FI81575C - A FREQUENCY FOR THE PREPARATION OF THERAPEUTIC ANALYZA SPIRO-IMIDAZOLIDINE-4,3'-AZAINDOLIN-2,2 ', 5-TRIONDERIVAT. - Google Patents

Description

1 81575

The present invention relates to novel imidazolidinedione derivatives which are of interest in the field of pharmaceutical chemistry and are part of a process for the preparation of new therapeutically useful spiro-imidazolidine-4,3'-azaindoline-2,2 ', 5-trione derivatives. and in the field of chemotherapy. More specifically, it relates to a process for the preparation of new therapeutically useful spiro [imidazolidine-4,3 '- (6'-azaindoline)] - 2,25-trione derivatives of formula IIa and spiro [imidazolidine-4,3' - (7 ' -azaindol-15 ni)] - 2,2 ', 5-trione derivatives of formula IIb HN F 0 HN - == o

20 0 \ / NH 0 = X

R -N'R 'R, —ζ J__JTr · 25 (Ha) (Hb) wherein R' is hydrogen or benzyl, the phenyl moiety of which is optionally mono-, di- or tri-substituted, where each ring substituent may be fluorine, chlorine it is bromine; and R "is hydrogen, chlorine or bromine; and for the preparation of their pharmaceutically acceptable salts.

These new compounds are suitable for the control of certain complications caused by chronic diabetes mellitus (e.g. diabetic cataracts, retinal disease and neurological disease).

2,81575

Previous attempts to develop new and better oral antidiabetic drugs have, for the most part, been aimed at lowering blood sugar levels. However, little is known about the effect of organic compounds in preventing or slowing down some chronic diabetic complications, such as diabetic cataracts, neurological disease, retinal disease, etc. In any case, K. Sestanj et al. disclose in U.S. Patent No. 3,821,383 that certain aldose-10 ductase inhibitors, such as 1,3-dioxo-1H-benz [d, e] -isoquinoline-2 (3H) -acetic acid and certain related derivatives, are suitable for these purposes, although they are not known to lower blood sugar. These compounds act by inhibiting the activity of the aldose reductase enzyme-15 min, which catalyzes the reduction of aldoses (such as glucose and galactose) in the human body to the corresponding polyols (such as sorbitol and galactitol). This prevents or reduces the harmful accumulation of galactitol in the lens of patients with elevated blood galactose levels and the harmful accumulation of sorbitol in the lens, retina, peripheral nervous system and kidney of diabetic patients. As a result, these compounds prevent some chronic diabetic complications, including those that are visual in nature, as it is already known in the art that the presence of polyols in the lens of the eye leads to cataract formation and concomitant loss of lens brightness.

FI patent publication 70 023 describes a process for the preparation of 30 novel 1'-substituted-spiro [imidazolidine-4,3'-indoline] -2,2 ', 5-triones suitable for the treatment of saccharitis or galcatosemia.

FI patent 78 699 granted to the main application relates to a process for the preparation of new therapeutically useful spiroimidazolidine-4,3-indoline-2,2'-5-trione derivatives of the formula I

II

3 81 575 HN - [= 0 0-J ^ NH R «5 χ" Π ^ ν? Ίι = 0 γτ \ -N- <c «2> n -e_7 (I)

Y N

Wherein X and Y are both halogen or one is hydrogen and the other is halogen, R 'is hydrogen, fluorine, chlorine, bromine or C 1-4 alkyl and n is 1, 2 or 3, and pharmaceutically acceptable salts thereof. order.

These spiro-imidazolidine-3,4-indolidine-2,2 ', 5-trione derivatives of formula I are useful as aldose reductase inhibitors in Tor-20 junctions of certain chronic complications in diabetic patients.

The novel spiro-imidazolidine-4,3'-azaindoline-2,2 ', 5-trione derivatives of formulas IIa and IIb are also useful in the treatment of certain chronic complications of aldose reductase inhibitory Rhine in diabetic patients.

Because the above compounds are aldose reductase inhibitors, they are capable of reducing or preventing the accumulation of sorbitol in the myocardium and peripheral nervous system of diabetic patients.

A group of novel compounds of formula IIa is a group of the formula wherein R "is hydrogen and R 'is hydrogen, rayon-substituted benzyl (e.g. p-fluorobenzyl or p-chlorobenzyl) or disubstituted benzyl (e.g. 3,4-dichlorobenzyl) .

Of particular interest in this context is a typical and preferred compound of the invention which is 4,881,575 spiro- [imidazolidine-4,3 '- (azaindoline)] - 2,2', 5-trione. Such compounds are very effective in terms of their activity as aldose reductase inhibitors. The process of this invention for the preparation of novel compounds of formulas IIa and Hb is characterized in that a) for the preparation of compounds of formulas IIa and Hb wherein R 'is benzyl as defined above, an azaindoline-2,3-dione derivative of formula IVa 10 or IVb 15 R 'R' (IVa) (IVb) 20 wherein R 'and R "are as defined above are condensed with an early metal cyanide and ammonium carbonate; or b) for the preparation of compounds of formulas IIa and Hb wherein R' is hydrogen sodium ethyl (hydrantoin-5-carboxylate) 30 I Θ COOEt N Na ®

B

alkylation with a suitable halonitro-disubstituted pyridine, followed by ring formation by conventional reduction using iron powder in the presence of an acid such as hydrochloric acid or glacial acetic acid at ambient temperature or at slightly elevated temperature; and / or thereafter converting the compound of formula Ha or Hb to a pharmaceutically acceptable salt, if desired.

In process a) the alkali metal cyanide is, for example, sodium cyanide or potassium cyanide. Process a) is usually carried out in a reaction-inert, polar organic solvent medium in which both the reactants and the reagents are mixed together. Preferred solvents for use herein include cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols such as ethylene glycol and tri-methylene glycol, water-miscible lower alkanols such as methanol, ethanol and isopropanol, as well as N, N-di (lower alkyl) lower alkanoyl) amides such as N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide, etc. In general, the reaction is carried out at a temperature in the range of about 50 to 150 ° C and a reaction time of about two hours. for about four days. Although the amount of reactant and reagents used in the reaction may vary to some extent, it is preferable to use a slightly greater than an equivalent molar amount of alkali metal cyanide reagent relative to the annular carbonyl compound used as the starting material to achieve the highest possible yield.

The ring-forming step of process b) is usually carried out using iron powder in the presence of an acid such as hydrochloric acid or glacial acetic acid in an aqueous-alcoholic medium, at ambient temperature or slightly above (e.g. at about 20-100 ° C). Thus, the use of 3-nitro-4-chloropyridine ultimately results in the desired spiro- [imidazolidine-4,3 '- (6'-azaindoline)] - 35,2', 5-trione final product.

6 81575

The ketone starting materials (i.e., cyclic carbonyl compounds of formula IVa or IVb) required to prepare the desired end products of formula IIa or Hb by the overall process of this invention are for the most part known compounds and are either commercially available or otherwise readily synthesized by those skilled in the art. as starting materials using standard chemical reagents as well as using conventional methods of organic chemistry.

Because all of the novel spiro-oxindole-imidazolidinedione compounds available in accordance with this invention have a single center of asymmetry, they can exist as optically active D- and L-forms as well as racemic or DL mixtures. All of these forms are within the scope of this invention. The optically active isomer can be obtained, for example, simply by resolution of the racemic mixture using conventional procedures known to those skilled in the art, for example, fractional crystallization of a spiro-oxindole-20-imidazolidinedione salt prepared from an optically active acid or base.

Alternatively, optically active isomers may be prepared using the appropriate enantiomers as starting materials in the above sequences.

The pharmaceutically acceptable acid addition salts of the spirooxindole imidates-solid solid dione bases of this invention are prepared simply by treating the above organic bases with various mineral acids or organic acids which form non-toxic, pharmaceutically acceptable anionic acid addition salts containing pharmaceutically acceptable anions. bromide, hydroiodide, sulphate or hydrogen sulphate, phosphate or hydrogen phosphate, acetate, lactate, maleate, fumarate, citrate or hydrogen citrate, tartrate or semi-tartrate, succinate, gluco-35 , saccharates, methanesulphonates, ethanesulphonates

II

7,81575 sodium, benzenesulfonate and p-toluenesulfonate salts. The salt formation step may be carried out, for example, using an approximately equivalent molar amount of the appropriate acid in an aqueous solvent or in a suitable organic solvent such as methanol or ethanol. The solid salt is easily obtained by careful evaporation of the solvent.

The base chemicals used as reagents in the preparation of the pharmaceutically acceptable base salts of this invention include bases that form non-toxic base salts with the acidic spirooxindole imidazolidinedione compounds disclosed herein. These specific non-toxic base salts include those obtained from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium, etc. These salts can be readily prepared simply by treating the above acidic spiro-oxindole-imidazolidinedione compounds with the desired pharmacologically acceptable cation. the resulting solution is then evaporated to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing the solutions of the acidic compounds in the lower alkanols and the desired alkali metal alkoxide with each other and then evaporating the resulting solution to dryness in the same manner as above.

In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

As previously mentioned, the spiro-oxindole-imidazolidinedione compounds of this invention are particularly suitable for use therapeutically as aldose reductase inhibitors in the treatment of chronic diabetes complications because of their ability to significantly reduce the sorbitol level of diabetic patients in diabetes. In addition, the novel compounds of formulas Ha and Hb disclosed herein, 8 81 575, may be administered either orally or parenterally. In general, these compounds are administered in doses ranging from about 0.10 mg to about 10 mg per 5 kg of body weight per day, although variations will necessarily occur depending on the weight and condition of the patient being treated and the route of administration being employed.

In the case of the use of spirooxine-10-diimidazolidinedione compounds of formulas IIa and Hb for the treatment of diabetic patients, it should be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers using either of the above routes of administration. either 15 as a single dose or in multiple doses.

In addition, the above-mentioned spiro-oxindole-imidate-solid-dione compounds can also be used as topical ophthalmic solutions which are applied to the eye dropwise.

The activity of the compounds of formulas IIa and Hb as agents for the treatment of chronic diabetic complications is demonstrated by their ability to successfully pass one or more of the following conventional biological or pharmacological tests, which are (1) a test measuring their ability to inhibit isolated aldose enzyme reductase (2) a test to measure their ability to reduce or prevent the accumulation of sorbitol in the sciatic nerves of acutely streptozotocin-treated (i.e., diabetic) rats; (3) a test measuring their ability to restore already elevated levels of sorbitol and lens of the sciatic nerve and lens in rats with chronic streptozotocin-induced diabetes; (4) a test measuring their ability to inhibit the formation of galactol in the lens of rats with a sudden increase in blood galactose levels; and (5) li 9 81 575 a test measuring their ability to slow cataract formation and reduce lens opacities in rats with chronically elevated blood galactose levels.

The following The ability of the spiro-oxindoleimidates-5 solidindione end products of Examples 1-4 to reduce or inhibit aldose reductase enzyme activity at a concentration level of 10-6M was studied using the method of S. Hayman et al. the procedure described in Journal of Biological Chemistry 240 (1965) and modified by K. Sestanj et al. U.S. Patent No. 3,821,383. In each case, a partially purified aldose reductase enzyme obtained from a calf lens was used as a substrate. The results obtained with each compound are reported below as the percentage inhibition of enzyme activity using the specified concentration of -15 soa (10'6M):

Compound Esto-% at a concentration of 10 .mu.m

Product of Example 1 49

Product of Example 2 88

Product of Example 3 90 20 Product of Example 4 98

In addition, the following table shows the aldose reductase activity of some of the compounds of the invention.

ίο 81575

Compound Inhibition -% _ SM model with concentration (M) 10 ~ 4 1Q-5 1q-6 ^ q-7 ^ 0 ~ 8 Dose Dilute 2%% JTT M ”" 11 98 88 30 8 5 «6 10 2. HN -j__p

oj M

3. | _j_p 1 98 90 73 81 5 71 17 A /

5. --t = P

n {1 99 98 84 18 5 «« 52

II

and 81575

Compound Inhibition -% _ SM model_ with concentration (M) 10 ^ 10 ^ 10 ® 10 ^ 10 ® Dose Nerve Lens%% «. H- O --- oj Γ M «. 1 yyS- ci 7. ”^ w j 1 81 74 34 8 5 -9 -1 ·? -, =? I I 98 89 80 20 5 * 5 31 y £ r ^ o- »· 1-T = ° I I 99 96 89 78 5 49 44 M β 99 95 86 18 0.75 -13 13 c. C yC 95 85 38 r 12 81 575

Preparation example A

A solution of 3.0 g (0.014 mol) of ethyl ureidomalonate dissolved in 43 ml of absolute ethanol was refluxed under a nitrogen blanket while a 0.017 M solution of sodium ethanolate (sodium in ethanol) was slowly added over 2.5 h. At the end of this step, the resulting mixture was cooled to room temperature (about 20 ° C), and the desired product was collected by suction filtration and then washed with two 20 mL portions of absolute ethanol and one 20 mL portion of anhydrous ether. This eventually gave pure sodium ethyl (hydantoin-5-carboxylate).

When the reaction was repeated using 10 g of starting material (ethyl ureidomalonate) and 1.06 g of sodium in 60 ml of 15 absolute ethanol, the yield of pure final product was 7.53 g (85%).

Preparation example B

A mixture of 20 g (0.14 mol) of 3-nitro-4-hydroxypyridine, 33.3 g of phosphorus pentachloride and 2 ml of phosphorus oxychloride was heated in a 130 ° C oil bath for 3 h. At the end of this step, the excess phosphorus oxychloride was removed from the reaction mixture by fractional distillation, and methylene chloride was then added to the residue. The latter solution was then washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and filtered. Evaporation of the solvent from the resulting filtrate then gave the desired product, namely 3-nitro-4-chloropyridine.

When the procedure was repeated using 2.8 g (0.02 mol) of starting material (3-nitro-4-hydroxypyridine), the yield of pure final product was 2.35 g (74%).

Preparation Example C

A solution of 20.2 g (0.182 mol) of p-fluoro-35 aniline and 22.1 g (0.182 mol) of p-fluorobenzaldehyde

II

13 81 575 dissolved in 100 ml of ethanol was refluxed for 5 min. At the end of this step, the reaction mixture was cooled to room temperature (about 20 ° C), and then the desired product was collected by suction filtration. Another batch of product was obtained by then concentrating the resulting filtrate under reduced pressure. A total of 33 g (84%) of pure 3 - [(p-fluorophenyl) methylidene] pyridine was obtained.

To a solution of 11.0 g of the intermediate obtained above in 50 ml of methanol was added 1.92 g of sodium 10 borohydride at room temperature. At the end of this step, the reaction mixture was diluted with water and extracted with diethyl ether, and the ether extraction solutions were then dried over anhydrous magnesium sulfate and filtered.

After the desiccant was removed by filtration and the solvent was removed by evaporation under reduced pressure, a crude product was finally obtained, which was then crystallized from n-hexane to give pure 3 - [(p-fluorophenyl) aminoethyl] pyridine. The yield of pure product was 8.6 g (77%).

20 Example 1

A solution of 639.2 mg (0.00403 mol) of 3-nitro-4-chloropyridine (product of Preparation B) and 1.0288 g (0.0053 mol) of sodium ethyl (hydantoin-5-carboxylate) (Preparation A) product) dissolved in 10 ml of dimethylformamide, allowed to stand at room temperature (about 20 ° C) overnight (about 16 h) while stirring mechanically. At the end of this step, the solvent was removed from the mixture by evaporation, and the crude residue was then dried under high vacuum and finally crystallized from methylene chloride to give 525 mg of pure ethyl 5- (3-nitro-4-pyridyl) hydantoin-5-carboxylate. mp. 203.5-204.5 ° C.

When the reaction was repeated using 2.35 g of 3-nitro-4-chloropyridine as starting material and 3.74 g of sodium ethyl (hydantoin-5-carboxylate) as alkylating agent, the yield of pure product obtained was 3.83 g (88.3%).

14 81 575

A mixture of 158.5 g (0.00054 mol) of ethyl 5- (3-nitro-4-pyridyl) hydantoin-5-carboxylate, 335.1 mg of iron flour and 5 ml of glacial acetic acid was heated to 100 ° C and then cooled to about 65 °, Reaction 5 was complete in about 10-15 minutes. At the end of this step, the reaction mixture was filtered through Filter-cel to remove harmful solids, and the resulting filtrate was then evaporated under reduced pressure to finally give pure spiro- [imidazolidine-10,3,3 '- (6-azaindoline)] - 2.2 ', 5-trione, which was the desired end product. The yield of pure product, melting at 265 ° C (decomposing), was 80 mg (68%). The pure product was further characterized by mass spectroscopy and NMR data.

Example 2 A mixture of 1- (3,4-dichlorobenzyl) -6-azaindoline-2,3-dione, potassium cyanide and ground ammonium carbonate in aqueous methanol was heated in an oil bath at 90 ° C for 1.5 h. the reaction mixture was cooled in an ice bath, quenched with concentrated hydrochloric acid (i.e., acidified), and diluted with water. After extraction of the resulting aqueous solution with ethyl acetate, several organic extraction solutions were obtained, which were later combined and then dried over anhydrous magnesium sulfate to give a clear solution. Removal of the drying filtrate by filtration and evaporation of the solvent under reduced pressure finally gave a residue which was then chromatographed using silica gel (30 g) as absorbent and ethyl acetate-30 as eluent. The appropriate fractions were combined and then evaporated under reduced pressure to give a pure solid as a residue. Recrystallization of the latter then gave pure 1 '- (3,4-dichlorobenzyl) -spiro [imidazolidine-4,3' - (6'-azaindoline)] - 2,2 *, 5 to 35 trione, which was isolated as the chloroform solvate, m.p. 160 -

II

15 81 575 163 ° C (dec). The yield of pure product was 20% of theory.

Analysis for C16H10Cl2N4O3 · 1/3 CHCl3:

Calculated: C 47.05, H 2.50, N 13.44% Found: C 47.16, H 3.78, N 13.40%

Example 3

By proceeding essentially as described in Example 2, but substituting 1- (3,4-10 dichlorobenzyl) -7-azaindoline-2,3-dione for 1- (3,4-dichlorobenzyl) -6-azaindoline-2,3-dione as starting material , using the same type of Bucherer-Berg reaction conditions as before. The final product was 1 '- (3,4-dichlorobenzyl) -spiro- [imidazolidine-4,3' - (7'-azaindoline)] - 2,2 ', 5-trione, which was isolated as the hydrochloride salt, mp 199-1520 ° C (decomposes). The yield of pure product was 50% of theory.

Analysis for C16H10Cl2N4O3 · HCl:

Calculated: C 46.45, H 2.68, N 13.55% Found: C 46.61, H 2.72, N 13.62% Example 4

By the method essentially as described in Example 2, but using 1- (3,4-dichlorobenzyl) -5-chloro-7-azaindoline-2 as a starting material instead of 1- (3,4-dichlorobenzyl) -6-azaindoline-2,3-dione, 3-dione, 25 using the same type of Bucherer-Berg reaction conditions as before. The final product was 1 '- (3,4-dichlorobenzyl) -5'-chloro-spiro- [imidazolidine-4,3' - (7'-azaindoline)] - 2,2 ', 5-trione, which was isolated as a hemihydrate , mp 210-212 ° C. The yield of pure product was 18% of the theoretical value of teo-30.

Analysis for C16H9Cl3N4O3 · 1/2 H2O:

Calculated: C 45.69, H 2.40, N 13.32% Found: C 45.48, H 2.21, N 13.03%

Claims (2)

A process for the preparation of novel therapeutically useful spiro [imidazolidine-4,3 '- (6'-azaindo-5-Iin)] -2,2', 5-trion derivatives of the formula (Ha) and spiro [imidazolidine] 4,3 '- (7'-azaindoline)] - 2,2', 5-trion derivative of formula (11b) 10 HN-1 = 0 HN f ^ 0 Λ 0 = 1 NH R "- R "- \ r] _N-R 'ζ} -N-R' (Ha) (Hb) where R 'is hydrogen or benzyl, the phenyl moiety of which is optionally mono-, di- or trisubstituted, each ring substituent being fluorine, chlorine or bromine; and R "is hydrogen, chlorine or bromine; and pharmaceutically acceptable salts thereof, characterized in that a) for the preparation of compounds of formulas (Ha) and (Hb) in which R 'is as defined above benzyl; an azaindoline-2,3-dione derivative of formula (IVa) or (IVb) 30 µl R '(IVa) (IVb) 19 81 575, wherein R' and R 'are the same as above, are condensed with an alkali metal cyanide and ammonium carbonate; or b) to produce compounds of formulas 5 (IIa) and (Hb), in which R 'is hydrogen, sodium ethyl (hydantoin-5-carboxylate) Nf hydrochloric acid or acetic acid at ambient temperature or at a slightly elevated temperature; and / or then, if desired, a compound of formula (Ha) or (Hb) is converted into a pharmaceutically acceptable site thereof. Process according to claim 1 for the preparation of spiro [imidazoline-4,3 '- (6'-azaindoline)] - 2,2', 5-25 trio, characterized by dSrav, that it is prepared by the method b.