Spiro-heteroazalones for treatment of diabetic complications

Spiro-heteroazolones are disclosed which are useful as aldose reductase inhibitors and as therapeutic agents for the treatment of complications arising from diabetes. Pharmaceutical compositions containing the spiro compounds and a method of treating diabetic complications are also disclosed.

Technical Field 
This invention relates to novel spiro-heteroazolones useful in the 
treatment of certain chronic complications arising from diabetes mellitus, 
such as diabetic cataracts, retinopathy and neuropathy, to pharmaceutical 
compositions containing such compounds and to a method of using these 
compounds. 
Background Art 
In the past various attempts have been made to obtain more effective oral 
anti-diabetic agents. Generally, these efforts have involved synthesis of 
new organic compounds, particularly sulfonyl ureas, and determination of 
their ability to substantially lower blood sugar levels when administered 
orally. However, little is known about the effect of organic compounds in 
preventing or alleviating chronic complications of diabetes, such as 
diabetic cataracts, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 
discloses aldose reductase inhibitors like 1,3-dioxo-lH-benz[d,e] 
isoquinoline-2(3H)-acetic acid and derivatives thereof to be useful for 
the treatment of these conditions. U.S. Pat. No. 4,117,230 teaches the use 
of certain hydantoins for treating complications of diabetes as aldose 
reductase inhibitors. Such aldose reductase inhibitors function by 
inhibiting the activity of the enzyme aldose reductase, which is primarily 
responsible for regulating the reduction of aldoses, such as glucose and 
galactose, to the corresponding polyols, such as sorbitol and galactitol, 
in humans and other animals. In this way unwanted accumulations of 
galactitol in the lens of galactosemic subjects and of sorbitol in the 
lens, or peripheral nervous cord and kidneys of various diabetic subjects 
are prevented or reduced. Accordingly, such compounds are of therapeutic 
value as aldose reductase inhibitors for controlling certain chronic 
diabetic complications, including those of an ocular nature, since it is 
known in the art that the presence of polyols in the lens of the eye leads 
to cataract formation, with a concomitant loss of lens clarity. 
Carr et al., U.S. Pat. No. 3,985,888, teach certain spiroalkanone-imides 
and their use as sedatives. European Patent Application Publication No. 
0065392 discloses certain spiro-succinimide derivatives and their use as 
aldose reductase inhibitors. 
Disclosure of Invention 
The compounds of the present invention are spiroheteroazolones of the 
formula 
##STR1## 
or a pharmaceutically acceptable salt thereof, wherein A is methylene, 
hydroxymethylene, or methine; Y is methylene, alkylmethylene, methine or 
alkylmethine, wherein alkyl in each instance has 1-4 carbon atoms; with 
the proviso that when A is methine, Y is methine or alkylmethine; 
Z is oxygen, sulfur, or nitrogen substituted by hydrogen; 
Q is nitrogen or nitrogen-N-oxide; and X is in the 3' position and is 
hydrogen, halo, alkyl, alkoxy having 1-4 carbon atoms, alkylthio, 
alkylsulfinyl, alkylsulfonyl, phenoxy, phenylthio, or nitro; or X is in 
the 2'-position and is hydrogen, alkyl or alkoxy having 1-4 carbon atoms; 
wherein alkyl in each instance has 1-4 carbon atoms; with the proviso that 
when Q is nitrogen-N-oxide, X is not alkylthio, alkylsufinyl or 
phenylthio. 
Preferred compounds include those wherein Z is nitrogen substituted by 
hydrogen, and Q is nitrogen or nitrogen-N-oxide. Further preferred are 
compounds wherein Y is methylmethylene, A is methylene or hydroxymethylene 
and X is hydrogen or chloro. Also preferred are compounds wherein A is 
methine, Y is methylmethine and X is hydrogen. 
Both mixtures of optically active isomers and partially or completely 
optically resolved isomers of the compounds claimed herein are within the 
scope of the present invention. 
Also embraced by the present invention are pharmaceutical compositions 
comprising a pharmaceutically acceptable carrier or diluent and a compound 
of formula I. The present invention further comprises a method of treating 
a diabetic host for diabetes-associated complications which comprises 
administering to the host an effective amount of a compound of formula I.

Detailed Description 
The numbering system of the spiro compounds of formula I is as shown. 
##STR2## 
The compounds are spiro[imidazolidine, oxazolidine or 
thiazolidine-4,5'(6'H)-quinoline or quinoline-N-oxide)]2,5-diones. The 
compounds can be substituted by X in the 2' or 3' positions and can be 
7',8'-dihydro derivatives. Diastereomers can be separated by methods known 
in the art such as recrystallization with a suitable solvent such as 
isopropanol, or trituration, for example, with an alcohol-ether solvent 
such as isopropanol-diethyl ether. The terms "Rel" and "(.+-.)" each mean 
a 1:1 racemic mixture of the two optically active enantiomers. 
When X is halo, halo includes fluoro, chloro, bromo and iodo. 
In the Synthetic Scheme a preparation of compounds of formula I is shown. 
Compounds of formulae IA-D are subclasses of compounds of formula I and 
are within the scope of the present invention. Starting diketone II 
wherein R is hydrogen or alkyl having 1-4 carbon atoms is reacted with 
ammonia in a refluxing solvent, such as benzene, which will remove the 
water of reaction as an azeotrope to obtain ketone eneamine III. When X is 
hydrogen, III is reacted with propynal in a polar aprotic organic solvent 
such as dimethylformamide at an initial temperature of between about 
-10.degree. and 25.degree. C., preferably about 0.degree. C., followed by 
a period of heating of between about 15 and 90 minutes, preferably about 
45 minutes, at a temperature of between about 100.degree. and 153.degree. 
C., preferably about 153.degree. C., to obtain tetrahydroquinoline 
derivative IV where X is hydrogen. 
When X is other than hydrogen, alkene aldehyde, V or VI, which are known 
compounds or can be prepared analogously to the known compounds, is 
reacted with ketone eneamine III in a polar, aprotic organic solvent such 
as dimethylformamide at between about -10.degree. and 25.degree. C., 
followed by heating at between about 100.degree. and 153.degree. C., to 
obtain tetrahydroquinoline derivative IV. 
##STR3## 
When Z is nitrogen substituted with hydrogen, the compound of formula IV 
can be reacted to obtain the corresponding compounds of formula IA, for 
example, by means of the methods described in U.S. Pat. No. 4.,117,230. A 
compound of formula IV is condensed with an alkali metal cyanide (e.g., 
sodium cyanide or potassium cyanide) and ammonium carbonate to form the 
desired spiro-hydantoin final product. This reaction is normally carried 
out in the presence of a reaction-inert polar organic solvent medium in 
which both the reactants and reagents are mutually miscible. Preferred 
organic solvents include cyclic ethers such as dioxane and 
tetrahydrofuran, lower alkylene glycols like ethylene glycol and 
trimethylene glycol, water-miscible lower alkanols such as methanol, 
ethanol and isopropanol, as well as N,N-di(lower alkyl) lower alkanoamides 
like N,N-dimethylformamide, N,N-diet,hylformamide and 
N,N-dimethylacetamide, etc. In general, the reaction is conducted at a 
temperature that is in the range of from about 20.degree. C. to about 
120.degree. C. for a period of about two hours to about four days. 
Although the amount of reactant and reagents employed in the reaction can 
vary to some extent, it is preferable to employ at least a slight molar 
excess of the alkali metal cyanide reagent with respect to the carbonyl 
ring compound starting material in order to effect maximum yield. Upon 
completion of the reaction, the desired product is easily isolated in a 
conventional manner, e.g., by first diluting the reaction mixture with 
water (boiling if necessary) and then cooling the resultant aqueous 
solution to room temperature, followed by acidification to afford the 
spiro-hydantoin compound in the form of a readily-recoverable precipitate. 
When X is 2'-alkoxy, the preferred method of preparing the corresponding 
compounds of formula I is according to the procedure of Dubas-Sluyter et 
al., Recueil Chim Pays Bas, 91, 157-160 (1972) wherein a compound of 
formula III is reacted with an alkyl propiolate VIII wherein R.sub.1 is 
alkyl having 1-4 carbon atoms, preferably methyl, in a polar aprotic 
solvent such as dimethylformamide or carbitol at a temperature range of 
between about 100.degree. and 153.degree. C., preferably about 153.degree. 
C., to obtain the hydroxy compound of formula IVA. It is to be understood 
that the compound of IVA may also be present as the 2-pyridone isomer. 
The compound of formula IVA is reacted with an a water soluble inorganic 
silver salt such as silver nitrate and aqueous base such as potassium 
hydroxide at a pH of between about 9 and 12, preferably about 10.5, and at 
a temperature of between about 0.degree. and 60.degree. C., preferably 
about 25.degree. C., to form a silver salt. The isolated silver salt is 
reacted with an alkyl iodide of the formula R.sub.2 -I wherein R.sub.2 is 
alkyl having 1-4 carbon atoms at a temperature of between about 25.degree. 
and 100.degree. C., preferably 60.degree. C., to obtain the 2-alkoxy 
quinoline derivative IVB. The conversion to compounds of formula I 
continues according to the procedures for, a compound of formula IV. 
When Z is oxygen, the compound of formula IV can be reacted to obtain the 
corresponding compounds of formula IA by means of the methods described, 
for example, in U.S. Pat. Nos. 4,226,875 and 4,267,342. In one procedure, 
a compound of formula IV is reacted with a trialkylsilyl cyanide, wherein 
each alkyl has 1-4 carbon atoms and is preferably methyl, to form the 
corresponding cyano trialkylsilyloxy derivative. The reaction is conducted 
in the presence of a Lewis acid catalyst, such as a zinc halide, aluminum 
halide or boron trifluoride, with zinc iodide being a preferred catalyst. 
Temperatures in the range of about 0.degree. C. to about 50.degree. C. are 
generally employed, preferably about 0.degree. C. to 20.degree. C., in an 
inert organic solvent, typically an ether such as diethyl ether, 
dimethoxyethane, tetrahydrofuran, dioxane and the like, or a 
halohydrocarbon such as methylene chloride, chloroform and similar 
solvents. The resulting cyano trialkylsilyloxy derivative is then 
converted to an alkyl-hydroxycarboximidate derivative by reaction with an 
acid in an alcohol solvent R.sub.4 OH. Suitable acids include hydrogen 
halides, especially hydrogen chloride. The alcohol R.sub.4 OH may be 
either a lower alkanol of 1 to 4 carbon atoms, benzyl alcohol or a 
substituted benzyl alcohol, the substituent including chloro, bromo, 
fluoro, hydroxy, alkyl of 1 to 3 carbon atoms and alkoxy of 1 to 3 carbon 
atoms. The reaction is generally conducted at temperatures in the range of 
about -10.degree. C. to about 25.degree. C., preferably at about 
0.degree. C. to 10.degree. C. 
The hydroxy carboximidate derivative may be converted directly to the 
desired spiro-oxazolidin-2,5dione IA by a number of methods. In all cases, 
a spiro4-alkoxy oxazolin-2-one is an intermediate and can, if desired, be 
isolated from the reaction mixture. However, it is generally preferred to 
convert directly without such isolation of the intermediate. The hydroxy 
carboximidate may be reacted with phosgene in the presence of a base such 
as triethylamine, or other trialkylamines having from 1 to 4 carbon atoms 
in each alkyl group, in an inert organic solvent such as an ether, for 
example, diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and the 
like. The phosgene is generally bubbled through the reaction solution at a 
temperature of about -10.degree. C. to about 10.degree. C., for about to 
15 minutes and the solution is subsequently stirred about 20.degree. C. to 
50.degree. C., preferably at about 25.degree. C. for about 12 to 48 hours, 
when the spiro-oxazolin-2-one is predominantly formed. This intermediate 
may then be converted to the desired spiro oxazolidin-2,5-dione IA either 
by a further perfusion of phosgene at about -10.degree. C. to about 
10.degree. C. for about 15 to 75 minutes, followed by stirring at room 
temperature for a further period of about 12 to 48 hours. Alternatively, 
an alkali metal carbonate, such as potassium or sodium carbonate, or 
ammonium carbonate can be added to a solution of the 15 intermediate in, 
for example, aqueous tetrahydrofuran, and stirred at a temperature of 
about 15.degree. C. to about .dbd. C., preferably at about 25.degree. C., 
for a period of about 6 to 24 hours to form the desired spirooxazolidin-2, 
5-dione IA. 
The desired spiro-oxazolidin-2,5-dione IA can also be prepared from the 
hydroxy carboximidate derivative by reaction with an alkyl haloformate, 
where the alkyl group is of 1 to 4 carbon atoms, a preferred reagent being 
ethyl chloroformate. The reaction is generally conducted by stirring the 
hydroxy carboximidate intermediate together with the alkyl haloformate in 
an inert solvent, such as pyridine, at a temperature of about -10.degree. 
C. to about 15.degree. C., preferably at about 0.degree. C. for a period 
of 30 minutes to about 2 hours, followed by heating the solution to a 
higher temperature, about 50.degree. C. to about 150.degree. C., 
preferably about 90.degree. C. to 120.degree. C., for example, to reflux 
temperature in pyridine, for about 2 to about 6 hours. If desired the 
spiro-oxazolidin-2-one intermediate can be isolated from the initial 
reaction mixture after heating the solution for relatively shorter 
periods, for example about 1 hour. 
The spiro-oxazolidin-2,5-diones can also be prepared from the hydroxy 
carboximidate derivative by reaction with 1,1'-carbonyl-diimidazole, the 
reaction being generally conducted at a temperature of about 50.degree. C. 
to 150.degree. C., preferably about 80.degree. C. to 110.degree. C., neat 
or in an inert organic solvent such as dioxane, tetrahydrofuran, 
dimethoxyethane, diethyl ether and the like, for a period of about 12 to 
36 hours. If desired, the intermediate spiro-oxazolin-2-one can be 
obtained by heating for only a relatively short period of time, for 
example, about 30 minutes to about 90 minutes. 
When Z is sulfur, the compounds of formula IA can be prepared by taking 
advantage of the hydroxy carboximidate derivatives previously discussed. 
These are converted to chlorocarboximidate derivatives by heating with 
thionyl chloride at between about 35.degree. C. and the reflux temperature 
of about 79.degree. C. for 1-3 hours, preferably about 2 hours. The 
resulting chlorocarboximate derivatives are reacted with thiourea in a 
refluxing alkanol of 1-4 carbons, preferably ethanol, for about 15-90 
minutes, preferably 30 minutes, followed by a brief aqueous hydrolysis 
either during column chromatography on acidic silica gel, or in aqueous 
tetrahydrofuran or dioxane containing about 0.1 to 6N hydrochloric acid at 
about 0-60.degree. C., preferably about 25.degree. C. 
The compound of formula IA can be oxidized to the compound of formula IB 
wherein Q is nitrogen -N-oxide by any procedure known in the art. In one 
procedure, about 30 percent by volume aqueous hydrogen peroxide in an 
acidic solvent such as acetic acid at a temperature of between about 
0.degree. and 100.degree. C., preferably about 85.degree. C. This 
oxidation procedure should be avoided when X is alkylthio, alkylsulfinyl 
or phenylthio in order to prevent oxidation of the sulfur moiety on X. 
The compound of formula IB can be transformed into a compound of formula IC 
or ID by the reaction with acetic anhydride in acetic acid or neat 
containing a trace of water at a temperature range of between about 
60.degree. and 95.degree. C., preferably about 95.degree. C. 
The resulting acetate salt VII is reacted at about 0.degree.-60.degree. C., 
preferably about 25.degree. C., in an aqueous solvent such as water, 
aqueous tetrahydrofuran or aqueous dioxane at a pH of between about 10 and 
14, preferably about 13, to obtain IC and ID. The hydroxide aqueous 
solution relative amounts formed of these product depends upon the 
reaction temperature, pH and nature of the R substituent. 
Because of the acidic hydrogen atom in the spiro 5-membered heterocyclic 
ring of the compounds of formula I, salts may be formed with 
pharmaceutically acceptable cations by conventional methods. Thus, these 
salts may be readily prepared by treating the compound of formula I with 
an aqueous solution of the desired pharmaceutically acceptable cation and 
evaporating the resulting solution to dryness, preferably under reduced 
pressure. Alternatively, a lower alkyl alcohol solution of the compound of 
formula I may be mixed with an alkoxide of the desired cation and 
evaporated the solution subsequently to dryness. Suitable pharmaceutically 
acceptable cations for this purpose include, but are not limited to, 
alkali metal cations such as potassium and sodium, ammonium or water 
soluble amine addition salts such as the lower alkanolammonium and other 
base salts with organic amines which are pharmaceutically acceptable and 
alkaline earth metal cations such as calcium and magnesium. 
Acid addition salts can be formed for compounds of formula I when Q is 
nitrogen. Suitable salts include those derived from hydrochloric acid, 
sulfuric acid or methylsulfonic acid. These acid addition salts can be 
prepared by the addition of the appropriate strong acid to a lower 
alcoholic solution of a compound of formula I at a temperature of 
0.degree.-60.degree. C., preferably 25.degree. C., followed by 
concentration to obtain the desired product. Alternatively, an aqueous 
slurry of a compound of formula I can be mixed with the appropriate strong 
acid at about 0.degree. -60.degree. C., preferably about 25.degree. C., 
followed by freeze drying and recrystallization from a lower alcohol. 
Pharmaceutically acceptable salts are those which do not cause unacceptable 
adverse reactions when administered. 
The novel compounds of formula I and the pharmaceutically acceptable salts 
thereof are useful as inhibitors of the enzyme aldose reductase in the 
treatment of chronic complications of diabetes, such as diabetic 
cataracts, retinopathy and neuropathy. As used in the claims and 
specification hereof, treatment is meant to include both the prevention 
and alleviation of such conditions. The compound may be administered to a 
subject in need of treatment by a variety of conventional routes of 
administration, including orally, parenterally and topically. In general, 
these compounds will be administered orally or parenterally at dosages 
between about 0.05 and 25 mg./kg. body weight of the subject to be treated 
per day, preferably from about 0.1 to 10 mg./kg. per day. However, some 
variation in dosage will necessarily occur depending on the condition of 
the subject being treated. The person responsible for administration will, 
in any event, determine the appropriate.. dose for the individual subject. 
The novel compounds of the invention may be administered alone or in 
combination with pharmaceutically acceptable carriers, in either single or 
multiple doses. Suitable pharmaceutical carriers include inert solid 
diluents or fillers, sterile aqueous solutions and various organic 
solvents. The pharmaceutical compositions formed by combining the novel 
compounds of formula I and the pharmaceutically acceptable carriers are 
then readily administered in a variety of dosage forms such as tablets, 
powders, lozenges, syrups, injectable solutions and the like. These 
pharmaceutical compositions can, if desired, contain additional 
ingredients such as flavorings, binders, excipients and the like. Thus, 
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, 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 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 for this include lactose or milk 
sugar and high molecular weight polyethylene glycols. When aqueous 
suspensions 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 desired, emulsifying or 
suspending agents, together with diluents such as water, ethanol, 
propylene glycol, glycerin and combinations thereof. 
For parenteral adminstration, solutions of the novel compound of formula I 
in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous 
solution may be employed. 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 adminsitration. In this connection, the sterile aqueous 
media employed are all readily available by standard techniques known to 
those skilled in the art. 
Compounds of formula I may not only be advantageously employed for the 
preparation of aqueous pharmaceutical compositions for parenteral 
administration, as described above, but more particularly for the 
preparation of pharmaceutical compositions suitable for use as ophthalmic 
solutions. Such ophthalmic solutions are of principal interest for the 
treatment of diabetic cataracts by topical administration and the 
treatment of such conditions in this manner is a preferred embodiment of 
the present invention. Thus, for the treatment of diabetic cataracts the 
compounds of this invention are administered to the eye of the subject in 
need of treatment in the form of an ophthalmic preparation prepared in 
accordance with conventional pharmaceutical practice, see for example 
"Remington's Pharmaceutical Sciences" 15th Edition, pages 1488 to 1501 
(Mack Publishing Co., Easton, Pa.). The ophthalmic preparation will 
contain a compound of formula I, or a pharmaceutically acceptable salt 
thereof, in a concentration from about 0.01 to about 1% by weight, 
preferably from about 0.05 to about 0.5% in a pharmaceutically acceptable 
solution, suspension or ointment. Some variation in concentration will 
necessarily occur, depending on the particular compound employed, the 
condition of the subject to be treated and the like, and the person 
responsible for treatment will determine the most suitable concentration 
for the individual subject. The ophthalmic preparation will preferably be 
in the form of a sterile aqueous solution containing, if desired, 
additional ingredients, for example preservatives, buffers, tonicity 
agents, antioxidants and stabilizers, nonionic wetting or clarifying 
agents, viscosity-increasing agents and the like. Suitable preservatives 
include benzalkonium chloride, benzethonium chloride, chlorobutanol, 
thimerosal and the like. Suitable buffers include boric acid, sodium and 
potassium bicarbonate, sodium and potasssium borate, sodium and potassium 
carbonate, sodium acetate, sodium biphosphate and the like, in amounts 
sufficient to maintain the pH at between about 6 and 8, preferably between 
about 7 and 7.5. Suitable tonicity agents are dextran 40, dextran 70, 
dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride, 
and the like, such that the sodium -chloride equivalent of the ophthalmic 
solution is in the range 0.9 plus or minus 0.2%. Suitable antioxidants and 
stabilizers include sodium bisulfite, sodium metabisulfite, sodium 
thiosulfite, thiourea and the like. Suitable wetting and clarifying agents 
include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. 
Suitable viscosity-increasing agents include dextran 40, dextran 70, 
gelatin, glycerin, hydroxyethylcellulose, hydroxmethylpropylcellulose, 
lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl 
alcohol, polyvinylpyrrolidone, carboxymethylcellulose and the like. The 
ophthalmic preparation will be administered topically to the eye of the 
subject in need of treatment by conventional methods, for example in the 
form of drops or by bathing the eye in the ophthalmic solution. 
The activity of the compounds of the present invention as agents for the 
control of chronic diabetic complications may be determined by a number of 
standard biological or pharmacological tests. Suitable tests include (1) 
measuring their ability to inhibit the enzyme activity of isolated aldose 
reductase; (2) measuring their ability to reduce or inhibit sorbitol 
accumulation in the sciatic nerve and lens of acutely streptozotocinized, 
i.e. diabetic, rats; (3) measuring their ability to reverse 
already-elevated sorbitol levels in the sciatic nerve and lens of chronic 
streptozotocin-induced diabetic rats; (4) measuring their ability to 
prevent or inhibit galacticol formation in the lens of acutely 
galactosemic rats; (5) measuring their ability to delay cataract formation 
and reduce the severity of lens opacities in chronic galactosemic rats; 
(6) measuring their ability to prevent sorbitol accumulation and cataract 
formation in isolated rat lens incubated with glucose; and (7) measuring 
their ability to reduce already elevated sorbitol levels in isolated rat 
lens incubated with glucose. 
The present invention is illustrated by the following examples. It will be 
understood, however, that the invention is not limited to the specific 
details of these examples. Proton nuclear magnetic resonance spectra (NMR) 
were measured at 250 MHz (unless otherwise indicated) for solutions in 
perdeuterodimethyl sulfoxide (DMSO-d.sub.6) and peak positions are 
expressed in parts per million (ppm) downfield from tetramethylsilane. The 
peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, 
quartet; m, multiplet; b, broad; very, v. 
EXAMPLE 1 
rel 4,5'S 7'R Spiro[imidazolidine-4,5'(6'H)-quinoline]2,5'-dione 
7',8'-dihydro-7'-methyl 
To a solution of 13.3 g (0.138 mol) of ammonium carbonate and 3.8 g (0.058 
mol) potassium cyanide in 53 ml water was added a solution of 4.75 g 
(0.029 mol) 7-methyl, 7,8-dihydro-quinolin-5(6H)-one in 53 ml ethanol. The 
reaction was heated at 65.degree. C for 72 hours. The solution was cooled 
and filtered and the filtrate was brought to pH 6.5 at which point a gummy 
solid precipitated. The solid was filtered and washed well with water. 
Recrystallization from ethanol gave 2.0 g of the title compound: mp. 
252-254.degree. C. as a mixture composed of 80% of the rel 7'R methyl 
diastereomer and 20% of the rel 7'S methyl diastereomer. NMR DMSO-6): 
11.03 (vbs, lH); 8.76 (s, 0.8.times.lH); 8.47 (m, lH); 8.36 (s, 
0.2.times.lH); 7.68 (m, 0.2.times.lH); 7.46 (m, 0.8.times.lH); 7.27 (m, 
lH); 2.85-3.0 (m, lH); 2.35-2.6 (m, lH); 2.0-2.2 (m, lH); 1.75-2.0 (m, 
0.8.times.lH); 1.64 (t, 0.2.times.lH); 1.09 (d, 0.8.times.3H); and 1.05 
(d, 0.2.times.3H) ppm. 
EXAMPLE 2 
rel, 4,5'S 7'S 
Spiro[imidazolidine-4,5'(6'H)-quinoline]-2,5-dione-7',8'-dihydro-7'-methyl 
Concentration of the ethanol mother liquors from preparation of material 
enriched in the rel 4,5'S 7'R diastereomer of Example 1 and 
recrystallization from ethyl acetate gave 1.45 g of material which was 
recrystallized from water to give 860 mg of rel 4,5'S 7'S 
spiro[imidazolidine-4,5'(6'H)-quinoline]-2,5-dione-7',8'-dihydro-7'-methyl 
: mp 145-152.degree. C. as a mixture of 90% rel 7'S methyl diastereomer and 
10% rel 7'R methyl diastereomer. NMR (DMSO-d.sub.6) 10.88 (vb s, lH); 8.76 
(0..times.lH); 8.5 (m,lH); 8.36 (s, 0.9.times.lH); 7.68 (m, 0.9.times.lH); 
7.46 (m, 0..times.lH); 7.27 (m, lH); 2.9-3.05 (m,lH); 2.5-2.75 (m, lH); 
2.35-2.5 (m,lH); 2.05-2.15 (b d, lH); 1.75-1.95 (m, 0.1.times.lH); 1.64 
(t, 0.9.times. lH), 1.09 (d, 0.l.times.3H); and 1.05 (d, 0.9.times.3H) 
ppm. 
EXAMPLE 3 
rel 4,5'S 7'R 
Spiro[imidazolidine-4,5'(6'H)-quinoline]2,5-dione-7',8'-dihydro-7'-methyl- 
l'-oxide 
1.0 g (4.32 mmol) of a 65:35 diastereomer mixture of rel 4,5'S 7'R and 
4,5'S 7'S 
spiro[imidazolidine-4,5'(6'H)-quinoline]-2,5-dione-7',8'-dihydro-7'-methyl 
was dissolved in a solution of 0.72 ml (7.0 mmol) of 30 percent hydrogen 
peroxide in 3.0 ml glacial acetic acid and was heated at 85.degree. C for 
15 hours. A test for peroxide with potassium iodide-starch test paper 
showed no peroxide present. The reaction was concentrated in vacuo to an 
orange foam which was triturated witn an ethyl acetate, diethyl ether, 
methanol mixture to afford a tan colored solid amounting to 650 mg: mp 
185-195.degree. C. of a 75:25 mixture of the 4,5'S 7'R to 4,5'S 7'S 
diastereomers. NMR (DMSO-d.sub.6) 8.8 (b s, lH); 8.32 (m, lH); 7.35 (m, 
lH); 7.1 (m, lH); 3.05-3.35 (m, H); 1.8-2.6 (m, H); 1.15 (d, 
0.75.times.3H); and 1.10 (d, 0.25.times.3H) ppm. 
EXAMPLE 4 
rel 4,5'S 7'S 
Spiro[imidazolidine-4,5'(6'H)-quinoline]2,5-dione-7',8'-dihydro-7'-methyl- 
1'-oxide 
Concentration of mother liquors from precipitation of the rel 4,5'S 7'R 
diastereomer of Example 3 and trituration with one-to-one diethyl 
ether-hexane gave 60 mg of a 70:30 mixture of the 4,5'S-7'S to 4,5'S- 7'R 
diastereomers: mp 261-264.degree. C. NMR (DMSO-d.sub.6) 8.82 (s, 
0.3.times.lH); 8.46 (s, 0.7.times.lH); 8.3 (t, lH); 7.35 (d, 
0.7.times.lH); 7.1 (d; 0.3.times.lH); 3.05-3.35 (m,2H); 1.5-2.3 (m, 3H): 
1.15 (d, 0.3.times.3H); and 1.0 (d, 0.7.times.3H) ppm. 
EXAMPLE 5 
rel 4,5'S 7'S, 8'R 
Spiro[imidazolidine-4,5'(6'H)-quinoline]-2,5-dione-7',8'-dihydro-8'-hydrox 
y-7'-methyl 
2.7 g (11.68 mmol) of a 65:35 diastereomer mixture of rel 4,5'S 7'R and 
4,5'S 7'S 
spiro[imidazolidine-4,5'(6'H)-quinoline]-2,5-dione-7',8'-dihydro-7'-methyl 
was dissolved in a solution of 2.11 ml (20.5 mmol) of 30 percent hydrogen 
peroxide in 8.1 ml glacial acetic acid and was heated at 90.degree. C. for 
17 hours. A test for peroxide with potassium iodide-starch paper showed no 
peroxide present. The reaction was concentrated in vacuo to a yellow oil. 
Trituration with ethanol gave 3.35 g of a yellow foam after the solvent 
was removed in vacuo. To the foam (3.33 g) was added 14 ml acetic 
anhydride plus 2 drops of water and the reaction was stirred at 95.degree. 
C for 20 min to give a clear yellow solution. The reaction was 
concentrated in vacuo, ethanol was added and was reconcentrated in vacuo. 
Repetition of this procedure gave 3.8 g of a tan foam, which was slurried 
in 100 ml water and a 5 percent aqueous sodium hydroxide solution was 
added. The reaction mixture was stirred until a clear solution resulted. 
Thin layer chromatographic analysis (20% methanol, 80% chloroform eluent) 
on silica gel plates showed the appearance of four new more polar spots 
visible using 254 nanometer ultraviolet light. The solution was 
neutralized with concentrated hydrochloric acid to pH 7, and was extracted 
with five 100 ml portions ethyl acetate. After drying over anhydrous 
sodium sulfate, concentration in vacuo gave 1.84 g of a tan foam. 
Diastereomer Separation Products were separated by high pressure liquid 
chromatography using a Dupont 8800 HPLC, Zorbax preparative silica gel 
column, linear gradient starting from 95:5 methylene chloride-methanol to 
85:15 methylene chloride-methanol over 20 min., 20 ml/min flow rate with 
ultraviolet detection at 254 nanometers 1.33 g of crude product was 
dissolved in 7 ml of 95:5 methylene chloride-methanol. Injections of 0.5 
to 1.0 ml were made. Peaks corresponding to 5 components were isolated 
which did not correspond to the elution order observed by thin layer 
chromatographic analysis. 
Peak 1 by high pressure liquid chromatography (HPLC) corresponded to the 
2nd least polar spot by thin layer chromatography (TLC). Peak 2 by HPLC 
corresponded to the 3rd least polar spot by TLC. Peak 3 by HPLC 
corresponded to least polar spot by TLC. Peak 4 by HPLC exhibited 
retention time identical with the 3rd least polar spot by TLC: Peak 5 by 
HPLC corresponded to the most polar spot by TLC. 
Material corresponding to HPLC peak 1 was recrystallized from methanol to 
give material with mp 239-242.degree. C. Based on the following nuclear 
magnetic resonance spectral properties it was identified as rel 4,5'S 7'S, 
8'R spiro[imidazolidine-4,5'(6'H)quinoline]-2,5-dione- 
7',8'-dihydro-8'-hydroxy-7'methyl. NMR (DMSO-d.sub.6): 11.1 (b s, lH); 
8.86 (s, lH); 8.61 (m, lH): 7.50 (m, lH); 7.38 (m,lH); 5.35 (b s, lH); 
4.13 (d, lH, 8'-H, D.sub.2 O addition J=7.5Hz); 1.8-2.15 (m, 3H); and 1.15 
(d, 3H)ppm. 
rel 4,5'S 7'R, 8'S 
spiro[imidazolidine-4,5'(6'H)quinoline]-2,5-dione-7',8'-dihydro-8'-hydroxy 
-7'-methyl 
Material corresponding to HPLC peak 2 was recrystallized from diethyl 
ether-methanol-ethanol mixture to give material with mp 236-239.degree. C. 
Based on the following nuclear magnetic resonance spectral properties it 
was identified as the title compound. NMR (DMSO-d.sub.6) 10.9 (vb s, lH); 
8.60 (m, lH); 8.36 (s, lH); 7.61 (m, lH); 7.36 (m, lH); 5.28 (b s, lH); 
4.08 (d, lH, J =10Hz); 2.5 (m, lH); 2.1 (d, lH); 1.87 (t, lH); and 1.12 
(d,3H) ppm. 
rel 4,5'S spiro[imidazolidine-4,5'(6'H)-quinoline]2,5-dione-7'8'-dihydro 
8'-hydroxy-7'-methyl 
Material corresponding to HPLC peak 3 was recrystallized material with mp 
252-256.degree. C. Based on the following nuclear magnetic resonance 
spectral properties it was identifed as the title compound. NMR 
(DSO-d.sub.6): 10.85 (vb s, lH); 8.55 (m, lH); 8.47 (s, lH); 7.37 (s, lH); 
5.42 (m, lH); 4.44 (b d, lH, J =2.5Hz); 2.5 (m, lH); 2.17 (m, lH); 1.77 
(m, lH); and 0.96 (d, 3H) ppm. 
rel 4,5'S 7'S, 8'S 
spiro[imidazolidine-4,5'(6'H)-quinoline]2,5-dione-7',8'-dihydro-8'-hydroxy 
Material corresponding to HPLC peak 5 was recrystallized from diethyl ether 
to give material with mp 238-241.degree. C. Based on the following nuclear 
magnetic resonance spectral properites it was identified as the title 
compound. NMR (DMSO-d.sub.6): 11.06 (vb s, lH); 8.71 (s, lH); 8.56 (m, 
lH); 7.5 (m, lH); 7.37 (m, lH); 5.40 (d, lH); 4.37 (b s, lH, 8'-H, D20 
addition, J =2.5Hz); 2.32 (t, lH); 2.14 (m, lH); 1.59 (d, lH); and 1.06 
(d, 3H) ppm. 
EXAMPLE 6 
Spiro[imidazoline-4,5'(6'H)-quinoline]-2,5-dione 
3'-chloro-7',8'-dihydro-7'-methYl 
To a solution of 28.8 mg (0.44 mmol) of potassium cyanide and 100 mg (1.04 
mmol) ammonium carbonate in 4 ml ethanol and 4 ml water was added 40 mg 
(0.204 mmol) 3-chloro-7-methyl-7,8-dihydroquinolin-5(6H)-one and the 
reaction was stirred at 65.degree. C. for 24 hours. An additional 101 mg 
of ammonium carbonate was added and heating was continued for 72 hours. An 
additional 101 mg of ammonium carbonate and 3 ml ethanol and 2 ml water, 
was added and heating was continued at 65.degree. C. for 24 hours. An 
additional 101 mg ammonium carbonate was added and heating was continued 
for 6 days. The ethanol was removed from the dark reaction solution by 
concentration in vacuo. The residue was diluted with water and the pH was 
brought to 7 with aqueous hydrochloric acid and the reaction was extracted 
with two 50 ml portions ethyl acetate. After drying over anhydrous sodium 
sulfate the solution was concentrated in vacuo to 30 mg of a dark green 
solid. High resolution mass spectroscopic analysis confirmed the presence 
of the title compound. Calculated for C.sub.12 H.sub.12 N.sub.3 O.sub.2 Cl 
exact mass m/e 265.0619. Found: 265.0624. 
PREATION 
3-Chloro-7-methyl-7,8-dihydroquinolin-5(6H)-one 
To 2.14 g (0.018 mol) of 2-chloro-3-dimethylaminoacrolein in 20 ml 
dimethylformamide was added 2.25 g (0.018 mol) of 
3-amino-5-methyl-cyclohex-2-enone. The reaction was heated at reflux for 
40 hours. Most of the solvent was removed in vacuo and the residue was 
triturated with petroleum ether and concentrated in vacuo. This procedure 
was repeated three times. The resultant amber oil was tritured with 50 ml 
ethyl acetate and filtered to remove an insoluble black powder. The ethyl 
acetate mother liquors were concentrated in vacuo to give 1.54 g of a dark 
brown oil. This material (0.93 g) was subjected to column chromatography 
on silica gel using ethyl acetate as eluent. Material with R.sub.f of 0.45 
was isolated as a brown oil. The material was identified as largely 
containing the title compound based on the following spectral data. Mass 
spectrum bar peak m/e 195, ratio 195:197 were 3:1 corresponding to 
chlorine isotopes. NMR (DMSO-d.sub.6): 8.78 (d, lH, J=2.52Hz); 8.15 (d, 
lH, J=2.5 Hz); 2.2-3.2 (m, 5H); and 1.14 (d, 5H) ppm.