Substituted imides of the following formula are antipsychotic, anxiolytic agents with very little extrapyramidal side effects: ##STR1## in which X is --O--, --S--, --SO--, --SO.sub.2 --, --CR.sub.3 R.sub.4 -- where R.sub.3 and R.sub.4, independently, are hydrogen, alkyl of 1 to 4 carbon atoms or, taken together with the carbon atom to which they are attached, R.sub.3 and R.sub.4 form a cycloalkyl group of of 3 to 5 carbon atoms; n is one of the integers 2, 3, 4 or 5; R is phenyl, halophenyl, trifluoromethylphenyl, alkoxyphenyl in which the alkoxy substituent contains 1 to 3 carbon atoms, 2-pyrimidinyl, halopyrimidin-2-yl, 2-pyrazinyl, halopyrazin-2-yl, 2-pyridinyl, cyanopyridin-2-yl, halopyridin-2-yl, quinolyl, or haloquinolyl; R.sub.1 and R.sub.2, taken together, are alkylene of 3 to 5 carbon atoms or alkenylene of 3 to 5 carbon atoms, or taken with the carbon atoms to which they are attached, R.sub.1 and R.sub.2 complete a benzene ring, or a group of the formula: ##STR2## where Y is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --O-- or --S-- and the dotted line represents optional unsaturation; or a pharmaceutically acceptable salt thereof. In addition, the intermediate b3-dicarboxylic and the corresponding anhydrides - 2,3,3a,3b,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene- 1,3-dicarboxylic acid and octahydro-1,5-methano-6,8,9-metheneopentaleno[1,2-d]oxepin-2,4(1H,5H)-dion e represent especially significant aspects of the invention.

BACKGROUND OF THE INVENTION 
Netherlands Pat. No. 7,017,031 discloses 
8-(heteroarylpiperazinylalkyl)-8-azaspiro[4,5]decane-7,9-diones as 
tranquilizers and anti-emetics. 
Japanese Pat. No. 60/87262 (C.A. 103: 215155K) discloses 
N-(heteroarylpiperazinylalkyl)cycloalkanosuccinimide derivatives as having 
anti-conflict activity. 
DESCRIPTION OF THE INVENTION 
In accordance with this invention there is provided a group of 
antipsychotic, anxiolytic N-(aryl and 
heteroarylpiperazinylalkyl)polycyclic-1,3-dicarboxylic acid imides of the 
formula: 
##STR3## 
in which X is --O--, --S--, --SO--, --SO.sub.2 --, --CR.sub.3 R.sub.4 -- 
where R.sub.3 and R.sub.4, independently, are hydrogen, alkyl of 1 to 4 
carbon atoms or, taken together with the carbon atom to which they are 
attached, R.sub.3 and R.sub.4 form a cycloalkyl group of 3 to 5 carbon 
atoms; 
n is one of the integers 2, 3, 4 or 5; 
R is phenyl, halophenyl, trifluoromethylphenyl, alkoxyphenyl in which the 
alkoxy substituent contains 1 to 3 carbon atoms, 2-pyrimidinyl, 
halopyrimidin-2-yl, 2-pyrazinyl, halopyrazin-2-yl, 2-pyridinyl, 
cyanopyridin-2-yl, halopyridin-2-yl, quinolyl, or haloquinolyl; 
R.sub.1 and R.sub.2, taken together, are alkylene of 3 to 5 carbon atoms or 
alkenylene of 3 to 5 carbon atoms, or taken with the carbon atoms to which 
they are attached, R.sub.1 and R.sub.2 complete a benzene ring, or a group 
of the formula 
##STR4## 
where Y is --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --O-- or --S-- and the 
dotted line represents optional unsaturation; or a pharmaceutically 
acceptable salt thereof. In these compounds, the R.sub.1 -R.sub.2 ring 
juncture is either endo or exo with respect to either of the bicyclic 
rings. 
The preferred compounds of the genus of this invention are those which X is 
--CH.sub.2 ; n is 3, 4 or 5 and most preferrably 4; and R.sub.1 and 
R.sub.2, taken with the carbon atoms to which they are attached, complete 
a cyclic alkane, alkene or aromatic hydrocarbon ring containing 5 to 10 
carbon atoms, such as cyclopentane, cyclopentene, norbornane, norbornene, 
perhydrometheno-pentalene, benzene, and the like. Of the halogen 
substituents fluoro, chloro and bromo, chloro is preferred. The 
pharmaceutically acceptable salts are those derived from such organic and 
inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, 
malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, 
sulfuric, methanesulfonic, and similarly known acceptable acids. 
Among the several intermediate 1,3-dicarboxylic acids prepared pursuant to 
obtaining the end products of this invention, of special interest is the 
compound 2,3,3a, 3b, 
4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene-1,3-dicarb 
oxylic acid-- 
##STR5## 
--and its corresponding anhydride, which are useful in preparation of 
several of the herein disclosed compounds as well as the most preferred, 
single embodiment of this invention disclosed in Example 6, infra. 
The compounds of the invention are prepared by conventional methods. For 
example, a suitable polycyclic 1,3-dicarboxylic acid, or the anhydride 
derived from it, is combined with the desired piperazinyl alkyl amine in a 
high boiling solvent such as toluene or xylene and refluxed for an 
extended period with either chemical (e.g. ethoxyacetylene) or mechanical 
(e.g. Dean-Stark trap) water removal, thusly: 
##STR6## 
Alternatively, the compounds of this invention are readily prepared from 
the appropriate polycyclic imide via alkylation with a suitable dihalo 
lower alkane in the presence of a strong base such as sodium hydride, 
followed by reaction of the intermediate product with the desired aryl- or 
heteroaryl substituted piperazine, thusly: 
##STR7## 
The polycyclic 1,3-dicarboxylic acids themselves are known compounds or 
they can be prepared from the appropriate polycyclic olefin by treatment 
with a suitable oxidizing agent such as potassium permanganate or 
ruthenium tetroxide (or from the appropriate polycyclic ketone by 
treatment with potassium permanganate or from the appropriate diketone via 
treatment with periodic acid). 
##STR8## 
The antipsychotic properties of the compounds of this invention were 
established by standard pharmacologically accepted procedures involving 
conditioned avoidance studies in which trained male CD rats (Charles 
River), 400-450 g. body weight are exposed to a fifteen second warning 
tone (conditioned stimulus) continued for an additional fifteen seconds 
accompanied by electric shock. The rat can avoid the electric shock by 
jumping to an exposed shelf (shelf-jump response). A response during the 
initial warning tone is considered an avoidance response, while a response 
during shock delivery is considered as escape response. The shelf-jump 
response test procedure follows that of Herman et al., Comm. in 
Psychopharm., 3, pp. 165-171 (1979). The compounds of this invention were 
tested at a single dose (40 mg./kg. i.p.) in this procedure and were rated 
relative to their inhibition of conditioned avoidance responding. A 
similar test procedure in which a lever press was substituted for a 
shelf-jump was used to establish the oral (p.o) activity of the test 
compounds. Orally active compounds were tested over a full dose range and 
the Avoidance Block activities reported as "AB.sub.50 's" (mg./kg.). 
As a further measure of antipsychotic activity, the compounds of this 
invention were also studied as antagonists of apomorphine-induced 
stereotyped behavior and climing wherein CF-1 mice (Charles River) receive 
the test compound i.p. at several dose levels (1, 10, 30 and 60 mg./kg.) 
(six mice per dose level) and thirty minutes later receive 1 mg./kg. 
apomorphine s.c. Five minutes after injection, the 
sniffing-licking-gnawing syndrome and climbing behavior induced by 
apomorphine are scored for each animal. Readings are repeated every five 
minutes during a thirty minute test session. An ED.sub.50 value (with 95% 
confidence intervals) is calculated for inhibition of apomorphine-induced 
stereotyped behavior and climbing using a non-linear least squares 
calculation with inverse prediction. The ratio of the ED.sub.50 for 
stereotyped behavior to the ED.sub.50 for climbing is calculated. High 
ratios indicate antipsychotic activity with low liability for the 
extrapyramidal side effects which attend long term treatment with such 
standard antipsychotic drugs as haloperidol (ratio=1.00), chlorpromazine 
(ratio=1.51) and thioridazine (ratio=1.83). 
In further support of the low potential for side-effects exhibited by the 
compounds of this invention, representative compounds were established to 
exhibit only weak binding to the D-2 dopamine receptor when tested in 
accordance with a modification of the procedure of Fields et al., Brain 
Res., 136, pp. 578-584 (1977) and Yamamura et al., eds., Neurotransmitter 
Receptor Binding, Raven Press, N.Y. (1978), wherein homogenized limbic 
brain tissue is incubated with .sup.3 H-spiroperidol and various 
concentrations of test compound, filtered and washed and shaken with 
Hydrofluor scintillation cocktail (National Diagnostics) and counted in a 
Packard 460CD scintillation counter. The results of this testing with 
compounds representative of the invention whose production is exemplified, 
infra, are as follows: 
______________________________________ 
Conditioned [.sup.3 H] 
Avoidance Spiroperi- 
Shelf- Discrete Apomorphine dol Binding 
Jump Trial Antagonism Inhibition 
40 mg/kg, AB.sub.50 
ED.sub.50, mg/kg, p.o. 
Ki, nM or 
Ex. i.p. p.o. Stereotypy 
Climbing 
% at 1 .mu.M 
______________________________________ 
1 &gt;20% 40.06 inactive 
4.08 54% 
2 &gt;20% inactive inactive 
24.21 20% 
3 .about.80% 
inactive 30.87 4.91 23% 
4 .about.80% 
weak inactive 
5.50 59% 
5 &gt;20% active inactive 
47.17 25% 
6 .about.80% 
33.76 inactive 
0.40 56 nM 
7 &gt;20% inactive inactive 
inactive 
54% 
8 &gt;20% inactive inactive 
inactive 
23% 
9 &gt;20% inactive 
&gt;50 0% 
10 &gt;20% inactive 10.00 4.71 18 nM 
11 &gt;20% 46.17 42.37 18.89 100% 
12 &lt;20% inactive 
inactive 
30 nM 
13 .about.80% 
40.24 32.34 5.44 51% 
14 .about.20% inactive 
44.05 45% 
15 &gt; 20% inactive 2.54 14.32 174 nM 
______________________________________ 
From these data, the activity profile of the compounds of this invention 
are seen to be that of antipsychotic agents with less potential for extra 
pyramidal side effects such as attend the use of major tranquillizers 
(sedation, pseudoparkinsonism, ataxia, muscle relaxation, etc.). This 
activity profile resembles that of the anxiolytic compound, buspirone. 
Further evidence that the pharmacological profile of the test compounds 
resembles that of buspirone was obtained by measuring the compound's 
ability to displace [.sup.3 H] 8-OH DPAT (dipropylaminotetralin) from the 
5-HT.sub.1A serotonin receptor by the procedure of Hall et al., J. 
Neurochem. 44: 1685-1696, 1985. Compounds of the invention, like 
buspirone, exhibited potent affinity for this serotonin receptor subtype. 
The anxiolytic activity of buspirone is currently believed to be due, at 
least in part, to this receptor (Vander Maclen et al., Eur. J. Pharmacol. 
1986, 129(1-2)123-130. The test results of this study are as follows: 
______________________________________ 
Inhibition of [.sup.3 H] 
8-OH DPAT Binding 
Example Ki, nM or % at 1 .mu.M 
______________________________________ 
1 3 nM 
2 31 nM 
3 41 nM 
4 3.5 nM 
5 60 nM 
6 0.23 nM 
7 6.95 nM 
8 89% 
9 61% 
10 0.29 nM 
11 2.0 nM 
12 0.2 nM 
13 4 nM 
14 86% 
15 0.5 nM 
______________________________________ 
Hence, the compounds of this invention are antipsychotic agents and 
anxiolytic agents useful in the treatment of psychoses such as paranoia 
and schizophrenia and in alleviating anxiety. As such, they may be 
administered neat or with a pharmaceutical carrier to a patient in need 
thereof. The pharmaceutical carrier may be solid or liquid. 
A solid carrier can include one or more substances which may also act as 
flavoring agents, lubricants, solubilisers, suspending agents, fillers, 
glidants, compression aids, binders or tablet-disintegrating agents; it 
can also be an encapsulating material. In powders the carrier is a finely 
divided solid which is in admixture with the finely divided active 
ingredient. In tablets the active ingredient is mixed with a carrier 
having the necessary compression properties in suitable proportions and 
compacted in the shape and size desired. The powders and tablets 
preferably contain up to 99% of the active ingredient. Suitable solid 
carriers include, for example, calcium phosphate, magnesium stearate, 
talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl 
cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low 
melting waxes and ion exchange resins. 
Liquid carriers are used in preparing solutions, suspensions, emulsions, 
syrups, elixirs and pressurized compositions. The active ingredient can be 
dissolved or suspended in a pharmaceutically acceptable liquid carrier 
such as water, an organic solvent, a mixture of both or pharmaceutically 
acceptable oils or fats. The liquid carrier can contain other suitable 
pharmaceutical additives such as solubilisers, emulsifiers, buffers, 
preservatives, sweeteners, flavoring agents, suspending agents, thickening 
agents, colors, viscosity regulators, stabilisers or osmo-regulators. 
Suitable examples of liquid carriers for oral and parenteral 
administration include water (particularly containing additives as above, 
e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose 
solution), alcohols (including monohydric alcohols and polyhydric alcohols 
e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut 
oil and arachis oil). For parenteral administration the carrier can also 
be an oily ester such as ethyl oleate and isopropyl myristate. Sterile 
liquid carriers are used in sterile liquid form compositions for 
parenteral administration. The liquid carrier for pressurized compositions 
can be halogenated hydrocarbon or other pharmaceutically acceptable 
propellent. 
Liquid pharmaceutical compositions which are sterile solutions or 
suspensions can be utilized by, for example, intramuscular, 
intraperitoneal or subcutaneous injection. Sterile solutions can also be 
administered intravenously. When the compound is orally active it can be 
administered orally either in liquid or solid composition form. 
Preferably the pharmaceutical composition is in unit dosage form, e.g. as 
tablets or capsules. In such form, the composition is sub-divided in unit 
dose containing appropriate quantities of the active ingredient; the unit 
dosage forms can be packaged compositions, for example packeted powders, 
vials, ampoules, prefilled syringes or sachets containing liquids. The 
unit dosage form can be, for example, a capsule or tablet itself, or it 
can be the appropriate number of any such compositions in package form. 
The dosage to be used in the treatment of a specific psychosis must be 
subjectively determined by the attending physician. The variables involved 
include the specific psychosis or state of anxiety and the size, age and 
response pattern of the patient.

The following examples illustrate the production of representative 
compounds of this invention. 
EXAMPLE 1 
Hexahydro-3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,5-methanocyclopent 
[d]azepine-2,4(1H,3H)-dione 
Bicyclo[3.3.0]-octane-2,4-dicarboxylic acid (1.6 g., 8.1 mmole) was 
converted to the anhydride by refluxing for three hours in 100 ml. of 
acetic anhydride. The excess reagent was removed in vacuo. Two hundred 
fifty (250) ml. of xylene was added along with 1.9 g. (8.1 mmole) of 
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine. The mixture was refluxed 
under nitrogen for 48 hours with water removal via a Dean-Stark trap. The 
solvent was then removed in vacuo and the residue filtered through 75 g. 
of silica gel with 2% ethanol/chloroform as eluent. Removal of solvent and 
recrystallization of the residue from isopropanol with the addition of 4N 
isopropanolic HCl, followed by a second recrystallization from 
isopropanol, gave 750 mg. of white solid title compound as hydrochloride, 
one quarter hydrate, m.p. 188.degree.-189.degree. C. 
Analysis for: C.sub.22 H.sub.31 N.sub.5 O.sub.2.HCl.1/4H.sub.2 O: 
Calculated: C, 60.26; H, 7.47; N, 15.97. Found: C, 60.31; H, 7.32; N, 
16.14. 
EXAMPLE 2 
Hexahydro-3-[4-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]butyl]-1,5-methanocy 
clopent[d]azepine-2,4(1H,3H)-dione 
The title compound was prepared from 4.58 g (25.4 mmoles) of 
bicyclo[3.3.0]-octane-2,4-dicarboxylic anhydride and 7.10 g (26 mmoles) of 
1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)-piperazine following the 
procedure in Example 1. 7.24 g of the hydrochloride salt was isolated as 
the one-quarter hydrate, m.p. 223.degree.-225.degree. C. 
Analysis for: C.sub.22 H.sub.30 N.sub.5 O.sub.2 Cl.HCl.1/4H.sub.2 O: 
Calculated: C, 55.87; H, 6.71; N, 14.81. Found: C, 55.99; H, 6.58; N, 
14.68. 
EXAMPLE 3 
Hexahydro-3-[4-[4-(2-pyrazinyl)-1-piperazinyl]butyl]-1,5-methanocyclopent[d 
]azepine-2,4(1H,3H)-dione 
The compound prepared in Example 2 (3 g., 7.0 mmol) was converted to the 
free base by washing a methylene chloride solution of the compound with 
saturated aqueous sodium bicarbonate and drying over Na.sub.2 SO.sub.4. 
After filtration and evaporation in vacuo, the residue was redissolved in 
200 ml. of ethanol and 4 ml. of triethylamine and 400 mg. of 10% palladium 
on carbon added. The mixture was hydrogenated at 60 p.s.i. for 5 hours, 
200 mg. additional 10% Pd/C added, and hydrogenation continued for an 
additional 5 hours. The mixture was then filtered through celite and the 
solvent removed under vacuum. The residue was filtered through 75 g. of 
silica gel with 2% EtOH/CHCl.sub.3 and the fractions containing product 
combined and concentrated. Recrystallization of the residue from 
isopropanol with the addition of 4N HCl in isopropanol gave 1.26 g. of 
white solid title compound as the hydrochloride salt, m.p. 
212.degree.-215.degree. C. 
Analysis for: C.sub.22 H.sub.31 N.sub.5 O.sub.2.HCl: Calculated: C, 60.89; 
H, 7.43; N, 16.14. Found: C, 60.84; H, 7.49; N, 16.03. 
EXAMPLE 4 
5,5a,8,8a-Tetrahydro-3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]1,5-methan 
ocyclopent[d]azepine-2,4(1H,3H)-dione 
Bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic acid (12.6 g., 67 mmol.) was 
converted to 4.24 g. of anhydride by treatment with excess acetic 
anhydride as in Example 1. In this instance, however, the anhydride was 
purified by extraction of the dark residual gum with hexane, filtration, 
and evaporation in vacuo. The anhydride was combined with 6.0 g. (24 
mmols) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 250 ml. of 
xylene and refluxed under N.sub.2 for 24 hours with water separation via a 
Dean-Stark trap. The supernatant liquid was removed at this point and 
replaced with an additional 150 ml. of xylene. Reflux under N.sub.2 was 
continued for 24 hours. The combined xylene solutions were then evaporated 
and the residue column chromatographed on 250 g. of silica gel with a 
gradient elution beginning with CHCl.sub.3 and ending with 10% CH.sub.3 
OH/CHCl.sub.3. The product-containing fractions were combined and 
evaporated and the residue crystallized from isopropanol with the addition 
of 4N HCl in isopropanol to give 3.25 g. of white solid title compound as 
the dihydrochloride salt, m.p. 232.degree.-234.degree. C. 
Analysis for: C.sub.22 H.sub.29 N.sub.5 O.sub.2.2HCl: Calculated: C, 56.41; 
H, 6.67; N, 14.95. Found: C, 56.51; H, 6.67; N, 15.27. 
EXAMPLE 5 
5,5a,8,8a-Tetrahydro-3-[4-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]butyl]-1, 
5-methanocyclopent[d]azepine-2,4(1H,3H)-dione 
The title compound was prepared from 2.1 g (12 mmoles) of 
bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic anhydride and 3.2 g (12 mmoles) 
of 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine following the 
procedure in Example 4. 620 mg of the hydrochloride salt was isolated as 
the hemihydrate, m.p. 222.degree.-224.degree. C., after two 
recrystallizations from isopropanol. 
Analysis for: C.sub.22 H.sub.28 N.sub.5 O.sub.2.HCl.1/2H.sub.2 O: 
Calculated: C, 55.58; H, 6.36; N, 14.73. Found: C, 55.78; H, 6.19; N, 
14.72. 
EXAMPLE 6 
Decahydro-3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,5-methano-6,7,9-me 
theno-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
Potassium permanganate (50 g., 0.32 mmoles) was dissolved in 500 ml. of 
water in a 1 l three neck flask equipped with a thermometer, addition 
funnel and overhead stirrer. To it was added a solution of 18.4 g. (0.10 
mole) of norbornadiene dimer and 5.0 g. (0.018 mole) of 
tetra-n-butylammonium chloride in 300 ml. of benzene. The internal 
temperature was kept below 40.degree. C. by means of a cold water bath. 
The reaction was stirred overnight at room temperature; then 60 g. of 
sodium bisulfite was added and the mixture acidified with concentrated 
hydrochloric acid. Five hundred milliliters of ethyl acetate was added and 
the organic phase was removed in a separatory funnel. The aqueous phase 
was extracted with two additional 500 ml. portions of ethyl acetate. The 
combined organic portions were washed with 300 ml. saturated brine, dried 
over Na.sub.2 SO.sub.4, filtered, and evaporated to obtain 24 g. of 
2,3,3a,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene-1,3 
-dicarboxylic acid. 
The diacid prepared above (2.5 g., 10 mmoles) was combined with 2.4 g. (10 
mmoles) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine in 300 ml. of 
xylene and refluxed under N.sub.2 for 48 hours with water separation via a 
Dean-Stark trap. The mixture was allowed to cool, concentrated in vacuum 
and filtered through 75 g. of silica gel in 2% EtOH/CHCl.sub.3. 
Concentration in vacuum and recrystallization from isopropanol with the 
addition of 4N HCl/isopropanol gave a pale pin solid title compound as the 
dihydrochloride, hemihydrate, 820 mg., m.p. 229.degree.-231.degree. C. 
Analysis for: C.sub.26 H.sub.33 N.sub.5 O.sub.2.2HCl.1/2H.sub.2 O: 
Calculated: C, 58.98; H, 6.85; N, 13.23. Found: C, 59.26; H, 6.78; N, 
13.04. 
EXAMPLE 7 
Decahydro-3-[4-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]butyl]-1,5-methano-6 
,7,9-metheno-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
2.5 g. (10 mmole) of the diacid prepared in Example 6 was converted to the 
anhydride, 
octahydro-1,5-methano-6,8,9-methenopentaleno[1,2-d]oxepin-2,4(1H,5H)-dione 
, with acetic anhydride and coupled with 2.4 g (10 mmoles) of 
1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine following the 
procedure in Example 1. 1.7 g. of white solid title compound as the 
hydrochloride salt, m.p. 269.degree.-270.degree. C., was obtained. 
Analysis for: C.sub.26 H.sub.32 N.sub.5 O.sub.2 Cl.HCl: Calculated: C, 
60.23; H, 6.42; N, 13.51. Found: C, 59.94; H, 6.47; N, 13.57. 
EXAMPLE 8 
2,3,4,5-Tetrahydro-3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-1,5-methano 
-1H-3-benzazepine-2,4(3H, 5H)-dione 
1,3-Indanedicarboxylic acid anhydride (1.9 g., 10 mmoles) was dissolved in 
methylene chloride and added to a solution of 
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine (3.0 g., 13 mmole) in the 
same solvent. The solvent was then removed in vacuo and replaced with 200 
ml. of acetonitrile. Ethoxyacetylene (1 g., 14 mmole) was added and the 
mixture was refluxed under N.sub.2 overnight. The solvent was then removed 
in vacuo and the residue redissolved in chloroform and filtered through 75 
g. of silica gel. The column was washed with 1% MeOH/CHCl.sub.3 and the 
extracts were combined and evaporated. The residue was crystallized from 
isopropanol with the addition of 4N HCl/isopropanol. A second 
recrystallization from isopropanol yielded 1.0 g. of tan solid title 
compound as the dihydrochloride salt, m.p. 259.degree.-262.degree. C. 
Analysis for: C.sub.23 H.sub.27 N.sub.5 O.sub.2.2HCl: Calculated: C, 57.74; 
H, 6.11; N, 14.64. Found: C, 57.65; H, 6.14; N, 14.71. 
EXAMPLE 9 
2,3,4,5-Tetrahydro-3-[4-[4-(6-chloro-2-pyrazinyl)-1-piperazinyl]butyl]-1,5- 
methano-1H-3-benzazepine-2,4(3H, 5H)-dione 
The title compound was prepared from 2.82 g. (15 mmoles) of 
1,3-indanedicarboxylic acid anhydride and 4.04 g. (15 mmoles) of 
1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine following the 
procedure in Example 8. 1.37 g. of the title compound was obtained as the 
monohydrochloride, m.p. 225.degree.-227.degree. C. 
Analysis for: C.sub.23 H.sub.26 N.sub.5 O.sub.2 Cl.HCl: Calculated: C, 
57.99; H, 5.71; N, 14.70. Found: C, 57.87; H, 5.79; N, 14.59. 
EXAMPLE 10 
Decahydro-3-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-1,5-methano-6,7,9- 
metheno-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
2.48 g. (10 mmoles) of 
2,3,3a,3b,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene- 
1,3-dicarboxylic acid was converted to the anhydride by refluxing with 
acetic anhydride and reacted with 
1-(4-aminobutyl)-(2-methoxyphenyl)piperazine (2.63 g., 10 mmoles) 
according to the procedure in Example 1. 2.5 g. of the title compound was 
obtained as the dihydrochloride, hemihydrate, m.p. 220.degree.-221.degree. 
C. 
Analysis for: C.sub.29 H.sub.37 N.sub.3 O.sub.3.2HCl.1/2H.sub.2 O: 
Calculated: C, 62.47; H, 7.23; N, 7.54. Found: C, 62.20; H, 7.12; N, 7.50. 
EXAMPLE 11 
Hexahydro-3-[4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]butyl]-1,5-methan 
o-cyclopent[d]azepine-2,4(1H, 3H)-dione 
2.5 g. (13 mmoles) of bicyclo[3.3.0]-octane-2,4-dicarboxylic acid was 
converted to the anhydride by refluxing with acetic anhydride and reacted 
with 3.4 g. (11.3 mmoles) of 
1-(4-aminobutyl)-4-(3-trifluoromethylphenyl)piperazine according to the 
procedure in Example 1. 3.0 g. of the title compound was obtained as the 
monohydrochloride, quarter hydrate, m.p. 205.degree.-207.degree. C. 
Analysis for: C.sub.25 H.sub.32 N.sub.3 O.sub.2 F.sub.3.HCl.1/4H.sub.2 O: 
Calculated: C, 59.52; H, 6.69; N, 8.33. Found: C, 59.62; H, 6.75; N, 8.10. 
EXAMPLE 12 
Decahydro-3-[4-[4-(3-trifluoromethylphenyl)-1-piperazinyl]butyl]-1,5-methan 
o-6,7,9-metheno-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
2.48 g. (10 mmoles) of 
2,3,3a,3b,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene- 
1,3-dicarboxylic acid was converted to the anhydride by refluxing with 
acetic anhydride and reacted with 3.0 g. (10 mmoles) of 
1-(4-aminobutyl)-4-(3-trifluoromethylphenyl)piperazine according to the 
procedure in Example 1. 2.1 g. of the title compound was obtained as the 
monohydrochloride, m.p. 238.degree.-239.degree. C. 
Analysis for: C.sub.29 H.sub.34 N.sub.3 O.sub.2 F.sub.3.HCl: Calculated: C, 
63.32; H, 6.41; N, 7.64. Found: C, 63.41; H, 6.58; N, 7.60. 
EXAMPLE 13 
Decahydro-3-[4-[4-(2-pyrazinyl)-1-piperazinyl]butyl]-1,5-methano-6,7,9-meth 
eno-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
2.48 g. (10 mmoles) of 
2,3,3a,3b,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene- 
1,3-dicarboxylic acid was converted to the anhydride by refluxing with 
acetic anhydride and reacted with 2.35 g. (10 mmoles) of 
1-(4-aminobutyl)-4-(2-pyrazinyl)piperazine according to the procedure in 
Example 1. Conversion to the salt by treatment with 4N isopropanolic HCl, 
followed by a second crystallization from isopropanol gave 670 mg. of the 
title compound as the monohydrochloride, hemihydrate, m.p. 
231.degree.-233.degree. C. 
Analysis for: C.sub.26 H.sub.33 N.sub.5 O.sub.2.HCl.1/2H.sub.2 O: 
Calculated: C, 63.33; H, 7.16; N, 14.21. Found: C, 63.43; H, 7.09; N, 
14.42. 
EXAMPLE 14 
Decahydro-3-[4-[4-(2-quinolyl)-1-piperazinyl]butyl]-1,5-methano-6,7,9-metha 
no-2H-pentaleno[1,2-d]azepine-2,4(3H)-dione 
2.48 g. (10 mmoles) of 
2,3,3a,3b,4,5,6,6a,7,7a-decahydro-4,6,7-metheno-1H-cyclopenta[a]pentalene- 
1,3-dicarboxylic acid was converted to the anhydride by refluxing with 
acetic anhydride and reacted with 2.84 g. (10 mmoles) of 
1-(4-aminobutyl)-4-(2-quinolyl)piperazine according to the procedure in 
Example 1. Conversion to the salt by treatment with 4N isopropanolic HCl, 
followed by a second crystallization from isopropanol and a final 
recrystallization from ethanol gave 1.3 g. of the title compound as the 
dihydrochloride, ethanolate, m.p. 252.degree.-255.degree. C. 
Analysis for: C.sub.31 H.sub.36 N.sub.4 O.sub.2.2HCl.C.sub.2 H.sub.5 OH: 
Calculated: C, 64.38; H, 7.20; N, 9.10. Found: C, 64.36; H, 7.23; N, 8.97. 
EXAMPLE 15 
Octahydro-3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-2H-1,5:6,9-dimethano 
-2H-3-benzazepine-2,4(3H)-dione 
5.26 g. (23.5 mmoles) of 
octahydro-endo-4,7-methanoindene-trans,trans-1,3-dicarboxylic acid was 
converted to the anhydride according to the procedure in Example 1, and 
this was purified by Kugelrohr distillation to give 4.67 g. (23 mmoles) of 
compound. The anhydride was reacted with 5.80 g. (25 mmoles) of 
1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine as in Example 1 and the 
product purified by chromatography on 200 g. of silica gel using 2% 
methanol in chloroform as eluent. Three crops of crystalline free base 
totaling 2.4 g. were obtained by crystallization from isopropanol and 
these were combined and recrystallized from isopropanol with the addition 
of 4N isopropanolic HCl. 2.72 g. of dihydrochloride (m.p. 
208.degree.-210.degree. C.) was obtained. 
Analysis for: C.sub.24 H.sub.33 N.sub.5 O.sub.2.2HCl: Calculated: C, 58.06; 
H, 7.11; N, 14.11. Found: C, 58.34; H, 7.40; N, 13.96.