Methods for treating female sexual dysfunctions

#This invention generally relates to pharmaceuticals and more specifically to a method and compositions for inducing penile erections in human males suffering from impotence, a method and compositions for treating female sexual dysfunction, and a method and compositions for treating human anal disease resulting from excessive anal sphincter tone.

#Male erectile dysfunction is a widespread disorder that is thought to affect about ten to fifteen percent of the adult men. In a similar fashion, it is now beginning to be recognized that female sexual dysfunction is also a significant problem among adult women. With the male cases, a number of causes of these insufficiencies, in addition to anatomical deficiencies of the penis that preclude an erection sufficient for vaginal penetration, have been identified. Causes of erectile dysfunction can be categorized as psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and in any male suffering from erectile dysfunction there may be more than one cause. Female sexual dysfunction may also be categorized as psychogenic, neurogenic, endocrinologic, drug-induced, or vasculogenic and a female with one or more of these etiologies may also experience a lack of satisfaction in sexual relations.

#Psychogenic impotence is often the result of anxiety or depression, with no apparent somatic or organic impairment. Neurogenic impotence may arise from, for example, surgery or a pelvic injury, involving the nervous system affecting the penis or vagina. Sexual dysfunction which is in endocrinologic in origin is most often associated with the disorders hypo- or hypergonadotropic hypogonadism and hyperprolactinein the male and decreases in estrogens in the female.

#To a solution of 3-mercapto-3-methylbutyric acid (B. J. Sweetman et al. J. Med Chem., 14, 868 (1971)) (4.6 g, 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5 ûC (internal temperature) was added trifluoroacetic acid (82 g, 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2,4,6-trimethoxybenzyl alcohol (M. C. Munson et al., J. Org. Chem., 57, 3013 (1992)) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5 ûC. After the addition was complete, the mixture was stirred for an additional 5 min at 5 ûC and the volatiles were removed in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material removed in vacuo. The residue was treated with activated charcoal and recrystalised from diethyl ether/hexane. The product was isolated as an white solid in 70% yield (7 g) mp 103-105° C. 1H NMR (CDCl3) δ6.12 (s, 2H), 3.80-3.85 (m, 11 H), 2.74 (s, 2H), 1.47 (s, 6H). 13C NMR (CDCl3) δ173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, 45.9, 43.6, 28.4, 21.0.

#Under a nitrogen atmosphere, dipyridamole (1.50 g, 2.97 mmol) was dissolved in anhydrous dimethylformamide (30 mL) and 4-dimethylaminopyridine (1.46 g, 11.9 mmol) was added, followed by the product of Example 1a (3.64 g, 11.9 mmol) and EDAC (2.28 g, 11.9 mmol). The resulting mixture was stirred 44 hours at 50° C. The solvent was evaporated in vacuo and, residue was partitioned between methylene chloride and water, washed with brine and dried over anhydrous sodium sulfate. Volatiles were evaporated and the residue was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to (1:1) to give the title compound (1.02 g, 23 % yield). 1HÊNMR (CDCl3, 300 MHz) δ1.45 (s, 24 H), 1.58-1.69 (m 12 H), 2.70 (s, 8 H), 3.64-3.88 (m, 52 H), 4.02-4.06 (m, 8 H), 4.25-4.32 (m, 8 H), 6.10 (s, 8H).

#The product of Example 1b (1.00 g, 0.63 mmol) was dissolved in methylene chloride (5.5 ÊmL) and anisole (4.0 mL, 36.9 mmol), phenol (0.400 g, 4.25 mmol), water (4.0 mL) and trifluoroacetic acid (16 mL, 208 mmol) were added. After 1 hour 30 minutes of stirring at room temperature, toluene (5 mL) was added and volatiles were evaporated. The residue was purified by flash chromatography on silica gel eluting with hexane/ ethyl acetate (5:1) to (3:1) to give the title compound (0.360 g, 59 % yield). 1H NMR (CDCl3, 300 MHz) δ1.47 (s 24 H), 1.68-1.72 (m, 12 H), 2.29 (s, 4H), 2.63 (s, 8 H), 3.85-3.92 (m, 8 H), 3.97-4.03 (m, 8 H), 4.284.35 (m, 8H).