MXPA97001530A - Use of estrogen antagonists and estrogen agonists to inhibit pathologi conditions - Google Patents

Abstract

The present invention relates to the use of an effective amount of a compound of formula I in the preparation of compositions for inhibiting pathological conditions related to organ systems that respond to estrogen agonists, the compositions being administered to a mammal in need of such treatment.

Description

USE OF ESTROGEN ANTAGONISTS AND ESTROGENQS AGONISTS TO INHIBIT PATHOLOGICAL CONDITIONS BACKGROUND OF THE INVENTION It has been indicated that certain agonists of this type are useful for inhibiting pathological conditions related to organ systems responsive to agonists or. Eestrogen antagonists. In particular- / 2-fem l ~ 3-aro? L- 10 benzot lofenos and 1- (al quiiarnmoetoxi feni 1) -1-fen? J -2-fen? J -but - 1-enos, represented by raJoxifene and tamox i ferio, have some application as estrogen agonists.

Ralox i fe no Tamo xi fe no 20 It has been claimed that raloxi feno is effective in the treatment of acne (patent US 5.439.923), alopecia (pa + ente FP 0659414 A), Rlzheirner's disease (pa + ente EP 0659418 Rl). skin and vagina atrophy (US patent 5,461,054), ' autoinrnune disease (paten + e EP06B4123), breast cancer (US patent 4.48.068), breast disease (patent EP 0659419), cartilage degeneration (US patent 5,418,252), central nervous system problems (pos. rnenopausí cos) (pat-en-te EP 94-0309470), pathology of objective endocrine organs (US Pat. No. 4,418,068), re-pubed puberty (US Pat. No. 5,451,509), migrant-desrniel disease (US Pat. No. 5,434,156), di rnenorrea (US patent 5,446,053), endo etpos ± s (US patent 5,461,065), female infertility (patent EP 659429 ñl), fertility disorders, hirsutísimo (patent EP 0659414 02), hypoglucernia (patent EP 635264 A2 ), increased libido (US patent 5,439,931), inhibition of fertility (US patent 5,462,949), oxidation of low density lipoproteins (EP 0664121 A), hypercholesterolerma (US patent 5,454,845), lupus epte atosus ( EP 0664125), impaired macrophage function (patent EP 659425 Al), male infertility (paten EP 0659424 Al), myocardial infarction, ischemia, rhomboembolic disorder, thrombin inhibition (EP 0664126), enopaus cos disorders (EP 0659415), menstruation disorders (US patent 5,462,950), obesity (paten e EP 94-0309481), obsessive-compulsive disorder (patent EP 0659428), osteoporosis (US patent 5,457,117), disgenes s ovarica (US patent 5,451,539), pepmenopausic syndrome (US patent 5,391,557), vascons peripheral (US Pat. No. 5,470,883), post-enopausal central nervous system (EP 0659415), premenstrual syndrome (US Pat. No. 5,389,670), prosthetic carcinoma, prosthetic hyperplasia, pulmonary hypertension (US patent 5,447,941), damage of reperfusion (3. Arn.

Cardioi., 25., 1890, 1993), resistant neoplasm (EP 0652004 ñ), restenosis (US patent 5,462,937), rheumatoid arthritis (EP 0664125 patent), seborrhea (US patent 5,439,923), d_.stunr - sexual, sexual precocity (U0 patent 5,451,590), expression of trornbornodulin (patent EP 0659427), Tur er syndrome (US patent 5,441,966), uterine fibrosis (US patent 5,457,116) and vasomotor symptoms (postrnenopausí cos) (patent EP 94-0309473). Ta oxifene has been used extensively in < - The treatment of breast cancer and it has been indicated that it is effective in the treatment of the following diseases and conditions: elevated lipid levels [Drug Ther., 22/3, 109 (1992) 1, CJ ovarian cancer. Clin. Oncol., 11, No. 10, 1957-1969 (1993)], renal cell carcinoma CBr, 3. Radiol., 56, p "670, 766-767 (1983) 7, suppression of the atherogenic factor homocysteine TEnv. Cancer, Supplement 29, 6, SI 10 (1993)], Metaphagic rnelanoma [J. Clin. Oncol., 12, No. 0, 1,553-1,560 (1994)], Mastalgia CDrugs, 32, No. 5, 477-480 (1986)], a tumor of the pituitary secreting prolactm TJ, Endocr nol Invest., 3/4, 343-347 (1980)], osteoporosis CProc ñnnu.

Hm. flssoc. Cancer Res., 33, ñ566 ~ 567 (1992)] and retropeptoneal fibroses CLancet, 341, n. 8,841, 382 (1993) 1. Small structural changes in the structure of estrogen agonists cause profound differences in their biological properties. For example, droloxifene (3-hydroxy to oxyphene), of the following formula T, has an affinity towards the estrogen receptor 10-60 times higher compared to tamox teno. Droloxifene is devoid of carcinogenic or mutagenic effects m vivo or in 1 ro, while tamox lf eno causes liver tumors in rat? CHasmarnu et al., Cancer Letter, 8_, 101-115 (1994) 1., Droloxifene has been reported to be effective in the treatment of breast cancer (US Pat. No. 5,047. '+31), ondornet posis (US Pat. 5,455,275), to reduce cholesterol levels (US patent 5,426,123), osteoporos s (US patent 5,254,594), prosthetic hyperplasia (US 5,441,986) and restenosis (US Patent 5,384,332).

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a method of inhibiting a pathological condition that is susceptible or parrically susceptible to being inhibited by a estrogen antigen or estrogen agonist, which comprises administering to a mammal that needs to inhibit a selected pathological condition of the drug. consisting of uterine cancer, auxiliary breast cancer, breast disorder, male breast cancer, migraine, incontinence, vaginal atrophy, bladder infection, senile g ecornastia, diabetes, hypoglycemia, failure to heal wounds, rnelanorna, impotence, inflammatory bowel disease, central nervous system and gastrointestinal disorders caused by an excess of tachyquinones, decreased libido, systemic disorders, decreased fertility, pulmonary hypertension, acne, seborrhea, autoimmune disease, syndrome of Turner, alopecia, hirsut smo, disorders related to an excess of neuroqumana and disorders obsessive-compulsive, including the abuse of tobacco and alcohol, an effective amount of a compound of formula 1 where: ñ < -e selects CH2 and NR; F), D and E are independently selected from CH and N and Y is (a) phenyl, optionally substituted menAe with 1-3 substituents independently selected from R *; (b) naphthyl, optionally substituted with 1-3 substituents selected independently from R >; (c) C 3 -C 8 -alkyl. optionally substituted with 1-2 substituents independently selected from R '; (d) c C3-C3alkyl, optionally substituted with 1-2 substituents independently selected from R *; (e) a five-membered heterocycle, containing up to two heteroates selected from the group consisting of -0-, -NR2 - and -S (0) n--, optionally substituted with 1-3 < -ustituyent.es selected independently of R *; (f) a heterocycle of its members, containing up to two heteroatoms selected from the group consisting of -0-, -NR2- and -S (0) n-, optionally substituted with 1-3 substituents independently selected from R *; or (g) a cyclic b-ring system, consisting of a five or six membered heterocyclic ring, condensed with a phenol ring, the said ocheric ring containing up to two heteroatoms selected from the group consisting of -0-, -NR2 and -S (0) n-, optionally substituted with 1-3 substituents independently selected from R *; Zi is (a) - (CH2) P U (CH2) q -; (b) -0 (CH2) PCR5R6-; (o) -0 (CH2) PU (CH2) q -; (d) -0CHR2CHR3 -; or (e) SCHR2CHR3-: 0 is (a) -NR7R8; (b) where n is 0, i, or 2; rn is 1, 2 or 3 and Z is -HH-, -0-, -S- or -CH2 ~; optionally condensed in adjacent carbon atoms with one or two rings, optionally and independently substituted in the carbons with one to three their heirs, and optionally substituted independently in the nitrogen with a suitable chemically selected substituent of R '; or (c) a bi-cyclic amine containing five or twelve carbon atoms, bridged or condensed, and optionally substituted with 1-3 substituents selected from RA: o Z1 and G, combined, can be -OR w (a) -0H2- / (10-CH-OH-; (c) -0-; (d) -NR2-; (e) -S (0) B-; (f) -C0-; ) -CR2 (OH) -; (h) -00NR2-; (i) -NR2C0-; (J) O U -C - C-; R is hydrogen or Ci-Cß alkyl; R2 and R3 on independently (a) hydrogen or (tO aLiCiCi; R * is (a) h rogono; (b) halogen; (c) Ci-Ce alkyl; , (i) (alkyl Cj.-c.-4) thio; (g) (Ci-C-alkyl) sul finyl; (h) (Ci-C-alkyl) sulfonyl; () h hydroxyalk Ci -CA (J) ani-alkyl Ci -O4; (V) -OO2 H; (1) -NC; (rn) -C0NH0R; fn) - S02 HR; (o) -NH2; (p) (Cj-C4 alkyl) Mino; (q) di (C 1-4 alkyl) amino; (r) -NHS02R; (s) -NO2; () - plo or (?) -OH; ps Rß are independently Ci-Cs alkyl or, together, form a C3-C10 carbocyclic ring; R7 and Rß are independent of each other () fem Lo; (LO? N C3-C10 carbocyclic ring, saturated or insured; (c) a C3-C10 heroc ring containing up to two seloccio-regulated heteroatoms of -0-, -N- and -S-; ) H (e) to the cyclo Ci-C, or (f) for an R3 or R6 ring with a nitrogen-containing 3 to 8-membered ring, R7 and Rβ in a linear or ring form, can optionally be substituted with up to three substituents independently selected from C 1 -Ce alkyl, halogen, alkoxy, hydroxy and box 1: a ring formed by R 7 and Rβ may optionally be fused with a ring of a fungus; THE e is 0, 1 or 2; rn i 2 or -n is 0, 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; and isomers and geometries thereof; and salts by addition of non-toxic and pharmacologically acceptable acids, N-oxides and quaternary ammonium salts of the same. The preferred formula I compounds are those of fo mul where G is ÍL and R * is H, OH, F or Cl; y and E are independently selected from CH and M. Especially preferred compounds are cis-6- (-fl uorophen? l) -5-C4- (2-pipen di-l-yl-ethoxy) phen? ll-5,6 , 7, 8- etr hi roña ai en- 2- ol; (-) -c? s-6-feml-5-C4- (p? rrolidin-1-l-ethoxy) phenyl L] -5,6,7,8-tetrahydro-ftai en-2-ol; ci s-6- feru 1-5- [4- (2- p rrol? d? n-1-yl-ethoxy) feml] 5,6,7, 8-etrahydronaphtal en-2 ol; c? e-l ~ r6'- ?? Rhododinoethoxy - '- pyridyl] -2-ferul-b-hydroxy-, 2,3, -tetrah? drofnaphthalene; 1 - (4'-R-Rididomethoxy phenyl) -2- (4"-Fluoroferul) -b-H Drox I-1, 2, 3, -tetrahydroxyquinol? na c? s-6- (4-h drox? feml) -5-r - (2 -? pep nl-? l-ethoxy?) -fen? l] -5, 6, 7, 8- et rahidron f talen -2-ol and l- (4'-pyrrolidinoethoxy fe l) ~ 2-feml -6-h? drox? -1,2,3, 4-tetrah? droisoqumol i na.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods for inhibiting pathological conditions that are susceptible or partially susceptible to being inhibited by an estrogen, antiestrogen or estrogen agonist. These conditions include uterine cancer, breast cancer, breast disorders, male breast cancer, migraine, incontinence, vaginal atrophy, bladder infection, senile gmecornastia, diabetes, hypogemia, failure to heal wounds, inelastic, impotence, inflammatory bowel disease, central nervous system and gastrointestinal disorders caused by an excess of t aquiquamic, decreased libido, disorders of the system in unology, decreased fertility, hypertension, pulmonary disease, acne, seborrhea, autoimmune disease, íurner, hi rsutisino, disorders related to an excess of neuroq? mna and obsessive-compulsive disorders, including smoking and alcohol abuse. The changes in skin appearance and texture L increase age are proverbial and are well documented both quantitatively and qualitatively. It is a very subjective matter in its evaluation and in its final effects on individuals. By far, the effect of general atrophy of the skin with age is cosmetic, but it can have pathological consequences, many of which are of a psychological nature, namely, feeling of "old" feeling, depression, loss of sexual attraction, etc. In some cases, skin atrophy in older people may have direct pathologies associated with that, for example, the ability of the skin to recover when the wounds heal. In general, the atrophy of the skin is considered a normal and progressive consequence of the aging process and becomes "willing". Despite the normal acceptance of aging, there is a particular time in the life of women, namely, menopause, when the progressive form of aging is accelerated, especially in relation to the atrophy of the vagina and the skin. Often this rapid acceleration and abruptness of change is what can contribute to pathological and psychological stresses. Additionally, vaginal atrophy can cause discomfort, for example, itching, dryness and painful sexual intercourse, which can cause loss of sexual pleasure and conjugal harmony and can, in some cases, cause social consequences, such as divorce. As mentioned previously, the atrophy or aging of the skin may have both qualitative and quantitative aspects. The qualitative aspects are: change of the softness and texture, which causes a "rough" look and feel on the outer surface of the skin, change of the elasticity of the skin, which affects the mechanical properties of the skin, and changes in pigmentation «Je 1 A piel. These qualitative changes originate The commonly described condition of atrophied skin: wrinkled, rough, withered and run spots. Quantitatively, the aging of the skin in posttrnenopausal women can be measured by: a mutation of the itotic speed of small cells, changes of the dermal thickness, decrease of glucosamine noglucans and soluble collagen that are bound to the moisture content of the skin. The decrease in urinary excretion in the urinary excretion, a decrease in the renewal of col geno. The qualitative changes in the skin, that is, ugliness and mechanical properties, are the result of quantitative changes, that is, of the loss or change of the extracellular matrix components. Therefore, it is possible to evaluate a beneficial effect of a therapy for posttrnenopausal atrophy of the skin without relying entirely on subjective analysis, even though a subjective improvement may be the desired final effect. In the case of vaginal atrophy, whose quantitative aspect is the amount of vaginal moisture, which is controlled by the amount of secretion of skin glands, the qualitative result is subjective well-being. Currently, there are two main therapies for the treatment of vaginal and skin atrophy in postnenopausal women. The first therapy is essentially a cosmetic solution, for example, using makeup, skin moisturizers, night creams, vaginal lubricants, etc. Although this cosmetic therapy does not affect the underlying physiological cause of the atrophy, it often provides the individual with a subjective benefit. The second type of therapy involves the treatment of the underlying physiological causes with active medicinal agents, mainly vitamin A and estrogens. Vitamin A is used although its efficacy is controversial and it is known to have substantial undesirable side effects that limit its use. At the time of menopause, the levels of estrogen produced by the ovaries rapidly decrease. This decrease in estrogen has pronounced effects on the skin and vagina that cause a rapid acceleration in the process of atrophy. Oestrogen replacement therapy is often beneficial in treating vaginal and skin atrophy. However, estrogen replacement therapy has undesirable side effects, the most serious of which is the possibility of developing a cancer threat. The inclusion of progestogens causes undesirable psychological effects. The use of estrogen replacement therapy for the sole purpose of treating vaginal and skin atrophy is not common, due to negative side effects. Obviously, an effective and innocuous agent would be useful that positively affect the underlying physiology and thus improve the qualitative aspects of the vaginal and skin properties in posttrnenopaic women. Due to advances in medicine, along with education, both the quality and the duration of life have increased. As a result, the population, as a whole, lives longer. As such, they are being more numerous and recognize situations that had arisen, although not in large numbers. One of the situations that have arisen but to which it is possibly not given enough importance is sexuality in middle age. While it has always been thought that older people are unable to enjoy sexual activities, which is partly supported by a definite decline in sexuality in both sexes as people age, sexual activity among mature people can not be ignored. . Therefore, the problems associated with this activity can not be ignored either. While men, from the first and middle years, have a relatively constant decline in their sexual capacity and activity, the same can not be said convincingly of women. There are studies that a woman's sexual capacity does not change much until late in life. 1-K? Nsey A.C. et al., Sexual Behavior m the Human Fernale, Saunders, PO, p. 353 (1953)]. In particular, Libido decreases substantially in a considerable percentage of cases after menopause Cl-auptzen et al., Estrogen Therapy: The Benefits and Risks, Third Symposium on estrogen therapy, Geneva, October 20-21, 1977, Frontiere of Horrnone Research, vol. 5, pag. LO (1978) 1. This opinion is supported by Pfeiffer E. et al., Terminus of Sexual Behavior in Middle and Old Age, Journal of He American Gepatric Socioty, p. 2.151-2.158 (1972), and by Pfeiffer et al., Sexual Behavior m Hiddle Life, American Journal of Psychology, 128, 1262-1 267 (1972). In Pfeiffer's studies, there was a much greater deficit of activity as well as of sexual interest, among women aged 45 to 71 years, compared to men of the same age, and the most notable change took place between the 50 and 60 years of age, which is, of course, usually the period during which women suffer from menopause or are postmenopausal. In the age group of 66-71 years, 50% of women say they have little or no sexual interest, compared to 1.0% of men in the same age group. Although there is no direct relationship between decreasing levels of estrogen and decreasing sexuality, it has been claimed that hormonal changes after a natural menopause and certainly after a surgical menopause can contribute to sexual decline in some women . Ho knows exactly how menopause contributes to the loss of libido, although it seems quite evident CBancroft, Human Sex? Ality and its Problems, 2nd edition, p. 292-293 (1989)]. Therefore, it would be useful to find compounds that increase libido in posttrnenopausal women. Contraceptive methods involving the administration of chemical substances are very common among women who wish to limit pregnancies. These methods control fertility through various biological mechanisms. Among the chemical methods of fertility control currently used, the most important are those that act by means of the following mechanisms: (a) suppression of ovulation by inhibiting the release of gonadotropins; (b) alteration of the female reproductive tract to prevent the migration of sperm to the site of fermentation or, if this occurs, to block the implantation of the zygote (nesting); (c) expected action or (cl) an abortive agent.

Oral contraceptives are the most outstanding chemical contraceptive agents. Two types of agents are: (a) an estrogen combined with a progestin and (1: 0 a progestin alone.) The contraceptives of type conbmado act fundamentally suppressing ovulation by retroa1 Negative irnentacion that prevents the release of gonadotropins (luteinizing hormone and stimulating hormone of the follicle) by the hypothalamus, but alterations of the reproductive tract can also contribute to the anti-fertility effect, which include changes in the cervical ucus (which increase the difficulty of sperm migration) and in the endornetrium (which decrease the possibility The action of a progestin alone in a very low oral dose ("rninipi Idora") seems to imply fundamental in alterations in the female reproductive tract but suppression of ovulation may occur, although oral contraceptives are very effective , its use is associated with unpleasant side effects (co nausea, depression, weight gain and headache) and a greater prolonged risk of serious diseases (such as trornboemboli srno, collapse, myocardial infarction, hepatic adenoma, gallbladder disease, and hypertension). Irregular and irregular irregularities are also frequent (such as hemorrhage advancement, irregular bleeding and amenorrhea). A progestin, when administered alone, causes a higher incidence of menstrual changes, especially a marked increase in L9. amount and duration of menstrual bleeding. Other chemical methods of anti-perception include l < ? administration, after sexual intercourse, of estrogen (for example, dietele ibest rol, antiprogest mas or etilest radiol) to prevent nesting or prostaglandies that act as abortive agents. Both are currently limited to emergency situations. Also in the very early stages of development, there are immunological methods (vaccination) and methods that involve direct control of the secretion of luteinizing hormone releasing hormone (LHRH) from the pituitary, by LHRH agonists or antagonists. Another group of chemical contraceptive agents are Local spermicides, such as monoxinol or octoxinol, which are placed in the vagina and mediately before intercourse in the form of creams, foams, gels or suppositories. The spermic action takes place in the vagina or in any other part of the reproductive tract. For this action to occur, the sperm agent is absorbed into sperm membranes or is transported to the uterus under the influence of uterine actions. The methods used are not completely reliable to avoid pregnancy and are uncomfortable to use. Therefore, it is evident that the methods of contraception currently available are inadequate for various reasons. Although many women practice contraception despite these inadequacies, there is a need in medicine for new methods.

I pulmonary hypertension r-epresents a serious and threatening spectrum of the outward, diseases of multiple etiology. These include free abnormalities of the lungs, thorax and diaphragm, valvular or congenital myocardial or acquired diseases and obstructive diseases of the lungs, and can be a complication of autoimmune diseases, vasculitis and collagen-based diseases (Rubin, Chest., 104: 236, 1993). Patients with pulmonary hypertension frequently present symptoms that include dyspnea, fatigue, syncope and chest pain, and have a higher pulmonary arterial pressure and show prominence of the main pulmonary arteries, enlargement of the vessels and peripheral vessels of smaller size in chest x-rays (RLch, Ann. I-nterna.] Med., 107: 216, 1987). Although pulmonary hypertension has multiple etiologies, primary pulmonary hypertension seems to involve an autoimmune component and has been considered a complication in patients with combined connective tissue diseases, reurnatoid arthritis, Sjogren's syndrome, systemic sclerosis, and Lupus (Sato, Hurn. Pa h, 24: 199, 1993).

Primary pulmonary hypertension is 1.7 times more frequent in women than in men, being more prevalent between the third and fourth decades of life (Rich, Flnn, Internal, Med., 107: 216, 1987). the higher incidence of primary pulmonary hypertension in women of childbearing age as well as the clinical observations that the disease may be exacerbated by pregnancy and by oral contraceptives (Ni 11 er-, flnn., Rheum.?, 46: 159 , 1987, and citations in Farhat et al., 1. PEÍ., 261: 686, 1992) suggest a role for estrogens in the disease process, in this respect, Farhat et al. have shown that estradiol potentiates the vasopressor response to an irnetico of thromboxane in rat per-fused lungs (J. PET, 261: 686, 1992). However, the role of estrogens in pulmonary hypertension is complex and may depend on the efioLogí of the disease process. In rat model of pulmonary hypertension induced by injection of rnonocrotal pyrethrol (Remclel, Tax. Flppl. Pharm., 106; 179, 1990) progressive pulmonary hypertension becomes evident, right ventricular hypertrophy and interstitial edema around the large air passages and blood vessels, similar to the pathology observed in man. Treatment with estradiol decreased right ventricular hypertrophy and prevented interstitial edema in this model (Farhat et al., Br. J. Pharrn 110: 719, 1993) thus attenuated the poxica vasoconstrictor response in isolated sheep lungs. (on et al., J. Flppl-Physiol., 61: 2,116, 1986). Current therapy for pulmonary hypertension is inadequate and depends largely on the use of vasodilators, diuretics and anticoagulants (Rubin, Drugs, 43: 37, 1992, Palevsl-y, JAMA, 265: 1014, 1991). Vasodilators are effective only in a subpopulation of patients with primary pulmonary hypertension and are complicated by hypotensive responses: > sisternicas Also, limited infusion of prostate and calcium channel biociders have been used at high doses. In patients who do not respond to a vasodilator therapy, a heart-lung transplant and a 5-lung transplant have been used alone; However, due to surgical comfort and mortality, this solution is usually limited to patients who continue to deteriorate despite aggressive therapy in centers specialized in the treatment of this disease. Patients frequently die of heart collapse The right and individuals who have signs of right heart collapse have an average survival of 6-12 months (Rubin, Drugs, 43: 37, 1992). Therefore, pulmonary hypertensive diseases are characterized by inadequate therapies, need of organ transplants and wing prognosis, and there is a need for new therapies. Acne and seborrhea are two general classes of skin diseases that are characterized by an abnormal function (usually, hractivity) of the sebaceous glands. of the skin. The object of this invention is the use of compounds that inhibit acne and seborrhea. Acne vulgaris is a disease of the pilosebaceous unit of the skin and is chronic and inflammatory in nature. It is caratepza by comedones (pimples), n i p pulas, pustules, cysts and nodules. The areas of the body more commonly affected by the disease are those that have the largest part of the sebaceous glands, namely, the car, neck, back and chest. Acne is a very common disease in both men and women and usually appears at the onset of puberty. Although the disease is only mild and resolves itself when the majority of people reach their twenties, in many cases it can be disfiguring and the origin of great isiological tensions. In some extreme cases, acne can be the source of serious infection and even threaten to go. The etiology and pathogenesis of the disease begins with cohesive hyperkeratis in which the corneous cells adhere and block the follicular canal between the pigeon pea and the surface of the skin. The sebaceous pigeons under hormonal control (osterone testosterone and dihydrotestosterone) are stimulated to enlarge and to produce increasing amounts of sebaceous secretions (mainly in the form of tpacylglycerols). These sebaceous secretions become trapped in the blocked follicular canal and accumulate forming a closed comedo. In this phase, common bacteria and that develop on the skin (mainly Prop oni bacten urn flches) begin rnetabol zar-Ios tpacilgl iceroles to free fatty acids. Released fatty acids are inflammatory and cause the formation of a pimple. This papule, on the other hand, rises and is the result of an inflammatory lesion, that is, red, edematous and painful. The papule can continue to expand and break the par-ed of the follicle, thus forming a pustule or cyst. The pustular phase 2? It is very painful and unsightly and is often the site of a secondary infection by other bacteria, such as Lococos ostafi. Pustules and cysts often cause scars and disfigurements seen in severe cases of c. Several drugs are available for the treatment of acne. In mild cases, benzoyl peroxide is used and is often moderately effective. It is believed that benzoyl peroxide acts by inhibiting cohesive hyperkeratosis and eliminating P. flcnes and, although benzoyl peroxide is effective in mild cases of acne, it suffers from several drawbacks: first, it must be applied topically and does not always penetrate the pilosebaceous unit where the acne lesion begins; Second, it can cause skin irritation that can exacerbate the disease. Another moderately effective drug is vitamin fl (retinoic acid, retino) that is used topically. Vitamin fl inhibits cohesive hyperskeratosis; however, as it is a topical preparation, it suffers from some of the same disadvantages as benzoyl peroxide and can also cause a deterioration of the protective corneum etratum-if used extensively. Also another group > or drugs commonly used in the treatment of acne are atiobiotic. These can be used topically or systematically. The most commonly used antibiotics are tet raciclinae and eritrornicin and, to a lesser extent, nycinicline, arnpicillin, clinacin, trirnetopri and sulfa ethoxazole. These antiobiotics inhibit P.

') K Ac é and other secondary bacterial infections. There are two main advantages in the prolonged use of antiobiotic for acne: first, continued prolonged exposure to antiobiotics often results in the formation of resistant bacterial strains both in the skin and systemically, and second, the continued use of Antibiotics may cause sensitization of the patient to the antibiotic. A newer brand name used for acne is isotretmomo (flccutane, acid 13 - (- i - 1 ethmoxy) This drug acts like vitamin F, however, it can be used systemically. Isotretinoin is often: chelitis, increased serum ppg in serum, high sedimentation rates and, most importantly, isotretinoin is teratogenic in humans and therefore can not be used if there is a possibility of pregnancy During the treatment, all the drugs mentioned above have some positive effect on the acne treatment but each one has its side effects that limit it.An hormonal therapy is also effective for acne triage in women. the administration of estrogens has a positive effect in the treatment of acne. The estrogens counteract the effect of endogenous androgens and, therefore, decrease sebaceous excretion, however, since the administration of estrogen s alone in women with uterus, raises the possibility of endornetpal cancer development, a cyclic estrogen therapy and a progestin is used for the treatment of acne. Typically, for the treatment of acne, women are prescribed normal birth control protocols. Although these protocols are often effective for acne, in many cases these regimens contain progenetics that have significant androgenic activity. This androgenic activity exacerbates the disease. Finally, it is well known that progestogens are caused by many negative psychological side effects. Obviously, a better hormonal agent will be beneficial. Seborrhea or seborrheic dermatitis is another group of skin diseases that are believed to be associated with abnormal function of the sebaceous glands. It occurs in areas where there is a large number of sebaceous glands and is characterized by the formation of blisters and slightly inflammatory red patches. Seborrhea is more common in the hair (a form of dandruff), margins of the scalp, eyebrows, nasolabial folds, channels «Jel external ear, atrial-posterior fold and pre-ernal area. Generally, mild seborrhea is controlled by topical medication, co or a glucocorticoid and LDH on Nivea oil. However, the more serious cases are more difficult to manage. There are vain conditions in which the ovaries do not develop and, in consequence, puberty does not occur. Gonadal dysgenesis causes a serious disease state, known as Turner syndrome, resulting from the absence of a second sex chromosome (onosynia of the X chromosome). The syndrome is associated with the female phenotype, height, sexual infantilism and various somatic abnormalities. In these patients typical vain characteristics are observed, 5 including different facial features, square chest and short neck with a canvas appearance. Additional abnormalities include C? Bitus valgus, Imfederna freezing of feet and hands, renal abnormalities, very arched palate, skeletal abnormalities, pigmented spots on the skin, formation of keloid LO, abnormal nails and recurrent otitis media. Cardiovascular abnormalities include aortic bicuspid valves, partial anomalous poisonous drainage, and hypoplastic syndrome on the left side of the heart [Mil ler M.3. et al., 3. Pedia r., 102: 47-50 (1983); Mazzant I. et al. , Helv Paed atr. Fleta, 43: 25-31 (1968), and Van Egrnond H. et al., Br.

He has 3, 60: 69-1 1 1988). Renal abnormalities include rotation of the kidney, kidney in horseshoe shape, duplication of the renal pelvis and ureter, and hydronephrosis secondary to urethral obstruction. 20 The maturation of the skeleton is normal or slightly delayed in childhood, but delayed in adolescence as a result of a gonadal steroid deficiency. Typically, an aspect of fishing net caused by localized rarefactions is caused. There is a reduction of : > < content of mineral substance in the bones as early as 8 years of age, as well as later in the purge. Changes in the spine, vertebral hypoplasia, and scoliosis are also common. Abnormalities of the carpus, wrist, knee and pelvis are also observed. The short stature, including the delay in uterine development, is not evident until after 3 years of age, after which the rate of growth -fPar- decreases appreciably. E. et al., Pedia * r. Res. 17: 1-7 (1983), and Lyon A. 3. et al., Flrch. Dis. Child , 60: 932-935 (1985) 1. In general, patients suffer from sexual infantilism being immature the genital ducts and external genitalia. As a result, ovarian development is delayed. Current therapy is aimed at correcting height and somatic abnormalities and inducing secondary sexual characteristics. Recent data indicate that hormonal growth is a viable therapy to improve the stature of TRosenfeld R.G. et al., 3. Pediatr., 113: 393 (1988) 3.

Patients not treated with estrogen often develop severe osteoporosis similar to that experienced by women after menopause. Fractures and vertebral collapse are common. A therapy with steroid hormones is usually postponed until after 15 years of age because it is believed that treatment at an earlier age may lead to premature maturation of the skeleton and, therefore, a decrease in height. In fact, pharmacological doses of estrogens can accelerate bone maturation and cause a physical epileptic fusion at an early age, without concomitant increases in height. Other studies have shown that low doses of estrogens allow patients to develop the thorax without causing changes in the tumor [fllexancler R.L. et al., Clin. Res, 26: 174A (1978) 1. However, other studies indicate a series of cases of endornetpal cancer in patients with gonadal dysgenesis, as a result of estrogen therapy fLovine LS, Pediatpcs, 62: Given the adverse side effects of eetrogens in patients with Turner syndrome , there is a need for a bone preservative agent that has no significant uterine rhetorical consequences. In the United States, one in four women require medical attention for breast or breast cancer. Although much more rarely, men also have breast disorders. Such disorders include galactorrhea, g ecornastia, hypertrophy, polyelia, rhostomnia / astalgia, hyperprolactinemia, and generally non-fibrocystic and non-cancerous mastopathies. Breast pain is common and it is estimated that it occurs in 50% of women. Normally the etiology is not clear. Discomforts are generally classified as (1) cyclic rheumatism or asymptonia that occurs immediately before menses, (2) changes in the ma, a, or ectasia of the sclerosing ducts and andenosis or (3) pain called costochondrosis.

The gynecysia is an enlargement of the tissue of the mammary glands in man (analogous in women, hypertrophy). This enlargement is located in the areolae and may be unilateral or more commonly bilateral. The condition is usually benign in nature; However, it can be the source of serious psychological disorders in the patient. Gmecornas is commonly found in men at the time of puberty, but it can happen at any age. The gmecornastia can have many underlying causes, for example, Klinefel er syndrome (chronic abnormality ica XXY), liver disorders, estrogen therapy for prostatic carcinoma, tumors of various endocrine organs and certain drugs (digitalis and Dilantm). The common relationship between all these causes and the resulting gynecornastia is the production of abnormal amounts of estrogen. Currently, the treatment of this disease is limited to three therapies: 1) determination and love of the underlying cause, 2) surgical removal of breast tissue and 3) treatment with ilbestrol and with rations. The determination and treatment of the underlying cause of ecomastia is not always possible. Surgery and treatment with d and ilestilbest rol and with radiations is not always successful, and involves a large cost and risk. Evidently, it is an effective and innocuous therapy. Gaiactorrhea is the production of milk in men or women, not immediately associated with pregnancy. The very appropriate and rare response in the man's breast is accompanied by severe psychological distress for the male patient. It is caused by an excessive production of estrogen and prolactum. Surgical treatment is usually the therapy of choice if the underlying cause can not be determined or treated. It would be useful a more innocuous and less expensive therapy. Diabetes inellitus is a systemic disease characterized by disorders in the actions of insulin and other regulating hormones in the metabolism of carbohydrates, fats and proteins and in the structure and function of blood vessels. The main symptom of diabetes is hyperglucernia, often accompanied by glucosupa (presence of large amounts of glucose in the urine) and polyuria (excretion of large volumes of urine). In chronic or long-term diabetes, additional symptoms arise. These symptoms include degeneration of the walls of blood vessels. Although these vascular changes affect many different organs, it seems that the nerves, or os and kidneys, are the most susceptible. As such, long-term diabetes mellitus, even when treated with insulin, is a cause that leads to blindness. There are two types of diabetes admitted. Type I diabetes is juvenile onset, prone to ketosis, develops early in life with much more severe symptoms and has an almost certain prospect of subsequent vascular involvement. The role of this type of diabetes is difficult and I require the administration of exogenous insulin. Type 1T diabetes mellitus is an adult onset, resistant to ketosis, develops later in life, is milder, and has a beginning onset. One of the most significant advances in the history of medicine came in 1922, when Banting and Best demonstrated the therapeutic effects of insulin in diabetic dogs. However, even now, a clear picture of the basic biochemical defects of the disease is not known and diabetes remains a serious health problem. It is believed that two percent of the population of the United States is affected by some form of dibs. The introduction of orally effective hypoglycemic agents was an important development in the treatment of hyperglycemia. Oral hypoglycemic agents are usually used in the treatment of adult iabetes. Observations in animal models on the metabolism of glucose in TT-type diabetes and in humans suggest that sex steroids play a permissive role in the phenotypic expression of hyperglycemia. These observations have prompted studies about the effects of androgens and estrogens on blood glucose levels. The administration of testosterone to female rats ovar-i ectomized or intact originated a marked resistance to insulin, which was related to morphological changes in the muscles [Holmang et al., flm. "3. Physiol., 259, E555-560 (1990) and Holrnang et:., Flm 3. Physiol 262, E851-855 (1992) 1. Ln diabetic rats by streptozotocin administration, implanted testosterone antagon zo ability of residual insulin to maintain a glycemic control (Le et al., Fndocrinology, 116, 2450-2455). In contrast, glycosuria disappeared in castrated diabetic KK mice and reappeared when: e androgenos were replenished in these mice TNonaka pi al., Jpn. 3. Vet .. Sci. , 50, 1121-1123 (1988), and Higu chi et al., Exp. Fln rn. , 38, 25-29 (1989) 1. The results of the administration of estrogens also support the hypothesis that the balance between androgens and estrogens is critical for the development of hyperglucernia. The daily administration of radiol to diabetic KK mice normalized the levels of glucose in the blood and eliminated the glucosupa [Toshiro et al., 3pn. 3. Vet. Sci., 51, 023-825 (1989) 1. Estradiol also reduced gLucose levels in the blood of mice C57BL / 63-ob / ob rDubuc, Pro ce. Soc. Exp. B ol. Med., 180, 468-473 (1985) 1 and of C57BL7Ks3-db / db mice [Garrís, Anatómica! Record, 225, 310-317 (1989) 3. In climacteric women, anxiety, depression, tension and irritability arise during the pepmenopause and can be related to the reduction of estrogen levels, and for the treatment of these symptoms, estrogen replacement therapy has been recommended. Malleal 3., Lancet, 2 : 158 (1953), and Wilson et al., 3. fln. Genatnc Soc. Il: 347 (1963) 1. In this case, the mechanism of protective effects of estrogens is not known, but they may be related to the potential effects of estrogens on biogenic amines such as the serotype Tflyl ard M., Int. Res.

Communications System Med. Sci. , 1: 30 (1973) 1. In this respect, circulating serotonin is reduced in post-mortem women? yes cas [Gonzalos G. et al., Matu ritas, 17: 23-29 (1993) 1 and serotomna (as well as between vain biogenic amines) have an assumed role in depression of behavior. Phillips and Sher in rPsychoneuroendocpnology, 17: 485-495 (1992) 1 indicated that in surgically enpapausal women, who were admitted to be estrogens, the results of immediate and delayed call trials are greater than in women similar to those who do not. estrogens were administered. Two potential hypotheses could explain this effect. There is evidence that partial estrogen (or antiestrogen) agons, such as tanoxifene, interact with the rnuscapnico receptor fBen-Baruch G. et al., Molec. Pharmacol., 21: 287-293 (1982) 1 and it is known that rnuscarinic agonists (2) produce positive effects in a number of functions associated with memory and may have clinical relevance in Alzheimer's disease. - Interesting possibility may be linked to neurochemicals, such as substance P, which is known to have neurotrophic effects as well as memory promoter [Thoenen H., Trends in Meuroscience, 14: 165-170 (1991), and Huston 3. ef al., Neuroscí, Biobehav. Rev., 13: 171-180 (1989) 1; thus, through an effect on a neurotransformer of the central nervous system or on a neuropeptide receptor, a tissue-selective estrogen agonist / antagonist can produce effects that improve memory and consciousness. Such activity could be more -varied in the most relevant way in man, although a variety of animal models are available (for example, orientation in a labyrinth, extinction, etc.) for preclinical trials. Perhaps the most frequent problem related to the central nervous system in climacteric women is the existence of hot flashes. While this is undoubtedly an LCO sornat effect mediated by effects on the cro-vascular system, current evidence strongly points in the direction of effect initiated in the central nervous system TLornax P. et < --0. , Ph rmac. Ther. , 57: 347-358 (1993) 1. Therefore, a tissue-selective estrogen agonist / antagonist can offer the ideal therapy that provides the desired effect in the absence of adverse side effects in the reproductive tissue. Obsessive-compulsive disorders are one of the most rare psychiatric diseases, although in a sixth of the population probably minor obsessive symptoms occur (Encyclopedia of Medicine, American Medical Association; Current Diagnosis, l.B. Saunders Company, 1985). They are characterized by one or both of two symptoms. The first comprises meditative, intruder and recurrent thoughts that the. The patient may realize they have no sense but can not stop thinking about them. The most common of these are thoughts of violence, contagion, doubt or personal illness. Normally, the patient does not believe that these thoughts are true reflections of reality. However, some patients are convinced that their obsessive meditations are true and suffer from psychic allutions. The second one I understand repetitive ritual behaviors that the patient recognizes are unnecessary but that he can not stop doing. Examples of such rituals are hand washing, counting, checking rituals and touching rituals. The performance of the ritual is not constant but fluctuates and reflects levels of anxiety. Normally there is an intense feeling of panic and anxiety if the patient is prevented from performing a ritual. While depressed, an examination of the history of obsessive-compulsive patients usually reveals that obsessions and compulsions precede the onset of states of mood dysfunction and that depressed feelings are related to the impact that compulsive obsessive behavior has on life. In severe cases, the patient will become incapacitated, completely dejected by the distraction of constant obsessive meditations or by the need to complete endless compulsive rituals. Consuming disorders include disorders in which the intake, usually oral, of an amount of a substance is outside a normal range, often to an extent where it harms health. Examples of these are appetite or corner disorders (obesity, bulimia, pica, anorexia nervosa, and psychogenic meditation) and abuse or overuse of some substances (smoking, nicotine dependence, alcoholism, alcohol abuse). It is well known that the chronic administration of nicotine causes tolerance and, finally, dependence. The use of tobacco is extremely widespread in all countries, despite the well-known adverse effects of tobacco use in all its forms. Thus, it is evident that the use of tobacco creates a lot of habit, if it is not addictive, and that its use provides sensations to the user that are pleasant and pleasant, even though the user is fully aware of the drastic effect in the long term harmful use. Cigarette smoking is the most dominant cause of preventable morbidity and premature death in developed countries. In the meantime, smokers die several years earlier than nonsmokers and have an increased risk of fatal heart failure, lung cancer, cancers of the mouth, throat, esophagus, pancreas, pneumonia, bladder and cervix, peptic ulcers and fractures of hip, wrist and vertebrae. Smell and taste are diminished in smokers and facial wrinkles are increased. Diabetic patients who smoke may have an increased risk of proteinupa. The cessation of smoking provides benefits, even late in life, such as reduction of the risk of death or myocardial infarction, in people with diseases of the coronary arteries, reduction in the progress of carotid atherosclerosis and reversal of chronic bronchitis. Children of people who smoke have lower birth weight, more frequent respiratory infections, less efficient lung function and a higher incidence of chronic ear infections than children of non-smokers, and it seems that it is more possible for them to be smokers themselves. It has been indicated that passive exposure to humans increases the risk of cervical cancer, lung cancer and heart disease and that it favors endothelial damage and platelet aggregation. Recently, vigorous campaigns against tobacco use have taken place and it is now common knowledge that quitting smoking leads to numerous unpleasant symptoms, which include rritability, anxiety, restlessness, lack of concentration, dizziness, insomnia, tremors, increased appetite and weight gain and, of course, a desire to smoke. Alcohol abuse and alcohol dependence (ie, alcoholism) are serious public health problems of modern society. In the United States alone, it is estimated that 13 million adults have symptoms of alcohol dependence due to excessive alcohol intake and about 7 million more abuse alcohol, without showing symptoms of dependency, according to projections by the government of the States. United from studies conducted in the mid-80s. The dependence and abuse of alcohol are very expensive because it is estimated that in the United States cost more than 200 billion dollars in 1991 without any prospect of falling or decreasing. The social and psychological damages caused to individuals as a consequence of alcohol abuse are immense, for example, children born with fetal alcohol syndrome (FAS) and victims of accidental deaths, homicides and suicides related to alcohol. While it is generally accepted that alcoholism and alcohol abuse are affiliations with astounding international psychological, medical, social and economic repercussions, avoiding or otherwise successfully improving the consequences of these problems has been a difficult goal to achieve. Only very recently, the public view that alcoholism and alcohol abuse can be remedied only by moral imperatives has been changed by including the consideration of alcoholism and alcohol abuse as physiological aberrations whose etiology can be understood and for which they can be understood. find a therapy through scientific monitoring. Both abuse and dependence on alcohol arise as a result of different, complex and incompletely understood processes. In the present, research on alcohol is in the mainstream of scientific endeavors. This invention provides methods for inhibiting consumptive and obsessive-compulsive disorders. Hirsutis or (hypertrichosis) is characterized by excessive hair growth. In women, hirsutis refers specifically to overgrowth of the uterus with a male configuration and distribution. Clinically, hirsutism in women is seen as a growth of terminal hair on the face (particularly on the upper lip), bar-billa, chest, back, and lower abdomen (shield). This hair growth is often unpleasant and can be a cause of embarrassment and psychological tension. Hirsutism commonly occurs in menopause although it can occur at any time after puberty. The etiology of this condition has been associated with an excessive production of androgens by the ovaries or by adrenal glands or both. Hirsutism in women can be treated in different ways. A cosmetic treatment of the condition, including shaving, plucked from the hairs and bleached, although effective to improve the appearance of the patient, is only palliative and must be reapplied constantly. Loyal glucocorf steroils are often effective; however, they have the potential for serious side effects, such as Cushing's syndrome. The oral iconceptives can be effective; However, care must be taken because certain progestins used in oral contraceptive regimens may actually contribute to hypertrism because of their androgenic side effects. The olirnetidine and espironolacfona have shown some effectiveness in the treatment of hirsutis; however, each of these may have unwanted side effects. And ideally, it would be a better tolerated agent and more effective. Alopecia (hair loss) can occur in women for various reasons. Female model alopecia is characterized by a chronic and progressive loss of hair, which often begins around the age of thirty and accelerates during menopause. Hair loss is limited to the central scalp in a diffuse pattern. This loss of hair is cosmetically detrimental and often psychologically upsets the patient. The etiology of this condition has been associated with a high level of androgens and the consequent exposure of androgen-sensitive cell follicles.The treatment of the condition is mainly of a cosmetic nature, for example, wigs, hairstyles that cover the affected area, etc. The spironolactone drug has been used but they have secondary effects, obviously, it would be an effective treatment for this condition.The nacrofagos play a central role in the defense of the host against various effector mechanisms that involve both related facts. with the membrane as secretors (Gordon et al., Curr. Opm. Irnmunol, 4, 25, 1992, and Filer, Brit. Med. 3. 48, 55, 1992.) Phagocytosis, quototaxis and antigen presentation. genos are membrane-related processes involved in the immune defense mechanisms necessary for the survival of the host.The importance of the tuktophages in the defense against microbes, control unites, destruction of tumoral cells and in the filtration of senescent erythrocytes has been documented in human and animal models characterized by the selective elimination of macrophages (Claassen et al., OLInmunol. Meth. , 134, 153, 1990). Macrophages also contribute to the defense of the host by secretion of bacteriocidal and bactericidal proteins, lipid mediators and eitoquinas, as well as reactive intermediates to oxygen and nitrogen. The secretory capacity of macrophages is central to their function because these cells secrete more than LOO distinctive mediators and are localized in all organs (Nathan, 3. Clin Tnvest .. 79, 319, 1987). Although the aberrant activity of macrofunctional functions is associated with autoimmune diseases as well as with chronic and inflammatory processes, the inverse condition, suppression of effector functions of the macrophages, is associated with recurrent infections of both opportunistic and non-opportunistic pathogens. and contributes to higher morbidity and mortality. Populations associated with an immunocompromised state include burned patients, transplant patients, affected individuals of HTV (human deficiency virus), cancer patients undergoing chemotherapy and surgical patients, notably those at higher risk. of infection, such as observed in thoracic-abdominal patients. Current therapeutic solutions for these patients include the use of intravenous infusion of macrophages derived from cytokines, notably the colony stimulating factors G-CSF, GM-CSF and M-CSF (Nemunaitis, Transfusion, 33:70, 1993). has used supportive therapy with antibiotics and fluids; However, the limitations of these solutions are demonstrated by the continuing problems of infection in immunocompromised patients and by the appearance of deadly strains of organisms resistant to antiobiotics. In addition, infections of immuno-compromised patients caused by opportunistic pathogens, including infections caused by necrotics and ctococci, continue to be important and cause complications despite protocols with various antiobiotics. Evidently, new therapies that can selectively activate effector functions of macrophages to increase host defenses play a central role in the clinical management of these patients. Estrogens have been shown to increase effector functions of macrophages, including Fc-mediated phagocytosis, expression of class II antigens and secretion of terleukin 1. These observations together with the known propensity of women to be more resistant to various infections (flh ed et al., flm 3. Path., 121, 531, 1985) suggest that estrogen-like compounds can increase effector functions of the acrotaggs, and thus be more beneficial in disease states associated with lower immune defenses. host, co or bladder infections or poor wound healing. The term "inhibit" is defined to include its generally accepted meaning, which includes prophylactically treating a patient to prevent one or more of these disease states from occurring, observing the symptoms of said state of illness and / or treating said symptoms. Therefore, the present methods include both therapeutic and prophylactic medical treatment, as appropriate. The methods of this invention are practiced by administering an effective amount of a compound of formula I to an individual in need of treatment. In the commonly-owned United States patent application serial number 08 / 369,054, incorporated herein by reference, it is disclosed that the formula I compounds are effective in the treatment of prostate diseases, breast cancer. , osteoporosis, endomet riosis, cardiovascular diseases and hypercholeeterolernia. The terms chloroalkyl Ci-C3 and fluoroalkyl C-C3 include methyl, ethyl, propane and isopropyl substituted to any desired degree with chlorine or fluorine atoms, from one atom to full substitution. The term cycloalkyl Cs -C7 includes cyclopent 1 lo. Halogen means chlorine, bromine, iodine and fluorine. flril? (Ar) includes phenyl and naphthyl, optionally substituted with one to three substituents, independently selected from R * defined above. DTT means dithiothreitol. DMSO means dirnet1 Ísulfox gone. EDTA means acid ot ilendiapu notet raa < or 1 co. Oestrogen agonists are defined herein as chemical compounds capable of binding to estrogen receptor sites in mammalian tissues, and mimic the actions of estrogens in one or more tissues.An expert in the art should recognize that certain substitutes are related. in this invention it may be chemically incompatible with other substituents, or with the heteroatoms of the compounds, and these incompatibilities should be avoided when selecting compounds of this invention.

Likewise, certain functional groups may require protective groups during synthesis procedures, which the chemist of ordinary skill should recognize. A chemist of ordinary skill should recognize that certain compounds of this invention will contain atoms which may be in a particular optical or geometrical configuration. All these isomers are included in this invention; isomeric isomers are preferred in cis configuration. Likewise, a chemist should recognize that various pharmaceutically acceptable esters and salts can be prepared from certain compounds of this invention. All these esters and salts are included in this invention. The remedies for the conditions and diseases, which are used in the methods of this invention, can be prepared by the procedures commonly employed using conventional organic or inorganic additives, such as an excipient (eg, sucrose, starch, amtoi, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate or calcium carbonate), a binder (for example, cellulose, ethylcellulose, hydroxyethylcellulose, polypropylpyrrole idone, polyvinyl pyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), a disintegrant (e.g., starch, carboxynet icelulose, hydroxypropyl lnidon, hydroxypropylcellulose3 little substituted, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (eg, magnesium stearate, light anhydrous silicic acid, talc or sodium lauplsulfate), a flavoring agent (eg, citric acid, rnentol, glycine or orange powder), a preservative (eg, sodium benzonate, bisulfite) or sodium, ethylparaben or propyl paraben), a stabilizer (for example, citric acid, sodium citrate or acetic acid), a suspending agent (for example, methicellulose, polyvinylidene rrolidone or aluminum stearate), a dispersing agent (for example , hydroxypropylmethylcellulose), a diluent (e.g., water) and a base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The amount of the active ingredient in the medicinal composition can be at a level that produces the desired therapeutic effect; for example, from approximately 0.1 mg to approximately 50 mg in unit dosage, for both oral and patent administration. The active ingredient can usually be administered to a human patient once or four times a day, with a unit dosage of 0.1 to 50 mg, but the above dosage can be appropriately varied, depending on the age, body weight and medical condition of the patient. patient and the type of administration. In human patients, a preferred dose is 0.25 ing at 25 rng. One dose per day is preferred. The compounds used in the methods of the invention are easily prepared by the reactions illustrated in the following schemes. Certain compounds of formula I are conveniently prepared from a hydrated intermediate by hydrogenation with a noble metal «-or catalyst, in a solvent inert to the reaction. The pressure and temperature are not critical and the hydrogenation is normally carried out in a few hours, at room temperature and at a hydrogen pressure of 138-552 kPa. The hydrogenated product is isolated and purified if desired, and the ether group is broken with an acid catalyst in a solvent inert to the reaction and at a temperature between 0 and 100 ° C, depending on the acid catalyst used. It has been found that hydrogen bromide at elevated temperatures and boron tbromide from 0 ° C to room temperature are effective for this reaction. The product of formula T is isolated and purified by P ro ce d i rn i n t or s are given. Intermediates of formula TI, wherein A is CH2, and B, D and E are CH, are described in US Pat. No. 3,274,213; 3. Med. Chem., 10, 78 (1967); 3. Med. Che., 10, 138 (1967) and 3. Med. Chem., L2, 881 (1969), the descriptions of which are incorporated herein by reference. They can also be prepared by procedures described below. The preparation of the compounds of formula I in which e = a, A-CH2, 7? = OCH2 CH2, G = cycloalkyla ine and B = CH is shown in scheme 1. Compounds 1-2 in which D and E are CH are prepared by alq? 4-brornophenol with the corresponding N-cl oroeti lamina, using potassium carbonate as the base, in a rotating solvent such as Dirneti Ifor amide, at elevated temperatures. A preferred temperature is 100 ° C. Compounds 1-2 in which C or E, or both, with N are synthesized using a nucleophilic displacement reaction, carried out on dibromides (ll), using hydroxyl cycloalkyl in phase transfer conditions, to give bronoainmas (1-2) [Synthesis, 7_7, 573 (1980) 1. After a halogeno-metal exchange using n-butyllithium, the bromoarnmas (1-2) give the corresponding lithium or magnesium reagents, which are allowed to react with 6-rnetoxy-1-ethyl ralone at low temperature, preferrably in the presence of oesium chloride (without cesium chloride, the reaction also occurs), to give carbinols (1-3) or styrenes (1-4), after an acid work-up. The treatment of carbinoles (1-3) or styrenes (1-4) with a brominating agent, such as pindinium bromide perbrornide, gives bromoesti reindeers (1-5). The heteroalkyl zinc chlorides or the heteroaplboronic acids, react with the bromides (1-5) in the presence of palladium metal catalysts, such as tet rak istrienyl phosphinopaladium (0), to give diaplestirenes fifi) CPure P < Applied Chern., 63., 419 (1991) and BuLL. Chern. Soc. 3? N, 61., 3,008-3,010 (1988) 1. To prepare the preferred compounds, substituted pheniizine chlorides or substituted phenylboromatic acids are used in this reaction. The anzzinc chlorides are prepared by abruptly inactivating the corresponding lithium reagent with anhydrous zinc chloride. The free acids, which can not be acquired coinerially, are prepared by abruptly activating the corresponding arylidene reagent with a basic borate, followed by aqueous acid preparation [Acta Chernnica Sean., 4_7, 221-230 (1993) 1. Lithium reagents that can not be purchased are prepared by halogen-metal exchange of the corresponding bromide or halide with n-butyl- or tert-butyl-lithium. Alternatively, the lithium reagent is prepared by lithiations facilitated by heteroatoms, as described in Organic Reactions, volume 27, chapter 1. t catalytic hydrogenation of the compound lh, for example, in the presence of palladium hydroxide on carbon, gives the corresponding dihydroethoxylated intermediates which are subsequently demethylated using boron tbromide in methylene chloride at 0 ° C or hydrogen bromide of 48% in acetic acid at B0-100 ° C, to give objective structures (1-7). These compounds are racernic and can be resolved in the enantiomers by high pressure liquid chromatography using a column with a stationary quiral phase, such as Chiracel OD columns. Alternatively, optical resolution can be performed by recrystallization of the diastereomeric salts formed, with optically pure acids, as 1,1 '-b? Naft? I-2,2'-d? L-h? Drogenophosphate (see example 8). The (1-7) cis compounds can be sornephed to the trans compounds by treatment with a base (see example 2). When D and / or E are nitrogen, the intermediates of formula II and compounds of formula T can be prepared from the corresponding d-halopides or pyrimidines, as illustrated in Scheme 1 and as described in full. -a 6-phenol-5- [6-p? rrol? dm-l-? l -e-tox?) ?? r? dm-3-yl 1-5, 6, 7, 8 -fet rah? dronophthalen-2-ol of Example 6. Methyl ether of the compound of formula I wherein e = 1, fl = CH2, Zl - OCH2CH2, G-pyrrolidone, D = E = B = CH and Y = Ph, can also be conveniently prepared by a first step of dro drogenation of nafoxidma (Upjohn a Co., 700 Portage Road, Kalamazoo, MI 49001) in a solvent inert to the reaction, in the presence of a noble metal as a catalyst. Pressure and temperature are not critical; the reaction is conveniently carried out in ethanol, at room temperature, at 345 l-'Pa and for approximately 20 hours. The second step is a breakdown of the methox1 group, which is conveniently carried out at room temperature with an acid catalyst, such as boron tribromide, in a solvent inert to the reaction, or at 80-100 ° C with hydrogen bromide in acetic acid. The product is then isolated by conventional procedures and, if desired, converted to a salt by the addition of acids.

- =.? SCHEME 1 H 1-6 1-7 Lus compounds of formula I in which B is nitrogen and prepare μor Processes illustrated in schemes 2 v 3 and in examples 0-5 v 10-12. The synthesis of compounds of the formula I ^ n B e N is shown in the diagram 2. Fl oating chlorides of aryl acids (1-2) with primary amines and secondary amides of aplo (2) -2), which are reduced with hydride of 1 it 10-alum? nium? n ethereal solvents to give secondary amines (2-J). The subsequent uciltion of the compounds (-3) with ammonium chloride of tertiary amine acids (2-4), which are cyclized in hot phosphorus oxychloride to give dihydroisoquinoline salts (2-5). The reduction with sodium hydrohydride to alkoxytetrahydroisoquinol inas, the second one of demethylation with boron bromide in chloride, the inetio n of the s u ct u r r a r s.

SCHEME 2 YNH, R0-H- ~~ R0"^; R (CHS), C0C1 ÍXd .CONHY 2-5 5 < ? l untes i: «the t oinpuestos of formula J in which i-i os h-l -.o describe m ien -n .-.! The burning of secondary amines (3-1) with benzyl loxaryl chlorides (3-2) gives tertiary amides (3-0) which, when cycled with hot phosphorus oxychloride, give salts < dihydroisoquinoi a (3-4). reduction of the compounds (3-4) with sodium borohydride, followed by debenzylation with aqueous hydrochloric acid, Ja i soq? mol i as -5), which are rented with the < They have been appropriately designed and devised in order to give the objective structures desired.

SCHEME 3 Although the compounds of formula I can be used in the free base form in the methods of the present invention, it is preferred to prepare and use a pharmaceutically acceptable salt. For the reason < or, the compounds used in the processes of this invention form pharmaceutically acceptable salts, by the addition of acid or by addition of the bases, with a wide variety of inorganic and, preferably, organic acids and include the salts isiologically acceptable. They are often used in pharmaceutical chemistry. Tale is also part of this invention. Typical inorganic acids used to form said salts include hydrochloric, brornhidpco, yodhidpco, nitric, sulfuric, phosphoric, hypophosphobic and similar acids. Salts derived from organic acids, such as rnono- and di-carboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids and aliphatic and aromatic sulphonic acids can also be used. Ace, such pharmaceutically acceptable salts include acetate, phenylacetat or, tn fluoroacetate, actable, ascorbate, benzoate, chlorobenzoate or, dinium trobonzoate or, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoaio, bromide, isob? tirato, phenylbutyrate, ß-hydrox b? t irato, but? no-1, -d? oato, hexy no-1, -d? oato, caprate, capplate, chloride, cmamate, ci trata, forrniato, fuinarato, glycolate, heptanoate, hippurate, lactate, inalate, maleate, hydroxyrnaleate, malonate, andelato, mesylate, nico + malo, h <; isonicot mato, nitrate, oxalate, phthalate, terephthalate, phosphate, rnonoh i d rogeno tos T t o, d hl d r o y no f o s fa o, net t o f ato, pi rotosfato, propiolate, propionate, phenyl propionate, - Icylate, < - bacato, succmato, suberato, sulfato, bisulfato. pyrosulfate, sulfite, bisulfite, sulonate, benzenesulphone * o. p-brornophenylsulphonate, chlorobenzenesulphonate, ethanesulphonate, 2-hydroquinone, methanesulfonate, nephene-1-sulfonate, nf aleno- 2 -sul phona to, pt or Luenosul fonato, ilonosul fonatc, + art rato and salts sirní Lares. A sai pre f in 1 .--. It is the salt trat o. The pharmaceutically acceptable salts, by the addition of acids, are formed by reacting a compound of a T-ring with an equimolar or an excess amount of the acid. The reactants are generally combined in a mutual solvent, such as diethyl or benzene. The salt normally precipitates the solution "-n? N iem o > "3 approximately one hour to 10 days and can be isolated or filtered or the solvent can be separated by convincing means 1. The pharmaceutically acceptable salts of compounds of formula T have "generally better solubility characteristics, compared to the compounds from which they are derived and, therefore, are often more sensitive to formulation as liquids or emulsions. Once prepared, the compounds < The formula T in free base form or salt can be administered to a individual who needs treatment by the procedures described here. The examples of non-limiting essays illustrate the procedures of this nvenci. In the methods of the present invention, the compounds of rule I are administered continuously or from 1 to 4 times a day. As used herein, the term "effective amount" means a combination of compounds of the methods of the present invention which is capable of inhibiting the symptoms of the pathological conditions described herein. The specific dose of a compound administered in accordance with this invention will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, route of administration, patient status. treat and severity < 1e the pathological condition to be treated. A typical daily dose will contain a non-toxic dose level of appropiate < 1 to 0.25 mg / day or about 100 mg / day of compound of the present invention. Preferred daily doses will be from about 1 mg / day to about 40 mg / day. The compounds of this invention can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, tramuscular or intranasal administration. These compounds are preferably formulated ant os of their "dmini stracion, whose selection" was decided by the attending physician. Typically, an ormula compound, or pharmaceutically acceptable salt thereof, is combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation. The total active ingredients in said formulations comprise 0.1%. to 99.9% by weight of the formulation. "Ac acceptable" means that the vehicle, the vehicle, excipients and / or salt must. r «-Drnpatibles with the other ingredients of the formulation and not harm the receiver of this. Pharmaceutical formulations containing a compound of formula I can be prepared by procedures known in the art using well known and readily available ingredients. For example, the compounds of formula I, can be substituted with common excipients, diluents or vehicles can be transformed into compounds, capsules, suspensions, powders and similar formulations. Examples of excipients, diluents and vehicles that are suitable for such formulations include fillers and extenders such as starch, sugars and mannitol; binding agents such as silicic derivatives, alginates, gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as sodium bicarbonate calcium carbonate; agents retarding the dissolution of petals; paraffin wax; such resorci tcelerators as O ammonium compounds c? aternar-i o; agents for surfactants such as: • Orno alcohol gossiping and moneterostoar glycerol; / Absorbent articles such as "Kaolin and Bentonite"; and Lubricants such as talc, calcium and magnesium stearate and polleth 11 solid glycols. The compounds may also be formulated as elixirs or suitable solutions for oral administration or as appropriate solutions for parenteral administration, for example, intramuscularly, subcutaneously or intravenously. Additionally, the compounds are very suitable for their formulation as forms of sustained release and the like. The formulations may be constituted so that they release the active ingredient alone or preferably in a particular physiological location, possibly over a period of time. Coatings, covers and protective matrices can be made, for example. polymer substances or coras. The compounds of formula T are admired generally in a convenient formulation. The following example of formulations are illustrative only and are not intended to limit the scope of the present invention. In the formulations "Thurs follow," active ingredient "means a compound of formula I or a salt thereof.

FORMULATION 1: GELATINE CAPSULES Oo prepare ".aps? J s hard gelatin man o The following are en i nyredi ons: 1 ngr-edie t es Can idad (ing / .ps? La) Active ingredient 0.25 -100 FN starch (National Form) 0-650 AlrniiJon easy flow powder 0-50 350 cylindrical silicone fluid Stok- es 0-15 A formulation in tablets is ¡> ro > . • « Using The following ingredients: Ingredients Quantity (rng / compprnidos) Active ingredient 0.25-100 Nicrocrystalline cellulose ma 200-600 Silicon dioxide fume condensate lO-iO O Magnesium stearate 5-15 The compounds are mixed and compressed to form compresses.

Alternatively, tablets containing each 0, 20-100 tng of active ingredient blunt < i guo: Formul ation 0: cornp i i mi "the Engrodient or Quantity (rng / cornpprnidos) active ingredient 0,25-100 Alrní don 40 Cellulose rnicropstalin Pol vinylprolidone (with 20% aqueous solution) Soluble sodium cartilage 4,5 Magnesium stearate 0.5 Talc L The active ingredient, starch, and cellulose are passed through a U.S. r < 2 45 and they mix perfectly. The polymer solution is mixed with the resulting powder, which is then passed through a U.S. mesh screen. nQ 14.1 The granules thus produced are dried at 50-60 ° C and passed through a sieve of badly the U.S. nQ? a. The sodium hydroxycellulose, starch, magnesium stearate and talc, which had previously been passed through a U.S. mesh sieve, are then added to the granules. No. 60, and, after mixing, compressed into a tabletting machine.

Suspensions are prepared, each containing 0.25-100 mg of medicament for 5 doses, as follows: Formulation 4: suspensions Ingre ientes Canti ad / 5 i Active ingredient 0,25-100 rng Carboxirnet ii cellulose s dica 0 ing Syrup 1,25 ing Benzoic acid solution 0,10 in 1 Aroma zante c. s. p. Colo -ante c.s.p. Purified water up to 5 mi I "1 drug is passed through a U.S. mesh screen "3 and mix with the carotenoid and the syrup to form a uniform paste.The solution of benzoic acid, flavoring and dye ce dilutes with some water and stirring is added. enough to produce the required volume. e produces a solution in the form of an aerosol containing the following ingredients; Formulation 5: spray Ingredient Quantity (% by weight) Active ingredient 0.25 fl anol 25.75 Propellant? 2 < chlorodi fluoro ethane) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C, and transferred to a filling device. The required quantity is then fed to a stainless steel vessel and the remaining propellant is added. The valves are then attached to the container. Suppositories are prepared as follows: Formulation 6: suppositories Ingredient Quantity (mg / suposi tone) Active ingredient 250 ßlicepdos of saturated fatty acids 2,000 The active ingredient is passed through a mesh screen U.S. So it is suspended in fatty acids - > to satur-ados, previously t-undi dos using the immuno heat necessary. The mixture is then poured onto mold suppositories of 2 g nominal capacity and allowed to cool. An intravenous solution is prepared as follows: Formulation 7: intravenous solution Ingre < Amount (mg) Active ingredient 20 ing Isotonic saline 1000 ing The solution of the above ingredients is administered intravenously to a patient at a rate of about 1 rnl per minute. Angers are compounds that prevent them from -strogens «naní fis-st -m -us affects in ^ ejidos objectives of? in < 1? Entities «le t? Str? Oyenos, anf agonizing by ron ° íg? (Rite various "estrogen" processes.) However, most anti-estrogens, such as tarnoxyphene, are not pure antagonists, since they present some kind of stigma.

The following methods allow "a skilled artisan to determine the estrogen and amphetrogen effect of the compounds of this invention. The U.S. patent No. 4,859,535, incorporated herein by reference, claims two alternative general protocols by which a substance can be characterized as a "estrogen agonist" and / or as an antagonist of faB. -st r genos.

PROCEDURES TO DETERMINE THE ESTROGENQ POTENTIAL AND ANTI-ESTROGEN TEST OF UTERINE WEIGHT T-torrulae compounds are orally added to immature female Oprague-Da law rats (20 days of age; 40% body weight; Charles Piver U ya, O? Lzfelc, Germany. -for 3 consecutive days [- to test the estrogen activity, in addition, each dose of a compound of formula I, is administered to young Sprague-Dawley rats, a standard dose of 1 mg / kg of radiolipus ost. To determine the antiestrogen effect of the compounds, to administer them, the compounds are suspended in 0.25% agar, the animals are killed on the fourth day, the uteri are removed, they are cleaned of any intrauterine fiber! They weigh < m been dry. The activity < : - < • - + oyena is calculated by the increase in uterine weight (uterotropic effect) initiated by the respective daily doses of the compounds of formula I. The antiestrogenic effect of the compounds is tested by the reduction of uterine weight (uterotropic effect) in presence of 1 rng / lg of stradiol.

UNION ASSAY FOR THE ESTROGENQS RECEIVER The estrogen receptors are used to measure the uterine cytosol of unripe white female rabbits in New Zealand (3 months of age). The uteri are separated from the surrounding fatty tissue, washed (with phosphate-buffered saline, and cooled with ice), and immediately transferred to liquid nitrogen.Frost-uterine tissue is placed in a covered, pre-wrapped teflon cylinder. in liquid nitrogen, which is made to vibrate (501 71) for at least 30 seconds in an icrodesrnernbrador (Braun, Melsungen, Germany) in the presence of a ball of ungsteno carbide of caliber 1. The resulting powder is mixed with units (1: 4 p / v) of Tris (Tris 0,01M, EDTA 0,001M, pH 7,5) ho ogenized with a Dounce honing and centrifuged at 105,0 0g «During L hour. The supernatant (cytosol) is decanted and the protein concentration is adjusted to 5 μg protein / ml.The concentration of proteins is according to Lowry et al., GB.] Parts are pipetted. Aliquots of cytosol in plastic tubes were added and [I7ß-3H], estradiol, 2.5xl ~ 9M, a range of concentrations "Je estradi" unlabeled ol and antiestrogen of formula i. The relative binding affinity of the ant estrogens to the estrogen receptor is carried out by the dextran-carbon procedure at 2 ° C described by Devleesch o-t al. [101. All stages are done in triplicate. The relative binding affinity is defined as a ratio of the concentrations of radiolabeled l7 | 3-estradol ol to the compound of formula T that is needed to achieve a 50% inhibition of the specific binding of [173-3.-11] estradiol. The radioactivity Linked to the highest concentration of Cl7ß-3H] estrad ol (2.5x10-7M) is considered as insepecific binding and subtracted from all values. Procedures for evaluating compounds for the treatment of "vaginal atrophy of the foot" are disclosed in U.S. Patent 5,461,064 < That is incorporated here as refer * enc? a.

SKIN ATROPHY Oo selects three to twenty women, who are post-traumatic and in good health. Additionally, these women are selected by washing in the various signs of rapid skin atrophy that they present, such as rapid increase in the number of facial wrinkles or crow's feet, rapid change in skin pigmentation, that is, "spots on the skin". age ", or other problems of rapid aging of the p. The doctor who treats them should remember the patients < These criteria should be very subjective and should take into account some consideration in the selection of patients. Also, thermal atrophy may be the result of other factors, such as damage from ultraviolet radiation from the sun and other environmental damage, and patients suffering from these effects should be excluded. The first component of the study - it's a qualitative and subjective, that is, an evaluation of the improvement in the appearance of patients. This evaluation requires an initial point for future comparisons. Some initial reference points may be in the form of a standardized set of questions about how the patient sees her own appearance, photographs of the patient, or a psychological profile of the patient's own image. The second quantitative component; This includes the measurement of the excretion of hydroxyproline in the urine, the moisture content of the skin, and 1 ucosaní noglucan in the skin and changes in the resilience and ployability of the skin. Methods to determine these factors are found in "The Menopause", edited by P. 3. Beard, Uiversity Press, chapter 7 (1977); in "Methods m Skin Research ", edited by D. Sherrow and C. 3. Sherrow, John Uiley \ Sons Ltd., chapter 22 (" Analyeis of Sebaceous L pids "), page 587-608 (1985), and in other cited references all of which are incorporated herein by reference, and an initial reference point of these quantitative factors is also obtained.Women, thus selected and evaluated, undergo a clinical protocol of administration by oral route. 20-100 rng of a compound of this invention, in a single dose or in divided doses.

Alternatively, these patients will be surprised + in a topical administration protocol to the skin areas affected by the atrophy. This topical protocol includes the use of a suitable formulation that with? 5-50% (by weight of active compound of this invention, applied to the affected area na or twice a day.) What is the use of these protocols continues for two to twelve months. , qualitative as quantitative, at appropriate intervals, it turns out that "Positive is an improvement in the overall qualitative index of appearance." The patient and / or an improvement in quantitative parameters, for example, an increase in the excretion of hydroxyproline, the urine, which means an increase in the renewal and synthesis of leucine, and an increase in the moisture content, jLucosaminoglycans, foldability or resilience of the p.

VAGINAL ATROPHY Three to twenty women with vaginal atrophy associated with menopause are selected. These women have good general health. Since the nature of this disorder is very ossential and subjective, the evaluation of the effectiveness of the disorder was necessarily subjective in nature. Tell patients that they keep a record of them by writing down such lethalities - facial signs and vaginal scaling and degree of pleasure in sexual relations. These women undergo a clinical protocol similar to descp? previously for The atrophy of the iel- Particular emphasis is placed on the use of vaginal suppositories containing 5-25% of active compounds of this invention. A positive result is an improvement in sexual pleasure and / or decrease in vaginal itching or scaling.

The usefulness of the compounds shown here is shown by the positive results observed in one or both of the previous trials. Procedures to evaluate the usefulness of a compound of this invention to increase the libido of post-menopausal women are included in the patent of the United States 5,419,931, which is incorporated herein by reference. TEST 1 The animals used are Sprague-Da l v ovapectized rats or ovate ectorated / adrenalect omitted rats (Anf ucnex free of specific pathogens, Estocolrno) weighing 250-300 j. They are accommodated in a room maintained at a temperature of 04C > C with inverted illumination (10 hor-s of darkness). They have food and water (or salt solution available to them by bitum.) A group is described as consisting of the invention and the other group is kept in check, and observations of the behavior are made by placing each female with 2 sexually experienced males, adapted to cages, for a period of 5 minutes during which approximately 20 assembled occur.The following measurements are recorded: 1. Proportion of males mounted that elicit a Lordosis response (L / M) 2. Intensity of the lordosis measured on a 3-point scale 3. Duration of the lordosis (in seconds) and n. 4. Relation and acceptance of the females (number of mounted fivi by number "1st attempts r-cast" mounted more number of mounted), a measure of the desire of the female to accept the male when he tried to ride. The activity of the compound is shown by a positive impact in any of the 4 observations, compiled with the cont rol. ASSAY 2 In the clinical study, five are selected. fifty women These women are posttrnenopausal, that is, they had stopped interfering between 6 and 12 months before the beginning of the study, they are in good general health and they suffer from self-described loss of freedom, especially after menopause. Because of the inherent and subjective nature of this symptom, the study has a group in two groups, one of which receives the active agent of this invention and the other receives a placebo. The women in the trial group receive orally between 50 and 200 mg of the drug per day. I continued this therapy for 3-12 months. Accurate records of the libido level of the women are recorded for both groups and these results are compared at the end of the study. the activity of the compounds of the invention is illustrated by their positive effects in at least one of the above tests. Testing procedures for measuring the ability of? N compounds of this invention to inhibit fertility in women are described in The United States Patent 0.46.94Q,, which is incorporated into "- ??? as reference . TEST 1 Enf r'e five and fifty female rats virgin adult young women who weigh 200-300 g each, are divided into groups that have the same number of rats. One of the groups serves as a control group and the other as experimental groups, each of the experimental groups raloxifene at a particular level and the others. The ralox i phono is replenished in fresh corn oil, with daily administration in 0.1 ml of vehicle. The designated amount of raloxifene in the vehicle is administered daily subcutaneously to each rat of the defined group. Alternatively, the administration can be done by an oral probe or intramuscularly. The control group receives only the vehicle. The administration of the vehicle or of "a" -brombinaeion and raloxifene and eicule is continued daily for 15 days, and on the fifth day of treatment, one or two adult male rats weighing at least 250 g are added to each group, and the cohabitation until the 15th day when the male rats are removed from the group, each group of rats is then kept for seven days, after which the rats are sacrificed and the presence of viable fetuses is examined or Resorption: The number of animals that show evidence of pregnancy with respect to the number of animals in the group, multiplied by one hundred, is the percentage of pregnancies (PRE). A compound is considered active when 1:. PPE ratio is 0 to 20%. A PREMIUM RELATIONSHIP 40% indicates a marginal activity and a higher relationship indicates inactivity. '5 TEST 2 Fnf r * e five and fifty virgin young adult female rats, who pose 200--00 g each, are divided into groups' l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l; on male rats. One «Je groups serves« orno group of "ontrol and the others as experimental groups. Vaginal smears are performed daily in the females until they find semen and vaginal plugs, which coincides with the day of vaginal estrus and is designated day one of the pregnancy. The male rats are removed and administered to the L5 experimental groups of female ralox pheo rats by oral gavage, intramuscular or bcutanea injection. the administration > - © continues daily until the 12th day of pregnancy, at which time all female testes are sacrificed and the presence of implantation sites is examined, a Or compound is considered active when the PRE ratio, defined above, is 60% or lower. The utility of the compounds described herein is shown by the activity in one of the foregoing assays. 5 Procedures for determining the efficacy of compounds of this invention < - > The treatment of a pulmonary hypertensive disease is described in U.S. Patent 5,447,341, which is incorporated herein by reference. ASSAY 1 The procedure is carried out as described in Farhat et al. in 3. PET, 261: 686 (1992) (which is incorporated herein by reference). Four to thirty rats are slaughtered. PuLs are bled by perfusion through the hepatic pulmonary vein. The pulmonary artery is cannulated to be the trachea which maintains ventilation and the pulsed cannula is connected to the perfusion tube and the entire ventilated lung is removed and suspended in an infusion chamber. The effects of vasoconstrictor substances on the perfusion pressure of the isolated perfused lung are measured using a Statharn pressure transducer. The increase in perfusion pressure (vasoconstriction) induced by mimetics-rornboxane in the presence of estradiol-is determined, and the ability to block the effects of the box box is determined with a compound formula, or potentiation. of the effects of thromboxane by estradiol. The activity of compounds of formula I is illustrated by a reduction in the increase in pulmonary perfusion pressure, after stimulation by a single thromboxane. TEST 2 A single dose of inotrocrotal mp is administered to five to fifty rats 83.5 ng / g) and pulmonary disease was assessed by histopathology, by the accumulation of fluorescein-conjugated dex- ane in alveolar lavage fluid L > «« u? al (blunt measure of pulmonary edema) and by measuring blood pressure using a pressure transducer Stafharn P231D TReindel et al. , Tax to d Ppplic. Ph rn. , 106: 179-200 H990), which is incorporated herein by reference]. A compound of formula I is administered and the effect on the ates is evaluated. The compound effect of formula I illustrates by a reduction in the absorption of dextran conjugated with fluorescein, "Je flu" Jos of bronchial alveolar lavage of animals treated with a compound of formula I, which indicates a reduction " Jel pulmonary edema. The lungs of the rats were also removed from the thorax, perfused with Karnovs-s fixative-modified and analyzed hi-topathologically. A reduction of the thickness of the arterial walls in treated r? T-.s? is vi of the protective role of compounds «Jo formula I, put« μie is a decrease in pulmonary arterial pressure-, ESSAY 3 For the clinical study five to fifty women are selected. Women suffer from hyper-pulmonary disease. Because of the idiosyncratic and subjective nature of these disorders, the study has a control group with a placebo, that is, the women are divided into groups, one of which receives a compound for the agent. active and the other receives a placebo. The women in the trial group receive between 50 and 200 of the drug per day orally. Continue this therapy «Jurante 3-12 months. Accurate records are recorded «The number and severity of symptoms in both groups, and these results are compared at the end of the study. The results are compared between members of each group and the results of each patient are also compared with the symptoms indicated by each patient before starting the study. The utility of the compounds of the formula is illustrated by the "positive impact" they have in at least one of the tests described above. The utility of a compound of this invention to inhibit acne or seborrhea is tested by the methods described in United States Patent 5,439,923, incorporated herein by reference.

ASSAY 1 Each of two to twenty patients selected for clinical evaluation are placed in a comfortable environment, that is, at temperature, humidity, lighting, etc. comfortable These patients have abstained from intense exercise and consumption of foods seasoned with spices for twelve hours before the evaluation. A zone of the body containing a large number of sebaceous glands affected by seborrhea or acne, such as In front, it cleans «on? gauze to eliminate accumulated lipids. A patch is extracted from the skin forming an angle of 2.5 by 1.8 c in size. A suitable compress of 2.5 by 1.8 crn in size is placed in the test area of the skin. First, before placing it in the test area, the absorbent material must have been degreased to remove essential liquids. The compress is kept in the uterus with a bandage. After «Je < ? n? minutes, the compress replaces - on a new compress (test pad). This procedure eliminates the essential lipids of the skin, so that the actual speed of the production of lipids by the sebaceous glands can be determined. The test pad is placed on the site for three to six hours and then removed. Then, the test pad is extracted with ether to remove the lipids and the ether is evaporated. Then, the lipids of the residue are weighed. The result -or expresses, as opposed to Jipi, two ebaceans 3? Ng) by 10 ein2 '. per hour. The patient then goes to 30-400 mg / day for the active ingredient via eral or a topical formulation containing 5-20% by weight of the active ingredient is applied daily, in both cases for three to nine weeks. The methodology of the test pad described above is repeated several times during the entire administration of the active ingredient to monitor progress. This test can be performed ambi in animals to verify its usefulness. A positive effect is reflected by a decrease in the speed of the production of lipids by the sebaceous glands.

TEST 2 Between two and twenty patients enroll in this clinical protocol and evaluate the mind by direct observation of the skin and lesions in osta. This is done by selecting sections "a square centimeter" of the affected skin and recording the number and type of injury (pimples, seborrhoeic lesions, etc.). The areas normally used are the cheeks, scalp or back. The patient then makes 30-400 mg / day of the active ingredient orally or is applied daily to a topical formulation containing 5-20% by weight of the active ingredient, in both cases for three or nine weeks. During the period of administration, the areas of the skin to be evaluated are controlled. Care must be taken to evaluate the same areas and, in order to achieve this, a mark or small markings with a permanent marker can be made on the skin. A positive result is reflected by a reduction in the number and / or severity of the lesions in the areas marked "Je La piel. The usefulness of the described compounds is shown by the positive results observed in one or both of the previous trials. The utility of the compounds of this invention for treating Turner syndrome is determined by the procedure described in U.S. Patent 5,441,966, incorporated herein by reference. 00 ASSAY PROCEDURE For the clinical study, <I piss thirty women. The women are between twelve and eighteen years of age and have characteristics of Turner syndrome but, therefore, have good general health. The study has a control group with a placebo, that is, the women are divided into two groups, one of which receives the active agent of this invention and the other receives a placebo. The women in the test group received orally «.-Between 10 and 100 rng of the active agent per day. They continue therapy for 3-12 months. In both groups are recorded precise records of the number and severity of the symptoms mentioned above and these results are compared at the end of the study. The results are compared between members of each group and the results of each patient are also compared with the symptoms indicated by each patient before starting the study. The utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the symptoms when they are used in a study like the previous one. Patent EP 0 659 419 Al, incorporated herein by reference, provides methods for evaluating compounds of the present invention in rnarna disorders.

ASSAY 1 For the clinical study -and select -me to fifty women. Women have a history of breast disorders "I love the" Jests "but they are in good general health Because of the subjective nature of these disorders, the study has a control group with a placebo. , that is, the women are divided into two groups, one of which receives the active agent of this invention and the other receives a placebo.The women of the trial group receive oral via 50. and 200 rng of the drug to the lia.They continue this therapy for 3-12 months In both groups precise records of the state of the disorders are recorded, and these results are compared at the end of the study.The results are compared among members of each group. group, and the results of each patient are also compared with the symptoms indicated by each patient before beginning the study.The usefulness of the compounds of the invention -, and illustrated by the positive impact "have on the disorder". or symptoms of this, when u san in a study like the previous one '. ASSAY 2 Three to twenty male patients are selected who suffer from ginoco astia or galactorrhea. The initial measurement of breast size and evidence of lactation is noted. Patients receive orally 30-100 mg of an active compound of this invention per day, in a single dose or in divided doses. This treatment is continued for 3-12 months .. At appropriate intervals, other measurements are made of the size of the breasts or evidence of lactation. The utility of the compounds of the invention is illustrated by the positive impact on the disorder or its symptoms. A method for determining the hypogiucemic activity of the compounds of this invention is set forth in -a ten e FP 0 635 064 A, incorporated herein by reference. To 6-month-old viable yellowish-obese consanguineous yellow mice. Viable yellow male mice are obese, hyperglycemic, hypertensive, and insulin resistant. The rains are housed 6 per plastic cage, with bed «1e drinking water / Purina Foinulab Chow 5008 (Purina Milis, St. I.o? Is, MO) td Libitu. at room temperature The animals are kept at 23 ± 2 ° C. The lighting n the animal rooms was < 1e 600 to 1,800 hours. Anties rogónos were tested at various doses in the form of mixtures of diets. Each dose of an amphestrogen is tested in 6 mice housed in the same cage. The compounds are mixed in food? Ulvepza «Ja and regranulated. The mice that served as controls are given a regranulated diet without any test compound. Blood samples are taken from the caudal vein, immediately before and one week after the start of the test. Glucose concentrations in the blood are determined by the "Hex glucose oxidase" procedure on an Alpkem Rapid Flow model 300 analyzer (Clac? Arnaus, OR). The concentration of glucose in the blood below the levels in the mice of "anti-estrogen-effective" control with utility in the treatment of diabetes and hypoglycemia. 1: 1 effect of compounds of the present invention on disorders of the central nervous system in post-neutropenic women can be evaluated by a procedure described in patent EP 0 659 413 A2, incorporated herein by reference. ASSAY PROCEDURE Five to fifty women are selected for the clinical study. The women are post-enopausal, that is, they have stopped menstruating between 6 and 12 months before the beginning of the study, they have good general health and they suffer from one or more The aforementioned central nervous system disorders.

Because of the idiosyncratic and subjective nature of these disorders, the study has a control group with a placebo, that is, women are divided into two groups, one of which receives the active agent of this invention and the other receives a placebo. The women in the trial group receive between 50 and LOO rng of the drug per day orally. They continue this therapy for 3-12 months. In both groups accurate records of the number and severity of the disorders are recorded before 04 The results are compared on each member of each group and the results of each patient are also compared with the disorders indicated by each patient before the study was started. The utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the central nervous system symptoms / disorders, which are used in a study like the previous one. Procedures for evaluating the effect of compounds of this invention for treating obsessive-compulsive and consumptive disorders are described in EP 0 659 428 AL, hereby incorporated by reference herein TEST 1 In order to demonstrate the living effect « < : omitted on it. Onsu or alcohol, experiments are designed to test the effect on voluntary ethanol intake in hamsters. Hamsters choose based on previous reports, that they are receptive to, and prefer, a high intake of ethanol, compared to other vain species of mammals. Kull-osl-y and Cornell (Pharmacol. Biochern., 3. Bßhav., 11; 439-444, 197) deduced that the difference in the species in the intake and prences of ethanol were related to the difference in the metabolism of the ethanol. The animals used for the experiments described here are two a: e? S h msteres «Jorados adult males. The animals are kept in a light / dark cycle of 14 hours of light per day and during a 6-week acclimation period. Animals have access to food and water ad libit? In. For the experiment, the animals are maintained as described above in a single large cage with four calibrated bottles of 250 ml. The drinking bottles are equipped with straight, stainless steel suction tubes, used to measure fluid consumption with an approximation of? neither. The exit of the tubes is collected in vessels of 57 g equipped with glass funnels and located near the suction tubes. The consumption of fluid by the masters is measured once every 3 days so that the volumes consumed are large enough to obtain reasonably accurate measurements. After a period of acclimation of 6 weeks, the corporal deposits of the animals turn and 1-- is written down. ingestion of cigua. Afterwards, the water "Je 2" of the 4 bottles of drink is replaced by a 15% ethanol solution and the consumption of water and aqueous ethane is considered for a period of 2 weeks. Two days later "I read the beginning of this phase of voluntary choice of baby, the hamsters establish an explicit preference for aqueous ethanol over water and the initial preference relation is recorded (intake of aqueous ethane L" Swallowed by ingestion of water). As control, the animals are fed later with 0.2 ml of water twice a day, using a stainless steel animal needle. The water supply does not seem to have an effect on the behavior of the animals, as measured by the total intake of water. After 6 days, a compound of formula 1 is administered to the same group of hamsters by a liquid mixture for a period of 3 to 12 weeks. The activity of the compounds of formula I is illustrated in that the preferred ratio is lower during the administration of said compound of the invention, than the initial reference ratio. fifty women Women are postmenopausal, if they have stopped menstruating between 6 and 12 months before the start of the study, they have good general health. Because of the natural or idiosyncratic nature of these disorders, "the study has a group that controls with a placebo, that is, the women are" in the groups, one of which he receives raloxifene as an active agent and the other receives a placebo. Women in the nsayo group receive between 50 and 200 of the drug per day orally. They continue therapy for 3-L2 months. In both groups, precise records of the number and severity of symptoms are recorded and these results are compared at the end of the study. The results are compared between members of each group and the results of each patient.

They are also compared with the symptoms indicated by each patient before starting the study. The use of the compounds of formula I is illustrated by the positive impact they have on one or more of the disorders / symptoms, when used in a trial such as that described above. EP 0 659 414 A2, incorporated herein by reference, discloses methods for evaluating compounds of the invention in the inhibition of hirsut \ srno and < 1e alopecia. HIRSUTISM Three to twenty women suffering from hirsutis are selected. In these patients, the extent and severity of hirsuti srno is initially classified. The clinical evaluation is done by the procedures described in the reference "Methods of Research", Oohn Uilley S Sons, p. 308-318 (1985) and in the references "i + adas en ella. Patients receive orally 10-400 mg of active compound of this invention per day, in a single dose or in divided doses. Alternatively, in the affected areas, a cream or lotion of 10% by weight of active ingredients is applied once or twice a day. The patient continues this protocol for six months. At appropriate intervals, a reassessment can be made by one of the procedures described above. ALOPECIA Twenty women suffering from alopecia are selected to be female. In these patients it is rated 08 i ni cialinente the extension and yraveda «J of alopecia. This procedure is performed by methods described in Method, of SI in Fosear ch, John, JU S Sons, pp. 308-318 (1085), T. Habif, "Cl n cal Dorna tology "," 0. V. Mosby Co., Chapter 23, pp. 493-504 < 98985), and references cited therein, "which are incorporated herein by reference. procedure of the "pull" hair "c" the measurement of the relationship of anagen to telogen.The patients receive orally 10-400 rny "1" or "or pue'ito" .ct ivo of this invention to the, in a single dose or in divided doses.Alternatively, in the affected areas Patients apply once or twice a day? cream, lotion or shampoo of 5-10% (by weight "Je? The compound of this invention.) This protocol continues for six months, at regular intervals, a re-evaluation is carried out for one of the procedures described above. an increase in the ratio of anagen to tolo and not for an increase in? 1 number of terminal hairs in the affected region of the scalp. The utility of the compounds of the invention is illustrated by the positive impact they have on one or more of the symptoms, when used in a study such as the previous one. Assays showing the ability of compounds of this invention and increasing the function of Acro phages are described in EP 0 659 425 Al, incorporated into "-] u? as re faith r 'gum. 09 ASSAY 1 It is carried out with certain modifications in the exposed procedure «Je Friedarnan et al., 3. Clin. Inve t. , 75, L62-L57 (1985). Oral doses are administered in the range of 1-10 ng / g of a compound of formula I, to between one-sixth and one hundred mice. After administration, rnacrofages are collected and the changes in phagocytosis are validated, both immune (by Fe for) and non-immune, using particles of yeast conjugated with Luoresce prepared according to Rags. Immunol. Meth., 123: 259 (1989) In immune-mediated phagocytosis, fluorescein-conjugated yeast is premixed with mouse serum to promote La opson acion. The increase in fluorescein uptake by the macrophages is quantified by an increase in fluorescence emission using excitation and emission wavelengths and the emission d? +82 and 520 n, respectively. This procedure: is used with ex vivo or in vitro cultures of rnacrofagos, and changes quantify in units of fluorescein. An increase of the fluorescent units, compared to the control, indicates the activity of the compounds of the formula I. TEST 2 The procedure described by Zuckerrnan et al., Cell Irnununol. , 103: 207 (1986) and 3. Imrn? Nol. 140: 978 (1988) (which is incorporated herein by reference) .. The ability to induce class II antigens and to promote the presentation of antigens is determined in macrophages 00 primary periph erals ex vivo e., with the line of ma roragos m? rinos P388D1. A compound of formula I is added to between five and one hundred mice, inaccuracies are collected and tested with antibodies against TT class antigens of haplotype D. Increased expression of ET class antigens is determined by flow rate using the appropriate secondary antibodies. In vitro studies evaluate the effects of the compounds of increasing the basal level and expression, indistinguishable by gamma terteron, "Je antigens of class 11 by cytometry" Je flux. An increase in TT class expression reflects an increase in the activation of macrophages. ASSAY 3 The procedure described by Seow et al., 3. Irnmunol. Meth. , 98, 113 (1987) (which is incorporated herein by reference). The assay is used to evaluate increases in the effector functions of the macro phages, which measures the absorption of 2-deoxyrism. Ex vivo and in vivo macrophages are plated in 96-well plates at 105 cells per well, incubated in phosphate-buffered saline in the presence of 0.78 C / mL of 3 H-deox. glucose, and is placed in the wells formula T, A reduction in the amount of extracellular glucose reflects the absorption of this non-metabolizable glucose analogue, and consequently provides an independent assay for the erminal glucose "Activation of the hormones mediated by the compound of formula I. An increase in the uptake of isosiglucose by the compound demonstrates the ability of the compounds to increase the activation status of the macrophages. TEST 4 The procedure set forth in r? Ckerrnan, Cir-c Shocl-, 29, 279 (1989) (which is incorporated herein by reference) is performed to illustrate the ability of the compounds of formula I to protect them in mup sepsis models. and of lethality by endotoxins. It is administered orally to re-unco and c in mice 1-10 mg / l-g of a compound of formula I one week before a sepsis stimulus. The stimulus is performed using a bolus injection of endotox to IV under conditions in which it obtains the LDioo (200 jg of lipopolisacapdo). Glucose and exogenous coids, such as dexarnefasone at 20 ng / g, serve as a positive control that increases survival. The effects of the compound of formula T are also determined using a ce? S model which involves cecal ligation and puncture. Sepsis is caused by both Gram-positive organisms such as Gr-am negative and LDioo within 40 hours despite the use of antibiotics. An increase in the number of annealing < - Survivors or survival time, purchased with control, demonstrates the activity «He compounds. TEST 5 The ability of the compounds of formula 1 to reduce oocyte secretion, as well as the tumor necrosis factor (TNF), is quantified in vivo by serum measurements. using ELISAs with TNF, commercially available, specific for mouse TNF. Five to one hundred mice were given orally 1-10 mg / kg of a compound of rormuia I, one week before they were injected with a lethal or sublethal dose of lipopolisacapdo (200 and 1 μg, respectively). One hour after the lipopolysaccharide injection, the mice are bled and the basal and lipopolysaccharide-induced amounts are determined in the serum. Ordinarily, TNF levels lower than 10 pg / ml are observed before injecting lipopolysapdate, and levels of 5-20 ng / inl are achieved after injecting 1 polyp sacapdo. The ability of the compounds to modulate the basal or inducible levels of TNF is determined. an increase in basal NF without triggering massive systemic release of TNF in mice treated with the compounds demonstrates the activity of the compounds promoting cytokine secretion. Finally, Ex vivo and in vitro measurements of TNF release of Les perifonea macrophages, exposed to 1-5 uM, of a vi tro compound, are performed to determine the extension of the cyclokinine increase mediated by a compound of formula T. TEST 6 For the clinical study, five to fifty women are selected. Women suffer from immunosuppression. Because of the idiosyncratic and subjective nature of these disorders, the study has a control group with a placebo, that is, women are divided into two groups, one of which receives a compound formula I as active agent and the another receives i-iacobo. The women in the trial group receive between 50 and 200 mg of the drug per day. They continue this therapy for 3-12 months. In both groups, precise records of the number and severity of the symptoms are recorded and these results are compared at the end of the study. The results are compared between members of each group and the results are compared between members of each group and the results of each patient are also compared with the symptoms indicated by each patient before starting the test. The utility of the compounds of formula I for increasing the function of macrophages is illustrated by the positive impact that at least one of the previously described assays have. Said compounds are useful for combating infections and favor wound healing.

Claims (2)

1. NOVELTY OF THE INVENTION CLAIMS 1. - The use of a compound of the formula I where: A is selected from H2 and NR; B, D and E are independently selected from CH and N; And it is (a) phenyl, optionally substituted with 1-3 substituents selected i depending «Je R *; (b) naphthyl, optionally substituted with L-3 substituents independently selected from P ^; (c) C3-C8 cycloalkyl, optionally substituted with 1-2 substituents independently selected from R *; (d) cycloal ienyl 3-8, optionally substituted with 1-2 substituents independently selected from R ^; fe) a five-membered heterocycle containing up to 'two heteroatoms selected from the group consisting of -0-, -NR2-y ~ S (0) n-, optionally substituted with R'; (f) a heterocycle or six members containing up to two selected heteroatoms "read a group consisting of -0-, -NR2- and -S (0) n-, their optionally with 1-3 substituents selected independently" Je R «, - or (g) a bicyclic ring system consisting of a five-membered heterocyclic ring condensed with a phenol ring, said heterocyclic ring containing up to 10 heterocycles selected from the group consisting of -0-, -NR2- and -S (0) n-, optionally substituted with 1-3 sub-constituents selected independently from R '; Z is fa) - (CH) PU (CH2) q -; ib) -0 (CH2) P CRS Rβ -. (c) -0 (CH2) P I (CH2) q-; (d) -0CHR2CHR3- or (e) -SCHR2CHR3-; G is (a) -NR7R8; (b) where n is o, 1 or 2; n is 1, 2 or; Z2 is -NH-, -0-, -5- or -GH2-; optional condensation on adjacent carbon atoms with one or two phenyl rings, optionally and independently substituted on the carbons with one to three substituents and optionally and independently substituted on the nitrogen with a suitable substituent chemistry, selected from R < , or (c) a bicyclic amine containing five to twelve carbon atoms, bridged or condensed, and optionally substituted with 1-3 substituents independently selected from R- *; Zl and G, combined, you know "Jen be U is (a) -CH2-; i) -CH-CH-; (c) -O-; (d) -NR2-; (e) -S (0) "-; (f) -CO-; (g) -CR2 (CH) -; (h) -C0NR2 -; (i) -NR2C0-; (3) or i'k) -C = C-; R is hydrogen or Ci-C alkyl; R2 and R3 on independently (a) hydrogen or ib) Ci-C4 alkyl; R is (a) hydrogen; (b) halogen; (c) C 1 -C e alkyl; (d) Ci-C * alkoxy; (e) acyloxy C? -C4; (f) (alkyl C? -C?) t? o; (g) (C? -C? alkyl) sulfini lo; (h) (Ci-C4 alkyl) sulfonyl; (1) hydroxy C1-C alkyl; (j) ap lalilo Ci -C «; (k) -C02H; (1) -CN; (, n) -C0NH0R; (n) -SO2NHR; (0) -NH2; fp) (C 1 -C 4 alkyl, lamino; iq) di (C 1-4 alkyl) amine; (r) -NHSO2R; (s) ~ N02; (t) ap lo or (u) -OH; R5 and F6 are independently C1-C6 alkyl or, together, form a C3-C10 carbocyclic ring; R7 and R8 are independently (a) phenyl; (b) a C3-C10 carbocyclic ring, saturated or unsaturated; (c) a C3-C10 heterocyclic ring containing up to two heteroatoms selected from -0-, -N ~ and -S-; (d) H; (e) Ci-Ce alkyl or (f) form with RS or R6 a ring of 3 to 8 nitrogen-containing members; R? and R8, in linear or ring form, may optionally be substituted with haeta fres sust it? yentes ~ -elecc? ona < independently of alkyl Gie, halogen, alkoxy, hydroxy and carboxy; a ring tornado by R7 and R8 can be optionally condensed with a phenol ring; e is, l or 2; is 1, 2 or 3; n is 0, L or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3; and optical and geometric isomers «Je Los mismo; and salts by the addition of acidic or pharmacologically acceptable acids, N-oxides, esters, and quaternary ammonium salts. The same, in the preparation of compositions for inhibiting a pathological condition which < • Susceptible, or partially susceptible, to be inhibited by an estrogen, antiestrogen or "estrogen" agonist, selected from the group consisting of uterine cancer, cancer-auxiliary breast, breast disorders, male breast cancer, migraine, incontinence, vaginal atrophy, bladder infection, senile ecornastia, diabetes, hyperglycemia, failure to heal wounds, melanoma, impotence, inflammatory bowel disease, nervous system disorders central and gastrointestinal caused by an excess of tachykinin nasal, decreased libido, disorders of the m unological system, decreased fertility, pulmonary hypertensive disease, acne, seborrhea, illness «Jad autoinrnune, Turner syndrome, alopecia, hirsutisrno, disorders related to an excess Neurosurgery and obsessive-compulsive disorders, including abuse of alcohol and alcohol.
2. 2. The use of a compound according to claim 1, wherein the compound of formula I is a compound of the sp r? Ct? Ra Where is it? L5 3. - The use of a compound according to claim 1, in which the compound "Formula I" is selected from the group consisting of: ci s-6 - (- fluorophenyl) -5-Í - (2 - ?? per? J? nl - 0 ethoxy) fem 11 -5, ß, 7, 8-tet rah? dron ft len-2-ol, (-) - ci s-6- f eni 1 - 5- T 4- í 2-p? Rrol? D? Nl-? 1-etox?) Phen? L] -5, S, 7,8-t et hydra-t-talen-2-ol, cis-5-fem-5- [4 - (2-? Rrol di nl- 1 - etox L) phen? l] -5,6,7, B-te rah? d on phthalen-2 -ol, c? sl- (6'- p? rrol od oe tox? -3 '-pipdil) - 2- fem l ~ 6-h? droxi -1, 2, 3, 4-5 tetrahydronaphthalene, 1- (4'-pyrrolnii noethoxy feni 1) -2- (4"-fluorophenyl) -6-h? drox? -1, 2, 3, 4- totrah d roí so uino lina, c? S-6- f 4 '-hi rox i fenni i) - - í 4 - (2 - iperidin- 1- 11 -efox i) fen113 -5, 6,7,8-tet rahydrona phthalen-2-ol and 1- (4'-pyrrole, idmoletoxy pheni 1) -2-phen? L-6-hi (Jrox? 1, 2, 3, 4- tetrahydroquinolone 4. The use of a compound according to claim 1, wherein said pathological condition is a breast disorder 5. The use of a compound according to claim 1, What is the aforementioned pathological condition? Vaginal atrophy, The use of a compound, according to claim 1, wherein said pathological condition is an infection of the bladder. The compound according to claim 1, wherein said pathological condition is senile gynecornastia 8. The use of a compound according to claim 1, wherein said pathological condition is diabetic 0. - Fl use «Je? n compound according to claim 1, wherein the cytological condition is hyperglutin uceinia 10. The use of a compound according to claim 1, wherein the pathological condition is failure of wound healing. 11. The use of a compound according to claim 1, in the < That the aforementioned pathological condition is l? b? «or disrm? ida. 12. The compound ueo according to claim 1, wherein the aforesaid pathological condition is a disorder of the nnununological system. 13. - EL? So de? N composed -eg? N The vindication 1, in the «tho the aforesaid pathological condition is fertile« J diminished. 14. The compound is a compound according to claim 1, wherein said pathological condition is a disease of the lung. 15.- The compound of the compound according to the claim L, in which the aforesaid pathological condition is acne. 16. The compound compound according to claim 1, wherein said pathological condition ee '-eborrhea. 17. The compound of claim according to claim 1, in ol < That the aforementioned pathological condition is an autoimmune disease. 16. The use of a compound according to claim 1, in the «]? And the appointment to pathological condition is the syndrome of T? Rn r. 19. The use of a compound according to claim 1, wherein said pathological condition hirsutism. 20. The use of a compound according to claim 1, in the aforementioned pathological condition is alopecia. 21.- The "so" a compound according to the renounce 1, in the. that the aforementioned pathological condition is not obsective-compulsive asthma. 22. The use of compound compound according to claim 1, wherein said pathological condition is an unwanted agent.