Benign prostatic hyperplasia (BPH) is a common disorder in aging males. Approximately 50% to 75% of all males over the age of 50 are known to develop this condition.3) This disorder is characterized by a progressive enlargement of the prostate grand, leading to an increase in pressure on the urethra; it results in obstruction of urinary flow. In light of the high incidence of this condition, it is obvious that some form of chemical therapy would be of immense potential importance in treating BPH.
4)Steroid 5a-reductase enzymatically converts testosterone (T) into 5a-dihydrotestosterone (DHT), which is the most active agonist for androgen receptors.5) An accumulation of DHT to high levels in the prostate gland or the skin is recognized as leading to various pathological conditions such as BPH, acne, female hirsutism, and male pattern baldness.
4)Therefore, therapy with a 5a-reductase inhibitor would be expected to lead to a decrease in DHT concentration within the prostate gland or other tissues, and may be an extremely useful agent for the treatment of BPH and other diseases.Though many laboratories have investigated 5a-reductase inhibitors, 6,7) these efforts have predominantly concentrated on compounds with a steroidal structure, for example finasteride 6a) (Table 1). However, due to the presence of a steroidal structure, there is the strong possibility of unwanted side-effects. 8) We previously reported 1) the discovery of an excellent nonsteroidal compound, FK143,methyl]amino]benzoyl]-1H-indol-1-yl]butyric acid (Table 1), which displays high in vitro inhibitory activity against human prostatic 5a-reductase (IC 50 ϭ1.9 nM) and in vivo inhibitory activity against the castrated young rat model. 9) In this model, the growth of ventral prostate was induced by the subcutaneous injection of testosterone propionate (TP) to castrated young rats and was reduced by administration of the inhibitor. In order to obtain a more clinically effective candidate, we have now investigated more active compounds against this in vivo model. We employed two types of modification, 1) altering the indole ring to other hetrocyclic rings, and 2) changing the benzoyl substituent at the 3-position.Chemistry The indolizine derivative 17 was prepared as shown in Charts 1 and 2. Friedel-Crafts acylation of indolizine was carried out with ethyl 3-(chloroformyl)propionate and aluminum chloride to obtain 1 and 2. The ketone 1 was reduced to 3 by a borane-tetrahydrofuran (THF) complex, and 3 was acylated with 3-nitrobenzoyl chloride to obtain 8. The catalytic reduction of 8 gave the amine 11, which was alkylated with bis(4-isobutylphenyl)chloromethane to afford 14. 17 was obtained by hydrolysis of the ester 14. The indolizine derivative 18 was prepared from 2 in a similar manner to 17 (Charts 1, 2). The imidazopyridine 19 was prepared as shown in Charts 1 and 2. 1-Formylimidazo[1,5-a]pyridine 10) was treated with Wittig reagent to give the b,gunsaturated acid 5. Esterification and catalytic reduction of 5 afforded 7, which was derived to 19 in a...