FI77235C - Process for the preparation of therapeutically useful spiro-polycyclic imidazolidinedione derivatives. - Google Patents

Description

1 77235

The present invention relates to novel spiro-polycyclic imidazolidinedione derivatives which are useful in the treatment of certain diabetic diseases and certain diabetic diseases which are useful in the treatment of certain diabetic diseases. nerve diseases.

. * Although many oral antidiabetic drugs, such as sulfonylureas, are effective in lowering blood levels: 15 diabetes levels have been shown to prevent and alleviate chronic diseases of chronic diabetes, such as diabetic cataracts, neurological diseases, retinal diseases, and kidney diseases. According to U.S. Patent 3,821,383, aldose reductase-20 inhibitors such as 1,3-dioxo-1H-benzo [H, e] isoquino-; linine-2- (3H) -acetic acid and its derivatives are useful in this regard. According to U.S. Patent No. 4,127,665, spirothienohydantoin derivatives are also aldose reductase inhibitors. Such compounds inhibit the enzymatic reduction of aldoses such as glucose and galactose to the corresponding polyols such as sorbitol and galactol, thereby preventing or reducing the harmful or undesired enrichment of the polyols in the lens or retina of the ocular or retina of the diabetic eye.

The invention relates to a process for the preparation of spiro-polycyclicimidazolidinedione derivatives of the formulas Ia, Ib, Ie and Id of 77235% _ 1 w HR 1 ίϋ) * -NH rf ^ n0 la / 10 • ϊ Y%

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Ua UI Hb 30. A '%> IQJ IIC iid 3 77235 and at least a stoichiometric amount of alkali metal cyanide and ammonium carbonate in an inert, polar organic solvent.

To synthesize the imidazolidinedione derivative, the ketone (formulas IIa to IIId) is condensed with an alkali metal cyanide such as sodium or potassium cyanide and ammonium carbonate. Normally the reaction is performed in an inert polar organic solvent in which the reagents are mixed. Preferred organic solvents include and tetrahydrofuran, lower alkylene glycols such as ethylene glycol and trimethylene glycol, water-miscible lower alkanols such as methanol, ethanol and isopropanol, and N, N-di (lower alkyl) lower alkanoamides such as N, N-dimethylformamide, Ν, Ν-diethylformamide and N, N-dimethylacetamide In general, the reaction is carried out at a temperature of about 50 to 150 ° C, preferably about 90 to 130 ° C, for about two hours to about four days, depending on the temperature used, although the reactants used in the reaction and The amount of reagents must be at least stoichiometric, it is recommended to obtain the maximum yield It is advisable to use a reasonable molar excess of alkali metal cyanide and ammonium carbonate reagents relative to the ketone starting material. Upon completion of the reaction, the desired product can be easily isolated by conventional methods. For example, the reaction mixture can be diluted with water and the resulting aqueous solution is cooled to room temperature and acidified to give the desired spiro-polycyclic imidazolidinedione derivative.

The starting ketones of formulas IIa-IId are readily available or can be prepared by known methods. A typical preparation method is Friedel-Crafts cyclization, in which 4- (1- or 2-naphthyl or anthracenyl) butyric acid is cyclized to form the desired cyclohexanone ring. The acids are prepared by condensing the appropriate naphthalene or anthracene compound and butyrolactone or by condensing the appropriate naphthol and acrylonitrile under basic conditions, followed by hydrolysis of the formed 3- (1- or 2-naphthoxy-5-propionitrile) using a Fridel-Crafts reaction. a polyphosphoric acid which attaches a propionic acid moiety to the naphthyl ring to give the corresponding starting material of formula IIa-IId.

. . The compounds of formula I can be readily prepared into pharmaceutically acceptable metal salts by conventional methods. Treatment of the spiro-poly-cyclic imidazolidinedione derivative with an aqueous solution of the desired pharmaceutically acceptable metal hydroxide or other metal base and evaporation of the resulting solution to dryness, preferably in vacuo, affords the salt. Alternatively, a lower alkano solution of a spiro-poly-cyclic imidazolidinedione derivative and an alkoxide of the desired metal can be mixed and then the alcohol solvent evaporated. Pharmaceutically acceptable metal hydroxide bases and alkoxides are those whose cations form metal salts with acidic compounds of formula I and which are non-toxic at doses administered to a subject in need of treatment. Examples of suitable cations are potassium, sodium, ammonium, calcium and magnesium.

The novel spiro-imidazolidinedione derivatives of this invention are useful aldose reductase inhibitors and as such have therapeutic use in the prevention and treatment of additional chronic diseases of diabetes, such as cataracts, retinal diseases and kidney diseases. The compounds can be administered to a subject in need of treatment by a variety of routes, such as orally, intravenously, intramuscularly, subcutaneously, topically, ocularly, and intraperitoneally. Generally, the compounds are administered at a dose of 1-250 mg / kg over 5 days. But the particular dose and route of administration will depend on the condition of the patient, which is best assessed by the attending physician.

The effect of spiro-polycyclic imidazolidinediones of formulas Ia-Id on chronic chronic diseases of diabetes can be determined by a number of standard biological or pharmacological tests. These experiments measure the effect of compounds of formulas Ia-Id on 1) decreased enzyme activity of isolated aldose reductase 2) inhibition of sorbitol accumulation in steptic-10 socine-induced diabetes mellitus and 5) slowing cataract formation and reducing the severity of lens opacification in chronically galactose hemorrhagic rats.

Aldose reductase inhibitory activity

The ability of spiro-polycyclic imidazolidinedione derivatives of formulas Ia-Id to reduce or inhibit aldose-20 reductase enzyme activity was tested by the method described in U.S. Patent 3,821,383, based on the method of Hayman et al., Journal of Biological Chemistry, 240, 877 (1965). The partially purified aldose reductase enzyme obtained from calf lens was used as a substrate. The test compound was tested at a concentration of -4 -m and optionally lower concentrations and the results are expressed as the percentage inhibition of enzyme activity.

Compound from Example Percent Inhibition -4 30 No. 10 -m 1 26 2 86+) 3 71 4 60 35 +) This value is the average of 3 experiments 6 77235

Inhibition of sorbitol accumulation

The ability of 2,3, -dihydrospiro / imidazolidine-4,1'-phenalene-~2,5-dione of formula Ie to reduce or prevent the accumulation of sorbitol in the sciatic nerve of streptozocin-treated (i.e., so-5 co-morbid) rats was tested by the method described in U.S. Pat. in U.S. Patent No. 3,821,383. Sorbitol accumulation in the sciatic nerve was measured 27 hours after induction of diabetes. The compound was administered orally at a dose of 5.0 mg / kg 4, 8 and 24 hours after streptozoin-10 administration. Results are calculated as the percentage inhibition compared to the control (untreated animal with sorbitol levels rising from a normal value of about 50-100 mmol / g to as much as 400 mmol / g during the 27 hour experiment). The inhibitory effect of the compound of formula Ie in this experiment at a dose of 5 mg / kg was 28%.

General Production Process

The compounds of formulas Ia-Id shown in Table 1 were synthesized using the formulas IIa-IId as starting materials. . ketones according to the following method.

In a steel bomb, about 1 g of starting ketone, 1/2 to 3 kg of potassium cyanide, 2-10 g of ammonium carbonate, 10-25 ml of ethanol and 0-25 ml of water were heated at 100-130 ° C for 15-72 hours. The reaction mixture was cooled, diluted with approximately the same volume of 1 N aqueous potassium hydroxide solution and washed about four times with ether. The cold aqueous layer was neutralized with 12 N hydrochloric acid, and the neutralized solution was extracted four times with 100-200 ml portions of ethyl acetate. The combined organic layers were re-extracted with saturated sodium chloride solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried. (MgSO 4), filtered, the solvent removed in vacuo and the residue recrystallized from a suitable organic solvent. The compounds prepared and their characteristic values are shown in Table 1.

7 77235

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Claims (1)

Process for the preparation of therapeutically useful spiro-polycyclic imidates-5 solidindione diones of the formulas Ia, Ib, Ie and Id. By? -1 »tl ^ (QJ» 15 o._ I o. Rf ^ i rr (öfj trVn0: > 20 | Ol • - Id Ie characterized by condensing the corresponding ketone of the formula Ha, Hb, Ile or Ild 3 ° SqA tQJ Hb Ha 35 ίδό ιοΛ tOJ iic 9 77235 and at least a stoichiometric amount of alkali metal cyanide and ammonium carbonate in an inert, polar organic solvent. 10 77235 For the preparation of a therapeutically active spiro-polycyclic-imidazolidinedione with a formulation of 5 Ia, Ib, Ie and Id - © O [OI ^ Ia K_ / J Ib —T —m 20 \ D \ id ic kännetecknat därav, fig the condenser of the ketone with the form of Ha, Hb, Ile or Ild - Ha 35 © 0 »-lOJ iic