This invention relates to 3-[1-thiazolidinylbutyl-4-piperazinyl]-1H-indazoles of the formula ##STR1## where R.sub.1 and R.sub.2 are each independently hydrogen or loweralkyl or R.sub.1 and R.sub.2 taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane or cycloheptane ring; R.sub.3 and R.sub.4 are independently hydrogen or loweralkyl or R.sub.3 and R.sub.4 taken together with the carbon atom to which they are attached form a cyclopentane, cyclohexane or cycloheptane ring; R.sub.5 is hydrogen, loweralkyl, alkanoyl or aroyl; X is hydrogen, halogen, loweralkyl or alkoxy; m is an integer of 1 to 3, the pharmaceutically acceptable acid addition salts thereof and where applicable, the optical, geometrical and stereoisomers and racemic mixtures thereof. The compounds of this invention are useful as antipsychotic agents.

This invention relates to compounds of the formula 
##STR2## 
where R.sub.1 and R.sub.2 are each independently hydrogen or loweralkyl or 
R.sub.1 and R.sub.2 taken together with the carbon atom to which they are 
attached form a cyclopentane, cyclohexane or cycloheptane ring; R.sub.3 
and R.sub.4 are independently hydrogen or loweralkyl or R.sub.3 and 
R.sub.4 taken together with the carbon atom to which they are attached 
form a cyclopentane, cyclohexane or cycloheptane ring; R.sub.5 is 
hydrogen, loweralkyl, alkanoyl or aroyl; X is hydrogen, halogen, 
loweralkyl or alkoxy; m is an integer of 1 to 3, the pharmaceutically 
acceptable acid addition salts thereof and where applicable, the optical, 
geometrical and stereoisomers and racemic mixtures thereof. The compounds 
of this invention are useful as antipsychotic agents. 
Preferred embodiments of the invention are those of Compound I where 
R.sub.1 and R.sub.2 taken together with the carbon atom to which they are 
attached form a cycloalkyl ring; X is fluorine and R.sub.5 is hydrogen. 
Throughout the specification and appended claims, a given chemical formula 
or name shall encompass all geometric, optical and stereoisomers thereof 
and racemic mixtures where such isomers and mixtures exist. 
In the above definitions, the term "lower" means the group it is describing 
contains from 1 to 6 carbon atoms. The term "alkyl" refers to a straight 
or branched chain hydrocarbon containing no unsaturation, e.g., methyl, 
ethyl, isopropyl, t-butyl, neopentyl, n-hexyl, etc.; the term "alkoxy" 
refers to a monovalent substituent which consists of an alkyl group linked 
through an ether oxygen having its free valence bond from the ether 
oxygen, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, etc.; the term 
alkanoyl refers to a substituent having the formula 
##STR3## 
where alkyl is as previously defined e.g., acetyl, etc.; the term aroyl 
refers to a substituent having the formula 
##STR4## 
e.g. benzoyl, naphthoyl, etc., where aryl is a group of the formula 
##STR5## 
where Z is hydrogen, halogen, loweralkyl, loweralkoxy, trifluoromethyl, 
nitro and amino, and n is an integer of 1 to 3, e.g., phenyl, o-tolyl, 
m-methoxyphenyl, etc.; the term "halogen" refers to a member of the 
halogen family consisting of fluorine, chlorine, bromine and iodine. 
The compounds of the present invention are prepared in the following 
manner: 
Compound II of the formula 
##STR6## 
is reacted with Compound III of the formula 
##STR7## 
to afford Compound I of the invention of the formula 
##STR8## 
The above reaction is typically conducted in the presence of a suitable 
medium such as dimethylformamide or acetonitrile, an acid scavenger such 
as potassium carbonate or sodium carbonate and a catalytic amount of 
potassium iodide or sodium iodide at a temperature of about 25.degree. to 
120.degree. C. 
To prepare Compound I where R.sub.5 =loweralkyl, Compound I, where R.sub.5 
is hydrogen, is reacted with NaH or other suitable alkylating agent in a 
suitable medium such as dimethylformamide or acetonitrile at a temperature 
of 60.degree. to 85.degree. C. 
Compound II is typically prepared as follows. A compound of the formula 
##STR9## 
is reacted with 1,4-dibromobutane to afford Compound II. This reaction is 
typically conducted in the presence of a suitable medium such as 
dimethylformamide or tetrahydrofuran and a base such as potassium 
hydroxide, sodium hydroxide or sodium hydride at a temperature of about 
23.degree. to 70.degree. C. 
Compound III is prepared as disclosed in pending U.S. application Ser. No. 
405,161, filed Sept. 11, 1989. 
One can obtain Compound IV of the formula 
##STR10## 
where the divalent group--R--plus the spiro carbon as combined constitutes 
a cyclopentane, cyclohexane or cycloheptane ring, in the following manner. 
3-(4-bromobutyl)-4-thiazolidinone of the formula 
##STR11## 
where R.sub.1 and R.sub.2 are hydrogen is reacted with lithium bis 
(trimethylsilyl)amide and Compound V of the formula 
EQU Hal--R.sub.6 --Hal (V) 
where R.sub.6 is loweralkyl and Hal is Br or I, in a suitable medium such 
as tetrahydrofuran and at a low temperature such as -75.degree. to 
-50.degree. C., to afford compound IV. 
##STR12## 
Similarly, if one uses a monobromide or monoiodide of the formula R.sub.6 
--Hal in place of Compound V, one can obtain compound VI and/or Compound 
VII. 
If one desires to obtain Compound VI of the formula 
##STR13## 
as the predominant product, it is preferable to adjust the molar ratio 
between R.sub.6 --Hal, Compound IIa of the formula 
##STR14## 
and lithium bis(trimethylsilyl)amide to about 1:1; whereas if one desires 
to obtain compound VII of the formula 
##STR15## 
as the predominant product, it is preferable to adjust the molar ratio to 
about 1:2. 
The compounds of the present invention are potentially useful as 
antipsychotic agents as determined in the Climbing Mouse Assay (CMA). 
The Climbing Mouse Assay is described by P. Protais, et al., 
Psychopharmacol., 50, 1 (1976) and B. Costall, Eur. J. Pharmacol., 50, 39 
(1978). 
The subject CK-1 male mice (23-27 grams) are group-housed under standard 
laboratory conditions. The mice are individually placed in wire mesh stick 
cages (4".times.4" by 10") and are allowed one hour for adaptation and 
exploration of the new environment. The apomorphine is injected 
subcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for 
30 minutes. Compounds to be tested for antipsychotic activity are injected 
intraperitoneally (i.p.) 30 minutes prior to the apomorphine challenge at 
a screening dose of 10 mg/kg. 
For evaluation of climbing, 3 readings are taken at 10, 20 and 30 minutes 
after apomorphine administration according to the following scale: 
______________________________________ 
Climbing Behavior 
Mice with: Score 
______________________________________ 
4 paws on bottom (no climbing) 
0 
2 paws on the wall (rearing) 
1 
4 paws on the wall (full climb) 
2 
______________________________________ 
Mice consistently climbing before the injection of apomorphine are 
discarded. 
With full-developed apomorphine climbing, the animals are hanging onto the 
cage walls, rather motionless, over longer periods of time. By contrast, 
climbs due to mere motion stimulation usually last only a few seconds. 
The climbing scores are individually totaled (maximum score: 6 per mouse 
over 3 readings) and the total score of the control group (vehicle 
intraperitoneally; apomorphine subcutaneously) is set to 100%. ED.sub.50 
values with 95% confidence limits, calculated by linear regression 
analyses of some of the compounds of this invention are presented in Table 
1. 
TABLE 1 
______________________________________ 
Climbing Mice 
Assay 
Compound ED.sub.50, Mg/kg 
______________________________________ 
3-(4-(1-[1H-Indazol-3-yl]-4-piperizinyl)- 
1.3 i.p. 
butyl)-5,5-dimethyl-4-thiazolidine 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)- 
1.3 i.p. 
butyl)-1-thia-3-azaspiro[4.4]nonan-4-one 
2.7 p.o. 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)- 
0.65 i.p. 
butyl)-1-thia-3-azaspiro[4.5]decan-4-one 
3-(4-[1-(6-Fluoro-1H-indazol-3-yl)-4- 
0.11 i.p. 
piperazinyl]butyl)-5-methyl-4-thazolidinone 
3-(4-[1-(6-Fluoro-1H-indzol-3-yl)-4- 
0.04 i.p. 
piperazinyl]butyl)-1-thia-3- 
0.67 p.o. 
azaspiro[4.5]decan-4-one 
Clozapine (standard) 8.1 i.p. 
Sulpiride (standard) 14.5 i.p. 
______________________________________ 
Antipsychotic response is achieved when the compounds of this invention are 
administered to a subject requiring such treatment at an effective oral, 
parenteral or intravenous dose of from 0.01 to 50 mg/kg of body weight per 
day. A particularly preferred effective amount is about 25 mg/kg of body 
weight per day. It is to be understood, however, that for any particular 
subject, specific dosage regimens should be adjusted according to the 
individual need and the professional judgment of the person administering 
or supervising the administration of the aforesaid compound. It is to be 
further understood that the dosages set forth herein are exemplary only 
and they do not to any extent, limit the scope of the invention. 
Effective amounts of the present invention may be administered to a subject 
by any one of various methods, for example, orally as in capsules or 
tablets, parenterally in the form of sterile solutions or suspensions, and 
in some cases intravenously in the form of sterile solutions. The 
compounds of the present invention, while effective themselves, may be 
formulated and administered in the form of their pharmaceutically 
acceptable addition salts for purposes of stability, convenience or 
crystallization, increased solubility and the like. 
Preferred pharmaceutically acceptable addition salts include salts of 
inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, 
phosphoric and perchloric acids; as well as organic acids such as 
tartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids. 
The active compounds of the present invention may be administered orally, 
for example, with an inert diluent or with an edible carrier. They may be 
enclosed in gelatin capsules or compressed into tablets. For the purpose 
of oral therapeutic administration, the compounds may be incorporated with 
excipients and used in the form of tablets, troches, capsules, elixirs, 
suspensions, syrups, wafers, chewing gums and the like. These preparations 
should contain at least 0.5% of active compound, but may be varied 
depending upon the particular form and may conveniently be between 4% to 
about 75% of the weight of the unit. The amount of compound present in 
such composition is such that a suitable dosage will be obtained. 
Preferred compositions and preparations according to the present invention 
are prepared so that an oral dosage unit form contains between 1.0-300 mgs 
of active compound. 
The tablets, pills, capsules, troches and the like may also contain the 
following ingredients: a binder such as microcrystalline cellulose, gum 
tragacanth or gelatin; an excipient such as starch or lactose, a 
disintegrating agent such as alginic acid, Primogel.RTM., corn starch and 
the like; a lubricant such as magnesium stearate or Sterotex.RTM.; a 
glidant such as colloidal silicon dioxide; and a sweetening agent such as 
sucrose or saccharin or a flavoring agent such as peppermint, methyl 
salicylate, or orange flavoring may be added. When the dosage unit form is 
a capsule, it may contain, in addition to materials of the above type, a 
liquid carrier such as fatty oil. Other dosage unit forms may contain 
other various materials which modify the physical form of the doseage 
unit, for example, as coatings. Thus tablets or pills may be coated with 
sugar, shellac, or other enteric coating agents. A syrup may contain, in 
addition to the active compounds, sucrose as a sweetening agent and 
certain preservatives, dyes and colorings and flavors. Materials used in 
preparing these various compositions should be pharmaceutically pure and 
non-toxic in the amounts used. 
For the purpose of parenteral therapeutic administration, the active 
compounds of the invention may be incorporated into a solution or 
suspension. These preparations should contain at least 0.1% of the 
aforesaid compound, but may be varied between 0.5 and about 30% of the 
weight thereof. The amount of active compound in such compositions is such 
that a suitable dosage will be obtained. Preferred compositions and 
preparations according to the present invention are prepared so that a 
parenteral dosage unit contains between 0.5 to 100 mgs of active compound. 
The solutions or suspensions may also include the following components; a 
sterile diluent such as water for injection, saline solution, fixed oils, 
polyethylene glycols, glycerine, propylene glycol or other synthetic 
solvents; antibacterial agents such as benzyl alcohol or methyl parabens; 
antioxidants such as ascorbic acid or sodium bisulfite; chelating agents 
such as ethylenediaminetetraacetic acid; buffers such as acetates, 
citrates or phosphates and agents for the adjustment of tonicity such as 
sodium chloride or dextrose. The parenteral preparation can be enclosed in 
ampules, disposable syringes or multiple dose vials made of glass or 
plastic. 
Examples of the compounds of this invention include: 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-2,5,5-trimethyl-4-t 
hiazolidinone; 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-2,2,5,5-tetramethyl 
-4-thiazolidinone; 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-2-methyl-1-thia-3-a 
zaspiro[4.4]nonan-4-one; 
3-(4-(1H-indazol-3-yl)-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.5] 
decan-4-one; 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-2-methyl-1-thia-3-a 
zaspiro[4.5]decan-4-one; 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-2,2-dimethyl-1-thia 
-3-azaspiro[4.5]decan-4-one; 
3-(4-[1-acetyl-1H-indazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4-thiazolidin 
one; 
3-(4-[1-(1-acetyl-6-fluoro-1H-indazol-3-yl)-4-piperazinyl]butyl)-1-thia-3-a 
zaspiro[4.5]decan-4-one; 
3-(4-(1-[1-acetyl-6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-5-methyl-4 
-thiazolidinone; 
3-(4-(1-[1-benzoyl-6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-5-methyl- 
4-thiazolidinone; 
3-(4-(1-[1-benzoyl-6-fluoro-1H-indazol-3-yl]-4-piperazinyl)butyl)-1-thia-3- 
azaspiro[4.5]decan-4-one.

The following examples are for illustrative purposes only and are not to be 
construed as limiting the invention. All temperatures are given in degrees 
centigrade (.degree.C.). 
EXAMPLE 1 
a. 3-(4-bromobutyl)-4-thiazolidinone 
A mixture of 4-oxothiazolidine (25 g,) dimethylformamide (500 ml), and KOH 
(27.16 g) was stirred under N.sub.2 at room temperature for 1.5 hours. To 
the resulting mixture was added 1,4-dibromobutane (101 ml) and stirring 
was continued at room temperature for 44 hours. The reaction mixture was 
poured into H.sub.2 O (1000 ml) and the aqueous mixture was extracted 
three times with 300 ml portions of ethyl acetate. The combined extracts 
were washed with H.sub.2 O (300 ml) and brine (300 ml), dried over 
Na.sub.2 SO.sub.4, and concentrated in vacuo to an oil. HPLC of a 44.95 g 
aliquot yielded 7.15 g of an oil which upon distillation yielded a clear 
liquid, b.p. 134.degree.-137.degree. C/0.12 mmHg. 
Analysis: Calculated for C.sub.7 H.sub.12 BrNOS: 35.30% C; 5.08% H; 5.88% 
N. Found: 35.24% C; 5.09% H; 5.83% N. 
b. 3-(4-Bromobutyl)-5-methyl-4-thiazolidinone 
To a -74.degree. C. solution of 3-(4-bromobutyl)-4-thiazolidinone (5.20 g) 
and tetrahydrofuran (70 ml) under nitrogen was rapidly added lithium 
bis(trimethylsilyl)amide (0.023 mol) in tetrahydrofuran (23 ml) followed 
immediately by methyl iodide (7.74 g). The resulting solution was stirred 
for 20 min (cooled by the CO.sub.2 /isopropanol bath), allowed to warm to 
-40.degree. C., and acidified with 1N HCl (200 ml). The resulting aqueous 
mixture was extracted three times with 100 ml portions of 25% 
benzene/ether. The combined extracts were washed with brine (200 ml), 
dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to a liquid which was 
chromatographed on silica gel, eluting with 45% ethyl acetate in hexanes, 
yielding 3.84 g of an oil. The oil was distilled to give 2.60 g of 
3-(4-bromobutyl)-5-methyl-4-thiazolidinone, b.p. 123.degree.-125.degree. 
C. at 0.20 mm Hg. 
Analysis: Calculated for C.sub.8 H.sub.14 BrNOS: 38.10% C; 5.60% H; 5.55% 
N. Found: 38.12% C; 5.58% H; 5.48% N. 
EXAMPLE 2 
a. 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone 
To a -73.degree. C. solution of 3-(4-bromobutyl)-2-methyl-4-thiazolidinone 
(6.00 g), methyl iodide (10.99 g), and tetrahydrofuran (50 ml) under 
nitrogen was added lithium bis(trimethylsilyl)amide (0.0500 mol) in 
tetrahydrofuran (50 ml) at a rate to maintain the internal temperature at 
less than -55.degree. C. The resulting solution was stirred at less than 
-55.degree. C. for 10 min, allowed to warm to -40.degree. C. at which 
temperature 1N HCl (250 ml) was added. The aqueous mixture was extracted 
three times with 125 ml portions of 25% benzene/ether. The combined 
extracts were washed with brine (200 ml), dried (Na.sub.2 SO.sub.4), and 
concentrated to a liquid which was chromatographed on silica gel (345 g), 
eluting with a 35-65% gradient of ethyl acetate in hexanes, yielding 5.07 
g of a liquid. The liquid was distilled to give 3.80 g of 
3-(4-bromobutyl)-2,5,5-trimethyl- 4-thiazolidinone, b.p. 
109.degree.-114.degree. C. at 0.20 mmHg. 
Analysis: Calculated for C.sub.10 H.sub.18 BrNOS: 42.86% C; 6.47% H; 5.00% 
N. Found: 42.93% C; 6.47% H; 5.00% N. 
b. 3-[4-[1-(1H-indazol-3-yl)piperazinyl]-2,5,5-trimethyl-4-thiazolidinone 
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.00 g), 
1-(1H-indazol-3-yl)piperazine (3.18 g), K.sub.2 CO.sub.3 (6.00 g), NaI 
(300 g), and acetonitrile (200 ml) was heated at 75.degree. C. under 
nitrogen. After 17 hours, TLC analysis showed the absence of starting 
bromide. The mixture was cooled to ambient temperature, filtered, the 
inorganics washed with dichloromethane, and the filtrate concentrated 
under reduced pressure to a liquid. The crude residue was taken up in 
dichloromethane (220 ml), washed with H.sub.2 O (130 ml), brine (130 ml), 
dried (NaSO.sub.4), and concentrated to a liquid. The liquid was purified 
by chromatography on silica gel. Elution with 5% methanol in 
dichloromethane afforded 4.22 g of a solid. Recrystallization from 
ether/hexanes provided 2.22 g of 
3-[4-[1-(1H-indazol-3-yl)piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidino 
ne, m.p. 111.degree.-112.degree. C. 
Analysis: Calculated for C.sub.21 H.sub.31 N.sub.5 OS: 62.81% C; 7.78% H; 
17.44% N. Found: 62.88% C; 7.66% H; 17.47% N. 
EXAMPLE 3 
a. 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one 
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in 
tetrahydrofuran (350 ml) cooled to -60.degree. C., was added 
1,5-diiodopentane (100 g). The resulting slurry was allowed to cool to 
-65.degree. C. and a solution of lithium bis(trimethylsilyl)amide in 
hexanes (220 ml) was added dropwise over a period of 30 minutes while 
maintaining the internal temperature at or below -55.degree. C. The 
resulting mixture was stirred for 15 minutes and the internal temperature 
allowed to rise to 0.degree. C. 0.5N HCl (500 ml) was added to quench the 
reaction and the mixture was concentrated in vacuo to remove the THF. The 
aqueous mixture was extracted twice with 250 ml portions of ether, washed 
with water (400 ml) and brine (400 ml), dried (Na.sub.2 SO.sub.4) and 
concentrated to a liquid. The liquid was chromatographed on silica gel 
(elution with 20% ethyl acetate/hexane) to give a liquid. 
b. 3-(4 
-(1-[1H-indazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan-4-o 
ne 
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one (4.06 g), 
3-(1-piperazinyl)-1H-indazole (2.95 g), K.sub.2 CO.sub.3 (5.50 g), and 
acetonitrile (250 ml) was heated at 80.degree. C. under nitrogen. After 20 
hours, TLC analysis (silica gel, 50% ether/hexanes) showed only a trace of 
starting bromide. The mixture was cooled to ambient temperature, ethyl 
acetate (150 ml) added, the inorganics filtered, and the filtrate 
concentrated under reduced pressure. The residue was taken up in 
dichloromethane (220 ml), washed with H.sub.2 O (110 ml), brine (130 ml), 
dried (NaSO.sub.4), and concentrated to a foam. The foam was 
chromatographed on silica gel, eluting with 10% methanol in 
dichloromethane, to give 4.83 g of a foam which solidified upon addition 
of ethyl acetate. The solid was recrystallized from ethyl acetate/hexanes 
yielding 2.76 g of 
3-(4-(1-[1H-indazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.5]decan 
-4-one, m.p. 159.degree.-161.degree. C. 
Analysis: Calculated for C.sub.23 H.sub.33 N.sub.5 OS: 64.60% C; 7.78% H; 
16.38% N. Found: 64.50% C; 7.86% H; 16.49% N. 
EXAMPLE 4 
2-(4-(4-(1-[1H-Indazol-3-yl]piperazinyl))-butyl)-5-methyl-thiazolidinone 
A mixture of 3-(4-bromobutyl)-5-methyl-4-thiazolidinone (3.9 g), 
3-(1-piperazinyl)-1H-indazole (3.0 g), K.sub.2 CO.sub.3 (4.1 g) and NaI 
(200 mg) in 150 ml dry acetontrile was heated to 80.degree. C. with 
stirring under N.sub.2. After 18 hours no starting piperazine remained as 
judged by TLC. The mixture was cooled to room temperature and filtered and 
the filtrate concentrated in vacuo. The residue was chromatographed on 
silica using 5:95 methanol:ethyl acetate eluent to give a solid. This 
product was recrystallized from ether/hexane to provide 2.593 g of 
2-(4-(4-(1-[1H-indazol-3-yl]-piperazinyl))butyl)-5-methyl-thiazolidinone, 
m.p. 105.degree.-108.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.27 N.sub.5 OS: 61.10% C; 7.29% H; 
18.75% N. Found: 61.13% C; 7.21% H; 18.67% N. 
EXAMPLE 5 
a. 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one 
To a -76.degree. C. solution of 3-(4-bromobutyl)-4-thiazolidinone (4.75 g) 
and tetrahydorfuran (120 ml) under nitrogen was added lithium 
bis(trimethylsilyl)amide (0.0203 mol) in tetrahydrofuran (20.3 ml) 
rapidly, immediately followed by 1,4-diiodobutane (15.51 g). After 12 min, 
a solution of lithium bis (trimethylsilylamide (0.0620 mol) in 
tetrahydrofuran (62 ml) was added over a period of 30 minutes. The 
resulting reaction was allowed to warm to -45.degree. C. at which 
temperature 1N HCl (250 ml) was added. The resulting aqueous mixture was 
extracted 4 times with 110 ml portions of ether. The combined extracts 
were washed with brine (250 ml), dried (Na.sub.2 SO.sub.4), and 
concentrated to a liquid. The liquid was chromatographed on silica gel 
(elution with 40% ethyl acetate in hexanes) to give 3.34 g of a liquid. 
The liquid was distilled using a short path distillation apparatus at 0.20 
mmHg to give 2.35 g of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one. 
Analysis: Calculated for C.sub.11 H.sub.18 NOS: 45.21% C; 6.21% H; 4.79% N. 
Found: 45.33% C; 6.19% H; 4.81% N. 
b. 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)butyl)-1thia-3-azaspiro[4.4]nonan- 
4-one 
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (4.00 g), 
3-(1-piperazinyl)-1H-indazole (3.05 g), K.sub.2 CO.sub.3 (6.63 g), NaI 
(320 mg), and acetonitrile (210 ml) was heated at 85.degree. C. under 
nitrogen. After 4 hours, TLC analysis (silica gel, 40% ethyl acetate in 
hexanes) showed the starting bromide to be consumed. The mixture was 
cooled to ambient temperature, ethyl acetate (100 ml) was added, the 
inorganics filtered, and the filtrate concentrated under reduced pressure. 
The residue was taken up in dichloromethane (210 ml), washed with H.sub.2 
O (100 ml), brine (100 ml), dried (Na.sub.2 SO.sub.4), and concentrated 
under reduced pressure to a liquid. The liquid was purified by 
chromatography on silica gel, eluting with 5% methanol in dichloromethane, 
to give 4.75 g of a foam which solidified upon addition of ether. The 
solid was recrystallized from ethyl acetate to yield 3.51 g of 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)butyl)-1-thia-3-azaspiro[4.4]nonan 
-4-one, m.p. 166.5.degree.-168.degree. C. 
Analysis: Calculated for C.sub.22 H.sub.31 N.sub.5 OS: 63.89% C; 7.56% H; 
16.93% N. Found: 63.61% C; 7.61% H; 16.73% N. 
EXAMPLE 6 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)butyl-2-methyl-1-thia-3-azaspiro[4. 
4]nonan-4-one 
A mixture of 3-(4-bromobutyl)-2-methyl-1-thia-3-azaspiro[4.4]nonan-4-one 
(4.20 g), 3-(1-piperazinyl)-1H-indazole (3.0 g), K.sub.2 CO.sub.3 (5.68 
g), NaI (310 mg), and acetonitrile (220 ml) was heated between 60.degree. 
and 80.degree. C. under nitrogen. After 18 hours, TLC analysis showed only 
a trace of the starting bromide. The mixture was cooled to ambient 
temperature, ethyl acetate (150 ml) was added, the inorganics filtered, 
and the filtrate concentrated under reduced pressure. The residue was 
taken up in dichloromethane (230 ml), washed with H.sub.2 O (130 ml), 
brine (130 ml), dried (Na.sub.2 SO.sub.4), and concentrated to a foam. The 
foam was chromatographed on silica gel, diluting with 8% methanol in 
dichloromethane, to furnish 5.04 g of a foam which solidified upon 
addition of ether/hexanes. The solid was recrystallized from ethyl 
acetate/hexanes to give 3.72 g of 3-(4-(1-[1 
H-indazol-3-yl]-4-piperazinyl)butyl)-2-methyl-1-thia-3-azaspiro[4.4]non-4- 
one, m.p. 113.degree.-115.degree. C. 
Analysis: Calculated for C.sub.23 H.sub.33 N.sub.5 OS: 64.60% C; 7.78% H; 
16.38% N. Found: 64.71% C; 8.08% H; 16.52% N. 
EXAMPLE 7 
a. 6-Fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride 
To a stirred mixture under N.sub.2 of 
4-(6-fluoro-1-phenylsulfonyl-1H-indazol-3-yl)-1-piperazinecarbonitrile 
(25.4 g) in tetrahydrofuran (400 ml), was added, dropwise, lithium 
aluminum hydride in tetrahydrofuran (130 ml of a 1M solution). The 
reaction was stirred and refluxed for 3 hours, cooled in an ice bath and 
H.sub.2 O was added dropwise. The reaction was filtered and the filter 
cake was washed with tetrahydrofuran and twice with methanol. 
Concentration of the filtrate afforded a gum, which when triturated with 
ether afforded 14.6 g of a solid. The solid was dissolved in methanol and 
ethereal HCl was added to the solution until it was acidic. Ether was then 
added to the solution, which initially precipitated a gum. The supernatant 
solution was decanted from the gum, and upon addition of more ether to the 
solution, 5.4 g of a hydrochloride salt was collected. Trituration of the 
gum with refluxing ethyl acetate gave an addition 3.2 g of salt. The 
larger sample was recrystallized twice from methanol/ether to afford 2.2 g 
of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride, m.p. 
268.degree.-270.degree. C. 
Analysis: Calculated for C.sub.11 H.sub.13 FN.sub.4.HCl: 51.47% C; 5.50% H; 
21.82% N. Found: 51.38% C; 5.37% H; 21.61% N. 
b. 
3-{4-[1-(6-Fluoro-1H-indazol-3-yl)-4-piperazinyl]butyl}-1-thia-3-azaspiro[ 
4.5]decan-4-one 
A mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (4.0 g), 
potassium carbonate (6.5 g), 
3-(4-bromobutyl)-1-thia-3-azaspiro[4.5]decan-4-one (5.2 g), potassium 
iodide (200 mg) and dimethylformamide (100 ml) was stirred at 75.degree. 
C. under N.sub.2 for 17 hours. The cooled reaction was poured into H.sub.2 
O and the aqueous mixture was extracted with ethyl acetate. The ethyl 
acetate extract was washed with H.sub.2 O, dried with MgSO.sub.4 and 
concentrated to yield 10.3 g of a solid. The sample was purified by 
preparative high performance liquid chromatography (HPLC) (silica gel, 6% 
methanol-dichloromethane as eluent) to provide 4.1 g. Recrystallization of 
the compound from isopropyl alcohol afforded 3.1 g of 
3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinyl]butyl}-1-thia-3-azaspiro[ 
4.5]decan-4-one, m.p. 163.degree.-165.degree. C. 
Analysis: Calculated for C.sub.23 H.sub.32 FN.sub.5 OS: 62.00% C; 7.24% H; 
15.72% N. Found: 61.81% C; 7.15% H; 15.62% N. 
EXAMPLE 8 
3-{4-[1-(6-Fluoro-1H-indazol-3-yl)-4-piperazinyl]-butyl}-1-thia-3-azaspiro[ 
4.4]nonan-4-one 
A mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (4.0 g), 
potassium carbonate (6.5 g), 
3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]nonan-4-one (5.0 g), 
dimethylformamide (100 ml) and potassium iodide (200 mg) was stirred for 
16 hours at 65.degree. under N.sub.2. The cooled reaction was then poured 
into H.sub.2 O and the aqueous mixture was extracted with ethyl acetate. 
The ethyl acetate extract was dried with MgSO.sub.4 and concentrated to 
yield 6.8 g of a solid. The sample was purified by preparative HPLC 
(silica gel, 6% methanol-dichloromethane) to afford 3.0 g. 
Recrystallization from isopropyl alcohol provided 2.1 g of 
3-{4-[1-(6-fluoro-1H-indazol-3-yl)-4-piperazinyl]-butyl}-1-thia-3-azaspiro 
[4.4]nonan-4-one, m.p. 132.degree.-134.degree.. 
Analysis: Calculated for C.sub.22 H.sub.30 FN.sub.5 OS: 61.23% C; 7.01% H; 
16.23% N. Found: 61.37% C; 6.93% H; 16.21% N. 
EXAMPLE 9 
3-{4-[1-(6-Fluoro-1H-indazol-3-yl)-piperazinyl]butyl}-5-methyl-4-thiazolidi 
none 
A mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole hydrochloride (4.0 g), 
potassium carbonate (6.5 g), 3-(4-bromobutyl)-5-methyl-4-thiazolidinone 
(4.3 g), potassium iodide (200 mg) and dimethylformamide (100 ml) was 
stirred at 80.degree. under N.sub.2 for 7.5 hours and then let stand for 
16 hours at room temperature. The reaction mixture was poured into H.sub.2 
O and the aqueous mixture was extracted with ethyl acetate. The ethyl 
acetate extract was dried with MgSO.sub.4 and concentrated to yield 8.0 g 
of a liquid. The sample was purified by preparative HPLC (silica gel, 6% 
methanol-dichloromethane) to afford 3.6 g. Recrystallization from 
isopropyl alcohol provided 2.2 g of 
3-{4-[1-(6-fluoro-1H-indazol-3-yl)-piperazinyl]butyl}-5-methyl-4-thiazolid 
inone, m.p. 119.degree.-120.degree.. 
Analysis: Calculated for C.sub.19 H.sub.26 FN.sub.5 OS: 58.29% C; 6.69% H; 
17.89% N. Found: 58.24% C; 6.74% H; 17.80% N. 
EXAMPLE 10 
3-(4-(1-[6-Fluoro-1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thi 
azolidinone 
To a stirred mixture of 6-fluoro-3-(1-piperazinyl)-1H-indazole (4.4 g), 
K.sub.2 CO.sub.3 (2.8 g), 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone 
(6.6 g) and dimethylformamide (75 ml) was heated at 75.degree. for 4 
hours. The reaction was poured into H.sub.2 O, and the aqueous mixture 
extracted with ethyl acetate. The ethyl acetate was washed (H.sub.2 O), 
dried (MgSO.sub.4) and the solvent concentrated to afford an oil. Upon 
standing the oil crystallized, and when the mass was triturated with 
ether, 3.3 g of a solid was collected. The compound was recrystallized 
from toluene-hexane to yield 2.8 g of 
3-(4-(1-[6-fluoro-1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-th 
iazolidinone, m.p. 123.degree.-125.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.28 FN.sub.5 OS: 59.24% C; 6.96% H; 
17.27% N. Found: 59.37% C; 6.99% H; 17.32% N. 
EXAMPLE 11 
a. 3-(1-piperazinyl)-1H-indazole 
A mixture of 4-(1H-indazol-3-yl)-1-piperazinecarbonitrile (8.0 g), and 25% 
H.sub.2 SO.sub.4 (100 ml) was stirred at reflux for 4.5 hours. The 
reaction was cooled in an ice bath and made basic by the dropwise addition 
of 50% NaOH. The basic solution was extracted with ethyl acetate. The 
ethyl acetate was washed with H.sub.2 O, dried with MgSO.sub.4 and 
concentrated to afford 5.2 g of the desired compound, as a solid. The 
sample was recrystallized twice from toluene to afford 3.0 g of the 
unsubstituted indazole, m.p. 153.degree.-155.degree. C. 
Analysis: Calculated for C.sub.11 H.sub.14 N.sub.4 : 65.32% C; 6.98% H; 
27.70% N. Found: 65.21% C; 6.99% H; 27.80% N. 
b. 
3-(4-(1-[1H-Indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidin 
one 
A stirred mixture of 3-(1-piperazinyl)-1H-indazole (5.0 g), 
3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (6.6 g) and 
dimethylformamide (120 ml) was heated at 70.degree.-75.degree. for 1.25 
hours. The reaction was poured into H.sub.2 O, dried (MgSO.sub.4) and the 
solvent concentrated to afford a solid. The solid was triturated with 
hexane and was collected to yield 7.2 g of a solid. Recrystallization from 
toluene afforded 5.7 g of 
3-(4-(1-[1H-indazol-3-yl]-4-piperazinyl)-butyl)-5,5-dimethyl-4-thiazolidin 
one, m.p. 139.degree.-142.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.29 N.sub.5 OS: 61.98% C; 7.54% H; 
18.07% N. Found: 62.12% C; 7.51% H; 17.85% N. 
EXAMPLE 12 
3-{4-[1-(1-Methyl-1H-indazol-3-yl)-4-piperazinyl]-butyl}-5,5-dimethyl-4-thi 
azolidine 
To a stirred mixture of sodium hydride (0.66 g), in dimethylformamide (20 
ml) under N.sub.2 was added, 
3-{4-[1-(1H-indazol-3-yl)-4-piperazinyl]-butyl}-5,5-dimethyl-4-thiazolidin 
e (4.4 g) dissolved in hot dimethylformamide (30 ml). The mixture was 
allowed to stir at ambient temperature for one hour and was then chilled 
to -1.degree. C. in an ice-salt bath. Iodomethane (1.78 g) dissolved in 
dimethylformamide (10 ml) was added dropwise so that the temperature did 
not exceed 1.degree. C. After complete addition the ice bath was removed 
and the reaction was allowed to stir under N.sub.2 at ambient temperature 
for 3.5 hours. The reaction was poured into H.sub.2 O, dried with 
MgSO.sub.4 and concentrated to afford 5.0 g of a liquid. The liquid was 
triturated with hexane to produce a solid, which was collected and dried 
to afford 2.5 g. The compound was recrystallized from hexane yielding 2.0 
g 3-{4-[1-(1-methyl-1H-indazol-3-yl)-4-piperazinyl]butyl}-5,5-dimethyl-4-t 
hiazolidine, m.p. 91.degree.-93.degree. C. 
Analysis: Calculated for C.sub.21 H.sub.31 N.sub.5 OS: 62.81% C; 7.78% H; 
17.44% N. Found: 62.97% C; 7.80% H; 17.42% N.