MXPA97001605A - Procedure to treat disorders with estrog agonists - Google Patents

Abstract

The present invention relates to: The use of compounds of the formula: (See Formula) in the preparation of compositions useful for treating or preventing Alzheimer's disease, premenstrual syndrome, perimenopausal syndrome, a thrombomodulin deficiency, uterine fibrosis, excessive myeloperoxidase activity, excessive thrombin, autoimmune disease, reperfusion injury of the ischemic myocardium and insufficient testosterone

Description

PROCEDURE PftRft TROTRR DISORDERS WITH ESTROGEN PIGONISTS BACKGROUND OF THE INVENTION It has been reported that certain estrogen agonists are useful for inhibiting pa ological disorders related to organ systems that respond to ista1 ', or estrogen antagonists. Fn particular, the 2-feml-3- aroj 1 benzothio tones and 1"(aJ qui lamí noetox fem]) - 1 - fem 1 -? - 10 fen? Lbut - J -enos represented by rajoxy ene and tamox feno I read a wide application as estrogen agonists.

Raloxifene Tamoxifen It has been claimed that raloxen is effective in the treatment against acne, U.S. 5,439.9 3; Alopecia, EP 0659414 R2; Rlzheimer's disease, document TP 0659418 Al; a + cutaneous and vaginal rofia, U.S. 5,461,064; autoinrnune disease, EP 0664123; breast cancer, U.S. 4,418, (168, breast disease, ? 5 EP 0659419; cartilage degeneration, U.S. 5,418,252; problems of the CNS (Central Nervous System) (postmenopausi os), document 94 EP 03094ÍO; pathology of endocrine target organs, U.S. 4,418,068; delayed puberty, U.S. 5,451,589; mzante desmiel disease, U.S., 5,434,166; di srnenorre, U.S. 5,446,053; endornetp osi s, U.S. 5,451,065; female sterility, EP 659429 Al; fertility disorders; hirsu + i mo, document FP 0659414 A ?, hi poglucerru eos, EP 635264 02; increase of libido, U.S. document 5,439,931; fertility inhibition, U.S. 5,462,949; Oxidation of LDL, EP 0664121 fl; hi pereolest rol ia, document U.S. 5,464,845; lupus eptomatous, document FP 0664125; damaged brain function, EP 659425 AL; male sterility, EP 0659424 Al; myocardial infarction, ischemia, tromerboembolic disorder, trichomba inhibition, EP 066412b, menopausal disorders, EP document (1659415; menstruation disorders, US document, 5,462,950; obesity, document 94 EP 0309481; obsessive-compulsive disorder, document EP 0659428, osteoporos, US 5,457,117, ovarian dysgenes, US 5,451,589, peprnenopaus co syndrome, US 5,391,557, peripheral vasoconstriction, US 5,470,883, post-mortem CNS disorder, EP 0659415, premenstrual syndrome, US Pat. No. 5,389,670, prostatic carcinoma, prostatic carcinoma, pulmonary hypertension, document US 5,447,941, re-fusion lesion, 3 Am. Cardiol., 25, 189A (1993), resistant neoplasm, EP 0652004 Al, restenosis, document U.S. 5,462,937; rtr + p +? s rheumatoid, EP 0664125; «Seborrhea, U. S. 5,439,923; sexual distress; sexual precocity, U.S. 5,451,590; expression of t rombotnodul i na, document FP 0659427; Turner syndrome, U.S. 5,441,966; Uterine fibrosis, U.S. . 457,116; and vasomotor symptoms f postrnenopau ico), document 94 LP 0309473. Tainoxifene was extensively used in the treatment of breast cancer and has been described as effective in the treatment of the following diseases and disorders: elevated levels of drugs, Drug, Thor 22/3, 109 ( 1992); ovarian cancer, 3. Clin. Oncol. 11, No. 1957-58 (1993); renal cell carcinoma, Br. 3. Radiol 56, NP 670, 766-7 (1983); suppression of ether factor genome of hornocistoj na, Fnv. "i.

Cancer 29 suppl., 6, S110 (1993); metastatic melanoma, i.

Clin, Oncol, 12, HQ e, 1553-60 (1994); mastalgict, Drugs 3 ?, No 6, 477-80 (1986); pituitary tumors that secrete prolactin, 3. Endocrine! , Invest. 3/4, 343-347 (1980); ost eoporos s, Proc. Annu Meet Am Assoc. Cancer Res .; 33: A566--7 (1992); retropireneal fibrosis, Lancet 341, N < ? 8841, 382 (1993). Small structural changes in the structure of estrogen agonists cause large differences in biological properties. For example, the droloxifene (3-hydroxyarynoxy phen?) Of formula I below has a binding affinity of 10 to 60 times higher than the estrogen receptor as compared to ta oxyphene. Phloraxi-phene is free from cinnamon-i or mutagenic effects m vivo or in vxtro, while thioxifene causes tumor-liver in rats, Hasrnarnu, and other cancer- Letter 84, 101-166 ( 1994) It has been reported that droloxy ene is effective in the treatment of breast cancer, US 5,047,431; endomet posis, U.S. document 5,455,275; decrease in cholesterol, U.S. 5,426,123; osteoporosis, U.S. 5,254,594; prostatic hyperplasia, document U. s. 5,441,986; and restenosis, U.S. 5,384,332 BRIEF DESCRIPTION OF THE INVENTION This invention provides a method for inhibiting a pathological disorder selected from the group consisting of Alzheimer's disease, premenstrual syndrome, pneumonia syndrome, rhombomodulin deficiency, uterine fibrosis, excessive activity of the myeloperoxidases, excessive thrombin, autoimmune disease, Jesión? or reperfusion of the ischemic myocardium and insufficient testosterone, which comprises administering to a mammal on need of inhibition of said pathological disorder, an effective amount of a compound of formula. where O or so selects between OH2 and NR; B, D and F are independently selected between CU and N; And it is (a) Phenyl, optionally substituted with 1 3 its 1-independently echoes between R *, - (b) naphthyl, optionally substituted with 1-3 its elements independently selected from R '; (c) C3Cycloalkyl Ce, optionally substituted with 1-2 substituents independently selected from R1; (d) C3-C3-cycloalkenyl, optionally substituted with 1-2 substituents, independently selected from R4; (e) a five-membered heterocycle (tere contains up to two heteroatoms selected from the group consisting of -0-, NR2, and -S (0) n-, opc lonally e us it io co 1-3 its 11 uyen < independently selected from R *, (f) a six-link heterocycle - containing up to two heteroamines selected from the group consisting of -0-, -NR2 -s (0) n-, optional substituted with 1- 3 substituents i dependently selected from R *, or (g) a bicyclic ring system composed of a heterocyclic ring of five to six links condensed with a phenol ring, said hot ring containing up to two heteroatoms selected from the group consisting of -0-, -NR2, and - (0) n -, option 1 ent and substituted with 1-3 substitutes independently selected from R *, s (a) ~ (CH2) PU (CH2 ) q- (b) -0 (CH2) PCRSR6-; (c) -0ÍCH2) pU (CII2) q; di) 0CHR2CHR3 -; 0 (e) SCHR2CHR3-. (. is (a) -NR7R8; (b) in (where n is 0, 1 or 2, n is 1, 2 or 3, Z2 is -NH-, -0-, ~ S- or -CH2-; optionally condensed in the adjacent carbon atoms, with one or two phenyl rings, optionally substituted independently on the carbon with one to three substituents and, optionally and independently, on the nitrogen with a chemically suitable substituent selected from R *, - or a bicyclic amine containing from five to twelve carbon atoms, either bridged or condensed and, optionally substituted with 1 to 3 substituents selected independently from *; 0 71 and G combined can be -OR U is (a) -CH2; (b) -CU-CU-; (c) -0-; (d) -NR2 -; (e) -S (0) n; . ) 0 __ (l) i. , (g) - CR2 (OH) -; (h) -C0NR2-; (i) -NR2C0; (J) or (K) - C ~ C-, R is hydrogen or alkyl Ci -Ce R2 and R3 -on j ndcpendient emento (a) hydrogen; or (b) the Ci-Ct; Rl os (a) hydrogen; (b) halogen; (c)? l what the C -C ?,? (d) C 1 -Ct alkoxy; (e) acyloxy Ci -Ct,; (f) l qui 1 uncle Ci -Ct,; (g) alkyl sulfini or CiCt,; (h) alquilsul foni lo C? -Ct,; (i) ludrox lal qui lo Ci -O4; (j) i-il ltjui lo C1-C-4; (I--) -CO2H; (1) - CN; (m) OONHOR: f) -SO2NHR; (o) -NI-I2; (p) to the quilammo Ci -Ct,; ((I) say l 1 a J not Ci -Ct,; (r) -NHSO2; (s) -N02; (t) - a 1 - 11 or; u (u) -OH, RS R6 yon independently Ci -Cß alkyl or together form a C3-C10 carbocyclic ring; 7 and R8 t> indecently (A) I (b) a C3-C10 carbocyclic ring, saturated or unsaturated; ) a C3-C10 heterocyclic ring containing up to two heteroatoines selected from -0-, -N- and -S-; (d) ll; (e) Ci-Ce alkyl; or (f) for-man a ring (th) contains a 3- to 8-membered nitrogen with Pß or R6, R7 and Rβ in a linear or ring form may be optionally substituted with up to three substitutes independently selected from Ci-C6 alkyl, halogen, alkoxy, hydroxyl and carboxyl. box i; an ani formed by R7 and Pβ can optionally be condensed with a phenyl ring; e e s 0, 1 or 2; rn is 1, '.' or 3; n 0, 1 o? - p is fi, l or 3 q is 0, 1, 2 or 3; and its geometric and optical isomers; and its non-toxic pharmacologically acceptable quaternary ammonium salts, acid addition salts, N-oxides and quaternary ammonium salts. The preferred compounds of formula 1 are those of foil: on what G - R1 is H, OH, F or Cl; and B and E are independently selected ent -e Ch and N. The compounds especially preterred are: ü? s-6- (4-f 1 uoro-f in 11) -5-C4. I 2. p i pend i n-l-11-ethoxy) feru 13-, 6-7, 3-trahydro-naphthale-2-ol; () Cis- 6-fen? 1-5-E4- (2-pi r-rol? D? -1-yl-ethoxy l fem 1) - 5, 6, 7, 8-t etrahí ro-naftalen - 2-ol; Ci s- 6- eni 1 -5-T - (-piron! ii -l -ll -et oxy) foni 11- 5, 6,, 8- etrahí dro- aft len-2 oi, C is - 1 - f 6 '-f) ir-role? d? noet x? -3 '-pi id? l] ~ 2 - faith ni 1-6-hi droxi -1.2.3.4 -tet rah? rona f tal eno; 1- (4'-pyrr-olid noethoxy feru 1) -2- (4"-f luor-ofenyl) -6-hydroxy-L, 2, 3, 4-tet there roixoquinol i na; C is - fi - (4-h? Drox? Phen? 1) -5-r4- (2-p? Pepd? Nl-? L-ethoxy) feni 11 - 5, 6, 7, 8-t ethere dro -naftalen- 2-ol; and 1 ~ (4 '? rrol i dinoeto i faith ni 1) -2- phenyl-b-hi xi-l,, 3,4-tet ra fu d ro i so < j u i no 1 i na.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods for inhibiting pathological disorders that are susceptible or partially susceptible to inhibition by an estrogen antigen estrogen or estrogen agonist. Such disorders include Alzheimer's disease, premensual syndrome, pepminopausal syndrome, rhombomodulin deficiency, uterine fibrosis, excessive myeloperox idase activity, excessive thrombin, autoimmune disease, reperfusion injury of the ischemic myocardium and insufficient testosterone. Alzheimer's disease (AD) is a degenerative disorder of the brain, clinically characterized by progressive loss of memory, cognition, reasoning ability, judgment and emotional stability, which gradually leads to profound mental deterioration and finally A 1? death. AD is a common cause of progressive mental failure (dementia) in the elderly and is considered the fourth most common medical cause of death in the United States, which has been observed in many races and ethnic groups throughout the United States. It is currently estimated that the disease affects approximately three million individuals in the United States alone, and to date, AD has proven to be incurable.The brains of individuals with AD present neurological degeneration and characteristic lesions, variously named emiloidogenic plaques, vascular-amyloid angiopathy, and neurofibrillary margins. Large numbers of these lesions, particularly plaques to iloidogenics and neurofibrillar tangles, are generally found in several areas of the human brain important for memory and cognitive function, in patients with AF, small amounts of these lesions with a The most restricted anatomical distribution is found in the bodies of older people who do not have clinical AD. Iloidogenic plaques and vascular iloid angiopathy also characterize the brains of individuals with tpsomia 21 (üown syndrome) and hereditary cerebral hemorrhage with a iloidosis of the Dutch type. At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients (who have died of disease, or in rare cases, in small samples of brain tissue biopsies taken during a neurosurgical procedure). Several lines of evidence indicate that progressive deposition gives proteins to particular iloi dogéni, proteins (ß-AP), plays a seminal role in the pathogenesis of AD and may precede years or decades to cognitive symptoms Tyease Sel koe (1991), Neuron 6; 4871. Recently it has been demon- strated that ß-APs are released from neuronal cells developed in cultures and are present in the cerebrospinal fluid (CSF) of both normal individuals and of patients with AD [see Se ert et al. (1992), Nature, 359; 325-3273.) A possible correlation with the pathology of the plaques., which demonstrates the direct neurotoxicity of ß-AP to cultured neurons, has been developed by 'several groups. It has recently been published that the direct neurotoxicity of β-AP can be attenuated by combined treatment with TGF-p (Chao et al., Soc. Neuroscí, Abs., 19: 1251 (1993).) More recently, in addition to direct neurotoxicity , an inflammatory response in the brain of patients with AD, possibly caused by ß-AP, also contributes to the pathology of the disease.A limited clinical trial with NSAID inhibition showed an improvement in the progress of Alzheimer's dementia. (Rogere and others, Science, 260; 260: 1. ? 19-1-720 (1999). European patent application 0659418 Al describes the use of certain benzothiophenes for the inhibition of Alzheimer's disease. Despite the progress that has been made in the knowledge of the underlying mechanisms of AD, there remains a need to develop compositions and procedures for the treatment of these diseases. Treatment procedures should be advantageously based on drugs that are capable of increasing the expression of TGF-β in the brain, thus alleviating the neurotoxicity induced by β-amyloid peptides and the inflammatory response associated with AF. Every month, for a few days before the onset of menstruation, many millions of healthy women develop symptoms of upset mood and appetite, which can be quite similar to those described by patients with Seasonal Affective Disorder (SAI)), obesity with desire for carbohydrates or non-anorexic variants of bulimia. This syndrome was initially called "tension emest a1" for R. T. Frank in .1031 and is a very common phenomenon. According to Ouy Ahrham of CLA, out of every ten patients who attend the ecological consultation, three or four suffer pre-menstrual t-insion and, in some, the symptoms will be of such severity that they include suicide attempts. Current Progress in Obstetrics and Gynecology, 3: 5-39 (1980), Early descriptions of Premestrual Syndrome (PMS) focused on its association with nervous tension, headaches and weight gain. The observed weight gain was attributed initially to excessive retention of > salts and water, which in fact occurs in some patients with PMS. However, it soon became clear that this too was a consequence of the widespread tendency among individuals suffering from PMS to desire and consume excess carbohydrates, particularly foods with a sweet taste. Currently, SPM is also called stage syndrome (or late luteal phase disorder) D.N..S.III, Revi sed, American Paych? Af laughs Associ a ion (1987). Numerous suggestions have been made about the etiology of PMS. For example, some suggest that it is caused by a uterine toxin. Others pointed out that their cause was excessive consumption of sweets, which was presumed to be blerne and followed by excessive insulin secretion, hypoglycaemia and inadequate level of glucose in the brain and caused the depression and anxiety frequently observed. It has also been explained that the symptoms of the behavior originate from the edema of the tissue frequently observed and that the psychological changes are originated by feelings of loss or social complexes generated by the discomfort of the adjustment. has maintained none of these theories, PMS may persist after hyperventilation and, therefore, can not be caused by uterine toxins, the hyper-sulphism of PMS is not associated with low blood glucose levels and probably, in of the cause is the consequence of an aberration of the behavior (say, the tendency of the premenopausal woman to choose diets rich in carbohydrates, which potentiate the secretion of insulin), the mood and appetite changes of the PMS they relate poorly to tissue swelling, and subhuman primates that are presumably exempt from the psychodynamic or social complexes of human life also exhibit changes in behavior premenstrual characteristics. Many treatments have been indicated to overcome or reduce the symptoms of PMS. These include carbohydrate-free diets, vitamin supplements, ovarian hormones, testoxylating agents, irradiation of the ovaries and pituitary and use of diuretics. All these techniques, however, have had limited success. Late Disfopco Late Luteal Disorder (TDFLT) is the common term associated with Premenstrual Syndrome (PMS). Many women describe a series of physical and emotional changes associated with specific phases of the menstrual cycle. Par-a Id rnayur part of these women, these changes are not serious, cause small sufferings and have no effe <social or occupational performance. As a contrast, the essential characteristic of TDFI T is a paron of clinically significant emotional and behavioral symptoms that occur during the last week of the luteal phase and remit in the first days after the follicular phase begins. In the majority of women, these symptoms appear in the previous week and remit a few days after the onset of menstruation. The TDFLT is diagnosed only if the symptoms are severe enough [to cause marked damage in social or occupational activity and has been present during a large part of the menstrual cycles in the last year. Among the most commonly experienced symptoms are marked effective frailty (for example, sudden episodes of crying, sadness or irritability), persistent feelings of irritability, anger or tension, feelings of depression, and self-deprecating thoughts. There is also less interest in habitual activities, fatigue and loss (energy, subjective feeling of difficulty in concentration, changes in appetite, desire for certain foods (especially carbohydrates) and disturbed sleep. Other physical symptoms, such as tenderness or swelling of the breasts, headaches, muscle or joint pain, wheezing and weight gain are present.Fn general non-steroidal anti-inflammatory drugs are administered with TDFI-T but these are only effective for some of the physical symptoms.The physical manifestations of PMS, if severe, can be treated symptomatically.Retention of water can be alleviated by diet or antidiuretic medication, but the severity of water retention is not always related to psychological symptoms, recent studies have suggested that spironolactone (Aldactone, Searle) can also be It is also effective in relieving depression and crying episodes. Other drugs have been tried, including progesterone, lithium carbonate, tiarides, diuretics, antidepressants and bromocpptine (Parlodel®, Sandoz) with unsurpassed success. U.S. Patent 5389670 describes the use of certain benzot lophenes for the treatment of TDFLT / SPM. In view of the drawbacks and insufficiencies with the existing procedures to treat SPM / TDELT, the search for new therapies continues. The term "pepmenopausic" refers to the time in a woman's life between premenopause (reproductive years) and postmenopause. This period usually runs from 40-60 years, but more often several years above or below 50 years of age. This period will be characterized by a rapid change in the hormonal balance of a woman. Although many different times are subject to rapid fluctuation during this time, the most notable are the sex hormones and, in particular, the estrogens and, to a lesser extent, the progestones. The cause of this fluctuation is the natural and time-dependent cessation of the ovapca function. The characteristic moment of the end of the pepanenopausal period and the beginning of the post-midpalaic period is the cessation of ovapca function or its inability to regulate the previously normal ovulation cycle in women. The cessation of function is clinically marked by the cessation of menstruation in a period of one year or more. The period of time during which the ovarian function persists, that is to say the perineuropausal time, is normally not a rapid or sudden event. The Pepanenopausal state may last from a few months to more commonly a year or more. As previously mentioned, perimenopause is marked by fluctuations in the female hormonal composition, and these fluctuations are marked in many sequelae. Sometimes, these sequelae occur without problems for the woman, however, there is often a source of discomfort and concern of moderate to severe and that are occasionally the origin of pathological events or even hardening for the sake of the vi ... These are sequels in the period pepminopausic the A list of common, fairly idiosyncratic sequelae resulting from the entry into the menopause are: hot flushes and sweats, "'atrophic aginitis, headaches, vertigo, lack of concentration, irri-ability, loss of libido. pain in the joints, lack of sleep, apathy, lassitude, muscle weakness and palpitations ("The Enopause", Ed. R. 3. Beard, Umversity of Paris, 1976, Chapter II). A "menopausal or pepernopausal syndrome" accentuated with depression Although there is some controversy in itself, it is really a psychiatric syndrome or not, pepminopause is a contributing factor ("Earpson's Principles of International Medicine", Ed. 3. 3. i Ibacher , and others, 9th ed McGra -hill hook Co., 1980, pp. 1782-1783) In extreme cases, some of these sequelae in certain women are pathological (such as fluid retention and imbalance) or even threaten their lives especially in those women predisposed to the effects of depression. However, for most women, an important cause of their gender and concern is not due to the appearance of one or more of these events but rather to the period that they will have to endure and their predictable nature. It is already unreasonable to believe that a treatment can reverse the course of aging, the clinical technique to the treatment of perirenepa syndrome, if it has been based on its relief, specifically, a peprinenopausal woman in need of treatment is administered a protocol. With the descending scale of exogenous estrogens, this has the effect of slowly taking the patient to the postmenopausal state, since, although the exogenous estrogens effectively treat the symptoms of the perimenopausal disease, they do not stop the inexorable decline of the ovarian function. Frequently, this therapy of descending scaling requires a prolonged period (as long as several years in extreme cases) in order to allow the cessation of ovarian function at the time when exogenous estrogen administration ends. Therapy is effective and is approved, with many side effects. Trogens are due not only to estrogen, but also to concomitant progestin. In many cases, estrogen and progestin should be administered to the woman with a uterus, either together or as usual in a cyclic protocol. The reason for this combined administration is to reduce the risk of endogenous cancer that has the only orthodontic administration. The effects of progestins are often poorly tolerated by many women, causing depression or even denying the healthy effects of estrogens. By themselves, estrogens often cause unwanted side effects such as water retention, weight gain, hypertension, etc. The result is frequently the lack of compliance by the patient with the therapy and the consequent suffering of the peprnenopausal symptoms. ideally, an improved therapy would be an agent that would relieve the symptoms of peppanopausal syndrome, but avoid or minimize the side effects.In addition, this ideal therapy would also reduce the period to bring the woman to a postmenopausal or stable state. U.S. Patent 5,391, 557 describes a treatment for the pep-enopausic syndrome comprising the administration of certain benzo compounds, the process of blood coagulation, thrombosis, is triggered by a complex proteolytic cascade that It leads to the formation of trichromb The thrombi annul etholytically the activation of the pep- tides of the chains Aay Eß of f ibp nogeno, which is soluble in the plasma, initiating the formation of insoluble fibrin.The anticoagulation is achieved Norrnalrriäte por- the administration of hepapnas and curnapnas.Parential pharmacological control of coagulation and thrombosis are based on the inhibition of thrombin through the use of hepapnas. Hepaps act indirectly on the thrombus by accelerating the inhibitory effect of the endogenous TTT antithrombin (the main inhibitor) of thrombin).

Due to the levels of Til vanan antitrombma in the plasma and due to the presence of resistance to this indirect mechanism, the hepaphas may be an ineffective treatment since certain coagulation assays are believed to be ineffective. are effectively and reliably associated with hepapine levels normally controlled by coagulation assays (particularly the activated parental activated thromboplast time assay (aPTT).) Coumarins prevent the generation of thrombin by blocking gamma carboxylation. After the translation in the synthesis of protrornbine and other proteins of this type, due to its mechanism of action, the effect of cumans can only develop slowly, 6-24 hours after administration. + as are not selective anticoaguLanf.es .. Cougars also need role with coagulation tests (particularly in time trial of p ot r'ornbi na). or the invention, the following brief description of the enzymatic coagulation system is included. The coagulation system, sometimes referred to as a "cascade", is best seen as a chain reaction involving the sequential activation of zirnogens in the activated senna proteases that ultimately lead to the production of the enzyme, trhubbin, trichina. , by means of a limited protein, converts the plasma fibpnogen into an insoluble gel, fibrin., Two fundamental events in the coagulation cascade are the conversion of the coagulation factor X into Xa by the coagulation factor TXa, and the conversion of protam bma in thrombin by the coagulation factor Xa. These reactions occur both on the surface of the cells, but especially the surfaces of platelets and endothelial cells and both reactions require eofactors. The main factors, factors V and VTIE, circulate as relatively inactive precursors, but when the first thrombin molecules are formed, trinbin 5 activates the cofactors, by means of limited proteolysis. The activated cofactors, Va and VTTIa, accelerate, approximately in three orders of magnitude, both the protornbi a conversion in trombombina and the conversion of factor X into factor Xa. Activated protein C prefers to do1 ', subst rats of plasmatic proteins that hydrolyzes and destillates irreversibly. These plasma protein substrates are the active forms of coagulation coagulants V and VIII (cofactors Va and Villa, respectively). Activated protein C only degrades minimally the precursor-is inactive, a knowing, coagulation factor V and VIII. In dogs, the prof cradle 0 activated Y) has been shown to increase the pronounced levels in circulation of the most important physiological fibrinolytic enzyme, the tissue plasm activator. The activation of protein C, however, implies thrombin, the final septa protease in the coagulation cascade, and a membrane-associated glycoprotein of 1? endoteliai cell, the ombomodul i na. The thrombus forms a strong 1: 1 stequimetic complex with the thrombus. When it is complexing with tro bma, the borodyodium tro modifies - > i: substantially the functional properties of the trumpet, in the coagulation pathway, normally coagulates the fibrinogen,. > > , activates the platelets and converts coagulation coagulators V and VIT into their activated forms, Va and Villa. Itetro Bina, by itself, activates Professor C, but only very slowly and ineffectively. In contrast, the trope when it is in the complex 1: 1 with fornomodulin, is unable to clot fibpnogen, does not activate the platelets and does not convert the coagulation factor V and VI into its activated forms. The complex t rornbi a: t rombomoduli a promotes the activation of protein C, being the constant of activation speed (Je the pr-ote to C up to 20,000 times higher for the complex tr bina-trombornodulma than the constant of speed for the to bina sola., Activated Rote C is an antio ro geous agent with a broader therapeutic response than other anticoagulants, such as hepanna and oral anticoagulants such as hidroxicu apna, such as warfapna. Neither protein 0 nor protein or mole a are effective until thromboma is generated at the exact site. Protein C activated is practically ineffective without trichinella, since the conversion by the trinbin of the coagulation factors V in Va and VIII in Villa is necessary. As indicated, the activated forms of these two cofactors are the preferred substrate of activated protein C. The zymogen of the C protein when infused into patients, remains inactive until trornb na is generated. Without the complex protein: trornomodulin, the zirnogen becomes protoin C at a very slow rate. US Pat. No. 5,476,862 discloses a method for increasing the expression of t-rombornodulin using certain benzoyl compounds. Uterine fibrosis is an old and always present clinical problem (it is known by a number of names including uterine hypertrophy, uterine linoin, iornetrium hypertrophy, fibrous uteri and fibrotic metritis.

Essentially, uterine fibrosis is a disorder in which there is inadequate deposition of fibroid tissue on the wall of the uterus. This disorder is a cause of dysfunction and sterility in women. The exact cause of this disorder is not well understood although the evidence suggests that it is an inadequate response of the fibroid tissue to the estrogens.

Said tr-astorno has been produced in rabbits by daily spraying administrations for 3 months. In guinea pigs, the disorder has occurred by the target administration of estrogens for four months. In addition, in rats, estrogens provoke a hyper optic immunity AI-. The most common treatment of uterine fibrosis involves surgical procedures, costly and often leading to complications such as the formation of abdominal adhesions and infections. In some patients, the initial surgery is temporary and the fibroids grow back. In these cases, a hysterectomy is performed that definitively forms with the fibroids, but also with the reproductive life of the patient. In addition, antagonists of gonadotropin-releasing hormone can be administered, although their use is limited by the fact that they can lead to usto? Poi'üsi s. U.S. Patent 5,457,116 describes a method of inhibiting uterine fibrosis by treatment with certain benzoth or phono compounds. Aufoinrnune diseases involve an aberrant regulation of cellular and humoral induced immunity and are often associated with enhanced functions of T cells, cells and the effects of macrophages directed towards the antigens themselves. It is believed that the activation of these cellular components towards the anti genos themselves, is related to the breakage > -n the mechanisms' le r et r-oal iment ation associated with own tolerance. The autoimmune diseases encompass a broad spectrum of clinical entities and, despite differences in the target organ, have many similarities, including their predominance in females of childbearing age with a female to male ratio that varies from 50: 1 in Hashirnoto's roidifis, at 10: 1 in systemic lupus enterostosis (SLE), at 2: 1 in severe asthenia (Ahmed and others Arn 3. Path., 121: 531 (1905). all characterized by chronicity, tendency to clinical remission and "bursting" for poorly understood reasons, and the involvement of other organs.Although all autoimmune diseases have been ritually denounced, the presence of autoantibodies, inadequate expression of ampoules type II, macrophage activation and infiltration of T cells in the target organ, neither the triggering mechanisms that originate the activation of the disease nor the progression of the disease are well understood. The use of gold, rnetotre to, antirnalpac, glycocorticoids (methiiprednisolone), and other immune suppressants, as well as plas- ranophoresis and attempts to induce tolerance, is very important for these diseases. The treatment of autoimmune diseases has not been significantly improved in the past decade and is mainly associated with the use of non-spheroidal antinuclear agents and spheroids to treat the symptoms of the disease. Clearly, although it is necessary to suppress the specific immune response directed against the host, generalized immunosuppression with gl icoids has greater risks in terms of profile of side effects and propensity of the patient in some cases to support a greater risk of other non-infectious diseases. Pelio orfonucloar leukocytes (PMNL) play a regulatory role in inflammatory diseases. These cells, when activated, synthesize and release mol- ecules with central oxygen, chemoattractants and hydrolytic enzymes.

There is evidence that central oxygen molecules play a damaging role in a number of diseases such as chronic inflammatory diseases., rheumatoid arthritis, SLE and others. In the case of an autoimmune disease, SLE, for example, the onset of an inflammatory response are the antigens themselves, which stimulate the neutrophil and those of a host or PMNL pair (to secrete strong oxidants that damage cells and surrounding tissue). Estrogens appear to be involved in autoimmune diseases although their role in the progression or regression of the disease is complex and depends on the nature of the autoimmune disease.For example, estrogens appear to have a relief effect on rheumatoid arthritis, while that have an exaeerbador effect on lupus in tematoso (Chander S Specfor; Ann, Rheurn. Dis, 50: 139). Co or has described 3ansson Free Rad Res Co ms, 13 (3), 195-208 (1991) (added in this reference), estrogens increase the activity of an enzyme generated by PMHL, the ielopero idasa, which regulates the production of oxidants from hydrogen peroxide. This enzyme converts hydrogen peroxide into hypochlorous acid, a strong oxidant. By increasing the activity of the enzyme, and therefore the presence of hypochlorous acid, the possibility of increased oxidative strength on the cells, tissue and various rnacromolecules in chronic inflammatory / autoimmune diseases is raised. IT document PE 664 126 Al describes that the inhibition of Iodoperoxidase can be carried out by means of oltage with certain 3-aroyl bentriotiums. Excess of inieloper'oxi dasa is associated with disorders including sys- temic lupus erythematosus, Hashirnoto thyroiditis, myasthenia gravis, remato- toid arthritis, and multiple sclerosis. It has been described that the derivatives of 2-fem-3-aroylbenzothiophenes inhibit trope, see EP 0664126 A1. It has been shown that estrogens play a suppressive role on the function of T cells and also a immuno-stimulatory effect. On the B cells, therefore, the compounds behave as estrogens dernost rara beneficial in autoimmune diseases associated with activated T cells, including rheumatoid arthritis, multiple sclerosis, syndrome (Je Guillan Earre and Hashunoto thyroiditis by the inhibition of T cell function 1-lol? nadahl, 3. Autouninu.2: 6 1 (198) "In addition to the estrogen suppressive effects on T cells, estrogens can play additional protective roles. al., (3. Clin., Tnvest. 92: 1866 (1993)) have recently described that antioxidant.es suppress the expression endoofel to that of VCAM-1. VCAM-l is the ligand of VI.A-4, the mtegpna of T cells and maerofagos associated with the movement of these cells outward-of the vasculature and into the interior of the pepvasc? Lar space and target organs. Since the spherogen is an 11 ant oxidant, it is anticipated that estrogens and related logs inhibit the transfer of VllLA-4 dependent cells and thus hinder the immune cascade, associated with the autoimmune and immune media. Estrogens play a damaging role in other forms of autoimmune diseases that include systemic lupus and glornerulonephritis, diseases associated with immune complexes, while the immune system (s) responsible for the progression of The estrogen-induced disease is not known, the ability of the genes to increase Fc-induced phagocytosis has been described (Friedman et al., 3. Clin. Invest. 75: 162 (1985) and the expression Type II antigens and production of IL-1 by macrophages on rodents treated with estrogens (FIynn, Life Sci., 38: 2455 (1986).) The potentiation of these effector functions induced by macrophages would be expected to contribute to the immune cascade associated with the Aut odest rucci n In EP 664123 Al it is described that certain 2-fem-3-aro-lbenzot-ofenos are effective inhibitors of in fe ry of sa ut oi nm u n s Pre-nosnopausal women have a lower risk of coronary heart disease (jue hom of their age, and it has been shown that treatment with estrogen protects against cardiovascular diseases in post-encephaly women. Hale and Kloner have shown that prior treatment with estradiol reduces the intensity of myocardial infarction caused by occlusion of the coronary artery in both male and female rabbits. 3. Arn. Coll. Cardiol. 25., 189A (1995). In men, small amounts of estrogens are produced by the aostation of testosterone in the testes and peripheral tissues. Although present only in small amounts, usually less than a quarter to a tenth of the pre-enopausal woman, estrogens play a role in the regulation of gonadal pituitary hypothalamus in men, bone development, development of the prostate and function et abol ica. In the hypothalamus, the conversion of testosterone to estrogen results in a negative feedback on the gonadotropin-releasing hormone and the subsequent release of ganadotropin. Thus, estrogens normally reduce circulating testosterone and antiestrogens produce the corresponding increases. As the age of man advances, the proportion of fat to lean tissue increases gradually. Gradually increasing the testosterone level in fat can lead to proportions of estrogen to testosterone and to the negative feedback that reduces the total levels of sphosterone. It is recognized that hypogonadism occurs commonly in elderly men. A number of studies have suggested that hypogonadism may cause some of the observed decreases in muscle and skeletal mass associated with increasing age. Recent studies have suggested that androgen therapy produces a small but significant improvement <; jn muscle strength in eugonadal males. Testosterone deficiency has been associated with hip fracture and bone mass has been related to levels (Je testosterone in elderly people) Men who received testosterone had a significant increase in the concentration of biodispoment osterone test, hernatocp, muscle strength in the right hand and concentration of osteolcal.These had a decrease in cholesterol levels (without a change in cholesterol).

HDL) and lower BUN / creatimna relations. Morley, et al., AGS 41: 149-150 (1993). The term "inhibit" is defined to include its generally accepted meaning, which includes the prophylactic treatment of a subject to prevent the onset of one or more of these disease states, to keep the symptoms under observation (said disease state and Thus, the present methods include therapeutic and / or prophylactic medical treatment, as appropriate, the procedures of this invention are carried out by administering to an individual in need of treatment an effective amount of treatment. a compound of formula I. In commonly owned U.S. Patent Application No. 08 / 369,954, which is added in the foregoing reference, it is disclosed that the compounds of Forrnulai I are effective in the treatment of prostatic disease, breast cancer, osoporosis, endo et al, cardiovascular disease and hyperocholesterole ia I Chloroalkyl Ci -3 and f1 uoralkyl Ci-5 C3 in ethyl, propyl and isopropyl methyl substituted to a desired degree with chlorine or fluorine atoms, from a Atom to the complete substitution. The term C5-C7 cycloalkyl includes c lopentyl, cyclohexyl and cycloheptyl. Halo means chlorine, bromine, iodine and fluoro, Aplo 10 (Ar) includes femlo and optional naphthyl substituted with one to three susphuents, independently selected from R * as defined above. DTT means ditiot reifol. DMSO means dimethyl sulfo gone. AEDT means acid eti lend iami no-tet raacetico. The estrogen agonists are defined herein as chemical compounds capable of binding to a estrogen receptor site in mammalian tissue and mimicking the actions of estrogen in one or more tissues. The estrogen antagonists are defined herein as chemical compounds capable of binding to an estrogen receptor site in mammalian tissue and blocking the actions of the ostrogens in one or more tissues. described in this invention will be chemically ' > > They are incompatible with others or with the compounds of the invention, and these incompatibilities in the selection of the compounds of this invention will be avoided. Likewise, certain functional groups may require protective groups during synthetic procedures (which the chemist initiated in the art will recognize) The chemist initiated in the art will recognize that certain compounds (ie, this invention will contain atoms which may be present in the art). A particular optical or geometric configuration All these isomers are included in this invention, by way of example, the left-handed isomers are preferred with configuration c.Also, the chemist will recognize that various esters and pharmaceutically acceptable salts can be prepared from ( All of these esters and salts are included in this invention.Remedies for disorders and diseases for use in the methods of this invention can be prepared by the procedures customarily employed using conventional organic or inorganic additives, such as excipients (eg sucrose, starch, a nitol, sorbitol, lactose, glucose, cellulose, talcum, calcium phosphate or calcium carbonate), a binder (for example, cellulose, methylous cell, hydroxymethyl cellulose, polypropylpyrope, polyvinylpyrrolidone). i donut, gelatin, gum arabic, po11 e111eng11co1, sucrose or starch), a disintegrant (for example, starch, carbohydrate 11 cel or slab, hid oxyprop 11 to Irní don, little substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (for example, magnesium raph, anhydrous silicic acid, talc or sodium lauplsulfate), a flavoring agent (for example, citric acid, menthol, glycine or orange powder), a preservative (e.g., sodium benzoate, sodium bisulfite, metho-11 paraben or propLlparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., inet i L-cellulose, poly vimlpyrrolidone or aluminum stearate), a dispersing agent (for example, hydroxypropyl cellulose), a diluent (e.g., water), and a waxy base (e.g., cocoa butter, petrolatum, or polyethylene glycol). The amount of active ingredient in the medical composition can reach a level of exert the desired therapeutic effect; for example, from approximately 0.1 mg to 50 mg per dose unit for both oral and parental administration. The active ingredient can be administered normally from one to four times a day with a dose unit of 0.1 to 50 g in human patients, but the previous dosage - I can vary appropriately depending on the age, body weight and medical condition of the patient and the type of administration. A preferred vain dose of 0.25 g to 25 mg in human patient. 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 T are conveniently prepared from an unsaturated intermediate by drowning with a catalyst of a noble metal in an inert solvent (reaction) The pressure and temperatures are not critical and the hydrogenation is usually carried out in a few hours at room temperature and from 13.8 x 10 * to 55.2 x 10 * Pa of hydrogen pressure The hydrogenated product is isolated, purified if desired and the ether group is broken with an acid catalyst in an inert solvent (Reaction), at a temperature of 0 ° C to 100 ° C. C, depending on the acid catalyst used, has been found (for this reaction they are effective, hydrogen bromide at high temperature, bromine bromide and aluminum chloride at 0 ° C at room temperature. Formula I is isolated and purified by conventional procedures Intermediates of Formula II wherein A is CH2 and B, D and E are CH are described in U.S. Patent 3,274,213; 3. Med. Chern. 10, 78 (1967), 3. Med. Chern., 10, 138 (1967), and 3. Med. Chern. 12, 881 (1969), whose Cryptions are added in the present as references. These can also be prepared by the procedures described below. the preparation of the compounds of Formula I in which e-1, A-CH2, Zi = 0CH2CH2 G = c? cloalq? lapu na, R = CH is shown in Scheme 1. Loe compounds 1-2 in the that I) and E are Cl-I are prepared by alkylation of 4-brornophenol with the corresponding N-cl oroet 1 sheet using potassium carbonate as the base in a polar aprotic solvent + at < orno dimet ilforrnamide at elevated temperatures. A preferred temperature is 100 ° C. Compounds 1-2 in which D or E or both are N are synthesized using a nucleophilic displacement reaction carried out on dibromides (1-1) using hydroxyethylcycloalkyl lamins under phase transfer conditions providing bro olamide (1). -2) Synthesis, J_, 573 (1980). After the metal exchange, using n-butyl 1-lithium or metallic magnesium, the broades (1-2) provide the corresponding lithium or magnesium reagent, which is to be reacted at low temperature in the presence, preferably, of cesium chloride uro (without cesium chloride also the reaction proceeds with 6-rnefoxy-1-tet ralone providing carbinols (1-3) or styrenes (1-4) After (Acid treatment) The treatment of carbinoles (1-3) or styrenes (1-4) with a tartar or pebble brominating agent (pipdimobromide), provides bromoesti (1-5) The chlorides of anl or heteroapl zinc or the acids ap 1 or heteroap Lbororu eos react with bromides (1-5) in the presence of metallic pallet catalyst such as tet r-aquist p-phenylphosphine palladium (0), providing diap lesfi renes (1-6). [Puré S Applied Chem. 6, 419 (1991) and Bull. Bhe. Soc. 3pn. 61, 3008-3010 (1988)]. To prepare the preterm compounds, substituted phenyl zinc chlorides or substituted fatty acids are used in this reaction. The zinc apl chlorides are prepared by stopping the corresponding lithium reagent with anhydrous zinc chloride. The aryl boron cos acids, which are not commercially available, are prepared by quenching the corresponding apolythium reagent with triallyl quiloborate, preferably trirnethyl or tisopropy 1-bor-ato, followed by treatment with aqueous acid. Acta Chernica S an. 47., 221-230 (1993). Lithium reagents that are not available commercially are prepared by halide metal exchange of the bromine or corresponding halide with n-butyl or t-butyl-lithium. Finally, the lithium reagent is prepared by lithiations provided by heteroatoms as described in Organic React, Volume 27, Chapter 1. The catalytic hydrogen of 1-6 in the presence of palladium hydroxide on carbon. n, for example, provides the corresponding dihydroxy dihydroxy intermediates that will subsequently be developed using tp boron bromide at 0 ° C in methyl chloride, or 48% hydrogen bromide in acetic acid at 80-100 ° C. providing the desired structures (1-7). These compounds are racemic and can be separated into the enanfanorans by high pressure liquid chromatography using a column with a quirai stationary phase or the Chiracel OD columns. Alternatively, the optical separation can be carried out by recollection of the s <.diastereoisomers with optically pure acids such as 1, 1 '-bi na flyl -2-2'-dulohydrogen phosphate (see Example fl). The cis (1-7) compounds can be isomerized to the compounds t ans by base treatment (see Example 2). When D and / or F is nitrogen, the intermediates (Formula II) and compounds (Je Formula I) can be prepared from the corresponding dihalopyrins or pinmidines as illustrated in Scheme 1 and is fully described for 6- phen? -5-T6- (2-p? rrol? d? nl-? l-eto?) p? p din -3- 111-5,6,7,8-ft rahidronaff alen-2-ol in Example 6. The methyl ether of the compound of Formula T in which ei, A-CH2, Z1 = 00122CH2 G = cycloalkyl, D, F, B = CH, Y = Ph can also be conveniently prepared by a first hydrogenation step of nafoxidma (Upjohn Co., 700 Portage Road, Kalamazoo, MI 49001) in an inert reaction solvent in the presence of a noble metal catalyst.The pressure and temperature are not critical; conveniently in ethanol at room temperature for about 20 hours at 34.5 x 10 * Pa. The second step is the breakdown of the methoxy group which is conveniently carried out at room temperature with a Acid catalyst such as boron-boron tp in an inert reaction solvent at 80-100 ° C are hydrogen bromide in acetic acid. The product is then isolated by conventional procedures and converted to the desired acid salt.

SCHEME 1 1-6 Compounds (Je fopnula T in which B is nitrogen are prepared by the procedures illustrated in Schemes 2 and 3 and in Figures 3-5 and 10-12 .The synthesis of the compounds of Formula T in the (Thu B = N is presented in Scheme 2. Acid chlorides from (1) to rtre with primary amines provide secondary arylamides (2-2) that are reduced with hydride (lithium and aluminum in ether solvents) providing secondary amines (2-3) The subsequent acylation of (2-3) with aplo chlorides leads to tertiary amides (2-4), which are cyclized in hot phosphorus oxychloride to give dihydroisoquinolium salts i (2-5) The reduction with sodium borohydride in alkoxyhydroquinolones, followed by desrnetification with tb boron bromide in methylene chloride provides the desired structures.

SCHEME 2 H2NHY to I 2-5 the synthesis of the compounds of Formula T wherein B = N are also described below in Scheme 3. Secondary amines (3-1) when acylated with chlorides (benzyloxyaryl (3-2) give tertiary amides (3-) 3), which when cycled with hot phosphorus oxychloride, provide dihydroisoquinol salts to (3-4). The reduction with sodium borohydride of (3-4) followed by debenzylation with aqueous hydrochloric acid provides the isoquinol ace (3-). 5), which are alkylated with the appropriately functionalized chlorides and de-neuter with tp boron bromide to provide the desired structures.

SCHEME 3 Although in the processes of the present invention the free base formulation of formula compounds can be used, it is necessary to prepare and use a pharmaceutically acceptable salt form. Therefore, the compounds used in the processes of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of inorganic acids and, preferably, organic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. This invention Typical inorganic acids used to form said salts include hydrochloric acid, hydrobromic acid, iodhydric acid, nitric acid, sulfuric acid, phosphoric acid, hypophosphorous acid and the like, salts derived from organic acids, such as acidic mono- and di-acidic acids, can also be used. carbox i 11 eos, alkanoic phenylsulphuric acids, hydroxyalkanoic and hydroxyalkane dioxide acids, aromatic acids aliphatic and aromatic sulfonic acids and acids. Said pharmaceutically acceptable salts include, therefore, acephate, phenylacetamide, tp fluoroacetafo, actable, ascorbate, benzoate, chlorobenzoate, dimethenobenzoate, hydroxybenzoate, rnetoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide,? SoL. ? time, fem lbutyrate, ß-hydroxybutyrate, but? no-1, -d? oato, hexmo-1, -d? oato, caprate, caprylate, chloride, cmamate, citrate, for iate, smokes time, gli collate, heptanoate, hipurate, lactate, malate, rnaleate, hydroxyrnaleate, malonate, mandelato, mesylate, icotinate, 4? ison cotinato, nitrate, oxalate, phthalate, tera phthalate, phosphate, rnonohi dro geno t osf ato, di hydrogen phosphate, rneta fos phito, pyrophosphate, propylate, proponate, reml propionate, salicylate, sebacate, succinate, suberate, sulfan , bisulfate, pyrosulfate, sulfite, bisulphite, sulfonate, benzenesulphone or, p-brornophenylsulphonate, chlorbenzenesulfonate, ethanesulfonate, 2-hydroxybenzoate, methanesulfate, naphthalene-1-sulphonate, naphthalene-2-sulphonate, p-toluenesulfonate, xi lenosulfonate, farfrate and the like. A preferred salt is the cyclic salt, The pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of an acid. The reactants are generally combined in a mutual solvent, such as ethyl ether or benzene. The salt normally precipitates in the solution in a time of about one hour to ten days and can be isolated by iltration or the solvent can be separated by convincing means. Pharmaceutically acceptable salts of compounds of formula? they have increased solubility characteristics, compared to the compound from which they are derived, and therefore are often as manageable for their formulation as liquids or emulsions. Once the free base or salt form of the compounds of formula 1 can be admixed by the methods described herein to an individual in need of treatment. The following non-limiting test examples illustrate the methods of the present invention. In the methods of the present invention, the compounds of formula I are administered continuously or 1 to 4 times daily. As used herein, the term "effective amount" means an amount of compound of the methods of the present invention that is capable of inhibiting the symptoms of the pathological conditions described herein, the specific dose of a compound administered in accordance therewith. invention will be determined, of course, by the particular circumstances surrounding the case, which include, for example, the compound administered, the route of administration, the condition of the patient and severity of the pathological disorders to be treated. A typical target dose will contain a non-toxic dose level of approximately 0.25 mg to approximately 100 mg / day of compound of the present invention. Preferred target doses will be from about 10 mg to about 0 mg / day. The compounds of this invention can be administered by a number of routes, including the oral, rectal, fransdernic, subcutaneous, intravenous, intramuscular or intranasal routes. . Preferably, these compounds are formulated before their administration, the selection of which will be decided by the attending physician. Typically, a compound (Formula I or a pharmaceutically acceptable salt) is combined. of the same, with a pharmaceutically acceptable vehicle, diluyenfe or excipient, to form a fariñaceut i ca formulation. The total active ingredients in these formulations constitute 0. 1% to 19. 1% by weight of the formulation. "Pharmaceutically acceptable" means that the carrier, diluent, excipients and / or salt must be compatible with the formulation ingredients and not deleterious to the recipient of this formulation. -mula I can be prepared by procedures known in the art, using well-known and readily available ingredients, For example, the compounds of formula r can be formulated with excipients, diluyent.es or common vehicles and formulated into tablets, capsules, suspensions, powders and the like Examples of excipients, diluents and vehicles which are suitable for such formulations include the following fillers and extenders such as starch, sugars and rnanitol, binding agents such as silicic derivatives, carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and pol nor Ipirroiidona; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; dissolving retarding agents such as par-atina; resorption accelerators such as quaternary ammonium compounds; surfactants such as cetyl alcohol and glycerol monostearate; adsorbent vehicles such as kaolin and bentor ta; and lubricants such as talc, calcium and magnesium stearate and polyethylene glycol and solvents. The compounds may also be formulated as elixirs or solutions for convenient oral administration, or as solutions suitable for parenteral administration, for example, intramuscularly, subcutaneously or intravenously. Accordingly, the compounds are suitable for formulations as sustained release dosage forms and the like. The formulations can be constituted in such a way that they release the active ingredient only or preferably in a particular physiological location, possibly over a period of time.The coatings, envelopes and protective matrices can be made-, for example, of substances Polymers or waxes The compounds of formula I will generally be administered in a convenient formulation The following examples of formulations are illustrative only and are not intended to limit the scope of the present invention In the following formulations, "active ingredient" means a compound Formula I or one of its salts For the purpose 1: Gelatin capsules Hard gelatin capsules are prepared using the following ingredients: Amount of Amount (mg / capsul) Active ingredient 0.25 100 Starch (ND 0-650 Fluid starch powder 0-50 Fluid syrup, 350 centimeter is 0-15 ^ Irepar-a formulation in tablets using the ingredients i gu lens; Formulation 2: com p p m i s s Ingredient Amount (ing / com r uní do) active ingredient 0.25-100 Cellulose rnicrocp stalma 200 -b50 Plicio dioxide p? rol? s? < 10-6 0 F s t e r rat e rna gne s i co 5-1 The components are mixed and compressed for f rprin es. Alternatively, they are prepared as follows tablets each containing 0.25-400 rng of active ingredient.

Formulation 3: tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25-100 Starch (NF) 45 Cellulose icrocristal ma 35 Polivi i 1 pirrol i dona (10% aqueous solution) 4 Garboxunetiicel ulosa sodium 4.5 Magnesium stearate Ll. 5 Talc 1 The active ingredient, starch and cellulose are thoroughly mixed and passed through a No. 45 mesh U.S. The polymer solution is mixed with the resulting powder, which is then passed through a No. 10 mesh U.S. Then the oarboxi et i Icelulosa, magnesium stearate and talc are added, previously passed through a No. 60 sieve (US mesh), to the granules which, after mixing, are compressed in a compression machine to produce compressors. Suspensions are prepared each containing 0.25-100 mg medically per 5 ml dose, as follows: Formulation 4; Suspensions Ingredient Can i a / 5 mi) Active ingredient 0.25-100 ing Carboximet ilceuiosa sodium 50 rng Will give be 1.25 rng Solution Benzoic acid 0.10 ml Aroma c.s.

Colorant c.s. Agua purifica (Ja c.s. for 5 mi The drug is passed through a No. 45 mesh U.S. and it is mixed with carboxy ef and sodium L-cellulose and with the syrup to form a smooth paste. The benzoic acid solution, the aroma and the dye are diluted with some water and added with agitation. Then enough water is added to produce the required volume. A solution of an aerosol containing the following ingredients is prepared: Formulation 5; a o o 1 Tongredient Quantity (% by weight) Active ingredient 0.25 Ftanol 25-75 Propellant 22 (chlorodi fl uor-ometane) 70 00 b4 The active ingredient is mixed with ethane 1 and the mixture is added to a portion of propellant 22, cooled to 30 ° C and transferred to a filling device. The added amount is then added to a stainless steel container and diluted with the remaining propellant. The valve units are then attached to the vessel. Suppositories are prepared as follows: Formulation 6: suppositories Ingreient Amount (mg / suppository) I ngrediente acti or 250 Glicepdos of saturated fatty acids 2,000 The active ingredient is passed through a sieve n ° 50 U.S. and is suspended in the glycends of saturated fatty acids, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of 2 g nominal capacity and allowed to cool. An intravenous formulation is prepared as if ue :: Formulation 7: intravenous solution Ingredient e Canti (J d Active ingredient 20 Saline solution ísotomca 1. 00 mi - > ' The solution of the above ingredients is administered intravenously to a patient, at a rate of approximately 1 rnl per minute.

Assays for the Inhibition of Alzheimer's Disease Fn patent PE 0659418 describes assays for compounds effective in the treatment of the disease of the incised zhei can acquire "my haines from Ha chern Inc., Tor ranee, California", Peninsula Laboratories Inc (Bel onf, California) and Sigina Chemicals (St. Louis, 110). One can acquire peptide 'fi-arniloid (1-40) and peptide of f3-am? Lo? Of reverse (40-1) (Je achein Inc.) It can be acquired ß2-rrucroglobulin from Sigina Chemicals (St. Louis Missouri Fresh peptide stock solutions (1 inM) are prepared in sterile, pyrogen-free water and diluted in defined culture media at the indicated concentrations.Red hippocampus cultures are treated (10-14 days vi tro) The viability of the cortical cultures of rats is visually evaluated by phase contrast microscopy and quantified by measuring the lactate dehydrogenase (LDH) released to the culture media.

Assay 1 Primary hippocampal neurons are cultured in vitro with standard cell culture techniques. It is added to the 5 b cultures of peptide cells gone amyloid beta (Aß) to a toxic concent - tion usually 25 to 50 μM. After 4 days of treatment, viability is evaluated by measuring lactate dehi (Jrogenase (LDH) released to the culture medium.) Lactate dehydrogenase (LDH) is measured in aliquots of 20 μl of defined D? EM conditioned, using an assay standard kinetics of LDH at 340 nrn (number 220-20 of the Si ma catalog) in a 96-well format The assays are performed at 37 ° C in a microplate Biol-inetics plate reader-computer-based- ( Biofek Inst uments), using a Delta Soft II (v.3.308, from Biofet to Tc.) Software for data analysis In each test, quality and control pat- The results are expressed as units and HDI of the serum (for example, controls of 2N and 2E enzymes, Je Sigma) .The results are expressed as units and IDH / l, (Jonde 1 unite. 'len enzyme that can catalyze! <-> formation of 1 ic ornol (Je nicot i na ida adenine dinucleot gone per minute, in the trial conditions. For protection studies, a compound of formula 1 is added to the cultures before, and / or simultaneously with, the treatment with arní loide ß. The activity of the compounds of formula 1 is illustrated by a decrease in the LDH released to the media (a neurotrophic indicator), compared to the control.

Test 2 Fnt c five and fifty are subjected to 15 minutes of occlusion (four blood vessels to induce total ischemia) A compound of the invention is administered to experimental and control animals before, simultaneously with, and / or after hours The animals are sacrificed 3 days after the ischemic lesion and the neurological damage in the hippocampus and in the striatum is evaluated visually by standard histological techniques. Formula 1 is illustrated by a decrease in neurological damage.

Trial 3 For the clinical study, five to fifty women are selected. The women are postmenopausal, that is to say, they have left behind between 6 and 12 months before the beginning of the study, they have been diagnosed with Alzheimer's disease in the initial phase and they are supposed to have worsening symptoms. period of the study, but therefore they 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 intervention and the other. -or receives a placebo.In patients, a reference point is marked in terms of memory, cognition, reasoning power and other symptoms associated with AF »Women in this group receive between 10 and 100 mg of agent 5B daily active orally. They continue this therapy for 6-36 months. Safe records of the symptoms are maintained with respect to the reference point 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 compared with the symptoms indicated by each patient before beginning the study. The activity of the drug tested is illustrated by an attenuation of the typical cognitive decline and / or the behavioral changes associated with f. The utility of the compounds of formula I is evidenced by their activity in at least one of the above tests.

ASSAY PROCEDURE FOR SPtl / TDFLT Three to fifty women are selected for the clinical study. Women have regular menstruation, have good general health, and have one or more of the symptoms of PMS / TDFLT mentioned above. Because of the somewhat subjective and idiosyncratic nature of these symptoms, the study has a placebo control group, that is, women are divided into groups., one of which receives the active agent of this invention and the other receives a placebo. Women in the trial group receive between 10-100 rng of the drug per day orally. They continue this therapy for 1-3 months. Safe records of the number and severity of symptoms are kept in both groups and at the end of the study these results are compared. The results are compared among the members of each group and the results are also compared for each patient with the symptoms described by each patient before (the study will begin.) See United States patent 5,389,670. The utility of the compounds of the invention to inhibit the symptoms of SPH / TDFLT is illustrated by the positive impact (these have on one or more symptoms when used in a study such as antiglobulin).

TEST PROCEDURE FOR INHIBITION OF THE SYNDROME PERIMENOPAUSICO Trial 1 Three women are selected between the age of 45-50 years as a trial group. Women present at least one of the consequences of impending menopause. A compound of the invention is administered in an amount of 10 to 100 g / day and the sequelae are closely monitored. The compound dosage of the invention is prolonged for a period of three (3) weeks.

Test 2 The same test as in Test 1 is carried out, however, the period of administration is three (3) months. 00 Test 3 r-e test is carried out as in Test 1, except that the dosing period is of ce? S (6) months. The activity, defined as the total cessation of one or more sequelae of the patient, or the reduction of the severity of its apap clone, or a more rapid advance to the menopausal state, in any of the above tests indicates that the compounds of the invention They are useful in the treatment of the syndrome inenopau í < ..or" ESSAYS FOR THE EXPRESSION OF INCREASED TROMBQMODULINE The following tests are described in the document FP 0659427 and in the United States Patent 5,476,862 which are hereby referenced.

Test 1 To further understand the action (s) of the compounds of formula 1, the intimal smooth muscle cells and their role in potentiating anticoagulation of the blood, it is necessary to investigate the changes in the activity (Thromboinodulm (TM) on the surface of these cell types.) The compounds of formula 1 can also be used to reverse / correct any effect of mediators that tend to regulate down to TM levels activity on the surface of the cell. These cells are planted approximately 40,000-80,000 cells endofeliales' committed to a premature arterial, venous or my crovascular passage) or of the intimate smooth muscle and reproduce until confluence in 24-well cell culture plates. The cell nucleus is then washed 2-3 times with saline-stabilized saline solution (SSHT), or with serum-free medium (MES). Over a period of 24 hours, various concentrations of a compound of formula 1 (ranging from micromolar to subpiconolar) are added to the cells by triplicate. The cells that are in the negative control wells are kept in serum-free medium with an equivalent amount of vehicle among all wells. The existing procedure is carried out to mediate TM activity on the cell surface by using a two-phase arnidolytic assay. During the first phase of the assay, after rinsing the cells with (SI-IT) or (MES), 0.4 ml of f ES) containing human protein C is added to the monolayer (final concentration 11..2 jjg / ml and a- human trichinella (final concentration 0.1 NIHI / ml) and incubated at 37 ° C and 5% CO2.After 15, 30 and 45 minutes, 100 , H) each of the wells and are added to 50 μl of excess hydrudm (anti-thrombin 20 U / ml) in wells for 5 minutes at 37 ° C to stop further thrombin activity. In the absence of cells, the MES as the G-prophecy and the alpha-rhombus, as described above, is used as a negative control and is similarly ratted. In the second phase of the assay, 50 μl of 2366 3 M, an erornogenic substrate of protein C, are added to the conditioned / hirudin mixture, and DO 05 (for a period of 4 minutes with a plate reader) is added. To control the kinetics of the TM activity, once this kinetic test is completed, the measurement of the total proteins is carried out using a BCA procedure.The final activity of the TM is expressed as% increase.

Trial 2 The mandrel model of sepsis induced by F. Coli, as described in the United States patent ,009,889 (added herein) to illustrate the effects of the compounds of formula 1 as ant 11. rornbot 1 eos and their ability to correct endothelial dysfunction induced by i flamation. The compounds of the invention are illustrated by the positive impact on the expression characteristics of thrombus or thrombotic disorder or the rate of activation of protein C, shown by any of the above tests.

ESSAYS FOR THE INHIBITION OF UTERINE FIBROSIS Trial 1 Three and 20 women who have uterine fibrosis with a compound are administered the invention The amount of compound administered ranges from 0.1 to 100 mg / day and the administration period is 3 months. during the period of administration and up to 3 months after the interruption of the compound to determine the effects of fibro uterine.

Test 2 The same procedure as in Test 1 is used, except that the administration period is 5 months.

Test 3 The same procedure as in Test 1 is used, except that the administration period is 1 year.

Test 4 A. Induction of fibroid tumors in guinea pigs. Prolonged stimulation with estrogens is used to induce-Jeioiniornas in sexually mature female guinea pigs. Animals are dosed with spradiol 3-5 times per week, by injection, for 2-4 months, or until the onset of tumors. The treatments consist of the daily administration of a compound of the invention or vehicle for 3-16 weeks and then the animals are sacrificed and the uteri are removed and analyzed to determine the regression of the tumor. B. Implantation of human uterine fibroid tissue in naked r-atons. Human leiomorphine tissue is implanted in the peritoneal cavity and / or the uterine myometrium of female mice, sexually mature, cast and naked. Exogenous rheugen estrogens are supplied to induce the growth of the explanted tissue. In some cases the tumor cells collected are cultured in vitro before implantation. The protein comprises a compound of the invention or vehicle that is delivered by enteral feeding daily for 3-16 weeks and the implants are removed and measured to determine growth or regression. At the time of sacrifice, the uteri are removed to assess the state of the organ.

Test 5 A. Tissue from fibroid tumors of human uterus is collected and maintained in a non-trans formed primary culture. Surgical specimens are passed through a sterile mesh or sieve or, alternatively, they are disintegrated with a needle separating from the tissue surrounding them to produce a suspension of single cells. The cells are maintained in a medium containing 10% serum and antibiotics. Growth rates are determined in the presence and absence of estrogen. The cells are tested for their ability to produce the complement component C3 and its response to growth factors and hb hormone increase. The in vitro cultures are evaluated for their response to the proliration after treatment with progestins, OnRH, a compound of the invention and vehicle. The levels of weekly steroid hormone receptors are evaluated to determine if the main characteristics of the cell are maintained in vitro. Tissue of 5-25 pacites is used. Act v i (Jad in at least one of the above tests indicates that the compounds of the invention have potential for the treatment of uterine fibrosis.

TESTS TO SHOW THE INHIBITION OF MYELOPEROXIDASE Test 1 In order to investigate the inhibition properties of the myeloperoxidase activity of the formula 1 compounds, tests 1 and 2 are used, as described in 3ansson (upra) In this test, PMN leukocytes are stimulated. human with strio !, to increase the activity of the ieloperoxidase in the presence of added hydrogen peroxide. The conversion (Je luminoi for the hypochlorous acid by chlumuminescence.) The reaction mixture comprises cells (106), agent or compound of formula 1 (1 μM), hydrogen peroxide (0.1 mM) and lurnmol (0.2 M) incubated «3r '° C. Estrogen and its analogs stimulate the activity of RNA peroxidase. The compounds of formula 1 antagonize the chemistry and the scenarios. Test 2 The purified human operoxidase was incubated with agent (estrogen or a compound of formula 1) in the presence of luminol at 37 ° C. The substrate, hydrogen peroxide, is added and the illumination is measured. The reaction mixture is MPF (ieloperoxidase) hurnna (250 ng), agent or compound of formula 1 (10 μM, titrated), hydrogen peroxide (1 nm) and lummol (0.2 inrn). The spherogens and their analogs have little, or no effect on the activity of the MPE, however, the compounds of the invention reduce the activity (ie, the purified MPE).

Trial 3 Five to fifty women are selected for the clinical trial, women have SLE or reurnatoid arthritis. Due to the subjective and idiosyncratic nature of these disorders, the study has a placebo control group, ie, women are divided into two groups, one of which receives a compound of formula 1 as active agent and the other receives a placebo. The women in the trial group receive between 50-100 mg of drug per day, orally. They continue with this therapy for 3-12 months. Safe records of the number and severity of symptoms are kept in both groups and at the end of the study these results are compared. The results are compared between the members of each group and the results for each patient are compared with the symptoms of each patient before the beginning of the study. The usefulness of the compounds formula 1 is illustrated by the positive impact they have in at least one of the tests described above.

TRIALS TO DEMONSTRATE THROMBIN INHIBITION Procedures - Effects on the Lysis of Human Plasma Clots by t-AP Human plasma clots are formed in test nucleotubes by the addition of 50 μl of trinbin (73 NIH units / ml) in 100 μl of human plasma containing 0.0229 μCi of fibnogen labeled with i25? (l) lysis of the clot is studied by covering the clots with 50 μl of urokinase or str-epfoqumase (50, 100 or 1000 units / rnl) and incubating dur-ante for 20 hours at room temperature. After incubation, the tubes are centrifuged in a Becl-'inan microcentrifuge, 25 μl of supernatant are added in a volume of 1.0 ml of 0.03 M tris buffer / 0.15 M NzCl for the gamma count. Per hundred lysis are obtained by the elimination of the troin (and substituting the buffer). The trhlorine inhibitors are evaluated to determine the possible interferences with fibnnol i si s, including the compounds in the solutions covered concentration nes 1, 5 and 10 μg / inl. Approximate IC 50 values are determined by linear extrapolation of the point junctions up to a value that can represent 50 percent of the lysis for that particular concentration of β 1 -polymer agent.

Anticoagulant Activity Materials Obtained rat plasma and dog plasma, conscious mixed-breed dogs (both sexes, Hazel ton-LRE, Kalainazoo, Michigan, USA) or anesthetized male Sprague-Dawley rats (Harían Sprague-Dawley, Inc ., Tndianapol i, Indiana, U.S.A) through a 3.8 percent citrate vempuncture. The fibrinogen is prepared from human blood ACD r-ec lens as fraction 1-2 according to the procedures and previous specifications. Srnith, Biochem. 3., 185. 1-11 (1900); and Sith, et al., Biochernist ry, 11, 2958-2967 (1972). Human fibpnogen is also purchased with a purity of 98 percent / plasmid-free, from American Diagnostica, Greenwich, Connecticut. ACTTN coagulation reagents, T romboplastm and human plasma are from Baxter Healthcare Corp., Dade Division, Miarru, Florida. Bovine thromboma is used Part-Davis (Ann Detroit, Michigan) for the plasma coagulation assays.

Procedures Anticoagulation Determinations The coagulation assay procedures are as previously described. Smith and others, Th rombosi Research, 50, 163-174 (1988). A GoAScreener coagulation instrument (Amen can Labor, Inc.) is used for all coagulation assay measurements. The prothrombin time (TP) is measured by the addition of 0.05 rnl of saline solution and 0.05 ml of Tromboplastma-C reagent in 0.05 i of test plasma. Activated partial boplastin time (aPTT) is measured by incubation of 0.05 rnl of test plasma with 0.05 ml of Actin reagent, for 120 seconds, followed by 0.05 rnl of CaCl2 (0.02 M). The rim time (TT) e measured by adding 0.05 ml of saline and 0.05 ml of thrombin (10 units MIH / ml) 0.05 rnl of test plasma. The compounds of formula I are added to human or animal plasma over a wide range of concentrations for long-term effects on TTP, TP and TT assays. Linear extrapolations are carried out to estimate the concentrations needed to double the coagulation time for each test.

Animals They are anesthetized with xylaze (20 mg / lgs.) And quet mine (120 mg / l-g, sc) male Dawley prague rats (350-425 g, Harlan Sprague Dawley Tnc. Tndianapol is, IN) and keep on a warm water blanket (37 ° C). A cuff is made in the jugular vein (s) to allow infusions.

Arteriovenous Derivation Model A cannula is made in the jugular-left vein and the right carotid artery with PE 60 polyethylene tubes 20 cm long. A large cross-section is adjusted by friction between the large sections of 6 cm of a larger tube (PE 190) with a cotton thread (5 c) in the tube cavity, to complete the arterio-venous shunt circuit. Blood is circulated through the shunt for 15 minutes before the thread is carefully removed and weighed. The weight of a wet yarn is subtracted from the total weight of the yarn and the thrombus (see 3. R. Smith, Br. 3. Pharmacol, 77:29, 1982).

Arterial Lesion Model by FeCl3 The carotid arteries are isolated by a ventral cervical incision in the central line. A thermocouple or each artery is placed and the temperature of the continuous form vessel is recorded on a recorder with recording tape. It is placed around each carotid directly on top of the pnopar tube sleeve (0.058 ID x 0.077 DF x 4 min, Baxter-Med. Grade Silicone), cut longitudinally. FeCl3 hexahydrate is dissolved in water and the n concentration (20 percent) in terms of the actual weight of FeCl3. To damage the artery and induce thrombosis, 2.85 μl is pipetted into the cuff to bathe the artery enclosed by the terrnopar probe. The arterial occlusion is indicated by a rapid drop in temperature. The occlusion time is expressed in minutes and represents the time elapsed between the application of FeCl3 and the rapid fall in vessel temperature (see K.D. Kurz, Thromb. Res., 60: 269, 1990).

Spontaneous Thrombolysis Model The data indicate that thrombin inhibitors inhibit thrombin and other septa proteases, such as plasma and the activator of the plasminogenum (Jel tissue) to assess whether the compounds inhibit fibpnolysis in vi t ro, the velocity is determined by spontaneous thrombolysis by implantation of a marked whole blood clot in the pulmonary circulation.The rat blood (1 ml) is mixed rapidly with bovine thromboembolism i " 4 Ul, Par e Davis) and human fibnogen I2s? (5 μCi, ICN), immediately extracted in the tubes and incubated at 37 ° C for 1 hour.The mature thrombi are removed from the tube, cut into segments of cm, washed 3 times in normal saline solution and each segment is counted in a gamma counter.A segment with a known count is aspirated into a catheter that is implanted followed (in the jugular vein only. catheter to the vicinity of the river The blood clot is expelled to allow it to float in the pulmonary circulation. One hour after the implant, the heart and lungs are collected and counted separately. Threadbolysis is expressed as a percentage in which: % of Tnbolbol i if s- (cp i nyectados-cpm of the lung) xl 00 crnp injected * -, The dissolution of the implanted clot that occurs depends on time (see P. Clozel, Cardiovas .. Pharmacol., 12: 520, 1988).

Parameters of the Coagulation The trilbin time (TT) and the time of activated partial trombomoplastin (YYPa) of the plasma are determined with a fibroinetro. The blood is extracted from a jugular catheter and it is? Collect in a nge (contains sodium treatment (3.0 percent, 1 part to 9 parts of blood) To measure the TT, mix rat plasma (0.1 ml) with saline solution (0.1 rnl) and bovine trichina (0.1 rni, 30 U / rnl in TRIS buffer, Par e Davis) a 37 ° C. For the aPTT, plasma (0.1 ml) and solution of APTT (0.2 ml, Organon Tekmka) for 5 minutes (37 ° C) and added (37 ° C) and CaCl2 (0.025 M) is added to initiate coagulation. The tests are carried out in duplicate and are averaged.

Bioavailability index A measure of the bioactivity, plasma time in the plasma (TT) serves as a substitute for the assay of the parent compound, based on the fact that the increases in TT are produced only by the inhibition of the hormone by the precursor. The time course of the effect of the + rhombus inhibitor on TT is determined after the administration of a bolus i.v. to anesthetized rats and after oral treatment of conscious rats subjected to fasting. Due to the blood volume measurements and the number of points needed to determine the time course from the treatment time to the time when the response returns to the predetermined values, two populations of rats are used. Each sample population represented alternating sequential times. The mean TT during the course of time is used to calculate the < -Under the curve (ABC). The biodi sponsiveness index is calculated using the formula shown below and expressed as a percentage of relative activity. The area under the curve (ABC) of the time course of the TT in the plasma is determined and adjusted for the dose. This mdLce (Je bioavailability is called "% Relative Activity" and is calculated as % Relative Activity- ABC p.o. x Do * isi "v, x 100 ABC iv, Dosi pO, Compounds Solutions of the compounds are prepared new each day in the normal saline solution and injected as an intravenous bolus or infused, beginning 15 minutes before, and it continues throughout the experimental disturbance. The volume of the bolus injected is l l / kg per i.v., and 5 rnl / l- * g p.o. and the infusion volume is 3 rnl / hour.

Statistics The results are expressed as the measure «- D.E.M (average standard derivation). A branch vapancy analysis is used to detect statistically significant differences and then a Dunnett's test is applied to determine what the different means are. The level (meaning) for rejection of the hypotheses not valid for the same year is P <0.05.

Animals Male bulls (Beagle, 18 months-2 years, 12-13 l> -g Marshall Farrns, North Rose, New Yorl- 14516) are fasted overnight and fed with Purina Certifield Prescnpt ion Diet (Purina Mills, St. Louis, Mossoup) 240 minutes after dosing. Water is available at 11 bitu. The temperature of the room is maintained between 18.9 and 23.3 ° C; 45-50 percent relative humidity; and the light ent-e 0600 and 1800 hours. ? 5 Pharmacokinetic Model The test compound is formulated immediately before dosing by dissolving in sterile 0.9% saline to a 5 g / ml preparation. Dogs are given a single dose of 2 mg / kg of the test compound by enteral feeding. Blood samples (4.5 ml) are taken from the cephalic vein at 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours after the dose. Samples are collected in tied Vac? Tainer eifr tubes and kept on ice before reduction to plasma by ccntp leakage. The plasma samples are denatured with dinitrogen peroxide and analyzed by HPLC (Zorbax SB-G8 column) eluting with 500 mM rnetanol / sodium acetate, adjusted to pH 7 with phosphoric acid (60:40, v / v). ). It is recorded at the plasma concentration of the test compound and used to calculate the pharmacokinetic parameters: elimination rate constant, Ke; total purification, Dt; volume of distribution, VD; time of the maximum concentration of the test compound in plasma, Tma?; maximum concentration of the test compound in the Tma ?, Cmax; average life in the plasma, + -0.5; V the area under the curve, A..B..C; fraction of the absorbed test compound, F.

Canine Model of Coronary Arterial Thrombosis Surgical preparation and instrumentation (such as described in Jack and others, Circulation, 82, 930-940 (1990).) Are anesthetized with pen + obart i tal sodium (30 mg / lg intravenously, i.v.) mixed-breed dogs (6-7 months old, both sexes, Hazelton-I RE, Kalamazoo, MT, E.U.A.), came in and found themselves with air from the room. The tidal volume and respiratory rate are adjusted to maintain the PO2 PGO2 and pH in blood within normal limits. Subdermal needle electrodes are inserted for the recording (a two-lead FCG encephalogram) The left jugular vein and the primitive carotid artery are isolated by a left inferior-lateral incision in the neck 3. The blood tension is continuously measured. arterial blood sample (PA) with a pre-calibrated 'Millar' transducer (model MPC-500, Millar Instruments, Houston, TX, USA) inserted into the carotid artery.A jugular vein cannula was made for the blood samples during the experiment. In addition, a cannula is made in the lomoral veins of the two legs + raseras for administration (Jel test compound) A left thoraeotomy is performed in the fifth intercostal space and the heart is suspended in a peccardic support. A segment of 1 to 2 crn is isolated from the left circumflex coronary artery (ACC) proxunally to the first main diagonal ventpular branch. An anodic electrode is inserted into the ACC with a and a 26 gauge needle at the end (coated with Teflon, 30 gauge plated copper wire) of 3-4 m length and placed in contact with the intimal surface of the artery (confirmed at the end of the experiment). The simulation circuit is completed by placing the cathode in a subcutaneous (s.c.) site. An adjustable plastic occluder is placed around the ACC, over the electrode region. A pre-calibrated electromagnetic flow probe (Carolina Medical Electronics, Umg, WC, U.S.A.) is placed around the ACC, proxunal to the anode f >for the measurement of coronary blood flow (CBF). The occluder is adjusted to produce a 40-50 percent inhibition of the hyperepuco blood flow response, observed after mechanical occlusion of 10 s of the ACG. All hernodic and ECG measurements are recorded and analyzed with a data entry system (model M3000, Modular Instruments, Malvern, PA, E.U.A.).

Thrombus Formation and Compound Administration Guidelines The electrolyte lesion of the intima of the ACC is produced by the application of a direct current of 100 μa (CD) at the anode. The current is maintained for 60 minutes and then removed, whether or not the vessel has occluded. The formation of thrombi occurs spontaneously until the ACC is completely occluded (determined as zero FSC (coronary blood flow) and an increase in the S-T segment). The administration of the compound is started after the thrombus occlusion is allowed to mature for 1 hour. A 2-hour infusion of the compounds of the present invention at a dose of 0.5 and 1 mg / kg / hour is initiated simultaneously, with an infusion of thrombotic agent (for example, tissue plasminogen activator). retoqumase, APSAC). Reperfusion is continued for 3 hours after the administration of the test compound. The reocclusion of the coronary arteries after thrombolysis occurs is defined as zero FSC, which persists for> 30 minutes.

Atheological and Bleeding Time Determinations Model The cell count values are determined in •• complete angre, hemoglobin and hetocrtium in a sample of 40 μl of blood, with citrate (3.8 percent) (1 part of citrate: 9 parts of blood) with a hematological analyzer (Cell-Dyn 900, Sequoia-Turner Mount View, CA, USA). The bleeding times model in the gingiva are determined with a device of the time (Je bleeding Simplate TI (organon Teknika Durha, NC, USA) .The device is used to make 2 horizontal incisions in the upper and lower jaw gingiva- Each incision is 3 mrn wide x 2 mm deep, the incisions are re-made and a stopwatch is used to determine how long the bleeding has taken place, a cotton swab is used to absorb the blood and This comes out of the incision The model bleeding time is the time from the incision to the stop of the blood, the bleeding times become just before the administration of the test compound (0 mm), 60 minutes in the infusion , at the end of the administration of the test compound (120 minutes) and At the end of the experiment, all the atos are analyzed by a branch valence analysis (ANOVA) followed by a Student-Neu an-Kuels t-test. dete to determine the level of significance. Repeated ANOVA measures are used to determine the significant differences between point times during the experiments. The value-is determined so that they are statistically different at least at the level of p < 0.05. All values are the mean + S.E.M. All studies are carried out in accordance with the principles determined by the Arnericarn Physiologi cal Society. Additional details regarding the procedures are described in ack on, and others, 3. Cardiovasc. Pharmacol., 21, 587-599 (1993). The compounds of the invention are also analyzed in the Bleeding Time model at 0.25, 0.50, and l.O mg / g. hr. The utility of the compounds of the invention is illustrated by the positive impact shown in any of the previous tests.

ESSAYS TO DEMONSTRATE THE INHIBITION OF AUTOIMMUNE DISEASE Test 1 The procedure is carried out as described in 00 Hol dahl et al., Clin. Exp. Tmniunol., 70, 373-378 (1987) (added in the present as reference). Four to thirty female mice are ovapectinized, with approximate ages of 8-10 weeks. The administration of a compound of the invention on the experimental group is started within three weeks after castration. After a week of rtd initiation of a compound of formula 1, the mice are immunized with collagen (Type II rat.) The r-atons are analyzed to determine the clinical severity of arthritis, as described in Holmdahl. and others, Arthptis Rheum., 29, 106 (1986), added in this reference. Serum is collected and tested with type II reactive anticolagen antibodies., cells are obtained from the spleen of the mice to determine the activity of the T cells. The activity is shown by a reduction in the concentration of anti-thelagen type TI antibodies determined by a conventional ELISA assay. The reduction in the activity of the T cells towards the type II col gene, exposed to the T cells of the spleen by the cells that present antigens, is evaluated by accounting for the synthesis of DNA by thymidine absorption. Finally, the clinical severity of the disease is evaluated daily by defining the first signs of erythema and inflammation of one or more limbs.The clinical assessment is corroborated by histological examination.

Test 2: Spr ague-Dawley food for animals and water ad libitu is administered to four young female rats. The experimental group receives a compound (Formula 1), and all rats receive rat medulla as generically as described in Arnason et al., Arch. Neurol., 21, 103-108 (1969), added In the present reference, the rabbits are valued for determining the signs of encephalomyelitis due to ex perior mental (FAF). Between three and seven weeks after the administration of a compound of formula 1 begins, They sacrifice the rats, remove their spinal cords and examine them.The activity is shown by the ease of a compound to inhibit EAE.

Test 3 Between five and fifty mice are used (MRL / lpr v NZB). The parameters evaluated are the reduction of anti-DNA antibodies, conti- nuised by ELISA, as well as changes in survival time and a histological examination of the kidneys. The r-atons are dosed with compounds of the invention and evaluated using the above parameters to determine the progression of the disease.

Trial 4 Five to fifty women are selected for the clinical study. Women are post-pneumonous, that is to say, they have ceased to enter the 6 and 12 months before the beginning of the study, they suffer from an autoimmune disease (which shows the symptoms, although on the other hand they are in good general health. Deludo to the idiosyncratic and subjective nature of these disorders, the study has a control group with placebo, that is, women are divided into two groups, one of which receives a compound of formula 1 as active agent and the other receives? placebo The women in the trial group receive 50-200 mg of the drug per day orally, they continue this therapy for 3-12 months, and safe records of the number and severity of the symptoms are maintained in both groups and These results are compared at the end of the study (the results are compared between the members of each group and the results for each patient are compared with the symptoms described by each patient before the start of the study. The utility of the compounds of formula I is illustrated by the positive impact (they have these in at least one of the tests described above.

ESSAY FOR THE PROTECTION OF THE ISCHEMIC MYOCARDIUM AGAINST REPERFUSION INJURY Ten male rabbits and ten females are treated with 1 mg of a compound of formula I. After 15 minutes, the rabbits are anesthetized and the coronary arteries are occluded (for 30 minutes, after four hours of reperfusion). The groups are treated with vehicle, the area of risk is assessed with blue dye and the area of infarction by staining with fetrazolium.A small size of the infarct area with respect to the control shows that the compound of formula I is effective to inhibit reperfusion damage to the ischemic myocardium.

Test Procedure to Demonstrate Increased Testosterone Level Sixty healthy males are selected from the ages of 62 to 75 years for evaluation according to the following criteria: Inclusions 1.- Body Weight between 90 and 130% of the average value of the ideal body weight as defined by Metropolifan Life Insurarance Table (Appendix 1) for men of average build. 2.- Serum testosterone in the examination less than 500 ng / dl. 3.- Specific prostatic antigen in serum less than or equal to 4 ng / ml. 4.- Clinical examination of the normal prostate and absence of suspicious nodules in the examination of the prostate by ultrasounds. 5.- Obvious absence of medical disease such as angina, myocardial infarction or angioplasty in the last 2 years, history of visceral cancer in the previous 5 years or prostate cancer in any omentum. 6.- Normal physical exploration examination, including normal cardiopulmonary examination, absence of vascular or peripheral venous disease or other evidence of systernic disease. 7 - The following values must be within 10% of the upper or lower range limits - normal when the report is made by the reference laboratory; RSC (coronary blood count), including hemoglobin, hernatocpto and total RSF (whole blood count).

Exclusions 1. - Men who smoke? . - Men with a previous history of boembolic disease or pulmonary embolism at any time of their lives., 3.- Men who consume more than 2 units of alcohol per day, equivalent to approximately 2 glasses of ./ino or 2 bottles. of ce i -ve a. 4.- Clinically significant abnormalities in the I1 Selection electrocardiogram. The study has a parallel design and is placebo controlled, comparing two doses of a compound of formula I at 10 and 40 rng / day versus placebo for 14 weeks. The subjects are randomly distributed in the compound or placebo. Testosterone levels are determined every two weeks with the RIA Case, Goaf-a-Count available from Diagnostic Products Go, 5700 U. 96th Street, Los Angeles, CA 90045. A statistically significant difference in testoeterone levels over placebo indicates that a compound of formula I is effective to increase serum testosterone.

Claims (11)

1. Ilh NOVELTY OF THE INVENTION CLAIMS l, - The use of a compound of formula in which A is selected from CH and NR; li, i) and F are independently selected from CU V N; Y e (a) femlo, optionally substituted with 1-3 substituents independently selected from R4; (b) naphthyl, optionally substituted with 1-3 20 sustifuyent.es independently selected from R «; (c) C3-C8 cycloaicil, optionally substituted with 1-2 independently selected substituents ent re R *; : > (d) ci cloalqueni C3-C8, optionally substituted with 1-2 sust 1? yent is independently \) 7 selected among R *; (e) a five-membered heterocycle containing up to two hexapheres selected from the group consisting of -0-, -NR2 - and -S (0) n-, optionally substituted with 1-3 substituents independently selected from R; () a six-link hot-cycle 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 R4; or (g) a bicyclic ring system composed of a heterocyclic ring of five to six links, condensed with a ring of femlo, said ring containing heterocyclic up to two heterotomes selected from the group consisting of -0 -, -HR2 and ~ S (0) n-, optionally substituted with 1-3 substituents independently selected from R *; (a) - (CH2) U (CH2) -; (b) -0 (GI-12) PCR5R6; (c) ~ 0 (CH
2. 2) P W (GH2) q; (d) -0GHR2GHR3 -; or (O - SGIIR CHR3 -; G is (a) -NR7 8; (b) wherein n is O, 1 or 2; rn is 1, 2 or 3; Z2 is -NH-, -0-, -S- or -CH2-; optionally condensed in the adjacent carbon atoms with one or two rings and optionally substituted independently on carbon with one to three substitutes and, optionally, independently on the nitrogen with a substitute . is chemically adequate selected ent re R *;; or (c) a biddic amine containing from five to twelve carbon atoms, either bridged or fused and optionally substituted with 1 to 3 substitutes is independently selected from R *; And G coinbi nados can be -OCH: U is (a) -CH2-; (b) --CH --- CH-; (c) -O-; (d) -NR2 - (e) -S (O) n -; (f) O 10 (g) -CR2 (0H) - (h) -G0NR2-; (l) -NR2G0-; (J) or (I-) - = - C-, 0 Hydrogen or alkyl Ci-C & 2 and R3? O independently (< ü hydr-ogen; or (b) to the cycli Ci-Ct,; K «is (b) halogen; (c) <? 1» μ? I 1 or Ci-C; d) to oox i Ci -Ct,; e) acilox i Ci -Ct,; ) al quilf ío Ci -Ct,; g) to the 1 i sulphi Ci -Ct,; h) alqui lsuí fomlo Ci -Ct,; i) hi droxialqui lo CiCt,; j) ar-ylalkyl C1-C; k) -CO2H; 1) - GN; 10) -CÜMHOR; n) -SO2NHR; o) -MH2; p) lquilammo Ci-C *; (I) dial qu 1 Lamí no Ci -Ct,; 15 r) -NH O2R; ) - N0; ) -a r-i lo; u u) -OH. R5 and 6 are independently Ci -Cß alkyl or, Together they form a C3-C10 carbocyclic ring; R7 and R8 are independently (a) f or 1 or; (b) a saturated or unsaturated carbocyclic ring or C3-Ci0; : > r-i (o) a ring heterooc 1 the ico G3-C10 containing up to two helices selected from -0-, -N- 9] and -S-; (d) H; () l uilo Ci -Cg; or (f) for-man a 3- to 8-membered ring (one containing a nitrogen with R5 or R6; R7 and R8 in a linear or ring form may optionally be substituted with up to three independently selected substituents in the C1- alkyl group. -Ce,, halogen, akoxy, hydroxy and carboxy; a ring formed by R? And R? Can be optionally condensed with a femium ring, e is 0, L or 2, is 1, 2 or 3; n is 0, 1 or 2, p is 0, 1, 2, 3, q 0, 1, 2 or, and their geometric and optical isomers, and their pharmaceutically acceptable acid addition salts, N-oxides and quaternary ammonium salts, non-toxic, in the preparation of compositions for inhibiting a pathological disorder selected from the group consisting of Alzheimer's disease, premestrual syndrome, perimenopausal syndrome, t rombomodulma deficiency, uterine fibrosis, excessive activity of inieloperox i dasa, excessive thiomhine, autoimmune disease, reperfusion injury of the myocardium ischemic and insufficient test, in a mammal. 2"- The use of a compound of formula 1, further characterized because the compound of formula I that is used is a compound of formula: 10 where G is
3. 3. - The use of a compound of the formula T according to claim 1, further characterized in that the compound of 2U formula I used is selected from the group consisting of: C? S-6- (4-f "luoro-feml) -5-r4- (2-??? epd? Nl-? L ~ ethoxy) fen? ll-5,6,7,8-tetrahydro-naphthalene-2-ol; (-) -C? s-6-phen? 1 -5- T4- (2-p? rol? d? nl ~? l -et oi) faith i 11- 5,6,7,8-tef raph idine phtalen - 2 - or 1; '. > 5 (-) -Gis- 6-f ni l - 5 -T - (2 irroli d? N-1-? 1 - tox i) eni 11- 5, fi, 7, H t ß trhid ro na phta 1 en 2 o 1; C i s - 1 - [6 '- ?? r-rolidinetoxy -3'-p? rid? ll-2- fe ni 1 -h-hi droxi -1, 2,3,4 -tet r-ahi drona ft le o; l- (4 '-pi r-rolidinoethoxifem) -2- (4' 'f luoro fen ll) -6-hydroxy-1,2,3,4-tet rahidroi soqui noJ ina; G i s -6- (4 '-hydroxy fem) -5-T4- (2-γ-er? Dm-l-? 1-ethoxy) pheny1] -5,6,7,8-. etrahí dronaftalen-2-ol; and! - (4'-p? rol? d oef oxy fem 1) -2-phen? l-6-h? drox? -1, 2.3, 4-tet rahí droisoqumo 1 i na.
4. 4. The use of a compound of formula T, according to claim 1, further characterized in that said pathological disorder is Alzheimer's disease.
5. 5. The use of a compound of the formula T, according to claim 1, further characterized in that said pathological disorder is a thrombomodulin deficiency.
6. 6. The one of a compound of formula I, according to r-oi vi ndication 1, further characterized because said pathological disorder is fibrosis or toruna.
7. 7. The use of a compound of formula 1, according to claim 1, further characterized in that said pathological disorder is excessive activity of ieloperoxi dasa.
8. The use of a compound of formula I, according to claim 1, further characterized because said pathological disorder is excessive t ro bina.
9. 9. The use of a compound of formula I, according to claim 1, further characterized in that said disorder p toLj < r or erifi medd'J. L? Foi n unites.
10. 10. The use of a compound of the formula I, according to claim 1, further characterized in that said pathological disorder is injury by reperfusion of the myocardium i squei i co.
11. 11. The use of a compound of formula I, according to claim 1, further characterized in that said pathological disorder is insufficient testorst erona. The use of a compound of formula I, according to the claim 1, further characterized by the fact that said pathological disorder is pre-mensual syndrome. 1 3. The use of a compound of formula I, according to claim 1, also characterized because said pathological disorder pre-enospausal syndrome.