considered an active antipsychotic agent 
because the CAR screen negative result may be due to site delivery 
problems which may be solved by a suitable delivery mechanism. 
TABLE 1 
______________________________________ 
Receptor 
Binding 
% Inhibition (K.sub..vertline. nM) 
CP # CAR, 5 mpk, PI % escape loss 
D2 
______________________________________ 
1 -56 18 33 
2 -72 34 24 
3 -8 3 30 
4 -41 3 28 
5 -58 3 68 
6 -63 5 333 
7 -85 (15 mpk) 0 2415 
______________________________________ 
To prepare the pharmaceutical compositions of this invention, one or more 
compounds or salts thereof of the invention, as the active ingredient, is 
intimately admixed with a pharmaceutical carrier according to conventional 
pharmaceutical compounding techniques, which carrier may take a wide 
variety of forms depending on the form of preparation desired for 
administration, e.g., oral or parenteral. In preparing the compositions in 
oral dosage form, any of the usual pharmaceutical media may be employed. 
Thus for liquid oral preparations, such as for example, suspensions, 
elixirs and solutions, suitable carriers and additives include water, 
glycols, oils, alcohols, flavoring agents, preservatives, coloring agents 
and the like; for solid oral preparations such as, for example, powders, 
capsules and tablets, suitable carriers and additives include starches, 
sugars, diluents, granulating agents, lubricants, binders, disintegrating 
agents and the like. Because of their ease in administration, tablets and 
capsules represent the most advantageous oral dosage form, in which case 
solid pharmaceutical carriers are obviously employed. If desired, tablets 
may be sugar coated or enteric coated by standard techniques. For 
parenterals, the carrier will usually comprise sterile water, though other 
ingredients, for example, for purposes such as aiding solubility or for 
preservation, may be included. Injectable suspensions may also be 
prepared, in which case appropriate liquid carriers, suspending agents and 
the like may be employed. The pharmaceutical compositions herein will 
preferably contain per dosage unit, e.g., tablet, capsule, powder, 
injection, teaspoonful and the like, from about 50 to about 100 mg of the 
active ingredient, although other unit dosages may be employed. 
In therapeutic use as an antipsychotic agent, the compounds of this 
invention may be administered in an amount of from about 0.5 to 5 mg/kg 
per day, and more preferably 1-3 mg/kg per day. The dosages, however may 
be varied depending upon the requirements of the patient, the severity of 
the condition being treated, and the compound being employed. 
Determination of optimum dosages for a particular situation is within the 
skill of the art. 
The following examples describe the invention in greater detail and are 
intended to illustrate the invention, but not to limit it. In the Examples 
and Table 1, the CP #'s refer to the same compounds and not to the 
compounds in the reaction schemes. In the Examples, the terms .sup.1 H 
NMR, Cl mass spec and IR indicate that the compounds produced were 
analyzed using such analyses and the results confirmed the structure. 
EXAMPLE 1 
1-[[5-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-2-thienyl]carbon 
yl]piperidine Fumarate 
(CP #1) 
A mixture of 5-bromomethyl-2-thiophenecarboxylic acid (13.00 g, 0.059 mole) 
and SOCl.sub.2 (20 mL) was refluxed for 1 hour. The excess SOCl.sub.2 was 
evaporated and the residue was dissolved in CH.sub.2 Cl.sub.2. After 
cooling in an ice bath, the solution was treated dropwise with a solution 
of piperidine (5.51 g, 0.065 mole), NEt.sub.3 (6.50 g, 0,064 mole), and 
CH.sub.2 Cl.sub.2 (25 mL) over 20 minutes. After stirring 15 minutes at 
0.degree. C., the reaction was poured onto ice and the organic layer was 
separated, washed with dilute HCl, 10% Na.sub.2 CO.sub.3, and water. The 
organic layer was dried over MgSO.sub.4, filtered and evaporated to a 
brown oil which was purified using HPLC (4:1/hexane/EtOAc eluant) 
affording a solid (8.10 g). 
This material (2.88 g, 0.01 mole), N-[2-(methylethoxy)phenyl]piperazine 
fumarate (3.20 g, 0.095 mole), and N-methylpyrrolidinone (20 mL) were 
combined and stirred at room temperature for 4 hours. Then, Na.sub.2 
CO.sub.3 (2.10 g, 0.19 mole) was added and the mixture was stirred 
overnight at room temperature and then heated for 1 hour on a steam bath. 
The reaction mixture was poured into water and extracted with Et.sub.2 O. 
The organic layer was washed with water, brine solution, dried over 
Na.sub.2 SO.sub.4, filtered, and evaporated to give 
1-[[5-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-2-thienyl]carbo 
nyl]piperidine as an oil (3.36 g). This material was chromatographed on 
flash silica (98:2/CHCl.sub.3 :10% NH.sub.4 OH eluant) to give an oil 
(2.10 g) which was treated with fumaric acid (0.57 g) in i-PrOH (40 mL). A 
crystalline solid formed which was collected and recrystallized from 
MeOH/i-PrOH producing 1-[[5-[[1-[2-(1-methylethoxy) 
phenyl]-4-piperazinyl]methyl]-2-thienyl]carbonyl]piperidine fumarate (2.08 
g, 40%), m.p. 147.5.degree.-148.5.degree. C. .sup.1 H NMR and CI-MS 
support the structure. 
Elemental Analysis: Calculated for C.sub.24 H.sub.33 N.sub.3 O.sub.2 
S.multidot.C.sub.4 H.sub.4 O.sub.4 : C, 61.86; H, 6.86; N, 7.72;. Found: 
C, 61.97; H, 6.92; N, 7.71. 
EXAMPLE 2 
1-[[5-[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thienyl]carbon 
yl]piperidine Monohydrochloride 
(CP #2) 
A mixture of 1-[2-(methylethoxy)phenyl]piperazine (6.30 g, 0.029 mol), 
prepared as described by Martin and Scott, et al., J. Med. Chem., 1989, 
32, 1052-1056, 4-bromo-2-thiophenecarboxaldehyde (5.50 g, 0.029 mol), 
NaBH(OAc).sub.3 (8.00 g, 0.038 mol), acetic acid (1.70 g, 0.029 mol), and 
dichloroethane was stirred for several hours at room temperature. The 
reaction was then partitioned between diethyl ether/aqueous 10% Na.sub.2 
CO.sub.3 and the ether layer was separated, washed with saturated NaCl 
solution, dried over anhydrous K.sub.2 CO.sub.3, filtered, and evaporated 
to give 1-[(4-bromo-2-thienyl) 
methyl]-4-[2-(1-methylethoxy)phenyl]piperazine (11.33 g) as a crude oil. 
Treatment of this material with HCl diethyl ether-isopropanol gave a 
crystalline solid which was recrystallized from methanol to give 
1-[(4-bromo-2-thienyl)methyl]-4-[2-(1-methylethoxy) phenyl]piperazine 
monohydrochloride (10 g, 77%). A 2.0 g sample of this was recrystallized 
twice from methanol, and chromatographed on flash silica (99:1/CHCl.sub.3 
:MeOH with 1% NH.sub.4 OH as eluant). The resulting oil was converted to 
the hydrochloride salt, as described previously, and was recrystallized 
from methanol , and dried to give 1-[(4-bromo-2-thienyl) 
methyl]-4-[2-(1-methylethoxy) phenyl]piperazine monohydrochloride, m.p. 
(darkens 240.degree. C.) 243.degree.-249.5.degree. C. .sup.1 H NMR and CI 
MS support the structure. 
Elemental Analysis: Calculated for C.sub.18 H.sub.23 BrN.sub.2 
OS.multidot.1.5 HCl.multidot.0.5 H.sub.2 O: C, 47.10; H, 5.60; N, 6.10; S, 
6.98; Cl, 11.58: H.sub.2 O, 1.96. Found: C, 47.50; H, 5.38; N, 6.15; S, 
6.97; Cl, 12.05; H.sub.2 O, 1.77. 
A mixture of 1-[(4-bromo-2-thienyl) methyl]-4-[2-(1-methylethoxy) 
phenyl]piperazine (3.0 g, 0.0076 mole), piperidine (6.45 g, 0.0076 mole), 
and Pd(PPh.sub.3).sub.2 Cl.sub.2 (100 mg) was placed in a bomb, purged 
with CO, and heated at 100.degree. C. for 3 hours. An additional amount of 
piperidine (6.45 g, 0.0076 mole) was added and heating was continued 
overnight. The reaction mixture was purified using HPLC (gradient elution, 
99:1/CHCl.sub.3 :10% NH.sub.4 OH in methanol changing to 98:2) to give 
1-[[5-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thienyl]carbo 
nyl]piperidine as a clear syrup, 2.6 g. This material was converted to the 
monohydrochloride salt in isopropanol, using Et.sub.2 O/HCl. 
Recrystallization from isopropanol produced 
1-[[5-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thienyl]carbo 
nyl]piperidine monohydrochloride (1.82 g, 53%), m.p. 
210.5.degree.-212.5.degree. C. .sup.1 H NMR and CI MS support the 
structure. 
Elemental Analysis: Calculated for C.sub.24 H.sub.33 N.sub.3 O.sub.2 
S.multidot.HCl: C, 62.12; H, 7.38; N, 9.05. Found: C, 62.02; H, 7.31; N, 
9.02 
EXAMPLE 3 
Hexahydro-1-[[5-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]2-thien 
yl]carbonyl]-1H-azepine Monohydrochloride Hemi Hydrate 
(CP #3) 
The title compound was prepared by the method described in Example 2 to 
give 2.08 g(40%), m.p. 212.degree.-215.5.degree. C., except 
hexamethyleneimine was used in place of piperidine. .sup.1 H NMR and CI MS 
support the structure. 
Elemental Analysis: Calculated for C.sub.25 H.sub.35 N.sub.3 O.sub.2 
S.multidot.HCl.multidot.0.50H.sub.2 O: C, 61.65; H, 7.66; N, 8.63; H.sub.2 
O, 1.85. Found: C, 61.28; H, 7.80; N, 8.56; H.sub.2 O, 2.70. 
EXAMPLE 4 
Hexahydro-1-[5-[[-1-[2-(1-Methylethoxy)phenyl-4-piperazinyl]methyl]-3-thien 
yl]carbonyl]-1-H-azepine Hydrochloride Hydrate 
(CP #4) 
Prepared as in Example 2, using hexahydroazepine in place of piperidine, 
was hexahydro-1-[[5 
[[1-[2-(1-Methylethoxy)phenyl]-4-piperazinyl]methyl]-3-thienyi]carbonyl]-1 
-H-azepine monohydrochloride monohydrate (0.75 g, 25%), m.p. (darkens 
195.degree. C.) 199.degree.-201.degree. C. H-1 NMR and CI-MS support the 
structure. 
Elemental Analysis: Calculated for C.sub.25 H.sub.35 N.sub.3 O.sub.2 
S.multidot.HCl.multidot.H.sub.2 O: C, 60.53; H, 7.72; N, 8.47; H.sub.2 O, 
3.63. Found: C, 60.87; H, 7.83; N, 8.61; H.sub.2 O, 3.35. 
EXAMPLE 5 
1-[[5-[[1-[2-(1-Methylethoxy)phenyl-4-piperazinyl]methyl]-2-thienyl]methyl] 
-2-piperidinone Hydrochloride 
(CP #5) 
To a mixture of NaH (1.95 g,0.065 mol) in toluene (100 mL) was added 
2-piperidinone (6.40 g, 0.065 mol) and the resulting mixture was stirred 
for 0.5 hour. After cooling in an ice bath, the mixture was treated 
dropwise with a solution of 5-bromomethyl-2-thiophenecarboxylic acid (11.8 
g. 0.05 mol) and toluene (50 mL). The resulting blood-red mixture was 
stirred 1 hour, poured into ice water, and extracted with Et.sub.2 O. The 
ether layer was washed with dilute HCl, 10% Na.sub.2 CO.sub.3, water, and 
brine. The ether layer was dried over MgSO.sub.4, filtered, treated with 
charcoal, filtered, and evaporated to give a yellow semisolid, 5.6 g. 
This material (4.40 g, 0.017 mol) and sodium borohydride (6.40 g, 0.017 
mol) were combined in EtOH (100 mL) and refluxed for 8 hours. Water was 
added and the reaction was extracted CHCl.sub.3. The organic layer was 
separated, dried over MgSO.sub.4, filtered, and evaporated. The residue 
was chromatographed on flash silica (2:1/hexane:acetone eluant) to give 
2.0 g of yellow oil. This material was dissolved in CH.sub.2 Cl.sub.2, 
washed with 10% Na.sub.2 CO.sub.3, separated, dried over MgSO.sub.4, 
filtered, and evaporated to a yellow oil, 1.8 g. 
The yellow oil material (1.70 g, 0.0075 mole) and MnO.sub.2 (8.50 g , 0.097 
mole) were combined in CH.sub.2 Cl.sub.2 (70 mL) and stirred at room 
temperature for 1 hour. The reaction was filtered through diatomaceous 
earth and evaporated to give a yellow oil, 1.45g. 
A solution of this oil (1.45 g, 0.0065 mole), 
N-[2-(methylethoxy)phenyl-piperazine (1.40 g, 0.0065 mole), glacial acetic 
acid (0.39 g, 0.0065 mole), and MeOH (20 mL) was treated with sodium 
cyanoborohydride (0.44 g, 0.007 mole) and the resulting mixture was 
stirred overnight at room temperature. The solvent was evaporated and the 
residue was slurried in 3N NaOH. Extraction with Et.sub.2 O, drying over 
Na.sub.2 SO.sub.4, treatment with charcoal, and filtration and evaporation 
produced a clear oil. The material was chromatographed on flash 
silica(98:2/CH.sub.2 Cl.sub.2 :10% NH.sub.4 OH) to give 
1-[[5-[[1-[2-(1-methylethoxy)phenyl-4-piperazinyl]methyl]-2-thienyl]methyl 
]-2-piperidinone, 0.65 g. The HCl salt was prepared in Et.sub.2 O and 
recrystallized from i-PrOH/Et.sub.2 O affording 
1-[[5-[[1-[2-(1-methylethoxy)phenyl-4-piperazinyl]methyl]-2-thienyl]methyl 
]-2-piperidinone monohydrochloride (0.64 g, 21%), m.p. 
205.degree.-209.degree. C. .sup.1 H NMR and CI-MS support the structure. 
Elemental Analysis: Calculated for C.sub.24 H.sub.33 N.sub.3 O.sub.2 
S.multidot.HCl: C, 62.12; H, 7.38; N, 9.05. Found: C, 61.84; H, 7.73; N, 
8.74. 
EXAMPLE 6 
1-[[5-[[1-(7-Benzofuranyl)-4-piperazinyl]methyl]-2-thienyl]methyl]-2-piperi 
dinone1.5 Fumarate Hydrate 
(CP #6) 
The title compound was prepared as described in Example 5, using 
4-benzofuranylpiperazine in place of N-[2-(methylethoxy)phenyl]piperazine, 
m.p. 215.degree.-220.degree. C. The benzofuranyl piperazine was prepared 
as described in I. van Wijngaarden et al. (J. Med. Chem. 1988, 31, 1934). 
.sup.1 H NMR and CI-MS support the structure. 
Elemental Analysis: Calculated for C.sub.23 H.sub.27 N.sub.3 O.sub.2 
S.multidot.1.5 C.sub.4 H.sub.4 O.sub.4 .multidot.H.sub.2 O: C, 57.89; H, 
5.86; N, 6.98. Found: C, 57.62; H, 6.19; N, 7.30. 
EXAMPLE 7 
1-[[6-[[1-[2-(Methylethoxy)phenyl]-4-piperazinyl]methyl]pyridinyl]methyl]-2 
-piperidinone Hydrochloride 
(CP #7) 
A solution of 20 g of 2-(isopropoxy)phenylpiperazine fumarate in a minimal 
volume of water was treated with saturated aqueous NaHCO.sub.3 until pH 8 
was achieved, and then extracted twice with CH.sub.2 Cl.sub.2. The 
combined organics were dried (MgSO.sub.4), filtered, and concentrated to 
give 12.4 g (56.6 mmol) of the free base as an oil. This was then treated 
with 2,6-dichloromethylpyridine (29.8 g, 0.170 mol; Baker et al. J. Chem. 
Soc. 1958, 3594) and triethylamine 97.89 mL, 56.6 mmol). The brownish 
solution was heated at reflux in 200 mL of THF. After 3 hours, the 
solution was cooled, treated with 5.7 mL of concentrated HCl, ether, and 
ca. 50 mL of water. The product was extracted into the aqueous phase. It 
was then basified (saturated aqueous NaHCO.sub.3), extracted into ether, 
and concentrated to give 19 g of 
6-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-2-chloromethylpyrid 
ine. The chemical-ionization MS was consistent with the assigned structure. 
A solution of .delta.-valerolactam (3.86 g, 38.9 mmol) in 50 mL of THF was 
treated with nBuLi (15.57 mL of 2.5 M/hexane, 38.9 mmol) at 9.degree. C. 
under nitrogen atmosphere. The resultant suspension was treated with 10 g 
(27.8 mmol) of 
6-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]-2-chloromethylpyrid 
ine dissolved in 50 mL of DMF. The solution was heated at reflux, whereupon 
the lactam anion went entirely into solution. After 2 hours, the solution 
was cooled and treated with water and the product was extracted twice into 
ether. The combined ether layers were dried (MgSO.sub.4), filtered, and 
concentrated. The resultant oil was washed with water and then purified on 
two Waters Prep 500 columns, first with CHCl.sub.3 /MeOH/NH.sub.4 OH 
(96:3.5:0.5), and then with CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH 
(94.3:5.0:0.7). A pure fraction of 5.84 g of material was obtained. This 
was dissolved in iPrOH and filtered through a Millipore filter and treated 
with 2.72 mL of concentrated HCl. Trituration with ether caused a 
voluminous precipitate to emerge, which was recrystallized from 
iPrOH/ether. This solid was dried at 65.degree. C. overnight under vacuum 
to give 3.3 g (23%) of 
1-[[6-[[1-[2-(methylethoxy)phenyl]-4-piperazinyl]methyl]pyridinyl]methyl]- 
2-piperidinone hydrochloride, m.p. 180.degree.-183.degree. C. The .sup.1 H 
NMR and CI-MS were consistent with the assigned structure. 
Elemental Analysis: Calculated for C.sub.25 H.sub.34 N.sub.4 O.sub.2 
.multidot.2.6HCl: C, 58.04; H, 7.13; N, 10.83; Cl, 17.82. Found: C, 57.75; 
H, 7.25; N, 10.64; Cl, 17.90.