The subject invention relates to 5-Substituted trans-1-piperazinoindan derivatives having general formula (I), ##STR1## wherein X is halogen, trifluromethyl, alkyl, alkylthio, alkyloxy, hydroxy, alkylsulphonyl, alkyl- or dialkylamino, triflouromethylthio or cyano; R is hydrogen, or alkyl, alkenyl, cycloalkyl, cycloalkyl lower alkyl, optionally substituted with hydroxy, or R is a substituent, ##STR2## wherein n is an integer from 1 to 6; U is CH or N; Y is, CH.sub.2, O, S or N-R.sup.1, R.sup.1 being hydrogen or cycloalkyl, cycloalkylmethyl, alkyl or alkenyl optionally substituted with hydroxy or an optionally substituted phenyl group; W is O or S; Z is --(CH.sub.2).sub.4 --, ##STR3## where R.sup.2 and R.sup.3 are hydrogen or lower alkyl, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2 --, optionally substituted 1,2-phenylene, 1,2-C.sub.6 H.sub.4 CH.sub.2 -- (to form a quinazolidinone or -thione ring system) or 1,2-C.sub.6 H.sub.4 CO-- (to form a quinazolidindion or thixoquinazolidinon ring system); and Ar is an optionally substituted phenyl, thiophene or furane ring; are selective, centrally acting 5-HT.sub.2 antagonists useful in the treatment of anxiety, depression, sleeping disorders, negative symptoms of schizophrenia and migraine.

The present invention relates to 5-substituted 1-piperazinoindan 
derivatives and acid addition salts thereof with selective antagonistic 
action on the serotonin-2 (5-hydroxytryptamin-2; 5-HT.sub.2) receptors in 
the central nervous system, to medicaments comprising such derivatives as 
active ingredients, to the use of such derivatives in the treatment of 
diseases in the central nervous system and to methods for the preparation 
of such compounds. 
The novel piperazinylindan derivatives of the invention are trans-isomers 
represented by the following Formula I: 
##STR4## 
wherein X is halogen, trifluoromethyl, lower alkyl, lower alkylthio, lower 
alkoxy, hydroxy, lower alkylsulphonyl, lower alkyl- or dialkylamino, 
trifluoromethylthio or a cyano group; 
R is hydrogen, lower alkyl or alkenyl, cycloalkyl, or cycloalkyl lower 
alkyl, optionally substituted with one or two hydroxy groups, any hydroxy 
group present being optionally esterified with an aliphatic carboxylic 
acid having from two to twentyfour carbon atoms inclusive, or R is a 
substituent 
##STR5## 
wherein n is an integer from 1 to 6; U is CH or N; 
Y is CH.sub.2, O,S or N-R.sup.1, R.sup.1 being hydrogen or a cycloalkyl or 
a cycloalkylmethyl or a lower alkyl or alkenyl group optionally 
substituted with one or two hydroxy groups or a phenyl group optionally 
substituted with halogen, trifluoromethyl or lower alkyl; 
W is O or S; 
Z is --(CH.sub.2).sub.4 --, 
##STR6## 
where R.sup.2 and R.sup.3 are hydrogen or lower alkyl, 
--CH.dbd.CH--CH.sub.2 --, --CH.dbd.CH--, 1,2-phenylene, optionally 
substituted with halogen or trifluoromethyl, or if U is nitrogen and Y is 
NR.sup.1 Z may also be 1,2-C.sub.6 H.sub.4 CH.sub.2 -- (to form a 
quinazolidinone or -thione ting system) or 1,2-C.sub.6 H4CO-- (to form a 
quinazolidindion or thioxoquinazolidinon ring system); and 
Ar is a phenyl ring optionally substituted with halogen, trifluoromethyl or 
lower alkyl or Ar is a thiophene or furane ring optionally substituted 
with lower alkyl. 
The term "lower alkyl" is intended to mean a straight or branched alkyl 
group having from one to four carbon atoms, such as methyl, ethyl, 
n-propyl, iso-propyl, n-butyl, sec-butyl, etc. Lower alkoxy, lower 
alkylthio, lower alkylsulfonyl, lower alkylamino and lower dialkylamino 
similarly designate such groups wherein the alkyl moiety is a lower alkyl 
group as defined above. 
Lower alkenyl is intended to mean an alkenyl group containing from 2 to 4 
carbon atoms, for example ethenyl, 1-propenyl, 2-butenyl, etc. 
Cycloalkyl is intended to mean cycloalkyl having from 3 to 8 carbon atoms 
incl. in the ring. 
The Z-group may be oriented in both directions in the ring. 
Halogen means fluoro, chloro, bromo or iodo. 
When Y is NR.sup.1 wherein R.sup.1 is H, the compound may exist in 
tautomeric form, i.e. wherein W is --OH or --SH, respectively, connected 
to the ring via a single bond, and having a double bond in the ring, i.e. 
from the Y to the carbon atom bearing the --OH or --OS group. Such 
tautomeric forms are intended to be embraced by Formula I. 
Compounds similar to the compounds of the present invention are disclosed 
in our own U.S. Pat. No. 4,443,448 which relates to 
1-piperazino-3-phenylindan derivatives having one substituent in the 
benzen moiety of the indan ring system and claimed to have neuroleptic or 
antidepressant activity. The neuroleptic activity of the compounds is 
based on tests showing dopamine antagonistic activity in vivo whereas 
antidepressant activity is shown by the ability of the compounds to 
inhibit the reuptake of dopamine. A number of the compounds of the general 
Formula I of the present invention are generically embraced by the general 
scope of said patent. However, only a few of the 5-substituted derivatives 
of the general Formula I of the present invention are specifically 
mentioned in said patent. All of said compounds are compounds of the 
general Formula I wherein Ar is 4-fluorophenyl R is lower alkyl optionally 
substituted with hydroxy. Only some of said compounds were tested and they 
were all found to be without significant activity as dopamine antagonists 
in the in vivo test used, cf. Table 8 of said patent. Accordingly they 
were regarded to be without value as neuroleptics. No results as to 
dopamine reuptake inhibiting effects are given for those compounds. 
Our own U.S. Pat. No. 4,684,650 discloses a series of optionally 
6-substituted 1-piperazino-3-phenylindans claimed to have a potent 
antiserotonergic activity without having any significant neuroleptic 
activity. It was shown that the compounds had a high affinity to 
5-HT.sub.2 receptors whereas they were weak or inactive in an in vivo 
model for antidopaminergic effect, i.e. the methylphenidate antagonism 
test. Many of the compounds were shown to have potent antihypertensive 
action. In a later publication about the same series of compounds (K. P. 
B.o slashed.ges.o slashed. et al., J. Med. Chem., 1988, 31,2247) it was 
shown that in despite of a selective antiserotonergic profile in vivo, 
nevertheless many of the compounds still had significant activity for both 
dopamine D-2 receptors and in particular .alpha..sub.1 adrenoceptors. 
The 5-HT.sub.2 antagonist ritanserin (Meert, T. F.; Janssen, P. A. J. Drug. 
Dev. Res. 1989, 18, 119.) has been shown to be effective in the treatment 
of anxiety and depression presumably through improvement of the sleep 
quality. Furthermore, selective, centrally acting 5-HT.sub.2 antagonists 
have been shown to have an effect towards the negative symptoms of 
schizophrenia and to reduce extra-pyramidal side-effects caused by 
treatment with classical neuroleptics in schizophrenic patients (Gelders, 
Y. G., British J. Psychiatry, 1989, 155 (suppl. 5), 33). Finally, 
selective 5-HT.sub.2 antagonists could be effective in the prophylaxis of 
migraine since it is known that 5-HT is involved in migraine attacks. The 
links between 5-HT and migraine attacks are several and they suggest a 
number of mechanisms whereby 5-HT may be involved (Scrip Report; 
"Migraine--Current trends in research and treatment"; PJB Publications 
Ltd.; May 1991 ). Various 5-HT.sub.2 antagonists are in clinical trials as 
anti-migraine agents, such as sergolexole (c.f. for example Pharma 
Projects, May 1991, 1359-1365). Obviously there is a strong demand for 
selective 5-HT.sub.2 antagonists without side effects. 
It has now surprisingly been found that the 5-substituted 1-piperazinoindan 
derivatives of Formula I, have high affinity for 5-HT.sub.2 receptors. As 
compared to the corresponding 6-substituted derivatives they have very low 
affinity to both dopamine D-2 receptors and .alpha..sub.1 adrenoceptors. 
In vivo the compounds have potent activity in animal models for central 
5-HT.sub.2 antagonism. Because of the very low affinity for adrenoceptors 
the 5-substituted compounds have, in contrast to the 6-substituted 
derivatives, substantially no effect on the blood pressure. 
Only trans-isomers of the 5-substituted 1-piperazinoindan derivatives of 
Formula I are active, cis-isomers being without significant 5-HT.sub.2 
antagonistic activity. 
Accordingly in a first aspect the present invention relates to 
trans-isomers of the compounds having the general Formula I as defined 
above and pharmaceutically acceptable acid addition salts thereof and 
prodrugs therefore with the proviso that R may not be hydrogen or lower 
alkyl or alkenyl optionally substituted with hydroxy when Ar is optionally 
substituted phenyl. 
The trans-isomers of the invention exist as pairs of optically active 
isomers and such isomers are within the scope of the present invention. 
Also any other stereoisomer of a compound having the general Formula I is 
embraced by the invention. It has so far been found that the 5-HT.sub.2 
antagonistic activity predominantly resides in one of the optical isomers. 
Prodrugs of the present invention may be conventional esters when hydroxy 
groups are available, or in particular if the compound is a compound of 
the general Formula I wherein W is O and Y is NR.sup.1, R.sup.1 being 
hydrogen, the prodrug may be a reaction product with an acid or an 
activated acid, with formaldehyde alone or in the presence of an alcohol 
or an amine, or with an acyloxymethylene halide, which product accordingly 
may be represented by a formula similar to the general Formula I defined 
above wherein W is O, Y however being a group NR.sup.1 ' wherein R.sup.1 ' 
designates a group--A--B where A is selected from CO, CS, or CH.sub.2, and 
if A is CO or CS, B is selected from the groups consisting of: 
i) hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl or 
cycloalk(en)ylalk(en)yl, optionally substituted with one or two hydroxy 
groups, or phenyl optionally substituted with one or more substituents 
selected from the group consisting of halogen, trifluoromethyl, lower 
alkyl, lower alkoxy, lower alkylthio, acyloxy, or cyano; or 
ii) QB.sup.1, wherein Q is O or S and B.sup.1 is selected from the 
substituents defined for B under i) above except hydrogen; and 
iii) NB.sup.2 B.sup.3, wherein B.sup.2 and B.sup.3 independently are 
selected from the substituents defined for B.sup.1 under ii) above, or 
B.sup.2 and B.sup.3 are combined to form a four to eight membered 
heterocyclic ring containing from one to three nitrogen atoms and from 
zero to three oxygen or sulfur atoms; or 
if A is CH.sub.2, B is selected from the groups consisting of: 
iv) a group QB.sup.1 as defined in ii); 
v) a group NB.sup.2 B.sup.3 as defined in iii); or 
vi) a group OC(O)B.sup.4, wherein B.sup.4 is as defined for B.sup.1. 
Although the latter prodrugs are not esters they would decompose properly 
in order to release the compound of the invention over a desired period of 
time when administered parenterally as a depote formulation in an 
apropriate oil, such as coconut oil, e.g. viscoleo.RTM., peanut oil, 
sesame oil, cotton seed oil, corn oil, soy bean oil, olive oil, etc. or 
synthetic esters of fatty acids and glycerol or propylenglycol. 
The pharmaceutically acceptable acid addition salts of the compounds used 
in the invention are salts formed with non-toxic organic or inorganic 
acids. Exemplary of such organic salts are those with maleic, fumaric, 
benzoic, ascorbic, embonic, succinic, oxalic, bis-methylenesalicylic, 
methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, 
citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, 
steadc, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene 
sulfonic and theophylline acetic acids, as well as the 
8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such 
inorganic salts are those with hydrochloric, hydrobromic, sulfuric, 
sulfamic, phosphoric and nitric acids. 
The compounds of the invention show high affinity to 5-HT.sub.2 receptors 
and very low receptor affinity to D-2 receptors and .alpha..sub.1 
adrenoceptors and consequently they are very selective with respect to the 
5-HT.sub.2 receptor. Accordingly, they are useful in the treatment of 
varios diseases of the central nervous system, such as anxiety, 
depression, sleeping disorders, negative symptoms of schizophrenia, 
extrapyramidal side-effects caused by treatment with classical 
neuroleptics, and migraine. 
Preferred 5-substituted trans-1-piperazinoindan derivatives according to 
the invention are those wherein: 
Ar is a phenyl ring optionally substituted with halogen or methyl, 
preferably 4-fluorophenyl; X is Cl or F and/or R is a group of the 
formula: 
##STR7## 
wherein n is 2, U is nitrogen; W is O or S; Z is --CH.sub.2 --CH.sub.2 -- 
or --CH.sub.2 --CH.sub.2 --CH.sub.2 --; and 
Y is a group NR.sup.1 wherein R.sup.1 is hydrogen or lower alkyl. 
Most preferably the compound of the invention is selected from the group 
of: 
(-)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]-ethyl]-3-isopropyl-2-imidazolidinone, dimaleate; 
(+)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pydmidinethione,dihydrochloride; 
(-)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dihydrochloride; 
(+)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate; and 
(-)-Trans- 
1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]piperazin-1 
-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate. 
In a second aspect the present invention relates to a pharmaceutical 
preparation comprising at least one derivative of the general Formula I as 
defined above together with a pharmaceutically acceptable carrier or 
diluent. 
The compounds of the Formula I and the pharmaceutically acceptable acid 
addition salts thereof may be administered by any suitable route, for 
example orally in the form of tablets, capsules, powders, syrups, etc., or 
parenterally in the form of solutions for injection. 
Suitable pharmaceutical preparations may be prepared by methods well known 
in the art. Conveniently, the compounds of the invention are administered 
in unit dosage form containing said compound in an amount of about 
0.05-100 mg, preferably about 1-50 mg. 
The total daily dose usually ranges from about 0.1 to 500 mg of the active 
compound of the invention. 
In a further aspect the present invention relates to the use of a compound 
having the general Formula I as defined above for the manufacture of a 
medicament for the treatment of a disease in the central nervous system, 
preferably anxiety, depression, sleeping disorders, negative symptoms of 
schizophrenia, extrapyramidal side-effects caused by treatment with 
classical neuroleptics, and migraine. 
The invention moreover relates to a method for the preparation of the novel 
5-substituted derivatives of Formula I, which comprises: 
a) treating a compound of the following Formula II: 
##STR8## 
with a piperazine derivative of formula: 
##STR9## 
in which formulas X, Ar and R are as defined above, and X.sup.1 is halogen 
or --OSO.sub.2 R.sup.4 wherein R.sup.4 is alkyl such as CH.sub.3 or aryl 
such as p-toluyl; 
b) treating a compound of the following Formula III: 
##STR10## 
wherein X and Ar are as defined above, with a compound of the formula 
X.sup.1 --R wherein R and X.sup.1 are as defined above except that R 
cannot be hydrogen; 
c) treating a compound of Formula III with a compound R'--CHO, wherein R' 
is such a group that R'--CH.sub.2 -- is as defined above for R, in the 
presence of a reducing agent; 
d) treating a compound of the following Formula IV: 
##STR11## 
wherein X, Ar, R.sup.1, Z and n are as defined above, with CS.sub.2, 
thiophosgene, urea or phosgene; 
e) treating a compound of the following Formula V: 
##STR12## 
wherein X, Ar, n, and Z are as defined above, and X.sup.1 is an alkali 
metal such as sodium or potassium, with a compound of formula R.sup.5 
-X.sup.1 wherein R.sup.5 is a lower alkyl group and X.sup.1 is as defined 
above; 
f) reducing a compound with the following Formula VI: 
##STR13## 
wherein X, Ar, n, U, Z and W are as defined above and R.sup.1 " is a 
cycloalkyl or lower alkyl group containing one or more ester, ketone or 
aldehyde groups, with a suitable reducing agent to a corresponding 
compound wherein R.sup.1 is a lower alkyl or a cycloalkyl group containing 
one or more hydroxy groups; 
g) reacting a compound of Formula I wherein R is a group of the formula: 
##STR14## 
wherein n, U, Z and Y are as defined above an W is O, with P.sub.2 S.sub.5 
or Lawessons reagent to obtain the corresponding compound wherein W is S. 
Method a) is preferably carried out in an inert solvent such as acetone or 
methylisobutylketone using either an excess of the piperazine reactant or 
by using equimolar amounts of reactants in the presence of an alkali metal 
carbonate such as potassium carbonate or another alkaline substance at 
reflux temperatures. 
Method b) is preferably carried out in an inert solvent such as ethanol or 
isobutylketone in the presence of an alkali metal carbonate such as 
potassium carbonate or another alkaline substance at reflux temperatures. 
Method c) is preferably carried out in an inert solvent such as an alcohol 
(eg methanol) or an ether (eg tetrahydrofuran) by hydrogenation in the 
presence of a suitable catalyst such as Pt or Pd or by using a borohydride 
such as NaCNBH.sub.3 at a pH of 5-6. 
Method d) is preferably carried out by treating a compound of Formula IV in 
an inert solvent, such as n-pentanol or n-butanol, with urea or carbon 
disulfide succeeded by heating at reflux temperatures. 
In Method e), the alkalimetal salt of Formula V is preferably formed by 
treating the corresponding hydrogen derivative with an alkali metal 
alkoxide such as potassium tert.-butoxide in an inert solvent such as 
toluene whereupon the salt is reacted directly with the alkylating agent, 
R.sup.5 -X.sup.1, at room or higher temperatures. 
Method f) is preferably carried out by reducing the derivative of Formula 
Vi with a suitable reducing agent such as lithium or sodium borohydride in 
an inert solvent such as tetrahydrofurane. 
Method g) is preferably carried out in hexamethyl phosphorous triamide 
(HMPA) or xylene at temperatures between 110.degree. C. and 200.degree. C. 
The acid addition salts of the compounds of the invention are easily 
prepared by methods well known in the art. The base is reacted with either 
the calculated amount of organic or inorganic acid in an aqueous miscible 
solvent, such as acetone or ethanol, with isolation of the salt by 
concentration and cooling, or with an excess of the acid in an aqueous 
immiscible solvent, such as ethyl ether or chloroform, with the desired 
salt separating directly. Of course, these salts may also be prepared by 
the classical method of double decomposition of appropriate salts. 
The preparation of the compounds of Formula II from the corresponding 
2,3-dihydroinden-1-ones may be carried out analogueously with the method 
described in U.S. Pat. No. 4,443,448, U.S. Pat. No. 4,684,650, and J. Med. 
Chem. 1983, 26, 935. The indanones were either prepared by cyclization of 
the corresponding diphenylpropionic acids or more conveniently as 
described for similar compounds in U.S. Pat. No. 4,873,344 and in J. Org. 
Chem. 1990, 55, 4822 from the proper 3,5-disubstituted 
1-amino-3-cyano-1-inden-2-carboxylic acid esters which in turn also may be 
prepared as described in U.S. Pat. No. 4,873,344. Hereby the following 
novel 3,5-disubstituted 1-amino-3-cyano-1-inden-2-carboxylic acid esters 
were prepared: 
1-Amino-3-cyano-3-(4-fluorophenyl)-5-methyl-1-inden-2-carboxylic acid 
methyl ester, mp 215.degree.-217.degree. C. 
1-Amino-5-chloro-3-cyano-3-phenyl-1-inden-2-carboxylic acid methyl ester, 
mp 192.degree.-194.degree. C. 
1-Amino-5-chloro-3-cyano-3-(2-fluorophenyl)-1-inden-2-carboxylic acid 
methyl ester, mp 227.degree.-228.degree. C. 
1-Amino-5-chloro-3-cyano-3-(3-fluorophenyl)-1-inden-2-carboxylic acid 
methyl ester, mp 191.degree.-193.degree. C. 
1-Amino-5-chloro-3-cyano-3-(2-methyl-4-thienyl)-1-inden-2-carboxylic acid 
methyl ester, mp 161.degree.-163.degree. C. 
1-Amino-5-chloro-3-cyano-3-(4-chlorophenyl)-1-inden-2-carboxylic acid 
methyl ester, mp 213.degree.-215.degree. C. 
1-Amino-5-chloro-3-cyano-3-(4-methylphenyl)-1-inden-2-carboxylic acid 
methyl ester, mp 228.degree.-230.degree. C. 
By the above method the following novel 2,3-dihydro-1H-inden-1-ones were 
prepared: 
3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one, 
mp105.degree.-106.degree. C. 
3-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-one, mp 
69.degree.-71.degree. C. 
5-chloro-3-phenyl-2,3-dihydro-1H-inden-1-one, mp 127.degree.-129.degree. C. 
5-chloro-3-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-one, mp 
83.degree.-85.degree. C. 
5-chloro-3-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-one, mp 
118.degree.-120.degree. C. 
3-(4-fluorophenyl)-5-methylthio-2,3-dihydro-1H-inden-1-one, mp 
74.degree.-76.degree. C. 
5-chloro-3-(2-methyl-4-thienyl)-2,3-dihydro-1H-inden-1-one, mp 
101.degree.-102.degree. C. 
5-chloro-3-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-one, mp 
140.degree.-142.degree. C. 
5-chloro-3-(4-methylphenyl)-2,3-dihydro-1H-inden-1-one, mp 
112.degree.-114.degree. C. 
As previously described (see references cited above) the 
2,3-dihydro-1H-inden-1-ones may be reduced with sodium borohydride to the 
corresponding cis-2,3-dihydro-H-inden-1-ols which serves as the starting 
materials for preparing the compounds of Formula II. The following new 
2,3-dihydro-1H-inden-1-ols were obtained: 
3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol, mp 
81.degree.-83.degree. C. 
3-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-ol, mp 
100.degree.-102.degree. C. 
5-chloro-3-phenyl-2,3-dihydro-1H-inden-1-ol, mp 110.degree.-111.degree. C. 
5-chloro-3-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-ol, mp 
78.degree.-80.degree. C. 
5-chloro-3-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-ol, mp 
110.degree.-112.degree. C. 
3-(4-fluorophenyl)-5-methylthio-2,3-dihydro-1H-inden-1-ol, mp 
114.degree.-116.degree. C. 
5-chloro-3-(2-methyl-4-thienyl)-2,3-dihydro-1H-inden-1-ol, mp 
119.degree.-121.degree. C. 
5-chloro-3-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-ol, mp 
129.degree.-131.degree. C. 
5-chloro-3-(4-methylphenyl)-2,3-dihydro-1H-inden-1-ol, mp 
107.degree.-109.degree. C.

In the following, the invention is further illustrated by way of examples 
which must in no way be construed as limiting for the invention. 
EXAMPLES 
EXAMPLE 1 
Trans 
-1-[2-[4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-11-y 
l]-1-piperazinyl]ethyl]-2-imidazolidinone, dimaleate (Compd. 1) 
A mixture of 
1-Chloro-3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden (8.5 
g) and 1-[(2-(piperazin-1-yl)ethyl]-2-imidazolidinone (20 g) in 
methylisobutylketone (250 ml) was stirred at 80.degree. C. for 18 hours. 
The reaction mixture was cooled, whereupon ether and water was added. The 
phases were separated, and the organic phase was washed with water. The 
ether phase was extracted with 1 N methane sulphonic acid. The base was 
liberated with 10 N sodium hydroxide and extracted with methylene 
chloride. The organic phase was dried (MgSO.sub.4) and evaporated in vacuo 
to give 10 g of crude 1. The crude base was dissolved in acetone and 
transformed to the maleate salt which was recrystallized from ethanol (100 
ml) to give 4.9 g of 1, as dimaleate; mp 169.degree.-171.degree. C. 
CHN calculated: 55.92%; 5.13%; 7.91%. CHN found: 55.94%; 5.02%; 7.94%. 
EXAMPLE 2 
Preparation of (+)-1 (the active enantiomer of 1) 
To a solution of 
trans-1-[3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl] 
piperazine (38 g) in ethanol (500 ml) was added a solution of 
L-(+)-tartaric acid (15 g) in water (25 ml). The mixture was left 
overnight at room temperature. The crystals were filtered and 
recrystallized from mehanol (400 ml) and water (400 ml) to give 17 g; mp 
221.degree.-223.degree. C. Optical rotation of the base: [.alpha.].sub.D 
=-3.2.degree. (c0.5, MeOH). 
The first filtrate from the L-(+)-tartrate salts was evaporated in vacuo 
and convened to the base. This base (25 g) was dissolved in methanol (400 
ml) and a solution of D-(-)tartaric acid (10 g) in water (50 ml) was 
added. The mixture was kept for 2 hours at room temperature. The crystals 
were filtered and recrystallized from methanol (250 ml) and water (250 ml) 
to give 13 g, mp 222.degree.-224.degree. C. Optical rotation of the base: 
[.alpha.].sub.D =+3.7.degree. (c0.5, MeOH). 
The D-(-)-tartrate salt was convened to the base (9.5,g) which was added to 
a mixture of 1-(2-chloroethyl)-2-imidazolidinone (9 g), potassium 
carbonate (10 g) and potassium iodide (0.5 g) in methylisobutylketone (250 
ml). The mixture was refluxed with stirring for 18 hours. The reaction 
mixture was worked up as described in Example 1, to give a crude base (15 
g). The base was converted to the dimaleate salt which was recrystallized 
three times from ethanol to give (+)-1, dimaleate salt, mp 
158.degree.-159.degree. C. [.alpha.]=+5,5.degree. (c0.5, CH.sub.3 OH). 
CHN calculated: 55.92%; 5.13%; 7.91%. CHN found: 55.92%; 5.09%; 7.95%. 
EXAMPLE 3 
Optical resolution of 
Trans-4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]-1-piperazi 
ne ethanol (Compd. 2) 
The dihydrochloride salt of Compd. 2 (11 g, c.f. U.S. Pat. No. 4,443,448) 
was converted to the base (9.5 g). A solution of the base and 
L-(+)-tartaric acid (4 g) in ethanol (250 ml) was kept at room temperature 
for 18 hours. The crystals were filtered off and dried (4.5 g), and 
recrystallized from methanol (600 ml) to give 3.2 g; mp 
216.degree.-217.degree. C.; [.alpha.].sub.D =+15.4.degree. (c0.5, DMSO). 
The L-(+)-tartrate salt was converted to the base, which was transferred 
to the dihydrochloride salt. The dihydrochloride salt was recrystallized 
from ethanol/ether to give 1 g of (+)-2, dihydrochloride; mp 
224.degree.-226.degree. C.; [.alpha.].sub.D =+27.1.degree. (c0.5, CH.sub.3 
OH). 
The first filtrate from the L-(+)-tartrate salt was evaporated and 
converted to the base. The base was converted to the D-(-)-tartaric salt 
which was recrystallized and converted to the dihydrochloride salt as 
described for (+)-2. 
0.6 g of (-)-2, dihydrochloride was obtained; mp 223.degree.-226.degree. 
C.; [.alpha.].sub.D =-2 27.1.degree. (c0.5, CH.sub.3 OH), 
Trans-4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)-1-piperazin 
e-ethanol (3, c.f. U.S. Pat. No. 4,443,448) was resolved in a similar way 
to give 
(+)-3, dihydrochloride; mp 224.degree.-227.degree. C.; [.alpha.].sub.D 
=+13.5.degree. (c0.5, H.sub.2 O) and 
(-)-3, dihydrochloride; mp 224.degree.-227.degree. C.; [.alpha.].sub.D 
=-14.1.degree. (c0.5, H.sub.2 O). 
The method described in Example was used for the preparation of the 
following compounds: 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zine-1-yl]ethyl]-2-imidazolidinone; mp 168.degree.-170.degree. C. Compd. 4. 
Trans-4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]- 
1-piperazineethanol, dimaleate; mp 172.degree.-174.degree. C. Compd. 5. 
Trans-4-[5-chloro-3-(2-methyl-4-thienyl)-2,3-dihydro-1H-inden-1-yl]-1-piper 
azineethanol, dimaleate; mp 175.degree.-177.degree. C. Compd. 6. 
Trans-1-[2-[4-[5-chloro-3-(2-methyl-4-thienyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazine-1-yl]ethyl]-2-imidazolidinone, dimaleate; mp 
174.degree.-176.degree. C. Compd. 7. 
Trans-4-[3-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-inden- 1-yl]- 
1-piperazine ethanol, dimaleate; mp 169.degree.-171.degree. C. Compd. 8. 
Trans-1-[2-[4-[3-(4-fluorophenyl)-5-methyl-2,3-dihydro-1H-inden-1-yl]pipera 
zine-1-yl]ethyl]-2-imidazolidinone, dimaleate; mp 180.degree.-181.degree. 
C. Compd. 9. 
EXAMPLE 4 
Trans-1-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden- 1-yl]piperazine, 
maleate (Compd. 10) 
Thionylchloride (44 ml) was added dropwise with water-cooling to a solution 
of 5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-ol in ether (2L) 
with a catalytic amount of DMF (0.5 ml). Then the mixture was stirred for 
2 hours at room temperature, poured into ice and neutralized with 9N NaOH. 
The organic phase was separated, dried (MgSO.sub.4) and evaporated to give 
140 g of crude 1,5-dichloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden. 
A mixture of the chloroderivative (140 g), piperazine (800 g) and acetone 
(2L) was refluxed with stirring for 18 hours. After cooling piperazine 
hydrochloride was filtered off and washed with ethyl acetate. The combined 
filtrate was concentrated in vacuo. The residue was dissolved in ether, 
washed with water and extracted with 1N methane sulphonic acid. The base 
was liberated from the acid extract with 9N sodium hydroxide, extracted 
with ether, dried (MgSO.sub.4) and evaporated in vacuo to give crude 
Compd. 10 (156 g). The residue was dissolved in acetone (600 ml) and 
ethanol (600 ml), whereupon maleic acid (110 g) was added. After 1 hour at 
room temperature the maleate salt of Compd. 10 was filtered and dried. 
Yield: 216 g; mp 190.degree.-191.degree. C. 
10 g were recrystallized from ethanol to give pure Compd. 10, maleate; mp: 
194.degree.-195.degree. C. 
CHN calculated: 61.81%; 5.42%; 6.27%. CHN found: 61.77%; 5.40%; 6.34%. 
EXAMPLE 5 
Optical resolution of Compd. 10 ((+)-10 and (-)-10) 
A solution of Compd. 10 (24 g) and (-)-dibenzoyl-L-tartaric acid hydrate 
((-)DBT) (27.3 g) in acetone (250 ml) was left for 18 hours at room 
temperature. The crystals were filtered and dried. The (-)DBT salt was 
boiled with methanol (1L), cooled, filtered and dried to give 13.5 g of 
(-)-DBT salt; mp: 213.degree.-214.degree. C. 
The first filtrate from the (-)-DBT salt was concentrated and converted to 
the base (13 g), which was treated with (+)-DBT in the same manner as 
described for the (-)-DBT salt. Yield: 11 g of (+)-DBT salt; mp: 
212.degree.-213.degree. C. 
The DBT salts were converted to the bases and then precipitated as maleate 
salts. The maleate salts were recrystallized from ethanol (200 ml) and 
methanol (50 ml) to give 
(+)-10, maleate salt; mp: 194.degree.-196.degree. C.; [.alpha.].sub.D 
=+30.6.degree. (c0.5, CH.sub.3 OH). (-)-10, maleate salt; mp: 
194.degree.-196.degree. C.; [.alpha.].sub.D =30.2.degree. (c0.5, CH.sub.3 
OH). 
EXAMPLE 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]-ethyl]-3-isopropyl-2-imidazolidinone, dimaleate (Compd. 11) 
A mixture of Compd. 10 (140 g as the maleate salt , see Example 4), 
1-(2-chloroethyl)-3-isopropyl-2-imidazolidinone (75 g), potassium 
carbonate (260 g) and potassium iodide (5 g) in methylisobutylketone (1 L) 
was refluxed with stirring for 18 hours. 
After cooling, water (500 ml) was added. The phases were separated and the 
organic layer was washed with water and then concentrated in vacuo. The 
residue was dissolved in ether, washed with water and extracted with 1N 
methane sulphonic acid. The base was liberated with 9N NaOH, extracted 
with ether, dried and concentrated in vacuo to give 157 g of crude Compd. 
11. The base was converted to the dimaleate salt in ethanol (2L) to give 
193 g of trans-isomer (11). 
A sample recrystallized from methanol melted at 188.degree.-190.degree. C. 
CHN calculated: 58.61%; 5.92%; 7.81%. CHN found: 58.78%; 5.90%; 7.88%. 
EXAMPLE 7 
Optical resolution of Compd. 11 ((+)-11 and (-)-11) 
The resolution was performed essentially as described in the Examples 2 and 
3 (using L-(+)- and D-(-)-tartaric acid) with the exception that tartrate 
salts were crystallized and recrystallized from water. From 126 g of 11 
(as the base) there was obtained 50 g of D-(-)-tartrate, mp 
102.degree.-104.degree. C., and 51 g of L-(+)-tartrate, mp 
102.degree.-104.degree. C. 
In a conventional manner the tartrate salts were converted to the maleate 
salts which were recrystallized from ethanol to give 
(+)-11, dimaleate, mp 175.degree. C., [.alpha.].sub.D =+17.0.degree. (c0.5, 
CH.sub.3 OH), and 
(-)-11, dimaleate, mp 175.degree. C., [.alpha.].sub.D =-17.5.degree. (c0.5, 
CH.sub.3 OH). 
The method described in Example 6 was used for the preparation of the 
following compounds: 
Trans-1-[2-[4-[3-(4-fluorophenyl)-5-methyl-2,3-dihydro-1-H-inden-1-yl]piper 
azin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
178.degree.-180 .degree. C. Compd. 12. 
Trans-1-[2-[4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1H-inden- 
1-yl]piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone, dimaleate; mp 
174.degree.-176.degree. C. Compd. 13. 
Trans-3-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1-H-inden-1-yl]piper 
azin-1-yl]ethyl]-2-oxazolidinone,diHCl; mp 244.degree.-246.degree. C. 
Compd. 14. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2-3-dihydro-1-H-inden-1-yl]piper 
azin-1-yl]ethyl]-2-pyrrolidinone,diHCl; mp 250.degree.-252.degree. C. 
Compd. 15. 
Trans-1-[3-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1-H-inden-1-yl]piper 
azin-1-yl]propan-1-yl]-2-imidazolidinone,dimaleate; mp 
159.degree.-160.degree. C. Compd. 16. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-phenyl-2-imidazolidinone,dimaleate; mp 
174.degree.-176.degree. C. Compd. 17. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-methyl-2-imidazolidinone:dimaleate; mp 
164.degree.-166.degree. C. Compd. 18. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-ethyl-2-imidazolidinone,dimaleate; mp 
178.degree.-180.degree. C. Compd. 19. 
Trans-1-[2-[4-[5-chloro-3-phenyl-2,3-dihydro-1H-inden-1-yl]piperazin-1-yl]e 
thyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 189.degree.-190 .degree. 
C. Compd. 20. 
Trans-1-[2-[4-[5-chloro-3-(2-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
190.degree.-192.degree. C. Compd. 21. 
Trans-1-[2-[4-[3-(4-fluorophenyl)-5-(methylthio)-2,3-dihydro-1H-inden-1-yl] 
piperazin-1-yl]ethyl]-2-imidazolidinone,dimaleate; mp 
182.degree.-184.degree. C. Compd. 22. 
Trans-1-[2-[4-[3-(4-fluorophenyl)-5-(methylthio)-2,3-dihydro-1H-inden-1-yl] 
piperazin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
186.degree.-188.degree. C. Compd. 23. 
Trans-1-[2-[4-[5-bromo-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]piperaz 
in-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
180.degree.-182.degree. C. Compd. 24. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-benzimidazolin-2-one,dimaleate; mp 192.degree.-194.degree. 
C. Compd. 25. 
Trans-1-[2-[4-[5-chloro-3-(4-methylphenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
184.degree.-186.degree. C. Compd. 26. 
Trans-1-[2-[4-[5-chloro-3-(4-chlorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
170.degree.-172.degree. C. Compd. 27. 
Trans-1-[2-[4-[5-chloro-3-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-3-isopropyl-2-imidazolidinone,dimaleate; mp 
180.degree.-182.degree. C. Compd. 28 
EXAMPLE 8 
Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]-ethyl]-2-imidazolidinthione, dimaleate (Compd. 29) 
A mixture of Compound 2 (140 g, base, c.f. U.S. Pat. No. 4,443,448), 
thionyl chloride (100 ml) and DMF (10 ml)in chloroform (2L) was refluxed 
for 2 hours. After cooling, the hydrochloride salt of the chloroethyl 
derivative of 2 was filtered, washed with ethyl acetate and dried (Yield: 
84 g). 
A mixture of 42 g of the hydrochloride salt and ethylendiamine (100 ml) in 
ethanol (500 ml) was refluxed with stirring for 3 hours. The mixture was 
concentrated in vacuo; the residue was dissolved in a mixture of methylene 
chloride and water, the organic layer was separated, washed with saturated 
NaCl solution, dried (MgSO.sub.4) and evaporated in vacuo to give 40 g of 
crude 
trans-1-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]-4-[2-[(2-a 
minoethyl)amino]ethyl]piperazine as an oil. Said ethylendiamine derivative 
was dissolved in methylene chloride, whereupon carbon disulfide (15 ml) 
was added. The mixture was kept for 1 hour at room temperature, and was 
then evaporated in vacuo. The crude dithiocarbamate salt was dissolved in 
n-pentanol and refluxed for 1 hour (evolution of hydrogen sulfide). The 
reaction mixture was concentrated in vacuo. The residue was dissolved in 
ether, extracted with 1N methanesulfonic acid, whereupon the base was 
liberated with 9N NaOH and extracted with ether. The ether solution was 
filtered through silica gel, and concentrated to yield 24 g of an oil, 
which was transformed to the dimaleate to give 29, dimaleate, mp 
172.degree.-174.degree. C. 
CHN calculated: 57.04%; 5.25%; 8.32%. CHN found: 57.30%; 5.43%; 8.17%. 
Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dimaleate. mp 
174.degree.-176.degree. C., Compd. 30 was prepared in a similar way, by 
replacing ethylendiamine with 1.3-propylendiamine. The enantiomers of this 
compound were prepared in a similar way starting from (+)-2 and (-)-2, 
respectively: 
(+)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dihydrochloride; mp 
205.degree.-206.degree. C., 26.7.degree. (c0.5, water). Compd. (+)-30. 
(-)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dihydrochloride; mp 
205.degree.-206.degree. C., [.alpha.].sub.D =-25.6.degree. (c0.5, water). 
Compd. (-)-30. 
The following compounds was prepared in a corresponding manner: 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-2-imidazolidinthione,dimaleate; mp 183.degree.-184.degree. 
C. Compd. 31. 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dimaleate; 
mp.184.degree.-185.degree. C. Compd. 32. 
(+)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dihydrochloride; mp 
212.degree.-213.degree. C., [.alpha.]D=+6.60 (c0.5, water). Compd. (+)-32. 
(-)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinethione,dihydrochloride; mp 
212.degree.-213.degree. C., [.alpha.].sub.D =-6.6.degree. (c0.5, water). 
Compd. (-)-32. 
The following compounds were also prepared as described in Example 8, 
except that the diamines were treated with urea instead of 
carbondisulfide. A mixture of the diamine and urea in NMP was heated for 4 
h at 140.degree.-160.degree. C., whereupon the reaction mixture was 
worked-up in a conventional manner. 
(+)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate; mp 
170.degree.-171.degree. C., [.alpha.].sub.D =+16.0.degree. (c0.5, water). 
Compd. (+)-33. 
(-)-Trans-1-[2-[4-[5-fluoro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate; mp 
170.degree.-171.degree. C., [.alpha.].sub.D =-15.0.degree. (c0.5, water). 
Compd. (-)-33. 
(+)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate; mp 
179.degree.-180.degree. C., [.alpha.].sub.D =+16.8.degree. (c0.5, water). 
Compd. (+)-34. 
(-)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-tetrahydro-2(1H)-pyrimidinone,dimaleate; mp 
179.degree.-180.degree. C., [.alpha.].sub.D =-17.2.degree. (c0.5, water). 
Compd. (-)-34. 
(+)-Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pi 
perazin-1-yl]ethyl]-5,5-dimethyl-tetrahydro-2(1H)-pyrimidinone,dimaleate; 
mp 166.degree.-168.degree. C., Compd. 35. 
EXAMPLE 9 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1-H-inden-1-yl]piper 
azin-1-yl]ethyl]-3-isopropyl-2-imidazolidinthione, dimaleate (Compd. 36) 
A mixture of 10 (15 g as the base), chloroacetonitrile (4.6 g) and 
potassium carbonate (10 g) in methyl ethylketone (400 ml) was refluxed 
overnight with stirring. After cooling and evaporation in vacuo the 
residue was treated with water and ether. The ether phase was dried and 
evaporated to give an oil which was chromatographed using 100 g of silica 
gel and ethyl acetate--methanol--triethylamine (80:10:10) as the mobile 
phase. Yield: 15 g, which was used without further purification. 
The acetonitrile derivative (15 g) in dry tetrahydrofurane (150 ml) was 
treated under cooling with 3 g of pelleted lithium aluminium hydride. The 
reaction mixture was refluxed for 4 hours and worked-up in a conventional 
manner to give 15 g of the; crude N-(2-aminoethyl)derivative of 10. 
Chloroacetylchloride (4.5 g) was added at 10.degree.-15.degree. C. to a 
stirred mixture of the aminoethyl derivative (15 g) and triethylamine (15 
g) in trichloroethane. The mixture was stirred for 1 hour, whereupon 
isopropylamine (25 ml) was added. The reaction mixture was refluxed for 5 
hours and was then treated with water. The organic phase was evaporated, 
and the resulting oil was dissolved in dry tetrahydrofurane (250 ml) and 
was then treated with 4 g of pelleted lithium aluminium hydride. After 2 
hours' reflux the reaction mixture was worked-up in a conventional manner 
to give 11 g of crude trans-1 
-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]-4-[2-[(2-isopropy 
laminoethyl)amino]ethyl]piperazine, which was used without further 
purification in the final step: 
Thiophosgene (2.8 g=1.9 ml) was added dropwise at 5.degree. C. to a mixture 
of the crude product mentioned above (11 g) and triethylamine (2.8 g) in 
trichloroethane. The resulting mixture was stirred at room temperature for 
15 min. and was then refluxed for 2 hours. After evaporation in vacuo the 
product was purified by extraction with 1N methanesulfonic acid followed 
by liberation of the base with 9N sodium hydroxide as described in Example 
8. The resulting oil was purified by column chromatography using silica 
gel and acetone-toluene -isopropylamine--ammonium hydroxide (60:40:2:2) as 
a mobile phase. There was obtained 1.1 g of a base, which was transformed 
to the dimaleate salt. This salt was recrystallized twice from 
acetone/ether to give 0.4 g of 36, dimaleate, mp: 156.degree.-159.degree. 
C. 
CHN calculated: 57.32%; 5.78%; 7.64%. CHN found: 57.33%; 5.76%; 7.17%. 
EXAMPLE 10 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl)-2,3-dihydro-1H-inden-1-yl]pipera 
zin-1-yl]-ethyl]-3-(2-hydroxyethyl)-2-imidazolidinone, dimaleate, (Compd, 
37) 
Compound 4 (4,4 g as the base) was added to a suspension of potassium 
tertbutoxide (1.7 g) in dry toluene (200 ml). The mixture was kept at room 
temperature for 1 hour with stirring, whereupon ethylbromoacetate (2.5 g) 
was added. The; mixture was stirred for 1 hour at room temperature and was 
then poured into ice, The organic phase was separated, washed with water, 
dried and evaporated in vacuo. The resulting oil was dissolved in dry 
tetrahydrofurane (150 ml) whereupon lithium borohydride (1 g) was added. 
The mixture was stirred for 1 hour at room temperature and was then 
evaporated in vacuo. The residue was treated with ether and 1N 
methanesulfonic acid. The acid phase was basified with 9N sodium hydroxide 
and extracted with methylene chloride. After drying and evaporation in 
vacuo there was obtained 2.5 g of 37, which was converted to the maleate 
salt (in acetone). The salt was recrystallized from ethanol-methanol to 
give 1.4 pure 37, mp: 168.degree.-170.degree. C. 
CHN calculated: 56.78%; 5.61%; 7.79%. CHN found: 56.45%; 5,62%; 7.83% 
EXAMPLE 11 
Trans-1-[2-[4-[5-chloro-3-(4-fluorophenyl-2,3-dihydro-1H-inden-1-yl]piperaz 
in-1-yl]-ethyl]-2-pyrrolidinthione, dimaleate, (Compd. 38) 
A mixture of Compound 15 (15 g) and Lawesson's reagent (5 g) in 
hexamethylphosphonic triamide (HMPA, 50 ml) was heated at 100.degree. C. 
in a N.sub.2 -atmosphere for 1.5 hours. The reaction mixture was poured 
into water, treated with 9N sodium hydroxide (25 ml) and extracted with 
ether. The etherphase was extracted with 1N methane sulphonic acid, 
whereupon the base was liberated with 9N sodium hydroxide and again 
extracted with ether. The organic phase was evaporated to give 3.5 g of an 
oil, which was transformed to the dimaleate salt. This salt was 
recrystallized from ethanol (200 ml) to give 38, mp: 
192.degree.-1930.degree. C. 
CHN calculated: 57.42%; 5.41%; 6.09%. CHN found: 57.50%; 5.49%; 6.17%. 
PHARMACOLOGICAL TESTS 
The compounds of the invention were tested in well recognized and reliable 
methods. The tests were as follows, and the results are given in the 
following Table I. The well-known 5-HT.sub.2 antagonists, ritanserin 
tefludazine and irindalone, and the corresponding analogues of Compounds 
1, 9 and 4, respectively, substituted in the 6-position of the indane ring 
system in stead of the 5-position, i.e. compounds Nos. 39, 40 and 41, were 
included in the tests for comparison purposes. The results of the tests 
are shown in the Table 1. 
INHIBITION OF .sup.3 H-KETANSERIN BINDING TO 5-HT.sub.2 RECEPTORS IN RAT 
CORTEX IN VITRO 
By this method the inhibition by drugs of the binding of .sup.3 
H-Ketanserin (0,5 nM) to Serotonin S.sub.2 (5-HT.sub.2) receptors in 
membranes from rat is determined in vitro. Method in Hyttel, Pharmacology 
& Toxicology, 61, 126-129, 1987. 
Procedure 
Male Wistar (Mol:Wist) rats (125-250 g) are sacrificed and cortical tissue 
is dissected and weighed. The tissue is homogenized (Ultra Turrax, 10 
sec.) in 10 ml of ice-cold 50 mM tris buffer pH 7.7 (at 25.degree. C.). 
The centrifuge glassware used in this step has been rinsed by sonication 
for 10 min. in ethanol. The homogenate is centrifuged twice at 20,000 g 
for 10 min. at 4.degree. C. with rehomogenization of the pellet in 10 ml 
ice-cold buffer. The final pellet is homogenized in 500 vol (w/v) ice-cold 
buffer. 
Incubation tubes kept on ice in triplicate receive 100 .mu.l of drug 
solution in water (or water for total binding) and 2000 .mu.l of tissue 
suspension (final tissue content corresponds to 4 mg original tissue). The 
binding experiment is initiated by addition of 100 .mu.l of .sup.3 
H-Ketanserin (final concentration 0.5 nM) and by placing the tubes in a 
37.degree. C. water bath. After incubation for 30 min. the samples are 
filtered under vacuum (0-50 mBar) through Whatman GF/F filters (25 mm). 
The tubes are rinsed with 5 ml ice-cold buffer which are then poured on 
the filters. Thereafter, the filters are washed with 2.times.5 ml of 
buffer. The filters are placed in counting vials and 4 ml of appropriate 
scintillation fluid (e.g. Picofluor.TM.15) are added. After shaking for 1 
h and storage 2 hrs in the dark the content of radioactivity is determined 
by liquid scintillation counting. Specific binding is obtained by 
subtracting the nonspecific binding in the presence of 1 .mu.M mianserin. 
For determination of the inhibition of binding five concentrations of drugs 
covering 3 decades are used. 
The measured cpm are plotted against drug concentration on semilogarithmic 
paper and the best fitting S-shaped curve is drawn. The IC.sub.50 value is 
determined as the concentration at which the binding is 50% of the total 
binding in control samples minus the nonspecific binding in the presence 
of 1 .mu.M mianserin. 
.sup.3 H-Ketanserin=[ethylene-.sup.3 H]-Ketanserin hydrochloride from New 
England Nuclear, specific activity 60-80 Ci/mmol). 
INHIBITION OF .sup.3 H-SPIPERONE BINDING TO DOPAMINE D-2 RECEPTORS IN RAT 
CORPUS STRIATUM IN VITRO 
By this method the inhibition by drugs of the binding of .sup.3 H-spiperone 
(0.5 nM) to dopamine D-2 receptors in membranes from rat corpus striatum 
is determined in vitro. Method and results in Hyttel & Larsen, J. 
Neurochem, 44, 1615-1622, 1985). 
Procedure 
Male Wistar (Mol:Wistar) rats (125-250 g) are sacrificed and striatal 
tissue is dissected and weighed. The tissue is homogenized (Ultra Turrax, 
10 sec.) in 10 ml of ice-cold 50 mM K-phosphate buffer pH 7.4 (at 
25.degree. C.). The homogenate is centrifuged twice at 20,000 g for 10 
min. at 4.degree. C. with rehomogenization of the pellet in 10 ml ice-cold 
buffer. The final pellet is homogenized in 1300 vol (w/v) ice-cold buffer. 
Incubation tubes kept on ice in triplicate receive 100 .mu.l of drug 
solution in water (or water for total binding) and 4000 .mu.l of tissue 
suspension (final tissue content corresponds to 3.08 mg original tissue). 
The binding experimental is initiated by addition of 100 .mu.l of .sup.3 
H-spiperone (final concentration 0.5 nM) and by placing the tubes in a 
37.degree. C. water bath. After incubation for 10 min. the samples are 
filtered under vacuum (0-50 mBar) through Whatman GF/F filters (25 mm). 
The tubes are rinsed with 5 ml ice-cold buffer which are then poured on 
the filters. Thereafter, the filters are washed with 2.times.5 ml of 
buffer. The filters are placed in counting vials and 4 ml of appropriate 
scintillation fluid (e.g. Picofluor .TM.15) are added. After shaking for 1 
h and storage 2 hrs in the dark the content of radioactivity is determined 
by liquid scintillation counting. Specific binding is obtained by 
subtracting the nonspecific binding in the presence of 10 .mu.M of 
6,7-ADTN. 
For determination of the inhibition of binding five concentrations of drugs 
covering 3 decades are used. 
The measured cpm are plotted against drug concentration on semilogarithmic 
paper and the best fitting S-shaped curve is drawn. The IC.sub.50 value is 
determined as the concentration at which the binding is 50% of the total 
binding in control samples minus the nonspecific binding in the presence 
of 10 .mu.M of 6,7-ADTN. 
.sup.3 H-Spiperone=[phenyl-4-.sup.3 H]-spiperone from Amersham 
International plc. England, specific activity 15-25 Ci/mmol. 
INHIBITION OF .sup.3 H-PRAZOSIN BINDING TO .alpha..sub.1 ADRENOCEPTORS IN 
RAT BRAIN IN VITRO 
By this method the inhibition of the binding of .sup.3 H-Prazosin (0.25 nM) 
to .alpha..sub.1 adrenoceptors in membranes from rat brain is determined 
in vitro. Method and results in Hyttel & Larsen, J. Neurochem, 44, 
1615-1622, 1985; Skarsfeldt & Hyttel, Eur. J. Pharmacol. 125, 323-340, 
1986. 
Procedure 
Male Wistar (Mol:Wist) rats (125-200 g) are sacrificed and brain tissue is 
dissected and weighed. The tissue is homogenized (Ultra Turrax, 10 sec.) 
in 10 ml of ice-cold 50 nM Tris buffer pH 7,7 (at 25.degree. C.). The 
homogenate is centrifuged twice at 20,000 g for 10 min. at 4.degree. C. 
with rehomogenization of the pellet in 10 ml ice-cold buffer. The final 
pellet is homogenized in 400 vol (w/v) ice-cold buffer. 
Incubation tubes kept on ice in triplicate receive 100 .mu.l of drug 
solution in water (or water for total binding) and 4000.mu.l of tissue 
suspension (final tissue content corresponds to 10 mg original tissue). 
The binding experiment is initiated by addition of 100 .mu.l of .sup.3 
H-Prazosin (final concentration 0.25 nM) and by placing the tubes in a 
25.degree. C. water bath. After incubation for 20 min. the samples are 
filtered under vacuum (0-50 mBar) through Whatman GF/F filters (25 mm). 
The tubes are rinsed with 5 ml ice-cold buffer which then are poured on 
the filters. Thereafter, the filters are washed with 5 ml of buffer. The 
filters are placed in counting vials and 4 ml of appropriate scintillation 
fluid (e.g. Picofluor.TM.15) are added. After shaking for 1 h and storage 
2 hrs in the dark the content of radioactivity is determined by liquid 
scintillation counting. Specific binding is obtained by subtracting the 
nonspecific binding in the presence of 1 .mu.M of Prazosin. 
For determination of the inhibition of binding five concentrations of drugs 
covering 3 decades are used. 
The measured cpm are plotted against drug concentration on semilogarithmic 
paper and the best fitting S-shaped curve is drawn. The IC.sub.50 value is 
determined as the concentration at which the binding is 50% of the total 
binding in control samples minus the nonspecific binding in the presence 
of 1 .mu.M of Prazosin. 
.sup.3 H-Prazosin=[furoyl-5-.sup.3 H]-Prazosin from New England Nuclear, 
specific activity approximately 20 Ci/mmol. 
TABLE 1 
______________________________________ 
Receptor Binding; IC.sub.50 (nM) 
5-HT.sub.2 DA D-2 .alpha..sub.1 
Compound No. 
.sup.3 H-Ket 
.sup.3 H-Spi 
.sup.3 H-Praz 
______________________________________ 
1 2.9 760 320 
(+)-1 2.0 290 330 
2 21 1100 150 
(+)-2 12 330 72 
(-)-2 500 22000 1100 
3 25 2200 230 
(-)-3 11 370 210 
(+)-3 230 6300 2500 
4 2.9 360 200 
5 8.9 1300 380 
6 56 2600 1000 
7 7.9 2800 240 
8 12 1000 270 
9 3.7 370 220 
10 11 2500 840 
(-)-10 15 730 390 
(+)-10 3300 28000 
11 3.9 280 260 
(+)-11 75 1300 340 
(-)-11 1.1 200 210 
12 3.0 450 120 
13 3.7 510 350 
14 23 550 140 
15 10 500 370 
16 10 160 73 
17 44 300 310 
18 2.8 190 600 
19 2.6 260 240 
20 9.9 750 510 
21 3.5 920 670 
22 3.5 1100 240 
23 4.0 720 250 
24 6.4 240 270 
25 5.6 110 66 
26 11 450 60 
27 15 280 180 
28 26 490 970 
29 1.5 230 110 
30 1.7 220 110 
(+)-30 0.95 140 43 
(-)-30 42 2900 
31 1.5 67 52 
32 1.5 93 170 
(+)-32 21 490 350 
(-)-32 0.75 33 67 
(+)-33 1.1 280 41 
(-)-33 57 4600 
(+)-34 120 1700 
(-)-34 1.3 94 62 
35 4.8 150 120 
36 3.6 260 69 
37 6.1 320 710 
38 5.3 290 260 
Tefludazine 4.6 10 17 
Irindalon 3.4 400 16 
Ritanserin 0.40 12 47 
39 21 8.3 
40 0.71 43 12 
41 17 3.1 
______________________________________ 
QUIPAZINE INHIBITION 
Quipazine is a 5-HT.sub.2 agonist, which induces head twitches in rats. The 
test is an in vivo test for 5-HT.sub.2 -antagonistic effect testing the 
ability to inhibit head twitches. The method and test results for some 
reference substances are published by Arnt et al. (Drug Development 
Research, 16, 59-70, 1989). 
In this test the compounds showed effects with ED.sub.50 values down to 
0.01 mg/kg. 
LIGHT/DARK DISCRIMATION TEST IN MICE 
This test was carried out in accordance with the method described in 
Costall et al. Br. J. Pharmacol. 90 275P (1987). 
The test was conducted using a two compartment activity box in which the 
actions of anxiolytic compounds to reduce aversion against a brightly-lit 
environment may be readily detected. The box is designed as an open-top 
experimental box (45*27*27 cm) one third of which was partitioned from the 
rest, painted black and illuminated with red light. The remainder of the 
box was painted white and brightly illuminated (1000 W). The floor of each 
area was lined into squares. Behavioral changes were determined for each 
area from video recordings for periods of 40 min. 
Data obtained from dose groups of 5 animals (male albino BKW mice, 25-30 g) 
were analysed using single factor analysis of variance, and Dunnett's 
t-test. Test compounds were given intraperitoneally 45 min before testing. 
In this test model Compounds (+)-30, (-)-32 and (+)-33 showed significant 
anxiolytic activity (p&lt;0.05) in doses from 0.01 to 1 mg/kg. 
LIGHT/DARK DISCRIMINATION TEST IN RATS 
The test was carried out similarly to the test in mice described above, 
however modified in accordance with F. C. Colpaert et al., 
Psychopharmacology (1985) 86:45-54. The test used Wistar WU rats. In this 
test model Compounds (-)-32 and (+)-33 showed significant anxiolytic 
activity (p&lt;0.05) in doses from 0.1 to 1 mg/kg. 
All the compounds except the weak or inactive stereoisomers of Compd. 2, 3, 
10, 11, 30, 32, 33, and 34 show high affinity to 5-HT.sub.2 receptors and 
have much lower affinity to D-2 receptors and .alpha..sub.1 adrenoceptors 
than the prior art compounds included in the tests for comparison 
purposes. Tefludazine, a 6-substituted 1-piperazino-3-phenylindan 
derivative representative for U. S. Pat. No. 4,443,448, shows high 
affinity to all three receptor types whereas irindalone, a 
1-piperazino-3-(fluorophenyl)indan derivative representative for U.S. Pat. 
No. 4,684,650, in addition to a high affinity to 5-HT.sub.2 receptors has 
a significant affinity to oh adrenoceptors. The dramatic effect of the 
change from 6- to 5-substitution is illustrated by comparison of the 
receptor profiles of the 6-substituted derivatives 39, 40 and 41 with 
their otherwise identical 5-substituted analouges 1, 9 and 4. 
FORMULATION EXAMPLES 
The pharmaceutical formulations of the invention may be prepared by 
conventional methods in the art. For example: Tablets may be prepared by 
mixing the active ingredient with ordinary adjuvants and/or diluents and 
subsequently compressing the mixture in a conventional tabletting machine. 
Examples of adjuvants or diluents comprise: corn starch, potato starch, 
talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any 
other adjuvants or additives usually used for such purposes such as 
colourings, flavourings, preservatives etc. may be used provided that they 
are compatible with the active ingredients. Solutions for injections may 
be prepared by dissolving the active ingredient and possible additives in 
a part of the solvent for injection, preferably sterile water, adjusting 
the solution to desired volume, sterilization of the solution and filling 
in suitable ampules or vials. Any suitable additive conventionally used in 
the art may be added, such as tonicity agents, preservatives, 
antioxidants, etc. 
Typical examples of recipes for the formulation of the invention are as 
follows: 
1) Tablets containing 5 milligrams of Compound 4c calculated as the free 
base: 
______________________________________ 
Comp. (+)-33 5 mg 
Lactose 18 mg 
Potato starch 27 mg 
Sucrose 58 mg 
Sorbitol 3 mg 
Talcum 5 mg 
Gelatine 2 mg 
Povidone 1 mg 
Magnesium stearate 0.5 mg 
______________________________________ 
2) Tablets containing 50 milligrams of Compound 4b calculated as the free 
base: 
______________________________________ 
Comp. (+)-30 50 mg 
Lactose 16 mg 
Potato starch 45 mg 
Sucrose 106 mg 
Sorbitol 6 mg 
Talcum 9 mg 
Gelatine 4 mg 
Povidone 3 mg 
Magnesium stearate 0.6 mg 
______________________________________ 
3) Syrup containing per milliliter: 
______________________________________ 
Comp. (-)-32 10 mg 
Sorbitol 500 mg 
Tragacanth 7 mg 
Glycerol 50 mg 
Methyl-paraben 1 mg 
Propyl-paraben 0.1 mg 
Ethanol 0.005 ml 
Water ad 1 ml 
______________________________________ 
4) Solution for injection containing per milliliter: 
______________________________________ 
Comp. (-)-34 50 mg 
Acetic acid 17.9 mg 
Sterile water ad 1 ml 
______________________________________ 
5) Solution for injection containing per milliliter: 
______________________________________ 
Comp. (-)-11 10 mg 
Sorbitol 42.9 mg 
Acetic acid 0.63 mg 
Sodium hydroxide 22 mg 
Sterile water ad 1 ml 
______________________________________