Propane-1,3-dione derivatives

#The present invention relates to a pharmaceutical composition containing a propane-1,3-dione derivative or a pharmaceutically acceptable salt thereof as the active ingredient and a novel propane-1,3-dione derivative.

#It is known that hypothalamic hormone or pituitary hormone takes part in a control system of secretion of peripheral hormones. In general, the secretion of anterior pituitary hormone is regulated by a secretion stimulating hormone or a secretion suppressing hormone secreted from an upper center, hypothalamus, a peripheral hormone secreted from the target organs them.

#Gonadotropin releasing hormone (hereinafter, abbreviated as GnRH; also, GnRH is called as luteinizing hormone releasing hormone; LHRH) is known as a hormone which controls the secretion of sex hormones at the highest position, and regulates the secretion of luteinizing hormone (hereinafter, abbreviated as LH), follicle stimulating hormone (hereinafter, abbreviated as FSH), and sex hormones in the gonads through the intermediary of the receptor (hereinafter, abbreviated as GnRH receptor) which is considered to be present in anterior pituitary (Horumon to Rinsyo (Hormones and Clinical), 46, 46-57 (1998)). A specific and selective antagonist against the GnRH receptor is expected to be a drug for preventing and treating sex hormone-dependent diseases since it regulates the action of GnRH and controls the secretion of lower LH, FSH and sex hormones (Horumon to Rinsyo (Hormones and Clinical) (1998), ibid.).

#The following will explain the invention further in detail based on Examples. The compounds of the invention are not limited to the compounds described in the following Examples. In this connection, production methods of starting compounds are shown in Reference Examples.

#To a boiling suspension of sodium hydride (60% in oil) (360 mg) in anhydrous THF (10 ml) was added dropwise a solution of acetophenone (720 mg) and ethyl 2-methylthiazol-4-carboxylate (1.20 g) in anhydrous THF (10 ml), followed by 10 minutes of heating under refluxing. After the reaction solution was cooled, a mixed solution of acetic acid (1 ml) and water (30 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate. The extracted solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1 (v/v)) to obtain 1-(2-methylthiazol-4-yl)-3-phenylpropan-1,3-dione (1.3 g, 88%) as yellow crystals. Hereinafter, the compounds of Reference Examples 2 to 10 were obtained similarly.

#To a solution of the compound (674 mg) obtained in Reference Example 1 in DMF (8 ml) was added potassium carbonate (1.14 g), followed by 1 hour of stirring at room temperature. After carbon disulfide (283 mg) was added to the reaction solution and the resulting mixture was stirred at room temperature for 2 hours, methyl iodide (0.369 ml) was further added, followed by 1.5 hours of stirring at room temperature. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The extract solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent (v/v): hexane:ethyl acetate=4:1) to obtain 2-(bismethylsulfanylmethylene)-1-(2-methylthiazol-4-yl)-3-phenylpropan-1,3-dione (555 mg, 64%) as a yellow oily substance. Hereinafter, the compounds of Reference Examples 12 to 23 were obtained similarly.