[(2-substituted 1,2-dihydro-1-oxo-1H-inden-5-yl)oxy]alkanesulfonic acids and salts thereof

This invention relates to novel [(2-substituted 1,2-dihydro-1-oxo-1H-inden-5-yl)oxy]alkanesulfonic acids and salts thereof. The compounds are useful for the treatment and prevention of injury to the brain and of edema due to head trauma, stroke (particularly ischemic), arrested breathing, cardiac arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, the neurological problems caused by AIDS, cerebral hemorrhage, cerebral tumors, encephalomyelitis, spinal cord injury, hydrocephalus, post-operative brain injury trauma, edema due to cerebral infections, various brain concussions, and elevated intracranial pressure.

BACKGROUND OF THE INVENTION 
Trauma to the brain or spinal cord caused by physical forces acting on the 
skull or spinal column, by ischemic stroke, arrested breathing, cardiac 
arrest, Reye's syndrome, cerebral thrombosis, cerebral embolism, the 
neurological problems caused by AIDS, cerebral hemorrhage, 
encephalomyelitis, hydrocephalus, post-operative brain injury, cerebral 
infections, various concussions, and elevated intracranial pressure 
results in edema and swelling of the affected tissues. This is followed by 
ischemia, hypoxia, necrosis, temporary or permanent brain or spinal cord 
injury and may result in death. The tissue mainly affected are classified 
as gray matter, more specifically astroglial cells. The specific therapy 
currently used for treatment of medical problems described include various 
kinds of diuretics (particularly osmotic diuretics), steroids (such as, 
6-.alpha.-methylprednisolone succinate), and barbiturates. The usefulness 
of these agents is questionable and they are associated with a variety of 
untoward complications and side effects. See e.g., E. J. Cragoe, Jr., 
Medicinal Research Reviews, 7, 271-35 (1987). Thus, the compounds of this 
invention comprise a novel and specific treatment of medical problems 
where no specific therapy is available. 
Certain (indanyloxy)alkanoic acid derivatives have been disclosed as useful 
agents for the treatment and prevention of injury to the brain and spinal 
cord. See Cragoe et al., J. Med. Chem., 25, 567-579 (1982) and U.S. Pat. 
Nos. 4,579,869, 4,465,850, 4,463,208, 4,394,285, and 4,389,417. None of 
these publications, however, discloses the 
[(1,2-dihydro-1-oxo-1H-inden-5-yl)oxy]alkanesulfonic acids or salts of the 
present invention nor suggests their utility for treatment of brain injury 
or edema. Moreover, the U.S. Pat. No. 4,394,385 discloses 
indeno[5,4-b]furancarboxylic acids that have a structurally distinct ring 
system from the compounds of the present invention. 
Certain [(tetrahydrofluoren-7-yl)oxy]alkanoic acid derivatives have also 
been disclosed as useful agents for the treatment and prevention of injury 
to the brain and spinal cord. See Cragoe et al., J. Med. Chem. 29, 825-841 
(1986) and U.S. Pat. Nos. 4,604, 396, 4,356,314, 4,356,313, 4,337,354, 
4,317,922, and 4,316,043. The compounds disclosed in these publications, 
however, are carboxylic acid derivatives having a fluorenyl ring nucleus 
and thus are structurally distinct from the 
[(1,2-dihydro-1-oxo-1H-inden-5-yl)oxy]alkanesulfonic acids and salts of 
the present invention. 
The compounds of the present invention have the added advantage of being 
devoid of the pharmacodynamic, toxic or various side effects 
characteristic of the diuretics, steroids and barbiturates. 
SUMMARY OF THE INVENTION 
This invention relates to novel 
[(2-substituted-1,2-dihydro-1-oxo-1H-inden-5-yl)oxy]alkanesulfonic acids 
and salts thereof of Formula I that are useful in the treatment and 
prevention of brain injury and edema. 
##STR1## 
or optical isomers thereof; or a hydrate or other solvate thereof; 
wherein R.sup.1 is: 
(a) C.sub.1 -C.sub.6 alkyl; 
(b) C.sub.3 -C.sub.7 cycloalkyl; 
(c) C.sub.4 -C.sub.11 (cycloalkyl)alkyl; 
(d) phenyl or phenyl substituted with one or more substituents selected 
from the group consisting of: 
(i) halogen; 
(ii) C.sub.1 -C.sub.6 alkyl; 
(iii) C.sub.1 -C.sub.6 alkoxy; 
(iv) C.sub.2 -C.sub.6 alkanoyl; and 
(v) hydroxy; or 
(e) phenyl(C.sub.1 -C.sub.6 alkyl) or phenyl(C.sub.1 -C.sub.6 alkyl) 
substituted in the benzene ring with one or more substituents selected 
from the group consisting of: 
(i) halogen; 
(ii) C.sub.1 -C.sub.6 alkyl; 
(iii) C.sub.1 -C.sub.6 alkoxy; 
(iv) C.sub.2 -C.sub.6 alkanoyl; and 
(v) hydroxy; 
R.sup.2 is: 
(a) hydrogen; or 
(b) C.sub.1 -C.sub.6 alkyl; 
X and Y are independently: 
(a) halogen; or 
(b) C.sub.1 -C.sub.6 alkyl; 
M.sup.+ is a pharmaceutically acceptable cation; and 
n is an integer of from 1 to 6. 
The term "C.sub.1 -C.sub.6 alkyl" refers to straight or branched chain 
aliphatic hydrocarbon groups having from 1 to 6 carbon atoms, also 
referred to as lower alkyl. Examples of C.sub.1 -C.sub.6 alkyl are methyl, 
ethyl, propyl, butyl, pentyl, hexyl, and the isomeric forms thereof. 
The term "C.sub.3 -C.sub.7 cycloalkyl" refers to saturated monocyclic 
hydrocarbon groups having from 3 to 7 carbon atoms in the ring. Examples 
of C.sub.3 -C.sub.7 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, 
cyclohexyl, and cycloheptyl. 
The term "C.sub.4 -C.sub.11 (cycloalkyl)alkyl" refers to straight or 
branched chain alkyl groups bearing a cycloalkyl group such that the total 
number of carbon atoms ranges from 4 to 11. Examples of C.sub.4 -C.sub.11 
(cycloalkyl)alkyl are cyclopropylmethyl, 2-cyclopropylethyl, 
3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 
cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, 
2-cyclohexylethyl, cycloheptymethyl, 2-cycloheptylethyl, and the like, and 
the isomeric forms thereof. 
The term "C.sub.1 -C.sub.6 alkoxy" refers to straight or branched chain 
alkyl oxy groups having from 1 to 6 carbon atoms. Examples of C.sub.1 
-C.sub.6 alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, 
and the isometric forms thereof. 
The term "C.sub.2 -C.sub.6 alkanoyl" refers to straight or branched chain 
alkanoyl groups having from 2 to 6 carbon atoms. Examples of C.sub.2 
-C.sub.6 alkanoyl are acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, 
and the isomeric forms thereof. 
Examples of halogen are fluorine, chlorine, bromine, and iodine. 
The term "pharmaceutically acceptable cation" refers to a positively 
charged inorganic or organic ion that is generally considered suitable for 
human consumption. Examples of pharmaceutically acceptable cations are 
hydrogen, alkali metal (lithium, sodium, and potassium), magnesium 
(1/2Mg.sup.++), calcium (1/2Ca.sup.++), ammonium, alkylammonium, 
dialkylammonium, trialkylammonium, tetraalkylammonium, diethanolaminium, 
triethanolaminium, and guanidinium ions, and protonated forms of lysine, 
benzathine, procaine, and choline. Cations may be interchanged by methods 
known in the art, such as ion exchange. Where compounds of Formula I are 
prepared in the sulfonic acid form (that is, where M.sup.+ is hydrogen 
ion), addition of a base form of the cation (such as a hydroxide or a free 
amine) will yield the appropriate cationic form. 
When the substituents R.sup.1 and R.sup.2 are different, the 2-position of 
the indanone ring system is asymmetric and the compounds of this invention 
of Formula I are racemic. One skilled in the art would understand that 
compounds of Formula I or their precursors could be resolved into 
enantiomeric components, which may vary somewhat as to desirable activity 
or toxicity. One skilled in the art could readily determine the most 
desirable isomeric composition. It is understood that this invention 
encompasses the racemic mixtures and the enantiomers. 
It is also understood that the compounds of Formula I may form hydrates or 
other solvates from the solvents in which they are prepared or from which 
they are crystallized. These hydrates or other solvates may be used per se 
or they may be dehydrated or desolvated by heating (for example, at about 
70.degree. C. to 100.degree. C.) in vacuo. 
Although this invention primarily involves novel compounds of Formula I, it 
also includes derivatives such as oximes, hydrazones, and the like. 
Additionally, this invention includes pharmaceutical compositions in unit 
dosage forms containing a pharmaceutical carrier and a pharmaceutically 
effective amount of a compound of Formula I (as racemate or as R or S 
enantiomer) for treating or preventing brain injury and edema. The method 
of treating a person with brain injury by administering said compounds or 
said pharmaceutical compositions is also part of this invention. 
DESCRIPTION OF THE INVENTION 
The compounds of this invention may be prepared from phenolic indanones of 
Formula II, which can be prepared using methods known in the art. See, for 
example, Cragoe et al., J. Med. Chem., 25, 567-579 (1982), and Woltersdorf 
et al., J. Med. Chem., 20, 1400-1408 (1977). 
##STR2## 
Phenolic indanones of Formula II react under suitably basic conditions in 
a suitable organic solvent with a suitable alkanesulfonate derivative to 
form compounds of this invention, Formula I, in which M.sup.+ is the 
cation moiety derived from the base employed. Suitably basic conditions 
are achieved by adding a base that can generate a sufficient phenoxide 
concentration for the reaction with the alkanesulfonate derivative to 
occur but that does not itself form significant quantities of byproducts 
by reaction with other chemical reagents or reaction products. Examples of 
such bases include alkali metal carbonates, such as lithium, sodium, or 
potassium carbonate; alkali metal alkoxides, such as sodium methoxide, 
sodium ethoxide, and potassium t-butoxide; alkali metal alkyls, such as 
n-butyllithium and t-butyllithium; and other such bases known in the art. 
In general, the base is added to a solution or suspension of a phenolic 
indanone of Formula II before adding the alkanesulfonate derivative. 
Suitable organic solvents are organic liquids in which reactants may be 
dissolved or suspended but which are otherwise chemically inert. Examples 
of suitable organic solvents include alkanols, such as methanol, ethanol, 
propanol, isopropyl alcohol, and the like; alkanes and cycloalkanes; 
ethers and cyclic ethers, such as diethyl ether, tetrahydrofuran, 
tetrahydropyran, and the like; aromatic hydrocarbons, such as benzene, 
toluene, and the like; N,N-disubstituted amides, such as 
dimethylformamide, dimethylacetamide, and the like; N-substituted lactams, 
such as N-methylpyrrolidinone, N-methylpiperidinone, and the like; and 
other solvents known in the art. The particular base used depends somewhat 
on the solvent used. For example, a preferred organic solvent is ethanol, 
for which the preferred base is sodium ethoxide. 
Suitable alkanesulfonate derivatives are compounds of the formula 
L--(CH.sub.2).sub.n --SO.sub.2 --OB, wherein L is a suitable leaving group 
for alkylating phenoxide oxygen atoms, and B is hydrogen or a suitable 
sulfonate blocking group that can later be removed. The group L can be, 
for example, halogen or methanesulfonate. Sulfonate blocking groups B can 
be, for example, alkyl or benzyl. For compounds of Formula I in which n is 
to be 3 or 4, L and B taken together may be a chemical bond such that the 
alkanesulfonate derivative is a sultone of Formula III 
##STR3## 
wherein n is 3 or 4. Such sultones are the preferred alkanesulfonate 
derivatives for preparing compounds of Formula I wherein n is 3 or 4. 
Not all groups M.sup.+ to be incorporated in compounds of Formula I are 
cations of bases sufficiently basic to generate suitable phenoxide 
concentrations from phenolic indanones of Formula II. One skilled in the 
art could readily exchange one group M.sup.+ of Formula I for another 
using, for example, ion exchange. Compounds of Formula I in which M.sup.+ 
is hydrogen ion may also be converted to other forms by addition of a base 
form of the cation, such as a hydroxide or a free amine. 
It is to be recognized that certain compounds of Formula I possess an 
asymmetric carbon atom (the 2-position of the indanone ring system) and 
therefore the compounds of the invention are racemates which consist of 
two enantiomers. These enantiomers may possess markedly different 
biological properties, thus it is advantageous to separate the enantiomers 
and use them in their pure form. The optically pure compounds of Formula I 
can be prepared from optically pure precursors of Formula II. 
Alternatively, the compounds of Formula I can be resolved to their pure 
enantiomers by one or more of several classical examples. For example, 
compounds of Formula I may be resolved by forming a salt of the racemic 
mixture with an optically active base such as (+) or (-)amphetamine, 
(-)cinchonidine, dehydroabiethylamine, (+) or 
(-)-.alpha.-methylbenzylamine, (+) or (-)-.alpha.-(1-naphthyl)ethylamine, 
(+)cinchonine, brucine, or strychnine and the like in a suitable solvent 
such as methanol, ethanol, isopropyl alcohol, benzene, acetonitrile, 
nitromethane, acetone, and the like. There is formed in the solution two 
diastereomeric salts one of which is usually less soluble in the solvent 
than the other. Repetitive recrystallization of the crystalline salt 
generally affords a pure diastereomeric salt from which is obtained the 
desired pure enantiomer. The optically pure enantiomer of the compound of 
Formula I is obtained by acidification of the salt with a mineral acid, 
isolation by filtration and recrystallization of the optically pure 
antipode. 
The other optically pure antipode may generally be obtained by using a 
different base to form the diastereomeric salt. It is of advantage to 
isolate the partially resolved acid from the filtrates of the purification 
of the first diastereomeric salt and to further purify this substance 
through the use of another optically active base. It is especially 
advantageous to use an optically active base for the isolation of the 
second enantiomer which is the antipode of the base used for the isolation 
of the first enantiomer. For example, if (+)-.alpha.-methylbenzylamine was 
used first, then (-)-.alpha.-methylbenzylamine is used for the isolation 
of the second (remaining) enantiomer. 
The preferred embodiments of this invention include compounds of the 
formula 
##STR4## 
and optical isomers thereof; and hydrates thereof; wherein R.sup.2 is 
C.sub.1 -C.sub.6 alkyl, M.sup.+ is an alkali metal ion, and n is 3 or 4. 
More preferred embodiments of this invention include compounds of the 
formula 
##STR5## 
and optical isomers thereof; and hydrates thereof; wherein R.sup.1 is 
straight-chain C.sub.1 -C.sub.4 alkyl and n is 3 or 4. 
Intrinsic activity in inhibiting the swelling of brain tissue was 
demonstrated in an in vitro cerebrocortical cat brain slice assay that 
simulates the edema seen in traumatic brain injury. See, e.g., Bourke et 
al., Neurochem. Res., 8, 5 (1983), and Cragoe et al., J. Med. Chem., 25, 
567 (1982). 
In Vitro Cerebrocortical Cat Brain Tissue Slice Assay 
Adult cats of 2-3 kg body weight were employed in tissue slice studies. 
Prior to sacrifice, the animals were anesthetized with ketamine 
hydrochloride, 10 mg/kg intramuscularly. Eight (three control, five 
experimental) pial surface cerebrocortical tissue slices (0.5 mm thick; 
approximately 150 mg initial fresh weight) were cut successively with a 
calibrated Stadie-Riggs fresh tissue microtome without moistening and 
weighed successively on a torsion balance. During the slice preparation 
all operations except weighing were confined to a humid chamber. Each 
slice was rapidly placed in an individual Warburg flask containing 2 ml of 
incubation medium at room temperature. The basic composition of the 
incubation media was as follows: glucose, 10 mM; CaCl.sub.2, 1.3 mM; 
MgSO.sub.4, 1.2 mM; KHSO.sub.4, 1.2 mM; HEPES 
(N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, titrated with NaOH 
to pH 7.4), 20 mM. Except when adding HCO.sub.3.sup.-, the osmolarity of 
the media was maintained isosmotic (approximately 285 mOsm/L) by 
reciprocal changes of N.sup.+ or K.sup.+ to achieve a concentration of 
K.sup.+ of 27 mM. The basic medium was saturated with oxygen by bubbling 
pure oxygen through the solution for 30 minutes before use. When added, 
sodium bicarbonate or triethylammonium bicarbonate was initially present 
in the sidearm of each flask at an initial concentration of 50 mM in 0.5 
ml of complete medium. Nonbicarbonate control slices were incubated at 
37.degree. C. in 2.5 ml of basic medium for 60 minutes. Bicarbonate 
control slices were similarly incubated for an initial 20 minutes at 
37.degree. C. in 2.0 ml of basic medium to which was added from the 
sidearm an additional 0.5 ml of incubation medium containing 50 mM 
HCO.sub.3.sup.-, which, after mixing, resulted in a HCO.sub.3.sup.- 
concentration of 10 mM and a total volume of 2.5 ml. The incubation is 
continued for an additional 40 minutes. The various compounds could be 
tested as aqueous solutions of salts which are formed by reaction with 
appropriate bases in water. Just prior to incubation, all flasks 
containing HCO.sub.3.sup.- were gassed for 5 minutes with 2.5% CO.sub.2 
/97.5% O.sub.2 instead of 100% O.sub.2. 
Following the 60-minute incubation period, tissue slices were separated 
from incubation medium by filtration, reweighed, and homogenized in 1N 
HClO.sub.4 (10% w/v) for electrolyte analysis. The tissue content of ion 
is expressed in micromoles per gram initial preswelling fresh weight. 
Control slice swelling is expressed as microliters per gram initial 
preswelling fresh weight. The effectiveness of an inhibitor at a given 
concentration was measured by the amount of HCO.sub.3.sup.- -stimulated 
swelling that occurred in its presence, computed as a percent of the 
maximum possible and is reported as an IC.sub.50, (See, e.g., Table I 
(Example 6)). Tissue and media Na.sup.+ and K.sup.+ levels were determined 
by emission flame photometry with Li.sup.+ internal standard; Cl.sup.- 
levels were determined by amperometric titration. Tissue viability during 
incubation is monitored by manometry. 
Inasmuch as there are a variety of symptoms and severity associated with 
grey matter edema, particularly when it is caused by head trauma, stroke, 
cerebral hemorrhage or embolism, post-operative brain surgery trauma, 
spinal cord injury, cerebral infections, various brain concussions, 
elevated intracranial pressure, arrested breathing, cardiac arrest, Reye's 
syndrome cerebral tumors, encephalomeylitis, hydrocephalus and 
neurological problem caused by AIDS, the precise treatment is left to the 
practioner. Generally, candidates for treatment will be indicated by the 
results of the patient's initial general neurological status, findings on 
specific clinical brain stem functions and findings on computerized axial 
tomography (CAT), nuclear magnetic resonance (NMR) or positron emission 
tomography (PET) scans of the brain. The sum of the neurological 
evaluation is presented in the Glascow Coma Score or similar scoring 
system. Such a scoring system is often valuable in selecting the patients 
who are candidates for therapy of this kind. 
The compounds of this invention can be administered by a variety of 
established methods, including intravenously, intramuscularly, 
subcutaneously, or orally. The parenteral route, particularly the 
intravenous route of administration, is preferred, especially for the very 
ill and comatose patient. Another advantage of the intravenous route of 
administration is the speed with which therapeutic brain levels of the 
drug are achieved. It is of paramount importance in brain injury of the 
type described to initiate therapy as rapidly as possible and to maintain 
it through the critical time periods. For this purpose, the intravenous 
administration of drugs of the type of Formula I in the form of their 
salts is superior. 
A recommended dosage range for treatment is expected to be from 0.05 mg/kg 
to 50 mg/kg of body weight as a single dose, preferably from 0.5 mg/kg to 
20 mg/kg. An alternative to the single dose schedule is to administer a 
primary loading dose followed by a sustaining dose of half to equal the 
primary dose, every 4 to 24 hours. When this multiple dose schedule is 
used the dosage range may be higher than that of the single dose method. 
Another alternative is to administer an ascending dose sequence of an 
initial dose followed by a sustaining dose of 11/2 to 2 times the initial 
dose every 4 to 24 hours. For example, three intravenous doses of 4, 8, 
12, or 16 mg/kg of body weight can be given at 6 hour intervals. If 
necessary, four additional doses of 4, 8, 12, or 16 mg/kg of body weight 
can be given at 12 hour intervals. Another effective dose regimen consists 
of a continuous intravenous infusion of from 0.05 mg/kg/hr to 3.0 
mg/kg/hr. Of course, other dosing schedules and amounts are possible. 
One aspect of this invention is the treatment of persons with grey matter 
edema by concomitant administration of a compound of Formula I and an 
antiinflammatory steroid. These steroids are of some, albeit limited, use 
in control of white matter edema associated with ischemic stroke and head 
injury. Steroid therapy is given according to established practice as a 
supplement to the compound of Formula I. Similarly, a barbiturate may be 
administered as a supplement to treatment with a compound of Formula I. 
The compounds of this invention are utilized by formulating a 
pharmaceutically effective amount of at least one compound of Formula I in 
a pharmaceutical composition such as tablet, capsule, or elixir for oral 
administration. Sterile solutions or suspensions can be used for 
parenteral administration. A compound or mixture of compounds of Formula I 
is compounded with a non-toxic pharmaceutically acceptable vehicle, 
carrier, excipient, binder, preservative, stabilizer, flavor, and the 
like, in a dosage form as called for by accepted pharmaceutical practice. 
Illustrative of the adjuvants which may be incorporated in tablets, 
capsules, and the like are the following: a binder such as gum tragacanth, 
acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; 
a disintegrating agent such as corn starch, potato starch, alginic acid 
and the like; a lubricant such as magnesium stearate; a sweetening agent 
such as sucrose, lactose, or saccharin; a flavoring agent such as 
peppermint, oil of wintergreen or cherry. When the dosage unit form is a 
capsule, it may contain in addition to materials of the above type a 
liquid carrier such as a fatty oil. Various other materials may be present 
as coatings or to otherwise enhance the pharmaceutical elegance of the 
preparation. For instance, tablets may be coated with shellac, sugar, or 
the like. A syrup or elixir may contain the active compound, sucrose as a 
sweetening agent, methyl and propyl parabens as preservatives, a dye, and 
a flavoring such as cherry or orange flavor. 
Sterile compositions for injection or infusion can be formulated according 
to conventional pharmaceutical practice by dissolving the active substance 
in a conventional vehicle such as water, saline, or dextrose solution by 
forming a soluble salt in water using an appropriate acid, such as a 
pharmaceutically acceptable carboxylic acids or mineral acids. 
Alternatively, a suspension of the active substance in a naturally 
occurring vegetable oil like sesame oil, coconut oil, peanut oil, 
cottonseed oil, and the like, or a synthetic fatty vehicle like ethyl 
oleate or the like may be formulated for injection or infusion. Buffer, 
preservatives, antioxidants, and the like can be incorporated as required. 
The following Examples are included to illustrate the preparation of 
representative compounds of Formula I. It is intended that the 
specification and examples be considered as exemplary only, with the true 
scope and spirit of the invention being indicated by the following claims. 
All temperatures in the examples are in Celsius unless otherwise indicated 
.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
EXAMPLE 1 
Sodium 
3-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)ox 
y]propanesulfonate hydrate 
##STR6## 
Sodium metal (1.25 g, 54.2 mmole) was added to ethanol (80 ml) and the 
resultant solution of sodium ethoxide was cooled to room temperature. To 
this solution was added with stirring 
6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one 
(16.22 g, 54.2 mmole), followed after five minutes by 1,3-propanesultone 
(6.61 g, 54.1 mmole). After 20 minutes stirring, the mixture was slowly 
heated to reflux and then maintained at reflux overnight. After the 
mixture was cooled, a precipitate was collected and washed with ethanol. 
The solid was suspended in a mixture of ethanol (75 ml), diethyl ether (75 
ml), and acetic acid (3 ml), and stirred at room temperature for three 
days. This solid was collected and recrystallized from water (ca. 100 ml). 
The precipitate was washed with water in small portions and dried 
overnight in a vacuum oven at about 65.degree. to yield the title compound 
as the hydrate (14 g). Structure assignment was supported by the nmr 
spectrum and by elemental analysis. 
Analysis. Calc'd for C.sub.18 H.sub.21 Cl.sub.2 O.sub.5 SNa.H.sub.2 O; C, 
46.85; H, 5.03; S, 6.95; Cl, 15.37. Found: C, 47.07; H, 4.96; S, 6.84; Cl, 
15.18. 
EXAMPLE 2 
Sodium 
(+)3-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl 
)oxy]propanesulfonate hydrate 
##STR7## 
Sodium ethoxide was prepared as in Example 1 using 0.262 g (11.4 mole) of 
sodium metal and 35 ml of ethanol. To the ethoxide solution was added 
(+)6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-on 
e (3.406 g, 11.4 mmole), followed by 1,3-propanesultone (1.390 g, 11.4 
mmole). The mixture was heated to reflux, diluted with ethanol (15 ml) to 
improve stirring, and further heated at 90.degree. for six hours. The 
slurry was diluted with ethanol (50 ml), diethyl ether (75 ml), and acetic 
acid (2 ml), and stirred vigorously for one hour. The solid was collected, 
washed with 1:1 ethanol-diethyl ether, dried partially under vacuum, and 
then recrystallized from water (30 ml). The precipitate was collected, 
washed with small portions of water, and dried at 100.degree. over 
phosphorus pentoxide to yield the title compound as the hydrate (2.9 g), 
m.p. ca. 277.degree.. Structure assignment was supported by the nmr 
spectrum and by elemental analysis. 
Analysis. Calc'd for C.sub.18 H.sub.21 Cl.sub.2 O.sub.5 SNa.H.sub.2 O: C, 
46.85; H, 5.03. Found: C, 47.20; H, 4.94. 
EXAMPLE 3 
Sodium 
(+)4-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl 
)oxy]butanesulfonate hydrate 
##STR8## 
The title compound is prepared by the method of Example 2 using 
1,4-butanesultone instead of 1,3-propanesultone. 
EXAMPLE 4 
Sodium 
3-[(6,7-dichloro-2-cyclopentyl-2-ethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy 
]propanesulfonate hydrate 
##STR9## 
The title compound is prepared by the method of Example 1 using 
6,7-dichloro-2-cyclopentyl-5-hydroxy-2-ethyl-2,3-dihydro-1H-inden-1-one 
instead of 
6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one. 
EXAMPLE 5 
Sodium 
3-[(3-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy 
]propanesulfonate hydrate 
##STR10## 
The title compound is prepared by the method of Example 1 using 
2-butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-1-one 
instead of 
6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one. 
EXAMPLE 6 
Biological results 
TABLE I 
______________________________________ 
In vitro Cerebrocortical Cat Brain Tissue Slice Assay 
Compound IC.sub.50 
(Example No.) 
(nM) 
______________________________________ 
1 20 
2 20 
______________________________________