Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-13
2004-08-17
Mckane, Joseph (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S312000, C514S313000, C514S314000, C546S153000, C546S155000, C546S156000, C546S159000, C546S164000, C546S168000, C546S169000, C546S170000, C546S171000, C546S174000, C546S175000, C546S176000, C546S177000, C546S178000, C546S180000
Reexamination Certificate
active
06777427
ABSTRACT:
TECHNICAL FIELD
This invention relates to tetrahydroquinoline compounds or pharmacologically acceptable salts thereof which have a specific and strong binding affinity for androgen receptors and exhibit androgen receptor agonism or antagonism, and pharmaceutical compositions containing the compounds or their pharmacologically acceptable salts.
BACKGROUND ART
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 5&agr;-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 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. Nowadays, 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 glucocorticoid receptors, and they build a nuclear steroid receptor family (Science 240, 324-326, 327-330, 1988). Androgens 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 dimers, 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.
As the AR agonists, androgen steroid preparations, such as testosterone esters and their derivatives, are currently used in the treatment of male hypogonadism, wasting diseases (malignant tumor, trauma, chronic renal disease, burns), and osteoporosis.
However, these androgen steroid preparations can cause side effects inherent in steroid preparations, such as hepatic dysfunction and gastrointestinal disorder, and may develop androgen-dependent tumor (e.g. prostatic cancer) or prostatic hypertrophy, or aggravate symptoms of these diseases, because they act excessively on the prostate if used in male patients, especially in elderly patients. If these preparations are administered to female patients, they pose major problems of virilizing actions, such as changes in the vocal cord (male-like hoarseness), hypertrichosis of the body trunk, alopecia and acne.
Hence, nonsteroidal AR agonists, which do not show excessive action on the prostate and are minimal in side effects, are desired for the treatment of hypogonadism, and have been under research and development. However, no compounds recognized throughout the world have been created.
For the treatment of wasting disease and osteoporosis, the desired AR agonists are those which do not show excessive action on the prostate, but exhibit potent AR agonism toward skeletal muscle tissue and bone tissue. However, such compounds have not 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).
Thus, AR antagonists, as nonsteroidal synthetic compounds diminished in the side effects of the steroids, are desired.
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 pharmacologically acceptable salts thereof, which are free from the side effects observed with androgen steroid preparations, have a specific and strong binding affinity for AR and exhibit AR agonism or antagonism; and to provide pharmaceutical compositions comprising these compounds or salts as active ingredients.
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted in-depth studies in an attempt to attain the above objects. As a result, they have found that tetrahydroquinoline compounds of the following formula (I) (hereinafter referred to as “compounds of the present invention”) have AR agonism or antagonism, have excellent therapeutic effects on AR-mediated diseases, particularly by not acting excessively on the prostate as AR agonists but by showing potent action on skeletal muscle tissue and bone tissue. Based on these findings, they have accomplished this invention.
That is, the present invention relates to a tetrahydroquinoline compound represented by the following formula (I) or pharmacologically acceptable salts thereof:
wherein R
1
and R
2
each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom, a nitro group, —NR
5
R
6
(wherein R
5
and R
6
each independently represent a hydrogen atom, an alkyl group having 1-9 carbon atoms, a cycloalkyl group having 3-7 carbon atoms, an aralkyl group having 7-9 carbon atoms which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom and a nitro group, an aryl or heteroaryl group which may optionally be substituted by one or more members selected from the group consisting of an alkyl group having 1-9 carbon atoms, an alkoxy group having 1-9 carbon atoms, a halogen atom and a nitro group, a formyl group, an aliphatic acyl group having 2-5 carbon atoms, an aliphatic acyloxy group having 2-5 carbon atoms, an aromatic acyl group, an alkylsulfonyl group having 1-4 carbon atoms, an arylsulfonyl group, an alkoxycarbonyl group having 2-5 carbon atoms, a hydroxyoxalyl group, or an alkoxyoxalyl group having 3-7 carbon atoms), a carboxyl group, an alkoxycarbonyl group having 2-5 carbon atoms, an amido group, an alkylamido group having 2-5 carbon atoms, an alkylthio group having 1-4 carbon atoms, an alkylsulfinyl group having 1-4 carbon atoms, an alkylsulfonyl group having 1-4 carbon atoms, a cyano group, a sulfamoyl group, an alk
Amano Seiji
Furuya Kazuyuki
Hanada Keigo
Kamei Misa
Miyakawa Motonori
Covington Raymond
Kaken Pharmaceutical Co. Ltd.
Mckane Joseph
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