SPIRO-TRICYCLICAROMATIC SUCCINIMIDE DERIVATIVES AS INHIBITORS OF ALDOSE REDUCTASE

Abstract: Disclosed are substituted or unsubstituted planar tricy­ clic fluorene or nuclear analogs thereof, spiro-coupled to a five-membered ring containing a secondary amide, and the pharmaceutically acceptable salts thereof. These com­ pounds are useful, inter alia, in the treatment of diabetes. Also disclosed are processes for the preparation of such compounds; pharmaceutical compositions comprising such compounds; and methods of treatment comprising adminis­ tering such compounds and compositions when indicated for, inter alia, long term, prophylactic treatment of the diabetes syndrome.

Description: This invention relates to novel Spiro-tricyclicaromatic succinimide derivatives and related spiro-heterocyclic analogs such as spiro-tricyclicaromatic-thiazolidine-dione,-imidazolidinedione, and -oxazolidine-dione derivatives and more particularly to the compounds defined by claim 1, compositions containing such a compound as well as more of such compounds for the treatment of complications of diabetes mellitus in humans and animals. As disclosed in US-A-3 821 383, aldose reductase inhibitors such as 1,3-dioxo-1 H -benz[d,e]-isoquinoline-2-(3 H )-acetic acid, and its derivatives, are useful as inhibitors of aldose reductase and alleviators of diabetes mellitus complications. Spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and spiro-[imidazolidine-4,4'-thiochroman]2,5-dione and their derivatives, disclosed in US-A-4 130 714 and US-A-4 209 630 are also indicated as being useful in this regard. Certain spiro-polycyclicimidazolidinedione dervatives from US-A-4 181 728 have been demonstrated to have inhibitory activity against aldose reductase and polyol accumulation. US-A-4 117 230 describes a series of spiro-hydantoin compounds which include the 6-fluoro and 6,8-dichloro derivatives of spiro-chroman imidazolidmediones. Spiro-fluorenhydantoin and its derivatives are disclosed in US-A-4 436 745 and US-A-4 438 272 and corresponding EP-A-O 092 385, as being potent human and rat aldose reductase inhibitors which prevent polyol accumulation in lenticular and nervous tissues of diabetic and galactosemic rats and prevent cataract and nerve dysfunction in diabetic rats. Pan et al, J. Med. Chem. 7 , 31-38 (1964), describes halogenfluorenes as potential antitumor agents, and Pan et al, J. Med. Chem. 10 , 957-959 (1967), describes spiro [fluoren-9,4'-imidazolidine]-2,5'-diones as potential antitumor agents. Published EP-A-O 065 392 describes pharmaceutical compositions containing spiro-succinimide derivatives which are useful in the treatment or prophylaxis of the side effects of diabetes or galactosemia. The compounds disclosed in this European application, however, contain different substituents on the rings and contain a central 6 membered ring as opposed to the central 5 membered ring of the present invention. US-A-4 127 665 discloses thienohydantoin derivatives useful as aldose reductase inhibitors. The spirohydantoin disclosed in this patent, however, contains only two condensed rings and differs from the present invention in the basic ring systems. In contrast to this prior art, the invention provides a novel series of spiro-tricyclicaromatic succinimide derivatives and related spiro-heterocyclic analogs, which compounds are useful as inhibitors of aldose reductase and alleviators of diabetes mellitus complications. The invention further provides pharmaceutical compositions which may be used for inhibiting aldose reductase and the treatment of diabetes mellitus wherein the active ingredient comprises a spiro-tricyclicaromatic succinimide derivative or spiro-heterocyclic analog. Other objects and advantages of the present invention will become apparent as the description thereof proceeds. The compounds of the present invention are inhibitors of the enzyme aldose reductase and, while applicant is not bound by any theory, the pharmaceutical utility of the compounds of the present invention appears to correlate with their observed aldose reductase inhibitory property. The inhibition of the enzyme aldose reductase and related reductases results in the inhibition of abnormal polyol accumulation at the expense of NADPH in those tissues containing aldose reductase and/or related aldehyde reductases. The inhibition of the formation of a polyol, such as sorbitol or galactitol, arising from the reduction of an aldose, such as glucose or galactose respectively, is believed beneficial to delay the progression of certain complications arising from hyperglycemia or hypergalactocemia. Hyperglycemia is associated with the complications of neuropathy, nephropathy, retinopathy, cataract, glaucoma, and impaired wound healing in diabetes mellitus patients. According to US-A-3 821 383, aldose reductase inhibitors such as 1,3-dioxo-1 H -benz[d,e]-isoquinoline-2-(3 H )-acetic acid and its derivatives are useful as inhibitors of aldose reductase and alleviators of diabetes mellitus complications. Spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and spiro-[imidazolidine-4,4'-thichroman]2,5-dione and their derivatives from US-A-4 130 714 and US-A-4 209 630 have also proven useful in this regard. Certain spiro-polycyclicimidazolidinedione derivatives from US-A-4 181 728 have been demonstrated to have inhibitory activity against aldose reductase and polyol accumulation. Spiro-fluorenhydantoin and its derivatives, according to the above-mentioned US-A-4 436 745 and US-A-4 438 272 are potent human and rat aldose reductase inhibitors which prevent polyol accumulation in lenticular and nervous tissues of diabetic and galactosemic rats and prevent cataract and nerve dysfunction in diabetic rats. Such compounds inhibit the reduction of aldoses such as glucose and galactose to sorbitol and galactitol, thus preventing the harmful accumulation of polyols in certain nervous, ocular, and vascular tissues. Effective aldose reductase inhibitor chemotherapy prevents, improves, or delays the onset, duration, or expression of certain sequalae of diabetes mellitus which include ocular sequalae (e.g., cataract and retinopathy), kidney damage (nephropathy), neurological dysfunction (e.g., peripheral sensory neuropathy), vascular disease (e.g., diabetic micro- and macro-vasculopathies), impaired wound healing (e.g., impaired corneal reepithelialization) and heart disease. The discussion of the aldose reductase utility as described in US-A-4 209 630 is hereby incorporated herein by reference. As a result, the compounds of the present invention are of significant value as aldose reductase inhibitors, since it is already known in the art that aldose reductase inhibitors prevent diabetic cataract, nerve tissue damage, and certain vascular changes. In accordance with the present invention, it has been surprisingly found that various spirocyclic imide containing derivatives of the tricycle fluorene and related hetereocyclic analogs of fluorene and their derivatives are extremely useful as inhibitors of aldose reductase, espescially human aldose reductase. In a more preferred embodiment, the spiro-cyclic aromatic imides of the present invention are of the follwing general formula: wherein A, B, U, X, Y, R¹, R², R³, Z, and t are as defined in claim 1. In the compounds of Formula I, Rings A and B are attached to the central five-membered ring at positions 1,2 and 3,4. In more preferred embodiments, the cycloalkyl groups have 4 to 7 carbon atoms and lower alkyl groups have 1 to 6 carbon atoms. In an especially preferred embodiment, Ring A is selected from: Ring B is selected from: and U = O, S, NHR' X = H, F Y = H, F, Cl, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH t = CH₂, NH, O, S R' = H, -CH₃ Z = H, CH₂.Cl The compounds of the present invention have important geometric and chemical similarities. These similarities include a planar, rigid tricyclic fluorene or fluorene-like aromatic ring system spiro-coupled to a five-membered imide (or cyclic secondary amide) ring such as succinimide, hydantoin, thiazolidinedione or oxazolidinedione. These spirocyclic derivatives of the various tricycles each contain a polarizable and hydrogen-bondable secondary amide, also called imide, radical (-CO-NH-CO-) . In those instances where, according to general Formulae I and I-A, A does not equal B, the spiro carbon is chiral. Activity of any such racemic mixture may be attributable to only one isomer. Resolution, or direct synthesis, of the enantiomers, as is known in the art, is recognized as a method to isolate or prepare the active or the more active enantiomer. It is also recognized that certain patterns of substitution on A and/or B according to Formulae I and I-A may create asymmetry, and the resulting diastereomeric mixtures may be separated by chromatography or solvent recrystallizations, as is known and practiced in the art. For example, if A has a methylsulfoxyl substituent and A is different from B, then there are at least two chiral centers: the spiro carbon and the sulfoxide sulfur. Physical separation of this diastereomeric mixture by chromatography or other methods practiced in the art will yield two racemic mixtures, each containing a pair of enantiomers. Stereospecific oxidation of a methylsulfide on A to yield a methylsulfoxide (e.g., vis sodium metaperiodate and albumin) when A is different than B (according to Formula I) will yield a diastereomeric mixture, which then can be separated by conventional physical methods known in the art, such as liquid chromatography or differential solvent solubility, to yield the purified diastereomers which are themselves purified optical isomers. Reduction of the two optically active sulfoxide diastereomers will yield the optically active pair of enantiomers or mirror image isomers. Of special interest in this invention are typical and preferred specie of Formula I such as these racemic mixtures: spiro-(6-fluoro-4 H -indeno[1,2-b] thiopben -4,4'-imidazolidine)-2',5'-dione; spiro-(7-fluoro-9 H -pyrrolo[1,2-a] indol-9,4'-imidazolidine)-2',4'-dione; spiro-(2-fluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione; spiro-(6-fluoro-8 H -indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione; spiro-(2-fluoro-9 H -fluoren-9,3'-succinimide); spiro-(2-fluor-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione; spiro-(7-fluoro-9 H -indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione; spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione; spiro-(7-fluoro-5H-indeno [1,2-c]pyridin-5,4'-imidazolidine)-2',5'-dione; spiro-(7-fluoro-9 H -indeno[2,1-b] pyridin-5,4'-imidazolidine)-2',5'-dione; spiro-(7-fluoro-5 H -indeno[1,2-c] pyridin-5,5'-thiazolidine)-2',4'-dione; spiro-(7-fluoro-5 H -indeno[1,2-b] pyridin-5,5'-thiazolidine)-2',4'-dione; spiro-(7-fluoro-9 H -indeno[2,1-c]pyridin-9,5'-thiazolidine)-2',4'-dione; spiro-(7-fluoro-9 H -[2,1-b]pyridin-9,5'-thiazolidine)-2',4'-dione; spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,3'-succinimide; spiro-(7-chloro-5 H -[1,2-b]pyridin-5,5'-thiazolidine)-2',4'-dione; spiro-(7-chloro-5 H -[1,2-b]pyridin-5,5'-oxazolidine)-2',4'-dione; spiro-(6-fluoro-4 H -indeno[1,2-b]thiophen-4,5'-thiazolidine)-2',4'-dione; spiro-(6-chloro-8 H -indeno[2,1-b]thiophen-8,5'-thiazolidine)-2',4'-dione; spiro-(2-fluoro,7-methylthiol-9 H -fluoren-9-,5'-thiazolidine)-2',4'-dione. Also of special interest in this invention are these achiral or nonracemic compounds: spiro-(2,7-difluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione; spiro-(2,7-difluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione; spiro-(2,7-difluoro-9 H -fluoren-9, 3'-succinimide); spiro-(2,7-difluoro-9 H -fluoren-9,5'-oxazolidine)-2',4'-dione. All the aforementioned compounds are highly potent as regards their aldose reductase inhibitory activities. All of the aforementioned preferred compounds as in Formula I may be formulated as the base salts thereof with pharmacologically acceptable cations (e.g., sodium salt). Alternatively, several preferred examples such as spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,5'-thiazolidine)-2',4'-dione and related examples which contain a basic nitrogen in ring(s) A and/or B according to Formula I can be formulated as the acid salt with pharmacologically acceptable strong acids (e.g., hydrochloride salt). The novel compounds of the present invention are readily prepared from appropriate ketones of Formula II of their methylene analogs of Formula III: wherein A and B are previously defined with the exception that introduction of a nitro substituent(s) is conducted after hydantoin derivatization. Similarly, certain other derivatizations, e.g., esterification of carboxylic acids, oxidation of alkyl sulfides to sulfoxides or sulfones and direct aromatic halogenations may be conveniently performed after the tricyclic aromatic is spiro-imide derivatized, e.g., converted to the hydantoin or thiazolidinedione. In addition, certain labile protecting groups may be employed as is known and practiced in the art. The four major derivatization methods to transform tricycles of Formulas II and III into derivatives of Formula I follow. Method I - Spiro-Tricyclicimidazolidinediones (Hydantoin Derivatization) The novel spiro-hydantoin derivatives of the present invention are readily prepared from appropriate ketones of Formula II, wherein A and B are previously defined. For example, spiro-imidazolidinedione derivatives (29) and (41) are prepared respectively from 5 H -indeno[1,2-b]pyridin-5-one and 9 H -pyrrolo[1,2-a]indolin-9-one: Similarly, spiro-imidazolidinedione derivative (39) is prepared from its starting muterial ketone 8 H -indeno[2,1-b]thiophen-8-one: To synthesize a spiro-imidazolidinedione derivative, the ketone in Formula II is condensed with an alkali metal cyanide, such as potassium cyanide, and ammonium carbonate. The reaction is typically conducted in the presence of a ketone solubilizing inert polar organic solvent which include, but is not limited to, water miscible alcohols such as ethanol and isopropanol, lower alkylene glycols such as ethylene glycol and trimethylene glycol, N, N-di(lower alkyl), lower alkanoamides such as N,N-dimethyl-formamide, acetamide. In general, the reaction is conducted at temperatures ranging from 60°C to about 180°C (preferably 100°C to 130°C) for 6 hours to about 4 days, depending upon the ketone, solvent and temperature used. In general reagents in this reaction are employed in excess of stoichiometric amounts to provide maximum conversion of the ketone substrate to the spirohydantoin derivative. For example, a moderate excess of potassium cyanide (i.e., 1.1 equiv) and a 1.5 to 4 fold excess of ammonium carbonate achieves an increased yield of spirohydantoin derivative based upon ketone starting material. Reaction ketone substrates of Formula II are prepared by methods known to those skilled in the art. Typical preparative methods for substrate ketones are represented by, but are not limited to, examples in Table A and in the example preparations which follow. Method II - Spiro-Tricyclicthiazolidinediones The novel spiro-tricyclicthiazolidinedione derivatives of the present invention ire readily prepared from appropriate fluorene and heterocyclic analogs of fluorene derivatives of Formula III, wherein A and B are previously defined. For example, spiro-thiazolidinedione derivative (26) is prepared from 5 H -indeno[1,2-b]pyridine: Likewise, the spiro-thiazolidinedione of example (12) is prepared from its starting material 2-fluoro-9 H -fluorene: The synthesis of a spiro-thiazolidinedione from the corresponding tricyclic fluorene or heterocyclic fluorene derivative is a multi-stepped synthesis as depicted in Example IV. The first step involves metalation with a lower alkyl lithium reagent such as n-butyllithium in an inert aprotic solvent such as diethyl ether or tetrahydrofuran under an inert atmosphere of nitrogen or argon, e.g., metalation of 2-fluoro-9 H -fluorene: Metalation occurs primarily at the methylene bridge. Reaction with carbon dioxide results in carbonation of the bridge carbon to yield upon isolation the carboxylic acid, e.g., 2-fluoro-9 H -fluoren-9-carboxylic acid: Isolation of the carboxylic acid derivative can be accomplished by a process including acidification, simple column chromatography and solvent recrystallization similar to the process cited in Example IV. In contrast to this general case, metalation and carbonation of 8 H -indeno[1,2-c] thiophene results in a significant formation of 8 H -indeno[1,2-c] thiophene-1-carboxylic acid and 8 H -indeno[1,2-c] thiophene-3-carboxylic acid in addition to the desired 8 H -indeno [1,2-c] thiophene-8-carboxylic acid, MacDowell and Jefferies; J . Org . Chem ., 35 (1970) 871. The tricyclic carboxylic acid product is then esterified with a lower alkylalcohol such as methanol in the presence of an acid catalyst such is a hydrogen halide, such is hydrochloric acid. In a typical procedure, the acid (e.g., 2-fluoro-9 H -fluorene-9-carboxylic acid) is esterified by the addition of acetyl chloride to methanolic solution of the carboxylic acid with reflux: Proton abstraction from the acidic methine bridge of the carboxylic ester by in alkali alkoxide such as sodium metal in methanol or alkali hydride such as potassium hydride in DMSO or DMF generates a carbanion. Introduction of purified dry oxygen results in oxidation of the methine carbon. Bisulfite reduction and a simple work-up involving filtration results in the isolation of an α-hydroxy ester product, e.g., 2-fluoro-9-hydroxy-9 H -fluoren-9-carboxylic acid methyl ester: α-Halogenation of the α-hydroxy ester by a thionyl halide such as thionyl chloride at reflux transforms 2-fluoro-9-hydroxy-9 H -fluoren-9-carboxylic acid methyl ester into 9-chloro-2-fluoro-9 H -fluoren-9-carboxylic acid methyl ester: In a typical work-up procedure the cooled reaction mixture is diluted with benzene or a similar inert solvent, is known to those skilled in the art, and the solution is evaporated with reduced pressure and heat to yield the α-halo ester. The α-halo ester, e.g., 9-chloro-2-fluoro-9 H -fluoren-9-carboxylic acid methyl ester, is reacted with thiourea in an anhydrous polar high boiling relatively nonbasic solvent such as dioxane at reflux for 6-24 hours. Work-up and simple chromatography as is known to those skilled in the art results in the isolation of a spiro-tricyclicaminothiazolone product, e.g., spiro-[2-fluoro-9 H -fluoren-9,5'-(2'-amino-4'-thiazolone]: Hydrolysis of the spiro-aminothiazolone in an acidic aqueous alcoholic solution such as concentrated hydrochloric acid in methanol yields the spiro-thiazolidinedione, e.g., spiro-(2-fluoro-9 H -fluorene-9,5'-thiazolidine)-2',4'-dione. Reaction starting materials, tricyclic fluorene and tricyclic heterocyclic flourene derivatives of Formula III, are prepared by methods known to those skilled in the art. Typical preparative methods are represented by, but are not limited to, preparation examples of Table A and in the examples which later follow. Method III - Spiro-Tricyclicoxazolidinediones The novel spiro-tricyclic-oxazolidinedione derivatives of the present invention are readily prepared from appropriate derivatives of flourene and heterotricyclic analogs of fluorene of Formula III, wherein A and B are previously defined. The synthesis of the spiro-oxazolidinediones and spiro-thiazolidinediones (see II) generally have common synthetic intermediates. For example, spiro-tricyclic-oxazolidinedione derivative (6) is prepared from the tricyclic α-hydroxy ester, 2-fluoro-9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester, which is an intermediate in the synthesis of spiro-tricyclic-thiazolidinedione (12). Reaction of the α-hydroxy ester with 1 to 2 (preferably 1.1) equivalents of urea and 1 to 2 (preferably 1.05) equivalents of an alkali alkoxide in a lower alkyl alcohol at reflux such as sodium ethoxide in ethanol yields the spiro-tricyclic-oxazolidinedione. The isolation procedure involves the addition of water to the reaction, acidification with a mineral acid such as hydrochloric acid, simple filtration and column chromatography. Such common product isolation procedures are well known to those skilled in the art. The isolated product, in this example, is spiro-(2-fluoro--9 H -fluorene-9,5'-oxazolidinedione)-2',4'-dione. Similarly, other tricyclic α-hydroxy esters known in the art are derived from the appropriate fluorene derivitives and heterotricyclic analogs of fluorene derivatives, as are represented in but not limited by those examples cited in Table A and in the following example preparations, can be utilized to prepare spiro-tricyclicoxazolidinediones according to this general scheme: M+ = alkali metal cation (e.g., Na+) R = lower alkyl (e.g., methyl) A and B are as previously defined. Method IV - Spiro-Tricyclicsuccinimides The novel spiro-tricyclicsuccinimide derivatives of the instant invention are readily prepared from appropriate fluorene derivatives and heterocyclic analogs of fluorene of Formula III, wherein A and B are previously defined. The synthesis of the spiro-tricyclicsuccinimides, spiro-oxazolidinediones and spiro-thiazolidinediones generally have common synthetic intermediates. For example, spiro-tricyclicsuccinimide derivatives (20) and (21) are prepared from the tricyclic acid esters, 9 H -fluorene-9-carboxylic acid methyl ester and 2-fluoro-9 H -fluorene-9-carboxylic acid methyl ester respectively which are intermediates in the synthesis of spiro-tricyclicthiazolidinediones (9) and (12) and spiro-tricyclicoxazolidinediones (2) and (6). Reaction of the carboxylic alkyl ester with 1 to 1.5 equivalents (preferably 1.1) of an alkali metal alkoxide such as sodium methoxide in an alkyl alcohol such as methanol followed by reaction with 1-2 equivalents (preferably 1.1) of 2-haloacetamide such as 2-chloroacetamide (Aldrich Chemical, Inc.) at 10° to 50°C (preferably ambient temperature) under in inert atmosphere such as nitrogen for a period of 8 hrs. to 4 days depending upon temperature, haloacetamide reagent and solvent employed. Typical reaction times with methanol solvent, chloroacetamide reagent at room temperature can be 48 hrs. The reacted mixture is typically poured into 1-4X volume of 1-5% alkali hydroxide such as 2.5% sodium hydroxide. Insolubles are removed by filtration. The filtrate is acidified with a dilute or concentrated mineral acid such as concentrated hydrochloric acid and the resulting precipitate is collected by filtration with cold water wash. Solvent recrystallizations may be employed is is known in the art to further purify the resulting spiro-tricyclicsuccinimide product. Specifically, 9 H -fluorene-9-carboxylic acid methyl ester and 2-fluoro-9 H -fluorene-9-carboxylic acid methyl ester yield respectively, after the above treatment, spiro-(9 H -fluoren-9,3'-succinimide) and spiro-(2-fluoro-9 H -fluorene-9,3'-succinimide). Similarly, other tricycliccarboxylic acid eaters known in the art are derived from the fluorene derivatives and heterotricyclic analogs of fluorene and derivatives, as are represented in but not limited to those examples cited in Table A and in the following example preparations can be utilized to prepare spiro-tricyclicsuccinimides according to this general scheme: M+ = alkali metal cation (e.g., Na+, K+) X = Cl, Br, I R¹= lower alkyl R² = H, lower alkyl (preferably methyl) A and B are as previously defined Method V - Halogenation and Derivatization of Fluorene, Fluorenone and Their Indeno-Heterocycle Analogs and Derivatives Halogenation of fluorene and fluorenone and related indeno heterocycle analogs such as 4-azafluorene or 4-azafluorenone and as exampled in Table A where Q is dihydrogen and oxygen can be accomplished by methods known and practiced in the art (e.g., Eckert and Langecker, J . Prakt . Chem ., 118 , 263 (1928); Courot, Ann . Chem ., 14 , 5 (1930); Bell and Mulholland, J . Chem . Soc ., 2020 (1949); Johnson and Klassen, J . Chem . Soc ., 988 (1962)). In general, chlorination of fluorenone and flourene derivatives and related heterocyclic indeno analogs is accomplished by dissolving the substrate in glacial acetic acid containing anhydrous ferric chloride (10-20% by weight of substrate) and chlorine gas or chlorine dissolved in glacial acetic acid (1.2 to 3.0 molar equiv.) is added. The reaction is stirred at a selected temperature for several hours and allowed to cool; the crude product is isolated and solvent recrystallized to yield the chlorinated derivative. The structure-reactivity of tricyclic azines, nitrogen analogs of fluorenone and fluorene, to electrophillic halogenation has bean characterized by Mlochowski and Szulc, J . Prakt . Chem ., 322 (1980) 971. Fluorination of selected derivatives of fluorene (and fluorenone) and indeno heterocyclic analogs involves a multistepped process wherein the substrate is first nitrated (Kretor and Litvinov, Zh . Obsch . Khim ., 31 , 2585 (1961); Org . Syntheses , Coll . Vol . II , 447 (1943); Org . Syntheses , Coll . Vol . V , 30 (1973)). The resulting nitro derivative is reduced via Raney nickel and hydrazine, zinc dust and calcium chloride, iron filings and concentrated hydrochloric acid, palladium on carbon with hydrazine and other methods known in the art ( Org . Syntheses Coll . Vol . II , 447 (1943); Org . Syntheses Coll . Vol . Y , 30 (1973); Fletcher and Namkung, J . Org . Chem ., 23 , 680 (1958)). The resulting aromatic amino(s): (a) is subjected to the Schiemann reaction according to the method of Fletcher and Namkung, Chem . and Ind ., 1961 , 179, wherein the ammonium fluoroborate salt, prepared in the presence of tetrahydrofuran is first diazotized and then decomposed in hot xylene to yield the corresponding fluoro derivative. Oxidation of the fluoro derivative, e.g., 2-fluoro-9 H -fluorene, according to Sprinzak, J . Amer . Chem . Soc ., 80 , 5449 (1958) or by other oxidation procedures known and practiced in the art, yields the ketone, e.g., 2-fluoro-9 H -fluoren-9-one. In a general and novel process cited in U.S. Application Nos. 368,630 and 368,631 the fluorinated ketone is converted into the corresponding alkylsulfide, alkylsulfoxide and/or alkylsulfone. An alkaline metal alkylthiolate nucleophile (e.g., sodium methylthiolate in DMF) displaces fluoride to yield the corresponding alkylsulfide derivative, e.g., 2-methylthiol-9 H -fluoren-9-one. The resulting alkylsulfide derivative can be oxidized by known procedures (e.g., sodium metaperiodate or hydrogen peroxide) to the corresponding sulfoxide and/or sulfone; (b) as hydrogen halide salt(s) is diazotized by sodium nitrite. Replacement of the diazonium group(s) in these aromatic derivatives by a halo or cyano group(s) (e.g., via KCN) salts (Sandmeyer), copper powder (Gatterman) or cupric salts (Korner-Contardi). See Organic Synthesis Vol . I , p. 170 (1932): E. Pfeil, Angew . Chem ., 65 , 155 (1953); Y. Nakatani, Tetrahedron Lett ., 1970, 4455. As is known in the art, the resulting cyano derivatives can be hydrolyzed into carboxylic acids; alcoholyzed to carboalkoxy esters, e.g., carboethoxy esters; hydrolyzed to carboxamide; reduced to methylamine, etc., as is well known and practiced in the art. Other aromatic derivatizations can similarly be made by those skilled in the art. According to a general process of Teulin et al., J . Med . Chem ., 21 (1978) 901, tricyclic indeno derivatives with the general formula: (where B is a previously defined) are derivatized to the corresponding arylisopropanoic and arylacetic acids. The process involves the following synthetic steps: M ⊕ = Na ⊕ , K ⊕ X = Cl, Br, I In accordance with Method VII the aforementioned indeno derivatives can be oxidized to the corresponding ketones which are starting material substrates for spiro-hydantoin derivatization in accordance with Method I. A serial process involving several of the aformentioned processes can be employed to introduce for example a fluoro, and a chloro substituent into the same tricyclcic-aromatic substrate. Other fluorene and fluorenone derivatives and indeno heterocyclic analog derivatives can be prepared in accordance with common synthetic procedures known and practiced in the art. Finally, tricyclic aromatic azine derivative such as 5 H -indeno[1,2b] pyridine-5-one or 5H-indeno[1,2-b]pyridine, can be pyridine N-oxidized to yield the corresponding pyridine N-oxide derivative. Such an N-oxide is employed to prepare the corresponding spiro-hydantoin derivative according to Method I or spiro-oxazolidinedione and spiro-succinimide according to Methods III and IV respectively. For example, Method VI - The novel spiro-tricyclic-imidazolidinediones, -thiazolidinediones, -oxazolidinediones and -succinimides may be further derivatized according to the following. Nitrated fluorenone will not easily derivatize to form the corresponding spiro-hydantoin. The preferred method of preparation of spiro-hydantoin aromatic nitro derivatives is via direct nitration (e.g., via nitric acid and 60% sulfuric acid) of the spiro-cyclic derivatives, especially spiro-hydantoin (see Example XI). After nitration of the selected spiro-tricyclic-imidazolidinediones, -thiazolidinediones, -oxazolidinediones and succinimides by methods well known and practiced in the art, the corresponding aromatic nitro group(s) of corresponding spiro-tricyclic derivative(s) of the present invention can be reduced to the corresponding amine derivative(s). Aromatic nitro group(s) reduction to the aromatic amime(s) can be accomplished by a number of methods including reduction by hydrazine hydrate and Raney Nickel (see Fletcher and Namkung, J . Org . Chem ., 23 , 680 (1958). The resulting amine(s) as hydrogen halide salt(s) is diazotized by sodium nitrite. Replacement of the diazonium group(s) in these aromatic derivatives by a halo or cyano group(s) (e.g., via KCN) salts (Sandmeyer), copper powder (Gatterman) or cupric salts (Korner-Contardi). See Organic Synthesis Vol . I . p. 170 (1932); E. Pfeil, Angew. Chem., 65, 155 (1953); Y. Nakatani, Tetrahedron Lett., 1970, 4455. As is known in the art, the resulting cyano derivatives can be hydrolyzed into carboxylic acids; alcoholyzed to carboalkoxy esters, e.g., carboethoxy esters; hydrolyzed to carboxamide; reduced to methylamine, etc., as is well known and practiced in the art. Other aromatic derivatizations can similarly be made by those skilled in the art. Spiro-tricyclic azine derivative, such as spiro-(7-fluoro-5 H -indeno [1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione, is oxidized to the corresponding N-oxide derivative according to the general procedure of Mosher et al., Org . Syn ., 33 (1953) 79 wherein peracetic acid is employed as the oxidizer. Such an N-oxide is active as aldose reductase inhibitor. For example, Method VII - Heterocyclic analogues of fluorene and fluorene derivatives such as 1-azafluorene and 2-fluoroflourene can be transformed into corresponding ketones (e.g., 1-azafluorenone or 2-fluorofluorenone) via a number of oxidation procedures which are well known to those skilled in the art. Some relevant representative methods include: a) Oxidation by oxygen under basic conditions according to a general procedure of U. Sprinzak, J . Amer . Chem . Soc ., 80 (1958) 5449. b) Oxidation by permanganate in which the flourene derivative is oxidized by potassium permanganate in acetone, e.g., see Urbina, Synthetic Communications 9 (1979), 245. c) Oxidation by selenium dioxide in a sealed vessel at 200-250°C when common oxidation procedures such as chromuim trioxide in acetic acid are ineffective. See Arcus and Barnett, J . Chem . Soc . (1960) 2098. Method VIII - Tricyclic ketones of the present invention may be reduced to the corresponding methylene reduction product by the Wolff-Kishner Reduction or by the Huang-Minlon modified Wolff-Kishner Reduction (see also MacDowell and Jefferies, J . Org . Chem ., 35 , 871 (1970)). Alternatively, these ketones may be reduced by lithium aluminum hydride in the presence of aluminum chloride (see Rault, Lancelot and Effi, Heterocycles 20 , 477 (1983)) or by other reduction methods known to those skilled in the art. Method of Treatment IX The spiro-tricyclic-thiazolidinedione, -imidazolidinedione, -oxazolidinedione and -succinimide compounds of the present invention are weak acids. In addition, several examples, as cited in Example XIX, are carboxylic acid derivatives and/or aromatic azines (i.e., contain a basic nitrogen(s) in the aromatic tricycle) and/or contain an alkylamine substituent. Therefore, these compounds are ameanble to preparation as base salts and in some cases, where basic amines are present, acid salts. Several examples contain both an acidic spiro functionality and carboxylic acid functionality. These cases can be prepared as mono- or di-basic salts. The chemical bases which are used as reagents to prepare the aforementioned pharmaceutically acceptable base salts are those which form nontoxic (pharmaceutically acceptable) salts with the various heroin described acidic spiro-imidazolidinedione, -thiazolidine-dione, -oxazolidinedione and -succinimdie derivatives such as spiro-(7-fluoro-5- H -indeno[1,2-b] pyridine-5,4'-imidazolidine)-2',5'-dione, for example. Similarly, herein described carboxylic acid containing derivatives, such as spiro-(2-carboxy-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione, can be prepared as nontoxic salts. These nontoxic base salts are of a nature not to be considered clinically toxic over a wide therapeutic dose range. Examples of such cations include those of sodium, potassium, calcium, magnesium, etc. These pharmacologically acceptable nontoxic salts can be prepared by treating the aforementioned acidic specie, e.g., spiro-thiazolidinedione, with aqueous metallic hydroxide solution, and than evaporating the resulting solution, preferably at reduced pressure, to dryness. Alternatively, where indicated, the base salts can be prepared by mixing a lower alkanolic solution (e.g., ethanol) of the acidic compound with a desired alkali metal alkoxide (e.g., sodium ethoxide) in a lower alkanolic solution, and evaporating the solution to dryness in the same manner as before. In any case stoichiometric quantities of reagents must be employed in order to ensure completeness of reaction and maximum production of yields with respect to the final base salt product. Acid salts of spiro-tricyclic azine derivatives, e.g., spiro-(7-fluoro-5 H -indeno[1,2-b]pyridine-5,5'-thiazolidine)-2',4'-dione, can be prepared with nontoxic pharmacologically acceptable acids, e.g., hydrochloric acid and sulfuric acid. Examples of such anions of said acid salts include those of hydrogensulfate, sulfate, chloride. etc. These pharmacologically acceptable nontoxic acid salts can be prepared by treating the aforementioned basic specie, e.g., spiro-azafluorene derivative, with an acidic aqueous solution of the desired acid. After the basic species is solubilized in the acid, the solution is evaporated to dryness, preferably with reduced pressure. In this case, stoichiometric quantities of acid are preferred. Alternatively, in some cases the acid salt may be precipitated or recrystallized from strong acid solution (e.g., 5% hydrochloric acid). The salt then is collected by filtration and dried. As previously indicated, the spiro-tricyclic-thiazolidinedione, -imidazolidinedione, -oxazolidinedione and -succinimide compounds of this invention are all readily adapted to therapeutic use as aldose reductase inhibitors for the control of chronic diabetic complications, in view of their ability to reduce lens sorbitol levels in diabetic subjects to a statistically significant degree. The herein described compounds of this invention can be administered by either the oral or parenteral routes of administration. In general, these compounds are ordinarily administered in dosages ranging from about 0.1 mg to about 10 mg/kg of body weight per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen; the preferred range is 0.5 to 4.0 mg/kg. Oral administration is preferred. While matters of administration are left to the routine discretion of the clinician, long term, prophylactic administration of the compounds of the present invention is generally indicated on diagnosis of diabetcs mellitus and/or neuropathy and/or retinopathy and/or vasculopathy and/or cataract and/or impaired wound healing and/or nephropathy and/or hyperglyceamia. In connection with the use of the spiro-tricycle compounds of this invention for the treatment of diabetic subjects, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the compounds of this invention can be administered in a wide variety of different 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 of fillers, sterile aqueous media and various nontoxic organic solvent, etc. Moreover, such oral pharmaceutical formulations may be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such purposes. In general, the therapeutically useful compounds of this 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 lactose or milk sugar as well as 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 of dyes, and if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For purposes of parenteral administration, solutions of those particular spiro-tricycles in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble, alkali metal or alkaline-earth metal or acid 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. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art. Additionally, it also is possible to administer the aforesaid spiro-tricycle compounds topically via an appropriate ophthalmic solution suitable for the present purposes at hand, which can then be given 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 inhibit the enzyme activity of isolated human aldose reductase; (2) measuring their ability to reduce or inhibit enzyme activity of rat lens aldose reductase in vitro ; (3) measuring their ability to preserve motor nerve conduction velocity in chronic streptozotocin-induced diabetic rats; (4) and measuring their ability to delay cataract formation and reduce the severity of lens opacities in chronic galsotosemic rats; (5) measuring with electron microscopy their ability to prevent basement membrane thickening in the kidney glomerulus and/or retina capillaries in chronic streptozotocin-induced diabetic rats (6) measuring their ability to maintain rat lenses in 30 mM xylose culture for 18 h. Typical preparative methods and synthetic design for substituted analogs of the tricycles of Table A and Formulas II and III are provided for instruction. x, y and z are as previously defined. Where Q = H₂ or O Preparation A Synthesis substrates 8 H -indeno[2,1-b]thiophen-8-one and 8 H -indeno [2,1-b]thiophene and their derivatives are prepared in accordance with the following by a general method of Venin, Brault and Kerfanto, C. R . Acad . Sc . Paris , 266 (c), 1650 (1968), various substituted phenylglyoxals are prepared in a three step process involving: gem dibromination of the substituted acetophenone (e.g., p-fluoroacetophenone) to the corresponding α, α-dibromoacetophenone; nucleophillic displacement of the gem bromides to yield the corresponding aminal; aqueous acid (e.g., dilute HCl) hydrolysis to yield the substituted phenylgloxal, e.g., p -fluorophenylglyoxal. By such a process the following substituted phenylglyoxals are prepared: X and Y = H, halogen, lower alkyl, lower cycloalkyl, COOH, C≡N, -O-R, -S-R, -S(O)R, -SO₂R R = Lower alkyl from commercially available substituted acetophenones (e.g., o -, p - or m - fluoro- chloro- or bromo - acetophenone may be purchased from Aldrich Chemical, Inc.). Other substituted acetophenones are prepared by methods well known to those skilled in the art. Phenglyoxal (Aldrich Chemical. Inc.) is commercially available. Such prepared substituted phenylglyoxals (e.g., 4'-fluorophenylglyoxal) are utilized to synthesize corresponding substituted 8 H -indeno[2,1-b]thiophen-8-one and 8 H -indeno[2,1-b]thiophene substrates which are derivatized by Methods I-IV. The synthesis of substituted 8 H -indeno[2,1-b]thiophen-8-one involves the Hinsberg Stobbe type condensation (Wolf and Folkers, Org . Reactions , 6 , 410 (1951)) between the substituted phenylglyoxal, e.g., 4'-fluorophenylglyoxal, and diethylthiodiglycolate using sodium ethoxide. After saponification, the isolated substituted 3-phenyl-2,5-thiophenedicarboxylic acid, e.g., 3-(4'-fluorophenyl)-2,5-thiophenedicarboxylic acid is treated with thionyl chloride to form the diacylchloride which is intramolecularly cyclized by a Friedel-Crafts reaction catalyzed by aluminum chloride or stannic chloride to give the correspondingly substituted 8-oxo-8 H -indeno-[2,1-b]thiophen-2-carboxylic acid, e.g., 6-fluoro-8-oxo-8 H -indeno-[2,1-b]thiophen-2-carboxylic acid, (A-1), which can be converted into a hydantoin derivative according to Method I. Decarboxylation of (A-1) by copper powder in anhydrous quinoline yields the corresponding substituted 8 H -indeno-[2,1-b]thiophen-8-one (A-2) which is converted (in accordance with Method I) into a hydantoin derivative such as spiro-(6-fluoro-8 H -indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione. See Example XIV for the preparation of spiro-(8 H -indeno[2,1-b] thiophen-8,4'-imidazolidine)-2',5'-dione. The Wolff-Kishner reduction (Method VIII) of (A-1) or (A-2), preferably (A-1), yields the corresponding substituted 8 H -indeno[2,1-b]thiophene, e.g., 6-fluoro-8 H -indeno-[2,1-b]thiophene. In the alkaline hydrazine (in excess) reduction of the ketoacid (A-1), both keto reduction and decarboxylation may occur. Product isolation is best accomplished by fractional distillation, but may involve other separation methods as are known in the art. Further derivatization may be accomplished according to Method V. The resulting substituted 8 H -indeno[2,1-b]thiophene is metalated by n-butyllithium and carbonated in the methylene bridge to yield the corresponding 8-carboxylic acid which, after esterification, at reflux with a lower alkyl alcohol such as methanol under acid catalyzed conditions such as concentrated hydrochloric acid yields the corresponding substituted or unsubstituted 8 H -indeno [2,1-b]thiophen-8-carboxylic acid alkyl ester, e.g., 6-fluoro-8 H -indeno[2,1-b]thiophen-8-carboxylic acid methyl ester. The ester is utilized according to Method II, III and IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidine-dione and spiro-succinimide such as spiro-(6-fluoro-8 H -indeno[2,1-b]thiophen-8,5'-thiazolidine)-2',4'-dione, spiro-(6-fluoro-8 H -indeno-8,5'-oxazolidine)-2,4'-dione and spiro-(6-fluoro-8 H -indeno[2,1-b]thiophen-8,3'-succinimide) respectively. Preparation B Synthesis substrates 4 H -indeno[1,2-b]thiophen-4-one and 4 H -indeno [1,2-b]thiophene can be prepared according to a general process of MacDowell and Jefferies, J . Org . Chem ., 35 , 871 (1970). In this process the 4-one substrate is prepared by the Ullmann coupling of ortho -iodo or ortho -bromo, di, tri and tetrasubstituted benzoic acid lower alkyl esters, such as 3-fluoro-2-iodo-benzoic acid ethyl or methyl ester (Chem. Abst.; 27:1339/G) or 2-bromo-4-fluoro-benzoic acid methyl ester (Chem. Abst. 99(1):5630j) or 2-bromo-5-chloro-benzoic acid methyl ester ( J . Med . Chem., 13 , 567-8 (1970)) with 2-iodo or 2-bromothiophene (Aldrich Chemical, Inc.). Saponification of the coupled product will yield the corresponding substituted 2-(2'-thienyl) benzoic acid (e.g., 5-chloro-2-(2'-thienyl)benzoic acid from 2-bromo-5-chloro-benzoic acid methyl ester). Cyclization of the acid is performed via the aroyl halide using stannic chloride or aluminum chloride to yield to substituted 4 H -indeno[1,2-b]thiophen-4-one (B-1) (e.g., 6-chloro-4 H -indeno[1,2-b]thiophen-4-one). This 4 one derivative is converted (in accordance with Method I) into a hydantoin derivative such as spiro- (6-chloro-1 H -indeno[1,2-b] thiophen-4,4'-imidazolidine)-2',5'-dione. See Example XIII for the preparation of spiro-(4 H -indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione. The Wolff-Kishner reduction (Method VIII) of (B-1) yields the corresponding 4 H -indeno[1,2-b]thiophene. Product isolation is best accomplished by fractional distillation, but may involve other separation methods as are known in the art. The resulting substituted or unsubstituted 4 H -indeno[1,2-b]thiophene (which may be further derivatized according to Method V) is metalated by n-butyllithium and carbonated in the methylene bridge to yield the corresponding 4-carboxylic acid which after esterification at reflux with a lower alkyl alcohol such as methanol under acid catalyzed conditions such as concentrated hydrochloric acid yields the corresponding substituted or unsubstituted 4 H -indeno[1,2-b]thiophen-4-carboxylic acid lower alkyl ester, e.g., 6-chloro-4 H -indeno[1,2-b] thiophen-4-carboxylic acid methyl ester. The ester is utilized according to Methods II, III and IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide such as spiro-(6-chloro-4 H -indeno[1,2-b]thiophen-4,5'thiazolidine]-2',4'-dione, spiro-(6-chloro-4 H -indeno[1,2-b]thiophen-4,5'-oxazolidine)-2',4'-dione and spiro-(6-chloro-4 H -indeno[1,2-b]thiophen-4,3'-succinimide) respectively. The resulting spiro-derivatives may be further derivatized according to Method VI. Preparation C Synthesis substrates 4 H -indeno[1,2-c]thiophen-4-one and 4 H -indeno [1,2-c]thiophene and their derivatives are prepared in accordance with MacDowell and Jefferies, J . Org . Chem ., 35 , 871 (1970). Wherein treatment of 4-bromo-3-thienyllithium with a commonly available lower alkyl substituted cyclohexanone or cyclohexanone, such as 4-methyl-cyclohexanone, at -65 to -75°C yields the corresponding cyclohexanol derivative which is dehydrated with para-toluenesulfonic acid in refluxing benzene or toluene to yield a cyclohexylthiophene product such as 3-bromo-4-(4-methyl-1'-cyclohexenyl)thiophene. Dehydrogenation with tetrachlorobenzoquinone in refluxing xylene for 8-24 hours yields the corresponding 3-bromo-4-phenylthiophene, e.g., 3-bromo-4-(4'-methylphenyl)thiophene. After purification by sublimation and/or chromatography over alumina, the bromide is subjected to halogen-metal exchange at -65 to -75°C with n--butyllithium in ether, followed by carbonation with carbon dioxide. The isolated 3-phenyl-thiophene-4-carboxylic acid derivative, e.g., 3-(4'-methylphenyl)thiophene-4 carboxylic acid, is converted with thionyl chloride to the acid halide. Ring closure to the ketone via heating the aroyl chloride and aluminum chloride in carbon disulfide for 18-36 hours yields the corresponding ketone, such as 6-methyl-8 H -indeno[1,2-c]thiophen-8-one. This 8-one derivative, which may be further derivatized according to Method V, is converted (in accordance with Method I) into a hydantoin derivative. Wolff-Kishner reduction (Method VIII) of the 8-one derivative (and optional derivatization according to Method V) and spiro-derivatization in accordance with Methods II, III and IV yields the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives respectively. These spiro-derivatives may be further derivatized according to Method VI. Preparation D Synthesis substrate 7 H -cyclopenta[1,2-b:4,3-b']dithiophene is prepared according to the method of Wynberg and Kraak, J . Org . Chem ., 29 , 2455 (1964). The corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives are prepared according to Methods II-IV respectively. The 7-one derivative is prepared from the cyclopentadithiophene in accordance with the oxidation procedures cited in Method VII. The ketone, 7 H -cyclopenta [1,2-b:4,3-b]dithiophen-7-one is converted into the spiro-hydantoin derivative in accordance with Method I. Preparation E Synthesis substrates 4 H -cyclopenta[2,1-b:3,4-b']dithiophene,7 H -cyclopenta [1,2-b:3,4-b']dithiophene,7 H -cyclopenta[1,2-c:3,4-c'] dithiophene, 7 H -cyclopenta[1,2-b:3,4-c']dithiophene and 7 H -cyclopenta[2,1-b:3,4-c']dithiophene are prepared according to the procedure of Wiersema and Wynberg, Tetrahedron , 24 , 3381 (1968). From these, the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives are prepared according to Methods II-IV respectively. The corresponding 4 H -cyclopenta[2,1-b:3,4-b']dithiophen-4-one, 7 H -cyclopenta[1,2-b:3,4-b'] dithiophen-7-one, 7 H -cyclopenta[1,2-c:3,4-c']dithiophen-7-one, 7 H -cyclopenta[1,2-b:3,4-c']dithiophen-7-one and 7 H -cyclopenta[2,1-b: 3,4-c']dithiophen-7-one are prepared in accordance with the oxidation procedures cited in Method VII. The resulting ketones are spiro-hydantoin derivatized in accordance with Method I. Preparation F Synthesis substrates 5 H -indeno[1,2-b]pyridin-5-one and 5 H -indeno [1,2-b]pyridine (as 4-azafluorene from Aldrich Chemical, Inc.) and their derivatives are prepared according to a general procedure of Parcell and Hauck, J . Org . Chem ., 21 , 3468 (1963), wherein the piperidineenamine of 2,3-dihydro-1 H -inden-1-one (available from Aldrich Chemical, Inc.), -4,-5 or -6-chloro or fluoro-2,3-dihydro-1 H -inden-1-one (Olivier and Marechal, Bull . Soc . Chim . France , (1973), 3092), 6-chloro-5-cyclopentylmethyl-2,3-dihydro-1 H -inden-1-one (Biere et al., Eur . J . Med ., 18 , 255 (1983)), 5,6-dimethoxy-2,3-dihydro-1 H -inden-1-one (Koo, J . Amer . Chem . Soc ., 75 , 1891 (1953)), 5 or 6-methoxy-2,3-dihydro-1 H -inden-1-one (available from Aldrich Chemical, Inc.) or other substituted 1-indanones is formed from piperidine in the presence of p-toluensulfonic acid catalyst according to the procedure of Heyl and Herr, J . Amer . Chem . Soc ., 75 , 1918 (1953). The resulting piperidineenamine is reacted with 3-bromopropylamine hydrobromide or hydrochloride (available from Aldrich Chemical, Inc.) to yield an imine product. The process typically involves the addition of 1.1 molar equivalents of the enamine to 1 molar equivalent of bromopropylamine hydrobromide in dimethylformamide at elevated temperature until the exothermic reaction is initiated wherein the temperature is kept at 90°-120°C for several hours. The product is isolated by a combination of acidification and other washing followed by basification and ether extractions. Evaporation yields the tetrahydroimine product such as: The tetrahydroimine product is aromatized in xylene and nitrobenzene and 10% palladium on charcoal according to Parcell and Hauch, ibid . The resulting product, e.g., 7-fluoro-5 H -indeno[1,2-b] pyridine (which may be further derivatized according to Method V) is derivatized according to Methods II to IV to yield the corresponding spiro-derivatives such as spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,5-thiazolidine)-2',4'-dione;spiro-(7-fluoro-5 H -inden[1,2-b]pyridin-5,5'-(oxazolidine)-2',4'-dione and spiro-(7-fluoro-5 H -indeno[1,2-b] pyridin-5,3'-suiccinimide. Oxidation (Method VII) of 5 H -indeno [1,2-b]pyridine or its derivatives according to the method of Sprinzak, J . Amer . Chem . Soc ., 80 , 5449 (1958) yields the corresponding 5-one or ketone derivative, which may be further derivatized according to Method V. When reacted in accordance with Method I, the ketone will yield a spiro-hydantoin derivative such as spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione. Any of the aforementioned spiro derivatives may be further derivatized, e.g., nitrated, in accordance with Method VI. See Examples XVIII, XI and XII. Preparation G Synthesis substrates 5 H -indeno[1,2-c]pyridin-5-one and 5 H -indeno [1,2-c]pyridine and their derivatives may be prepared in accordance with the following. 3-Azafluorenone (5 H -indeno[1,2-c]pyridin-5-one) is prepared according to the method of Mayor and Wentrup, J . Amer . Chem . Soc ., 9 7, 7467 (1975). The ketone can be derivatized in accordance with Method V. The ketone, e.g., 5 H -indeno[1,2-c]pyridin-5-one, is hydantoin derivatized according to Method I. A Wolff-Kishner reduction (Method VIII) of this 3-azafluorenone can be accomplished according to Kloc at al., Heterocycles 9 , 849 (1978) to yield the corresponding 5 H -indeno[1,2-c]pyridine which is derivatized in accordance with Methods II-IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide respectively. The aforementioned spiro-derivatives may be further derivatized according to Method VI. Preparation H Synthesis substrates 9 H -indeno[2,1-c]pyridin-9-one and 9 H -indeno [2,1-c]pyridine are prepared according to the method of Mayor and Wentrup, J . Amer . Chem . Soc ., 97 , 7467 (1975). Further derivatization may be accomplished in accordance with Method V. The resulting indenopyridine or 2-azafluorene product is further derivatized according to Methods II-IV to yield the spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives. Oxidation of the indenopyridine to the corresponding ketone is accomplished by sodium dichromate or other oxidation procedures as cited in Table A. The resulting ketone may be derivatized in accordance with Method V. The selected 2-azafluoreneone derivative is derivatized to yield the spiro-hydantoin. See Example XVI for the preparation of spiro-(9 H -indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione. The aforementioned spiro-derivatives may be further derivatized according to Method VI. Furthermore, in example, 7-amino-2-azafluorene or 7-amino-9 H -indeno[2,1-c]pyridine can be prepared according to the method of Perin-Roussel and Jacquignon, C . R . Acad . Sc . Paris , 278 , 279 (1974). This amino product in accordance with Method V, can be transformed via the Schiemann reaction into 7-fluoro-9 H -indeno[2,1-c]pyridine. This substrate, as above, can be transformed by Methods I-IV into spiro-(7-fluoro 9 H -indeno[2,1-c]pyridin-9,4'-imidazolidine)2',5'-dione, spiro-(7-fluoro 9 H -indeno[2,1-c]pyridin-9,5'-thiazolidinedione)-2',4'-dione, spiro-(7-fluoro 9 H -indeno[2,1-c]pyridin-9,5'-oxazolidine)-2,4'-dione and spiro-(7-fluoro 9 H -indeno[2,1-c]pyridin-9,3'-succinimide). Preparation I The ketone substrate, 9 H -indeno[2,1-b]pyridin-9-one may be prepared by the method of Kloc, Michowski and Szulc, J . prakt . chemie , 319 , 95q (1977). This ketone can be derivatized according to Method V. The substituted or unsubstituted ketone is then derivatized in accordance with Method I to yield the spiro-hydantoin which may be further modified according to Method VI. The ketone, from the above, is reduced to a method cited in Method VIII or in general the Wolff-Kishner reduction to yield corresponding 9 H -indeno[2,1-b]pyridine which is then derivatized in accordance with Methods II, III and IV to yield spiro-thiazolidinedione, spiro-succinimide. Alternatively, 5 H -indeno[2,1-b]pyridine-5-one(also called 1-azafluoren-9-one) and 5 to 8 position fluoro or chloro derivatives are prepared according to a general procedure of Urbina, Synthetic Comm ., 9 , 245(1979). Where to a substituted or unsubstituted 1-phenyl-2-propanone (e.g., 1-(4'-fluorophenyl)-2-propanone) is added acrylonitrile producing a corresponding 5-cyano-3-phenyl-2-pentanone, e.g., 5-cyano-3-(4'-fluorophenyl)-2-pentanone. The pentanone product is hydrogenated and cyclized to the corresponding 2-methyl-3-phenylpiperidine, e.g., 2-methyl-3-(4'-fluorophenyl)piperidine. Aromatization of the 2-methyl-3-phenyl piperidine is carried out in vapor phase with catalyst K-16 (Prostakon, Mathew and Kurisher, Khim - Geterotsikl . Socd ., 876 (1970)) at 380° to 420°C to yield the corresponding 2-methyl-3-phenylpyridine. Alternatively, aromatization can be achieved with Pd/C. Dehydrocyclization of the methyl-3-phenylpyridine at 500° to 550°C over K-16 will produce the appropriate 1-azafluorene, e.g., 7-fluoro-1-azafluorene. The 9 H -indeno [2,1-b]pyridine and its derivatives (e.g., 7-fluoro-9 H -indeno[2,1-b] pyridine) are converted in accordance with Method II, III and IV into spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives. The 9 H -indeno[2,1-b]pyridine is oxidized according to general procedures cited in Method VII or potassium permanganate (Urbina, ibid). The resulting ketone, e.g., 7-fluoro-9 H -indeno[2,1-b]pyridin-5-one. is derivatized in accordance with Method I to yield the spiro-hydantoin derivative, such as spiro-(7-fluoro-9 H -indeno[2,1-b]pyridin-9,4'-imidazolidine)-2',5'-dione. Preparation J Synthetic substrates 5 H -cyclopenta[2,1-b:4,3-b']dipyridin-5-one, 5 H -cyclopenta[1,2-b:3,4-c']dipyridin-5-one, 5 H -cyclopenta[1,2-b:4,3-b'] dipyridin-5-one, 5 H -cyclopenta[2,1-b:4,3-c']dipyridin-5-one, 5 H -cyclopenta,,[1,2-b:3,4-c']dipyridin-5-one, 5 H -cyclopenta-[1,2-b: 4,3-b']dipyridin-5-one, 5 H -cyclopenta[2,1-b:4,3-c']dipyridin-5-one, 5 H -cyclopenta-[2,1-b:3,4-c']dipyridin-5-one, and 5 H -cyclopenta-[2,1-b:3,4-b']dipyridin-5-one can be prepared according to the method of Kloc, Michowski and Szulc, J . prakt . chemie , 319 , 95q(1977). These ketones in accordance with Method I are derivatized into the spiro-hydantoin products. Wolff-Kishner reduction or reduction according to Method VIII of the aforementioned ketones yields the corresponding diazafluorene substrates such as 5 H -cyclopenta[2,1-b: 4,3-b']dipyridine. These diazafluorene substrates are derivatized according to Methods II-IV to yield the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives. Preparation K Synthetic substrates 8 H -indeno[2,1-b]furan-8-one and 8 H -indeno[2,1-b] furan and their derivatives are prepared in accordance with the following. Substituted and unsubstituted 3-arylfuran-2-carboxylic acids are prepared according to a general procedure of Burgess, J . Org . Chem ., 21 , 102 (1956), wherein, 4,5-dimethoxy-1-phenyl-2-butanone and related 2' to 4' substituted phenyl analogs (e.g., 4,4-dimethoxy-1-(4'-fluorophenyl)-2-butanone, prepared according to the general procedure of Royals and Brannoch, J . Amer . Chem . Soc ., 75 , 2050 (1953)) are converted into 3-phenylfuran-2-carboxylic acid methyl ester (e.g., 3'-(4'-fluorophenylfuran-2-carboxylic acid methyl ester) by the Darzens glycidic ester condensation (Darzens, Compt . Rend ., 139 , 1214 (1904)). This rearrangement of the glycidic ester yields the furoic ester. The furoic ester can be hydrolyzed in alkaline methanolic solution to yield, for example, 3-(4'-fluorophenyl)-furan-2-carboxylic acid. The furoic acid product can be cyclized via the aroyl chloride in the presence of stannic chloride or aluminum chloride to yield the ketone, e.g., 6-fluoro-8 H -indeno [2,1-b]furan-8-one. This ketone can be derivatized in accordance with Method V. Hydantoin derivatization (Method I) yields the spiro-hydantoin. e.g., spiro-(6-fluoro-8 H -indeno[2,1-b]furan-8,4'-imidazolidine)-2',5'-dione. Reduction according to methods cited in Method VIII yields the corresponding 8 H -indeno[2,1-b]furan derivative which can be derivatized in accordance with Methods II, III and IV into the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide. Furthermore, the spiro-derivatives may be further derivatized according to Method VI. Preparation L Synthetic substrates 4 H -indeno[1,2-b]furan-4-one and 4 H -indeno[1,2-b] furan and their substituted analogs are prepared from the corresonding substituted and unsubstituted 2-arylfuran-3-carboxylic acids which are prepared according to a general procedure of Johnson, J . Chem . Soc ., 1946, 895. The procedure involves the condensation of 1,2-dichlorodiethyl ether with aroylacetic esters, such as ethyl benzoylacetate (Aldrich Chemical, Inc.), in the presence of 10% ammonium hydroxide, yields a mixture of the 2-arylfuran-3-carboxylic ester and 2-arylpyrrole-3-carboxylic ester (which can be used to prepare the corresponding 4 H -indeno[1,2-b]pyrrole-4-one) which are separated by fractionation. Saponification (10% KOH in 50% methanol) of the furan ester, acidification and isolation yields the corresponding 2-arylfuran-3-carboxylic acid. Treatment with phosphorus pentachloride followed by stannic chloride effects the Friedel-Crafts cyclization to the ketone. Alternatively, thionyl chloride may be employed to prepare the acyl chloride followed by aluminum trichloride or stannic chloride as the Friedel-Crafts catalyst in a solvent such as methylene chloride to yield the process is summarized by this example: Then according to Method I, the spiro-hydantoin derivative is prepared, e.g., spiro-(6-chloro-4 H -indeno[1,2-b]furan-4,4'-imidazolidine'2',5'-dione. Analogous to earlier preparations, the ketone can be reduced according to Method VIII (Wolff-Kishner reduction) to yield the corresponding 4 H -indeno[1,2-b]furan. This heterocycle can be derivatized according to Method V. The derivatized or underivatized 4 H -indeno [1,2-b]furan according to Method II, III and IV is derivatized to the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide respectively. These spiro derivatives may be further derivatized in accordance with Method VI. Preparation M Synthesis substrates 9 H -pyrrolol[1,2-a]indole and 9 H -pyrrolol[1,2-a] indol-9-one and their derivatives are prepared in accordance with the general methods of Josey and Jennor, J . Org . Chem ., 27 (1962) 2466 and Mazzola et al., J . Org . Chem ., 32 (1967) 486. The process involves condensation of a substituted or unsubstituted methyl anthranilate (Aldrich Chemical, Inc.) with 2,5-dimethoxytetrahydrofuran (Aldrich Chemical, Inc.) in glacial acetic acid. Ester hydrolysis of the resulting 1-(2-methoxycarbonylphenyl)pyrrole with 10-15% potassium or sodium hydroxide in aqueous alcohol (e.g., 50% methanol) yields after acidification and subsequent work-up yields the corresponding 1-(2-carboxyphenyl)pyrrole. This acid is then converted into the corresponding acyl chloride to facilitate a Friedel-Crafts cyclization to the ketone. The preferred method of preparing the acyl chloride is with phosphorus pentachloride followed with stannic chloride as the Friedel-Crafts catalyst to cyclize the acyl chloride to the desired ketone. R = CH₃, OCH₃, H Z = Cl, H Wolf-Kishner reduction, see also Method VIII, via the semicarbazones of the ketone yields the corresponding 9 H -pyrrolol[1,2-a]indole heterocycle. The resulting ketone, such as 9 H -pyrrolol[1,2-a]indole-9-one, is converted into the corresponding spiro-hydantoin according to Method I, see Example XV. The resulting spiro-hydantoin can be further derivatized in accordance with Method VI. Alternatively, the ketone may be derivatized according to Method V prior to spiro-hydantoin derivatization. Similarly, 9 H -pyrrolol[1,2-a]indole or its derivetives may be derivatized according to Method V. The derivatized or underivatized heterocycle then may be further derivatized according to Methods II, III or IV to yield the corresponding spiro-thiazolidinedione, spiro-ozazolidinedione or spiro-succinimide respectively. These spiro-derivatives in turn may be derivatized in accordance with Method VI. Preparation N Synthesis substrates 4 H -indeno[2,3-c]-1,2,5-thiadiazol-4-one and 4 H -indeno[2,3-c]-1,25-thiadiazole and their derivatives are prepared in accordance with the procedure of Mataka et al., Synthesis , 1979, 524 and Mataka et al., J . Hetero . Chem ., 17 (1980) 1681. The process involves reacting totranitrogentetrasulfide with 1,3-dihydro-2 H -indeno-2-one (Aldrich Chemical, Inc.) in toluene at reflux yields: Alternatively, 5-fluoro-1,3-dihydro-2 H -indeno-2-one (Flammang et al., Eur . J . Med . Chem ., 11 (1976) 83). 4-chloro-1,3-dihydro-2 H -indeno-2-one (CA80:146166a) and 5-chloro-1,3-dihydro-2 H -indeno-2-one (Olivier et al., Bull . Soc . Chem . Fr ., 11 (1973) 3096) can similarly be rated with tetranitrogentetrasulfide to yield the corresponding substituted indenothiadiazole heterocycles. Those heterocycles may be further derivatized in accordance with Method V and according to Methods II, III and IV derivatized into the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimides respectively. These spiro derivatives in turn may be further derivatized according to Method VI. Oxidation of the 4 H -indeno[2,3-c]-1,2,5-thiadiazole in accordance with Method VII yields the ketone which may be derivatized in accordance with Method I to yield the corresponding spiro-hydantoin, e.g., spiro(4 H -indeno[2,3-c']-1,2,5-thiadiazol-4,4'-imidazolidine)-2',5'-dione. This spiro hydantoin in turn may be derivatized further in accordance with Method VI. Preparation O The triheterocyclic substrates thieno[2,3-b]pyrrolizine and thieno [2,3-b]pyrrolizin-4-one; thieno[3,2-b]pyrrolizine and thieno[3,2-b) pyrrolizin-4-one are prepared exactly according to Rault et al., Heterocycles , 20 (1983) 477. The process involves the cyclization in boiling phosphoryl chloride of amide derivatives of 2-(1-pyrrolyl)-3-thienylcarboxylic acid and 3-(1-pyrrolyl)-2-thienylcarboxylic acid to yield thieno[2,3-b]pyrrolizin-4-one and thieno[3,2-b]pyrrolizin-4-one respectively. These ketones in accordance with Method I can be derivatized to the corresponding spiro-hydantoins: spiro-(thieno [3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione and spiro-(thieno [3,2-b]pyrrolizin-4,4'-imidazolidine)-2',5'-dione Both thieno [2,3-b]pyrrolizin-4-one and thieno[3,2-b]pyrrolizin-4-one can be reduced with 1.75 equivalents of lithium aluminum hydride in the presence of 3.5 equivalents aluminum chloride to yield the corresponding 4 H -thieno-pyrrolizines quantitatively. The resulting thieno[2,3-b]pyrrolizine and thieno[3,2-b]pyrrolizine can be derivatived according to Methods II, III and IV into the corresponding spiro-thiazolidinediones, spiro-oxazolidinediones and spiro-succinimides, such as spiro-(thieno[3,2-b]pyrrolizin-4,5'-thiazolidine)-2',4'-dione, spiro-(thieno[2,3-b]pyrrolizin-4,5'-oxazolidine)-2',4'-dione and spiro-(thieno[3,2-b]pyrrolizin-4,3'-succinimide). Preparation P In an analogous manner to the preceding, the following starting materials may be derivatized in accordance with Methods I, II, III, IV, V, VII and VIII. Resulting spiro-derivative products may be further derivatized in agreement with Method VI. a) 1- and 2- substituted -1 H -indeno[1,2-c]pyrazol-4-ones R₁ = H, lower alkyl R² = lower alkyl, lower cycloalkyl are prepared according to Lemke and Sawney, J . Heterocyclic Chem . 19 (1982) 1335 and Mosher and Soeder, J . Heterocyclic Chem ., 8 (1971) 855. b) 3-alkyl-4 H -indeno[1,2-c]isoxazol-4-one R² = lower alkyl (preferably methyl) is prepared according to Lemke et al., J . Heterocyclic Chem ., 19 (1982) 363. c) 3-alkyl-4 H -indeno[1,2-c]isoxazol-4-one R² = lower alkyl (preferably methyl) is prepared according to Lemke and Martin, J . Heterocyclic Chem ., 19 (1982) 1105. d) 3-methyl-1 H -pyrazolo[3',4':3,4]cyclopenta[1,2-b]pyridin-4-one and 3-methyl-1 H -pyrazolo[3',4':3,4]cyclopenta[2,1-c]pyridin-4-one respectively are prepared according to Mosher and Banks, J . Heterocyclic Chem ., 8 (1972) 1005. e) The following indenopyrimidinone is prepared according to CA90:38958q. f) 5 H -indeno[1,2-c]pyridazine and 3-methyl-5 H -indeno[1,2-c] pyridazine R = H, CH₃ is prepared according to Loriga et al., Farmaco , Ed . Sci ., 34 (1979) 72. After spiro-derivatization the corresponding spiro-hydantoin, spirothiazolidinedione, spiro-oxazolidinedione and spiro-succinimide products are obtained. Preparation Q Synthesis substrates, 4 H -indeno[2,3-c]-1,2,5-oxadiazol-4-one and 4 H -indeno-[2,3-c]-1,2,5-oxadiazole and their derivatives are prepared in accordance with the following process (see Korte and Storiko, Chemische Berichte , 94 (1961) 1956). The starting material 4-oximino-3--phenyl-isoxazole is prepared according to Ber . dtsch . Chem . Ges ., 24 (1891) 140, see also Hantzsch and Heilbron, Chemische Berichte , 43 (1910) 68: and hydrolyzed with water and treated with sodium carbonate to effect a rearrangement according to Korte, ibid . The resulting acid is cyclized by stepwise treatment with phosphorus pentachloride in methylene chloride followed by Friedel-Crafts cyclization catalyzed by stannic chloride. The resulting ketone is derivatized in accordance with Method I to yield the spiro-hydantoin which may be further derivatized according to Method VI. The ketone may be reduced according to Method VIII (Wolff-Kishner reduction) and further derivatized in accordance with Method V. The substituted heterocycle may be oxidized back to the ketone in accordance to Method VII and then derivatized to the spiro-hydantoin. Alternately the heterocycle may be derivatized in accordance with Methods II, III and IV to the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide. These may be further derivatized in accordance with Method VI. Example I 9-Hydroxy-9H-fluorene-9-carboxylic acid methyl ester (1) : 9-Hydroxy-9 H -fluorene-9-carboxylic acid (Aldrich Chemical, Inc.) (20.0 g, 88.4 mmol) was added to 100 mL methanol saturated with hydrogen chloride and mixture was stirred at reflux for 4 h. The crystalline material obtained on cooling was collected by filtration and washed with cold 1:1 ethyl acetate/hexane to provide after drying (1), 15.8 g (74%). Spiro-(9H-fluorene-9,5'-oxazolidine)-2',4'-dione (2) : To a stirred solution of sodium (190 mg, 8.26 mmol) in 20 mL absolute ethanol was added area (500 mg, 8.26 mmol) and 9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester (1) (2.00 g, 8.26 mmol). The mixture was stirred at reflux under nitrogen for 15 h. After cooling to room temperature, the reaction mixture was poured into 100 mL water and acidified with 2 N aqueous hydrochloric acid to precipitate the product which was collected by filtration, washed with water, and dried to provide 1.5 g crude (2). Recrystallization from ethyl acetate gave 260 mg (12%): m.p. 225-257°C. A second crop, 620 mg (30%), was obtained by evaporation of the mother liquor followed by recrystallization from ethyl acetate/hexane. M/e +. 251. For the preparation of oxazolidinediones from α-hydroxy esters using urea and sodium ethoxide, see: Stoughton, J . Am . Chem . Soc . (1941) 63 , 2376. Example II 2-Fluoro-9H-fluorene-9-carboxylic acid (3) : Under nitrogen atmosphere, n-butyllithium (1.25 eq, 0.170 mL, 65 mL of a 2.6 M hexane solution) was added dropwise over 30 min. to a stirred 0.5°C solution of 2-fluorofluorene (prepared according to U.S. Application Nos. 368,630 and 368,631) (25.0 g, 0.136 mmol) in 500 mL dry THF. After an additional 35 min. a flow of dry carbon dioxide gas into the solution was commenced and continued for 15 min. at 0-15°C and 45 min. at room temperature. 2 N aqueous hydrochloric acid (200 mL) was added, and the mixture was transferred to a separatory funnel. The aqueous layer was separated and extracted 1 x 100 mL ethyl acetate. The combined organic phases were washed 1 x 100 mL brine, dried (MgSO₄), and evaporated to leave a dark residue which was triturated with 250 mL hexane to leave 16.6 g crude acid. Recrystallation from acetonitrile gave 10.2 g of the acid (3). A second crop of 2.0 g was obtained from the concentrated filtrate. Chromatography of the filtrate and the concentrated hexane extract on silica gel using 10-50% ethyl acetate/hexane provided another 2.8 g. Total yield: 15.0 g (48%). 2-Fluoro-9H-fluorene-9-carboxylic acid methyl ester (4) : Acetyl chloride (33 mL) was added dropwise to a stirred, ice-cold solution of 2-fluoro-9 H -fluorene-9-carboxylic acid (3) (16.7 g, 73.2 mmol) in 200 mL methanol and the solution was then refluxed for 4 h. Solvent removal left the crude product which was recrystallized from methanol to provide (4), 14.1 g (79%): m.p. 90-92°C (from hexane). For the preparation of 9 H -fluorene-9-carboxylic acid from fluorene using phenyllithium and esterification using methanolic hydrogen chloride see: Bavin, Anal . Chem . (1960) 32 , 554. 2-Fluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (5) : To a stirred solution of sodium (1.25 eq, 22.3 mmol, 510 mg) in 100 mL methanol was added 2-fluoro-9 H -fluorene-9-carboxylic acid methyl ester (4) (4.33 g, 17.9 mmol). After 15 min. a flow of dry oxygen into the solution was commenced and continued for 1 h. Some of a solution of sodium bisulfite (24.5 g) in 300 mL water was added until the reaction became cloudy. The mixture was then poured into the remaining bisulfite solution. After cooling in ice, the solid that separated was collected by filtration, washed well with water, and dried to provide (5), 4.05 g (88%). Spiro-(2-fluoro-9H-fluorene-9,5'-oxazolidine)-2',4'-dione (6) : To a stirred solution of sodium (1.03 eq, 130 mg) in 13 mL, absolute ethanol was added 2-fluoro-9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester (5) (1.42 g, 5.5 mmol) and urea (5.5 mmol, 330 mg). The mixture was then refluxed 15 h. After cooling to room temperature, the mixture was poured into 65 ml water and acidified with 2 N aqueous hydrochloric acid. The yellow solid that separated was collected, washed with water, and dried to give 1.19 g crude material. Chromatography on silica gel using 1-100% methanol/chloroform gave pure (6), 580 mg (39%). m/e +. 269. Example III 9-Chlor-9H-fluorene-9-carboxylic acid methyl ester (7) : A mixture of 9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester (1) (5.00 g, 20.8 mmol) and 50 mL thionyl chloride was heated at reflux for 3 h. The thionyl chloride was removed on the rotavapor to leave a solid residue which was redissolved in 50 mL benzene and then evaporated to remove traces of thionyl chloride. The resulting material was recrystallized from acetic acid to give (7), 3.23 g (60%): m.p. 111-114°C. An additional 960 mg (18%) of product was obtained by chromatography of the reduced filtrate on silica gel using 10% ethyl acetate/hexane. Spiro-[9H-fluorene-9,5'-(2'-amino-4'-thiazolone)](8) : A mixture of 9-chloro-9 H -fluorene-9-carboxylic acid methyl ester (7) (4.21 g, 16.3 mmol) and thiourea (1.24 g, 16.3 mmol) in 150 mL dioxane was heated at reflux for 10 h. After cooling to room temperature, the fine white solid present was collected by filtration and washed with dioxane providing (8), 1.31 g (30%). The gummy residue which remained in the flask was chromatographed on silica gel using 10-20% methanol/chloroform to give another 220 mg (5%) of (7): m.p. 320-322°C (dec). For the preparation of 2-imino-4-thiazolidinones from α-halo acid halides using thiourea in dioxane, see: Skinner, J . Org . Chem . (1961) 26 , 1450. Spiro-(9H-fluorene-9, 5'-thiazolidine)-2',4'-dione (9) : A mixture of spiro-[9 H -fluorene-9,5'-(2'-amino-4'-thiazolone)] (8) (1.19 g, 4.47 mmol), 24 mL methanol, and 24 mL concentrated hydrochloric acid was refluxed 4 h. The reaction mixture was cooled in ice and the white precipitate was collected by filtration, washed with water, and dried to provide 640 mg crude (9). Recrystallization from acetonitrile gave 490 mg (41%): m.p. 253-255°C. A second crop of 80 mg (7%) was obtained from the mother liquor. Calc. %C 67.40. %H 3.39; %N 5.24: meas. %C 67.46, %H 3.34, N 5.32. For the hydrolysis of 2-amino-4-thiazolones to thiazolidinediones using methanolic hydrogen chloride, see: Koltai, Tetrahedron (1973) 29 , 2781. Example IV 9-Chloro-2-fluoro-9H-fluorene-9-carboxylic acid methyl ester (10) : A mixture of 2-fluoro-9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester (5) (4.00 g, 15.5 mmol) and 50 mL thionyl chloride was refluxed 3 h. After the thionyl chloride was removed on the rotavapor, the material was redissolved in 50 mL benzene and the benzene then evaporated to remove trace thionyl chloride. The crude product, 4.3 g (100%), was used without further purification. Spiro-[2-fluoro-9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (11) : A mixture of 9-chloro-2-fluoro-9 H -fluorene-9-carboxylic acid methyl ester (10) (4.31 g, 15.6 mmol) and thiourea (1.1 eq, 17.2 mmol, 1.31 g) in 140 mL dioxane was refluxed for 10 h. After cooling to room temperature, the fine white precipitate was collected by filtration and washed with water providing (11), 1.28 g (29%). An additional 1.3 g (29%) of (11) was obtained by chromatography of the reduced filtrate on silica gel using 5-50% methanol/chloroform. Spiro-(2-fluoro-9H-fluorene-9,5'-thiazolidine)-2',4'-dione (12) : A mixture of spiro-[2-fluoro-9 H -fluorene-9,5'-(2'-amino-4'-thiazolone)] (11) (1.85 g, 6.51 mmol), 35 mL methanol, and 35 mL concentrated hydrochloric acid was heated at reflux for 6 h. After cooling to room temperature, the white precipitate was collected by filtration and washed with water to provide 1.22 g of crude (12). Recrystallization from ethanol provided three crops totaling 870 mg (47%): m.p. 272-276°C (dec). m/e +. 285. Example V 2,7-Difluoro-9H-fluorene-9-carboxylic acid (13) : To a stirred, room temperature solution of 2,7-difluorofluorene (prepared according to U.S. Application Nos. 368,630 and 368,631) (10.0 g, 49.5 mmol in 75 mL dry diethyl other under a nitrogen atmosphere was added over 15 min n-butyllithium (1.15 eq, 61.9 mmol, 24 mL of a 2.6 M hexane solution). The solution was refluxed 30 min., cooled to room temperature, and then quickly poured onto an ether slurry of a large excess of powdered dry ice. After the dry ice evaporated, the mixture was transferred to a separatory funnel along with 100 mL 2 N aqueous hydrochloric acid and 50 mL ethyl acetate. After shaking well, the organic layer was separated and evaporated to dryness. The residue was extracted 2 x 100 mL warm (50°C) 2% aqueous sodium hydroxide and then the extract was acidified with concentrated hydrochloric acid to precipitate the impure acid which was collected by filtration and washed with water. This material was dissolved in 50% ethyl acetate/hexane and passed through a 50 mm x 7 silica gel column using the same solvent to remove highly colored, baseline impurities and to provide (13) sufficiently pure to be used in the next step, 7.91 g (65%): m.p. 128-130°C (from benzene). 2,7-Difluoro-9H-fluorene-9-carboxylic acid methyl ester (14) : Acetyl chloride (13 mL) was added dropwise to a stirred, ice-cold solution of 2,7-difluoro-9 H -fluorene-9-carboxylic acid (14) (6.90 g, 28 mmol) in 77 mL methanol. The mixture was then heated at reflux for 4 h. The product which crystallized upon cooling in ice was collected by filtration and washed with cold methanol to provide (14), 5.15 g (71%): m.p. 161-163°C (from toluene). 2,7-Difluoro-9-hydroxy-9H-fluorene-9-carboxylic acid methyl ester (15) : 2,7-Difluoro-9 H -fluorene-9-carboxylic acid methyl ester (14) (4.73 g, 18.2 mmol) was added to a solution of sodium (1.25 eq, 22.7 mmol, 520 mg) in 100 mL methanol. After 15 min., a flow of dry oxygen into the solution as commenced and continued for 1 h. Some of a solution of 24.5 g sodium bisulfite in 800 mL water was added until the mixture turned cloudy and then the whole was poured into the remaining bisulfite solution. The solid was collected by filtration, washed with water, and dried to provide (15), 4.68 g (93%): m.p. 174-176°C (from benzene). 9-Chloro-2,7-difluoro-9H-fluorene-9-carboxylic acid methyl ester (16) : A mixture of 2,7-difluoro-9-hydroxy-9 H -fluorene-9-carboxylic acid methyl ester (15) (3.63 g, 13.1 mmol) and 50 mL thionyl chloride was heated at reflux for 4 h. The reaction mixture was then diluted with 300 mL benzene and evaporated to leave (16), 3.7 g (96%), which was used in the next step without further purification: m.p. 140-142°C (from acetonitrile). Spiro-[2,7-difluoro-9H-fluorene-9,5'-(2'-amino-4'-thiazolone)] (17) : A mixture of 9-chloro-2,7-difluoro-9 H -fluorene-9-carboxylic acid methyl ester (16) (3.56 g, 12.1 mmol) and thiourea (1.1 eq, 13.3 mmol, 1.01 g) in 110 mL dry dioxane was heated at reflux for 12 h. After cooling to room temperature and in ice, the white precipitate was collected by filtration, washed with dioxane, and dried to provide (17), 490 mg (13%). The concentrated filtrate and the gummy residue which remained in the flask were individually chromatographed on silica gel using 5-20% methanol/chloroform to provide another 1.00 g (27%) product: m.p. > 300°C. Spiro-(2,7-difluoro-9H-fluorene-9,5'-thiazolidine)-2',4'-dione (18) : A mixture of spiro-[2,7-difluoro-9 H -fluorene-(2'-amino-4'-thiazolone)] (17) (1.17 g, 3.87 mmol), 21 mL methanol, and 21 mL concentrated hydrochloric acid was refluxed for 6 h. The reaction mixture was cooled in ice and the off-white precipitate was collected by filtration, washed with water, and dried to provide 900 mg crude (18). This material was chromatographed on silica gel using 5-10% methanol/chloroform to yield pure (18), 530 mg (45%): m.p. 260-263°C (dec). Calc. %C 59.40, %H 2.33, %N 4.62: meas. %C 59.47, %H 2.42, %N 4.64. Example VI Spiro-(9H-fluoren-9,3'-succinimide) (20) : 9 H -fluoren-9-carboxylic acid methyl ester (19), which was prepared by refluxing 9 H -fluoren-9-carboxylic acid (Aldrich Chemical, Inc.) in HCl/MeOH, (10.0 g, 44.6 mmol) was added to a solution of sodium (1.2 eq, 53.5 mmol, 1.23 g) in 100 mL methanol. After 15 min., 2-chloroacetamide (1.1 eq, 49.1 mmol, 4.59 g) was added and the mixture was allowed to stir at room temperature under nitrogen for two (2) days. The reaction mixture was poured into 400 mL of cold 2.5% w/v aqueous sodium hydroxide and the insoluble material was removed by filtration. The filtrate was chilled and acidified with concentrated hydrochloric acid to precipitate the spiro-succinimide which was collected and air dried to provide 6.7 g (60%). Recrystallization from methanol gave purified (20), 4.28 g (39%). m.p. 237-239°C. Calc. %C 77.09, %H 4.45, %N 5.62: meas. %C 77.17, %H 4.55, %N 5.58. Example VII Spiro-(2-fluoro-9H-fluoren-9,3'-succinimide) (21) : The spiro-succinimide (21), m.p. 248-250°C, was prepared analogous to Example VI except from (4) in 25% yield. Calc. %C 71.90, %H 3.77, %N 5.24: mess. %C 71.97, %H 3.87, %N 5.33 Example VIII 5H-Indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (22) : Under a nitrogen atmosphere, n-butyllithium (1.2 eq, 105 mmol, 65 mL of a 2.6 M hexane solution) was added dropwise over a 30 min. period to a stirred 0-5°C solution of 4-azafluorene (14.65 g, 87.6 mmol) in 150 mL dry tetrahydrofuran (dried and distilled from LAH). After 1 h 20 min. the reaction mixture was poured into an ether slurry containing a large excess of dry ice. Solvents were allowed to evaporate overnight. The residue was suspended in 300 mL methanol, chilled and 60 mL acetyl chloride was added dropwise over 45 min. and the mixture stirred for 22 h at room temperature. Purification by chromatography (30% ethyl acetate/hexanes on silica gel) and solvent evaporation yields 16.3 g (83%) of (22). 5-Hydroxy-5H-indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (23) : To a stirred solution of sodium (1.1 eq, 60.1 mmol, 1.38 g) in 150 mL dry methanol was added a solution of 5-hydroxy-5 H -indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (22) (12.3 g, 54.6 mmol) in 50 mL dry methanol. The solution was cooled in ice and, after 15 min., a flow of dry oxygen was begun and continued for 1 h. Then the reaction mixture was poured into a solution of 12 g sodium bisulfite in 200 mL water. After 30 min. the mixture was evaporated to dryness. The resulting solid was triturated with 2X 100 mL acetone and filtered. The remaining inorganic salts were removed by filtration, The filtrate was evaporated to yield 24.2 g wet pink solid of (23). Drying in vacuo over phosphorus pentaoxide yielded 12.5 g crude (23). Recrystallization from ethyl acetate yielded two crops 8.06 g (61%) and 2.54 g (19%) of (23). 5-Chloro-5H-indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (24) : A mixture of 5-hydroxy-5 H -indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (23) (8.06 g, 33.4 mmol) in 200 mL thionyl chloride was heated at reflux for 4 h. The thionyl chloride was removed on the rotavapor to leave a residue which was partitioned between water and chloroform and neutralized with saturated sodium bicarbonate. After further extractions with chloroform the combined chloroform extracts were dried over magnesium sulfate and evaporated to yield 7.87 g (91%) of (24). Spiro-[5H-indeno[1,2-b]pyridine-5,5'-(2'-amino-4'-thiazolone)] (25): A mixture of 5-chloro-5 H -indeno[1,2-b]pyridine-5-carboxylic acid methyl ester (24) (7.87 g, 30.4 mmol), thiourea (1.2 eq, 36.4 mmol, 2.77 g) and sodium acetate (1.1 eq, 33.4 mmol, 2.74 g) in 140 mL glacial acetic acid was refluxed for 40 min. Then 100 mL water was added and the pH was adjusted to 6.7 with hydrochloric acid. The aqueous portion was decanted from the precipitate, followed by additional 50 mL water wash. The dried residue was treated with ethyl acetate and the resulting crystalline solid was collected by filtration and dried to yield 1.81 g (32%) of (25). Spiro-(5H-indeno[1,2-b]pyridine-5,5'-thiazolidine)-2',4'-dione (26) : A mixture of spiro-[5 H -indeno[1,2-b]pyridine-5,5'-(2'-amino-4'-thiazolone)] (25) (1.00 g, 3.74 mmol) was stirred at reflux in a solution of 100 mL methanol and concentrated hydrochloric acid (1:1) for 2 h. The mixture was then concentrated to approximately 10 mL with heat and reduced pressure, chilled on ice and neutralized with sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water. Purification of the dried precipitate by chromatography (silica gel using 2.5-7% methanol/chloroform) yielded a product after solvent evaporation, 400 mg. Recrystallization of the residue from ethanol yielded crystalline (26). m/e +. 268. IR strong bands at 1700 and 1745 cm⁻¹. Example IX Spiro-(5H-indeno[1,2-b]pyridine-5,3'-succinimide) (27) : The ester (22) (4.00 g, 17.8 mmol) was added all at once to a stirred, room temperature solution of sodium methoxide in methanol (sodium metal, 1.2 eq, 21.3 mmol, 490 mg and 40 mL dry methanol). After 15 min., chloroacetamide (1.1 eq, 19.5 mmol, 1.83 g) was added and the mixture was left to stir at room temperature under nitrogen. After two days the reaction mixture was poured into 100 mL 1 N sodium hydroxide, cooled in ice and the pH was adjusted with concentrated hydrochloric acid to pH 7. The precipitated solid was collected by filtration and washed with cold water. The dried solid (2.02 g) was recrystallized from ethyl acetate with charcoal treatment to yield 1.03 g (23%) crystalline (27). m.p. 245-246°C. Calc. %C 71.99, %H 4.03, %N 11.20: meas. %C 71.85, %H 4.14, %N 11.17. Example X 5H-Indeno[1,2-b]pyridin-5-one (28) : See general oxidation method of Sprinzak, J . Am . Chem . Soc ., 80 (1958) 5449. 4-Azafluorene (5.0 g, 30 mmol) was dissolved in 50 mL anhydrous pyridine containing in solution 2 mL Triton B solution (prepared by evaporating 5 mL of 40% Triton B in methanol (Aldrich Chemical, Inc.) and 5 mL pyridine with heat and reduced pressure followed by q.s. to 10 mL with pyridine). Then air was continuously bubbled through the solution with stirring. Am addition of 2 mL Triton B solution was made twice more at two-hour intervals. After six hours the reaction mixture was evaporated to dryness. The residue was triturated in 30 mL water and extracted four times with ethyl acetate (total volume 200 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was chromatographed (silica gel and chloroform) to yield after evaporation of the solvent 4.5 g (83%) of (28). m.p. 132-136°C (reported 142°C). Spiro-(5H-Indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione (29) : 5 H -Indeno[1,2-b]pyridine-5-one (4.0 g, 22 mmol) was mixed with potassium cyanide (1.6 g, 24 mmol) and ammonium carbonate (5.3 g, 55 mmol) in 90% ethanol (75 mL) in a pressure reactor and heated at 105°C for 40 hr. The mixture was poured into 300 mL of water, acidified with conc. HCl (pH 1), and filtered. The filtrate was neutralized and the solid which formed collected by filtration, washed with water, and dried to yield 4.5 g. This solid was crystallized from ethyl acetate to yield 3.2 g of product. (This material was no longer soluble in ethyl acetate after the first crystallization). m/e +. 251. Example XI Spiro-(7-nitro-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione (30) : Spiro-(indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione (20) (1.0 g, 4 mmol) was added to cold concentrated sulfuric acid (10 mL) and stirred in an ice bath as concentrated nitric acid was added dropwise over about 10 min. The mixture was allowed to warm to room temperature and stirred overnight; the resulting solution was poured onto ice and the solution neutralized with concentrated aqueous sodium hydroxide. The solid which formed was collected by filtration, washed with a small volume of water, and dried. The product was dissolved in warm water (30 mL) by the addition of sodium hydroxide solution, treated with Norite decoloring charcoal, filtered through a celite bed and the bed washed with a small volume of warm dilute base. The combined filtrate and wash were neutralized with hydrochloric acid to yield a solid which was collected by filtration, washed with water and dried to yield 0.76 g of (30). Calc. %C 56.76, %H 2.72, %N 18.91: meas. %C 56.59, %H 2.83, %N 18.87. m/e +. 296. Example XII Spiro-(7-bromo-indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione (31) : Spiro-(indeno[1,2-b]pyridin-5,4'-imidazolidine)2',5'-dione (29) (1.0 g, 4 mmol) was dissolved in cold 70% sulfuric acid (50 mL). The solution was heated to 50°C, and N-bromosuccinimide (0.78 g, 4.3 mmol) was added in small portions with stirring. After stirring at 50°C for 2 h, the reaction was poured onto ice, and the solution was neutralized with concentrated aqueous sodium hydroxide. The solid which formed was collected by filtration and washed with water. The sample was dissolved in 30 mL of warm water by addition of aqueous sodium hydroxide then treated with Norite, filtered through a celite bed and washed with warm dilute base, and the combined filtrate and wash were acidified with hydrochloric acid (to pH 6). The solid was collected by filtration, washed with water, and dried to yield 0.88 g of (31). m/e +. 329. Example XIII 4H-indeno[1,2-b]thiophen-4-one (35) : To methyl anthranilate (90.0 g, 77 mL, 595 mmol, 1.0 eq) was added hydrochloric acid (120 mL of conc., 1450 mmol, 2.4 eq diluted with 100 mL distilled water). The resulting mixture of solid and liquid was heated to reflux with stirring while protected from light. The hot clear solution was cooled to 5°C whereupon a solid precipitated. To this stirred mixture was added sodium nitrite solution (41.09 g, 596 mmol, 1.0 eq in 90 mL distilled water) at a rate to maintain the reaction temperature below 5°C. After 1.5 h fluoroboric acid (95 g, 48% in water) was added rapidly and the resulting suspension was stirred for an additional 30 min. at -10 to 0°C. The suspended solid was collected by filtration, washed with 100 mL cold water, 120 mL cold methanol and 500 mL ether. The resulting pink solid wad dried in vacuo over concentrated sulfuric acid to yield 39.5 g of (32) as a pink solid (m.p. 93-98°C with decomposition, reported 102°C with decomposition Org . Reactions 5 , 219). To a diazo salt (32) (39.5 g, 158 mmol, 1.0 eq) in thiophene (75 mL) stirred suspension was dropwise added during 1 h a solution consisting of 3,5-dimethylpyrazole (15.80 g, 164 mmol, 1.04 eq) and hydroquinone (1.91 g, 17 mmol, 0.11 eq) in 125 mL thiophene at 0°C. After 2.5 h additional stirring at 0-5°C the reaction was stirred overnight at ambient temperature (see J . Org . Chem ., 46 (1981) 3960). Evaporation with heat and reduced pressure yielded a brown semisolid. Column chromatography (silica gel, 1:9 to 1:4 ethyl ether/petroleum ether) yields 19.4 g. Distillation (bp 141-160°C, 4 mmHg) yields 15.1 g of (33). To 15.1 g of (33) was added methanolic potassium hydroxide (12.8 g KOH in 200 mL methanol) and the reaction mixture was refluxed for 4 h whereupon potassium hydroxide (2.5 g) was added. After 5 h total refluxing, the starting material (33) was completely hydrolyzed (silica gel, 40% Pet ether/ether). To the cooled mixture was added 250 mL water and the diluted mixture was extracted with 250 mL ethyl ether. The ether extract was back extracted with 150 mL 10% KOH. The combined aqueous fractions were cooled and acidified with concentrated hydrochloric acid to pH 2. The acidified slurry was then extracted with diethyl ether (3 x 200 mL), the ether extracts washed with brine (150 mL) then dried with anhydrous magnesium sulfate. After filtration and evaporation, 23.7 g tan solid resulted. m.p. 80°C (reported m.p. 93-94°C, J . Med . Chem ., 9 (1966) 551). To the acid (13.7 g, 69.2 mmol, 1.0 eq) was added thionyl chloride (25.3 mL, 213 mmol, 3.1 eq) and the mixture was refluxed for 2 h. After cooling the reaction mixture was evaporated with reduced pressure and heat with 3 x 100mL benzene additions to result in 15 g of (34) as a dark oil. Under nitrogen, a stannic chloride solution (SnCl₄, 9.1 g, 4.1 mL, 1.25 eq in 40 mL benzene) was added over 20 min. to a benzene (100 mL) solution of the acid chloride (34) (15 g, 69.2 mmol) at 0-4°C with mechanical stirring. After a total of 30 min. the reaction mixture was poured into 200 cc ice containing 100 mL 1 N hydrochloric acid. (See J . Org . Chem ., 35 (1970) 872). Ethyl acetate extractions (600 mL) of the aqueous mixture yielded a dark organic extract. Washing the organic extract with 100 mL 100% sodium hydroxide, 100 mL water (2X) yielded an orange ethyl acetate extract which was dried over anhydrous magnesium sulfate. Filtration and evaporation yielded a dark residue. Column chromatography (silica gel, 1:9 ethyl ether/petroleum ether) yields a purified 4.5 g sample of orange (35). m.p. 99.5-101.5°C from hexane. (lit. 101°C, J . Org . Chem . 35 (1970) 872). Calc. %C 70.94, %H 3.25, %S 17.22: meas. %C 70.98, %H 3.33, %S 17.16. Spiro-(4H-indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione (36) : To a glass-lined, high-pressure steel reaction vessel was added ketone (35) (373 mg, 2 mmol), potassium cyanide (406 mg, 5 mmol), ammonium carbonate (577 mg, 6 mmol) and ethanol (15 mL). The sealed vessel was heated at 110°C for 24 h. The dark reaction mixture was poured into water and acidified with concentrated hydrochloric acid to pH 1. The resulting dark solid was collected by filtration and resolubilized in 10% sodium hydroxide (30 mL), treated with charcoal and filtered. The filtrate was acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried. The solid was dissolved in dimethylformamide, treated with Darco G-60 and filtered through a Celite pad. Dilution with water (3X volume) resulted in a precipitate which was collected by filtration. The collected solid was dissolved in 10% sodium hydroxide (3 mL), filtered, and the filtrate was acidified with conc. hydrochloric acid, the white precipitate collected by filtration, washed with water and dried at 105°C to yield 110 mg of (36). m.p. 336-8°C. Calc. %C 60.92, %H 3.15, %N 10.96: meas. %C 60.83, %H 3.22, %N 10.97. Example XIV 8H-Indeno[2,1-b]thiophen-8-one (38) : Thionyl chloride (60.3 g, 37 mL, 500 mmol, 3.6 eq) was added at 25°C to o-bromobenzoic acid (Aldrich Chemical, Inc.) (28.1 g, 140 mmol, 1.0 eq). After addition the reaction mixture was heated to 80°C for 13 h. Evaporation with beat and reduced pressure partially reduced the volume. Then under nitrogen atmosphere 100 mL methylene chloride followed by 3-bromothiophene (Aldrich Chemical, Inc.) (22.8 g, 13.1 mL, 140 mmol, 1.0 eq) in 100 mL methylene chloride were added to acyl chloride intermediate. Then aluminum trichloride (23.9 g, 179 mmol, 1.3 eq) was added in small portions to the reaction mixture at 0°C. After addition, the reaction mixture was allowed to slowly reach room temperature. After 17 h the reaction was quenched by the slow addition of 150 mL 2 N hydrochloric acid. Water (2 x 150 mL) and brine (100 mL) washing, drying over anhydrous magnesium sulfate, filtration and evaporation of the filtrate in vacuo yielded approximately 50 g of an oil of (37) which solidified in the freezer. IR 1645 cm⁻¹ for diaryl ketone. Diaryl ketone (37) (44 g, 480 mmol, 4 eq) and activated copper (prepared from aqueous copper sulfate, zinc dust, 5% hydrochloric acid) (30 g, 480 mmol, 4 eq) in 200 mL dimethylformamide were refluxed for 6.5 h. After the cooling the reaction mixture was filtered and 150 mL water added. The filtrate was extracted with ethyl ether (5 x 150 mL). The combined ether extracts were washed with 150 mL 1 N hydrochloric acid, 150 mL water and 150 mL brine. Then the ether solution was dried over anhydrous magnesium sulfate, filtered and evapoarted to yield a solid, 18.6 g (79%). Recrystallization from hexane yielded purified (38) m.p. 111-112°C. Calc. %C 70.97, %H 3.25, %S 17.22: meas. %C 70.71, %H 3.26, %S 17.12. Spiro-(8H-indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione (39) : To a glass-lined, high-pressure steel reaction vessel was added ketone (38) (931.2 mg, 5 mmol), potassium cyanide (1.01 g, 12.5 mmol), ammonium carbonate (1.45 g, 18 mmol) and 25 mL ethanol. The sealed vessel was heated at 115-120°C for 20 h. The work-up procedure was very similar to that for spiro-hydantoin (36) of Example XIII. The purified product (39), 200 mg, gave m/e +. 256. Calc. %C 60.92, %H 3.15, %N 10.96: meas. %C 60.88, %H 3.22, %H 10.79. Example XV Spiro-(9H-pyrrolo[1,2-a]indol-9,4'-imidazolidine)-2',4'-dione (41) : 9 H -Pyrrolol[1,2-a]indole-9-one (40) was prepared exactly according to Josey and Jenner, J . Org . Chem ., 27 (1962) 2466. The ketone (40) (2.5 g, 15 mmol), potassium cyanide (2.44 g, 37.5 mmol), ammonium carbonate (4.85 g, 45 mmol) and 50 mL 90% ethanol were added with mixing to a 125 cc stainless steel pressure reaction vessel. The sealed vessel was heated to 115-118°C for 48 h. The work-up was as in Example XIII in the work-up of (36). The collected and dried sample, 650 mg of (41), gave decomposition at > 290°C. Calc. %C 65.26, %H 3.79, %N 17.56: meas. %C 65.16, %H 4.00, %N 17.59. Example XVI Spiro-(9H-indeno[2,1-c]pyridin-9,4'-imidazolidine]-2',5'-dione (43) : 2-Azafluoren-9-one (42) was prepared from 3-mesitoyl-4-phenyl-pyridine exactly according to Fuson and Miller, J . Am . Chem . Soc ., 79 (1957) 3477. m.p. 152-153°C (reported 155.5-156.5°C by Fuson and Miller, ibid ). The ketone (42) (0.5 g, 2.8 mmol), potassium cyanide (0.2 g, 3.1%mmol), ammonium carbonate (1.0 g, 11 mmol) and 10 mL absolute ethanol were added with mixing to a 40 cc stainless steel pressure reactor. The sealed vessel was heated at 115-120°C for 30 h. The cooled reaction mixture was poured into 75 mL water, acidified with concentrated hydrochloric acid, filtered, the filtrate was made basic with 10% sodium hydroxide and filtered. The filtrate was neutralized with hydrochloric acid, the precipitate collected, washed with cold water and dried to yield 0.11 g of (43). m/e +. 251. Example XVII Spiro-(2-chloro-7-fluoro-9H-flouren-9,4'-imidazolidine)-2',5'-dione (45) : The spiro-hydantoin (44), spiro-(2-fluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione, was prepared exactly according to U.S. Application Nos. 368,630 and 368,631. A mixture of (44) (5.36 g, 20 mmol), ferric chloride (0.25 g), glacial acetic acid solution of chlorine gas (5 g Cl₂ in 25 mL HOAc) and 200 mL glacial acetic acid were heated at 75°C overnight. The cooled reaction mixture was poured into 200 mL water, stirred and the solid was collected by filtration. After water washes, the solid product was dried with 50°C heat in vacuo to yield 2.3 g of (45). Calc. %C 59.52, %H 2.66, %N 9.25: meas. %C 59.35, %H 2.77, %N 9.26. Example XVIII 7-fluoro-5H-indeno[1,2-b]pyridine (50) : The procedure used for the preparation of 5-fluoro-1-indanone is that of Olivier and Marechal ( E . Bull . Soc . Chim . Fr . (1973) 3092-3095) with modifications. The conversion of the ketone to 7-fluoro-5 H -indeno[1,2-b]pyridine followed the general procedure described by Parcell and Hauck ( J . Org . Chem . (1963) 28 , 3468-3473) for the preparation of 5 H -indeno[1,2-b]pyridine from 1-indanone. Aluminum chloride (350 g, 2.62 mol) was covered with 650 mL methylene chloride and, while stirring under nitrogen, a solution of 3-chloropropionyl chloride (400 g, 3.15 mol, 300 mL) in 250 mL methylene chloride was added over 80 min. After 15 min., a solution of fluorobenzene (256 g, 2.66 mol, 250 mL) in 250 mL methylene chloride was added over 1 h 35 min. The reaction mixture was stirred, under nitrogen, at room temperature overnight ( ca 18 h). The mixture was then poured onto 2.5 kg ice and transferred to a 4 L separatory funnel. After shaking well, the organic layer was removed and the aqueous portion was extracted with 2 x 50 mL methylene chloride. The combined organic extracts were washed with 3 x 200 mL saturated aqueous sodium bicarbonate and 1 x 200 mL brine, dried (MgSO₄), and evaporated to leave an oil which crystallized on cooling. Recrystallization from 2 L hexane gave 325 g (67%). The filtrate was concentrated to 500 mL and cooled to provide another 42 g (9%) of product (46). 3-Chloro-1-(4-fluorophenyl)propanone (46) (366 g, 1.97 mol) and 2.2 L concentrated sulfuric acid were combined in a 5 L flask equipped with a mechanical stirrer and heated over a period of 80 min. to 120°C and then maintained at that temperature for 30 min. Hydrogen chloride evolution began at about 80°C. The reaction mixture was then cooled to 20°C, poured onto 5 kg of ice in a 22 L flask equipped with a bottom drain and a mechanical stirrer, and extracted with 6 x 1 L chloroform. The combined extracts were washed with 2 x 1 L saturated aqueous sodium bicarbonate and 1 x 1 L brine, dried (MgSO₄), and concentrated to leave a dark oil. Distillation gave the ketone, (47) 97.9 g (33%), bp 61-66°C/0.15-0.2 mm, discolored by some dark material which was carried over during the process. A solution of 5-fluoro-1-indanone (47) (20.2 g, 0.135 mol), p-toluene-sulfonic acid monohydrate (0.015 eq, 390 mg), and piperidine (1.1 eq, 0.148 mol, 15 mL) in 300 mL toluene was refluxed under a Dean-Stark trap for 30 h. The reaction mixture was concentrated and distilled to provide the enamine, (48) 8.6 g (29%); bp 95-100°C/1.5 mm. A solution of the enamine (8.6 g, 40 mmol) in 10 mL dry DMF was added all at once to a stirred solution of bromopropylamine hydrobromide (1.0 eq, 8.67 g) in 15 mL DMF. The stirred mixture was heated to 100°C under nitrogen and then kept at that temperature for 4 h. The reaction mixture was poured into 60 mL cold 2 N aqueous hydrochloric acid and extracted with 2 x 50 mL ethyl ether to remove any non-basic material. The aqueous solution was then covered with 50 mL ether, chilled, end basified using concentrated sodium hydroxide. After separating the organic layer, the aqueous portion was extracted with 2 x 50 mL ether and the combined extracts were washed with 1 x 50 mL brine, dried (MgSO₄), and concentrated to leave 7.8 g of a dark oil. Distillation provided the tetrahydropyridine, 3.46 g (46%); bp 83-86°C/0.15 mm. A mixture of the tetrahydropyridine (49) (3.19 g, 16.9 mmol), 10 mL xylene, 10 mL nitrobenzene, and 350 mg 10% palladium on carbon was refluxed for 4 h under a Dean-Stark trap under nitrogen. The reaction mixture was then cooled to room temperature and filtered through Celite, washing with ethyl acetate. The filtrate was extracted with 3 x 20 mL 2 N aqueous hydrochloric acid and then the combined extracts were washed with 2 x 25 mL ethyl ether to remove non-basic material. Basification using solid potassium carbonate resulted in the precipitation of a dark green solid that was collected by filtration and washed well with water. This material 2.3 g (75%), was judged sufficiently pure by NMR to use in the next step. The material can further be purified by chromatography on silica gel using 30% ethyl acetate/hexane to give a yellow solid of (50) mp 80-84°C. The product (50) can be oxidized in accordance with Method VII and derivatized according to Method I into the corresponding spiro-hydantoin. The product (50) can be derivatized in accordance with Methods II, III and IV into the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide. Example XIX Following the foregoing text of preparations and examples, from readily available starting materials, the following spiro-derivatives of the present invention are prepared by analogy. All structional permutations occasioned by the substitution patterns and the values of U and Z on the following tricyclic structures are fully contemplated and intended as evidenced by the table entries. Example XX t = CH₂, O, NH Preferred derivatives from Example XIX may be oxidized in accordance with Method VI to yield the corresponding N-oxides. Similarly, other N-oxides are prepared from other spiro-tricyclic aromatic azine derivatives of the present invention. Alternatively, an indenopyridine or indenopyridine ketone may be oxidized in accordance with Method V to the corresponding N-oxide prior to spiro derivatization according to Methods I, III or IV. Q = H₂, O Example XXI The sodium salt of spiro-(2-fluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione, spiro-(6-fluoro-9 H -pyrrolol[1,2-a]indol-9,4'-imidazolidine)-2,4'-dione, spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione or any of their related spiro tricyclic congeners which are the subject of the present invention are prepared by dissolving any of said compounds 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 spiro-hydantoin, spiro-thiazolidinedione, spiro-oxazolidinedione or spiro-succinimide can be prepared. In those cases where the aromatic substituents contain carboxylic acid moieties (e.g., isopropinoic acid substituent), one equivalent of base will yield the corresponding sodium carboxylate salt. In such cases as the aforementioned, two mole equivalents will yield the disodium salt. By this method, the desired alkali metal suit is obtained as an amorphous powder which is soluble in water. In like manner, the potassium and lithium salts are analogously prepared, as are the alkali metal salts of all other spiro-tricyole compounds of this invention which are reported in Exmaples I-XVII and XIX, respectively. Example XXII The calcium salt of spiro-(2-fluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione is 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 this manner, is are all other alkaline-earth metal salts not only of this particular compound, but also those spiro-tricyclic analogs previously described in Examples I-XVII and XIX, respectively. Example XXIII The hydrogen chloride salt of spiro-(7-fluoro-9 H -indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione, spiro-(7-fluoro-5 H -indeno[1,2-b]pyridine-5,4'-imidazolidine)-2',5'-dione or spiro-(7-fluoro-5 H -indeno[1,2-b]-5,5'-thiazolidine)-2',4'-dione in 1.0 to 1.5 equivalent amount of 1 N to 10 N hydrochloric acid and then freeze-drying the mixture in a manner to remove excess hydrochloric acid. By this method the aforementioned and related spiro-tricyclic azine analogs, previously described in Example XIX, and prepared as hydrogen chloride salt powders which are soluble in water. Example XXIV A dry solid pharmaceutical composition is prepared by mixing the following materials together in the proportions by weight specified: Spiro-(2-fluoro-9,5'-thiazolidine)-2',4'-dione 50 Sodium Citrate 20 Alginic Acid 5 Polyvinylpyrrolidone 15 Magnesium Stearate 5 The dry composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such size that it contains 100 mg of the active ingredient. Other tablets are also prepared in a likewise manner containing 10, 25 and 200 mg of active ingredient, respectively, by merely using an appropriate quantity by weight of the spiro-thiazolidinedione in each case. Likewise other related examples of spiro-thiazoidinediones, spiro-imidazolidinediones, spiro-ozazolidinediones, spiro-succinimides can be formulated as tablets on a respective weight proportion. Example XXV A dry solid pharmaceutical composition is prepared by combining the following materials together in the weight proportions indicated below: Spiro-(7-fluoro-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione 50 Calcium Carbonate 20 Polyethylene glycol, Average Molecular Weight 30 The dried solid mixture is thoroughly mixed until uniform in composition. The powdered product is then used to fill soft elastic and hard-gelatin capsules so as to provide capsules containing 200 mg of the active ingredient. Example XXVI The following spiro-tricyclic compounds of the Examples and Preparations previously described were tested for their ability to inhibit or reduce aldose reductase enzyme activity. The procedure for the aldose reductase enzyme activity inhibition test is described in the following publications: a) P. F. Kador, L. O. Merola and J. H. Kinoshita, Docum . Ophthal . Proc . Series , 18 , 117-124 (1979); b) P. F. Kador, J. H. Kinoshita, W. H Tung and L. T. Chylack, Jr., Invest . Ophthalmol . Vis . Sci ., 19 , 980-982 (1980); c) P. F. Kador, D. Carper and J. H. Kinoshita, Analytical Biochemistry , 114 , 53-58 (1981). Wherein the assay mixture used in the tests containing 0.1 M potassium phosphate buffer, pH 6.2, 0.2 mM nictoinamide adenine dinucleotide phosphate (NADPH), 10 mM D,L-glyceraldehyde, and an appropriate volume of the enzyme preparation, thermostated at 25°C in the cell compartment of a spectrophotometer. These conditions are identical to those published in references (a), (b) and (c), except that a larger NADPH concentration was employed. This insured a linear reaction rate for longer time periods since one product of the reaction, NADP+, markedly inhibits the enzyme. The control sample contained no added inhibitor. In order to measure aldose reductase inhibition activity, varying concentrations of the inhibitor examples set forth below were added to the standard incubation mixture. The control, containing the enzyme and NADPH, gave a very small, but measurable rate; thus, it served as the blank against which to measure the glyceraldehyde-dapendent rate of NADPH oxidation. The tests were conducted with human placental aldose reductase enzyme. The results of the tests are the product of multiple essays. The IC50 data for each compound is expressed below in terms of concentration of compound required to inhibit 50% human placental aldose reductase enzyme activity. A test compound is considered active if it inhibits or reduces human aldose reductase activity at 1 x 10⁻⁴ M concentration or less. The following list is provided as a representative sample of the biological activity of the spiro-tricyclic derivatives of the present invention. A. d,1-Spiro-(2-fluoro-9 H -fluoren-9,4'-imidazolidine)-2'5'-dione B. Spiro-(2,7-Difluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione C. d,1-Spiro-(2-fluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione D. Spiro-(2,7-difluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione E. d,1-Spiro-(5 H -indeno[1,2-b]pyridine-5,3'-succinimide) F. d,1-Spiro-(2-fluoro-9 H -fluoren-9,3'-succinimide) G. Spiro-(9 H -fluoren-9,3'-succinimide) H. d,1-Spiro-(2-chloro-7-fluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione I. d,1-Spiro-(9 H -pyrrolol[1,2-a]indol-9,4'-imidazolidine-2',4'-dione J. d,1-Spiro-(7-nitro-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione K. d,1-Spiro-(7-bromo-5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',-5'-dione L. d,1-Spiro-(2-chloro-9 H -fluoren-9,4'imidazolidine)-2',5'-dione M. Spiro-(9 H -fluoren-9,5'-thiazolidine)-2',4'-dione N. Spiro-(9 H -fluoren-9,5'-oxazolidine)-2',4'-dione O. d,1-Spiro-(2-fluoro-9 H -fluoren-9,5'-oxazolidine)-2',4'-dione P. d,1-Spiro-(9 H -indeno[2,1-c]pyridin-9,4'-imidazolidine)-2',5'-dione Q. d,1-Spiro-(4 H -indeno[1,2-b]thiophen-4,4'-imidazolidine)-2',5'-dione R. d,1-Spiro-(8 H -indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione S. d,1-Spiro-(5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione Research (Kador, Merola and Kinoshite, Docum . Ophthal . Proc . Series . 18 (1979) 117) has indicated that the evaluation of aldose reductase inhibitors for potential human chemotherapy may require testing with human aldose reductase. There are species-linked differences in the susceptibility for inhibition of aldose reductase. For example, rat lens aldose reductase behaves differently from human placental aldose reductase with respect to inhibition by synthetic chemical inhibitors. Example XXVII According to the procedures of Kador, Merola and Kinoshite, Docum . Ophthal . Proc . Series , 18 (1979) 117 and Kador and Sharpless, Biophysical Chemistry , 8 (1978) 81 the inhibition exerted by examples of the present invention where evaluated against rat lens aldose reductase. Otherwise, the inhibitor assay is identical to that employed against human aldose reductase in Example XXVI. Representative rat lens aldose reductase inhibition is presented in terms of the concentration of test compound required to reduce rat lens aldose reductase enzyme activity by 50%. A test compound is considered active if it inhibits or reduces rat lens aldose reductase activity at 1 x 10⁻⁴ M concentration or less. A. Spiro-(2-fluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione B. Spiro-(2,7-difluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione C. Spiro-(2-fluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione D. Spiro-(2,7-difluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione E. Spiro-(2-fluoro-9 H -fluoren-9,3'-succinimide) F. Spiro-(9 H -fluoren-9,5'-thiazolidine)-2',4'-dione G. Spiro-(2-methylthio-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione H. Spiro-(5 H -indeno[1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione I. Spiro-(2-fluoro-9 H -fluoren-9,5'-oxazolidine)-2',4'-dione J. Spiro-(5 H -indeno[1,2-b]pyridine-5,3'-succinimide) K. Spiro-(8 H -indeno[2,1-b]thiophen-8,4'-imidazolidine)-2',5'-dione Example XXVIII Aldose reductase inhibitor potency may be evaluated in rat lens culture assays where 30 mM of glucose, galactose or xylose can be used in culture to induce a 'sugar' cataract. In addition to monitoring lens clarity, certain biochemical radiolabeled markers (e.g., choline -³H and ⁸⁶Rb) are employed to measure lens function. See Obazawa, Merola and Kinoshita, Invest . Ophthalmol ., 13 (1974) 204 and Jernigan, Kador and Kinoshita, Exp . Eye Res ., 32 (1981) 709. In the present case, the 30 mM xylose cataract model was selected because 30 mM xylose is more effective in product 'sugar' cataracts than either 30 mM glucose or 30 mM galactose. The general procedure is as folows: a) Sprague-Dawley rats of 75-100 g body weight are sacrificed and the lenses removed immediately; b) the contralateral lens of the pair of lenses is employed as untreated control lens; c) the test lens is cultured in TC-199 culture media in the presence of 30 mM xylose, 30 mM xylose plus a selected concentration of test compound of a selected concentration of test compound; d) the contralateral control lens is treated identical to the test lens except no test compound or xylose is included; e) the matched lens pairs arc cultured for 18 h in a CO₂ incubator; f) the lenses are compared morphologically and weighed. All lenses, control and test groups, are allowed to preincubate for 1 h in respective control media or drug control media prior to transfer to xylose media or xylose-drug media. In those cases where radiolabelled markers are to be measured, the lenses are treated as aforementioned except the radiolabelled marker(s) are added to the culture at four hours before harvesting. Radiolabelled markers include choline -³H ([methyl-¹⁴C]-choline chloride available from New England Nuclear), AIBA -¹⁴C (α-[1-¹⁴C]-(CH₃)₂C(NH₂)COOH available from New England Nuclear) and ⁸⁶Rb. The effect of xylose on lens uptake of ⁸⁶Rb, lens uptake of amino acid (AIBA -¹⁴C) and lens uptake of choline -³H and the effectiveness of representative compounds of the present invention to preserve normal lens morphology is reported here. The effect of 30 mM xylose and 30 mM xylose plus selected concentrations of test compound on radioactivity ratio is expressed as L/M% of control. L/M% of control is defined as the test lens radioactivity divided by culture media radioactivity as a percentage of the control contralateral lens radioactivity to media radioactivity ratio under identical test conditions but always without xylose or test compound in the control. The effect of 30 mM xylose in the culture media gives a reproducible deleterious effect on the lens as measured by the various L/M%. Furthermore, after incubation of the lens in 30 mM xylose in the TC-199 culture media, the lens gains 20% weight (mostly water weight increase based on dry lens weight measurements) and becomes opaque in the cortex of the lens. Each experiment requires 20-40 pairs of lenses to determine the potency of a selected aldose reductase inhibitor. For comparison purposes, representative examples of the present invention will be profiled in the following table against examples from U.S. Application Nos. 368,630 and 368,631. Representative Compounds Evaluated A. Spiro-(-2-fluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione; B. Spiro-(2,7-difluoro-9 H -fluoren-9,4'-imidazolidine)-2',5'-dione; C. Spiro-(2-fluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione; D. Spiro-(2,7-difluoro-9 H -fluoren-9,5'-thiazolidine)-2',4'-dione. Radiolabel Uptake-L/M% Table Compound (1) L/M% (2) L/M% (3) L/M% None 47 33 45 A 73 50 55 B 105 87 82 C 77 58 70 D 109 85 83 D 109 85 83 (1) L/M% = Lens uptake of choline -³H after 18 h 30 mM xylose culture. (2) L/M% = Lens uptake of AIBA -¹⁴C (amino acid) after 18 h 30 mM xylose culture. (3) L/M% = Lens uptake of ⁸⁶Rb affter 18 h 30 mM xylose culture. In all cases Compounds A, B, C and D prevented lens opacification and lens wet weight increase at compound concentration of 7.5 x 10-⁷ M in the culture media. Compound A and B according to U.S. Application Nos. 368,360 and 368,631 are wholly effective in preventing cataract in galactosemic rats when administered per oral by gauge once a daily at 1.26 and 0.4 mg/kg respectively. In another efficacy study reported in the same applications, Compound A was found to prevent cataract and significantly preserve motor nerve conduction velocity in chronic streptozotocin-induced rate at 8 mg/kg per oral per day. The invention has been described herein with reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL A compound of the formula: and the pharmaceutically acceptable salts thereof, wherein t is selected from the group consisting of CHR¹, NH, O, and S; and A and B are aromatic rings connected through two adjacent positions to a central five-membered ring, and are independently selected from the group consisting of: wherein: U is selected from the group consisting of O, S and NR¹; X is selected from the group consisting of H, F, lower alkylthio, and lower alkylsulfinyl; Y is selected from H, -OH, OCOR³, F, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulphonyl, -CF₃, -S-CF₃, -SO₂CF₃, CO-N(R¹)-R², hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, carboxy, amino lower alkyl, caboxy lower alkyl, lower alkanoyloxy lower alkyl, and C₃ - C₇ cycloalkyl, and Y can be Cl when t is CHR¹, O or S; provided that when both of rings A and B are phenyl and t is NH: when one of X or Y is H, at least one of the other of X or Y must be other than H on at least one of rings A and B; and when one or both of X or Y is H, at least one of the other of X or Y on Rings A and B must be other than H, F, methylthio, methylsulfinyl, methylsulfonyl, methoxy or methyl; R¹ and R² are selected from the group consisting of hydrogen and lower alkyl; and R³ is lower alkyl; and Z is selected from the group consisting of hydrogen, lower alkyl, and halogen. A compound according to claim 1 where A is selected from: where B is selected from: u = O, S, NHR¹ x = H, F y = H, F, Cl, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH t = CH₂, NH, O, S R¹ = H, -CH₃ Z = H, -CH₂.Cl Compound according to claim 1 where B is selected from: wherein X, U, and Z are as defined above. A compound according to claim 1 where U = S. A compound according to claim 1 where U = O. A compound according to claim 1 where U = NR¹ and R¹ = H, CH₃. A compound according to claim 1 where: t = CH₂; X = H, F; Y = H, F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S. A compound according to claim 1 where: t = S; X = H, F; Y = H, F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S. A compound according to claim 1 where: t = NH; X = H, F; Y = F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S, NR¹ and R¹ = H, -CH₃. A compound according to claim 1 where t = O; X = H, F; Y = F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH: U = O, S. A spiro-tricyclic compound according to claim 1 which is one of the following formulae: where R¹ = lower alkyl (C₁ to C₄) where R¹ = lower alkyl (C₁ to C₄) Composition containing a compound of any of claims 1 to 11 for the treatment of complications of diabetes mellitus in humans and animals. The use of a compound of any of claims 1 to 11 for treating diabetic complications in mammals comprising administering an effective amount of said compound. A compound according to claim 1 wherein rings A and B are X = H or F; and Y = F, Cl, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulphonyl, or carboxy lower alkyl. A compound according to claim 14 wherein X = H or F; and Y = F, Cl, methyl, methoxy, -SCH₃, -S(O)CH₃, or -CH(CH₃)COOH. A compound according to claim 15, wherein X = H or F; and Y = F or methoxy. A compound according to any of claims 14 to 16 wherein t = NH. Claims for the following contracting State : AT A process for the manufacture of the spiro-hydantoin compounds which are useful for the treatment of complications of diabetes mellitus in humans and animals, the compounds being of the following formula: and the pharmaceutically acceptable salts thereof, wherein A and B are aromatic rings connected through two adjacent positions to a central five-membered ring, and are independently selected from the group consisting of: U is selected from the group consisting of O, S, and NR¹; X is selected from the group consisting of H, F, lower alkyl sulfide, and lower alkylsulfinyl; Y is selected from H, -OH, -OCOR³, F, Cl, lower alkoxy, lower alkylsulfide, lower alkylsulfinyl, lower alkylsulfonyl, -CF₃, -S-CF₃, -SO₂CF₃, CO-N(R¹)-R², lower alkyl alcohol, lower alkyl ether, nitro, lower alkyl sulfide, lower alkyl, lower alkylamine, lower alkyl esters, -COOH and lower alkyl esters thereof, lower alkyl carboxylic acids and lower alkyl esters, and lower cycloalkyl, provided that when both of Rings A and B are phenyl and t is NH: when one of X or Y is H, at least one of the other of X or Y must be other than H on at least one of Rings A and B; and when one or both of X or Y is H, at least one of the other of X or Y on Rings A and B must be other than H, F, methylthio, methylsulfinyl, methylsulfonyl, methoxy or methyl; R¹ and R² are selected from the group consisting of hydrogen and lower alkyl; end R³ is lower alkyl; Z is selected from the group consisting of hydrogen, lower alkyl, and halogen; t is selected from the group consisting of CHR¹, NH, O, and S, the spiro-hydantoin compounds being prepared from the following ketone tricycles of formula II or their methylene analog tricycles of formula III: wherein A and B are previously defined, except that introduction of a nitro substituent(s), esterification of carboxylic acids, oxidation of alkyl sulfides to sulfoxides or sulfones, and direct aromatic halogenations are performed after the tricyclic aromatic compound is converted to the appropriate hydantoin or thiazolidinedione compound, and wherein certain labile protecting groups may be used during processing, the transformation of the tricycles of Formulas II and III into derivatives of Formula I being according to one or more of the following methods: Method I - Spiro-Tricyclicimidazolidinediones (Hydantoin Derivatization): forming the spiro-tricyclicimidazolidinediones by condensing the appropriate ketones of Formula II with an alkali metal cyanide and ammonium carbonate in the presence of a ketone solubilizing inert polar organic solvent, the reaction being conducted at temperatures ranging from about 6⊘ o to about 18⊘ o C; Method II - Spiro-Tricyclicthiazolidinediones forming the spiro-tricyclicthiazolidinediones from the appropriate fluorene and heterocyclic analogs of fluorene derivatives of Formula III, using a multi-stepped synthesis comprising (a) metalation with a lower alkyl lithium reagent in an inert aprotic solvent under an inert atmosphere to effect metalation at the methylene bridge, (b) then reacting with carbon dioxide to result in carbonation of the bridge carbon to yield upon isolation the corresponding tricyclic carboxylic acid, (c) isolating the tricyclic carboxylic acid derivative by a process including acidification, simple column chromatography and solvent recrystallization, (d) esterifying the tricyclic carboxylic acid with a lower alkyl alcohol in the presence of an acid catalyst, (e) effecting proton abstraction from the acidic methine bridge of the tricyclic carboxylic ester by use of an alkali alkoxide to generate a carbanion, (f) introducing a purified dry oxygen to result in oxidation of the methine carbon, (g) carrying out bisulfite reduction, (h) recovering an α-hydroxy 9-carboxylic acid ester product, (i) effecting α-Halogenation of the α-hydroxy ester substituent with a halide to transform the α-hydroxy group to halide, (j) reacting the α-halo 9-carboxylic acid ester with thiourea in an anhydrous polar high boiling relatively nonbasic solvent to produce a spiro-tricyclicaminothiazolone intermediate, and (k) hydrolyzing the spiro-tricyclicaminothiazolone in an acidic aqueous alcoholic solution to produce the spiro-thiazolidinedione; Method III - Spiro-Tricyclicoxazolidinediones forming the spiro-tricyclic-oxazolidinedione derivatives from the appropriate derivatives of fluorene and heterotricyclic analogs of fluorene of Formula III, comprising preparing the spiro-tricyclic-oxazolidinedione derivative from the tricyclic α-hydroxy ester, reacting the α-hydroxy ester with 1 to 2 equivalents of urea and 1 to 2 equivalents of an alkali alkoxide in a lower alkyl alcohol to yield the spiro-tricyclic-oxazolidinedione, adding water to the reaction, acidifying with a mineral acid, and recovering the product; or Method IV - Spiro-Tricyclicsuccinimides forming the spiro-tricyclicsuccinimide derivatives from the appropriate fluorene derivatives and heterocyclic analogs of fluorene of Formula III, comprising reaction of the corresponding carboxylic alkyl ester with 1 to 1.5 equivalents of an alkali metal alkoxide followed by reaction with 1-2 equivalents of 2-haloacetamide at 1⊘ o to 5⊘ o C under an inert atmosphere, removing solids, acidifying the liquids with an acid,and collecting the resulting precipitate. Process according to claim 1 where A is selected from: where B is selected from: u = O, S, NHR¹ x = H, F y = H, F, Cl, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH t = CH₂, NH, O, S R¹ = H, -CH₃ Z = H, -CH₂. Cl Process according to claim 1 where B is selected from: wherein X, U, and Z are as defined above. Process according to claim 1 where U = S. Process according to claim 1 where U = O. Process according to claim 1 where U = NR¹ and R¹ = H, CH₃. Process according to claim 1 where: t = CH₂; X = H, F; Y = H, F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S. Process according to claim 1 where: t = S; X = H, F; Y = H, F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S. Process according to claim 1 where: t = NH; X = H, F; Y = F. Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S, NR¹ and R¹ = H, -CH₃. Process according to claim 1 where t = O; X = H, F; Y = F, Cl, methoxy, -SCH₃, -S(O)CH₃, -CH(CH₃)COOH; U = O, S. A process for the manufacture of a spiro-tricyclic compound according to claim 1 which is one of the following formulae: where R¹ = lower alkyl (C₁ to C₄) where R¹ = lower alkyl (C₁ to C₄) Process according to claim 1 wherein rings A and B are X = H or F; and Y = F, Cl, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulphonyl, or carboxy lower alkyl. Process according to claim 12 wherein X = H or F; and Y = F, Cl methyl, methoxy, -SCH₃, -S(O)CH₃, or -CH(CH₃)COOH. Process according to claim 13 wherein X = H or F; and Y = F or methoxy. Process according to any of claims 12 to 14 wherein t = NH. Process for preparing a composition containing a compound of any of claims 1 to 15 for the treatment of complications of diabetes mellitus in humans and animals by admixing the active ingredients with conventional carrier and diluents. The use of a compound prepared according to any of claims 1 to 15 for treating diabetic complications in mammals comprising administering an effective amount of said compound.

Inventors: YORK, BILLIE M. JR.
Applicants: ALCON LABORATORIES INC
Application year: 1984
Main classification: C07D209
IPC codes: C07D495, C07D487, C07D513, C07D263, A61K31, C07D498, C07D235, C07D333, C07D471, A61P27, C07D209, C09D127, C07D277, A61P3, C07D221, C07C45, A61P43, C07D491, C07D295