Compositions containing aldose reductase inhibitors for the treatment of ulcers

Abstract: A therapeutic preparation for the treatment of dermal, labial, intra-oral and gastro-intestinal tract ulcers, corrosive wounds, bed sores, burns, frost-bite and scleroderma contains as a primary ingredient a compound having an aldose reductase inhibitory activity and which can accelerate dermal metabolism. Preferred compounds are optically active hydantoin derivatives.

Description: This invention relates to a therapeutic composition for the treatment of ulcers and containing an aldose reductase as a primary component. The compositions may be administered externally for the treatment gastro-intestinal tract ulcers. In recent years, it has been found that one of the causes of cataract, retinitis and various nervous disorders induced by diabetes is an intracellular accumulation of sorbitol formed by way of the polyol pathway, and attention has been paid to various aldose reductase inhibitory substances, because enzymatic inhibition of the exchange between aldose and polyol reduces the production or accumulation of sorbitol. The applicant has already filed patent applications to patent per se the compounds used in this invention (see Japanese Patent Kokai Publication No. 61(1986)-200991 and US Patent No. 4,861,792). Hitherto, many aldose reductase inhibitors have been studied for treating diabetic complications (see US Patent No. 4,900,739). Further, both US-A-4717725 and US-A-4600717 disclose the treatment of wounds with aldose reductase inhibitors exemplified by the treatment of ocular wounds in diabetic patients. However, it has not previously been known that aldose reductase inhibition systems take part in the promotion of tissue metabolism, and that they also have an effect upon inhibiting ulceration. According to the present invention a use is provided, in the manufacture of a medicament for the treatment of ulcers of the stomach and gastrointestinal tract by oral administration, of an antiulcer effective amount of a compound selected from d-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxyamide, d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione and d-2-bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzo-pyran-4,4'-imidazolidine]-2',5'-dione. If desired, the hydantoin derivatives of the present invention may be provided in the form of a composition to which stabilizers, absorption accelerators have been added. Examples of the carriers that may be used are carboxylmethylcellulose, polyvinyl pyrrolidone and cyclodextrin. The therapeutic compositions according to this invention activate tissue metabolism and so are efficacious against all aspects of exhaustion tissue necroses particularly ulcers of the stomach and gastro-intestinal tract. The present invention will now be illustrated more specifically with reference to pharmacological Tests and non-limiting Examples. EXAMPLES Preparation Examples Three hydantoin derivatives, i.e., d-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro [4H-1-benzopyran-4,4'-imidazolidine]-2-carboxyamide (hereinafter called Compound A), d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione (hereinafter called Compound B) and d-2-bromomethyl-6-fluoro-2,3-dihydro-spiro [4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione (hereinafter called Compound C) are used to obtained the following forms of preparation (a) suppository and (b) tablet: (a) Suppository Compound A 100 mg Cacao butter 1600 mg 1700 mg per suppository Compound A is dispersed in a cacao butter (higher fatty acid glyceride) melt that is an oil and fat base, and then formed in conventional manner to obtain suppositories. (b) Tablet Compound A 50 g Sodium citrate 25 g Arginine 10 g Polyvinyl pyrrolidone 10 g Magnesium stearate 5 g In conventional manner the above-mentioned components are tableted to prepare 1000 tablets for oral administration, each containing 50 mg of the active component. Pharmacological Test Example 1 Effect on Inhibiting Ulcer Induced by Water Immersion Stress After 24-hour fasting, S.D. masculine rats weighing 250-270 g were immersed to their breasts in a water tank maintained at 23 1 to load a water immersion stress on them. Seven hours later, the stomachs were evulsed and filled with 10 ml of a 2% formalin solution according to the method described in "Jap. J. Pharmac.", 18 , pp. 9-18 (1968) for temporal fixation. The stomachs were incised to find the sum of lengths of ulcerated regions on the stomach bodies - an ulcer factor. A solution of 20 mg/kg of the instant compound dissolved in physiological saline was orally administered to the animals 10 minutes before stress loading. As reported in Table 1, the instant compound showed an inhibitory action upon the ulceration of the stomach bodies. Number of animals Ulcer Factor Control Group 10 14.8 2.0 Compound A 10 11.5 1.5 B 10 10.6 1.2 C 10 12.2 2.6 Sorbinil 10 12.6 1.8

Claims: The use of an antiulcer effective amount of a compound selected from d-6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxyamide, d-2-chloromethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5'-dione and d-2-bromomethyl-6-fluoro-2,3-dihydro-spiro[4H-1-benzo-pyran-4,4'-imidazolidine]-2',5'-dione in the manufacture of a medicament for the treatment of ulcers of the stomach and gastro-intestinal tract by oral administration.

Inventors: ITO TAKASHI C O SANWA KAGAKU K, KONDO YOSHIYA C O SANWA KAGAKU, KUBOYAMA NOBORU C O SANWA KAGA, KURONI MASAYASU C O SANWA KAGA, NAKANO KAZUMASA C O SANWA KAGA, SATO MAKOTO C O SANWA KAGAKU K, SAWAI KIICHI C O SANWA KAGAKU, ITO, TAKASHI, C/O SANWA KAGAKU KENKYUSHO CO., LTD., KONDO, YOSHIYA, C/O SANWA KAGAKU KENKYUSHO CO., KUBOYAMA, NOBORU, C/O SANWA KAGAKU KENKYUSHO CO., KURONI, MASAYASU, C/O SANWA KAGAKU KENKYUSHO CO.,, NAKANO, KAZUMASA, C/O SANWA KAGAKU KENKYUSHO CO.,, SATO, MAKOTO, C/O SANWA KAGAKU KENKYUSHO CO., LTD., SAWAI, KIICHI, C/O SANWA KAGAKU KENKYUSHO CO. LTD.
Applicants: SANWA KAGAKU KENKYUSHO CO, SANWA KAGAKU KENKYUSHO CO., LTD.
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61K9, A61P17, A61P43, A61K45