Method for lowering sorbitol levels using spiro-imides

A series of spiro-imide compounds and their base salts with pharmacologically acceptable cations are disclosed. These particular compounds are useful in therapy as agents for the control of certain chronic diabetic complications. Preferred member compounds include 2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidone]-2',5'-dione, 2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione, 3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione, 3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione, 6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione and 6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. Methods for preparing these compounds from known starting materials are provided.

BACKGROUND OF THE INVENTION 
This invention relates to new and useful imide derivatives of principal 
interest to those in the field of medicinal chemistry and/or chemotherapy. 
More particularly, it is concerned with a novel series of spiro-imide 
compounds, which are of especial value in view of their ability to 
effectively control certain chronic complications arising from diabetes 
mellitus (e.g., diabetic cataracts, retinopathy and neuropathy). The 
invention also includes a new method of therapy within its scope. 
In the past, various attempts have been made by numerous investigators in 
the field of organic medicinal chemistry to obtain new and better oral 
antidiabetic agents. For the most part, these efforts have involved the 
testing of various organic compounds in an endeavor to determine their 
ability to lower blood sugar (i.e., glucose) levels. However, in the 
search for newer and still more effective antidiabetic agents, little is 
known about the effect of other organic compounds in preventing or 
arresting certain chronic complications of diabetes, such as diabetic 
cataracts, neuropathy and retinopathy, etc. Nevertheless, K. Sestanj et 
al. in U.S. Pat. No. 3,821,383 do disclose that certain aldose reductase 
inhibitors like 1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and 
some closely-related derivatives thereof are useful for these purposes 
even though they are not known to be hypoglycemic. These compounds 
function by inhibiting the activity of the enzyme aldose reductase, which 
is primarily responsible for catalyzing the reduction of aldoses (like 
glucose and galactose) to the corresponding polyols (such as sorbitol and 
galactitol) in the human body. In this way, unwanted accumulations of 
galactitol in the lens of galactosemic subjects and of sorbitol in the 
lens, retina, peripheral nervous system and kidney of various diabetic 
subjects are thereby prevented or reduced. As a result, these compounds 
control certain chronic diabetic complications, including those of an 
ocular nature, since it is already known in the art that the presence of 
polyols in the lens of the eye quite often leads to cataract formation and 
concomitant loss of lens clarity. 
SUMMARY OF THE INVENTION 
In accordance with the present invention, it has now been rather 
surprisingly found that various spiroimide compounds are extremely useful 
when employed in therapy as agents for the control of certain chronic 
complications arising in a diabetic subject even though they are not 
outstanding aldose reductase inhibitors per se. More specifically, the 
novel method of treatment of the present invention involves treating a 
diabetic host to prevent or alleviate diabetes-associated chronic ocular 
and neuritic complications by administering to said host an effective 
amount of a compound of the formulae: 
##STR1## 
and the base salts thereof with pharmacologically acceptable cations, 
wherein W is --(CH.sub.2).sub.n --; X is hydrogen, chlorine, lower alkyl 
or lower alkoxy; X.sup.1 is hydrogen, fluorine, chlorine, bromine, lower 
alkyl, lower alkoxy or phenyl, with the proviso that when X.sup.1 is 
fluorine, bromine or phenyl, X is hydrogen; Y is oxygen or sulfur; Z is W, 
Y or Q wherein Q is oxosulfur or dioxosulfur; m is one or two; and n is 
zero or one. These compounds possess the ability to markedly reduce or 
even inhibit sorbitol accumulation in the lens and peripheral nerves of 
various diabetic subjects. 
The compounds of this invention which are novel are those of formula I 
wherein Z is Z or Q as previously defined or Z is (CH.sub.2).sub.n and n 
is zero. Additionally, those compounds of formula II per se are also all 
novel compounds. Accordingly, the novel compounds of this invention 
comprise spiro-imides of the formulae: 
##STR2## 
and the base salts thereof with pharmacologically acceptable cations, 
wherein W is --(CH.sub.2).sub.n --; X is hydrogen, chlorine, lower alkyl 
or lower alkoxy; X.sup.1 is hydrogen, fluorine, chlorine, bromine, lower 
alkyl, lower alkoxy or phenyl, with the proviso that when X.sup.1 is 
fluorine, bromine or phenyl, X is hydrogen; Y is oxygen or sulfur; V is 
oxygen, sulfur, oxosulfur or dioxosulfur; m is one or two; and n is zero 
or one. 
Of especial interest in this connection are such typical and preferred 
member compounds of the invention as 
2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione, 
2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione, 
3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione, 
3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione, 
6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione 
and 6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione, 
respectively. These key compounds are all particularly effective in 
lowering sorbitol levels in the sciatic nerve and lens of diabetic 
subjects as well as galactitol levels in the lens of galactosemic subjects 
for the present purposes at hand. The preferred compounds are, as 
previously indicated, all new compounds with the sole exception of 
3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione which, 
although a known compound, was not previously recognized to be of value 
for the herein disclosed use. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the process employed for preparing the compounds of this 
invention of formula I when m is one and of formulae IA-II as previously 
defined, an appropriately substituted carbonyl ring compound, such as the 
corresponding 1-indanone, 2-indanone, 1-tetralone, 4-chromanone, 
thiochroman-4-one, 6,7-dihydrobenzo(b)furan-4(5H)-one and 
6,7-dihydrobenzo(b)thiophene-4(5H)-one, of the respective formulae: 
##STR3## 
wherein W, X, X.sup.1, Y and Z are all as previously defined, is condensed 
with a lower alkyl .alpha.-cyanoacetate to give the corresponding 
cyano-iylidene acetate such as, for example, 
.alpha.-cyano-.alpha.-(2,3-dihydro-1H-indene-1-ylidene)acetic acid, which 
is then treated with potassium cyanide to form the corresponding dicyano 
compound followed by acid hydrolysis in a conventional manner to yield the 
corresponding dicarboxylic acid and finally, heat treatment of the latter 
compound with ammonium hydroxide to ultimately yield the desired 
spiro-imide final product of the structural formulae previously indicated. 
In practice, the last step of the process is usually conducted by heating 
the reaction mixture in an oil bath at high temperatures and preferably at 
a temperature that is in the range of from about 200.degree. C. up to 
about 300.degree. C., i.e., until at least all the volatile material is 
removed from the mixture and the resultant product forms a homogeneous 
mass. In this way, 1-indanone is converted via 
.alpha.-cyano-.alpha.-(2,3-dihydro-1H-indene-1-ylidene)acetic acid ethyl 
ester and .alpha.-cyano-.alpha.-(2,3-dihydro-1H-indene-1-yl)butanedioic 
acid, respectively, to 
2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione per se. 
On the other hand, compounds of the invention of formula I where m is two 
are best prepared by a series of reactions starting from the corresponding 
.alpha.-cyano ring compound of the formula: 
##STR4## 
wherein X, X.sup.1 and Z are each as previously defined, which series of 
reactions involves treating said starting material with 
3-bromopropanenitrile in the presence of a basic condensing agent like 
sodium hydride to form the corresponding dinitrile, followed by alkaline 
hydrolysis of the latter compound to yield the monoamide of the 
corresponding dicarboxylic acid and finally, heat treatment of the latter 
acid-amide with ammonium hydroxide in the same manner as that described 
previously for the last step of the first process to ultimately yield the 
desired spiro-imide of structural formula I wherein m is two. In this way, 
.alpha.-cyanotetralin is converted via 
.alpha.-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dinitrile and 
.alpha.-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dioic acid 
monoamide, respectively, to 
3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione per se. 
Compounds of the invention in which Z of formula I is Q and Q is 
##STR5## 
can be prepared from those compounds wherein Z is sulfur by merely 
oxidizing the latter group of compounds in accordance with standard 
techniques well known to those skilled in the art. For instance, the use 
of sodium periodate in this connection leads to the formation of the 
oxosulfur compounds, while peroxy acids like peracetic acid, perbenzoic 
acid and m-chloroperoxybenzoic acid, etc., are preferably employed to 
afford the corresponding dioxosulfur compounds. On the other hand, certain 
compounds of the invention having a ring substituent (X, X.sup.1, etc.) 
which is halogen (as previously defined) may alternatively be prepared 
from the corresponding unsubstituted compounds wherein at least one of X 
and X.sup.1 is hydrogen by means of direct halogenation techniques well 
known to those in the field of synthetic organic chemistry. 
The ketone starting materials (i.e., carbonyl ring compounds) required for 
preparing the spiro-imide intermediates of this invention are, for the 
most part, known compounds and are either readily available commercially, 
like 1-indanone, 2-indanone, 6-chloro-4-chromanone and 
6,7-dihydrobenzo(b)thiophene-4(5H)-one, etc., or else they can easily be 
synthesized by those skilled in the art starting from common chemical 
reagents and using conventional methods of organic synthesis. For 
instance, 6-fluoro-4-chromanone is obtained by condensing 
.beta.-(p-fluorophenoxy)propionic acid in the presence of polyphosphoric 
acid, while 6,7-dichlorothiochroman-4-one is obtained by condensing 
.beta.-(3,4-dichlorophenylthio)propionic acid in the presence of 
concentrated sulfuric acid. In both cases, the starting organic acid is 
ultimately derived from a commercially available compound. 
The chemical bases which are used as reagents in this invention to prepare 
the aforementioned pharmaceutically acceptable base salts are those which 
form non-toxic salts with the herein described acidic spiroimides such as 
2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione, for example. 
These particular non-toxic base salts are of such a nature that their 
cations are essentially non-toxic in character over the wide range of 
dosage administered. Examples of such cations include those of sodium, 
potassium, calcium and magnesium, etc. These salts can easily be prepared 
by simply treating the aforementioned spiro-imide compounds with an 
aqueous solution of the desired pharmacologically acceptable base, such as 
the hydroxide, carbonate or bicarbonate of one of the aforementioned 
cations, and then evaporating the resulting solution to dryness while 
preferably being placed under reduced pressure. Alternatively, they may 
also be prepared by mixing lower alkanolic solutions of the said acidic 
compounds and the desired alkali metal alkoxide together, and then 
evaporating the resulting solution to dryness in the same manner as 
before. In either case, stoichiometric quantities of reagents should be 
employed in order to ensure completeness of reaction and maximum yields of 
the desired final product. 
As previously indicated, the spiro-imide compounds of this invention reduce 
lens sorbitol levels in diabetic subjects. For instance, 
2,3-dihydro-spiro-]1H-indene-1,3'-pyrrolidine]-2',5'-dione, a typical and 
preferred agent of the present invention, has been found to inhibit the 
formation of sorbitol levels in the sciatic nerve of diabetic rats to a 
significant degree when given by the oral route of administration at a 
dose level as low as 2.5 mg./kg. without showing any substantial signs of 
toxic side effects. The other compounds of this invention also cause 
similar results. Furthermore, the herein described compounds can be 
administered by either the oral or parenteral routes of administration 
without causing any significant untoward pharmacological side reactions in 
the subjects to whom they are so administered. These compounds are 
ordinarily administered in dosages ranging from about 0.25 mg. to about 25 
mg. per kg. of body weight per day, although variations will necessarily 
occur depending upon the actual condition of the subject being treated and 
the particular route of administration chosen. 
The spiro-imide compounds of this invention may be administered either 
alone or in combination with pharmaceutically acceptable carriers, and 
such administration can be carried out in both single and multiple 
dosages. The compounds of this invention can be administered in a wide 
variety of dosage forms, i.e., they may be combined with various 
pharmaceutically-acceptable inert carriers in the form of tablets, 
capsules, lozenges, troches, hard candies, powders, sprays, aqueous 
suspensions, injectable solutions, elixirs, syrups, and the like. Such 
carriers include solid diluents or fillers, sterile aqueous media and 
various non-toxic organic solvents. The oral pharmaceutical formulations 
can be suitably sweetened and/or flavored by means of various agents of 
the type commonly employed for such purposes. In general, the compounds of 
the invention are present in such dosage forms at concentration levels 
ranging from about 0.5% to about 90% by weight of the total composition, 
i.e., in amounts which are sufficient to provide the desired unit dosage. 
For purposes of oral administration, tablets containing various excipients 
such as sodium citrate, calcium carbonate and calcium phosphate may be 
employed along with various disintegrants such as starch and preferably 
potato or tapioca starch, alginic acid and certain complex silicates, 
together with binding agents such as polyvinylpyrrolidone, sucrose, 
gelatin and acacia. Additionally, lubricating agents such as magnesium 
stearate, sodium lauryl sulfate and talc are often very useful for 
tabletting purposes. Solid compositions of a similar type may also be 
employed as fillers in soft and hard-filled gelatin capsules; preferred 
materials in this connection would also include the high molecular weight 
polyethylene glycols. When aqueous suspensions and/or elixirs are desired 
for oral administration, the essential active ingredient therein may be 
combined with various sweetening or flavoring agents, coloring matter or 
dyes, and if so desired, emulsifying and/or suspending agents as well, 
together with such diluents as water, ethanol, propylene glycol, glycerin 
and various combinations thereof. 
For parenteral administration, solutions of these spiro-imides in sesame or 
peanut oil or in aqueous propylene glycol or N,N-dimethylformamide may be 
employed, as well as sterile aqueous solutions of the corresponding 
water-soluble, alkali metal or alkaline-earth metal salts previously 
enumerated. Such aqueous solutions should be suitably buffered if 
necessary and the liquid diluent first rendered isotonic with sufficient 
saline or glucose. These particular aqueous solutions are especially 
suitable for intravenous, intramuscular, subcutaneous and intraperitoneal 
injection purposes. The sterile aqueous media employed are all readily 
obtainable by standard techniques well-known to those skilled in the art. 
Additionally, it is also possible to administer the aforesaid spiro-imide 
compounds topically via an appropriate ophthalmic solution which can then 
be applied dropwise to the eye. 
The activity of the compounds of the present invention, as agents for the 
control of chronic diabetic complications, is determined by their ability 
to successfully pass one or more of the following standard biological 
and/or pharmacological tests, viz., (1) measuring their ability to reduce 
or inhibit sorbitol accumulation in the sciatic nerve of acutely 
streptozotocinized (i.e., diabetic) rats; (2) measuring their ability to 
reverse already-elevated sorbitol levels in the sciatic nerve and lens of 
chronic streptozotocin-induced diabetic rats; (3) measuring their ability 
to prevent or inhibit galactitol formation in the lens of acutely 
galactosemic rats, and (4) measuring their ability to delay cataract 
formation and reduce the severity of lens opacities in chronic 
galactosemic rats. 
PREATION A 
6-Fluoro-4-chromanone was prepared according to the procedure described by 
R. Sarges in U.S. Pat. No. 4,117,230, starting from 
.beta.-(p-fluorophenoxy)propionic acid [Finger et al., Journal of the 
American Chemical Society, Vol. 81, p. 94 (1959)] and using polyphosphoric 
acid as the condensing agent. The product obtained was identical in every 
respect with the prior art compound. 
PREATION B 
6,7-Dichlorothiochroman-4-one was prepared according to the procedure 
described by R. Sarges in U.S. Pat. No. 4,117,230, starting from 
3,4-dichlorobenzenethiol (available from the Aldrich Chemical Company, 
Inc., Milwaukee, Wis.) and proceeding thru 
.beta.-(3,4-dichlorophenylthio)propionic acid, which was then condensed in 
the presence of concentrated sulfuric acid to afford the desired product. 
The latter material was identical in every respect with the prior art 
compound. 
PREATION C 
The procedure described by J. A. Faust et al., in the Journal of the 
American Pharmaceutical Association, Vol. XLVI, No. 2, p. 118 (1957), for 
the preparation of 
1,2,3,4-tetrahydro-spiro-[naphthalene-2,3'-pyrrolidine]-2',5'-dione, 
starting from 2-carboxy-1,2,3,4-tetrahydronaphthaleneacetic acid and using 
28% aqueous ammonia as the reagent, was followed here except that 
1-carboxy-1,2,3,4-tetrahydro-1-naphthaleneacetic acid was the actual 
starting material employed in place of the corresponding 2-positional 
isomer. In this particular case, the corresponding final product obtained 
was 3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione, m.p. 
153.degree.-156.degree. C. (literature m.p. 155.degree.-157.degree. C., 
according to R. V. Sandberg in U.S. Pat. No. 3,507,881). 
Anal. Calcd. for C.sub.13 H.sub.13 NO.sub.2 : C, 72.54; H, 6.09; N, 6.51. 
Found: C, 72.19; H, 6.17; N, 6.30.

EXAMPLE 1 
A mixture consisting of 10 g. (0.0758 mole) of 1-indanone (available from 
the Aldrich Chemical Company, Inc., Milwaukee, Wis.), 12 ml. (12.6 g., 
0.1115 mole) of ethyl cyanoacetate, 3 ml. of glacial acetic acid and 3 g. 
of ammonium acetate in 100 ml. of benzene was heated under reflux in a 
suitable reaction flask equipped with a Dean-Stark trap (water separator) 
for a period of 18 hours. An additional 2 g. of ammonium acetate were then 
added, followed by further refluxing for a period of 24 hours. At the end 
of this time, the spent reaction mixture was cooled to room temperature 
(.about.25.degree. C.), diluted with benzene and then washed with water. 
The separated organic layer was subsequently dried over anhydrous 
magnesium sulfate and filtered, followed by removal of the solvent via 
evaporation under reduced pressure. In this manner, there was obtained a 
crystalline residue which was later recrystallized from ethyl acetate to 
yield 12 g. (70%) of pure .alpha.-cyano-.alpha.-(2,3-dihydro-1H-indene-1 
-ylidene)acetic acid ethyl ester, m.p. 98.degree.-101.degree. C. 
To a stirred solution consisting of 3.0 g. (0.0132 mole) of the 
1-indenylidene compound obtained above dissolved in 20 ml. of ethanol at 
room temperature (.about.25.degree. C.), there were added 2.5 g. (0.0385 
mole) of potassium cyanide dissolved in 20 ml. of water. The resulting 
mixture was then refluxed for a period of 20 minutes and at the end of 
this time, it was cooled and subsequently acidified with concentrated 
hydrochloric acid. The spent reaction mixture was then extracted three 
times with benzene and the benzene layers were saved, and subsequently 
combined and evaporated to near dryness while under reduced pressure to 
afford a highly viscous residue. The latter residue was then dissolved in 
15 ml. of glacial acetic acid, and the resulting solution subsequently 
treated with 28 ml. of 12 N hydrochloric acid and refluxed for a period of 
48 hours. At the end of this time, the strongly acid solution was cooled 
to room temperature and concentrated in vacuo to afford a residue that 
later was triturated with water. The precipitated solids so obtained were 
then recovered by means of suction filtration and thereafter 
recrystallized from ethanol to give 1.26 g. (43%) of pure (2,3-dihydro-1 
H-indene-1-yl)butanedioic acid, m.p. 185.degree.-187.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.12 O.sub.4 : C, 65.44; H, 5.49. Found: C, 
65.39; H, 5.53. 
A mixture consisting of 3.0 g (0.0136 mole) of the above diacid and 3.5 ml. 
of concentrated ammonium hydroxide was heated in an oil bath maintained at 
260.degree. C., allowing the liquid to be removed from the mixture by 
means of distillation under reduced pressure (a pressure of 60 mm. Hg was 
actually employed). The residue so obtained was then triturated with 
isopropanol, and the resulting precipitated solids were subsequently 
recovered by means of suction filtration and thereafter recrystallized 
from ethyl acetate to yield 1.3 g. (48%) of pure 
2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione, m.p. 
148.degree.-150.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.11 NO.sub.2 : C, 71.72; H, 5.51; N, 6.96. 
Found: C, 71.31; H, 5.56; N, 6.93. 
EXAMPLE 2 
A mixture consisting of 3.0 g. (0.017 mole) of 6-chloro-4-chromanone 
(available from the Aldrich Chemical Company, Inc., Milwaukee, Wisconsin), 
15 ml. (15.75 g., 0.1394 mole) of ethyl cyanoacetate and 10 g. of ammonium 
acetate in 300 ml. of benzene was heated according to the procedure 
described in Example 1 (where the corresponding 1-indanone compound was 
the starting material employed) to give 1.3 g. (29%) of crude ethyl 
.alpha.-cyano-.alpha.-(6-chloro-2,3-dihydro-4H-1-benzopyran-4-ylidene)acet 
ic acid ethyl ester, which was used in the next reaction step without any 
further purification being necessary. 
To a stirred solution consisting of the above benzopyranylidene compound 
(1.3 g., 0.00493 mole) in 9.5 ml. of ethanol, there were added 1.13 g. of 
potassium cyanide in 9.5 ml. of water and the resulting mixture was 
refluxed according to the procedure described in Example 1 (where the 
corresponding 1-indenylidene compound was the starting material employed) 
and worked up in essentially the same manner as before (except that the 
residue was dissolved in 6 ml. of glacial acetic acid and treated with 
12.7 ml. of concentrated hydrochloric acid prior to refluxing for the last 
time). In this manner, there was ultimately obtained 0.39 g. (29%) of 
crude .alpha.-(6-chloro-2,3-dihydro-4H-1-benzopyran-4-yl)butanedioic acid, 
m.p. 189.degree.-190.5.degree. C. after further recrystallization from 
ethanol. 
A mixture consisting of 237 mg. (0.00088 mole) of the above diacid and 4.5 
ml. of concentrated ammonium hydroxide was then heated in the same manner 
as described in Example 1 for the corresponding 1-carboxy-1-indanacetic 
acid and isolated in the same manner as before to give pure 
6-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione, 
m.p. 225.degree.-226.degree. C. after recrystallization from ethyl 
acetate/ethanol/n-hexane. 
Anal. Calcd. for C.sub.12 H.sub.10 ClNO.sub.3 : C, 57.27; H, 4.00; N, 5.57. 
Found: C, 57.25; H, 4.00; N, 5.54. 
EXAMPLE 3 
A mixture consisting of 10 g. (0.0758 mole) of 2-indanone (available from 
the Aldrich Chemical Company, Inc., Milwaukee, Wis.), 8.6 g. (0.0761 mole) 
of ethyl cyanoacetate, 1 ml. of piperidine and 1 ml. of glacial acetic 
acid in 65 ml. of benzene was heated under reflux in suitable reaction 
flask equipped with a Dean-Stark trap for a period of 18 hours. Upon 
completion of this step, the reaction mixture was cooled to room 
temperature (.about.25.degree. C.) and poured into 250 ml. of water, 
followed by separation of the resulting organic layers and then drying of 
same over anhydrous magnesium sulfate. After removal of the drying agent 
by means of filtration and the solvent by means of evaporation under 
reduced pressure, there was obtained a crystalline residue, which was 
subsequently recrystallized from n-hexane to yield 6.5 g. (38%) of pure 
.alpha.-cyano-.alpha.-(2,3-dihydro-1H-indene-2-ylidene)acetic acid ethyl 
ester, m.p. 112.degree.-114.degree. C. [literature m.p. 116.degree. C., 
according to the Journal of the Chemical Society, Vol. 115, p. 150 
(1919)]. 
Anal. Calcd. for C.sub.14 H.sub.13 NO.sub.2 : C, 73.99; H, 5.76; N, 6.17. 
Found: C, 74.10; H, 5.84; N, 6.22. 
To a stirred solution consisting of 6.5 g. (0.0286 mole) of the 
2-indenylidene compound obtained above dissolved in 35 ml. of ethanol at 
room temperature, there were added 3.8 g. (0.0385 mole) of potassium 
cyanide dissolved in 35 ml. of water and the resulting mixture was 
refluxed for a period of 15 minutes according to the procedure described 
in Example 1 (where the corresponding 1-indanone compound was the starting 
material employed) and worked up in essentially the same manner as before 
(except that ethyl acetate rather than benzene was the solvent employed in 
the extraction step, and the residue was dissolved in 25 ml. of glacial 
acetic acid and treated with 50 ml. of concentrated hydrochloric acid 
prior to refluxing for the last time). However, in this particular case, 
the final residue obtained was diluted with 50 ml. of water and then 
extracted three times with ethyl acetate, followed by a re-extraction of 
the combined organic layers (three times) with dilute aqueous sodium 
bicarbonate solution. On acidification of the combined aqueous layers with 
6 N hydrochloric acid, there was finally obtained a fine crystalline 
precipitate, which was subsequently collected by means of suction 
filtration and air dried to constant weight to yield 4.5 g. of crude 
product. Recrystallization of the latter material from ethyl 
acetate/n-hexane then gave 3.1 g. (49%) of pure 
.alpha.-(2,3-dihydro-1H-indene-2-yl)butanedioic acid, m.p. 
166.degree.-168.degree. C. 
A mixture consisting of 1.5 g. (0.0068 mole) of the above diacid and 2.0 
ml. of concentrated ammonium hydroxide was heated gradually to 300.degree. 
C. (bath temperature) according to the same general procedure described in 
Example 1 for the preparation of the corresponding 1-isomer. The residue 
so obtained was then cooled to room temperature and dissolved in 200 ml. 
of isopropanol, followed by treatment with charcoal and filtration in the 
usual manner. The clear alcoholic filtrate which resulted was then 
concentrated in vacuo to ca. 75 ml. and the desired product was allowed to 
crystallize slowly therefrom while at room temperature. The precipitated 
solids (480 mg.) were subsequently collected by means of suction 
filtration and thereafter recrystallized from isopropanol to give 260 mg. 
(19%) of pure 2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione, 
m.p. 173.degree.-175.degree. C. 
Anal. Calcd. for C.sub.12 H.sub.11 NO.sub.2 : C, 71.62; H, 5.51; N, 6.96. 
Found: C, 71.65; H, 5.58; N, 6.91. 
EXAMPLE 4 
A mixture consisting of 10 g. (0.0657 mole) of 
6,7-dihydrobenzo(b)thiophene-4(5H)-one (available from the Aldrich 
Chemical Company, Inc., Milwaukee, Wis.), 7.5 g. (0.0664 mole) of ethyl 
cyanoacetate, 1 ml. of piperidine and 1 ml. of glacial acetic acid in 65 
ml. of benzene was heated according to the general procedure described in 
Example 1 (where the corresponding 1-indanone compound was the starting 
material employed) to ultimately give (after distillation of the oily 
residue) 4.5 g. (28%) of pure 
.alpha.-cyano-.alpha.-[6,7-dihydro-5H-benzo(b)thiophene-4-ylidine]acetic 
acid ethyl ester, b.p. 156.degree.-160.degree. C./0.3 mm Hg. 
To a stirred solution consisting of 4.5 g. (0.0182 mole) of the 
4-thiopheneylidene compound obtained above dissolved in 20 ml. of ethanol, 
there were added 2.34 g. (0.036 mole) of potassium cyanide dissolved in 20 
ml. of water and the resulting mixture was refluxed according to the 
procedure described in Example 1 (where the corresponding 1-indenylidene 
compound was the starting material employed) and work-up in essentially 
the same manner as before. In this manner, there were ultimately obtained 
2.83 g. (65%) of pure 
.alpha.-[6,7-dihydro-5H-benzo(b)thiophene-4-yl]butanedioc acid, m.p. 
164.degree.-167.degree. C. 
A mixture consisting of 1.4 g. (0.00583 mole) of the above diacid and 2.0 
ml. of concentrated ammonium hydroxide was then heated in the same manner 
as described in Example 1 for the corresponding 1-carboxy-1-indanacetic 
acid and isolated in the same manner as before to ultimately yield 290 mg. 
(23%) of pure 
6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dione, 
m.p. 188.degree.-190.degree. C. after recrystallization from 
isopropanol/diethyl ether. 
Anal. Calcd. for C.sub.11 H.sub.11 NO.sub.2 S: C, 59.70; H, 5.01; N, 6.33. 
Found: C, 59.87; H, 5.17; N, 6.48. 
EXAMPLE 5 
A solution consisting of 760 mg. (0.0048 mole) of .alpha.-cyanotetralin 
[Chemical Abstracts, Vol. 47, p. 80576 (1953)] dissolved in 15 ml. of dry 
dimethylformamide was heated to 45.degree. C. in a three-necked 
round-bottomed reaction flask, while under a dry nitrogen atmosphere, with 
228 mg. (0.0050 mole) of 56% sodium hydride (in mineral oil) for a period 
of 45 minutes. At the end of this time, 0.6 ml. (969 mg., 0.00723 mole) of 
3-bromopropanenitrile was added to the mixture and the latter mixture was 
then stirred at room temperature (.about.25.degree. C.) overnight for a 
period of approximately 16 hours. The resulting reaction mixture was then 
diluted with water, followed by the addition of 600 ml. of ethyl acetate 
to the cooled aqueous mixture. The separated organic layer was then washed 
with water and dried over anhydrous magnesium sulfate. After removal of 
the drying agent by means of filtration and the solvent by means of 
evaporation under reduced pressure, there was obtained 1.1 g. of crude 
.alpha.-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dinitrile in the 
form of an oil as residue. 
A mixture consisting of 2.2 g. (0.0105 mole) of the above crude dinitrile 
in 25 ml. of ethanol and 23 ml. of 4 N aqueous potassium hydroxide was 
heated under reflux for a period of two days. At the end of this time, the 
reaction mixture was cooled to room temperature (.about.25.degree. C.) and 
diluted with 50 ml. of water and 300 ml. of methylene chloride, followed 
by treatment with 3 N hydrochloric until acidification was achieved. The 
resulting organic layer was then collected and subsequently extracted 
three times with 4 N aqueous potassium hydroxide solution, followed by 
acidification of the combined aqueous layers and their subsequent 
extraction with fresh methylene chloride. Upon removal of the latter 
solvent from the final (i.e., separated) organic layer by means of 
evaporation under reduced pressure, there was obtained a crystalline 
residue which was subsequently recrystallized from ethylene 
chloride/n-hexane/diethyl ether to give 628 mg. (24%) of pure 
.alpha.-(3,4-dihydro-2H-naphthalene-1-yl)-n-pentane-1,5-dioic acid 
monoamide, m.p. 143.degree.-145.degree. C. 
Anal. Calcd. for C.sub.14 H.sub.17 NO.sub.3 : C, 67.99; H, 6.93; N, 5.66. 
Found: C, 67.50; H, 6.68; N, 5.47. 
A mixture consisting of 600 mg. (0.00243 mole) of the above acid-amide and 
20 ml. of concentrated ammonium hydroxide was heated according to the same 
general procedure described in Example 1 for a period of three hours to 
ultimately give (after isolation in the usual manner as before) 343 mg. 
(62%) of pure 
3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',6'-dione, m.p. 
173.degree.-175.degree. C. after recrystallization from ethanol/n-hexane. 
Anal. Calcd. for C.sub.14 H.sub.15 NO.sub.2 : C, 73.34; H, 6.59; N, 6.11. 
Found: C, 73.24; H, 6.47; N, 6.09. 
EXAMPLE 6 
The following spiro-imide compounds may be prepared by employing the 
procedures described in the previous examples, starting from readily 
available materials in each instance: 
6-methoxy-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione. 
6-fluoro-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione. 
5,6-dimethoxy-2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione. 
5-methoxy-2,3-dihydro-spiro-[1-H-indene-2,3'-pyrrolidine]-2',5'-dione. 
6-chloro-2,3-dihydro-spiro-[1H-indene-1,3'-piperidine]-2',5'-dione. 
6-bromo-2,3-dihydro-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione. 
5-methyl-2,3-dihydro-spiro-[1H-indene-1,3'-piperidine]-2',5'-dione. 
6-(n-butyl)-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione. 
5-phenyl-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione. 
5,6-dichloro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione. 
5,6-dimethyl-spiro-[1H-indene-2,3'-pyrrolidine]-2',5'-dione. 
7-methoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione. 
6,7-dimethoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dio 
ne. 
6-methoxy-3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',5'-dione. 
5-methoxy-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dione. 
7-fluoro-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione. 
7-chloro-3,4-dihydro-spiro-[2H-naphthalene-1,3'piperidine]-2',5'-dione. 
6-bromo-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dione. 
6-methyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione. 
7-(n-butoxy)-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dion 
e. 
6-phenyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dione 
6,7-dichloro-3,4-dihydro-spiro-[2H-naphthalene-1,3'-pyrrolidine]-2',5'-dion 
e. 
6,7-diethyl-3,4-dihydro-spiro-[2H-naphthalene-1,3'-piperidine]-2',5'-dione. 
6,7-dimethoxy-3,4-dihydro-spiro-[2H-naphthalene-2,3'-pyrrolidine]-2',5'-dio 
ne. 
6-methoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 
6-methoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 
6-fluoro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 
6,7-dichloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5'-dion 
e. 
8-chloro-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 
6-bromo-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5-dione. 
6,8-dimethyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
6-(n-butyl)-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dion 
e. 
7-methyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-piperidine]-2',5'-dione. 
6-(n-butoxy)-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-di 
one. 
7-phenyl-2,3-dihydro-spiro-[4H-1-benzopyran-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dihyro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione. 
6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-di 
one. 
6-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
6-bromo-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione 
. 
6,7-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5' 
-dione. 
6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
7-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dion 
e. 
6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne. 
7-(n-butyl)-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'- 
dione. 
7-(n-butoxy)-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5' 
-dione. 
6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'dion 
e. 
6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'- 
dione. 
6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5' 
-dione. 
6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5 
'-dione. 
2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1-oxid 
e. 
6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1-oxide. 
8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1-oxide. 
6-bromo-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'-dione 
-1-oxide. 
6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1-oxide. 
6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-di 
one-1-oxide. 
6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1-oxide. 
6,8-dichloro-2,3-dihydro-spiro-[1H-1-benzothiapyran-4,3'-piperidine]-2',5'- 
dione-1-oxide. 
6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5' 
-dione-1-oxide. 
6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5 
'-dione-1-oxide. 
2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dione-1,1-di 
oxide. 
6-fluoro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1,1-dioxide. 
8-chloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1,1-dioxide. 
6-methyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1,1-dioxide. 
6-methoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-di 
one-1,1-dioxide. 
6-phenyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5'-dio 
ne-1,1-dioxide. 
6,8-dichloro-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-piperidine]-2',5'- 
dione-1,1-dioxide. 
6,7-dimethyl-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5' 
-dione-1,1-dioxide. 
6,7-dimethoxy-2,3-dihydro-spiro-[4H-1-benzothiapyran-4,3'-pyrrolidine]-2',5 
'-dione-1,1-dioxide. 
2-chloro-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-di 
one. 
2-bromo-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-dio 
ne. 
2-methyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-di 
one. 
2-methoxy-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-d 
ione. 
2-phenyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5'-di 
one. 
2,3-dichloro-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5 
'-dione. 
2,3-dimethyl-6,7-dihydro-spiro-[5H-benzo(b)thiophene-4,3'-pyrrolidine]-2',5 
'-dione. 
2,3-dimethoxy-6,7-dihydro-spiro-[5H-benzo(b)-thiophene-4,3'-pyrrolidine]-2' 
,5'-dione. 
spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2-chloro-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2-(n-propyl)-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2-ethoxy-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2-phenyl-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dichloro-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dimethyl-spiro-[cyclopenta(b)thiophene-4,3'-pyrrolidine]-2',5'-dione. 
6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-chloro-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-methyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-methoxy-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione 
. 
2-phenyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dichloro-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-di 
one. 
2,3-dimethyl-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-di 
one. 
2,3-dimethoxy-6,7-dihydro-spiro-[5H-benzo(b)furan-4,3'-pyrrolidine]-2',5'-d 
ione. 
spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-chloro-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-methyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-methoxy-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2-phenyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dichloro-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
2,3-dimethyl-spiro-[cyclopenta(b)furan-4,3'-pyrrolidine]-2',5'-dione. 
EXAMPLE 7 
The sodium salt of 
3,4-dihydro-spiro-[1H-indene-1,3'-pyrrolidino]-2',5'-dione may be prepared 
by dissolving said compound in water containing an equivalent amount in 
moles of sodium hydroxide and then freeze-drying the mixture. In this way, 
the desired alkali metal salt of the imide is obtained in the form of an 
amorphous powder which is freely-soluble in water. 
In like manner, the potassium and lithium salts are also similarly 
prepared, as are the other alkali metal salts of all the other spiro-imide 
compounds of this invention which are reported earlier in Preparation C 
and Examples 2-6, respectively. 
EXAMPLE 8 
The calcium salt of 
2,3-dihydro-spiro-[1H-indene-1,3'-pyrrolidine]-2',5'-dione may be prepared 
by dissolving said compound in water containing an equivalent amount in 
moles of calcium hydroxide and then freeze-drying the mixture. The 
corresponding magnesium salt is also prepared in like manner, as are all 
the other alkaline-earth metal salts not only of this particular compound, 
but also of those spiro-imides previously described in Preparation C and 
Examples 2-6, respectively. 
EXAMPLE 9 
A dry solid pharmaceutical composition may be prepared by blending the 
following materials together in the proportions by weight specified below: 
______________________________________ 
3,4-dihydro-spiro- 
[H-indene-1,3'-pyrrolidine]- 
2',5'-dione 50 
Sodium citrate 25 
Alginic acid 10 
Polyvinylpyrrolidone 10 
Magnesium stearate 5 
______________________________________ 
After the dried compound is thoroughly blended, tablets are punched from 
the resulting mixture, each tablet being of such size that it contains 200 
mg. of the active ingredient. Other tablets are also prepared in a similar 
fashion containing 25, 50 and 100 mg. of the active ingredient, 
respectively, by merely using the appropriate amount of the spiro-imide 
compound in each case. 
EXAMPLE 10 
A dry solid pharmaceutical composition may be prepared by combining the 
following materials together in the proportions by weight indicated below: 
______________________________________ 
2,3-Dihydro-[1H-indene-1,3-pyrrolidine]- 
2',5'-dione 50 
Calcium carbonate 20 
Polyethylene glycol, average molecular 
weight 4000 30 
______________________________________ 
The dried solid mixture so prepared is then thoroughly agitated so as to 
obtain a powdered product that is completely uniform in every respect. 
Soft elastic and hard-filled gelatin capsules containing this 
pharmaceutical composition are then prepared, employing a sufficient 
quantity of material in each instance so as to provide each capsule with 
250 mg. of the active ingredient. 
EXAMPLE 11 
The following spiro-imide compounds of Preparation C and Examples 1-5, 
respectively, were tested for their ability to reduce or inhibit sorbitol 
accumulation in the sciatic nerve of streptozotocinized (i.e., diabetic) 
rats essentially by the procedure described in U.S. Pat. No. 3,821,383. In 
the present study, the amount of sorbitol accumulation in the sciatic 
nerves was measured 27 hours after induction of diabetes. The compounds 
were administered orally at the dose levels indicated 4, 8 and 24 hours 
following the administration of streptozotocin. The results obtained in 
this manner are presented below in terms of percent inhibition (%) 
afforded by the test compound as compared to the case where no compound 
was administered (i.e., the untreated animal where sorbitol levels 
normally rise from approximately 50-100 mM/g. tissue to as high as 400 
mM/g. tissue in the 27-hour test period): 
______________________________________ 
Percent Inhibition (%) 
Compound 2.5 5.0 25 mg./kg. 
______________________________________ 
Product of Prep. C 
-- 46 -- 
Product of Ex. 1 
28 -- -- 
Product of Ex. 2 
-- 13 -- 
Product of Ex. 3 
-- -- 33 
Product of Ex. 4 
-- -- 51 
Product of Ex. 5 
-- -- 23 
______________________________________