MXPA99003614A - A method for lowering plasma levels of lipoprotein(a) - Google Patents

Abstract

A method of lowering plasma levels of Lp(a) or inhibiting the generation of apo(a) in a human by administering an effective amount of a compound of formula (I) wherein:R1 is hydrogen or alkyl;A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the&bgr;-position;or R2 with R4, R4 with A, A with R3, B with D, D with E, or G with R2 is a bond, and the other substituents are each hydrogen;or R2 is alkyl in the&bgr;-position and A, B, D, E, G, R3 and R4 are each hydrogen;or R3 is alkoxy in the&bgr;-position and A, B, D, E, G, R2 and R4 are each hydrogen;or R4 is hydrogen in the&agr;-position and A, B, D, E, G, R2 and R3 are each hydrogen;and R5 is methyl or ethyl, is disclosed.

Description

A METHOD TO REDUCE THE LEVELS OF LIPOPROTEIN (A) IN THE PLASMA FIELD OF THE INVENTION This invention is directed to a method for reducing the levels of 1 ipopro tein (a) in plasma in humans. In particular, this invention is directed to the use of certain 17-di f luo rome ti 1 en-estratriene s to reduce the levels of 1 ipopro tein (a) in the plasma of human beings, thus being useful in the treatment and prevention of premature occlusive arterial disease.

DESCRIPTION OF THE INVENTION 1 ipopro tein (a) (Lp (a)) is a single lipoprotein found in the plasma only of humans, some subhuman primates and the European hedgehog. Lp (a) is considered an independent risk factor for premature occlusive arterial diseases, such as atherosclerosis, coronary artery disease, myocardial infarction, cerebral infarction (shock), peripheral arterial disease and restenosis followed by balloon angioplasty. The structure of Lp (a) is closely related to LDL since it consists of LDL with an apo 1 ipopro t and ína linked with additional disulfide, apo (a). Apo (a) is covalently bound to the glycoprotein Apo B100 an integral part of LDL. Apo B100 allows the LDL molecule to carry hydrophobic cholesterol in the plasma and tissue fluids. In contrast, it is soluble in water and does not bind to liquids. The main site of apo (a) synthesis in plasma appears to be the liver. However, it is currently unknown where Lp (a) is assembled. LDL and apo (a) can be secreted independently from each other, and in assembly can occur in the plasma. This mechanism can explain why only a fraction of LDL, which varies from subject to subject, forms complex with apo (a). This fraction is determined by the amount of apo (a) secreted in place of the concentration of LDL in the plasma. From studies of in vitro production of Lp (a) in humans, it has been concluded that differences in plasma Lp (a) concentrations between individuals are a result of differences in synthesis rather than differences in the catabolism of Lp (a). High levels of Lp (a) in the plasma are associated with premature occlusive arterial disease, such as coronary heart disease (CHD) and shock. In addition, the association between concentrations of Lp (a) in serum and coronary artery disease (CAD) has been shown. In addition, the level of Lp (a) in plasma has been shown to correlate independently with the regimen of restenosis (after balloon angioplasty), peripheral arterial occlusive disease, diabetic vasculitis in Type II diabetes mellitus, risk increased CHD in patients undergoing continuous ambulatory peritoneal dialysis and pacemaker graft stenosis. Surprisingly, the associations of Lp (a) with other known risk factors for CHD, for example, plasma lipid levels (triglycerides, LDL, "HDL"), dietary fat intake, hypertension, diabetes, overweight and cigarette smoking have been consistently weak or absent and do not seem to explain the relationship of Lp (a) to CHD It is widely believed that the level of Lp (a) in the plasma is under strong genetic control, with non-genetic factors, including gender, diabetes mellitus and end-stage renal disease, having some influence.Lp (a) levels in men and women differ significantly and are influenced by physiological conditions such as puberty and menopause when the production of sex hormones is altered. L (a) in women continue to increase with age, particularly in the pre-menopausal years, while in men they level out at approximately 25 years of age. Levels of Lp (a) in plasma have been found to be higher in women than in menopausal women than in pre-menopausal women of comparable age. A genre related to the difference can also be observed in studies that have correlated Lp (a) levels with the degree of CAD angiography and documented. Levels of Lp ~ (a) in - plasma have also been shown to be more predictive of CAD in men than in women. The use of steroidal hormones (for example, estrogen, progesterone and testosterone) to reduce the levels of Lp (a) in the plasma. For example, it has been shown that plasma concentrations of Lp (a) are influenced by the administration of anabolic steroids, progesterone, estrogen and combination of estrogen and progestogen in post-menopausal women in men affected by prostate cancer, L (a) levels in plasma reduced by estrogen therapy are seen in 50%, whereas treatment or quidec t ómi co slightly increased the concentration of Lp (a) in plasma, suggesting that plasma and Testosterone exerts a regulatory role in serum Lp (a) levels in men, and it has now been found that certain 17-di f luo rorne ti 1 en-ratios are effective in inhibiting apo (a) generation. ) and are, consequently, effective in reducing plasma Lp (a) levels, and therefore are useful for treating disease states that are alleviated by inhibiting the generation of apo (a) or by reducing Lp levels (a ) at These compounds have not previously been described as having this functionality.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, an aspect of the invention is directed to a method for reducing the levels of Lp (a) in the plasma of a human being, said method comprises administering to a human being with the need thereof a effective amount of a compound of Formula (I): wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the ß position; or R2 with R4, R4 with A, A with R3, B with D, D with E, or G with R2 is a bond, and the other substituents are each a hydrogen; or R2 is "alkyl in the β-position and A, B, D, E, G, R3 and R4 are each hydrogen; or R3 is alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the position and A, B, D, E, G, R2 and R3 are each hydrogen; and R5 is methyl or ethyl. A further aspect of this invention is directed to a method for inhibiting the apolaj generation in a human being, said method comprising administering to a human being with the need thereof an effective amount of a compound of the formula (I) as It was defined earlier. Another aspect of this invention is directed to a method for treating a human being that has a disease state, which is alleviated by reducing the levels of Lp (a), said method comprises administering to the human being with the need thereof an amount therapeutically effective of a compound of the formula (I) as defined above. A further aspect of this invention is directed to a method for treating a human being that has a disease state that is alleviated by inhibiting the generation of apo (a), said method comprises administering to the human being with the need thereof a quantity therapeutically effective of a compound of the formula (I) as defined above. Another aspect of this invention is directed to a pharmaceutical composition useful for reducing the levels of Lp (a) in plasma in a human being, said composition comprising an effective amount of a compound of the formula (I) as defined above and a pharmaceutically acceptable excipient. A further aspect of this invention is directed to a pharmaceutical composition useful for inhibiting the generation of apo (a) in a human being, said composition comprising an effective amount of a compound of the formula (I) as defined above and an excipient pharmaceutically acceptable. Another aspect of this invention is directed to a method for inhibiting the generation of apo (a) in vi trooin by administering a compound of the formula "(I)" as defined above.

"DETAILED DESCRIPTION OF THE INVENTION Definitions As used in the specification --- and appended claims, unless otherwise specified / the following terms have the indicated meanings:" Alkyl "_. Refers to a radical of cad-ena straight or branched consisting only of carbon atoms e- hydrogen, containing no unsaturation and having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, butyl, 1-methylethyl (i so-propyl), 1, 1-dimethylethyl (e t-but i 1), pentyl, n-hexyl, n-decyl, and the like "" Alkoxy "refers to a radical of the formula -0Ra where Ra is alkyl as defined above, for example, methoxy, ethoxy, n-propoxy, n-heptoxy, and the like. "Premature occlusive arterial disease" refers to those disease states for the purposes of this invention, which are characterized by progressive narrowing and final closure of an artery or the narrowing process p rogressive and final closure of an artery, and where a) develops early in life than normal, and b) are associated with high levels of Lp (a) in the plasma, and includes, among other things, arteriosclerosis, atherosclerosis, coronary artery disease, peripheral artery disease, myocardial infarction, shock, restenosis and graft stenosis bypass. "Effective amount" refers to that amount of a compound of the formula (I) which, when administered to a human being, is sufficient to reduce the level of Lp (a) in the plasma or to inhibit the generation of apo ( to) .

"Therapeutically effective amount" refers to that amount of a compound of the formula (I) which, when administered to a human being with the need thereof is sufficient to effect the treatment, as defined below, for disease states which are alleviated through the reduction of Lp (a) levels in plasma or through inhibition of apo (a) generation. The amount of a compound of the formula (I) which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, and the age of the human being being treated, but can be routinely administered. some ordinary expert in the art considering his own knowledge and description. "Treat" or "treatment" as used herein covers the disease state in a human being, said disease status being alleviated through the reduction of plasma Lp (a) levels or inhibition in the apo (a) generation; and it includes: (i) preventing the occurrence of the disease state in a human being, in particular when said human being is predisposed to the state of the disease but has not yet been diagnosed as having it; (ii) inhibit the disease state, that is, stop its development; or (iii) alleviate the state of illness, that is, cause the regression of the condition of illness.

BRIEF DESCRIPTION OF THE DRAWINGS Several other objects, aspects and advantages of the invention will be more fully appreciated as it is better understood when considered together with the accompanying drawings, wherein: Figure 1 shows apo (a) levels in the plasma and uterine dry weight of transgenic mice with apo (a) from females or var ec omitted after treatment with any compound of formula (I) or vehicle.

Preferred Modes Of the various aspects of this invention set forth above, a preferred aspect is the method for reducing the levels of Lp (a) in the plasma in a human being, said method comprising administering to a human being with the need thereof a quantity effective of a compound of the formula (I) of the following formula: mainly 17-difluoromethylene-18-m.ethyl-tetra-1,3,5 (10) -trien-3-ol. Another preferred aspect of this invention is the method for inhibiting the generation of apo (a) in a human being, said method comprising administering to a human being with the need thereof an effective amount of the compound of the formula (I) as described previously. Another preferred aspect of this invention is the method to treat a human being who has a premature occlusive vascular disease, which is alleviated through the reduction of the levels of Lp (a) in the plasma, said method comprises administering to the being human with the need thereof a therapeutically effective amount of the compound of the formula (I) as described above.

Another preferred aspect of this invention is the method for treating a human being who has a premature occlusive vascular disease, which is alleviated through the inhibition of the generation of apq (a), said method comprises administering to the human being with the need thereof a therapeutically effective amount of the compound of the formula (I) as described above.

Utility of the Invention This invention is directed to methods for reducing the level of Lp (a) in plasma or for inhibiting-apo (a) generation in humans, particularly in women without a significant lateral effect on the endometrium. As discussed above, there is a direct correlation between high levels of Lp (a) and premature occlusive arterial disease. However, the exact physiological function of either apo (a) or Lp (a) is still being investigated. Apparently, even close to the absence of Lp (a) in the plasma does not cause a deficiency syndrome or any type of disease. Also, Lp (a) and apo (a) are apparently absent in the plasma of most of the evolutionary species below the Old World monkeys. NeverthelessRecently, several pathological functions have been postulated for both Lp (a) and apo (a) based on the results of certain studies in vi and ro vi as indicators of premature occlusive arterial diseases. For example, it is known that from the total combination of cholesterol that is transported in the blood, only a very small fraction is associated with Lp (a). However, this small combination is believed to act as a "quick response" reservoir for areas where rapid cell production, membrane biosynthesis or inflammatory processes occur, such as the atheromatous plaque. In fact, it has been found that high levels of Lp (a) are located in the intimal vascular (significantly more than the level of plasma and circulation is indicated), especially in the intima site of atheromatous lesions and vein bypass grafts saphenous stenotic. _ "Another proposed function indicates the endothelium, which is usually ant i thrombus geni co.The luminal surface of endothelial cells binds plasminogen, which is activated by the tissue plasminogen activator (TPA) on the endothelial cell surface for It is postulated that Lp (a) binds competitively to the plasminogen binding site and reduces the amount of plasmin generated by TPA.This leads to reduced antigenic and antifibrinolytic properties of the endopeptide. 1 It has also been shown that Lp (a) binds to fibrin, which can prevent the degradation of an existing thrombus via plasminogen and can contribute to the accumulation of Lp (a) in atherosclerotic plaques. showed that Lp (a) prolongs the time "required for fibrinolysis in an assay where the fibrolytic activity is stimulated by a fibrinolytic agent, for example, T PA / e s t r ep t o machine s a. The mechanism for this seems to be an inhibition in the conversion of plasminogen to plasmin through the active agent. Additional evidence for this potential role in atherosclerosis is provided by studies that show the expression of monocyte adhesion glycoprotein by endothelial cells as a result of treatment with Lp (a). In addition, a recent study showed that Lp (a) can contribute to the activation of immune response in atheromatous lesions. Recently, transgenic mice expressing the human apo (a) gene have been shown to develop atherosclerotic lesions in response to a high fat diet, suggesting a causative link between atherogenesis and apo (a), a component necessary of Lp (a). See, Lawn, R.M. e t a l. , Na t ure 1992, Vol. 360, pp. 670-672. To demonstrate the utility of the compounds of the invention as therapeutic agents for treating disease states that are alleviated through the reduction of plasma Lp (a) levels, the compounds were valued for their ability to inhibit generation. of apo (a) in mice made transgenic for the human apo (a) gene (see Frazer, KA et al., Na ture Gen etics (1995), Vol. 9, pp. 424-431, for description of the mice transgenic). In particular, the transgenic mice were treated with the compounds of the invention and their apo (a) levels in the plasma were determined. In addition, the uterine dry weight of each mouse was determined to demonstrate any side effects of treatment in the uterus.

As illustrated in FIGURE 1, a significant reduction in apo (a) levels in the plasma of the treated mice was observed. In addition, as illustrated in FIGURE 1, the compounds appear to have little or no significant effect on the uterus, as evidenced by the uterine dry weight of the mice after treatment. Since apo (a) is a necessary component of Lp (a), a reduction in the apo (a) level could also reduce the level of Lp (a) in the plasma. Compounds that reduce Lp (a) levels in plasma can alleviate, after administration, those disease states which are characterized by high levels of Lp (a), such as premature arterial occlusive diseases.

B. Preparation of the compounds of the invention The compounds used in this invention are selected from the following formula (I): wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the ß position; or R2 with R4, R4 with A, A with R3, B with D. D with E, or G with R2 is a bond, and the other substituents are each a hydrogen; or R2 is alkyl in the β position and A, B, D, E, G, R3 and R4 are each hydrogen; or R3 is alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the position and A, B, D, E, G, R2 and R3 are each hydrogen; and R5 is methyl or ethyl.

These compounds are prepared by treating the corresponding 17-oxo compound of the following formula: wherein R1 is a hydroxy protecting group and A, B, D, E ~, "G, R2, R3, R4 and R5 are as described above in the Brief description of the invention, with difluoroethyl ethyl diphenyl oxide. phosphine or diethyl phosphonate (di f luome ti lo) in the presence of a strong base in an aprotic solvent at a reflux temperature of about 5- 0 ° C to about 100 ° C, and then optionally the 3-hydroxy protecting group it is divided under the action of an acid to produce the corresponding 3-hydroxy group, which can be optionally etherified The 3-hydroxy protecting group is either a radical that can be easily divided into an acidic or basic environment, such as, for example, a tetrahydropyranyl group (THP) or a cylindrical group which is substituted with three identical radicals, two identical or three different straight and branched chain alkyl and / or aryl radicals (such as phenyl or naphthyl), such as example, the timethyl group, t-but ild I think you, I know you, I think, or you, or I, I think, or a methyl group, which can be removed, however, only under more drastic conditions. Lithium diisopropyl amide, sodium hydride, potassium t-butylate, butyl lithium and the like are suitable as the strong base The reaction of the 17.-oxo compound is carried out in an aprotic solvent, such as, for example, tetrahydrofuran , dimethyl sulfoxide, dimethylformamide, dioxane, or a mixture thereof The conditions for the cleavage of the 3-hydroxy protecting group depend on their nature.Protective groups such as tetrahydropyranyl or a cylil radical can be removed under the action of a weak acid such as oxalic acid or an acid ion exchanger, while the methyl group can be divided under the action of strong Lewis acids, for example, di-butyl aluminum hydride. The esterification of the free 3-hydroxy group is carried out with a reagent that produces R1 groups in a manner known to those skilled in the art. The production of the 3-hydroxy-protected compounds with 17-oxo used in the preparation of the compounds is carried out by the reaction of the corresponding known 3-hydroxy compound with dihydropyran under the effect of parato luensulphonic acid in tetrahydrofuran or other method known to those skilled in the art to protect hydroxy groups. The detailed synthesis of these compounds is described in detail in PCT Published Patent Application WO 96/28462 (Bohlmann et al.), Which is incorporated herein by reference in its entirety.

C. General Administration The administration of the compounds of the invention, in pure form or in an appropriate pharmaceutical composition, can be carried out by any of the accepted modes of administration or agents serving similar utilities. Thus, the administration can be for example, oral, nasal, parenteral, topical, transdermal, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets. , suppositories, pills, soft and hard elastic gelatin capsules, powders, suspensions or aerosols, or the like, preferably in dosage unit forms suitable for simple administration of precise doses. The compositions will include a conventional pharmaceutically acceptable carrier or excipient and a compound of the invention as the active agent, and in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to 99% by weight of a compound or compounds of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a f-pharmaceutically acceptable excipient. Preferably, the composition will be from about 5% to 75% by weight of a compound or compounds of the invention, or a pharmaceutically acceptable salt thereof, the remainder being suitable pharmaceutical excipients. The preferred route of administration is oral, using a convenient daily dose regimen that can be adjusted according to the degree of severity of the disease state to be treated. For such oral administration, "a pharmaceutically acceptable composition containing a compound of the invention, or a pharmaceutically acceptable salt thereof, is formed through the incorporation of any of the commonly acceptable pharmaceutically acceptable excipients, such as, for example, pharmaceutical grades of mannitol, lactose, "starch, pregelatinized starch, agressive stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, propyl gallate, and the like. Said compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Preferably, said compositions will be in the form of a capsule, or tablet and will therefore also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a "disintegrating agent" such as croscarmellose sodium or derivatives thereof, a lubricant such as magnesium stearate and the like, and a binder such as a starch, acacia gum, polyvinylpyrrolidone, gelatin, cellulose ether derivatives and the like. compounds of the invention, or their pharmaceutically acceptable salts, can also be formulated into a suppository using, for example, about 0.5% to about 50% of an active ingredient disposed in a carrier that slowly dissolves within the body, eg - polyoxyethylene glycols and polyethylene glycols (PEG), for example PEG 1000 (96%) "and PEG 4000 (4%). The liquid compositions pharmaceutically adm or str ab 1 can be, for example, prepared by dissolving, dispersing, etc., a compound or compounds of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting agents or emulsifiers, pH regulating agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, oleate of ethane 1-amine, butylated hydroxytoluene, etc. "Current methods for preparing such dosage forms are known, or will be apparent to those skilled in the art, for example, see Remitting g s Ph a rma c e u t i c a l S c i e n s, 18th ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition that will be administered will in any case contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of a disease state that is alleviated by reducing the levels of the disease. Lp (a) in plasma or through the inhibition of apo (a) generation according to the teachings of this invention. The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending on a variety of factors including the activity of the specific compound employed; the metabolic stability and the length of action of the compound; age, body weight, general health, sex and diet of the patient, the mode and time of administration, the rate of excretion, the combination of the drug, the severity of the particular disease states, and the patient Generally, a therapeutically effective daily dose is about 0.14 mg to about 14.3 mg / kg of the body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably , about 0.7 mg to about 10 mg / kg body weight per day, and most preferably from 1.4 mg to about 7.2 mg / kg of body weight per day, for example, for the administration of a person of 70 kg., the dose scale could be from about 10 mg to about 1.0 grams per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg p day, and most preferably around 100 mg to about 500 mg per day. The following specific examples are presented as a guide to assist in the practice of the invention, and are not intended to be a limitation of the scope of the invention.

EXAMPLE 1 Effect of a Compound of Formula (I) on Apo (a) in Transgenic Mice? Three transgenic mice with apo (a) females or various variants were randomly assigned to each group, each containing 3 animals. "The test compound was 1-di f luo ronene 1 en- 18 -me ti 1 estr a- 1, 3, 5 (10) - 1 ri en- 3 -o 1. The mice were treated with injections subcutaneous daily doses of 1 mg / kg of the test compound in the vehicle, 10 mg / kg of the test compound in vehicle and the vehicle (benzyl benzoate: castor oil, 1: 9). through bleeding at the end of the first week and through a puncture in the heart at the end of the second week of treatment when the mice were sacrificed.At the sacrifice, the uteri of the animals were dissected, cleaned of adherent connective tissues, They were placed on an aluminum sheet and dried in a furnace for 24 hours, during which time the dry weight of the organ was determined.The levels of Apo (a) were determined using Macra ELISA equipment (Stretegic Di agno stic). The results of the study, as illustrated in FIGURE 1, demonstrated that the compound of Test significantly reduced apo (a) levels at a dose of 1 mg / kg. and 10 mg / kg., while significant uterotropic activity (* p < 0.05) was measured only at the dose of 10 mg / kg.

This dissociation in the efficacy of the test compound to reduce levels of apo (a) and increase the uterine weight demonstrates the con fi dence to "of 1 test compound as an apo (a) / Lp (a) reducing agent without significant lateral effects on the uterus.

~ "EXAMPLE 2 This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing the compound used in the invention, for example, 17-difluoromethylene-18-methylestra-1, 35 (10) -trien-3-ol:. % p / p Compound of the invention 20.0% Lactose 79.5% Magnesium stearate 0.5% " The above ingredients were mixed and filled into hard shell gelatin capsules each containing 100mg.

B. Ingredients% w / w Compound of the invention 20.0% Magnesium stearate 0.9% Starch 8.6% Lac to s at 69.6% PVP (polyvinylpyrrolidine) 0.9% The above ingredients with the exception of magnesium stearate, were combined and granulated using water as a granulation liquid. The formulation was then dried, mixed with magnesium stearate and formed into tablets with a suitable tabletting machine.

C. Ingredients Compound of the invention 0.1% Propylene glycol 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water q.s. 100 mL The compound of the invention was dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient amount of water was then added with stirring to provide 100 mL of the solution which was filtered and bottled.

D. I n g r e d i n t e s% p / p Compound of the invention 20.0% Peanut oil 78.0% Span 60 2.0% The above ingredients were melted, mixed and placed in soft elastic capsules.

E. Ingredients% P / P Compound of the invention 1.0% Methyl or carboxymethyl cellulose 2.0% 0.9% saline c.s. 100 mL The compound of the invention was dissolved in the saline solution in saline solution, filtered and bottled for use.

EXAMPLE 3 This example illustrates the preparation of a representative pharmaceutical composition for parenteral administration containing a compound used in the invention, for example, 17-di f uo r or e tilen-18-metilestra-l, 3, 5 (10) -trien -3-ol: . Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% saline solution q.s. 100 mL The compound of the invention was dissolved in glycol-propylene, polyethylene glycol 400 and polysorbate 80. A sufficient amount of 0.9% saline was then added with stirring to provide 100 mL of IV solution: which was filtered through a 0.2m membrane filter was packed under sterile conditions.

EXAMPLE 4 This example illustrates the preparation of a representative pharmaceutical composition in the form of a suppository containing a compound used in the invention, for example, 17-di-fluo-rnene-1-en-18-methylstra-1, 3, 5 (10) -trien-3-ol: Ingredients% w / w Compound of the invention 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5% The ingredients were melted together and mixed in a steam bath, and emptied into molds containing a weight total of 2.5 g.

EXAMPLE 5 This example illustrates the preparation of a representative pharmaceutical composition for insufflation containing a compound used in the invention, for example, 17-di f luo rorne ti 1 en-18-methylstra-1, 3, 5 (10) - trien-3-ol: Inventors% p / p Micronized compound of the invention 1.0% Micronized lactose 99.0% The ingredients were milled, mixed and packed in an insufflator equipped with a dosing pump.

EXAMPLE 6 This example illustrates the preparation of a pharmaceutical composition represented in nebulized form containing a compound used in the invention, for example, 17-di-fluoromene-1-en-18-metilestra-1, 3, 5 (10) -trien-3-ol: Ingredients or p / p Compound of the invention 0.005% Water 89.995% Ethanol 10,000% The compound of the invention was dissolved in ethanol and mixed with water. The formulation was then packed in a nebulizer equipped with a dosing pump.

EXAMPLE 7 This example illustrates the preparation of a representative pharmaceutical composition in the form of an aerosol containing a compound used in the invention, for example, 17-di-fluorine-1-in-1-methyl-tetra-1,3,5 (10) -trien-3-ol: Ingredients . % p / p Compound of the invention 0.10% Propulsol 11/12 98.90% Oleic acid 1.00% The compound of the invention was dispersed in oleic acid and the propulsives The resulting mixture was then emptied into an aerosol container equipped with a metering valve, although the present invention has been described with reference to its specific embodiments, "It should be understood.-by those skilled in the art that various changes and equivalents can be made can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, procedure, step by step procedure, to the object, spirit and scope of the present invention. All these modifications are "intended to be within the scope of the appended claims.

Claims (24)

1. A method to reduce the levels of Lp (a) in the plasma in a human being, said method comprises administering to the human with the need thereof an effective amount of a compound of formula (I): wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the ß position; or R2 with R4, R4 with A, A with R3, B with D, D with E, or G with R2 is a bond, and the other s s t tu tutes are each a hydrogen; or R2 is alkyl in the β position and A, B, D, E, G, R3 and R4 are each hydrogen; or R3 is alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the a position and A, B, D, E, G, R2 and R3 are each hydrogen; and R5 is methyl or ethyl.

2. The method of claim 1, which comprises administering a compound of the formula: mainly, 17-dif luoromethylene-1-methyl-tetra-1, 3, 5 (10) -trien-3-ol.

3. A method for inhibiting the generation of apo (a) in a human being, said method comprises administering to a human being with the need thereof an effective amount of a compound of the f or rmul a (I): wherein R1 is hydrogen or alkyl; A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the ß position; or R2 - with R4, R4 - with A, A with R3, B with D, D with E, or G with R2 is a bond, and the other substituents are each a hydrogen; or R2 is alkyl in the β position and A, B, D, E, "G, R3 and R4 are each hydrogen, or R3 is alkoxy in the β position and A, B, D, E, G, R2 and R4 they are each -one hydrogen, or R4 is hydrogen in the position a and A, B, "DE, G," R2 and R3 are each hydrogen, and R5-is methyl or ethyl ...

4. The method of claim 3, which comprises administering a compound of the formula: mainly, 17-dif luoromethylene-18-methylestra-l, 3,5 (10) -trien-3-ol.

5. A method to treat a human being that has a disease state that is alleviated through the reduction of -levels- of Lp (a) in the plasma, the method comprises administering to the human being "with the need of same a therapeutically effective amount of a compound of - the f or rmu 1 a ("I): wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R and R3 are each hydrogen, and R4 is hydrogen in the β position; or R2 with R4, R4 with A, A with R3, B with D, D with E, or G with R 'is a bond, and the other substituents are c to d to a a hydrogen; or R2 is alkyl in the β position and A, B, D, E, G, R 'and R4 are each hydrogen; or R- is alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the position a - and A, B, D, E, G, R2 and R_ are each hydrogen; and R5 is methyl or ethyl.

6. The method of claim 5, which comprises administering a compound of the formula: mainly, 17-dif luoromethylene-18-methylestra-1, 3, 5 (10) -trien-3-ol.

7. The method of claim 5, wherein the disease state is a premature occlusive vascular disease.

8. The method of claim 7, wherein the condition of the disease is a shock.

9. The method of claim 7, wherein the condition of the disease is coronary heart disease.

10. The method of claim 7, wherein the state of the disease is diabetes me 11 i tus.

11. The method of claim 7, wherein the disease state is atherosclerosis.

12. The method of claim 7, which comprises administering a compound of the formula a: mainly, 17-difluoromethylene --- 1 met-lestra-1, 3, 5 (10) -trien-3-ol.

13. A method for treating a human being that has a disease state that is alleviated through the inhibition of apo (a) generation, said method comprises administering to a human being with the need thereof a therapeutically effective amount. of a compound of the formula (I): wherein: R1 is hydrogen or alkali; A, B, D, E, G, R2 and R3 each are hydrogen, and R4 is hydrogen in the ß position; or - R2 with R4, R4 with A, A with R3, B with D, D with E, or G with R "is a bond, and the other substituents are each with a hydrogen; or R2 is -alkyl in the β-position and A, B, D, E, G, .R 'and R4 are each hydrogen; or RJ e s- alkoxy in the ß position and A, B D, G, R 'and R4 are each hydrogen; or R4 is hydrogen at the a position and A, B, "D, E, G, R2 and R3 are each hydrogen, and R5 is methyl or ethyl.

The method according to claim 13, which comprises administering a compound of the formula: mainly, 17-difluoromethylene-1-methyl-1, 3, 5 (10) -trien-3-ol.

15 The rei indication method 13, where the disease state is a premature occlusive disease.

16. The method of re-indication 15, where the state of the disease is a shock. _ _ _ _ _ _

17. The method of the indication 15, where the state of the disease is a coronary heart disease.

18. The method of claim 15, wherein the condition of the disease is diabetes.

19. The method of claim 15, wherein the disease state is atherosclerosis.

20. The method of claim 15, which comprises administering a compound of the formula: mainly, 17-difluoromethylene-1-methyl-1, 3, 5 (10) -trien-3-ol.

21. A pharmaceutical composition useful for treating a human being having a diseased condition which is alleviated through the "reduction" of plasma Lp (a) levels, said composition comprises a therapeutically effective amount of a compound of the formula (I): wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R "and R3 each are hydrogen, and R is hydrogen in the ß position, or R2 with Rd, R4 with A, A with R3, B with D. D with E, or G with R 'is a bond, and the others are each a hydrogen, or R2 is alkyl at the β-position and A, B, D, E, G, R "and R4 are each hydrogen; or R3 is alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the a position and A, B, D, E, G, R2 and R3 are each hydrogen; and _R_5 _e s_ me t i_l o or ethyl.

22. The composition of claim 21, which comprises a therapeutically effective amount of a compound of the formula: mainly, 17-difluoromethylene-1-methyl-1, 3, 5 (10) -trien-3-ol.

236 A pharmaceutical composition useful for treating a human serum that has a disease state that is alleviated through the inhibition of apo (a) generation, said composition comprises a therapeutically effective amount of a compound of the formula (I) : wherein: R1 is hydrogen or alkyl; A, B, D, E, G, R2 and R3 are each hydrogen, and R 'is hydrogen in the β position; or R2 with R4, R4 with A, A with R3, B with D. D with E, or G with R2 is a bond, and the other substituents are each a hydrogen; or R2 is alkyl in the β position and A, B, D, E, G, R "'and R4 are each hydrogen, or R3 is" alkoxy in the β position and A, B, D, E, G, R2 and R4 are each hydrogen; or R4 is hydrogen at the a position and A, B, D, E, G, R2 and R3 are each hydrogen; and -R5 is methyl or ethyl.

24. The composition of claim 23, which comprises a therapeutically effective amount of a compound of the formula: mainly, 17 -dif luoromet i len- 1 met? lestra-1, 3, 5 (10) -trien-3-ol.