FI63579B - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC ANALYZA SPIRO-BENZO (B) THIOPHENE (3,4 ') IMIDAZOLIDINE-2,5-DION-1,1-DIOXIDE - Google Patents

Description

1 63579

The present invention relates to a process for the preparation of a novel therapeutically useful spiro-benzo [b] thiophene / 3,4-imidazolidine-2,5-dione-1,1-dioxide. Separated from application 773 060 (patent 62307) Ig7 thiophene / 3,4'-imidazolidine-2,5-dione to prepare 1,1-dioxide.

The spirohydantoin compound of the invention is effective against certain additional diseases caused by diabetes (e.g., lens opacity and neurological diseases caused by diabetes).

Recently, many researchers in the field of organic drug-15 chemistry have sought different ways to find new and better oral antidiabetic drugs. The main topic has been the synthesis and testing of various hitherto unknown and unavailable organic compounds, especially sulfonylureas, in which their ability to lower blood sugar (i.e., glucose) levels has been determined. In the search for new and increasingly effective antidiabetic drugs, little attention has been paid to other organic compounds that prevent or stop certain additional diseases of diabetes, such as lens opacities, neural disease, and retinal disease. However, K. Sestanj et al. are disclosed in U.S. Pat. U.S. Patent No. 3,821,383 discloses that certain aldose reductase inhibitors such as 1,3-dioxo-1H-benzo / d, eisoquinoline-2 (3H) -acetic acid and some of its related derivatives are useful in this regard, 30 although these compounds are not known to lower blood sugar. . All of these aldose reductase inhibitors act by blocking the action of the enzyme aldose reductase, which in the human body primarily regulates the reduction of aldoses (e.g., glucose and galactose) to polyols 35 (e.g., sorbitol and galactitol). In this way, the unwanted accumulation of galactitol in the lens of 2,63579 individuals with galactose hemorrhage and the accumulation of sorbitol in the lens, peripheral nerve body and kidneys of diabetes are prevented or possibly reduced. Thus, these compounds are clearly useful as aldose reductase inhibitors in the treatment of certain additional chronic diseases of diabetes, e.g. in eye diseases, as it is already known in the art that polyols in the lens of the eye inevitably lead to lens loss.

According to the invention, it has now surprisingly been found that spiro-benzo [b] thiophene-3,4'-imidazolidine-2,5-dione-1,1-dioxide is a useful aldose reductase inhibitor which prevents certain additional diseases of diabetes, in particular chronic ocular diseases associated with diabetes.

The present invention relates to a process for the preparation of a novel therapeutically useful spiro-benzo [b] thiophene-3,4'-imidazolidine-2,5-dione-1,1-dioxide of the formula: .0 HN-r

0 J NH

-sd2 or pharmaceutically acceptable base salts thereof. The process according to the invention is characterized in that the thioindan-2-one-1,1-dioxide of the formula ηΛ30 -S ° 2 is reacted with alkali metal cyanide and ammonium carbonate, and the compound obtained 3,63579 is optionally converted into a pharmaceutically acceptable base salt.

The reaction according to the invention is usually carried out in an inert, polar organic solvent in which both the reactants and the reagents are mixed. Suitable organic solvents include, for example, cyclic ethers such as dioxane and tetrahydrofuran, lower alkylene glycols such as ethylene glycol and trimethylene glycol, water-miscible lower alkanols such as methanol, ethanol and isopropanol, N, N-di- (lower alkyl) lower alkano Ν-dimethylformamide, Ν, Ν-diethylformamide and Ν, Ν-dimethylacetamide, etc. In general, the reaction is carried out at a temperature of about 20 ° to about 120 ° C. The reaction time can range from about two hours to four days.

Although the amount of reactants and reagents used in the reaction may vary to some extent, it is preferable to use an alkali metal cyanide reagent in excess of the starting material of formula II for maximum yield. Upon completion of the reaction, the desired product can be readily isolated in the usual manner, e.g., by first diluting the reaction mixture with water (boiling if necessary) and cooling the aqueous solution to room temperature, and acidifying the solution to give the spirohydantoin compound as an easily isolated precipitate.

The thioindan-3-one-1,1-dioxide used as starting material is a known compound (Rogitz, Chemische Berichte, Vol. 98, p. 36 (1965)).

The base salts of the compound of formula I are of a nature whose cations are non-toxic over a wide dosage range. Examples of such cations are sodium, potassium, calcium and magnesium. These salts are readily prepared by treating a compound of formula I with an aqueous solution of the desired pharmacologically acceptable cation and evaporating the resulting solution to dryness, preferably in vacuo. Alternatively, they can be prepared by mixing a lower alkanol solution of a compound of formula I and the desired alkali metal alkoxide and evaporating the resulting solution to dryness as described above. In either case, the reagents are most preferably used in stoichiometric amounts.

5 Pharmacological experiments

As mentioned above, the spirohydantoin compound of the invention is therapeutically useful as an aldose reductase inhibitor in the treatment of chronic chronic diseases of diabetes because it statistically significantly reduces lens sorbitol levels in individuals with diabetes.

The ability of the compound of the invention and the known reference compound, 3 ', 41-dihydrospiro (imidazolidine-4,1' (2H) -naphthalene) -2,5-dione, to reduce or inhibit the activity of the aldose reductase enzyme was tested by S. Hayman et al. (Journal of Biological Chemistry, Vol. 240, p. 877 (1965)) (K. Sestanj et al., U.S. Patent 3,821,383). Partially purified aldose reductase seed-20 enzyme from calf mycelium was used in the experiments.

The following results were obtained:

Inhibition-%

Compound 10 ^ -m 10 ^ -m 10 ^ -m 10 ^ -m 25 ---

Compound of Example 1 81 64 22 4

Reference compound 72 34 13 7 30

The ability of the same compounds to reduce or prevent the accumulation of sorbitol in the sciatic nerve of streptozotocin-treated (diabetic) rats was tested by the method described in U.S. Patent 3,821,383. The accumulation of sorbitol in the sciatic nerve 35 was determined 27 hours after the onset of diabetes. Compound 63579 was administered orally 4, 8, and 24 hours after streptozotocin administration. Results are expressed as% inhibition compared to sorbitolita obtained in an animal that did not receive the test compound. The sorbitol level of the untreated animal rose from a normal level of about 50-100 mmol / g up to 400 mmol / g tissue in 27 hours in this experiment.

At a dose of 5.0 mg / kg, the compound of Example 1 gave an inhibition of 5% and the reference compound 3%, respectively. Generally, the compound will be administered from about 0.1 to about 10 mg / kg body weight / day, although the dose will vary depending on the weight and condition of the subject being treated and the route of administration chosen. The administration of the drug takes place either orally or parenterally, and the active ingredient is preferably in the form of a suitable pharmaceutical preparation.

Efficacy of a Compound of the Invention In the treatment of chronic chronic diseases caused by diabetes, the following standard biological and / or pharmacological tests can be used: 1) to measure the ability of a compound to inhibit the enzymatic activity of isolated aldose-20 reductase, 2) to measure the ability of a compound to reduce or prevent acute accumulation diabetes) to the sciatic nerve of rats, 3) to measure the ability of the compound to reduce the already elevated sor-25 bitol content in the sciatic nerve and lens of streptozotocin-treated chronic diabetes mellitus, 4) to measure the ability of the compound to prevent acute accumulation of galactitol severity of lens opacity in chronically galactose-blooded rats.

Example 1

Spiro-benzo [b] thiophene / 3,4 '. , 0.613 g (0.0094 mol) of potassium cyanide and 63579 21.9 g (0.021 mol) of ammonium carbonate in 14 ml of a 50% aqueous ethanol solution were heated in a 50 ml round-bottomed flask under nitrogen at 60 ° C for 48 hours. To the reaction mixture was added 70 ml of water, and the resulting small precipitate was filtered. The filtrate was acidified with 6N hydrochloric acid.

The precipitate was filtered and then dissolved in 4N aqueous KOH. The solution was acidified with 6N hydrochloric acid, saturated with sodium chloride and extracted with freshly distilled ethyl acetate (6 x 150 mL). The organic extracts were combined and dried over magnesium sulfate. After filtration of the magnesium sulfate, the filtrate was evaporated, and the evaporation residue was crystallized twice from ethanol-ethyl acetate-n-hexane. Yield: 0.50 g (36%) of pure spiro-benzo [c] thiophene] * 3,4-imidazolidine-2,5-dione-1,1-dioxide, m.p. 287 ° C (decomposes).

Example 2

Sodium salt of spiro-benzo [b] thi-O-phenol:

The sodium salt of the compound prepared in Example 1 was prepared by dissolving the compound in an aqueous solution containing an equivalent amount of sodium hydroxide and lyophilizing the mixture. The sodium salt was obtained as an amorphous, water-soluble powder.

Potassium, lithium, calcium and magnesium salts were prepared in a similar manner.

Claims (1)

A process for the preparation of a novel, therapeutically useful spiro-benzo [L] thiophene / 3,4 '-imidazolidine-2,5-dione-1,1-dioxide 5 having the formula: HN4? For the preparation of O-io -so2 15 or pharmaceutically acceptable base salts thereof, characterized in that the thioindan-3-one-1,1-dioxide of the formula: is -so2 25 is reacted with an alkali metal cyanide and ammonium carbonate, and the resulting compound is optionally modified as a pharmaceutically acceptable base salt.