DD234265A5 - PROCESS FOR PREPARING SPIRO-3-HETERO-AZOLONES - Google Patents

Abstract

The invention relates to a process for the preparation of spiro-oxazolidones, -thiazolidonen and -imidazolidonen, which are useful as aldose reductase inhibitors and as therapeutic agents for the treatment of diabetic complications.

Description

Field of application of the invention

The invention relates to novel spiro-3-hetero-azolidinediones useful in the treatment of certain chronic complications resulting from diabetes mellitus, such as diabetic cataracts, retinopathy and neuropathy, to pharmaceutical compositions containing such compounds and to a method for Application of these compounds.

Characteristic of the known technical solutions

Various attempts have been made in the past to obtain more effective oral anti-diabetic agents. In general, these efforts have involved the synthesis of novel organic compounds, particularly sulfonylureas, and the determination of their ability to significantly lower blood glucose levels when administered orally. However, little is known about the influence of organic compounds in preventing or ameliorating chronic complications of diabetes such as diabetic cataracts, neuropathy, and retinopathy. U.S. Patent No. 3,821,383 discloses aldose reductase inhibitors such as 1,3-dioxo-1H-benz [d, e] -isoquinoline-2 (3H) -acetic acid and its derivatives useful for the treatment of these conditions. U.S. Patent No. 4117230 teaches the use of certain hydantoins for the treatment of diabetes complications as aldose reductase inhibitors. Such aldose reductase inhibitors act by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. Thus, unwanted accumulations of galactitol in the lenses of galactosemic patients and of sorbitol in the lens, peripheral nerve cord and kidneys of various diabetic subjects are prevented or reduced. Therefore, such compounds are of therapeutic value as aldose reductase inhibitors for controlling certain chronic diabetes complications, including those involving the eyes, since it is known in the art that the presence of polyols in the crystalline lens leads to cataract formation with concomitant loss the clarity of the lens leads.

Aim and presentation of the essence of the invention

The compounds prepared according to the invention are spiro-hetero-azolidinediones of the formula

-B

and their pharmaceutically acceptable salts, wherein U is oxygen, sulfur or nitrogen, substituted by hydrogen or alkyl of 1 to 4 carbon atoms,

η zero or one,

X is hydrogen, chlorine, bromine, iodine, alkyl of 1-4 carbon atoms, dimethyl or (CH ₂ ) _m Q, wherein m is 1 or 2 and Q is phenyl or halophenyl, with the proviso that when X is dimethyl, η is one is

Y is hydrogen, halogen, nitro, trifluoromethyl, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms

Z is hydrogen, halogen, nitro, trifluoromethyl, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, provided that when either Y or Z is nitro, the other group is hydrogen.

The invention includes compounds in which U is nitrogen, substituted by hydrogen, η is zero, X, Y and Z are each hydrogen and X and Z are each hydrogen and Y is fluorine.

The invention also includes compounds in which U is nitrogen, substituted by hydrogen, η 1, X, Y and Z are each hydrogen or X and Z are each hydrogen and Y is fluorine.

A group of compounds encompassed by this invention includes those wherein U is nitrogen, substituted by hydrogen, η 1, X is methyl, Y is fluorine and Z is hydrogen.

Both mixtures of optically active isomers and partly or completely optically resolved isomers of the compounds claimed herein fall within the scope of the invention.

The invention also includes pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of formula B. Preferred compositions are those wherein U is nitrogen substituted by a hydrogen atom, η is 1, X and Z are hydrogen, Y is fluorine, and the compound is the positive-rotating enantiomer. Preferred compositions are also those wherein U is nitrogen substituted with a hydrogen atom, η 1, X is methyl and Y is fluorine, and more preferably the compound is the positive-rotating enantiomer.

The invention further includes a method for treating a diabetic patient for diabetes-related complications wherein the diabetic is administered an effective amount of a compound of Formula B. A preferred method is one in which η is 1, X and Z are hydrogen, Y is fluorine, and the compound is the positive-rotating enantiomer. Also preferred is the method wherein η 1, X is methyl, Z is hydrogen and Y is fluorine, and more preferably, the compound is the positive-rotating enantiomer.

The system of numbering the spiro compounds of formula B, wherein η is zero (Bl), is as shown.

BI

These compounds (B1) are 6'-Y-4'- or 5'-Z-2'-X-spiro [imidazolidine, oxazolidine-oderthiazolidine-4,1'-indane] -2,5-dione derivatives, W = Hydroxymethylene.

The system of numbering compounds of formula B, wherein η is one (BII), is as shown. These compounds are,

when W is hydroxymethylene, 4'-hydroxy-7'-Y-6'- or 5'-Z-3'-X-spiro [imidazolidine, oxazolidine, or thiazolidine-4,1'-1 ', 2', 3 ' '4'-tetrahydronaphthalene] -2,5-diones.

Compounds of formula B can be prepared according to two different synthetic schemes (A and B) (U is NH).

Starting materials for Scheme A are 1-indanone and i-tetralone (VI). 1-indanones are well-known compounds, and starting lndanones not described in the literature can be prepared by routes analogous to those used to prepare the known compounds.

A particularly useful way of producing 1-indanones is by cyclizing a hydrocinnamic acid derivative. In turn, these intermediates are prepared by hydrogenating cinnamic acid, which in turn is prepared by condensing a suitable benzaldehyde derivative with malonic acid and then decarboxylating.

A representative procedure is that of R. Fox and J. A. Caputo, J. Org. Chem., 31, 1524-6 (1966).

Starting benzaldehydes with the appropriate substitution pattern are known compounds. Using the appropriate benzaldehyde, the desired i-indanones (VI) can be prepared.

1-Tetralones are also well-known compounds, and starting 1-tetraiones not described in the literature can be prepared by routes analogous to those used to prepare the known compounds.

A particularly useful way to prepare 1-tetralone is the method of L. F. Fieser and A. M. Seligman, J. Amer. Chem. Soc., 60, 176-6 (1938), which uses the cyclization of a suitable 4-phenylbutyric acid. These acids in turn can be prepared by Clemmenson reduction of 3-benzoylpropionic acids. 3-Benzoylpropionic acids with a suitable substitution scheme are known, can be prepared by literature methods or by the procedure to be discussed below. These acids are the precursors for the 1-tetralone used in Scheme A. Alternatively, these same acid intermediates according to Scheme B allow the preparation of end products of formula B with different substitution patterns.

A particularly useful route to 3-benzoyl-propionic acids involves condensing a benzaldehyde derivative with acrylonitrile or α-substituted acrylonitrile in the presence of potassium cyanide in dimethylformamide to give a 3-benzoyl-propionitrile, which then hydrolyzes in concentrated mineral acids such as hydrochloric acid to the corresponding 3-benzoyl-propionic acid becomes.

A representative procedure for the condensation step is that of H. Stelter and M. Schreck, Chem. Ber. 107.210-14

It will be appreciated that 3-benzoyl-propionic acids other than substituted by hydrogen in the 2-position result in 3-benzoyl-propionic acids useful in the synthesis of tetrahydronaphthalene end-products according to Scheme A.

3-Substituted 3-benzoylpropionic acids are also useful in the preparation of tetrahydronaphthalene end-products of Formula B according to Scheme A. 3-Substituted 3-benzoylpropionic acids, which are not described in the literature, can be prepared by procedures analogous to those described for U.S. Pat Preparation of known compounds according to the method of FJ McEvoy and GR Allen Jr., J. Org. Chem. 38, 4044-48 (1973).

It will be understood that 3-benzoyl-propionic acids substituted in the 2-position other than by hydrogen give rise to 3-benzoyl-propionic acids useful in the synthesis of tetrahydronaphthalene end-products according to Scheme B.

This route is particularly useful because of the ready availability of substituted benzaldehydes and because α-substituted acrylonitrile (X other than hydrogen), such as methacrylonitrile, are commercially available or according to the general procedure of R. B. Miller and B.F. Smith, Syn. Comm. 413-17 (1973). 2-Substituted 3-benzoylpropionic acids can also be prepared in this way.

3-Benzoylpropionic acids can also be prepared from known substituted bromobenzenes. The bromobenzene derivative is converted to a Grignard reagent and then to a cadmium reagent which is reacted with the half acid halide, half ester of succinic acid to the ester of 3-benzoyl propionic acid. The ester can then be cleaved to the free acid by basic hydrolysis.

This procedure is particularly useful for preparing tetrahydronaphthalene end-products in which X is dimethyl.

For example, α, α-dimethyl succinate in / 3-carbomethoxyisovaleryl chloride (X is dimethyl) can be prepared according to the procedure of

C. C. Price and T. Padmanathan, J. Org. Chem. 30, 2064-67 (1965).

This acid chloride can be reacted with various bromobenzene derivatives to 3,3-dimethyl-3-substituted benzoylpropionic acids. These derivatives can be used in Scheme A to prepare final tetrahydronaphthalene products wherein X is dimethyl.

A useful procedure for the preparation of 3-benzoylpropionic acids is the Friedel-Crafts acylation of a bromobenzene derivative to directly produce a 3-benzoylpropionic acid according to the general procedure of L.F. Fieser and

E. B. Heishberg, J. Amer. Soc. 58,2314 (1936). The nature of the product is determined both by the directing effect of the substituents Y and Z in the benzene ring and by the nature of X when it has a meaning other than hydrogen. When X is dimethyl, the benzoylpropionic acid formed is that in which the gem.-dimethyl radical is adjacent to the carboxyl group rather than the ketone carbonyl. Thus, using as-dimethyl succinic anhydride, 3-benzoyl-2,2-dimethyl-propionic acids can be prepared, which can be converted to tetrahydronaphthalene end-products according to Scheme B, where X is dimethyl.

A useful method of increasing the versatility of the synthesis of 3-benzoylpropionic acids involves converting the ketone carbonyl of the initially formed 3-benzoylpropionic acid into a strongly electron withdrawing group by complexing with AICI ₃ such that the aromatic ring is in the m position to the AICI ₃ Complexed carbonyl group can be halogenated.

The method is particularly useful for converting 3,3-dimethyl-3- (4-substituted benzoyl) propionic acids to 3,4-disubstituted benzoyl derivatives. These in turn can be converted according to Scheme B into 6 ', 7'-disubstituted tetrahydronaphthalenes.

Another useful method for the preparation of 3-benzoylpropionic acids is the reaction of an aryl Grignard reagent prepared from an aryl iodide, such as commercially available iodobenzene derivatives, with a silylated γ-butyrolactone, followed by oxidation.

2-Benzoylacetic acids and their ester derivatives can be used as starting materials for the preparation of dihydroindicarboxylic acids.

Ground end products've rwendet w.

The compounds of formula VI can be converted to the corresponding compounds of formula II wherein U is substituted by nitrogen (oxygen), oxygen (O) or sulfur (S) by a hydrogen atom (NH) or a lower alkyl group (NR) such as N-CH ₃ become. Synthetic Scheme A discloses the preparation of compounds of the formula II (see US Pat. No. 4,111,730 [U = NH]). The preparation of compounds of formula II, wherein U = NR, is carried out from compounds of formula VI on the reaction with chlorosulfonyl isocyanate of the carboxyimine adducts of compounds of formula VI with amines (H ₂ NR) according to the von Reinhard Sarges, Harry R.Howard Jr., Paul R. Kelbaugh, J. Org. Chem. 47.4081-5.1982, described procedure. Compounds of formula B wherein U is oxygen may be prepared according to Scheme A or B similar to that when U is NH. Of course, the reagents used with the carbonyl precursor (Vl or IV) to form the oxazolidinedione ring (U = oxygen) are different than the reagents that react to the hydantoin ring (U = NH). The compounds of formula II wherein U is oxygen are known or can be prepared from the corresponding 1-tetralone or 1-indanone (VI) according to the methods described in US Pat. No. 4,226,875. The synthesis of certain spirooxazolidinones is disclosed in RC Schnur et al., Journal of Medicinal Chemistry, 25, 1451-4 (1982).

These compounds of formula II are reacted at about 0 to 60 ° C, preferably about 25 ° C, with a perfluorocarboxylimine having N-dialkylsilyl and O-dialkylsilyl groups, e.g. B. with N-dimethylsilyl-O-dimethylsilyl-perfluoroacetic acid imine, which acts as a protective group for the imide nitrogen, in a non-reactive, halogenated solvent such as chloroform, which does not interfere with the subsequent halogenation reaction.

The in situ halogenation is preferably carried out with a molecular halogen such as bromine, chlorine or iodine, most preferably bromine. For example, leads to the in situ bromination with bromine at a temperature range of about 25 to 100 ⁰ C, preferably from about 6O ⁰ C, the 4'-bromo derivative IM or 4'-Hal derivative D.

The 4'-halo derivative D is hydrolyzed in water having a pH in the range of about 1 to 7, preferably about 4, in a temperature range of about 0 to 60 ⁰ C, preferably about 25 ° C. The resulting alcohol B (W is hydroxymethylene) may be further to the corresponding ketone (A, W is carbonyl) may be oxidized with any suitable oxidizing agent such as chromium trioxide in acetic acid at about 0 to 60 ⁰ C, preferably about 25 ° C.

Compounds of formula A wherein W is carbonyl and X is hydrogen may be halogenated to an α-haloketone wherein X is halogen. The halogenation can be carried out with a molecular halogen (Br ₂ , Cl ₂ , J ₂ ) in a suitable solvent such as a lower carboxylic acid of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably acetic acid, using a mineral acid catalyst such as hydrobromic acid at between about 0 to 100 ⁰ C, preferably 25 to 80 ° C, take place.

Alternatively, the compound of formula A, wherein X is hydrogen and W is carbonyl, may be halogenated such that X is halogen, first by reacting B with a perfluorocarboxylimine having N-trialkylsilyl and O-trialkylsilyl groups, e.g. N-trimethylsilyl-O-trimethylsilyl perfluoroacetic acid imine, is treated in a non-reactive halogenated solvent such as chloroform and then reacted with the desired molecular halogen as previously described for the conversion of II into III in Scheme A.

Alternatively, for compounds of formula B wherein UNH is, the synthetic Scheme B can be used. The corresponding benzene-y-oxo acids IV, which are known or can be prepared by procedures analogous to those described for the known compound, are preferably used with an ammonium salt such as ammonium carbonate and an alkali metal cyanide such as sodium or potassium cyanide Sodium cyanide, in aqueous solution, such as water or a

Water / alcohol mixture, ζ. As water / ethanol, at a pH of about 9 to 10, preferably 10, and at a temperature range of about 50 to 100 ⁰ C, preferably about 70 ⁰ C to the compound of formula V (U = NH) implemented.

The resulting condensation product V is reacted with a strong Lewis acid, such as polyphosphoric acid, at a temperature in the range of 100 to 200 ⁰ C, preferably about 150 ° C, to B. Alternatively, concentrated sulfuric acid (6 to 9 M, preferably 9M) at about 60 to 18O ⁰ C, preferably about 120 ⁰ C, are used. Other strong Lewis acids such as mineral acids, aluminum chloride, ferric chloride and the like can also be used.

The compound of formula A wherein W is carbonyl may be reduced by any of a variety of commonly used reducing agents such as lithium aluminum hydride, sodium borohydride, aluminum isopropylate and the like.

Preferred solvents for lithium aluminum hydride related derivatives are non-hydroxylic solvent such as ether, dioxane or tetrahydrofuran and preferred temperatures are about -30 ⁰ C to 25 ⁰ C, preferably about 0 ⁰ C. Preferred solvents for sodium borohydride and related derivatives are hydroxylic lower alcohol solvents such as methanol or ethanol, at about 0 to 6O ⁰ C, preferably about 25 ⁰ C. the preferred solvent for reduction with aluminum isopropoxide is isopropyl alcohol at reflux with slow distillation of the acetone byproduct.

In addition, compounds of formula A prepared according to Scheme B, wherein W is carbonyl and X is hydrogen, can of course be converted to the α-halo ketone by the same procedure as described above.

Synthesis Scheme A

₃₂ CF ₃ C = NSi (CH ₃ )

^(CI Vn

II

III br ^H 2 ° (D) >

CrO.

^(C Vn

^(CH 2 »n

7th

OH

Synthetic Scheme B

< ^CH 2> n

(CH) ι λ η

IV

H +

^(C Vn <_

^(CH 2> n

Cl ₂ or

A (W = CO, X = Br ₁ -Cl or I)

Alternatively, compounds of formula B wherein U is oxygen may also be prepared according to Scheme B. The corresponding benzene-y-oxo acids IV, which are known or can be prepared by procedures closely analogous to those described for known compounds, are added with a trialkylsilyl cyanide (R ') 3 SiCN wherein R' is lower alkyl a cyanotrialkylsilyloxy derivative according to the general procedure of US Pat. No. 4,267,342. Compounds of formula B wherein U is S can be prepared according to the synthetic schemes A or B in a manner similar to that used to prepare the compounds of formula B wherein UNH is employed. It takes advantage of the preparation of cyanotrialkylsilyloxy derivatives which are intermediates in the preparation of compounds of formula B wherein U is O. These cyanotrialkylsilyloxy derivatives can be converted by similar methods into thiazolidinedione intermediate of structure II, wherein U is S (synthetic residue A) and intermediates of structure V, wherein U is S (synthetic Scheme B).

Intermediates of structure II, wherein U is S (Synthetic Scheme A), and intermediates of structure V, wherein U is S (Synthetic Scheme B), can be converted to final products of structure B as previously described for U = NH. Due to the acidic hydrogen atom in the spiro-heterocyclic ring of the compounds of formula B, salts with pharmaceutically acceptable cations can be formed by conventional methods. Thus, these salts can be readily prepared by treating compound B with an aqueous solution of the desired pharmaceutically acceptable cation and concentrating the resulting solution to dryness, preferably under reduced pressure. Alternatively, a lower alkyl alcohol solution of the compound of formula B may be mixed with an alcoholate of the desired metal and then concentrated to dryness. Suitable pharmaceutically acceptable cations for this purpose include, but are not limited to, alkali metal cations such as potassium and sodium, ammonium, or water-soluble amine addition salts such as the lower alkanolammonium and other base salts with organic amines that are pharmaceutically acceptable, and alkaline earth metal cations. like calcium and magnesium. It is clear that by using the term pharmaceutically acceptable salts in the present disclosure and the

Both the acid addition salts and the salts formed with suitable cations as described above should be included.

The invention also includes derivatives which are degraded in vivo to compounds of the formula Bl or BII by the metabolism. In particular, derivatives are disclosed in which the acidic NH group in the 1-position in the formula Bl and BII is converted into an NR group, wherein R is a lower alkyl radical having generally 1 to 4 carbon atoms, preferably methyl. Such compounds can be prepared by alkylating a compound of formula Bl or BII in the presence of a suitable base with an alkylating agent. Suitable bases include, but are not limited to, alkali metal hydroxides, such as sodium or potassium hydroxide, alkali metal carbonate or alcoholate, such as sodium carbonate or sodium ethylate, or alkali metal hydride in a non-protic solvent, such as sodium hydride in N, N-dimethylformamide, at one temperature between about 0 and 50 ^c C, preferably about 25 ⁰ C. Suitable alkylating agents include, but are not limited to, methyl iodide, dimethyl sulfate, ethyl bromide. Alkylating agents that can be used in the absence of base include diazoalkanes, such as diazomethane.

A particularly convenient method for the preparation of derivatives in which the acidic NH group in the 1-position in the formula Bl and BII is converted into an NR group consists in dissolving the compound of the formula Bl or BII in dry N, N- Dimethylformamide and adding one equivalent of sodium hydride at a temperature between about 0 to 5O ⁰ C, preferably about 25 ⁰ C. The reaction mixture is stirred until the foaming stops. One mole equivalent of the alkylating agent, such as lower alkyl halide or alkyl sulfate, is added dropwise and the reaction is stirred until the alkylation is complete. A preferred alkylating agent is methyl iodide, and the reaction time with this halide is about 25 h ⁰ C approximately. 1 The reaction mixture can be worked up by pouring on ice-water. The di-alkylated products can be separated from starting materials utilizing the acidity of the starting compounds of formula Bl or BII as opposed to the neutral character of the alkylated products. For example, the compound of Example 28 has a pK _A of about 8.3 in water, and any unreacted compound can be removed by distributing the crude product between an organic solvent such as ethyl acetate or methylene chloride and an aqueous-basic solution. The alkylated product is soluble in the organic solvent while any unreacted starting material is soluble in the aqueous base.

The novel compounds of formula B and their pharmaceutically acceptable salts are useful as inhibitors of the enzyme aldose reductase in the treatment of chronic complications of diabetes such as diabetic cataracts, retinopathy and neuropathy. As used in the claims and the description, treatment is intended to mean both prevention and alleviation of such conditions. The compound may be administered to a patient in need of treatment by a variety of conventional routes of administration, including orally, parenterally and topically. In general, these compounds will be administered orally or parenterally at dosages between about 0.05 and 25 mg / kg body weight of the person being treated per day, preferably about 0.1 to 10 mg / kg. However, there will necessarily be some variation in dosage depending on the condition of the person being treated. The person responsible for the administration will in each case determine the appropriate dose for the individual.

The novel compound prepared according to the invention may be administered alone or in combination with pharmaceutically acceptable carriers, either in a single dose or in multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by contacting the novel compounds of Formula B and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms, such as tablets, powders, lozenges, syrups, injection solutions, and the like. These pharmaceutical compositions may, if desired, contain additional ingredients such as flavoring agents, excipients, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients, such as sodium citrate, calcium carbonate and calcium phosphate, may be used together with various disintegrating agents, such as starch, alginic acid and certain complex silicates, together with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia resin become. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of similar type can also be used as fillers in soft and hard-filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient may be combined with various sweetening or flavoring agents, coloring material or dyes and, if desired, emulsifying or suspending agents together with diluents such as water, ethanol, propylene glycol, glycerine and Combinations thereof, be brought together. .__

For parenteral administration, solutions of the novel compound of formula B in sesame or peanut oil, aqueous propylene glycol or in sterile aqueous solution may be used. 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 particularly suitable for intravenous, intramuscular, subcutaneous and interperitoneal administration. In this context, the sterile aqueous media used are all readily available to standard techniques known to those skilled in the art.

Compounds of the formula B can be used not only advantageously for the preparation of aqueous pharmaceutical compositions for parenteral administration as described above, but more particularly for the preparation of pharmaceutical compositions suitable for use as ophthalmic solutions. Such ophthalmic solutions are of fundamental interest for the treatment of diabetic cataracts by topical administration, and the treatment of such conditions in this manner is a preferred embodiment of the invention. Thus, for the treatment of diabetic cataracts, the compounds of the invention are administered to the eye of the patient in need of treatment in the form of an ophthalmic preparation prepared according to conventional pharmaceutical practice, see e.g. "Remington's Pharmaceutical Sciences", 15th Edition, pp 1488-1501 (Mack Publishing Co., Eaton, Pa.) The ophthalmic preparation contains a compound of formula B or a pharmaceutically acceptable salt thereof at a concentration of about 0.01 to about 1% by weight, preferably from about 0.05 to about 0.5%, in a pharmaceutically acceptable solution, suspension or ointment A certain variation in concentration will necessarily occur, depending on the particular compound used, the The condition of the patient to be treated, and the like, and the person responsible for the treatment will determine the most appropriate concentration for each individual The ophthalmic preparation is

preferably in the form of a sterile aqueous solution containing, if desired, other ingredients, e.g. Preservatives, buffers, tonicity agents, antioxidants and stabilizers, nonionic wetting or clarifying agents, viscosity increasing agents, and the like. Suitable preservatives include benzalkonium chloride, benzethonium chloride, chlorobutanol, thimerosal and the like. Suitable buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borate, sodium and potassium carbonate, sodium acetate, sodium biphosphate, and the like, in amounts sufficient to maintain the pH between about 6 and 8, preferably between about 7 and 7.5 , Suitable tonicity agents are dextran 40, dextran 70, dextrose, glycerol, potassium chloride, propylene glycol, sodium chloride, and the like such that the sodium chloride equivalent of the ophthalmic solution is in the range of 0.9 ± 0.2%. Suitable oxidants and stabilizers include sodium bisulfite, sodium metabisulfite, sodium thiosulfite, thiourea and the like. Suitable wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol. Suitable viscosity increasing agents include dextran 40, dextran 70, gelatin, glycerin, hydroxyethylcellulose, hydroxymethylpropylcellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, and the like. The ophthalmic preparation is administered topically to the eye of the person in need of treatment by conventional methods, e.g. B. in the form of drops or by bathing the eye in the ophthalmic solution.

The activity of the compounds of the invention as agents for the control of chronic diabetes complications can be determined by a series of standard biological or pharmacological tests. Suitable assays include (1) measuring their ability to inhibit enzyme activity of isolated aldose reductase; (2) measuring their ability to reduce or inhibit sorbitol accumulation in the sciatic nerve and the lens of acute streptozotocinised, d. H. diabetic, rats; (3) measuring their ability to reverse already elevated sorbitol levels in the sciatic nerve and in the lens of chronic streptozotqcin-induced diabetic rats; (4) measuring their ability to prevent or inhibit galacticol formation in the lens of acute galactosemic rats; (5) measuring their ability to delay cataract formation by reducing the severity of lens opacities in chronic galactosemic rats; (6) measuring their ability to prevent sorbitol accumulation and cataract formation in the isolated rat lens incubated with glucose; and (7) measuring their ability to lower already elevated sorbitol levels in the isolated rat lens incubated with glucose.

embodiments

The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance (NMR) spectra were measured at 60 MHz (unless otherwise indicated) for solutions in perdeuterodimethylsulfoxide (DMSO-d ₆ ) and peak plots are reported in parts per million (ppm) from the low field of tetramethylsilane. The peak shapes are denoted as follows: s = singlet; d = doublet; t = triplet; q = quadruples «; m = multiple «; b = wide.

example 1

3'-Hydroxy-spiro [imidazolidine-4,1'-indan] 2,5-dione

Spiro [imidazolidine-4,1'-indan] 2,5-dione, (CA Reg. No. 6252-98-8) (6.06g, 30mMoI) was mixed with 7.95ml (30mMoI) of bis (trimethylsilyltrifluoroacetamide and 4, The reaction mixture was cooled to 25 ° C and, after stirring for 45 min, a solid which had crystallized out was collected by filtration to give 2, 8 g (30 μmol) of bromine in 50 ml of chloroform and heated to reflux. 45g (29%) of crude 3'-bromo-spiro [imidazolidine-4,1'-indan] 2,5-dione The chloroform mother liquors deposited a further 2.18g (26% yield), mp 58-65 ⁰ C from. 2g (7.1 mmol) of material, mp. 58-65 ⁰ C, were added together with 25 ml of water to a slurry After 22h stirring, the solid was collected by filtration and dried to give 0.52 g (33. %) of the title compound: mp. 260-263 ⁰ C.

Analysis for CnH ₁₀ N ₂ Os: calc .: C 60.55 H 4.62 N 12.84 F: C 60.84 H 4.74 N 12.80

Example 2

3'-hydroxy-6'-fluorouro [imidazolidine-4,1'-indan] 2,5-dione

6'-fluoro-spiroimidazolidine-4,1'-indan-2, 5-dione, (CA Reg. No. 66892-38-4) (1.1 g, 5 mmol) was mixed with 2.65 ml (10mMoI). Combined bis (trimethylsilyl) trifluoroacetamide, 0.8 g (5 mmol) bromine and 30 ml ethylene dichloride and heated at reflux for 2.5 hours. During this time, the reaction mixture lost its color. The reaction mixture was concentrated in vacuo to an amber oil which was diluted with 10 mL of water. Over 16h at 25 ⁰ C, a solid gradually formed. This material was isolated by filtration and dried in vacuo at 100 ° C to give 1.0 g (85% yield) of the unlatching compound, m.p. 209-211 ° C.

Examples 4-Hydroxy-spiro [imidazolidine-4,1, -V, 2% 3S4'-tetrahydronaphthalene] 2,5-dione spiro [imidazolidine-4,1'-1 ', 2', 3 ', 4'- hydronaphthalene] 2,5-dione (CA Reg. No. 57998-96-6) 4.33g, 20mMoI) was mixed with 10.40 ml (40.4 mmol) of bis (trimethylsilyl) trifluoroacetimide and 3.69 g (23.1 mmol) bromine in 40 ml of chloroform as solvent at 25 ° C. The slurry was stirred for 60 hours, with discoloration observed. The reaction mixture was filtered and the filtrate concentrated in vacuo to an oil. This oil was mixed with 15 ml of water and triturated the resulting resinous solid for 22 h. A solid was collected by filtration and dried to give 3.3 g (82% yield) of the title compound, mp. 180-185 ⁰ C to give.

Calc .: C 62.06 H 5.21 N 12.06 Found: C 62.08 H 4.78 N 12.46

Example 4 7'-Fluoro-4'-hydroxy-3'-methyl-sprio [imidazolidine-4,1'-1 ', 2'-3', 4'-tetrahydronaphthalene] 2,5-dione 7'-fluoro 3'-Methyl spiro [imidazolidine-4,1'-3'H-1 ', 2'-dihydronaphthalene-4'-one] 2,5-dione (1.31g, 5, OmMoI) was dissolved in 25ml of methanol slurried at 0 ⁰ C, and 378 mg (10, OmMoI) of sodium borohydride were added. Solution progressed as the reaction progressed. After the gas evolution ceased, the reaction mixture was concentrated in vacuo to a solid. This was dissolved in 15 ml of water and 6N hydrochloric acid was added until a final pH of 1 was achieved. It formed a white solid which was collected by filtration, washed with water and dried to give 1.0 g (76% yield) of the title compound, mp. 279-281 ⁰ C.

 Analysis for C13H13N2O3F: calc .: C 59.09 H 4.96 N 10.60 Found: C 58.00 H 4.93 N 10.46.

Example 5

7'-fluoro-4'-hydroxy-spiro [imidazolidine-4,1'-1 ', 2' _/ 3 ', 4'-tetrahydronaphthalene] 2,5-dione 7'-fluoro-spiro [imidazolidine-4,1 '-3'H-1', 2'-dihydronaphthalene-4'-one] 2,5-dione (2.0g, 8.1mmol) was dissolved in 50ml of methanol and cooled to ⁰ ° C. Sodium borohydride (0.6g, 16, OmMoI) was added in small portions over 15 min. After stirring for one hour at 0 ° C, the reaction mixture was poured into 10% aqueous hydrochloric acid and methanol was removed under reduced pressure. The resulting solid was collected by filtration and dried and then recrystallized from water to give 0.7 g (35% yield) of the title compound, mp. 258-259 ⁰ C.

Analysis for C ₁₂ Hn N ₂ O ₃ F: calc .: C 57.59 H 4.43 N 11.20 Found: C 57.70 H 4.41 N 11.31.

Example 6

{+) 7-Fluoro-4'-hydroxy-3'-methyl-spiro-pentimidazolidine-4,1'-1 ', 2', 3 ', 4'-tetrahydronaphthalene] 2,5-dione 99.51 g (0.379 mol ) (±) 7-Fluoro-4'-hydroxy-3-methyl-spiro [imidazolidine-4,1'-1 ', 2', 3 ', 4'-tetrahydronaphthalene] 2,5-dione was mixed with 171.0g (0.398 mole) of brucine dihydrate and dissolved in 1.41 ethanol at reflux. The ethanol was filtered while hot to remove no small amount of insoluble material and was then concentrated in vacuo to a foam. This foam was combined with 3.01 acetonitrile at reflux. This formed some solid. The reaction mixture was allowed to cool to 23 ° C. The resulting solid was collected by filtration to 128,96g solid, mp. 222-224 ⁰ C, [a] o ⁵ = -6.4 ° (methanol, C = 1) to give. Similarly, from 20.34 g of the racemic alcohol, 24.82 g of the brucine salt, m.p. 224-226 ° C, [a] g ^s = -5.8 ° (methanol, C = 1) were isolated. The combined salts (153.78 g) were added to 1.51 acetonitrile at reflux; 200 ml of acetonitrile were evaporated and the reaction mixture was allowed to cool to 23 ° C over 20h. The resulting solid was filtered off and dried to give 137.63g, m.p. 226-227 ° C, [a] § ⁵ = 3.6 ° (methanol, C = 1). This material was slurried in 1% boiling acetonitrile, allowed to cool to 23 ° C, and the resulting solid was collected by filtration and dried to yield 128.63g, mp 227-228 ° C, [α] § ⁵ = +5, 0 ° (methanol, C = 1) to give. The salt components were separated by one hour at 23 ° C was slurried in 11 of chloroform, and then the reaction mixture was maintained at 23 ⁰ C 20h. The resulting solid was collected by filtration and dried to 45,45g of the title compound, mp. 257.5 to 258.5 ⁰ C, [a] o ⁵ = + 120.1 ° (methanol, C = D to yield.

The absolute configuration at the 4,1 ', 3' and 4 'centers are assigned 4,1'S, 3'R and 4'S based on a combination of single crystal X-ray, NMR and chemical conversion studies.

Example 7 (-) 7'-Fluoro-4'-hydroxy-3'-methyl-spiro [imidazolidine-4,1 ' _/ -1', -, 2 ', 3', 4'-tetrahydronaphthalene] 2.5- The acetonitrile mother liquors remaining after removal of 137.63 g of solid of mp 226-227 ° C (Example 27), [a] & ^s = + 3.6 ° C (CH 3 OH, C = 1), were concentrated in vacuo to a foam. This foam was stirred with 11% chloroform and a solid formed which was collected by filtration and washed thoroughly with five 11 portions of chloroform and dried to give 48.22g of the title compound, mp 253-254 ° C, dec. [a] o ⁵ = -114.2 ° (CH ₃ OH, C = 1).

Example 8

Compounds of Formula B of Examples 1-7 were tested for their ability to reduce or inhibit aldose reductase enzyme activity by the method described in U.S. Patent 3,821,383 and the method based on Hayman et al., Journal of Biological Chemistry 240,877 (1965) , Where the same compound has been prepared by more than one method, the results of the compounds tested are identical, regardless of the method of preparation. The substrate used was partially purified enzyme aldose reductase obtained from human placenta. The compounds were tested at levels of 10 ~ ⁴ to 10 ^"9 m and proved retardant, relative to untreated control samples as the enzymatic activity.

Production A

2,5-dioxo-4-m-fluorophenyl-4-imidazolinpropionsäure

M-fluorobenzene-γ-oxo-butyric acid (1.57 g, 8 mmol) (Eur. J. Med. Chem. 13, 533 [1978]) was mixed with 7.7 g (8OmMoI) ammonium carbonate, 1.04 g (16 mmol) potassium cyanide in 60 mL water brought together and heated to 7O ⁰ C for 20h. The reaction mixture was cooled to 25 ° C and the acidity adjusted to pH 2 with concentrated hydrochloric acid. The resulting pale yellow solid was isolated by filtration and dried in vacuum at 100 ⁰ C to 206-208 ⁰ C, to give 1.8g (85% yield) of the title compound, mp.. NMR (DMSO-d ₆ ) 11.0 (bs, 1H), 8.86 (bs, 1H), 7.67-6.83 (m, 4H) and 2.25 (bs, 4H) ppm ,

Production B

2,5-dioxo-4-m-methoxyphenyl-4-imidazoiidinpropionsäure

m-Methoxybenzene-y-oxo-butyric acid (CA Reg. No. 38102-67-9) (10.0g, 48 mmol) was mixed with 22.75 g (235 mmol) ammonium carbonate, 6.5 g (10 mole%) potassium cyanide in 100 ml ethanol and 100 ml of water at 65 ° C brought together. After 5 h at 65 ⁰ C for a further 22,75g (235mMol) of ammonium carbonate were added and it was heated for a further 18 h. The reaction mixture was concentrated in vacuo, triturated with water and the acidity adjusted to pH 4 with concentrated hydrochloric acid. A white solid formed, which was collected by filtration and dried in vacuo at 80 ° C for 20 hours to give 10.6 g (79% yield) of the title compound, m.p. 138 ° C

Analysis for C ₁₃ H ₁₄ N ₂ O ₅ : calc .: C 56.11 H 5.07 N 10.07 Found: C 55.46 H 5.02 N 10.02.

Production C

2,5-Dioxo-4-m-nitrophenyl-4-imidazoiidinopropionic acid

For the preparation of the title compound, the procedure of Preparation A is applied. The starting material is 3-nitrobenzene-y-oxo-butyric acid instead of the 3-fluorobenzene compound

Production D

2,5-dioxo-4- (m-chloro-p-methylphenyl) -4-imidazolidine-propionic acid

m-chloro-p-methylbenzene-y-oxo-butyric acid (22.7g, 10OmMoI) (Bull. Chem. Soc. Jap. 52, 2441-42 [1979]) was reacted with 90 g (0.94 mol) of ammonium carbonate and 13 , 7g (21 OmMoI) potassium cyanide in 300 ml of water and heated to 65 ⁰ C for 22 h. The reaction mixture was cooled to 25 ⁰ C and the resulting solid collected by filtration and suspended in 200 ml of water. The aqueous suspension was brought to pH 2 with concentrated hydrochloric acid and the resulting solid collected by filtration, washed with water and dried to give 27.8 g (94%) of the title compound, mp. 196-199 ⁰ C to give.

Production E

2,5-dioxo-4- (m-chlorophenyl) -4-imidazoiidinpropionsäure

3-Chloro-benzene-r-oxo-butyric acid (Chem. Abstr. Reg. No. 62903-14-4) (10.6 g of 5OmMoI) was mixed with 47.2 g (49OmMoI) of ammonium carbonate and 6.5 g (10OmMoI) of potassium cyanide brought together in 100 ml of water and heated to 65 ⁰ C for 65h. The reaction mixture was cooled to 0 ^° C. The resulting precipitate was collected by filtration and stirred in 100 ml of water. Concentrated hydrochloric acid was added to adjust the aqueous pH to 0.5, and the resulting solid was collected by filtration, washed with 300 ml of water and dried to give 11.47 g (84% yield) of crude title compound, m.p. 196-217 ⁰ C, with decomposition and purple discoloration.

Production F

2,5-dioxo-4-m-tolyl-4-imidazoiidinpropionsäure

3-Methylbenzene-y-oxo-butyric acid (Chem. Abstr. Reg. No. 569618-44-9) (3.0 g, 10mMoI) was mixed with 14.0 g (144 mmol) of ammonium carbonate and 2.2 g (34 mmol) of potassium cyanide 50ml of water combined and heated to 65-70 ° C for 22h. The reaction mixture was cooled and brought to pH 2 with concentrated hydrochloric acid to precipitate a solid. The solid was collected by filtration, washed with water and dried to give a crude product, mp. 173-178 ⁰ C. This crude product was dissolved in boiling water and an insoluble orange resin was filtered off. Concentration of the resulting aqueous solution in vacuo gave 1.34 g (32% yield) of the title compound, mp 195-198 ° C. Analysis for Ci ₃ Hi ₄ N ₂ O ₄ : calc .: C 59.54 H 5.38 N 10 ^ 68 Found: C 59.25 H 5.30 N 10.32.

Production G

2,5-dioxo-4-m-xyiyl-4-imidazoiidinpropionsäure

3,5-Dimethylbenzene-y-oxo-butyric acid (Chem. Abstr. Reg. No. 36440-58-1) (3.5 g) was mixed with 14 g (146 mmol) of ammonium carbonate and 2.2 g (33.8 mmol) of potassium cyanide brought together in 50 ml of water and heated to 60 ⁰ C for 26 h. The reaction mixture was cooled to 25 ° C and filtered to remove oily material. The pH of the filtrate was adjusted to 3.5 with concentrated hydrochloric acid, and the resulting white precipitate was filtered off and dried to give 1.0 g (22% yield) of the title compound, m.p., 232-234 ⁰ C to give.

Preparation H 3- (m-fluorobenzoyl) -2-methylpropionic acid

To 180 ml of dry dimethylformamide was added 6.5 g (0.10 mol) of powdered potassium cyanide. The well-stirred slurry was heated to 80 ^° C. over 30 minutes and cooled to 35 ^° C. A solution of 124.1 g (1.0 mol) of m-fluorobenzaldehyde in 50 ml of dimethylformamide was added dropwise over 50 min, the reaction temperature at 30 ⁰ C remained. After another 30 minutes at room temperature, 67.1 g (1.0 mole) of methacrylonitrile dissolved in 50 ml of dimethylformamide was added over 20 minutes. After 3 h of room temperature, the reaction mixture was fritted and poured onto 1500 ml of water, and the oily organic layer was separated. Saturated saline was added to the aqueous layer, which was then extracted with 3 × 150 ml of chloroform. The combined organic portions were washed successively with dilute sulfuric acid, dilute aqueous sodium carbonate solution and water. After drying over anhydrous sodium sulfate, the chloroform was not more than 35 ⁰ C vacuum stripped at a temperature to give 199,8g crude oil. To this oil was added 200 ml of concentrated hydrochloric acid, and the reaction mixture was heated at 125 ^° C for 3 hours. The reaction mixture was cooled to 60 ° C and the supernatant hydrochloric acid decanted from a heavier red oil which solidified on cooling. The red oil / solid was dissolved in 500 ml of 3N sodium hydroxide and the aqueous layer

was extracted with 4 χ 250 ml of diethyl ether. After cooling in an ice bath, the aqueous layer was brought to pH 2 with concentrated hydrochloric acid to precipitate a pale pink solid. This was collected by filtration and dried to give 84,4g (40% yield) of 3- (m-fluorobenzoyl) -2-methyl-propionic acid, 90-91 ^0, melting point. C.

Preparation I 2,5-Dioxo-3,3-dimethyl-4- (m-chlorophenyl) -4-imidazolidinopropionic acid 3- (m-chlorobenzoyl) -2,2-dimethyl-propionic acid (14.4g, 0.06 mol ) was combined with 28.8 g (0.3 mol) of ammonium carbonate and 7.81 g (0.12 mol) of potassium cyanide in 150 ml of water and heated to 70 ⁰ C for 24 h. Additional 5.7 g of ammonium carbonate were added and stirring continued for 60 h at 70 ⁰ C heated. The reaction mixture was cooled in an ice bath and concentrated hydrochloric acid was added dropwise. A tan solid formed, was filtered off, washed with water and dried to 17.34 g of crude product. This material was brought to a Kieselsäuie and initially eluted with 5% methanol in chloroform and then with 10% methanol in chloroform to give 3.21 g of the title compound as a yellow solid, mp. 198-200 ⁰ C to give, with decomposition.

Production J

3- (m-chlorobenzoyl) -2,2-dimethyl propionic acid

According to the procedure of T. Joyima et al., Bull. Chem. Soc. Jap. 52 (8), 2441-2442 (1979), 3-benzoyl-2,2-dimethylpropionic acid was converted to the title compound by chlorination in the presence of excess aluminum chloride.

Production K

2,5-dioxo-3-methyl-4- (m-chlorophenyl) -4-imidazolidine-propionic acid

3- (m-Chlorobenzoyl) -2-methyl-propionic acid (10.36 g, 0.046 mol) was combined with 24.02 g (0.25 mol) of ammonium carbonate and 6.5 g (0.10 mol) of potassium cyanide in 150 ml of water and frequently 7O ⁰ C heated. The reaction mixture was cooled to 20 ⁰ C and acidified with concentrated hydrochloric acid. A resinous solid formed, which was collected and dissolved in diethyl ether, and the diethyl ether solution was washed with 25 ml of water. The diethyl ether layer was concentrated in vacuo to a white-yellow solid, which was overnight at 7O ⁰ C in a vacuum oven to 11.28g of 2,5-dioxo-3-methyl-4- (mchlorphenyl-4-imidazolidinpropinsäure, m.p. 183-185 ° C, partial melting, 198-200 ⁰ C decomposition, was dried.

Preparation of L 3- (m-chlorobenzoyl) -2-methylpropionic acid

Sodium cyanide (1.47g, 30mmol) was combined with 100ml of Ν, Ν-dimethylformamide and then stirred at 35 ° C for 1 hour under nitrogen to give a clear solution. 34.0 ml (0.3 mol) of 3-chlorobenzaldehyde, dissolved in 50 ml of Ν, Ν-dimethylformamide, were added dropwise to this solution over 1 hour. After a further hour stirring at 35 ⁰ C, a solution of 25,0ml (0.3 mol) methacrylonitrile in 50 ml of Ν, Ν-dimethylformamide was added dropwise over 2h and the reaction mixture stirred 16 h at 25 ⁰ C. Methylene chloride (200 ml) and 4.0 g diatomaceous earth filtration aid were added and the mixture was slurried and filtered. The filtrate was washed successively with 500 ml of 0.22N hydrochloric acid, two 200 ml portions of water, 200 ml of 2.5% aqueous sodium bicarbonate solution, 200 ml of 1N hydrochloric acid, 200 ml of water and 200 ml of brine. The methylene chloride layer was dried over anhydrous sodium sulfate and concentrated in vacuo to 49.65 g of crude 3- (m-chlorobenzoyl) -2-methylpropionitrile) a yellow solid, m.p. at 5O ⁰ C, partial melting, melting at 79-81 ° C. 15.57 g (0.075 mol) of this product were combined with 25 ml of concentrated hydrochloric acid and 25 ml of formic acid and heated at reflux for 2.5 hours. After cooling, 150 ml of water were added and the aqueous solution was extracted with two 150 ml portions of ethyl acetate. The ethyl acetate extract, in turn, was extracted with two 150 ml portions of 20% sodium hydroxide in water. The aqueous extract was acidified with concentrated hydrochloric acid to precipitate a solid which was collected by filtration, was washed with water and dried to 10,86g 3- (m-chlorobenzoyl) -2-methylpropionic acid, mp. 100-102 ⁰ C. to surrender.

Claims (4)

Invention claim: 1. A process for the preparation of a compound of the formula or a pharmaceutically acceptable salt thereof, wherein U is oxygen, sulfur or nitrogen, substituted by hydrogen or alkyl having 1 to 4 carbon atoms, η is zero or one, X is hydrogen, chlorine, bromine, iodine, alkyl of 1-4 carbon atoms, dimethyl or (CH ₂ ) _m Q, wherein m is 1 or 2 and Q is phenyl or halophenyl, with the proviso that when X is dimethyl, η is one Y is hydrogen, halogen, nitro, trifluoromethyl, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms Z is hydrogen, halogen, nitro, trifluoromethyl, alkoxy of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, provided that when either Y or Z is nitro, the other group is hydrogen, characterized in that (a) a compound of the formula wherein Hal is bromine, chlorine or iodine, hydrolyzed in water at a pH of about 1 to 7 and a temperature of about 0 to 60 ^c or C (b) a compound of the formula Z o is reduced with a reducing agent. 2. The method according to item 1, characterized in that it is carried out for U in der meaning nitrogen, substituted by hydrogen, η zero, X, Y and Z are each hydrogen or X and Z are each hydrogen and Y fluorine. 3. The method according to item 1, characterized in that it is carried out for U in the meaning of nitrogen, substituted by hydrogen, η one, X, Y and Z are each hydrogen or X and Z are each hydrogen and Y fluorine. 4. The method according to item!, Characterized in that it is carried out for U meaning nitrogen, substituted by hydrogen, η one, X is methyl, Y is fluorine and Z is hydrogen.