Androgens are a generic name for C19. steroids. They are sex hormones important for the normal sexual differentiation and growth of males, masculinization at puberty, activation of initial spermatogenesis in the testes, and maintenance of male function. About 90% of androgens are produced by Leydig cells of the testes, the remaining, 10% by the adrenal gland, mainly as testosterone, and secreted into the blood. Testosterone is taken up into target cells, and converted by 5α-reductase into dihydrotestosterone (DHT) with potent biological activity. DHT, as well as testosterone, plays an important role in the development of male secondary sex characteristics (growth of sebaceous glands, acne, development of body hair, voice deepening, development of beards), growth of external genitalia (penis, testis), growth of sex accessory organs (prostate, seminal vesicles), sexual stimuli, and occurrence of erection.
In addition to these major actions, androgens have actions other than those on the reproductive system, such as protein anabolic action (increases in skeletal muscles mass and bone mass), suppression of gonadotropin secretion, and acceleration of erythropoiesis promoting action. Target cells for androgens are localized in external and sex accessory tissues, and are widely distributed in the brain, pituitary gland, muscular tissues, bones, and kidneys (N. Engl. J. Med. 334, 707-714, 1996).
In addition to these roles, androgens are reported to show an anti-inflammatory action. Recently, it is becoming clear that androgens attenuate arthritis and autoimmune disease by inhibiting the proliferation of inflammatory cells or suppressing the production of cytokines such as IL-6 (Ann. Rheum. Dis. 55, 811-815, 1996).
All androgenic actions are mediated through androgen receptor (hereinafter referred to as AR) having a molecular weight of about 100,000 which is present in the nuclei of target cells. The gene of AR was cloned by Chang and Lubahn et al. in 1988. Their study demonstrated that AR has a similar structure to estrogen, progesterone, mineral corticoid, and glucocortlcoid receptors, and they built a nuclear steroid receptor family (Science 240, 324-326, 327-330, 1988). Androgen with high liposolubility penetrate the target cell membrane by passive diffusion, and bind to the hormone-binding region of AR specifically and with high affinity to form dimmers, which bind to an androgen responsive DNA region (androgen response element: ARE) localized upstream from a particular gene. As a result, transcription of the target gene is initiated to induce the expression of mRNA, thereby producing a functional protein responsible for an androgenic action, thus exhibiting this action (Trend in Endocrinology and Metabolism 9, 317-324, 1998). In connection with this mechanism, compounds which bind to AR and show the same actions as natural ligands such as testosterone are defined as agonists, while compounds which inhibit their action are named antagonists.
The AR agonists used since olden days are injection drugs of testosterone esters (testosterone enanthate, testosterone propionate) with enhanced persistence after administration into the body, and oral drugs having a methyl group introduced at the 17α-position to protect the hydroxyl group at the 17β-position from inactivation due to its oxidation, thereby enhancing activity (i.e., methyltestosterone, fluoxymesterone). These preparations of androgen steroids are often used for target diseases at relatively large doses and for long periods. Thus, these preparations cause side effects, such as hepatic dysfunction, virilization, changes in the female vocal cord (male-like hoarseness), gastrointestinal disorder, euphoria, hypertrichosis of the body trunk, and alopecia. Especially androgen preparations having a methyl group at the 17α-position, have been reported to evoke serious hepatic dysfunction (N. Engl. J. Med. 334, 707-714, 1996). In recent years, nonsteroidal AR agonists, which attenuate the side effects of the steroids and are more selective for target tissues, have been under development. However, no compounds recognized throughout the world have been created.
As AR antagonists, steroidal anti-androgen preparations, such as chlormadinone acetate and cyproterone acetate, which are gestagen derivatives, have been used as therapeutic agents. It has been pointed out, however, that these steroid preparations accelerate the negative feedback mechanism of the hypothalamic-pituitary axis by their progesterone action, thereby lowering the blood testosterone level and decreasing sexual function and libido (Drugs Aging 5, 59-80, 1994).
To overcome them, flutamide and bicalutamide have been developed as nonsteroidal AR antagonists. Flutamide, an acylanilide derivative, is known to have no AR antagonistic action by itself, but produce activity when converted into hydroxyflutamide by substitution of a hydroxyl group for the α-carbon atom directly bonded to the carbonyl group as a result of metabolism. This hydroxyl group is presumed to be essential to the antagonistic action (J. Med. Chem. 31. 954-959, 1988). Flutamide is the nonsteroidal AR antagonist that became available clinically for the first time in the world. However, the blood half-life of its active metabolite is so short that a high dose should be administered three times daily, posing a problem of drug compliance (Clin. Pharmacokinet. 34, 405-417, 1998). Moreover, flutamide has been reported to cause side effects, such as diarrhea and serious hepatic disorders leading to death, thus hampering its clinical use (J. Urol. 57, 172-174, 1985; J. Urol. 155, 209-212, 1996).
Bicalutamide, an acylanilide derivative having a hydroxyl group at the α-carbon atom, is characterized with a stronger binding affinity for AR and a longer blood half-life (about 8 days) after administration, than hydroxyflutamide. Thus, bicalutamide can be administered once daily. However, tenderness and swelling of breasts, considered to be due to the action on central nervous system, occur frequently as side effects (J. New Remedies & Cinics 48, 307-321, 1999).
In animal experiments, it was reported that the conception rate of normal female rats mated to male rats administered flutamide and bicalutamide was decreased (The 80th Annual Meeting of The Endocrine Society, P3-126, June 24-27, New Orleans, La., 1998). Another problem with nonsteroidal AR antagonists is the occurrence of agonism during long-term use (J. Urol. 153, 1070-1072, 1995). Particularly in the treatment of prostatic cancer, the androgenic action needs to be blocked completely, so that the occurrence of the agonistic action raises a major problem in treatment.
In recent years, nonsteroidal AR antagonists with little effect on the central nervous system and the reproductive system and with potent AR antagonistic activity have been under development. However, no compounds recognized globally have been created.
The present invention has been accomplished in view of the therapies of and therapeutic researches on the diseases mediated through AR. The objects of the present invention are to provide novel nonsteroidal compounds and salts thereof, which have a specific and strong binding affinity for AR and exhibit AR agonism or antagonism; and to provide pharmaceuticals containing these, compounds or salts as active ingredients.