KR20040107482A - Combination of an aldosterone receptor antagonist and a fibric acid derivative - Google Patents

Abstract

A new method and mixture for the treatment and / or prevention of a disease in a subject, the method comprising administering at least one aldosterone receptor antagonist and at least one fibric acid derivative, the mixture comprising at least one aldosterone receptor antagonist and At least one such fibric acid derivative.

Description

A mixture of aldosterone receptor antagonists and fibric acid derivatives {COMBINATION OF AN ALDOSTERONE RECEPTOR ANTAGONIST AND A FIBRIC ACID DERIVATIVE}

Aldosterone receptor antagonists

Aldosterone is the most effective mineral corticosteroid hormone of the human body known. As implied in the term mineral corticoids, the steroid hormones have mineral-modulating activity. The hormone promotes sodium (Na ⁺ ) resorption in epithelial cells through binding and activation with mineral corticoid receptors (MR). Aldosterone increases the resorption of sodium and water in the distal nephron and promotes potassium (K ⁺ ) and magnesium (Mg ²⁺ ) secretion.

Aldosterone can also cause reactions in non-epithelial cells. In fact, aldosterone receptors have recently been identified in brain tissue, heart tissue and blood vessels. These aldosterone-mediated responses can adversely affect the structure and function of the cardiovascular system. Thus, inappropriate aldosterone exposure can cause organ damage in a disease environment.

The effects of aldosterone can be reduced by the use of aldosterone receptor antagonists. Many aldosterone receptor blocking compounds have been disclosed in the literature. For example, one commercially available aldosterone receptor antagonist is spironolactone (Aldactone® (also known as Pharmacia, Chicago, Ill.)). According to United States Pharmacopeia, Rockville, MD, spironolactone is essential for hypertension, primary aldosteroneism, hypokalemia, and edema diseases such as congestive heart failure, cirrhosis and kidney. Applied to the control of the syndrome. The administration of spironolactone to patients with severe heart failure was assessed in the Randomized Aldactone Evaluation Study (RALES). RALES has a severe heart failure and a left ventricular ejection coefficient of 35% or less and is a randomized, double-blind, placebo-controlled trial that typically includes participants undergoing standard therapy, including angiotensin-converting enzyme inhibitors, loop diuretics, and digoxin in some cases. It was. RALES subjects treated with spironolactone showed a statistically significant reduction in mortality and hospitalization rates compared to placebo-treated subjects [ New England Journal of Medicine , 341 , 709-717, 1999].

Another class of steroidal aldosterone receptor antagonists exemplified by epoxy-containing spirolactone derivatives is described in US Pat. No. 4,559,332 to Grob et al. The patent describes 9α, 11α-epoxy-containing spirolactone derivatives as aldosterone receptor antagonists useful in the treatment of hypertension, heart failure and cirrhosis. One of the epoxy-steroidal aldosterone antagonist compounds described in US Pat. No. 4,559,332 is eplerenone (also known as epoxymexrenone). Eplerenone is an aldosterone receptor antagonist with higher specificity for MR compared to spironolactone.

Another class of steroidal aldosterone receptor antagonists is exemplified by drospirenone. The compound developed by Schering AG is an antagonist of inorganic corticoids and androgen receptors and also has progestagen properties.

Another use of aldosterone receptor antagonists is disclosed in the literature. For example, WO 01/95892 and WO 01/95893 relate to methods for treating or preventing aldosterone-mediated diseases in a subject using aldosterone receptor antagonists. WO 02/09683 relates to a method of modulating inflammation using aldosterone antagonists.

Therapies including the administration of aldosterone receptor antagonists with several other pharmacologically active compounds have been reported in the literature.

WO 96/40258 to MacLaughlan et al. Discloses a combination therapy treatment using spironolactone and angiotensin II receptor antagonists to treat congestive heart failure.

WO 96/40255 to Egan et al. Discloses a combination therapy using epoxy-steroidal aldosterone receptor antagonists and angiotensin II antagonists to treat cardiac fibrosis.

Alexander et al., WO 94/40257, disclose a combination therapy using epoxy-steroidal aldosterone receptor antagonists and angiotensin II antagonists to treat congestive heart failure.

WO 00/27380 to Perez et al. Discloses a combination therapy using angiotensin converting enzyme inhibitors and aldosterone receptor antagonists to reduce morbidity and mortality resulting from cardiovascular disease.

WO 00/51642 to Alexander et al. Discloses a combination therapy utilizing angiotensin converting enzyme inhibitors and epoxy-steroidal aldosterone receptor antagonists to treat cardiovascular disease.

WO 02/09760 to Alexander et al. Uses a combination therapy using epoxy-steroidal aldosterone receptor antagonists and beta-adrenergic antagonists to treat circulatory diseases including cardiovascular diseases such as hypertension, congestive heart failure, cirrhosis and ascites. Is starting.

Schu WO 02/09761 discloses a combination therapy using epoxy-steroidal aldosterone receptor antagonists and calcium channel blockers to treat hypertension, congestive heart failure, cirrhosis and ascites.

WO 02/09759 to Rocha et al. Discloses a combination therapy using epoxy-steroidal aldosterone receptor antagonists and cyclooxygenase-2 inhibitors to treat inflammation-related cardiovascular diseases.

WO 03/07993 to Keller et al. Discloses a combination therapy using aldosterone receptor antagonists and HMG-CoA reductase inhibitors to treat or prevent disease.

U.S. Patent 5,569,652 discloses a mixture of aldosterone receptor antagonist drospirenone and estrogen for use as an oral contraceptive.

Fibric acid derivatives

Fibric acid derivatives include a class of drugs that affect lipoprotein levels. The first of these fibric acid derivatives to be developed is the clofibrate disclosed in US Pat. No. 3,262,850, which is incorporated herein by reference. Clofibrate is the ethyl ester of p-chlorophenoxyisobutyric acid. A widely used drug of this class is gemfibrozil, disclosed in US Pat. No. 3,674,836, which is incorporated herein by reference. Gempfibrozil is often used to reduce triglyceride levels or to increase HDL cholesterol levels [ The Pharmacological Basis of Therapeutics , p.893]. Fenofibrate (US Pat. No. 4,058,552) has a similar effect to gemfibrozil but further reduces LDL levels. Cypropibrate (US Pat. No. 3,948,973) has a similar effect to fenofibrate. Another drug of this class is bezafibrate (US Pat. No. 3,781,328). Signs of side effects resulting from the use of fibric acid derivatives include gallbladder disease (chololithiasis), rhabdomyolysis and acute renal failure. Some of these signs are exacerbated when fibrate is mixed with an HMG CoA reductase inhibitor.

Some combination therapies for treating cardiovascular disease are described in the literature. Zema [ J. Am. Coll. Cardiol ., 35 , 640-646, 2000 describe advantageous changes in the lipid profile of patients with hypoalphalipoproteinemia when treated with a mixture of gemfibrozil and niacin.

Keller et al. (WO 00/38725) disclose therapeutic mixtures comprising fibric acid derivatives and ileal bile acid transport inhibitors or cholesteryl ester transport protein inhibitors.

Li et al. (US Pat. No. 6,316,503) disclose a method of treating LXR-reactive diseases comprising administering LXR-modulating compounds and fibric acid derivatives.

Magnin et al. (US Pat. No. 5,470,845) claim a method for treating dyslipidemia comprising administering a squalene synthetase inhibitor with a fibric acid derivative.

Tschollar et al. (US Pat. No. 5,593,971) claim a method of inhibiting hypertension in normal blood pressure mammals with insulin resistance, comprising administering an angiotensin converting enzyme inhibitor and fibric acid derivatives.

Buntin et al. (US Pat. No. 4,759,923) disclose a method for lowering serum cholesterol by administering a mixture of bile acid sequestering resins and fibric acid derivatives.

Gregg et al. (US Pat. No. 5,883,109) claim a pharmaceutical mixture comprising microsomal triglyceride transport protein (MTP) inhibitors and fibric acid derivatives.

Keller et al. (WO 00/38727) disclose a therapeutic mixture comprising ileal bile acid transport inhibitors and fibric acid derivatives.

Ginsberg, "Update on the Treatment of Hypercholesterolemia, with a Focus on HMG Co-A Reductase Inhibitors and Combination Regimens", Clin. Cardiol ., Vol. 18 (6), pp. 307-315, June 1995] report that, in the case of resistance to hypercholesterolemia, therapies combining HMG Co-A reductase inhibitors with bile acid sequestrant resins, niacin or fibric acid derivatives are generally effective and well tolerated.

There is a great need for improved drug therapy for the treatment of subjects suffering from or susceptible to disease. In particular, (1) provide good control over disease, (2) further reduce pathological risk factors, (3) provide improved treatment and / or prevention of disease, and (4) a greater proportion of Or (5) for drug therapies that are effective in diseased or susceptible subjects, particularly those who do not respond satisfactorily to conventional drug therapies, and (5) provide improved side effect profiles compared to conventional drug therapies. The demand still exists.

The present invention relates to the treatment of one or more diseases, particularly in subjects arising from or aggravated by endogenous mineral corticosteroid activity, in the presence of dyslipidemia, or in subjects susceptible to or suffering from dyslipidemia. And / or methods for preventing. In particular, the present invention is selected from, but is not limited to, cardiovascular-related diseases, inflammation-related diseases, nervous system-related diseases, musculoskeletal-related diseases, metabolic-related diseases, endocrine-related diseases, dermatological-related diseases and cancer-related diseases. The invention relates to the use of an aldosterone receptor antagonist in combination with the use of a fibric acid derivative for the treatment or prevention of one or more diseases. More particularly, the present invention relates to treating or preventing one or more of the above diseases with the combination therapy, wherein the aldosterone receptor antagonist is an epoxy-steroidal compound such as eplerenone.

In a first aspect, the present invention treats and / or treats one or more diseases in a subject arising from or exacerbated by endogenous mineral corticoid activity, comprising administering a therapeutically effective amount of an aldosterone receptor antagonist and fibric acid derivatives. It is about a method for preventing.

In another aspect, the invention provides a cardiovascular-related disease, inflammation-related disease, nervous system-related disease, musculoskeletal-related disease, metabolic-related, comprising administering a therapeutically effective amount of an aldosterone receptor antagonist and a fibric acid derivative. A method for treating one or more diseases selected from the group consisting of diseases, endocrine-related diseases, dermatosis-related diseases and cancer-related diseases.

In another aspect, the present invention relates to a method of treating one or more of said diseases with said combination therapy wherein the aldosterone receptor antagonist is an epoxy-steroidal compound such as eplerenone.

In another aspect, the invention relates to a method of treating one or more of the above diseases with the combination therapy wherein the aldosterone receptor antagonist is a spirolalactone compound such as spironolactone.

In another aspect, the present invention relates to a mixture comprising a pharmaceutical composition comprising at least one aldosterone receptor antagonist and at least one fibric acid derivative.

In another aspect, the invention relates to a mixture comprising at least one fibric acid derivative and at least one aldosterone receptor antagonist, wherein at least one of the antagonists is an epoxy-steroidal compound such as eplerenone.

In another aspect, the invention relates to a mixture comprising at least one fibric acid derivative and at least one aldosterone receptor antagonist, wherein at least one of the antagonists is a spirolalactone compound such as spironolactone.

In another aspect, the present invention relates to a kit comprising one or more aldosterone receptor antagonists and one or more fibric acid derivatives.

In another aspect, the invention relates to the manufacture of a medicament comprising at least one aldosterone receptor antagonist and at least one fibric acid derivative.

Other aspects of the invention will be apparent in part and in part pointed out hereinafter.

There is a great need for improved drug therapy, particularly in patients who do not respond satisfactorily to conventional drug therapy. In addition, diseases, particularly diseases selected from the group consisting of cardiovascular-related diseases, inflammation-related diseases, nervous system-related diseases, musculoskeletal-related diseases, metabolic-related diseases, endocrine-related diseases, dermatological-related diseases and cancer-related diseases This increasingly widespread suggests that new therapeutic interventions and methods are needed to replace or supplement current approaches. The present invention addresses this need and to treat one or more of the above diseases arising from or exacerbated by endogenous mineral corticoid activity in a population characterized by dyslipidemia or susceptible to dyslipidemia New drug therapies comprising the administration of one or more compounds that are aldosterone antagonists with the use of one or more compounds.

In a particular group consisting of one or more aldosterone receptor antagonists (e.g., an aldosterone receptor antagonist selected from the specific group consisting of compounds described below) and one or more fibric acid derivatives (e.g., compounds described below). Administration of selected fibric acid derivatives) to the subject, particularly in subjects arising from or exacerbated by endogenous mineral corticoid activity in the presence of dyslipidemia, or subject to dyslipidemia or suffering from dyslipidemia It has been found that improved results are provided in the prevention and / or treatment of one or more diseases. In particular, the present invention is one selected from the group consisting of cardiovascular-related diseases, inflammation-related diseases, nervous system-related diseases, musculoskeletal-related diseases, metabolic-related diseases, endocrine-related diseases, skin diseases-related diseases and cancer-related diseases The present invention relates to the use of an aldosterone receptor antagonist with fibric acid derivatives for the treatment of the above diseases.

Diseases that can be treated or prevented according to the present invention include arteriosclerosis, hypertension, cardiovascular disease, renal dysfunction, liver disease, cerebrovascular disease, vascular disease, retinopathy, neuropathy (eg, peripheral neuritis), insulinosis, Edema, endothelial dysfunction, seizure dysfunction, migraine, burning, premenstrual tension, and the like.

Cardiovascular diseases include heart failure (eg congestive heart failure), arrhythmia, diastolic dysfunction (eg left ventricular diastolic dysfunction, diastolic heart failure and diastolic fullness disorder), systolic dysfunction, ischemia, hypertrophic cardiomyopathy, cardiac death , Myocardial and vascular fibrosis, arterial elastic injury, myocardial necrotic lesions, vascular damage, myocardial infarction, left ventricular hypertrophy, decreased ejection fraction, heart damage, vascular wall hypertrophy, endothelial cell enlargement, fibrinoid necrosis of coronary arteries, It is not limited to this.

Renal dysfunction includes glomerulosclerosis, end stage renal disease, diabetic nephropathy, decreased renal blood flow, increased glomerular filtration fraction, proteinuria, decreased glomerular filtration rate, decreased creatinine clearance, microalbuminuria, renal artery disease, ischemic lesions, thrombotic lesions, spherical fibrils Nooid necrosis, focal thrombosis of glomerular capillaries, swelling and proliferation of intracapillary (endothelial and hemangioblasts) and / or extracapillary cells (menorrhagic cells), interreticular matrix with or without severe hypercellularity Swelling, malignant neurosis (eg, ischemic contraction, thrombotic necrosis of the capillary gun, arterial fibrinoid necrosis, and thrombotic microangiopathy lesions involving the glomeruli and microvessels), and the like. Does not.

Liver diseases include, but are not limited to, cirrhosis, liver ascites, liver congestion, and the like.

Cerebrovascular diseases include, but are not limited to, strokes.

Vascular diseases include thrombotic vascular diseases (e.g., intravascular vascular fibronoid necrosis, red blood cell outflow and division, and lumen and vascular thrombosis), and proliferative arterial diseases (e.g., mucosal extracellular matrix). Swelling and nodular hypertrophy of enclosed myocardial cells), arteriosclerosis, decreased vascular elasticity (eg, stiffness, decreased ventricular elasticity and decreased vascular elasticity), endothelial cell dysfunction, and the like.

Edema includes, but is not limited to, terminal tissue edema, hepatic congestion, spleen congestion, hepatic ascites, respiratory or pulmonary congestion, and the like. Insulin symptoms include, but are not limited to, insulin resistance, type I diabetes, type II diabetes, glucose sensitivity, prediabetes, syndrome X, and the like.

In one embodiment, a therapeutically effective mixture of an epoxy steroidal compound (especially an eplerenone) and a fibric acid derivative is used to treat a congenital disorder, a valve disorder, a coronary disorder, a pathogenic disorder, a surgery-induced disorder, a cardiomyopathy disorder, a virus- Causative Disorder, Bacterial-Induced Disorder, Anatomical Disorder, Vascular Disorder, Graft-Induced Disorder, Ischemic Disorder, Cardiac Arrhythmia Disorder, Conduction Disorder, Thrombotic Disorder, Aortic Disorder, Coagulation Disorder, Connective Tissue Disorder, Neuromuscular Disorder To a subject in need of treatment or prevention of cardiovascular disorders selected from the group consisting of hematological disorders, low specific gravity disorders, endocrine disorders, lung disorders, non-malignant tumor disorders, malignant tumor disorders and pregnancy-induced disorders. One class of cardiovascular disorders of interest includes cardiovascular disorders selected from the group consisting of coronary artery disorders, cardiomyopathy disorders, aortic disorders and connective tissue disorders. Another class of cardiovascular disorders of interest include congenital disorders, valve disorders, pathogenic disorders, surgical-induced disorders, virus-induced disorders, bacterial-induced disorders, anatomical disorders, transplant-induced disorders, conduction disorders, Cardiovascular disorders selected from the group consisting of coagulation disorders, neuromuscular disorders, hematological disorders, low specific gravity disorders, endocrine disorders, lung disorders, non-malignant tumor disorders, malignant tumor disorders and pregnancy-induced disorders.

Of particular interest are diseases resulting from atherosclerosis. Thus, in another aspect, the combination therapy of the present invention is used to prevent or treat myocardial infarction or stroke or endothelial dysfunction.

In another embodiment, the combination therapy is used to prevent or treat a disease selected from the group consisting of hypertension, heart failure, left ventricular hypertrophy, cardiac death and vascular disease.

In another embodiment, combination therapy is used to prevent or treat a disease selected from the group consisting of renal dysfunction and organ damage.

In another embodiment, the combination therapy is used to prevent or treat a disease selected from the group consisting of diabetes, obesity, X syndrome, cachexia and skin disorders.

In another aspect, combination therapy is used to prevent or treat a disease selected from the group consisting of Alzheimer's disease, dementia, depression, memory loss, drug addiction, drug withdrawal and brain damage.

In another embodiment, combination therapy is used to prevent or treat a disease selected from the group consisting of osteoporosis and muscle weakness.

In another embodiment, combination therapy is used to prevent or treat a disease selected from the group consisting of arthritis, tissue rejection, septic shock, hypersensitivity and tobacco-related diseases.

In another aspect, combination therapy is used to prevent or treat diseases caused after coronary artery bypass graft (CABG) surgery.

In another embodiment, the combination therapy is used to prevent or treat a disease selected from the group consisting of thrombosis and cardiac arrhythmia.

In another aspect, combination therapy is used to prevent or treat a disease selected from the group consisting of tissue proliferative disease and cancer.

In another embodiment, the aldosterone receptor antagonist is used in the manufacture of a pharmaceutical composition for administration with a fibric acid derivative for the prevention or treatment of a disease.

In another embodiment, the aldosterone receptor antagonist is also mixed with fibric acid derivatives for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease.

In various aspects of the invention, the aldosterone receptor antagonist used is preferably a spironolactone or an epoxy-steroidal compound. More preferably, the aldosterone receptor antagonist is eplerenone.

In addition, the combination therapy of the present invention is not limited to two components, and may include one or more additional therapeutic compounds to treat the same or related disease and provide some additional benefit to the patient (eg, triple therapy ).

In another aspect of the combination therapy of the present invention, the aldosterone receptor antagonist and fibric acid derivatives are angiotensin II receptor antagonists, angiotensin converting enzyme inhibitors, non-aldosterone antagonist-type diuretics, digoxin, calcium channel blockers, beta-adrenaline It is administered with one or more additional compounds selected from the group consisting of receptor blockers, COX-2 inhibitors, cholesterol synthesis inhibitors, non-steroidal anti-inflammatory compounds, alpha-adrenergic receptor antagonists and alpha2-adrenergic receptor agonists.

In addition to being particularly suitable for human use, the combination therapy of the invention is also suitable for the treatment of animals, including mammals such as horses, dogs, cats, rats, mice, sheep, pigs and the like.

The novel mixtures of the present invention exhibit improved efficacy, improved potency, and / or reduced administration conditions for the active compounds, for example, compared to the therapies previously disclosed in the publications.

Aldosterone receptor antagonists

The term "aldosterone antagonist" or "aldosterone receptor antagonist" refers to a compound that can bind to the aldosterone receptor and modulate the receptor-mediated activity of the aldosterone as a competitive inhibitor of the action of the aldosterone itself at the receptor site.

Aldosterone antagonists used in the methods of the invention are generally spirolactone type steroidal compounds. The term "spirololactone type" means characterized by a structure comprising lactone moieties that are bound to the steroid nucleus, typically in the steroid "D" ring, through the spiro binding coordination. The subclass of spirolactone aldosterone antagonist compounds consists of epoxy-steroidal aldosterone antagonist compounds such as eplerenone. Another subclass of spirolactone antagonist compounds consists of non-epoxy-steroidal aldosterone antagonist compounds such as spironolactone.

Epoxy-steroidal aldosterone antagonist compounds used in the methods of the invention generally have a steroid nucleus substituted with an epoxy-type moiety. The term "epoxy-type" moiety includes any moiety characterized by having an oxygen atom as a bridge between two carbon atoms, examples of which include the following moieties:

As used in the phrase "epoxy-steroidal", the term "steroidal" refers to cyclopenteno-phenanthrene moieties having the usual "A", "B", "C" and "D" rings. Means the nucleus provided by. Epoxy type moieties may be bonded to the cyclopentenophenanthrene nucleus at any linkable or substitutable position, ie, fused to one of the rings of the steroidal nucleus or the moiety is to be substituted on a ring member of the ring system. Can be. The phrase "epoxy-steroidal system" is intended to include steroidal nuclei in which one or more epoxy-type moieties are attached thereto.

Suitable epoxy-steroidal aldosterone antagonists for use in the methods of the invention include a class of compounds having epoxy moieties fused to the "C" ring of the steroid nucleus. Particular preference is given to 20-spiroxane compounds characterized by the presence of 9α, 11α-substituted epoxy residues. Compounds 1 to 11 below are exemplary 9α, 11α-epoxy-steroidal compounds that can be used in the methods of the present invention. A particular advantage of using epoxy-steroidal aldosterone antagonists as exemplified by eplerenone is the high selectivity of the family of aldosterone antagonists for mineral corticosteroid receptors. Good selectivity of eplerenone reduces the side effects that can be caused by aldosterone antagonists that exhibit non-selective binding to non-mineral corticoid receptors, such as androgen or progesterone receptors.

These epoxy steroids can be prepared by the procedures described in US Pat. No. 4,559,332 to Grob et al. Further methods for the preparation of 9,11-epoxy steroid compounds and salts thereof are disclosed in WO 97/21720 to Ng et al. And WO 98/25948 to Angie et al.

Of particular note is the Eplerenone compound (also known as Epoxymexrenone and CGP 30 083) which is Compound 1 as indicated above. The chemical names for the eplerenones are pregan-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo, γ-lactone, methyl ester, (7α, 11α, 17α) -to be. The chemical name corresponds to the CAS Registry Name for Eplerenone (the CAS Registry Number for Eplerenone is 107724-20-9). US Pat. No. 4,559,332 defines eplerenone under the alternative designation 9α, 11α-epoxy-7α-methoxycarbonyl-20-spirox-4-ene-3,21-dione. The "spiroxane" name is further described, for example, in columns 4, 48 in columns 2, 16 of US Pat. No. 4,559,332.

Eplerenone is an aldosterone receptor antagonist and, for example, has higher specificity for aldosterone receptors than spironolactone. Choosing eplerenone as an aldosterone antagonist in the methods of the present invention will be beneficial in reducing certain side effects such as gynecomastia in men caused by the use of aldosterone antagonists with lower specificity.

Suitable non-epoxy-steroidal aldosterone antagonists for use in the methods of the invention include the class of spirolactone compounds defined by Formula I:

Where

Is or ego;

R is lower alkyl having up to 5 carbon atoms;

Is , or to be.

Lower alkyl residues include branched and unbranched groups, preferably methyl, ethyl and n-propyl.

Specific compounds of interest belonging to formula (I) are as follows:

7α-acetylthio-3-oxo-4,15-androstadiene- [17 (β-1 ')-spiro-5'] perhydrofuran-2'-one;

3-oxo-7α-propionylthio-4,15-androstadiene- [17 (β-1 ')-spiro-5'] perhydrofuran-2'-one;

6β, 7β-methylthio-3-oxo-4,15-androstadiene- [17 (β-1 ′)-spiro-5 ′] perhydrofuran-2′-one;

15α, 16α-methylene-3-oxo-4,7α-propionylthio-4-androstan [17 (β-1 ')-spiro-5'] perhydrofuran-2'-one;

6β, 7β, 15α, 16α-dimethylene-3-oxo-4-androsten- [17 (β-1 ′)-spiro-5 ′] perhydrofuran-2′-one;

7α-acetylthio-15β, 16β-methylene-3-oxo-4-androsten- [17 (β-1 ′)-spiro-5 ′] perhydrofuran-2′-one;

15β, 16β-methylene-3-oxo-7β-propionylthio-4-androsten- [17 (β-1 ′)-spiro-5 ′] perhydrofuran-2′-one; And

6β, 7β, 15β, 16β-dimethylene-3-oxo-4-androsten- [17 (β-1 ′)-spiro-5 ′] perhydrofuran-2′-one.

Methods for preparing compounds of Formula (I) are described in US Pat. No. 4,129,564, issued to Wiechart et al. On December 12, 1978.

Another class of non-epoxy-steroidal compounds of interest is defined by Formula II:

Where

R ¹ is C _1-3 -alkyl or C _1-3 acyl;

R ² is H or C _1-3 -alkyl.

Specific compounds of interest belonging to formula II are:

1α-acetylthio-15β, 16β-methylene-7α-methylthio-3-oxo-17α-pregan-4-ene-21,17-carbolactone; And

15β, 16β-methylene-1α, 7α-dimethylthio-3-oxo-17α-pregin-4-ene-21,17-carbolactone.

Methods for preparing compounds of Formula II are described in US Pat. No. 4,789,668, issued to Nikkisch et al. On December 6, 1998.

Another class of non-epoxy-steroid compounds of interest is defined by the structure of Formula III:

Where

R is lower alkyl and preferred lower alkyl groups are methyl, ethyl, propyl and butyl. Specific compounds of interest include:

3β, 21-dihydroxy-17α-pregna-5,15-diene-17-carboxylic acid γ-lactone;

3β, 21-dihydroxy-17α-pregna-5,15-diene-17-carboxylic acid γ-lactone 3-acetate;

3β, 21-dihydroxy-17α-pregan-5-ene-17-carboxylic acid γ-lactone;

3β, 21-dihydroxy-17α-pregan-5-ene-17-carboxylic acid γ-lactone 3-acetate;

21-hydroxy-3-oxo-17α-pregin-4-ene-17-carboxylic acid γ-lactone;

21-hydroxy-3-oxo-17α-pregna-4,6-diene-17-carboxylic acid γ-lactone;

21-hydroxy-3-oxo-17α-pregna-1,4-diene-17-carboxylic acid γ-lactone;

7α-acylthio-21-hydroxy-3-oxo-17α-pregan-4-ene-17-carboxylic acid γ-lactone; And

7α-acetylthio-21-hydroxy-3-oxo-17α-pregin-4-ene-17-carboxylic acid γ-lactone.

Methods of preparing compounds of Formula III are described in US Pat. No. 3,257,390, issued to Patchett on June 21, 1966.

Another class of non-epoxy-steroid compounds of interest is represented by Formula IV:

Where

E 'is selected from the group consisting of ethylene, vinylene and (lower alkanoyl) thioethylene radicals;

E ″ is selected from the group consisting of ethylene, vinylene, (lower alkanoyl) thioethylene and (lower alkanoyl) thiopropylidene radicals;

R is a methyl radical except when E 'and E "are ethylene and (lower alkanoyl) thioethylene radicals, in which case R is selected from the group consisting of hydrogen and methyl radicals, and E' and E" Is selected so that at least one (lower alkanoyl) thio radical is present.

A preferred class of non-epoxy-steroid compounds belonging to formula IV are represented by formula V:

More preferred compound of formula V is 1-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-androst-4-en-3-one lactone.

Another preferred class of non-epoxy-steroid compounds belonging to Formula IV are represented by Formula VI:

More preferred compounds of formula VI include:

7α-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-androst-4-en-3-one lactone;

7β-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-androst-4-en-3-one lactone;

1α, 7α-diacetylthio-17α- (2-carboxyethyl) -17β-hydroxy-androsta-4,6-dien-3-one lactone;

7α-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-androstar-1,4-dien-3-one lactone;

7α-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-19-norandrost-4-en-3-one lactone; And

7α-acetylthio-17α- (2-carboxyethyl) -17β-hydroxy-6α-methylandrost-4-en-3-one lactone.

In the formulas (IV) to (VI), the term "alkyl" is intended to include linear and branched alkyl radicals containing from 1 to about 8 carbons. The term "(lower alkanoyl) thio" refers to And lower alkyl radicals.

Of particular note are spironolactone compounds having the following structure and official names:

"Spironolactone": 17-hydroxy-7α-mercapto-3-oxo-17α-pregin-4-ene-21-carboxylic acid γ-lactone acetate.

Methods for the preparation of compounds of Formulas IV-VI are described in US Pat. No. 3,013,012 to Dec. 12, 1961 to Cella et al. Spironolactone is a tablet dosage form of 25 mg, 50 mg and 100 mg doses per tablet and is sold by Pharmacia Corp. under the trade name "ALDACTONE". Spironolactone, together with hydrochlorothiazide, is a tablet dosage form of spironolactone at 25 mg and 50 mg per tablet, sold by Pharmacia Corporation under the trade name "ALDACTAZIDE".

Another class of steroid aldosterone antagonists is drospirenone, [6R- (6α, 7α, 8β, 9α, 10β, 13β, 14α, 15α, 16α, 17β)]-1,3 ', 4', 6,7 , 8,9,10,11,12,13,14,15,16,20,21-hexa decahydro-10,13-dimethylspiro [17H-dicyclopropa [6,7: 15,16] Cyclopenta [a] phenanthrene-17,2 '(5'H) -furan] -3,5' (2H) -dione, CAS Registry No. 67392-87-4. The preparation and use of drospirenone is described in patent GB 1550568 (1979), priority DE 2652761 (1976).

Fibric acid derivatives

Fibric acid derivatives useful in the mixtures and methods of the present invention include a wide variety of structures and functional groups. In one embodiment, the fibric acid derivatives used in the present invention are selected from Table 2 below. The therapeutic compounds of Table 2 can be used in the present invention in a variety of forms, including acid forms, salt forms, racemates, enantiomers, zwitterions and tautomers. Each of the patent documents referred to in Table 2 is each incorporated herein by reference.

In one embodiment the fibric acid derivative is selected from the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate.

In another embodiment, the fibric acid derivative is clofibrate.

In another embodiment, the fibric acid derivative is fenofibrate.

In another embodiment, the fibric acid derivative is cypropibrate.

In another embodiment, the fibric acid derivative is bezafibrate.

In another embodiment, the fibric acid derivative is gemfibrozil.

In another embodiment, the fibric acid derivative is clinofibrate.

In another embodiment, the fibric acid derivative is bainifibrate.

In another embodiment, the fibric acid derivative is selected from the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and the aldosterone receptor antagonist is efle It is selected from the group consisting of lennon and spironolactone.

In another embodiment, the fibric acid derivative is clofibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is fenofibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is cypropibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is bezafibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is gemfibrozil and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is clinofibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is bunifibrate and the aldosterone receptor antagonist is eplerenone.

In another embodiment, the fibric acid derivative is clofibrate and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is fenofibrate and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is cypropibrate and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is bezafibrate and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is gemfibrozil and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is clinofibrate and the aldosterone receptor antagonist is spironolactone.

In another embodiment, the fibric acid derivative is bunifibrate and the aldosterone receptor antagonist is spironolactone.

As mentioned above, aldosterone receptor antagonists and fibric acid derivatives useful in the combination therapy of the present invention may also include racemates and stereoisomers such as diastereomers and enantiomers of the medicament. Such stereoisomers can be prepared, isolated and used using conventional techniques by reacting enantiomeric starting materials or by separating isomers of the compounds of the invention. Isomers may include geometric isomers, for example cis isomers or trans isomers intersecting double bonds. All of these isomers are included in the compounds of the present invention. The isomers may be used in pure form or in combination with the active agents described above. The stereoisomers can be prepared using conventional techniques by reacting enantiomeric starting materials or by separating the isomers of the compounds of the invention.

Isomers may include geometric isomers, for example cis isomers or trans isomers intersecting double bonds. All of these isomers are included in the compounds of the present invention.

Compounds useful in the present invention as discussed below include salts, solvates and prodrugs thereof.

Compounds useful in the present invention also include tautomers.

Crystalline Form Of Active Compound

Crystalline forms that are easy to handle, reproducible in form, readily prepared, stable and non-hygroscopic have been identified for aldosterone antagonist eplerenone. These include Form H, Form L, various crystalline solvates and amorphous eplerenones. Such forms, methods of making such forms, and the use of such forms in the preparation of compositions and medicaments are disclosed in WO 01/41535 and WO 01/42272, which are incorporated herein by reference.

In one aspect of the invention, the aldosterone antagonist used comprises L-type eplerenone.

In another aspect of the invention, the aldosterone antagonist used comprises H-type eplerenone.

Justice

The term "combination therapy" means the administration of two or more therapeutic agents to treat a disease. The administration includes co-administering the therapeutic agents in a substantially simultaneous manner, eg, in a single capsule with a fixed ratio of active ingredients, or in several separate capsules for each active agent. The administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the therapy will provide the beneficial effect of the drug mixture in treating the disease.

The term "pharmaceutically acceptable" is used herein adjectively to mean that a noun modified is suitable for use in a pharmaceutical product. Pharmaceutically acceptable cations include metal ions and organic ions. More preferred metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts and other physiologically acceptable metal ions. Representative ions include aluminum, calcium, lithium, magnesium, calcium, sodium and zinc of their usual valences. Preferred organic ions are partially trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, chlorine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) And procaine, including quantized tertiary amines and quaternary ammonium cations. Representative pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, iso citric acid, succinic acid, lactic acid, gluconic acid, glucuic acid Lonic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid and the like.

The term “prodrug” refers to a chemical compound that can be converted into a therapeutic compound by metabolic or simple chemical processes in the subject's body.

The terms "prevention" and "prevention" include either preventing the onset of a clinically apparent disease or preventing the onset of an apparent preclinical phase of the disease in a subject. The term includes prophylactic treatment of a subject at risk of developing the disease.

As used herein, the term "subject" refers to an animal, preferably a mammal, especially a human, that has become an object of treatment, observation or experiment.

The phrase "treatment-effective" refers to the amount of each agent that will typically achieve the goal of improving the severity of the disease and the incidence rate during treatment with each agent alone, while minimizing the side effects typically associated with alternative therapies.

The term "treatment" includes any process, action, application, therapy, procedure, etc., of which a mammal, particularly a human, receives medical assistance for the purpose of directly or indirectly ameliorating a disease in a mammal. Treatment may also include delaying or stopping the progress of clinically evident cardiovascular disease as a whole, or delaying or stopping the onset of an apparent preclinical phase of cardiovascular disease in a subject.

The term "hydrido" means a single hydrogen atom (H). The hydrido radical may, for example, be bonded to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be bonded to a carbon atom to form a methylene (—CH ₂ —) radical. The term "alkyl", when used alone or in other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", refers to 1 to about 20 carbon atoms, or It preferably comprises a linear or branched radical having 1 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having from 1 to about 10 carbon atoms. Most preferred are lower alkyl radicals having 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, phenyl, iso-amyl, hexyl and the like. The term "alkenyl" includes linear or branched radicals having one or more carbon-carbon double bonds having 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferred alkyl radicals are "lower alkenyl" radicals having from 2 to about 6 carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, butenyl and 4-methylbutenyl. The term "alkynyl" means a linear or branched radical having 2 to about 20 carbon atoms, or preferably 2 to about 12 carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having 2 to about 10 carbon atoms. Most preferred are lower alkynyl radicals having 2 to about 6 carbon atoms. Examples of such radicals include propargyl, butynil and the like. The terms "alkenyl", "lower alkenyl" include radicals having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. The term "cycloalkyl" includes saturated carboxyl radicals having 3 to 12 carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having 3 to about 8 carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkenyl" includes partially unsaturated carboxyl radicals having 3 to 12 carbon atoms. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having from 4 to about 8 carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. The term "halo" means a halogen such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" includes radicals in which any one or more of the alkyl carbon atoms are substituted with halo as defined above. In particular, monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are included. In one example, the monohaloalkyl radical may have iodo, bromo, chloro or fluoro atoms in the radical. Dihalo and polyhaloalkyl radicals may have two or more identical halo atoms or have a mixture of different halo radicals. "Lower haloalkyl" includes radicals having 1 to 6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoro Chloromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyalkyl" includes linear or branched alkyl radicals having from 1 to about 10 carbon atoms in which any of the carbon atoms may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having 1 to 6 carbon atoms and at least one hydroxyl radical. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" include linear or branched oxy-containing radicals each having an alkyl moiety having from 1 to about 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" includes alkyl radicals having at least one alkoxy radical bonded to an alkyl radical, ie, alkyl radicals forming monoalkoxyalkyl and dialkoxyalkyl radicals. "Alkoxy" radicals may also be substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide a haloalkoxy radical. More preferred haloalkoxy radicals are "lower haloalkoxy" radicals having 1 to 6 carbon atoms and at least one halo radical. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term "aryl", alone or together, refers to a carbocyclic aromatic system containing one, two or three rings that can be bonded or fused to each other in a pendant manner. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at alkyl, alkoxyalkyl, alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, nitro, alkylamino, acyl, It may be substituted with one or more substituents independently selected from cyano, carboxy, aminocarbonyl, alkoxycarbonyl and aralkoxycarbonyl. The term "heterocyclyl" includes saturated, partially unsaturated and unsaturated heteroatom-containing cyclic radicals, wherein the heteroatom may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3-6 membered heteromonocyclic groups containing 1-4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl) Etc); Saturated 3-6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl, etc.); Saturated 3 to 6-membered heteromonocyclic groups (eg, thiazolidinyl, etc.) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms are included. Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term "heteroaryl" includes unsaturated heterocyclyl radicals. Examples of unsaturated heterocyclyl radicals, also called "heteroaryl", include unsaturated 3-6 membered heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyra Zolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1 , 2,3-triazolyl and the like), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl and the like); Unsaturated condensed heterocyclyl groups containing 1 to 5 nitrogen atoms such as indolyl, isoindoleyl, indolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, Tetrazolopyradazinyl (for example, tetrazolo [1,5-b] pyridazinyl, etc.); Unsaturated 3 to 6 membered heteromonocyclic groups containing oxygen atoms such as pyranyl, furyl and the like; Unsaturated 3 to 6-membered heteromonocyclic groups containing sulfur atoms such as thienyl and the like; Unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxdiazolyl (e.g. 1,2, 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl and the like); Unsaturated condensed heterocyclyl groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, benzoxazolyl, benzoxadiazolyl, etc.); Unsaturated 3-6 membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (eg 1,2,4-thiadia) Jolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like); Unsaturated condensed heterocyclyl groups (eg, benzothiazolyl, benzothiadiazolyl, etc.) containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms. The term also includes radicals in which heterocyclyl radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene and the like. The "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino and alkylamino. The term "alkylthio" includes radicals containing linear or branched alkyl radicals having from 1 to about 10 carbon atoms bonded to divalent sulfur atoms. More preferred alkylthio radicals are "lower alkylthio" radicals having 1 to 6 carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthioalkyl" includes radicals containing alkylthio radicals bonded to an alkyl radical having 1 to about 10 carbon atoms via a divalent sulfur atom. More preferred alkylthioalkyl radicals are "lower alkylthioalkyl" radicals having 1 to 6 carbon atoms. Examples of such lower alkylthioalkyl radicals include methylthiomethyl. The term "alkylsulfinyl" includes radicals containing linear or branched alkyl radicals having 1 to 10 carbon atoms, bonded to a divalent -S (= 0)-radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having 1 to 6 carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "sulfonyl" refers to a divalent radical -SO ₂ -each, whether used alone or bonded to other terms such as alkylsulfonyl. "Alkylsulfonyl" includes an alkyl radical bonded to a sulfonyl radical, wherein alkyl is defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having 1 to 6 carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. “Alkylsulfonyl” radicals may be further substituted with one or more halo atoms such as fluoro, chloro or bromo to provide the haloalkylsulfonyl radicals. The terms "sulfamil", "aminosulfonyl" and "sulfonamidyl" mean NH ₂ O ₂ S-. The term "acyl" refers to a radical provided by the residue after removal of hydroxyl from the organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such lower alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl. The term "carnoyl", when used alone or in combination with other terms such as "alkoxycarbonyl", refers to-(C = O)-. The term "aroyl" includes aryl radicals having carbonyl radicals as defined above. Examples of aroyl include benzoyl, naphthoyl and the like, and the aryl in the aroyl may be further substituted. The term "carboxy" or "carboxyl" denotes CO ₂ H, whether used alone or in combination with other terms such as "carboxyalkyl". The term "carboxyalkyl" includes alkyl radicals substituted with carboxy radicals. More preferred are "lower carboxyalkyl" comprising lower alkyl radicals as defined above, which may be further substituted with halo on the alkyl radicals. Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical containing an alkoxy radical as defined above, which is bonded to a carbonyl radical via an oxygen atom. More preferred are "lower alkoxycarbonyl" radicals having alkyl moieties having 1 to 6 carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The terms "alkylcarbonyl", "arylcarbonyl" and "aralkylcarbonyl" include radicals having alkyl, aryl and aralkyl radicals as defined above, bonded to carbonyl radicals. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbonyl and benzylcarbonyl. The term “aralkyl” includes aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. Aryl in the aralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term “heterocyclylalkyl” refers to saturated and partially unsaturated heterocyclyl-substituted alkyl radicals such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals such as pyridylmethyl, quinolylmethyl , Thienylmethyl, furylethyl and quinolylethyl. Heteroaryl in the heteroaralkyl may be further substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The term "aralkoxy" includes aralkyl radicals bonded to another radical via an oxygen atom. The term "aralkoxyalkyl" includes an aralkoxy radical bonded to an alkyl radical via an oxygen atom. The term "aralkylthio" includes aralkyl radicals bonded to sulfur atoms. The term “aralkylthioalkyl” includes aralkylthio radicals bonded to an alkyl radical via a sulfur atom. The term "aminoalkyl" includes alkyl radicals substituted with one or more amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl and the like. The term "alkylamino" refers to an amino group substituted with one or two alkyl radicals. Preference is given to "lower N-alkylamino" radicals having alkyl moieties having 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino and the like. The term "arylamino" refers to an amino group substituted with one or two aryl radicals, such as N-phenylamino. An "arylamino" radical may be further substituted on the aryl ring portion of the radical. The term “aralkylamino” includes aralkyl radicals bonded to other radicals via amino nitrogen atoms. The terms "N-arylaminoalkyl" and "N-aryl-N-alkyl-aminoalkyl" refer to amino groups having an amino group bonded to an alkyl radical, each substituted with one aryl radical or one aryl and one alkyl radical it means. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term “aminocarbonyl” means an amide group of the formula —C (═O) NH ₂ . The term "alkylaminocarbonyl" refers to an aminocarbonyl group substituted with one or two alkyl radicals on an amino nitrogen atom. Preferred are the "N-alkylaminocarbonyl" and "N, N-dialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl", "lower N, N-dialkylaminocarbonyl" radicals having lower alkyl moieties as defined above. The term "alkylaminoalkyl" includes radicals having one or more alkyl radicals bonded to an aminoalkyl radical. The term "aryloxyalkyl" includes radicals having an aryl radical bonded to an alkyl radical via a divalent oxygen atom. The term "arylthioalkyl" includes radicals having an aryl radical bonded to an alkyl radical via a divalent sulfur atom.

The compounds used in the methods of the invention may exist in the form of free bases or pharmaceutically acceptable acid addition salts thereof. The term "pharmaceutically acceptable salts" includes salts commonly used to produce alkali metal salts and to addition salts of free acids or free bases. The nature of the salts is not critical but should be pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic acid and sulfonic acid classes of organic acids, examples being formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, Malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embon acid (Phamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alzenic acid, b-hydroxy Butyric acid, salicylic acid, galactaric acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine Organic salts prepared from ethylenediamine, melgumin (N-methylglucamine) and procaine. All of these salts can be prepared from the corresponding compounds by conventional means, for example by reacting the appropriate acid or base with the compound.

Mechanism of action

Without being bound to a specific mechanism of action for the combination therapy of the present invention, administration of the selected aldosterone receptor antagonist and fibric acid derivatives together, simultaneously and correlated of tissues and / or organs to these two classes of drugs Response: Assumed to be effective due to significant down-regulation of aldosterone-stimulated genetic effects on aldosterone antagonists, and triglyceridemia relief for fibric acid derivatives and increased plasma HDL cholesterol. This effect will provide a synergistic advantage for the therapeutic use of aldosterone receptor antagonists. Another mechanism for the therapeutic interaction between aldosterone antagonists and fibric acid derivatives may result from the anti-inflammatory effects of these drugs, with a decrease in serum triglycerides and hypertension, and an increase in HDL levels, which are atherosclerosis -Will provide additional therapeutic benefits in treating or preventing related diseases.

Benefits of Combination Therapy

Selected aldosterone receptor antagonists and fibric acid derivatives of the present invention work together to provide even more additional benefits. For example, administration of a mixture of aldosterone receptor antagonists and fibric acid derivatives can lead to atherosclerosis, such as high triglyceride levels, low HDL levels, high aldosterone levels, high blood pressure, endothelial dysfunction, plaque formation and rupture, etc. It can cause a nearly simultaneous reduction in the onset effect of several risk factors.

The methods of the present invention also provide effective prevention and / or treatment of diseases with reduced side effects compared to conventional methods known in the art. For example, administration of fibric acid derivatives can cause side effects such as myxotoxicity or myopathy, including rhabdomyopathy, and associated clinical sequelae. In addition, most fibric acid derivatives require a relatively large capacity. Reduction of the fibric acid derivative dose in the combination therapy of the present invention below the conventional monotherapeutic dose, for example, results in adverse reaction profiles associated with the combination therapy of the present invention as compared to the adverse event profile associated with monotherapy administration of the fibric acid derivative. Will be minimized or even excluded. Reducing the dose of fibric acid derivatives in the combination therapy of the present invention below conventional monotherapy doses will likewise facilitate the administration of fibric acid derivatives to a subject as compared to monotherapy administration of fibric acid derivatives.

Another advantage of the combination therapy of the present invention includes, but is not limited to, the use of selected groups of aldosterone receptor antagonists that provide a relatively rapid onset of therapeutic effect and a relatively long duration of action. For example, a single dose of one of the selected aldosterone receptor antagonists can remain bound to the aldosterone receptor in a manner that can provide for continuous blocking of mineral corticosteroid receptor activation. Another advantage of the combination therapy of the present invention is the highly selective aldosterone, with the reduction of side effects that may be caused by aldosterone antagonists that exhibit non-selective binding to non-mineral corticoid receptors, such as androgen or progesterone receptors. The use of a selected group of aldosterone receptor antagonists, such as epoxy-steroidal aldosterone antagonists, exemplified by eplerenone, which acts as an antagonist, is included. In addition, the use of aldosterone antagonists can provide direct benefits in preventing or treating liver dysfunction, including ascites production and liver fibrosis.

Another advantage of the combination therapies of the invention includes, but is not limited to, the use of the methods of the invention to treat individuals belonging to one or more specific ethnic groups that are particularly responsive to the disclosed therapies. Thus, for example, African or Asian individuals may be particularly advantageous as a combination therapy of aldosterone antagonists and fibric acid derivatives in the treatment or prevention of diseases.

Target group

Certain populations tend to be more compliant with the disease control effects of aldosterone. Members of these populations that are sensitive to aldosterone are typically also sensitive to salinity, with the individual's blood pressure generally rising or falling, respectively, as the sodium consumption increases and decreases. While not intending to limit the practice of the invention to such populations, it is contemplated that certain subject populations may be particularly suited to the therapy according to the invention. Accordingly, subjects that may benefit from treatment or prevention according to the methods of the present invention are generally human subjects exhibiting one or more of the following characteristics:

(a) The average daily intake of sodium chloride by the subject is greater than or equal to about 4 g, especially if the conditions are met for a particular one month period for at least one or more monthly intervals over a given one year period. The average daily intake of sodium by the subject is preferably at least about 6 g, more preferably at least about 8 g, even more preferably at least about 12 g.

(b) if the daily sodium chloride intake by the subject is increased from less than about 3 g / day to about 10 g / day or more, the subject is at least about 5%, preferably at least about 7%, more preferably about 10% Abnormal systolic and / or diastolic blood pressure increase.

(c) the activity ratio of plasma aldosterone (ng / dL) to plasma renin (ng / ml / hr) in the subject is greater than about 30, preferably greater than about 40, more preferably greater than about 50, and even more preferred To be greater than about 60.

(d) the subject has low plasma renin levels; For example, morning plasma renin activity in the subject is less than about 1.0 ng / dl / hr and / or active renin value in the subject is less than about 15 pg / ml.

(e) Subject has or is likely to have elevated systolic and / or diastolic blood pressure. Generally, the systolic blood pressure of the subject (eg, measured by a sitting cuff mercury sphygmomanometer) is at least about 130 mmHg, preferably at least about 140 mmHg, more preferably at least about 150 mmHg, and the subject's diastolic blood pressure (eg For example, a sitting cuff mercury sphygmomanometer) is at least about 85 mmHg, preferably at least about 90 mmHg, more preferably at least about 100 mmHg.

(f) The subject's urine sodium to potassium ratio (millimoles / millimoles) is less than about 6, preferably less than about 5.5, more preferably less than about 5, even more preferably less than about 4.5.

(g) The subject's urine sodium level is at least 60 mmol / day, especially if the condition is met for a particular one month period for at least one or more monthly intervals over a given one year period. The urine sodium level in the subject is preferably at least about 100 mmol / day, more preferably at least about 150 mmol / day, even more preferably at least 200 mmol / day.

(h) Elevate the plasma concentration of one or more endothelial cells in the subject, in particular the plasma immunoreactive ET-1. The plasma concentration of ET-1 is preferably greater than about 2.0 picomols / l, more preferably greater than about 4.0 picomoles / l, even more preferably greater than about 8.0 picomoles / l.

(i) the subject has a blood pressure that is substantially difficult to treat with an ACE inhibitor; In particular, subjects have a blood pressure lowered to less than about 8 mmHg, preferably less than 5 mmHg, more preferably less than 3 mmHg for 10 mg / day of enalapril compared to the blood pressure of a subject not receiving hypertension therapy.

(j) The subject has blood volume-extension hypertension or blood volume-extension limit hypertension, ie increased blood volume as a result of increased sodium retention, which contributes to blood pressure.

(k) The subject is a non-regulated individual, ie, in particular, the response is less than the response of an individual selected from a general geographic population (eg, an individual selected from the country in which the subject was born or from a country in which the subject resides). If mild, preferably if the response is less than 40%, more preferably less than 30%, even more preferably less than 20% of the mean of the population, the individual may be responsive to increased sodium intake or angiotensin II administration. Blunt positive responses in blood flow and / or adrenal production of aldosterone.

(l) Subject has or is prone to renal dysfunction, particularly renal dysfunction selected from one or more members of the group consisting of glomerular filtration rate reduction, microalbuminuria and proteinuria.

(m) The subject has or is susceptible to cardiovascular disease, in particular cardiovascular disease selected from one or more members of the group consisting of heart failure, left ventricular diastolic dysfunction, hypertrophic cardiomyopathy and diastolic heart failure.

(n) The subject has or is prone to liver disease, especially cirrhosis.

(o) The subject has or is susceptible to edema selected from one or more members of the group consisting of edema, in particular terminal tissue edema, liver or spleen congestion, hepatic ascites and respiratory or pulmonary congestion.

(p) Subjects have or tend to have insulin resistance, especially type I or type II diabetes and / or glucose sensitivity.

(q) The subject is at least 55 years old, preferably at least about 60 years old, more preferably at least about 65 years old.

(r) The subject is a member, in whole or in part, of one or more ethnic groups selected from Asian (especially Japanese) ethnic groups, American Indian ethnic groups, and black ethnic groups.

(s) The subject has one or more genetic markers associated with salinity sensitivity.

(t) The subject is obese, preferably having more than 25% body fat, more preferably more than 30% body fat, even more preferably more than 35% body fat.

(u) has one or more primary, secondary or tertiary relatives, either salt sensitive or susceptible, wherein primary relatives are relatives that share one or more of the parents or the same parent, and secondary relatives are grandparents and the same A relative who shares one or more of the grandparents, and the third kin means a relative who shares one or more of the great-grandparent and the same great-grandparent. Preferably, the individual has at least four salt sensitive primary, secondary or tertiary relatives; More preferably 8 or more of the above relatives; Even more preferably at least 16 said relatives; Even more preferably have at least 32 such relatives.

Unless stated otherwise, the values listed above preferably represent average values, more preferably daily average values based on two or more measurements.

Preferably, the subject in need of treatment satisfies at least two or more of the above characteristics, or at least three or more of the above characteristics, or at least four of the above characteristics.

Dosage and Treatment

Aldosterone Receptor Antagonist Dose

The amount of aldosterone receptor antagonist blocker administered and the regimen for the method of the present invention can vary depending on the subject's age, weight, sex and medical condition, severity of the disease, route and frequency of administration, and the particular aldosterone blocker used. It can vary widely, so it can vary widely. The subject has about 0.001 to 30 mg / kg body weight, preferably about 0.005 to about 20 mg / kg body weight, more preferably about 0.01 to about 15 mg / kg body weight, even more preferably about 0.05 to about 10 mg / kg Daily doses of kg body weight, most preferably about 0.01-5 mg / kg body weight, may be appropriate.

The daily dose of aldosterone antagonist administered to a human subject will typically range from about 0.1 mg to about 2000 mg. In one embodiment of the present invention, the daily dose range is about 0.1 to about 400 mg. In another aspect of the invention, the daily dose range is about 1 to about 200 mg. In another aspect of the invention, the daily dose range is about 1 to about 100 mg. In another aspect of the invention, the daily dose range is about 10 to about 100 mg. In another aspect of the invention, the daily dose range is about 25 to about 100 mg. In another aspect of the invention, the daily dose is selected from the group consisting of about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 50 mg, about 75 mg and about 100 mg. In another aspect of the invention, the daily dose is selected from the group consisting of about 25 mg, about 50 mg and about 100 mg. Daily doses of aldosterone blockers that do not provide substantial diuretic and / or hypertensive effects in the subject are particularly included in the methods of the invention. The daily dose may be administered in one to four doses per day.

The dose of the aldosterone antagonist can be determined and adjusted based on the measurement of blood pressure or an appropriate surrogate label (including but not limited to natriuretic peptides, endothelial cells and other surrogate labels discussed below). Blood pressure and / or surrogate labels after aldosterone antagonist administration can be compared against the corresponding basal level prior to aldosterone antagonist administration and titrated as necessary to determine the effectiveness of the methods of the invention. Non-limiting examples of surrogate labels useful in the method are surrogate labels for kidney and cardiovascular disease.

Preventive dose

It is advantageous to administer the aldosterone antagonist prophylactically prior to the diagnosis of the cardiovascular disease and to continue the administration of the aldosterone antagonist for a period of time subject is susceptible to cardiovascular disease. Therefore, individuals who are susceptible to disease, even though there are no clear clinical signs, may apply a prophylactic dose of aldosterone antagonist compounds. The prophylactic dose of the aldosterone antagonist may, but is not necessarily, be lower than the dose used to treat the particular disease of interest.

Cardiovascular Pathology Dosage

Dosages for treating diseases of cardiovascular function can be determined and adjusted based on blood concentration measurements of natriuretic peptides. Natriuretic peptides are a group of structurally similar but genetically distinct peptides with varying actions in cardiovascular, renal and endocrine homeostasis. Atrial natriuretic peptide (“ANP”) and brain natriuretic peptide (“BNP”) are derived from cardiomyocytes and C-type natriuretic peptide (“CNP”) is derived from endothelial cells. ANP and BNP are natriuretic peptides that modulate natriuresis, vasodilation, renin inhibition, antimitosis and lusitropic properties by 3 ', 5'-cyclic guanosine monophosphate (cGMP). Binds to the A receptor (“NPR-A”). Increased natriuretic peptide levels in the blood, in particular blood BNP levels, are generally observed in subjects with blood volume dilatation and after vascular injury such as acute myocardial infarction and remain elevated for prolonged time after infarction [Uusimaa et al. , Int. J. Cardiol ., 69 : 5-14, 1999].

Reduction of natriuretic peptide levels relative to basal levels measured prior to aldosterone antagonist administration indicates a reduction in aldosterone disease and thus correlates with inhibition of disease. Therefore, the blood levels of the preferred natriuretic peptide levels can be compared against the corresponding basal level prior to the administration of the aldosterone antagonist to determine the effectiveness of the methods of the invention in treating the disease. Based on the natriuretic peptide concentration measurement, the dose of aldosterone antagonist may be adjusted to reduce cardiovascular disease. Similarly, heart disease can also be identified and appropriate dosage can be determined based on circulating and urine cGMP levels. Increasing plasma levels of cGMP is comparable with a drop in mean arterial blood pressure. Increased urinary excretion of cGMP is correlated with sodium urinary excretion.

Heart disease can also be identified by decreased ejection fraction or the presence of myocardial infarction or heart failure or left ventricular hypertrophy. Left ventricular hypertrophy can be confirmed by electrocardiogram or magnetic resonance imaging and can be used to monitor the course of treatment and the appropriateness of dose.

Therefore, in another aspect of the present invention, the method of the present invention can be used to reduce natriuretic peptide levels, in particular BNP levels, thereby also treating related cardiovascular diseases.

Cardiovascular disease can also be confirmed by the presence of increased blood or tissue levels of C-reactive protein (CRP).

Therefore, in another aspect of the present invention, related cardiovascular diseases may also be treated by reducing C-reactive protein levels using the methods of the present invention.

Renal Pathology Dose

Dosages for treating pathology of renal function can be determined and adjusted based on measurements of proteinuria, microalbuminuria, glomerular filtration rate (GFR) reduction or creatinine clearance. Proteinuria is identified by the presence of more than about 0.3 g of urine protein in a 24-hour urine collection. Microalbuminuria is identified by an increase in analytical urinary albumin. Based on these measurements, the dose of aldosterone antagonist can be adjusted to improve the renal pathological effect.

Neuropathy Pathology Dose

Neuropathy, especially peripheral neuritis, can be identified and adjusted based on neurological examination of sensory deficits or sensorimotor capacity.

Retinopathy pathology dose

Retinopathy can be confirmed by ophthalmologic examination and the dose adjusted.

Fibric Acid Derivative Capacity

The total daily dose of the fibric acid derivative may generally range from about 1000 to about 3000 mg / day in single or divided doses. For example, gemfibrozil or clinofibrate are often administered separately at doses of 1200 mg / day each. Clofibrate is often administered at a dose of 2000 mg / day. Binifibrate is often administered at a dose of 1800 mg / day.

However, the specific dosage level for each patient will vary depending on the activity, age, weight, general health, sex, diet, time of administration, secretion rate, selected active agent mixture, severity of the particular condition or disease being treated, and It should be noted that this will vary depending on various factors including the dosage form. Appropriate dosages can be determined by trial. However, the ratio (weight / weight) of the aldosterone receptor antagonist to the fibric acid derivative is typically about 1: 1,000 to about 1: 1, or about 1: 500 to about 1:10, or about 1: 200 to about 1: 20, or about 1: 100 to about 1:50.

The total daily dose of each drug may be administered to the patient in a single dose or in multiple balanced small doses. Small doses may be administered from two to eight times a day. The dose may be immediate release or sustained release effective for obtaining the desired result. Single dosage forms comprising aldosterone receptor antagonists and fibric acid derivatives may be used where desired.

Dosing

As mentioned above, the dosage regimen for the prevention, treatment, alleviation or amelioration of a disease using the mixtures and compositions of the present invention is selected according to a variety of factors. Such factors include the type, age, weight, sex, diet and medical condition of the patient, type and severity of the disease, route of administration, pharmacological considerations, e.g. activity, efficacy, pharmacokinetics and toxicity profile of the specific active agent used. , Whether a drug delivery system is used, and whether the drug is administered with other ingredients. Thus, the dosage regimen actually used may vary widely and therefore may differ from the preferred dosage regime shown above.

Initial treatment of a patient suffering from a hyperlipidemic disease or condition may begin with the abovementioned dosages. Treatment should generally last for several weeks to months or years until the hyperlipidemic disease or condition is controlled or eliminated as needed. Patients undergoing treatment with the mixtures or compositions disclosed herein routinely receive blood pressure, ejection counts, serum LDL or HDL or total cholesterol levels or total triglyceride levels, for example in treating certain cardiovascular diseases. By measuring by any method known in the art, it can be monitored to determine the effect of the combination therapy. By continuous analysis of the data, the therapy can be modified during treatment so that the optimum effective amount of each type of active agent is administered at any time and the duration of treatment can also be determined. In this way, the treatment / dose schedule is administered during the course of treatment so that the lowest amount of aldosterone receptor antagonist and fibric acid derivative that together produce a satisfactory effect is maintained and lasts only as long as necessary for successful treatment or prevention of the disease. It can be modified reasonably.

In combination therapy, administration of the aldosterone receptor antagonist and fibric acid derivatives may occur sequentially in separate formulations, or may be performed by simultaneous administration in a single formulation or in separate formulations. Administration can be carried out by any suitable route, with oral administration being preferred. The dosage unit used may advantageously contain one or more aldosterone receptor antagonists and fibric acid derivatives in the amounts described below.

Dosages for oral administration may be used as a single daily dose, several spaced doses throughout the day, a single dose every other day, a regimen requiring a single dose every few days, or other suitable regimen. The aldosterone receptor antagonists and fibric acid derivatives used in the combination therapy may be administered simultaneously in a combination dosage form or in separate dosage forms for substantially simultaneous oral administration. Aldosterone receptor antagonists and fibric acid derivatives may also be administered sequentially, wherein either active agent is administered in a regimen requiring two-step intake. Thus, the regimen may require sequential administration of aldosterone receptor antagonists and fibric acid derivatives by spaced ingestion of the separate active agents. The time period between the different intake stages ranges from several minutes to several hours, depending on the nature of each active agent, eg, the efficacy, solubility, bioavailability, plasma half-life and dynamic profile of the agent, and depending on the age and condition of the patient. Can be. The dosing time may also vary depending on the 24 hours or other rhythm for the disease of the medicament, such as aldosterone, which may be optimally blocked at that peak concentration. Whether the administration is performed simultaneously or substantially simultaneously or sequentially, the combination therapy comprises the administration of the aldosterone receptor antagonist by the oral or intravenous route and the fibric acid derivative by the oral or intravenous route. This may involve a regimen required. Regardless of whether the active agents are administered separately or together by the oral or intravenous route, each of the active agents will be contained in a suitable pharmaceutical formulation of pharmaceutically acceptable excipients, diluents or other formulation components. Examples of suitable pharmaceutically acceptable formulations are shown above.

Mixtures and Compositions

The invention also relates to a mixture comprising one or more aldosterone receptor antagonists and fibric acid derivatives, including pharmaceutical compositions. In one aspect, the invention provides a pharmaceutical composition comprising a first amount of an aldosterone receptor antagonist or a pharmaceutically acceptable salt, ester or prodrug thereof; A second amount of fibric acid derivative or a pharmaceutically acceptable salt, ester, conjugate acid or prodrug thereof; And a pharmaceutically acceptable carrier. Preferably, said first and second amounts of active agent together comprise a therapeutically effective amount of the agent. Preferred aldosterone receptor antagonists and fibric acid derivatives used in the preparation of the compositions are as indicated above. Mixtures and compositions comprising aldosterone receptor antagonists and fibric acid derivatives of the present invention may be used for the prevention and / or prevention of diseases as indicated above by any means that cause contact between the agents and their site of action in the human body. Or for treatment.

In the prevention or treatment of the above mentioned pathological diseases, the mixture to be administered may comprise the active compound itself. Alternatively, pharmaceutically acceptable salts are particularly suitable for medical use because of their greater water solubility for the parent compound.

Mixtures of the present invention may also be provided in the form of a pharmaceutical composition using an acceptable carrier. The carrier should be acceptable in view of compatibility with other components of the composition and should not be harmful to the recipient. The carrier may be solid or liquid or both, and is preferably formulated as a unit-dose composition, for example a tablet, which may contain from 0.05 to 95% by weight of active compound using the compound. Other pharmacologically active substances may also be present, including other compounds useful in the present invention. The pharmaceutical composition of the present invention may be prepared by any known pharmaceutical technique, such as mixing of ingredients.

The mixtures and compositions of the present invention may be administered by any conventional means useful for use with a medicament. Oral delivery of aldosterone receptor antagonists and fibric acid derivatives is generally preferred. The amount of each active agent in the mixture or composition necessary to achieve the desired biological effect will depend on a number of factors, including the factors discussed below in relation to the therapy.

Orally administrable unit dose formulations such as tablets or capsules are, for example, about 0.1 to about 2000 mg, or about 0.5 to about 500 mg, or about 0.75 to about 250 mg, or about 1 to about 100 mg of aldosterone receptor. Antagonists, and / or about 50 to about 500 mg, or about 200 to about 1000 mg, or about 500 to about 3000 mg of fibric acid derivatives.

Oral delivery of aldosterone receptor antagonists and fibric acid derivatives of the invention can include formulations as known in the art to provide immediate or delayed or sustained delivery of the drug to the gastrointestinal tract by a number of mechanisms. Immediate delivery formulations include, but are not limited to, oral solutions, oral suspensions, rapid tablets or capsules, disintegrating tablets, and the like. Delayed or sustained delivery formulations include pH sensitive release from the dosage form based on pH changes in the gastrointestinal tract, slow corrosion of tablets or capsules, retention of the stomach based on the physical properties of the dosage form, and biometrics of the dosage form for the mucous contents of the intestinal tract. Enzymatic release of the active drug from the attachment, or dosage form, includes, but is not limited to. The intended effect is to prolong the time that the active drug molecule is delivered to the site of action by the preparation of the dosage form. Thus, enteric coating formulations and enteric coating release controlling formulations are within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units, such as capsules, cachets, lozenges or tablets, each containing a predetermined amount of one or more compounds of the present invention; As a powder or granules; As a solution or a suspension in an aqueous or non-aqueous liquid; Or oil-in-water or water-in-oil emulsions. As indicated, the composition may be prepared by any suitable pharmaceutical method comprising the step of mixing the active agent (s) and the carrier (which may constitute one or more accessory ingredients). Generally, the composition is prepared by uniformly and intimately mixing the active agent (s) with a liquid or finely divided solid carrier, or both, and then molding the product, if necessary. For example, tablets may be made by compacting or molding powders or granules of active agents in the presence or absence of one or more accessory ingredients. Compressed tablets may be prepared by compressing the compound in a suitable machine into a free-flowing form, such as a powder or granules, with or without a binder, lubricant, inert diluent and / or surface active / dispersant (s). Molded tablets can be produced, for example, by molding powdered compounds in a suitable machine.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing conventionally used inert diluents such as water. The composition may also include auxiliaries such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and fragrances.

In either case, the amount of aldosterone receptor antagonist and fibric acid derivative that can be mixed with the carrier material to produce a single dosage form to be administered will depend upon the host treated and the particular mode of administration. Solid dosage forms for oral administration, including the aforementioned capsules, tablets, pills, powders and granules, comprise the active agents of the invention in admixture with one or more inert diluents, for example sucrose, lactose or starch. The dosage form can also include other additional substances besides inert diluents, such as lubricants such as magnesium stearate, as in standard practice. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Tablets and pills can further be prepared using enteric coatings.

Pharmaceutically acceptable carriers include all of the foregoing, and the like. The above discussion of effective formulations and administration procedures is known in the art and described in standard textbooks. Drug formulations are described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms , Marcel Decker, New York, NY, 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3 ^rd Ed.), American Pharmaceutical Association, Washington, 1999.

Pharmaceutical mixtures suitable for use in the present invention are described in Table 3.

For therapeutic purposes, the active ingredient of the combination therapy of the present invention is typically mixed with one or more adjuvants appropriate for the indicated route of administration. When administered orally, the components include lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia It may be mixed with rubber, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol and then compressed or encapsulated for ease of administration. The capsule or tablet may contain a release-modulating formulation as may be provided in a dispersion of the active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. Such solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulation for oral administration. The components may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art.

Kit

The invention also includes kits suitable for use in carrying out the methods of treatment and / or prophylaxis described above. In one embodiment, the kit contains a first dosage form comprising one or more aldosterone receptor antagonists and a second dosage form comprising one or more fibric acid derivatives in an amount sufficient to carry out the methods of the invention. Preferably, the first dosage form and the second dosage form together comprise a therapeutically effective amount of the above agents for the prophylaxis and / or treatment of a disease.

In one embodiment, the kit contains a first dosage form comprising eplerenone or spironolactone and a second dosage form comprising a fibric acid derivative as defined in Table 2 in an amount sufficient to carry out the method of the invention. do.

In another aspect, the kit contains a first dosage form comprising eplerenone and a second dosage form comprising a fibric acid derivative.

In another embodiment, the kit contains a first dosage form comprising eplerenone and a second dosage form comprising a fibric acid derivative as defined in Table 2.

In another embodiment, the kit contains a first dosage form comprising eplerenone and a second dosage form comprising a fibric acid derivative selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil.

In another embodiment, the kit contains a first dosage form comprising spironolactone and a second dosage form comprising a fibric acid derivative.

In another embodiment, the kit contains a first dosage form comprising spironolactone and a second dosage form comprising a fibric acid derivative as defined in Table 2.

In another embodiment, the kit contains a first dosage form comprising spironolactone and a second dosage form comprising a fibric acid derivative selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil.

In another aspect, the kit further includes written instructions stating how the subject can use the contents of the kit. Written instructions will be useful, for example, in achieving a therapeutic effect without causing the subject to unwanted side effects. In another aspect, the written instructions include all or part of the product label approved by the drug regulatory agency for the kit.

The following non-limiting examples are intended to illustrate various aspects of the invention.

Example 1

Therapeutic treatment

Non-limiting examples of in vitro and in vivo test plans and protocols that can be used separately or together to evaluate the therapeutic benefits of aldosterone receptor antagonists and fibric acid derivatives for the treatment or prevention of diseases are incorporated herein by reference. It is described in the references listed below:

Example 2

Therapeutic Treatment to Improve Endothelial Dysfunction in Dietary Induced Atherosclerosis in Rabbits

A study was conducted to test the efficacy of therapeutic mixtures of aldosterone receptor antagonists and fibric acid derivatives to evaluate whether the combination therapy could improve or prevent endothelial dysfunction that occurs with atherosclerosis.

Methods: New Zealand white rabbits were randomly divided into four treatment groups. Thirty-two rabbits were given 8 weeks of standard food (NC) or 1% cholesterol food (HC). After the first two weeks, 16 rabbits were randomly challenged with either saline (S) or aldosterone receptor antagonists, eplerenone (20 mg / kg, twice daily, gavage) and fibric acid derivative gemfibrozil (50 mg). / Kg, twice daily, gavage) was provided for 6 more weeks. At the end of week 8 the rabbits were euthanized and the aorta was pulled out for isotropic strain studies in vascular segments and evaluation of the production of superoxide (O ₂ ⁻ ) by lucigenin chemiluminescence (250 μM). Blood vessels were preshrunk with phenylephrine (3 × 10 ⁻⁷ ) up to about 50% of peak contraction and tested for dose response to acetylcholine (Ach) and nitroglycerin (NTG).

Results: Ach, peak relaxation for NTG, ED ₅₀ (M) value and O ₂ ⁻ number (per mg dry weight) were measured. Combination therapy is expected to improve endothelial function and reduce O ₂ ⁻ production in dietary induced atherosclerosis.

In another aspect of this embodiment, different or additional aldosterone receptor antagonists such as spironolactone, and / or different or additional fibric acid derivatives such as fenofibrate, cypropibrate or bezafibrate Therapeutic benefits can also be obtained with other mixtures used.

Example 3

Comparative study of efficacy and safety of eplerenone and gemfibrozil, alone and in combination with each other in patients with left ventricular hypertrophy and essential hypertension

Zempfibrozil and Efple after 9 months of treatment for blood pressure (BP) changes and left ventricular weight (LVM) changes as measured by magnetic resonance imaging (MRI) in patients with LVH and essential hypertension Clinical studies are conducted to evaluate the effect of Lennon alone and as a mixture with each other. The study included at least 150 patients with LVH and essential hypertension, consisting of a two-week single-blind placebo administration period and a nine-month double-blind treatment period after a one- to two-week pretreatment screening period. Central randomized double-blind placebo administration, comparative group trial.

Patients to be introduced during the single-blind placebo administration period are either (1) (a) by Sokolow Lyon voltage criteria (Sokolow M, et al., Am Heart J , 37 : 161, 1949), or (b ) On the Debrix criterion (LVMI = 134 g / m ^{2 for} men and 110 g / m ^{2 for} women; see Neaton JD, et al., JAMA , 27 : 713-724, 1993). Will have a previous electrocardiogram indicative of LVH; (2) have a seated blood pressure, such as: (a) a seated diastolic blood pressure (seDBP) of less than 110 mmHg and a seated systolic blood pressure (seSBP) of 180 mmHg, or (b) high blood pressure when treated generally with a hypertensive drug Seated diastolic blood pressure (seDBP) of greater than or equal to 85 mmHg and less than 114 mmHg, and of seated systolic blood pressure (seSBP) of greater than 140 mmHg and less than or equal to 200 mmHg, unless generally treated with a therapeutic drug.

During the single-blind placebo administration in the second trial, patients should all have an electrocardiogram showing LVH per debrix criterion. After the two week single-blind placebo administration period was completed and MRIs were taken and certified as allowed in the core laboratory, patients were randomly selected from groups 1 to 3: eplerenone, gemfibrozil or eplerenone and gempy. Divided into broilers. During the first two weeks of double-blind treatment, patients received (1) 50 mg of eplerenone and placebo, (2) 600 mg of gemfibrozil and placebo, or (3) 50 mg of eplerenone and 600 mg of gemfibrozil. Receive. The dose of study drug was (1) 100 mg Eplerenone and placebo, (2) 1200 mg and gemfibrozil, or (3) 100 mg Eplerenone and gemfibrozil 1200 mg for all patients at week 2. Forced-titrated. At week 4, the dose of study drug was administered for (1) 200 mg and placebo, (2) gemfibrozil 1800 mg and placebo, or (3) 200 mg and empfibrozil 1800 for all patients. Force-titrated to mg. If, at week 16 or any subsequent trial, the patient exhibits a sustained uncontrolled DBP (ie, seDBP of 90 mmHg or seSBP greater than 180 mmHg that persists in two consecutive trials at 3 to 10 day intervals), the patient will study Exclude from participation. Patients with signs of hepatotoxicity or rhabdomyopathy are also excluded from the study.

If a patient receives only double-blind treatment and experiences signs of hypertension at any time during the trial, that patient is also excluded. Patients who are receiving open-label drugs will have down-titrated open-label drugs in the reverse order in which they are administered until hypertension is resolved. If there are still signs of hypertension after all open-label drugs have been discontinued, the patient is also excluded from the trial. At any time during the study, if the serum potassium levels increase (above 5.5 mEq / L) (BUN and creatinine levels also increase in repeated measurements in two consecutive runs at 1 to 3 day intervals), samples are sent to the adipose and central laboratories , Treatment decisions based on fat value), and those patients are also excluded. Caution: If BUN and / or creatinine levels increase significantly above baseline (creatinine = 2.0 mg / dL or 1.5 times the baseline, or BUN = 35 mg / dL or 2 times the baseline), the patient will have drug until resolve You must be treated.

Patients are treated for monthly evaluation for 0, 2, 4, 6, 8, 10, 12, 16 weeks and subsequent 9 months in total. Heart rate, blood pressure, serum potassium levels, plasma lipid and lipoprotein levels and side effects are evaluated in each trial. BUN and creatinine levels are measured at weeks 2 and 6. Additional laboratory evaluations of blood for clinical safety are conducted monthly. Regular urinalysis is done every three months. Neurohormone profiles (plasma renin (total renin and active renin), serum aldosterone and plasma cortisol) and specific studies (PIIINP, PAI, microalbuminuria and tPA) are conducted at 0 and 12 weeks, and at 6 and 9 months. Blood samples for genotyping are collected at the beginning week (week 0). At screening and at 9 months, 12-derived ECG and physical examinations are performed. MRI to assess changes in LV weight, blood samples for storage reserves, blood samples for thyroid stimulating hormone (TSH), and 24-hour urine collection for albumin, potassium, sodium and creatinine are performed at weeks 0 and 9 months. 24-hour urine collection for urine aldosterone is done at 0 and 12 weeks and 6 and 9 months. If terminated prematurely, blood samples for MRI and TSH are performed in patients who have undergone double-blind treatment for at least 3 months. At 0 and 12 weeks, and 6 and 9 months, pharmacoeconomic data is collected from all patients.

The primary measure of efficacy is the change from baseline in LVM as assessed by MRI. Secondary measures of efficacy are: (1) change from baseline in LVM in the three treatment groups; (2) change from baseline of sitting trough cuff DBP (seDBP) and SBP (seSBP) in each of the three treatment groups; (3) aortic elasticity and ventricular filling parameters; (4) plasma lipid and lipoprotein levels, and (5) specific studies (PIIINP, microalbuminuria, PAI and tPA). In addition, the long-term safety and tolerability of the three treatment groups are compared.

The primary purpose of this study was to compare the effects of different therapies on changes in left ventricular weight (LVM) in patients with LVH and essential hypertension. The secondary objective of the study was to (1) compare the change from baseline of LVM in the three treatment groups; (2) comparing the effect of hypertension on the three treatment groups as measured by sitting trough cuff DBP and SBP; (3) comparing the effects of the three treatment groups on aortic elasticity and ventricular filling parameters as measured by MRI; (4) comparing the effect of the three treatment groups on plasma labeling of fibrosis by measuring the amino terminal propeptide of type III procollagen (PIIINP) and comparing the effect on renal glomerular function by measuring microalbuminuri, Comparing the effect on fibrinolysis balance by measuring minogen activator inhibitor (PAI) and tissue plasminogen activator (tPA); (5) comparing the effects of the three treatment groups on plasma lipid and lipoprotein levels; (6) Three treatment groups compare long-term safety and resistance.

Subgroup analyzes of primary and secondary efficacy measures include, for example, sex, age, plasma renin levels, aldosterone / renin activity ratios, urinary sodium to potassium ratios, presence of diabetes, history of hypertension, history of heart failure, history of renal dysfunction, Other subgroups may be performed based on baseline records of factors such as dyslipidemia. Small groups based on continuous measures, such as age, can be divided from the median to two.

In another aspect of this embodiment, different or additional aldosterone receptor antagonists such as spironolactone, and / or different or additional fibric acid derivatives such as fenofibrate, cypropibrate or bezafibrate Therapeutic benefits can also be obtained with other mixtures employed.

Example 4

Therapies to Prevent or Treat Endothelial Dysfunction in Humans

Patients at risk for or suffering from cardiovascular disease are divided into two groups: (1) group treated with 50 mg of aldosterone receptor antagonist eprerenone and 600 mg gemfibrozil for 2 months, or (2) Placebo administration group for 2 months. Beginning one month prior to treatment, at two week intervals, the patient is tested for endothelial function as follows: Lying down and resting for 20 minutes, the cannula is inserted under local anesthesia into the non-dominant forearm artery. Thirty minutes after saline injection, baseline forearm blood flow was measured by forearm vein-occluded hemometry. The drug was then injected into the arm under study using a constant flow injector. Forearm blood flow is measured for each drug infusion over the last 2 minutes at each baseline. Blood pressure is measured at regular intervals throughout the study on non-injected (control) arms.

Drug Injection: First, acetylcholine (endothelial cell-dependent vasodilator) is injected at 25, 50 and 100 mmol / min for 5 minutes, respectively. Sodium nitroprusside (endothelial cell independent vasodilator) was then injected at 4.2, 12.6 and 37.8 nanomoles / min for 5 minutes each, followed by N-monoethyl-L-arginine (L-NMMA; competitive synthetase inhibitor Is injected at 1, 2 and 4 micromoles / minute for 5 minutes each. Angiotensin I (vasoconstrictor only by conversion to angiotensin II) is then injected at 64, 256 and 1024 picomoles / minute for 7 minutes each. Between different drugs, drug infusion flushes with saline for 20-30 minutes to allow enough time for the forearm blood flow to return to baseline values.

Results: Treatment with a mixture of eplerenone and gemfibrozil is expected to significantly increase the forearm blood response (% change in forearm blood flow) to acetylcholine with an increase in vasoconstriction caused by L-NMMA.

In another aspect of this embodiment, different or additional aldosterone receptor antagonists such as spironolactone, and / or different or additional fibric acid derivatives such as fenofibrate, cypropibrate or bezafibrate Therapeutic benefits can also be obtained with other mixtures employed.

Example 5

Double-blind Study to Assess Changes of Coronary Atherosclerosis After Heart Transplantation as Measured by IVUS After 12 Months of Dosing.

PURPOSE: The primary objective of this study was anteriorly descending as assessed by intravascular ultrasonography (IVUS) (centered reading) after 12 months of treatment with the combination therapy of the aldosterone receptor antagonist eplerenone and fibric acid derivative gemfibrozil. To determine the change in the maximum mean endovascular thickness of a coronary artery. A 30% change from baseline in endovascular thickness is considered clinically meaningful. The secondary objective of this study was to measure the effects on coronary atherosclerosis and to compare the effects of the combination therapy by the following evaluation:

Evidence of organ rejection as assessed by side reports.

Determination of circulating label concentrations of LDL-C, HDL-C, ApoB, ApoA-1, Lp (a) concentrations, ex vivo platelet aggregation, fibrinogen, and vascular inflammation.

Comparison of plasma lipid and lipoprotein values after 52 weeks of treatment.

52 measurement of inflammatory markers after treatment (HLA antigen VCAM / ICAM expression as assessed by biopsy).

Determination of safety and tolerance of drugs.

Type and number of subjects: Approximately 40 men and women (age 18 years or older) after heart transplant with hypercholesterolemia and less than 400 mg / dL triglycerides at randomization.

Trial Treatment: The dose is titrated once daily with 2 doses of eplerenone (50 mg) or gemfibrozil (600 mg) followed by 100 mg of eplerenone and 1200 mg of gemfibrozil. Patients whose dose is titrated upside down may titrate the dose at the discretion of the investigator.

Duration of Treatment: 52 weeks of treatment with standard care and combination therapy, or standard care and placebo, to suitable subjects randomized to one of the two care groups.

Primary Measurement: Average change from baseline in maximum mean endovascular thickness as assessed by IVUS (centered reading).

Secondary measurement: % change from baseline of LDL-C at 6 and 12 months. Total Cholesterol (TC), Low Density Lipoprotein Cholesterol (LDL-C), High Density Lipoprotein Cholesterol (HDL-C), LDL-C / HDL-C, TC / HDL-C, Non-HDL-C / HDL-C, and Tri % Change from baseline in glycerides (TG). % Change from baseline in ApoB, ApoB / ApoA-1, ApoA-1, Lp (a), and particle subfractions at 6 and 12 months. Percentage of subjects for each of the appropriate doses available at 12 months. Endocardial rejection is considered a side effect. % Change from baseline in inflammatory markers (HLA antigen levels and ICAM / VCAM expression). Safety assessment as measured by side effects, physical examination and laboratory data.

Trial design: This is a multicenter, randomized, double-blind clinical trial. Within 1 to 4 weeks after surgery, subjects are randomly given 52 weeks of combination therapy or placebo. Subjects should not have received any other lipid-lowering treatment after surgery.

Inclusion Criteria: (1) received a heart transplant at least 4 weeks prior to randomization, and (2) fasting TG concentrations below 4.52 mmol / L (400 mg / dL). Exclusion Criteria. Any of the following are considered criteria to be excluded from the trial: (1) the use of other cholesterol lowering drugs or lipid lowering dietary supplements or food additives after transplantation prior to introduction into the study; (2) a history of severe or hypersensitivity reactions to aldosterone receptor antagonists or fibric acid derivative sequestration resins; (3) participate in other study drug trials less than 4 weeks prior to randomization to this trial; (4) Subjects randomly selected for excluded double-blind treatments may not be reintroduced into this trial; (5) A serious or unstable medical or physiological condition that, in the opinion of the investigator, would compromise the subject's safety or successful participation in testing.

In another aspect of this embodiment, different or additional aldosterone receptor antagonists such as spironolactone, and / or different or additional fibric acid derivatives such as fenofibrate, cypropibrate or bezafibrate Therapeutic benefits can also be obtained with other mixtures employed.

Example 6

Evaluation of Combination Therapies in Rabbits Fed Cholesterol

Studies are conducted to test the efficacy of therapeutic mixtures of aldosterone receptor antagonists eplerenone and fibric acid derivative gemfibrozil to determine whether combination therapy can improve or prevent atherosclerosis in cholesterol fed rabbits.

Methods: Male New Zealand white rabbits were fed a standard diet (100 g / day) supplemented with 0.3% cholesterol and 2% corn oil (Ziegler Brothers, Inc., Gardner, PA). It was. Water can be used arbitrarily. Half of the animals received 20 mg / kg / day of eplerenone and 100 mg / kg / day of gemfibrozil at the start of the diet. The remaining rabbits were untreated controls. Controlled and treated animal groups were killed one to three months after treatment. Tissues were cut for characterization of atherosclerotic lesions. Blood samples were taken to determine plasma lipid and lipoprotein concentrations. Mean arterial blood pressure was measured in conscious animals at the end of the study.

Plasma Lipids: Blood is drawn from the ear vein into an EDTA-containing tube (vacuum tube; Becton Dickinson & Co., Lutherford, NJ), followed by centrifugation of cells to obtain plasma for lipid analysis. Obtained. Total cholesterol is measured enzymatically using a cholesterol oxidase reaction. HDL cholesterol is also measured enzymatically after selective precipitation of LDL and VLDL with dextran sulfate under magnesium. Plasma triglyceride levels are determined by measuring the amount of glycerol released by lipoprotein lipase via enzyme-binding assays.

Blood pressure: On the day of blood pressure measurement, animals are orally administered in the morning as usual. The blood pressure catheter is then implanted in an anesthetized animal with a ketamine / xylazine mixture. The measurement was started 4 hours after collection and about 5 hours after oral administration. The mean arterial blood pressure at rest is conscious using a pressure transducer (Statham Instruments, Inc., Oxnard, Calif.) Connected to a catheter introduced through the right carotid artery and located in the ascending aorta. Measure in this rabbit. Multiple infusions of increasing concentrations of peptide are made at intervals of 5 to 10 minutes after blood pressure returns to baseline. The duration of drug effect on blood pressure-promoting response to peptide infusion is measured at intervals ranging from 0.5 to 24 hours after a single oral administration in conscious and catheterized animals.

Atherosclerosis: Animals are killed by injecting pentobarbital. The thoracic aorta is rapidly removed and immersed in 10% neutral buffered formalin and stained with oil red O (0.3%). After a single incision in the longitudinal direction along the wall opposite the arterial cavity, the blood vessels were opened with pins to assess plaque area. The plaque range% is calculated from the values for the total area inspected and the stained area from a true color image analyzer (Videometric 150; San Diego, Calif.) Connected to a color camera (Toshiba 3CCD) mounted on an anatomical microscope. Measured by titer analysis using American Innovasion, Inc. Tissue cholesterol is measured enzymatically as described after extraction from the chloroform / methanol mixture (2: 1).

In Vitro Vascular Response: Abdominal aorta is rapidly excised after sodium pentobarbital infusion and placed in oxygenated Krebs-bicarbonate buffer. After removal of peripheral vascular tissue, a 3 mm ring fragment is cut, placed in a 37 ° C. muscle electrolyser containing Krebs-bicarbonate solution, and suspended between two stainless steel wires, one of which is a force transducer (Massachusetts, USA). It is attached to Grass Instrument Co., Quincy. The change in force for Angiotensin II added to the electrolyzer is recorded on a chart recorder (Model 8, Grass Instrument Company).

Results: The primary measure of efficacy was the reduction in lipid staining aortic area size for the treatment group compared to the control. Secondary measures of efficacy include improvement in in vitro vascular response (a measure of endothelial dysfunction) to the treatment group compared to the control group. In addition, lowering blood pressure and improved plasma lipid and lipoprotein profiles for the treatment group compared to the control group also indicate efficacy for the combination therapy. The safety and tolerability of the drug mixture will also provide useful data for evaluating the therapy.

In another aspect of this embodiment, different or additional aldosterone receptor antagonists such as spironolactone, and / or different or additional fibric acid derivatives such as fenofibrate, cypropibrate or bezafibrate Therapeutic benefits can also be obtained with other mixtures employed.

Example 7

Pharmaceutical composition

Tablets having the compositions shown in Table X-2 are prepared using wet granulation or direct compression techniques:

Example 8

Pharmaceutical composition

Tablets having the compositions shown in Table X-3 are prepared using wet granulation or direct compression techniques:

Example 9

Pharmaceutical composition

Tablets having the compositions shown in Table X-4 are prepared using wet granulation or direct compression techniques:

The examples herein can be carried out by replacing those used in the preceding examples with generally or specifically described reactants and / or working conditions of the invention.

In view of the above, it will be appreciated that several objects of the present invention are achieved. As various changes may be made in the above methods, mixtures and compositions of the invention without departing from the scope of the invention, all of the materials contained in the above description are to be interpreted as illustrative and not in a limiting sense. All documents mentioned in this application are expressly incorporated by reference as if set forth in sufficient detail.

When introducing elements of the invention or preferred aspects thereof, the terms "a", "an", "the" and "the" refer to the presence of one or more elements. It means. The terms "comprising", "containing" and "having" are all inclusive and mean that there may be additional elements other than the listed elements.

Claims (138)

A mixture comprising an aldosterone receptor antagonist and a fibric acid derivative. The method of claim 1, A mixture wherein the aldosterone receptor antagonist is eplerenone. The method of claim 1, A mixture wherein the aldosterone receptor antagonist is spironolactone. The method of claim 1, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Mixture selected. The method of claim 2, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Mixture selected. The method of claim 3, wherein Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Mixture selected. A pharmaceutical composition comprising a first amount of aldosterone receptor antagonist, a second amount of fibric acid derivative, and a pharmaceutically acceptable carrier. The method of claim 7, wherein A composition wherein the first amount of aldosterone receptor antagonist and the second amount of fibric acid derivative together comprise a therapeutically effective amount of the aldosterone receptor antagonist and fibric acid derivative for the treatment or prevention of a disease. The method of claim 7, wherein The aldosterone receptor antagonist is an epoxy-steroidal compound characterized in that it has a 9α, 11α-substituted epoxy moiety. The method of claim 9, The epoxy-steroid compound is an eplerenone. The method of claim 7, wherein Composition wherein the aldosterone antagonist is a spirolatone compound. The method of claim 11, A composition in which the spirolactone compound is spironolactone. The method of claim 7, wherein Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Composition selected. The method of claim 7, wherein The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 7, wherein The fibric acid derivative is gemfibrozil. The method of claim 7, wherein The fibric acid derivative is fenofibrate. The method of claim 7, wherein Wherein the fibric acid derivative is clofibrate. The method of claim 7, wherein A composition wherein the fibric acid derivative is cypropibrate. The method of claim 7, wherein The fibric acid derivative is bezafibrate. The method of claim 7, wherein Wherein the fibric acid derivative is clinofibrate. The method of claim 7, wherein A composition wherein the fibric acid derivative is bainifibrate. The method of claim 10, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Composition selected. The method of claim 10, The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 10, The fibric acid derivative is gemfibrozil. The method of claim 10, The fibric acid derivative is fenofibrate. The method of claim 10, Wherein the fibric acid derivative is clofibrate. The method of claim 10, A composition wherein the fibric acid derivative is cypropibrate. The method of claim 10, The fibric acid derivative is bezafibrate. The method of claim 10, Wherein the fibric acid derivative is clinofibrate. The method of claim 10, A composition wherein the fibric acid derivative is bainifibrate. The method of claim 10, Wherein the first amount of eplerenone is from about 0.1 to about 400 mg. The method of claim 10, Wherein the first amount of eplerenone is from about 1 to about 200 mg. The method of claim 10, Wherein the first amount of eplerenone is from about 1 to about 100 mg. The method of claim 10, Wherein the first amount of eplerenone is about 10 to about 100 mg. The method of claim 10, Wherein the first amount of eplerenone is from about 25 to about 100 mg. The method of claim 10, Wherein the first amount of eplerenone is selected from the group consisting of about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 50 mg, about 75 mg, and about 100 mg. The method of claim 10, Wherein the first amount of eplerenone is selected from the group consisting of about 25 mg, about 50 mg, and about 100 mg. The method of claim 12, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Composition selected. The method of claim 12, The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 12, The fibric acid derivative is gemfibrozil. The method of claim 12, The fibric acid derivative is fenofibrate. The method of claim 12, Wherein the fibric acid derivative is clofibrate. The method of claim 12, A composition wherein the fibric acid derivative is cypropibrate. The method of claim 12, The fibric acid derivative is bezafibrate. The method of claim 12, Wherein the fibric acid derivative is clinofibrate. The method of claim 12, A composition wherein the fibric acid derivative is bainifibrate. A method of treating or preventing a disease comprising administering to a subject susceptible to or suffering from a disease, a therapeutically effective amount of an aldosterone receptor antagonist and a fibric acid derivative. The method of claim 47, The aldosterone receptor antagonist and the fibric acid derivative are administered in a sequential manner. The method of claim 47, The aldosterone receptor antagonist and the fibric acid derivative are administered in a substantially simultaneous manner. The method of claim 47, The disease is selected from the group consisting of cardiovascular-related diseases, inflammation-related diseases, nervous system-related diseases, musculoskeletal-related diseases, metabolic-related diseases, endocrine-related diseases, dermatological-related diseases and cancer-related diseases. The method of claim 47, The disease is selected from the group consisting of cardiovascular-related diseases. The method of claim 51, wherein Cardiovascular disease is selected from the group consisting of atherosclerosis, hypertension, heart failure, vascular disease, renal dysfunction, stroke, myocardial infarction, endothelial dysfunction, ventricular hypertrophy, target organ damage, thrombosis, cardiac arrhythmia, plaque rupture and aneurysm. The method of claim 47, The disease is selected from the group consisting of inflammation-related diseases. The method of claim 53, wherein The inflammatory disease is selected from the group consisting of arthritis, tissue rejection, septic shock, hypersensitivity and tobacco-induced disease. The method of claim 47, The disease is selected from the group consisting of nervous system-related diseases. The method of claim 55, The nervous system-related disease is selected from the group consisting of Alzheimer's disease, dementia, depression, memory loss, drug addiction, drug withdrawal and brain damage. The method of claim 47, The disease is selected from the group consisting of musculoskeletal-related diseases. The method of claim 57, The musculoskeletal-related disease is selected from the group consisting of osteoporosis and muscle weakness. The method of claim 47, The disease is selected from the group consisting of metabolic-related diseases. The method of claim 59, Metabolic-related disease is selected from the group consisting of diabetes, obesity, syndrome X and cachexia. The method of claim 47, The disease is selected from the group consisting of endocrine-related diseases. The method of claim 47, The disease is selected from the group consisting of skin disease-related diseases. The method of claim 47, The disease is selected from the group consisting of cancer-related diseases. The method of claim 47, The disease is a proliferative disease-related disease. The method of claim 64, wherein The proliferative disease-related disease is cancer. The method of claim 47, The aldosterone receptor antagonist is an epoxy-steroidal compound characterized by having 9α, 11α-substituted epoxy residues. The method of claim 66, wherein The epoxy-steroid compound is an eplerenone. The method of claim 47, The aldosterone antagonist is a spirolactone compound. The method of claim 68, wherein Spirolactone type compound is a spironolactone. The method of claim 47, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof The method chosen. The method of claim 47, The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 47, The fibric acid derivative is gemfibrozil. The method of claim 47, The fibric acid derivative is fenofibrate. The method of claim 47, The fibric acid derivative is clofibrate. The method of claim 47, The fibric acid derivative is cypropibrate. The method of claim 47, The fibric acid derivative is bezafibrate. The method of claim 47, The fibric acid derivative is clinofibrate. The method of claim 47, The fibric acid derivative is bunifibrate. The method of claim 67 wherein Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof The method chosen. The method of claim 67 wherein The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 67 wherein The fibric acid derivative is gemfibrozil. The method of claim 67 wherein The fibric acid derivative is fenofibrate. The method of claim 67 wherein The fibric acid derivative is clofibrate. The method of claim 67 wherein The fibric acid derivative is cypropibrate. The method of claim 67 wherein The fibric acid derivative is bezafibrate. The method of claim 67 wherein The fibric acid derivative is clinofibrate. The method of claim 67 wherein The fibric acid derivative is bunifibrate. The method of claim 67 wherein Eplerenone is administered in a daily dose range of about 0.1 to about 400 mg. The method of claim 67 wherein Eplerenone is administered in a daily dose range of about 1 to about 200 mg. The method of claim 67 wherein Eplerenone is administered in a daily dose range of about 1 to about 100 mg. The method of claim 67 wherein Eplerenone is administered in a daily dose range of about 10 to about 100 mg. The method of claim 67 wherein Eplerenone is administered in the daily dosage range of about 25 to about 100 mg. The method of claim 67 wherein Wherein the eplerenone is administered in a daily dose selected from the group consisting of about 5 mg, about 10 mg, about 12.5 mg, about 25 mg, about 50 mg, about 75 mg and about 100 mg. The method of claim 67 wherein Wherein the eplerenone is administered in a daily dose selected from the group consisting of about 25 mg, about 50 mg and about 100 mg. The method of claim 69, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof The method chosen. The method of claim 69, The fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. The method of claim 69, The fibric acid derivative is gemfibrozil. The method of claim 69, The fibric acid derivative is fenofibrate. The method of claim 69, The fibric acid derivative is clofibrate. The method of claim 69, The fibric acid derivative is cypropibrate. The method of claim 69, The fibric acid derivative is bezafibrate. The method of claim 69, The fibric acid derivative is clinofibrate. The method of claim 69, The fibric acid derivative is bunifibrate. A kit for treating or preventing a disease, comprising an aldosterone receptor antagonist and a fibric acid derivative. 105. The method of claim 104, The kit is an epoxy-steroidal compound, characterized in that the aldosterone receptor antagonist has 9α, 11α-substituted epoxy residues. 105. The method of claim 105, A kit wherein the epoxy-steroidal compound is eplerenone. 105. The method of claim 104, Kit wherein the aldosterone antagonist is a spirolactone compound. 108. The method of claim 107 wherein A kit in which the spirolactone compound is spironolactone. 105. The method of claim 104, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Kit selected. 105. The method of claim 104, A kit wherein the fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. 105. The method of claim 104, The kit wherein the fibric acid derivative is gemfibrozil. 105. The method of claim 104, A kit wherein the fibric acid derivative is fenofibrate. 105. The method of claim 104, The kit wherein the fibric acid derivative is clofibrate. 105. The method of claim 104, A kit wherein the fibric acid derivative is cypropibrate. 105. The method of claim 104, The kit wherein the fibric acid derivative is bezafibrate. 105. The method of claim 104, The kit wherein the fibric acid derivative is clinofibrate. 105. The method of claim 104, The kit wherein the fibric acid derivative is bainifibrate. 107. The method of claim 106, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Kit selected. 107. The method of claim 106, A kit wherein the fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. 107. The method of claim 106, The kit wherein the fibric acid derivative is gemfibrozil. 107. The method of claim 106, A kit wherein the fibric acid derivative is fenofibrate. 107. The method of claim 106, The kit wherein the fibric acid derivative is clofibrate. 107. The method of claim 106, A kit wherein the fibric acid derivative is cypropibrate. 107. The method of claim 106, The kit wherein the fibric acid derivative is bezafibrate. 107. The method of claim 106, The kit wherein the fibric acid derivative is clinofibrate. 107. The method of claim 106, The kit wherein the fibric acid derivative is bainifibrate. 109. The method of claim 108, Fibric acid derivatives in the group consisting of clofibrate, fenofibrate, cypropibrate, bezafibrate, gemfibrozil, clinofibrate and binifibrate, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof Kit selected. 109. The method of claim 108, A kit wherein the fibric acid derivative is selected from the group consisting of fenofibrate, cypropibrate, bezafibrate and gemfibrozil, and pharmaceutically acceptable salts, esters, conjugate acids and prodrugs thereof. 109. The method of claim 108, The kit wherein the fibric acid derivative is gemfibrozil. 109. The method of claim 108, A kit wherein the fibric acid derivative is fenofibrate. 109. The method of claim 108, The kit wherein the fibric acid derivative is clofibrate. 109. The method of claim 108, A kit wherein the fibric acid derivative is cypropibrate. 109. The method of claim 108, The kit wherein the fibric acid derivative is bezafibrate. 109. The method of claim 108, The kit wherein the fibric acid derivative is clinofibrate. 109. The method of claim 108, The kit wherein the fibric acid derivative is bainifibrate. 105. The method of claim 104, The kit further includes written instructions for the subject to use the kit. 136. The method of claim 136, A kit in which written instructions state how a subject can use the kit to achieve a therapeutic effect without causing unwanted side effects. 136. The method of claim 136, A kit in which written instructions include all or part of a product label approved by a drug regulatory agency for the kit.