Method to treat cardiofibrosis with a combination of an angiotensin II antagonist and spironolactone

Abstract

A therapeutic method is described for treating cardiofibrosis or cardiac hypertrophy using a combination therapy comprising a therapeutically-effective amount of an epoxy-free spirolactone-type aldosterone receptor antagonist and a therapeutically-effective amount of an angiotensin II receptor antagonist. Preferred angiotensin II receptor antagonists are those compounds having high potency and bioavailability and which are characterized in having an imidazole or triazole moiety attached to a biphenylmethyl or pyridinyl/phenylmethyl moiety. A preferred epoxy-free spirolactone-type aldosterone receptor antagonist is spironolactone. A preferred combination therapy includes the angiotensin II receptor antagonist 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole and the aldosterone receptor antagonist spironolactone.

Description

FIELD OF THE INVENTION

[0001] Therapeutic methods are described for treatment of cardiofibrosis and cardiac hypertrophy. Of particular interest are therapies using an epoxy-free spirolactone-type aldosterone receptor antagonist compound such as spironolactone in combination with an angiotensin II receptor antagonist compound.

BACKGROUND OF THE INVENTION

[0002] Myocardial (or cardiac) failure, whether a consequence of a previous myocardial infarction, heart disease associated with hypertension, or primary cardiomyopathy, is a major health problem of worldwide proportions. The incidence of symptomatic heart failure has risen steadily over the past several decades.

[0003] In clinical terms, decompensated cardiac failure consists of a constellation of signs and symptoms that arises from congested organs and hypoperfused tissues to form the congestive heart failure (CHF) syndrome. Congestion is caused largely by increased venous pressure and by inadequate sodium (Na+) excretion, relative to dietary Na+ intake, and is importantly related to circulating levels of aldosterone (ALDO). An abnormal retention of Na+ occurs via tubular epithelial cells throughout the nephron, including the later portion of the distal tubule and cortical collecting ducts, where ALDO receptor sites are present.

[0004] ALDO is the body's most potent mineralocorticoid hormone. As connoted by the term mineralocorticoid, this steroid hormone has mineral-regulating activity. It promotes Na+ reabsorption not only in the kidney, but also from the lower gastrointestinal tract and salivary and sweat glands, each of which represents classic ALDO-responsive tissues. ALDO regulates Na+ and water resorption at the expense of potassium (K+) and magnesium (Mg2+) excretion.

[0005] ALDO can also provoke responses in nonepithelial cells. Elicited by a chronic elevation in plasma ALDO level that is inappropriate relative to dietary Na+ intake, these responses can have adverse consequences on the structure of the cardiovascular system. Hence, ALDO can contribute to the progressive nature of myocardial failure for multiple reasons.

[0006] Multiple factors regulate ALDO synthesis and metabolism, many of which are operative in the patient with myocardial failure. These include renin as well as non-renin-dependent factors (such as K+, ACTH) that promote ALDO synthesis. Hepatic blood flow, by regulating the clearance of circulating ALDO, helps determine its plasma concentration, an important factor in heart failure characterized by reduction in cardiac output and hepatic blood flow.

[0007] The renin-angiotensin-aldosterone system (RAAS) is one of the hormonal mechanisms involved in regulating pressure/volume homeostasis and also in the development of hypertension. Activation of the renin-angiotensin-aldosterone system begins with renin secretion from the juxtaglomerular cells in the kidney and culminates in the formation of angiotensin II, the primary active species of this system. This octapeptide, angiotensin II, is a potent vasoconstrictor and also produces other physiological effects such as stimulating aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, stimulating vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.

[0008] Previous studies have shown that antagonizing angiotensin II binding at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin-angiotensin system through interaction with various tissue receptors. There are several known angiotensin II antagonists, most of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailability or their short duration of action. Also, commercially-available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limit their therapeutic application.

[0009] Non-peptidic compounds with angiotensin II antagonist properties are known. For example, early descriptions of such non-peptidic compounds include the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid which has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Exp. Ther., 247(1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol., 157, 31-21 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther., 250(3), 867-874 (1989)]. U.S. Pat. No. 4,816,463 to Blankey et al describes a family of 4,5,6,7-tetrahydro-1H-imidazo(4,5-c)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. Other families of non-peptidic angiotensin II antagonists have been characterized by molecules having a biphenylmethyl moiety attached to a heterocyclic moiety. For example, EP No. 253,310, published Jan. 20, 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841 published Jul. 12, 1989 describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2′-carboxybiphenyl-4-yl)methyl]-4H-1,2,4-triazole. U.S. Pat. No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.

[0010] Many aldosterone receptor blocking drugs are known. For example, spironolactone is a drug which acts at the mineralocorticoid receptor level by competitively inhibiting aldosterone binding. This steroidal compound has been used for blocking aldosterone-dependent sodium transport in the distal tubule of the kidney in order to reduce edema and to treat essential hypertension and primary hyperaldosteronism [F. Mantero et al, Clin. Sci. Mol. Med., 45 (Suppl 1), 219s-224s (1973)]. Spironolactone is also used commonly in the treatment of other hyperaldosterone-related diseases such as liver cirrhosis and congestive heart failure [F. J. Saunders et al, Aldactone; Spironolactone: Comprehensive Review, Searle, N.Y. (1978)]. Progressively-increasing doses of spironolactone from 1 mg to 400 mg per day [i.e., 1 mg/day, 5 mg/day, 20 mg/day] were administered to a spironolactone-intolerant patient to treat cirrhosis-related ascites [P. A. Greenberger et al, N. Eng. Reg. Allergy Proc., 7(4) , 343-345 (July-August, 1986)]. It has been recognized that development of myocardial fibrosis is sensitive to circulating levels of both Angiotensin II and aldosterone, and that the aldosterone antagonist spironolactone prevents myocardial fibrosis in animal models, thereby linking aldosterone to excessive collagen deposition [D. Klug et al, Am. J. Cardiol., 71 (3), 46A-54A (1993)]. Spironolactone has been shown to prevent fibrosis in animal models irrespective of the development of left ventricular hypertrophy and the presence of hypertension [C. G. Brilla et al, J. Mol. Cell. Cardiol., 25(5), 563-575 (1993)]. Spironolactone at a dosage ranging from 25 mg to 100 mg daily is used to treat diuretic-induced hypokalemia, when orally-administered potassium supplements or other potassium-sparing regimens are considered inappropriate [Physicians' Desk Reference, 46th Edn., p. 2153, Medical Economics Company Inc., Montvale, N.J. (1992)].

[0011] Previous studies have shown that inhibiting ACE inhibits the renin-angiotensin system by substantially complete blockade of the formation of angiotensin II. Many ACE inhibitors have been used clinically to control hypertension. While ACE, inhibitors may effectively control hypertension, side effects are common including chronic cough, skin rash, loss of taste sense, proteinuria and neutropenia.

[0012] Moreover, although ACE inhibitors effectively block the formation of angiotensin II, aldosterone levels are not well controlled in certain patients having cardiovascular diseases. For example, despite continued ACE inhibition in hypertensive patients receiving captopril, there has been observed a gradual return of plasma aldosterone to baseline levels [J. Staessen et al, J. Endocrinol., 91, 457-465 (1981)]. A similar effect has been observed for patients with myocardial infarction receiving zofenopril [C. Borghi et al, J. Clin. Pharmacol., 33, 40-45 (1993)]. This phenomenon has been termed “aldosterone escape”.

[0013] Another series of steroidal-type aldosterone receptor antagonists is exemplified by epoxy-containing spironolactone derivatives. For example, U.S. Pat. No. 4,559,332 issued to Grob et al describes 9α,11α-epoxy-containing spironolactone derivatives as aldosterone antagonists useful as diuretics. These 9α,11α-epoxy steroids have been evaluated for endocrine effects in comparison to spironolactone [M. de Gasparo et al, J. Pharm. Exp. Ther., 240(2), 650-656 (1987)].

[0014] Combinations of an aldosterone antagonist and an ACE inhibitor have been investigated for treatment of heart failure. It is known that mortality is higher in patients with elevated levels of plasma aldosterone and that aldosterone levels increase as CHF progresses from activation of the Renin-Angiontensin-Aldosterone System (RAAS). Routine use of a diuretic may further elevate aldosterone levels. ACE inhibitors consistently inhibit angiotensin II production but exert only a mild and transient antialdosterone effect.

[0015] Combining an ACE inhibitor and spironolactone has been suggested to provide substantial inhibition of the entire RAAS. For example, a combination of enalapril and spironolactone has been administered to ambulatory patients with monitoring of blood pressure [P. Poncelet et al, Am. J. Cardiol., 665(2), 33K-35K (1990)]. In a 90-patient study, a combination of captopril and spironolactone was administered and found effective to control refractory CHF without serious incidents of hyperkalemia [U. Dahlstrom et al, Am. J. Cardiol., 71, 29A-33A (Jan. 21, 1993)]. Spironolactone coadministered with an ACE inhibitor was reported to be highly effective in 13 of 16 patients afflicted with congestive heart failure [A. A. van Vliet et al, Am. J. Cardiol., 71, 21A-28A (Jan. 21, 1993)]. Clinical improvements have been reported for patients receiving a co-therapy of spironolactone and the ACE inhibitor enalapril, although this report mentions that controlled trials are needed to determine the lowest effective doses and to identify which patients would benefit most from combined therapy [F. Zannad, Am. J. Cardiol., 71(3), 34A-39A (1993)].

[0016] Combinations of an angiotensin II receptor antagonist and aldosterone receptor antagonist, are known. For example, PCT Application No. US91/09362 published Jun. 25, 1992 describes treatment of hypertension using a combination of an imidazole-containing angiotensin II antagonist compound and a diuretic such as spironolactone.

SUMMARY OF THE INVENTION

[0017] A therapeutic method for treating or preventing progression of cardiofibrosis or cardiac hypertrophy is provided by a combination therapy comprising a therapeutically-effective amount of an angiotensin II receptor antagonist and a therapeutically-effective amount of an epoxy-free spirolactone-type aldosterone receptor antagonist.

[0018] The phrase “angiotensin II receptor antagonist” is intended to embrace one or more compounds or agents having the ability to interact with a receptor site located on various human body tissues, which site is a receptor having a relatively high affinity for angiotensin II and which receptor site is associated with mediating one or more biological functions or events such as vasoconstriction or vasorelaxation, kidney-mediated sodium and fluid retention, sympathetic nervous system activity, and in modulating secretion of various substances such as aldosterone, vasopressin and renin, to lower blood pressure in a subject susceptible to or afflicted with elevated blood pressure. Interactions of such angiotensin II receptor antagonist with this receptor site may be characterized as being either “competitive” (i.e., “surmountable”) or as being “insurmountable”. These terms, “competitive” and “insurmountable”, characterize the relative rates, faster for the former term and slower for the latter term, at which the antagonist compound dissociates from binding with the receptor site.

[0019] The phrase “epoxy-free spirolactone-type aldosterone receptor antagonist” embraces an agent or compound, or a combination of two or more of such agents or compounds, which agent or compound binds to the aldosterone receptor as a competitive inhibitor of the action of aldosterone itself at the receptor site in the renal tubules, so as to modulate the receptor-mediated activity of aldosterone. Typical of such aldosterone receptor antagonists are spirolactone-type compounds. The term “spirolactone-type” is intended to characterize a steroidal structure comprising a lactone moiety attached to a steroid nucleus, typically at the steroid “D” ring, through a spiro bond configuration. Preferred spirolactone-type compounds are epoxy-free, e.g., compounds which do not contain an epoxy moiety attached to any portion of the steroid nucleus.

[0020] The phrase “combination therapy”, in defining use of an angiotensin II antagonist and a spirolactone-type aldosterone receptor antagonist, is intended to embrace administration of each antagonist in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended to embrace co-administration of the antagonist agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each antagonist agent.

[0021] The phrase “therapeutically-effective” is intended to qualify the amount of each antagonist agent for use in the combination therapy which will improve cardiac sufficiency by reducing or preventing the progression of myocardial fibrosis or cardiac hypertrophy.

[0022] The phrase “low-dose amount”, in characterizing a therapeutically-effective amount of the aldosterone receptor antagonist agent in the combination therapy, is intended to define a quantity of such agent, or a range of quantity of such agent, that is capable of improving cardiac sufficiency while reducing or avoiding one or more aldosterone-antagonist-induced side effects, such as hyperkalemia. A dosage of an aldosterone receptor antagonist, e.g , spironolactone, which would accomplish the therapic goal of favorably enhancing cardiac sufficiency, while reducing or avoiding side effects, would be a dosage that substantially avoids inducing diuresis, that is, a substantially non-diuresis-effective dosage or a non-diuretic-effective amount of an aldosterone receptor antagonist.

[0023] Another combination therapy of interest would consist essentially of three active agents, namely, an AII antagonist, an aldosterone receptor antagonist agent and a diuretic.

[0024] For a combination of AII antagonist agent and an ALDO antagonist agent, the agents would be used in combination in a weight ratio range from about 0.5-to-one to about twenty-to-one of the AII antagonist agent to the aldosterone receptor antagonist agent. A preferred range of these two agents (AII antagonist-to-ALDO antagonist) would be from about one-to-one to about fifteen-to-one, while a more preferred range would be from about one-to-one to about five-to-one, depending ultimately on the selection of the AII antagonist and ALDO antagonist. The diuretic agent may be present in a ratio range of 0.1-to-one to about ten to one (AII antagonist to diuretic).

DETAILED DESCRIPTION OF THE INVENTION

[0025] Examples of angiotensin II (AII) antagonists which may be used in the combination therapy are shown in the following categories:

[0026] A first group of AII antagonists consists of the following compounds:

[0027] saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A-81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, isoteoline, KRI-1177, L-158809, L-158978, L-159874, LR B087, LY-285434, LY-302289, LY-3l5995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319.

[0028] A second group of AII antagonists of interest consists of the following compounds:

[0029] saralasin acetate, candesartan cilexetil, CGP-63170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD-150304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-15928-, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007 and PD-123177.

[0030] A family of spirolactone-type compounds of interest for use in the combination therapy is defined by Formula A 1

[0031] wherein R is lower alkyl of up to 5 carbon atoms, and 2

[0032] Lower alkyl residues include branched and unbranched groups, preferably methyl, ethyl and n-propyl.

[0033] Specific compounds of interest within Formula A are the following:

[0034] 7α-Aceylythio-3-oxo-4,15-androstadiene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0035] 3-oxo-7α-propionylthio-4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;

[0036] 6β,7β-Methylene-3-oxo4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;

[0037] 15α,16α-Methylene-3 -oxo-4,7α-propionylthio-4-androstene[17(β-1′)-spiro-5]perhydrofuran-2′-one;

[0038] 6β,7β,15α, 16α-Dimethylene-3-oxo-4-androstene [17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0039] 7α-Aceylythio-15β,16β-Methylene-3-oxo-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;

[0040] 15β,16β-Methylene-3-oxo-7β-propionylthio-4-androstene-[17(β-1′)-spiro-5′]perhydrofulran-2′-one; and

[0041] 6β,7β,15β,16β-Dimethylene-3 -oxo-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one.

[0042] Methods to make compounds of Formula A are described in U.S. Pat. No. 4,129,564 to Wiechart en al issued on Dec. 12, 1978.

[0043] A second family of spirolactone-type compounds of interest for use in the combination therapy is defined by Formula B: 3

[0044] wherein

[0045] R1 is C1-3-alkyl or C1-3 acyl and R2 is hydrogen or C1-3-alkyl.

[0046] Specific compounds of interest within Formula B are the following:

[0047] 1α-Acetylthio-15β,16β-methylene-7α-methylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone; and

[0048] 15β,16β-Methylene-1α,7α-dimethylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone.

[0049] Methods to make the compounds of Formula B are described in U.S. Pat. No. 4,789,668 to Nickisch et al which issued Dec. 6, 19888.

[0050] A third family of spirolactone-type compounds of interest for use in the combination therapy is defined by a structure of Formula C: 4

[0051] Specific compounds of interest include:

[0052] 7α-Acylthio-21-hydroxy-3-oxo-17α-pregn-4-ene-17-carboxylic acid lactones; and

[0053] 21-hydroxy-3-oxo-17α-pregn-1,4-diene-17-carboxylic acid lactone.

[0054] Methods to make the compounds of Formula C are described in U.S. Pat. No. 3,257,390 to Patchett which issued Jun. 21, 1966. Of particular interest is the compound spironolactone having the following structure and formal name: 5

[0055] “spironolactone”:17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate

[0056] Spironolactone is sold by G. D. Searle & Co., Skokie, Ill., under the trademark “ALDACTONE”, in tablet dosage form at doses of 25 mg, 50 mg and 100 mg per tablet.

[0057] A diuretic agent may be used in the combination of ACE inhibitor and aldosterone receptor antagonist. Such diuretic agent may be selected from several known classes, such as thiazides and related sulfonamides, potassium-sparing diuretics, loop diuretics and organic mercurial diuretics.

[0058] Angiotensin II receptor antagonist compounds suitable for use in the combination therapy are described in Table II, below. Preferred compounds for use in the combination therapy may be generally characterized structurally as having two portions. A first portion constitutes a mono-aryl-alkyl moiety, or a bi-aryl-alkyl moiety, or a mono-heteroaryl-alkyl moiety, or a bi-heteroaryl-alkyl moiety. A second portion constitutes a heterocyclic moiety or an open chain hetero-atom-containing moiety.

[0059] Typically, the first-portion mono/bi-aryl/heteroaryl-alkyl moiety is attached to the second portion heterocyclic/open-chain moiety through the alkyl group of the mono/bi-aryl/heteroaryl-alkyl moiety to any substitutable position on the heterocyclic/open-chain moiety second portion. Suitable first-portion mono/bi-aryl/heteroaryl-alkyl moieties are defined by any of the various moieties listed under Formula I:

Ar—Alk—L Ar—L—Ar—Alk—L Het—L—Ar—Alk—L Het—L—Het—Alk—L Ar—L—Het—Alk—L Het—L—Alk—L  (I)

[0060] wherein the abbreviated notation used in the moieties of Formula I is defined as follows:

[0061] “Ar” means a five or six-membered carbocyclic ring system consisting of one ring or two fused rings, with such ring or rings being typically fully unsaturated but which also may be partially or fully saturated. “Phenyl” radical most typically exemplifies “Ar”.

[0062] “Het” means a monocyclic or bicyclic fused ring system having from five to eleven ring members, and having at least one of such ring members being a hetero atom selected from oxygen, nitrogen and sulfur, and with such ring system containing up to six of such hetero atoms as ring members.

[0063] “Alk” means an alkyl radical or alkylene chain, linear or branched, containing from one to about five carbon atoms. Typically, “Alk” means “methylene”, i.e., —CH2—.

[0064] “L” designates a single bond or a bivalent linker moiety selected from carbon, oxygen and sulfur. When “L” is carbon, such carbon has two hydrido atoms attached thereto.

[0065] Suitable second-portion heterocyclic moieties of the angiotensin II antagonist compounds, for use in the combination therapy, are defined by any of the various moieties listed under Formula IIa or IIb: 6

[0066] wherein each of X1 through X6 is selected from —CH═, —CH2—, —N═, —NH—, 0, and S, with the proviso that at least one of X1 through X6 in each of Formula IIa and Formula IIb must be a hetero atom. The heterocyclic moiety of Formula IIa or IIb may be attached through a bond from any ring member of the Formula IIa or IIb heterocyclic moiety having a substitutable or a bond-forming position.

[0067] Examples of monocyclic heterocyclic moieties of Formula IIa include thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, furanyl, thiophenyl, isopyrrolyl, 3-isopyrrolyl, 2-isoimidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, oxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, 1,2-pyronyl, 1,4-pyronyl, pyridinyl, piperazinyl, s-triazinyl, as-triazinyl, v-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl, 1,3,5,2-oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.

[0068] Examples of bicyclic heterocyclic moieties of Formula IIb include benzo[b]thienyl, isobenzofuranyl, chrorenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purilayl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d[]1,2]oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, cyclopenta[b]pyranyl, 4H-[1,3]oxathiolo-[5,4-b]pyrrolyl, thieno[2,3-b]furanyl, imidazo[1,2-b][1,2,4]triazinyl and 4H-1,3-dioxolo[4,5-d]imidazolyl.

[0069] The angiotensin II receptor antagonist compounds, as provided by the first-and-second-portion moieties of Formula I and II, are further characterized by an acidic moiety attached to either of said first-and-second-portion moieties. Preferably this acidic moiety is attached to the first-portion moiety of Formula I and is defined by Formula III:

—UnA  (III)

[0070] wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein U is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms.

[0071] The phrase “acidic group selected to contain at least one acidic hydrogen atom”, as used to define the —UnA moiety, is intended to embrace chemical groups which, when attached to any substitutable position of the Formula I-IIa/b moiety, confers acidic character to the compound of Formula I-IIa/b. “Acidic character” means proton-donor capability, that is, the capacity of the compound of Formula I-IIa/b to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I-IIa/b has a pKa in a range from about one to about twelve. More typically, the Formula I-IIa/b compound would have a pKa in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (—COOH). Where n is zero and A is —COOH, in the —UnA moiety, such carboxyl group would be attached directly to one of the Formula I-IIa/b positions. The Formula I-IIa/b compound may have one —UnA moiety attached at one of the Formula I-IIa/b positions, or may have a plurality of such —UnA moieties attached at more than one of the Formula I-IIa/b positions. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as “bioisosteres of carboxylic acid” or referred to as “acidic bioisosteres”. Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I-IIa/b may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I-IIa/b compound as conferred by the —UnA moiety be in a range from about two to about seven. The —UnA moiety may be attached to one of the Formula I-IIa/b positions through any portion of the —UnA moiety which results in a Formula I-IIa/b compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the —UnA acid moiety is tetrazole, the tetrazole is typically attached at the tetrazole ring carbon atom.

[0072] For any of the moieties embraced by Formula I and Formula II, such moieties may be substituted at any substitutable position by one or more radicals selected from hydrido, hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula 7

[0073] wherein W is oxygen atom or sulfur atom; wherein each of R1 through R5 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, YR6 and 8

[0074] wherein Y is selected from oxygen atom and sulfur atom and R6 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R1, R2, R3, R4, R5, R7 and R8 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R1, R2, R3, R4, R5, R7 and R8 is further independently selected from amino and amido radicals of the formula 9

[0075] wherein W is oxygen atom or sulfur atom;

[0076] wherein each of R9, R10, R11, R12, R13 and R14 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R2 and R3 taken together and each of R4 and R5 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R2 and R3 taken together and each of R7 and R8 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0077] The combination therapy of the invention would be useful in treating myocardial fibrosis or cardiac hypertrophy, particularly left ventricular hypertrophy. The combination therapy would also be useful with adjunctive therapies. For example, the combination therapy may be used in combination with other drugs, such as a diuretic, to aid in treatment of hypertension.

[0078] Table II, below, contains description of angiotensin II antagonist compounds which may be used in the combination therapy. Associated with each compound listed in Table II is a published patent document describing the chemical preparation of the angiotensin II antagonist compound as well as the biological properties of such compound. The content of each of these patent documents is incorporated herein by reference.

TABLE II
Angiotensin II Antagonists
Compound #	Structure	Source
1	10	WO #91/17148 pub. November 14, 1991
2	11	WO #91/17148 pub. November 14, 1991
3	12	WO #91/17148 pub. November 14, 1991
4	13	WO #91/17148 pub. November 14, 1991
5	14	WO #91/17148 pub. November 14, 1991
6	15	WO #91/17148 pub. November 14, 1991
7	16	WO #91/17148 pub. November 14, 1991
8	17	WO #91/17148 pub. November 14, 1991
9	18	WO #91/17148 pub. November 14, 1991
10	19	WO #91/17148 pub. November 14, 1991
11	20	WO #91/17148 pub. November 14, 1991
12	21	WO #91/17148 pub. November 14, 1991
13	22	WO #91/17148 pub. November 14, 1991
14	23	WO #91/17148 pub. November 14, 1991
15	24	WO #91/17148 pub. November 14, 1991
16	25	WO #91/17148 pub. November 14, 1991
17	26	WO #91/17148 pub. November 14, 1991
18	27	WO #91/17148 pub. November 14, 1991
19	28	WO #91/17148 pub. November 14, 1991
20	29	WO #91/17148 pub. November 14, 1991
21	30	WO #91/17148 pub. November 14, 1991
22	31	WO #91/17148 pub. November 14, 1991
23	32	WO #91/17148 pub. November 14, 1991
24	33	WO #91/17148 pub. November 14, 1991
25	34	WO #91/17148 pub. November 14, 1991
26	35	WO #91/17148 pub. November 14, 1991
27	36	WO #91/17148 pub. November 14, 1991
28	37	WO #91/17148 pub. November 14, 1991
29	38	WO #91/17148 pub. November 14, 1991
30	39	WO #91/17148 pub. November 14, 1991
31	40	WO #91/17148 pub. November 14, 1991
32	41	WO #91/17148 pub. November 14, 1991
33	42	WO #91/17148 pub. November 14, 1991
34	43	WO #91/17148 pub. November 14, 1991
35	44	WO #91/17148 pub. November 14, 1991
36	45	WO #91/17148 pub. November 14, 1991
37	46	WO #91/17148 pub. November 14, 1991
38	47	WO #91/17148 pub. November 14, 1991
39	48	WO #91/17148 pub. November 14, 1991
40	49	WO #91/17148 pub. November 14, 1991
41	50	WO #91/17148 pub. November 14, 1991
42	51	WO #91/17148 pub. November 14, 1991
43	52	WO #91/17148 pub. November 14, 1991
44	53	WO #91/17148 pub. November 14, 1991
45	54	WO #91/17148 pub. November 14, 1991
46	55	WO #91/17148 pub. November 14, 1991
47	56	WO #91/17148 pub. November 14, 1991
48	57	WO #91/17148 pub. November 14, 1991
49	58	WO #91/17148 pub. November 14, 1991
50	59	WO #91/17148 pub. November 14, 1991
51	60	WO #91/17148 pub. November 14, 1991
52	61	WO #91/17148 pub. November 14, 1991
53	62	WO #91/17148 pub. November 14, 1991
54	63	WO #91/17148 pub. November 14, 1991
55	64	WO #91/17148 pub. November 14, 1991
56	65	WO #91/17148 pub. November 14, 1991
57	66	WO #91/17148 pub. November 14, 1991
58	67	WO #91/17148 pub. November 14, 1991
59	68	WO #91/17148 pub. November 14, 1991
60	69	WO #91/17148 pub. November 14, 1991
61	70	WO #91/17148 pub. November 14, 1991
62	71	WO #91/17148 pub. November 14, 1991
63	72	WO #91/17148 pub. November 14, 1991
64	73	WO #91/17148 pub. November 14, 1991
65	74	WO #91/17148 pub. November 14, 1991
66	75	WO #91/17148 pub. November 14, 1991
67	76	WO #91/17148 pub. November 14, 1991
68	77	WO #91/17148 pub. November 14, 1991
69	78	WO #91/17148 pub. November 14, 1991
70	79	WO #91/17148 pub. November 14, 1991
71	80	WO #91/17148 pub. November 14, 1991
72	81	WO #91/17148 pub. November 14, 1991
73	82	WO #91/17148 pub. November 14, 1991
74	83	WO #91/17148 pub. November 14, 1991
75	84	WO #91/17148 pub. November 14, 1991
76	85	WO #91/17148 pub. November 14, 1991
77	86	WO #91/17148 pub. November 14, 1991

[0079]

TABLE II
Angiotensin II Antagonists
Compound
#	Structure	Source
78	87	WO #91/1888 pub.
79	88	WO #91/18888 pub.
80	89	WO #91/18888 pub.
81	90	WO #91/18888 pub.
82	91	WO #91/18888 pub.
83	92	WO #91/18888 pub.
84	93	WO #91/18888 pub.
85	94	WO #91/18888 pub.
86	95	WO #91/18888 pub.
87	96	WO #91/18888 pub.
88	97	WO #91/18888 pub.
89	98	WO #91/18888 pub.
90	99	WO #91/18888 pub.
91	100	WO #91/18888 pub.
92	101	WO #91/18888 pub.
93	102	WO #91/18888 pub.
94	103	WO #91/18888 pub.
95	104	WO #91/18888 pub.
96	105	WO #91/18888 pub.
97	106	WO #91/18888 pub.
98	107	WO #91/18888 pub.
99	108	WO #91/18888 pub.
100	109	WO #91/18888 pub.
101	110	WO #91/18888 pub.
102	111	WO #91/18888 pub.
103	112	WO #91/18888 pub.
104	113	WO #91/18888 pub.
105	114	WO #91/18888 pub.
106	115	WO #91/18888 pub.
107	116	WO #91/18888 pub.
108	117	WO #91/19715 pub. 26 Dec. 1991
109	118	WO #91/19715 pub. 26 Dec. 1991
110	119	WO #91/19715 pub. 26 Dec. 1991
111	120	WO #91/19715 pub. 26 Dec. 1991
112	121	WO #91/19715 pub. 26 Dec. 1991
113	122	WO #91/19715 pub. 26 Dec. 1991
114	123	WO #91/19715 pub. 26 Dec. 1991
115	124	WO #91/19715 pub. 26 Dec. 1991
116	125	WO #91/19715 pub. 26 Dec. 1991
117	126	WO #91/19715 pub. 26 Dec. 1991
118	127	WO #91/19715 pub. 26 Dec. 1991
119	128	WO #91/19715 pub. 26 Dec. 1991
120	129	WO #91/19715 pub. 26 Dec. 1991
121	130	WO #91/19715 pub. 26 Dec. 1991
122	131	WO #91/19715 pub. 26 Dec. 1991
123	132	WO #91/19715 pub. 26 Dec. 1991
124	133	WO #91/19715 pub. 26 Dec. 1991
125	134	WO #91/19715 pub. 26 Dec. 1991
126	135	WO #92/05161 pub. 2 Apr. 1992
127	136	WO #92/05161 pub. 2 Apr. 1992
128	137	WO #92/05161 pub. 2 Apr. 1992
129	138	WO #92/05161 pub. 2 Apr. 1992
130	139	WO #92/05161 pub. 2 Apr. 1992
131	140	WO #92/05161 pub. 2 Apr. 1992
132	141	WO #92/07834 pub. 14 May 1992
133	142	WO #92/07834 pub. 14 May 1992
134	143	WO #92/07834 pub. 14 May 1992
135	144	WO #92/07834 pub. 14 May 1992
136	145	WO #92/07834 pub. 14 May 1992
137	146	WO #92/07834 pub. 14 May 1992
138	147	WO #92/07834 pub. 14 May 1992
139	148	WO #92/11255 pub. 9 Jul. 1992
140	149	WO #92/11255 pub. 9 Jul. 1992
141	150	WO #92/11255 pub. 9 Jul. 1992
142	151	WO #92/11255 pub. 9 Jul. 1992
143	152	WO #92/11255 pub. 9 Jul. 1992
144	153	WO #92/11255 pub. 9 Jul. 1992
145	154	WO #92/11255 pub. 9 Jul. 1992
146	155	WO #92/11255 pub. 9 Jul. 1992
147	156	WO #92/11577 pub. 17 Sep. 1992
148	157	WO #92/11577 pub. 17 Sep. 1992
149	158	WO #92/11577 pub. 17 Sep. 1992
150	159	WO #92/16523 pub. 1 Oct. 1992
151	160	WO #92/16523 pub. 1 Oct. 1992
152	161	WO #92/16523 pub. 1 Oct. 1992
153	162	WO #92/16523 pub. 1 Oct. 1992
154	163	WO #92/16523 pub. 1 Oct. 1992
155	164	WO #92/16523 pub. 1 Oct. 1992
156	165	WO #92/16523 pub. 1 Oct. 1992
157	166	WO #92/16523 pub. 1 Oct. 1992
158	167	WO #92/16523 pub. 1 Oct. 1992
159	168	WO #92/16523 pub. 1 Oct. 1992
160	169	WO #92/16523 pub. 1 Oct. 1992
161	170	WO #92/16523 pub. 1 Oct. 1992
162	171	WO #92/16523 pub. 1 Oct. 1992
163	172	WO #92/16523 pub. 1 Oct. 1992
164	173	WO #92/16523 pub. 1 Oct. 1992
165	174	WO #92/16523 pub. 1 Oct. 1992
166	175	WO #92/16523 pub. 1 Oct. 1992
167	176	WO #92/16523 pub. 1 Oct. 1992
168	177	WO #92/16523 pub. 1 Oct. 1992
169	178	WO #92/16523 pub. 1 Oct. 1992
170	179	WO #92/16523 pub. 1 Oct. 1992
171	180	WO #92/16523 pub. 1 Oct. 1992
172	181	WO #92/16523 pub. 1 Oct. 1992
173	182	WO #92/16523 pub. 1 Oct. 1992
174	183	WO #92/16523 pub. 1 Oct. 1992
175	184	WO #92/16523 pub. 1 Oct. 1992
176	185	WO #92/16523 pub. 1 Oct. 1992
177	186	WO #92/16523 pub. 1 Oct. 1992
178	187	WO #92/16523 pub. 1 Oct. 1992
179	188	WO #92/16523 pub. 1 Oct. 1992
180	189	WO #92/16523 pub. 1 Oct. 1992
181	190	WO #92/16523 pub. 1 Oct. 1992
182	191	WO #92/16523 pub. 1 Oct. 1992
183	192	WO #92/16523 pub. 1 Oct. 1992
184	193	WO #92/16523 pub. 1 Oct. 1992
185	194	WO #92/17469 pub. 15 Oct. 1992
186	195	WO #92/17469 pub. 15 Oct. 1992
187	196	WO #92/17469 pub. 15 Oct. 1992
188	197	WO #92/17469 pub. 15 Oct. 1992
189	198	WO #92/17469 pub. 15 Oct. 1992
190	199	WO #92/17469 pub. 15 Oct. 1992
191	200	WO #92/17469 pub. 15 Oct. 1992
192	201	WO #92/17469 pub. 15 Oct. 1992
193	202	WO #92/17469 pub. 15 Oct. 1992
194	203	WO #92/17469 pub. 15 Oct. 1992
195	204	WO #92/17469 pub. 15 Oct. 1992
196	205	WO #92/17469 pub. 15 Oct. 1992
197	206	WO #92/17469 pub. 15 Oct. 1992
198	207	WO #92/17469 pub. 15 Oct. 1992
199	208	WO #92/17469 pub. 15 Oct. 1992
200	209	WO #92/17469 pub. 15 Oct. 1992
201	210	WO #92/17469 pub. 15 Oct. 1992
202	211	WO #92/17469 pub. 15 Oct. 1992
203	212	WO #92/17469 pub. 15 Oct. 1992
204	213	WO #92/17469 pub. 15 Oct. 1992
205	214	WO #92/17469 pub. 15 Oct. 1992
206	215	WO #92/17469 pub. 15 Oct. 1992
207	216	WO #92/17469 pub. 15 Oct. 1992
208	217	WO #92/17469 pub. 15 Oct. 1992
209	218	WO #92/17469 pub. 15 Oct. 1992
210	219	WO #92/17469 pub. 15 Oct. 1992
211	220	WO #92/17469 pub. 15 Oct. 1992
212	221	WO #92/17469 pub. 15 Oct. 1992
213	222	WO #92/17469 pub. 15 Oct. 1992
214	223	WO #92/17469 pub. 15 Oct. 1992
215	224	WO #92/17469 pub. 15 Oct. 1992
216	225	WO #92/17469 pub. 15 Oct. 1992
217	226	WO #92/17469 pub. 15 Oct. 1992
218	227	WO #92/17469 pub. 15 Oct. 1992
219	228	WO #92/17469 pub. 15 Oct. 1992
220	229	WO #92/17469 pub. 15 Oct. 1992
221	230	WO #92/17469 pub. 15 Oct. 1992
222	231	WO #92/17469 pub. 15 Oct. 1992
223	232	WO #92/17469 pub. 15 Oct. 1992
224	233	WO #92/17469 pub. 15 Oct. 1992
225	234	WO #92/17469 pub. 15 Oct. 1992
226	235	WO #92/17469 pub. 15 Oct. 1992
227	236	WO #92/17469 pub. 15 Oct. 1992
228	237
229	238
230	239
231	240
232	241
233	242
234	243
235	244
236	245
237	246
238	247
239	248	WO #92/18092 pub. 29 Oct. 1992
240	249	WO #92/18092 pub. 29 Oct. 1992
241	250	WO #92/18092 pub. 29 Oct. 1992
242	251	WO #92/18092 pub. 29 Oct. 1992
243	252	WO #92/18092 pub. 29 Oct. 1992
244	253	WO #92/18092 pub. 29 Oct. 1992
245	254	WO #92/18092 pub. 29 Oct. 1992
246	255	WO #92/18092 pub. 29 Oct. 1992
247	256	WO #92/18092 pub. 29 Oct. 1992
248	257	WO #92/18092 pub. 29 Oct. 1992
249	258	WO #92/18092 pub. 29 Oct. 1992
250	259	WO #92/18092 pub. 29 Oct. 1992
251	260	WO #92/18092 pub. 29 Oct. 1992
252	261	WO #92/18092 pub. 29 Oct. 1992
253	262	WO #92/18092 pub. 29 Oct. 1992
254	263	WO #92/18092 pub. 29 Oct. 1992
255	264	WO #92/18092 pub. 29 Oct. 1992
256	265	WO #92/18092 pub. 29 Oct. 1992
257	266	WO #92/18092 pub. 29 Oct. 1992
258	267	WO #92/18092 pub. 29 Oct. 1992
259	268	WO #92/18092 pub. 29 Oct. 1992
260	269	WO #92/18092 pub. 29 Oct. 1992
261	270	WO #92/18092 pub. 29 Oct. 1992
262	271	WO #92/18092 pub. 29 Oct. 1992
263	272	WO #92/18092 pub. 29 Oct. 1992
264	273	WO #92/18092 pub. 29 Oct. 1992
265	274	WO #92/18092 pub. 29 Oct. 1992
266	275	WO #92/18092 pub. 29 Oct. 1992
267	276	WO #92/18092 pub. 29 Oct. 1992
268	277	WO #92/18092 pub. 29 Oct. 1992
269	278	WO #92/18092 pub. 29 Oct. 1992
270	279	WO #92/18092 pub. 29 Oct. 1992
271	280	PCT/US95/02156 filed 8 Mar. 1994
272	281	PCT/US94/02156 filed 8 Mar. 1994
273	282	PCT/US94/02156 filed 8 Mar. 1994
274	283	PCT/US94/02156 filed 8 Mar. 1994
275	284	PCT/US94/02156 filed 8 Mar. 1994
276	285	PCT/US94/02156 filed 8 Mar. 1994
277	286	PCT/US94/02156 filed 8 Mar. 1994
278	287	PCT/US94/02156 filed 8 Mar. 1994
279	288	PCT/US94/02156 filed 8 Mar. 1994
280	289	WO #91/17148 pub. 14 Nov. 1991
281	290	EP #475,206 pub. 18 Mar. 1992
282	291	WO #93/18035 pub. 16 Sep. 1993
283	292	WO #93/17628 pub. 16 Sep. 1993
284	293	WO #93/17681 pub. 16 Sep. 1993
285	294	EP #513,533 pub. 19 Nov. 1992
286	295	EP #535,463 pub. 07 Apr. 1993
287	296	EP #535,465 pub. 07 Apr. 1993
288	297	EP #539,713 pub. 05 May 1993
289	298	EP #542,059 pub. 19 May 1993
290	299	EP #05 557,843 pub. 01 Sep. 1993
291	300	EP #563,705 pub. 06 Oct. 1993
292	301	EP #562,261 pub. 29 Sep. 1993
293	302	EP #05 557,843 pub. 15 Sep. 1993
294	303	EP #560,163 pub. 15 Sep. 1993
295	304	EP #564,788 pub. 13 Oct. 1993
296	305	EP #565,986 pub. 20 Oct. 1993
297	306	EP #0,569,795 pub. 18 Nov. 1993
298	307	EP #0,569,794 pub. 18 Nov. 1993
299	308	EP #0,578,002 pub. 12 Jan. 1994
300	309	EP #581,003 pub. 2 Feb. 1994
301	310	EP #392,317 pub. 17 Oct. 1990
302	311	EP #392,317 pub. 17 Oct. 1990
303	312	EP #502,314 pub. 9 Sep. 1992
304	313	EP #468,740 pub. 29 Jan. 1992
305	314	EP #470,543 pub. 12 Feb. 1992
306	315	EP #502,314 pub. 09 Sep. 1992
307	316	EP #529,253 pub. 03 Mar. 1993
308	317	EP #543,263 pub. 26 May 1993
309	318	EP #552,765 pub. 28 Jul. 1993
310	319	EP #555,825 pub. 18 Aug. 1993
311	320	EP #556,789 pub. 25 Aug. 1993
312	321	EP #560,330 pub. 15 Sep. 1993
313	322	EP #566,020 pub. 20 Oct. 1993
314	323	EP #581,166 pub. 2 Feb. 1994
315	324	WO #94/01436 pub. 20 Jan. 1994
316	325	EP #253,310 pub. 20 Jan. 1988
317	326	EP #324,377 pub. 19 Jul. 1989
318	327	U.S. Pat. No. 5,043,349 issued 27 Aug. 1991
319	328	WO #91/00281 pub. 10 Jan. 1991
320	329	U.S. Pat. No. 5,015,651 pub. 14 May 1991
321	330
322	331	WO #92/00977 pub. 23 Jan. 1992
323	332
324	333	WO #93/04046 pub. 04 Mar. 1993
325	334	WO #93/10106 pub. 27 May 1993
326	335	U.S. Pat. No. 5,219,856 pub. 15 Jun. 1993
327	336	U.S. Pat. No. 5,260,325 pub. 9, Nov. 1993
328	337	U.S. Pat. No. 5,264,581 pub. 23 Nov. 1993
329	338	EP #400,974 pub. 5 Dec. 1990
330	339	EP #411,766 pub. 6 Feb. 1991
331	340	EP #412,594 pub. 13 Feb. 1991
332	341	EP #419,048 pub. 27 Mar. 1991
333	342	WO #91/12,001 pub. 22 Aug. 1991
334	343	WO #91/11,999 pub. 22 Aug. 1991
335	344	WO #91/11,909 pub. 22 Aug. 1991
336	345	WO #91/12,002 pub. 22 Aug. 1991
337	346	U.S. Pat. No. 5,053,329 pub. 1 Oct. 1991
338	347	U.S. Pat. No. 5,057,522 pub 15 Oct. 1991
339	348	WO #91/15,479 pub. 17 Oct. 1991
340	349	EP #456,510 pub. 13 Nov. 1991
341	350	EP #467,715 pub. 22 Jan. 1992
342	351	U.S. Pat. No. 5,087,702 pub. 11 Feb. 1992
343	352	EP #479,479 pub. 8 Apr. 1992
344	353
345	354	EP #481,614 pub. 22 Apr. 1992
346	355	EP #490,587 pub. 17 Jun. 1992
347	356	U.S. Pat. No. #5,128,327 pub. 07 Jul. 1992
348	357	U.S. Pat. No. #5,132,216 pub. 21 Jul. 1992
349	358	EP #497,516 pub. 5 Aug. 1992
350	359	EP #502,725 pub. 9 Sep. 1992
351	360	EP #502,575 pub. 9 Sep. 1992
352	361	EP #503,838 pub. 16 Sep. 1992
353	362	EP #505,111 pub. 23 Sep. 1992
354	363	EP #505,098 pub. 23 Sep. 1992
355	364	EP #507,594 pub. 7 Oct. 1992
356	365	EP #508,723 pub. 14 Oct. 1992
357	366
358	367	EP #512,675 pub. 11 Nov. 1992
359	368	EP #512,676 pub. 11 Nov. 1992
360	369	EP #512,870 pub. 11 Nov. 1992
361	370	EP #513,979 pub. 19 Nov. 1992
362	371	WO #92/20,660 pub. 26 Nov. 1992
363	372	WO #92,20,661 pub. 26 Nov. 1992
364	373	WO #92/20,662 pub. 26 Nov. 1992
365	374	WO #92/20,687 pub. 26 Nov. 1992
366	375	EP #517,357 pub. 9 Dec. 1992
367	376	WO #93/01177 pub. 21 Jan. 1993
368	377	U.S. Pat. No. 5,187,159 pub. 16 Feb. 1993
369	378	U.S. Pat. No. 5,198,438 pub. 30 Mar. 1993
370	379	U.S. Pat. No. 5,202,322 pub. 13 Apr. 1993
371	380	EP #537,937 pub. 21 Apr. 1993
372	381	U.S. Pat. No. 5,217,882 pub. 8 Jun. 1993
373	382	U.S. Pat. No. 5,214.153 pub. 25 May 1993
374	383	U.S. Pat. No. 5,218,125 pub. 8 Jun. 1993
375	384	U.S. Pat. No. 5,236,928 pub. 17 Aug. 1993
376	385	U.S. Pat. No. 5,240,938 pub. 31 Aug. 1993
377	386	GB #2,264,709 pub. 8 Sep. 1993
378	387	GB #2,264,710 pub. 8 Sep. 1993
379	388	U.S. Pat. No. 5,256,667 pub. 26 Oct. 1993
380	389	U.S. Pat. No. 5,525,574 pub. 12 Oct. 1993
381	390	WO #93/23,399 pub. 25 Nov. 1993
382	391	U.S. Pat. No. 5,262,412 pub. 16 Nov. 1993
383	392	U.S. Pat. No. 5,264,447 pub. 23 Nov. 1993
384	393	U.S. Pat. No. 5,266,583 pub. 1 Sep. 1992
385	394	U.S. Pat. No. 5,276,054 pub. 4 Jan 1994
	395
386	396	U.S. Pat. No. 5,278,068 pub. 11 Jan. 1994
387	397	WO #94/02142 pub. 3 Feb. 1994
388	398	WO #94/02467 pub. 3 Feb. 1994
389	399	EP #403,159 pub. 19 Dec. 1990
390	400	EP #425,211 pub. 2 May 1991
391	401	EP #427,463 pub 15 May 1991
392	402	WO #92/00068 pub. 9 Jan. 1992
393	403	WO #92/02,510 pub. 20 Feb. 1992
394	404	WO #92/09278 pub. 11 Jun. 1992
395	405	WO #92/10181 pub. 25 Jun. 1992
396	406
397	407
398	408
399	409
400	410
401	411
402	412
403	413	WO #92/10097 pub. 25 Jun. 1992
404	414
405	415
406	416
407	417	WO #92/20651 pub. 26 Nov. 1992
408	418	WO #93/03018 pub. 18 Feb. 1993
409	419	WO #94/00120 pub. 6 Jan. 1994
410	420	EP #459,136 pub. 4 Dec. 1991
411	421	EP #411,507 pub. 5 Feb. 1991
412	422	EP #425,921 pub. 8 May 1991
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415	425	EP #442,473 pub. 21 Aug. 1991
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418	428	EP #483,683 pub. 5 May 1992
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424	434	WO #93/00341 pub. 7 Jan. 1993
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428	438	WO #93/15734 pub. 19 Aug. 1993
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[0080] The term “hydrido” denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a 440

[0081] group; or as another example, two hydrido atoms may be attached to a carbon atom to form a —CH2— group. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The term “cycloalkyl” embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term “haloalkyl”, are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3-tetrafluoropropyl groups. The term “difluoroalkyl” embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The terms “alkylol” and “hydroxyalkyl” embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term “alkenyl” embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety. The term “alkynyl” embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term “cycloalkenyl” embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms “alkoxyl” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term “alkoxyalkyl” also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The “alkoxy” or “alkoxyalkyl” radicals may be further substi-tuted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term “alkylthio” embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. Preferred aryl groups are those consisting of one, two, or three benzene rings. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl and biphenyl. The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenyl-ethyl, phenylbutyl and diphenylethyl. The terms “benzyl” and “phenylmethyl” are interchangeable. The terms “phenalkyl” and “phenylalkyl” are interchangeable. An example of “phenalkyl” is “phenethyl” which is interchangeable with “phenylethyl”. The terms “alkylaryl”, “alkoxyaryl” and “haloaryl” denote, respectively, the substitution of one or more “alkyl”, “alkoxy” and “halo” groups, respectively, substituted on an “aryl” nucleus, such as a phenyl moiety. The terms “aryloxy” and “arylthio” denote radicals respectively, provided by aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of wnich are phenoxy and phenylthio. The terms “sulfinyl” and “sulfonyl”, whether used alone or linked to other terms, denotes, respectively, divalent radicals SO and SO2. The term “aralkoxy”, alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term “acyl” whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. “Lower alkanoyl” is an example of a more prefered sub-class of acyl. The term “amido” denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. The term “monoalkylaminocarbonyl” is interchangeable with “N-alkylamido”. The term “dialkylaminocarbonyl” is interchangeable with “N,N-dialkylamido”. The term “alkenylalkyl” denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term “heteroaryl”, where not otherwised defined before, embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment. For any of the foregoing defined radicals, preferred radicals are those containing from one to about ten carbon atoms.

[0082] Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropy, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.

[0083] Also included in the combination of the invention are the isomeric forms of the above-described angiotensin II receptor compounds and the epoxy-free spirolactone-type aldosterone receptor compounds, including diastereoisomers, regioisomers and the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with such compound.

BIOLOGICAL EVALUATION

[0084] In order to determine the probable effectiveness of a combination therapy for treating or preventing the progression of cardiofibrosis or cardiac hypertrophy, it is important to determine the potency of individual components of the combination therapy. Accordingly, in Assays “A” through “C”, the angiotensin II receptor antagonist profiles were determined for many of the compounds described in Table II, herein. In Assay “D”, there is described a method for evaluating a combination therapy of the invention, namely, an angiotensin II receptor antagonist of Table II and an epoxy-free spirolactone-type aldosterone receptor antagonist. The efficacy of each of the individual drugs, spironolactone and the angiotensin II receptor blocker, and of these drugs given together at various doses, is evaluated in a rodent model. The methods and results of such assays are described below.

[0085] Assay A: Antiotensin II Binding Activity

[0086] Compounds of the invention were tested for ability to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin II (AII) was purchased from Peninsula Labs. 125I-angiotensin II (specific activity of 2200 Ci/mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Sigma Chemical Co. This assay was carried out according to the method of Douglas et al [Endocrinology, 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4° C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at pH 7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500×g for 20 min., and the supernatant was recentrifuged at 100,000×g for 60 min. The pellet was resuspended in buffer consisting of 2 mM EDTA and 50 mM Tris-HCl (pH 7.5) to a final protein concentration of 4 mg/ml. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgCl2, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and 125I-AII (approximately 105 cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiates by the addition of membrane protein and the mixture was incubated at 25° C. for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μM of unlabelled AII. Specific binding was calculated as total binding minus nonspecific binding. The receptor binding affinity of an AII antagonist compound was indicated by the concentration (IC50) of the tested AII antagonist which gives 50% displacement of the total specifically bound 125I-AII from the angiotensin II AT1 receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table III.

[0087] Assay B: In vitro Vascular Smooth Muscle-response for AII

[0088] The compounds of the invention were tested for antagonist activity in rabbit aortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificed using an overdose of pentobarbital and exsanguinated via the carotid arteries. The thoracic aorta was removed, cleaned of adherent fat and connective tissue and then cut into 3-mm ring segments. The endothelium was removed from the rings by gently sliding a rolled-up piece of filter paper into the vessel lumen. The rings were then mounted in a water-jacketed tissue bath, maintained at 37° C., between moveable and fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 7D Grass Polygraph for recording isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (mM): 130 NaCl, 15 NaHCO3, 15 KCl, 1.2 NaH2P04, 1.2 MgS04, 2.5 CaCl2, and 11.4 glucose. The preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings. Angiotensin II concentration-response curves were then recorded (3×10−10 to 1×10−5 M). Each concentration of AII was allowed to elicit its maximal contraction, and then AII was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of AII. Aorta rings were exposed to the test antagonist at 10−5 M for 5 minutes before challenging with AII. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H. O. Schild [Br. J. Pharmacol. Chemother., 2, 189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for AII by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table III.

[0089] Assay C: In vivo Intragastric Pressor Assay Response for All Antagonists

[0090] Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with methohexital (30 mg/kg, i.p.) and catheters were implanted into the femoral artery and vein. The catheters were tunneled subcutaneously to exit dorsally, posterior to the head and between the scapulae. The catheters were filled with heparin (1000 units/ml of saline). The rats were returned to their cage and allowed regular rat chow and water ad libitum. After full recovery from surgery (3-4 days), rats were placed in Lucite holders and the arterial line was connected to a pressure transducer. Arterial pressure was recorded on a Gould polygraph (mmHg). Angiotensin II was administered as a 30 ng/kg bolus via the venous catheter delivered in a 50 μl volume with a 0.2 ml saline flush. The pressor response in mm Hg was measured by the difference from pre-injection arterial pressure to the maximum pressure achieved. The AII injection was repeated every 10 minutes until three consecutive injections yielded responses within 4 mmHg of each other. These three responses were then averaged and represented the control response to AII. The test compound was suspended in 0.5% methylcellulose in water and was administered by gavage. The volume administered was 2 ml/kg body weight. The standard dose was 3 mg/kg. Angiotensin II bolus injections were given at 30, 45, 60, 75, 120, 150, and 180 minutes after gavage. The pressor response to AII was measured at each time point. The rats were then returned to their cage for future testing. A minimum of 3 days was allowed between tests. Percent inhibition was calculated for each time point following gavage by the following formula: [(Control Response—Response at time point)/Control Response]×100. Results are shown in Table III.

[0091] Assay “D”: Renal Hypertensive Rat Model

[0092] A combination therapy of an angiotensin II receptor antagonist and an epoxy-free spirolactone-type aldosterone receptor antagonist e.g., spironolactone, may be evaluated for blood pressure lowering activity in the renal-artery ligated hypertensive rat, a model of high renin hypertension. In this model, six days after ligation of the left renal artery, both plasma renin activity and blood pressure are elevated significantly [J. L. Cangiano et al, J. Pharmacol. Exp. Ther., 206, 310-313 (1979)]. Male Sprague-Dawley rats are instrumented with a radiotelemetry blood pressure transmitter for continuous monitoring of blood pressure. The rats are anesthetized with a mixture of ketamine-HCl (100 mg/kg) and acepromazine maleate (2.2 mg/kg). The abdominal aorta is exposed via a midline incision. Microvascular clamps are placed on the aorta distal to the renal arteries and at the iliac bifurcation. The aorta is punctured with a 22-guage needle and the tip of a catheter is introduced. The catheter, which is held in place by a ligature in the psoas muscle, is connected to a radiotelemetry blood pressure transmitter (Mini-Mitter Co., Inc., Sunriver, Oreg.). The transmitter is placed in the peritoneal cavity and sutured to abdominal muscle upon closing of the incision. Rats are housed singly above a radiotelemetry receiver and are allowed standard rat chow and water ad libitum. At least 5 days are allowed for recovery from surgery. Mean arterial pressure and heart rate are measured on a Compaq DeskPro 286 AT computer. Data are sampled for 10 seconds at 200-500 hz at 2.5 to 10 min intervals 24 hours per day. After collecting control data for 24 hours, the rats are anesthetized with methohexital (30 mg/kg, i.p.) and supplemented as needed. A midline abdominal incision is made, approximately 2 cm in length to expose the left kidney. The renal artery is separated from the vein near the aorta, with care taken not to traumatize the vein. The artery is completely ligated with sterile 4-O silk. The incision is closed by careful suturing of the muscle layer and skin. Six days later, when MAP is typically elevated by 50-70 mmHg, an AII receptor antagonist, or an aldosterone receptor antagonist, or a combination of the two compounds are administered by gavage each day for about 8 weeks. Single drug dosing is carried out using 20 and 200 mg/kg/day of spironolactone and 1,3,10,30 and 100 mg/kg/day of an AII receptor antagonist. Drug mixtures are obtained by administering a combination of a dose of 1,3,10,30 or 100 mg/kg/day of the AII receptor antagonist with a dose of either 20 or 200 mg/kg/day of the aldosterone antagonist. Blood pressure lowering is monitored by the radiotelemetry system and responses with the compounds are compared to responses obtained in vehicle-treated animals. Plasma and urinary sodium and potassium levels are monitored as a measure of the effectiveness of the aldosterone blockade. Urine samples are collected overnight using metabolic cages to isolate the samples. Plasma samples are obtained by venous catheterization. Sodium and potassium are measured by flame photometry. Cardiac fibrosis is determined by histological and chemical measurements of the excised hearts following perfusion fixation. Left and right ventricles are weighed, embedded and sectioned. Subsequently, sections are stained with picrosirius red and the red staining collagen areas are quantitated by computerized image analysis. The apex of the heart is acid digested and the free hydroxyproline measured calorimetrically. It is expected that MAP will be significantly lowered toward normal pressures in the test animals, treated with the combination therapy and that the condition of myocardial fibrosis will be arrested or avoided.

TABLE III
In Vivo and In Vitro Angiotensin II
Activity of Compounds of the Invention
Test	1Assay A			3Assay C
Compound	IC50	2Assay B	Dose	Inhibition	Duration
Example #	(nM)	pA2	(mg/kg)	(%)	(min.)
1	NT	NT	NT	NT	NT
2	95	7.37/7.59	10	95	60
			30	98	90-120
3	5.4	8.70 ± 0.2	10	50	>180
			30	100	200+
4	NT	NT	NT	NT	NT
5	200	7.48/6.91	30	38	20-30
6	1300	6.55/6.82	100	90	120
7	84	8.01/8.05	30	90	130
8	17,000	NT	NT	NT	NT
9	700	6.67/6.12	30	80	75
			100	100	130
10	4.9	8.19/7.59	3	86	100
			30	100	240
11	160	6.45/6.77	NT	NT	NT
12	6.0	8.66/8.59	NT	NT	NT
13	17	8.70/8.85	NT	NT	NT
14	7.2	8.84/8.71	NT	NT	NT
15	16	8.31/8.30	NT	NT	NT
16	6.4	8.95/9.24	NT	NT	NT
17	4.0	8.64/8.40	NT	NT	NT
18	970	6.14/6.09	NT	NT	NT
19	12,000	5.18/5.35	NT	NT	NT
20	78,000	5.89/5.99	100	10	45
21	7	7.71.7.21	NT	NT	NT
22	460	6.60/6.46	NT	NT	NT
23	430	6.48/7.15	NT	NT	NT
24	10	7.56/7.73	NT	NT	NT
25	480	6.80/6.73	NT	NT	NT
26	3.2	9.83/9.66	10	50	>180
27	180	NT	NT	NT	NT
28	570	5.57/6.00	NT	NT	NT
29	160	NT	NT	NT	NT
30	22	7.73/7.88	30	50	>180
31	14	NT	NT	NT	NT
32	16	7.68/7.29	NT	NT	NT
33	630	6.73/6.36	NT	NT	NT
34	640	5.34/5.69	NT	NT	NT
35	41	7.25/7.47	NT	NT	NT
36	1400	5.92/5.68	NT	NT	NT
37	340	6.90/6.85	NT	NT	NT
38	10	7.82/8.36	NT	NT	NT
39	10	7.88/7.84	NT	NT	NT
40	83	7.94/7.61	NT	NT	NT
41	3700	5.68/5.96	NT	NT	NT
42	370	6.56/6.26	NT	NT	NT
43	19	8.97/8.61	NT	NT	NT
44	16	8.23/7.70	NT	NT	NT
45	4.4	8.41/8.24	NT	NT	NT
46	110	6.80/6.64	NT	NT	NT
47	21	7.85/7.58	NT	NT	NT
48	680	6.27/6.75	NT	NT	NT
49	120	7.06/7.07	NT	NT	NT
50	54	7.71/7.89	NT	NT	NT
51	8.7	8.39/8.51	NT	NT	NT
52	100	8.14/8.12	NT	NT	NT
53	65	7.56/7.83	NT	NT	NT
54	3100	6.02	NT	NT	NT
55	80	6.56/7.13	NT	NT	NT
56	5.0	9.04/8.35	NT	NT	NT
57	2300	6.00	NT	NT	NT
58	140	6.45/6.57	NT	NT	NT
59	120	7.23/7.59	NT	NT	NT
60	2200	6.40/6.03	NT	NT	NT
61	110	7.29/7.70	NT	NT	NT
62	26	8.69/8.61	NT	NT	NT
63	61	7.77/7.67	NT	NT	NT
64	54	7.00/6.77	NT	NT	NT
65	23	7.85/7.75	NT	NT	NT
66	12	9.34/8.58	NT	NT	NT
67	3100	5.88/5.78	NT	NT	NT
68	8.6	8.19/8.65	NT	NT	NT
69	15	7.80/8.28	NT	NT	NT
70	44	7.71/8.05	NT	NT	NT
71	12,000	*	NT	NT	NT
72	83	6.11/6.10	NT	NT	NT
73	790	7.65/7.46	NT	NT	NT
74	6.5	8.56/8.39	NT	NT	NT
75	570	6.00/5.45	NT	NT	NT
76	5400	5.52/5.78	NT	NT	NT
77	15,000	5.77	NT	NT	NT
78	101	7.0		93	60-100
79	4.9	9.2		100	>200
				50	>180
80	25	8.1		NT	NT
81	18	8.0		40	180
82	7.9	8.5		20	180
83	3.6	8.3		15	>180
84	16	7.1		20	30
85	8.7	8.9		NT	NT
86	9	7.8		NT	NT
87	91	7.8		NT	NT
88	50	7.7		NT	NT
89	18	7.9		NT	NT
90	5.6	9.0		NT	NT
91	30	8.6		40	>180
92	35	7.9		NT	NT
93	480	NT		NT	NT
94	5,800	NT		NT	NT
95	66	8.2		NT	NT
96	21	8.0		NT	NT
97	280	7.7		NT	NT
98	22	8.1		NT	NT
99	280	6.5		NT	NT
100	4.4	9.4		NT	NT
101	36	7.8		NT	NT
102	43	7.7		NT	NT
103	12	8.0		NT	NT
104	15	8.0		NT	NT
105	290	6.6		NT	NT
106	48	7.7		NT	NT
107	180	8.3		NT	NT
108	720	5.3	100	45	90
109	250	7.3	30	50	30
110	590	6.4		NT	NT
111	45	9.0	30	87	160
112	2000	5.2		NT	NT
113	12	8.4	10	60	180
114	400	6.4		NT
115	11	8.2	3	40	>240
116	230	6.5		NT
117	170	6.5		NT
118	37	9.21/9.17	10	70	120
119	16	9.21/9.00	3	20	60
120	25	9.05/8.77	10	80	240
121	46	NT		NT
122	46	NT		NT
123	50	NT		NT
124	40	9.42/9.12	3	45	>180
125	40	9.25/8.80	3	35	>240
126	240	7.20/7.05		NT
127	12,000	4.96		NT
128	16	8.63/8.40		NT
129	6,700	5.30		NT
130	40	8.10/7.94		NT
131	9.5	7.53/8.25
132	12	8.6		NT
133	10	8.7	3	20	180
					90-120
134	22	9.3	3	35	180
135	16	8.5	3	35	>180
136	NT	NT		NT
137	220	8.3		NT
138	130	8.2		NT
139	0.270	6.3		NT
140	0.031	8.1		100	160
141	0.110	8.02		NT	NT
142	2.000	NA		NT	NT
143	0.052	7.7		85	75
144	0.088	7.7		50	125
145	0.480	6.7		NT	NT
146	0.072	6.4		NT	NT
147	5.8	5.6	3	74	5-10
148	0.87	5.8	3	92	20-30
149	1.1	6.1	3	NT	NT
150	14	8.03/7.80	3	25	>180
151	17	7.76/7.97	3	15	180
152	150	7.46/7.23	3	10	140
153	13	8.30/7.69	3	25	>180
154	97	8.19/8.38		NA
155	86	7.60/7.14		NA
156	78	8.03/7.66		NA
157	530	−/6.22		NA
158	54	8.23/8.14	3	30	>180
159	21	7.92/7.56	3	10	150
160	64	7.87/7.71
161	28			NA
162	380	6.21/6.55		NA
163	420	7.42/6.75		NA
164	1700			NA
165	410	6.90/7.18		NA
166	160	7.57/7.74		NA
167	370	7.08/7.11		NA
168	420	7.69/7.58		NA
169	150	7.78/7.58	3	15	180
170	26	7.08/7.77	3	40	>180
171	28	7.52/7.11	3	0	0
172	70	7.15/7.04		NA
173	90	7.49/6.92		NA
174	180	7.29/7.02		NA
175	27	NA	3	0	0
176	9.8	7.69/7.55	3	10	150
177	26	7.41/7.85	3	15	180
178	88	7.54/7.47		NA
179	310	6.67/−		NA
180	20	7.56/7.15	3	25	180
181	21	7.70/7.12	3	20	180
182	59	NA		NA
183	390	NA		NA
184	1100	6.78/−		NA
135	6.5	8.82/8.53	3	50	>180
186	38	8.13/7.40	3	25	180
187	770	7.46/6.95		NA
188	140	7.72/7.09		NA
189	29	8.64/8.23		NA
190	10	7.87/7.89	3	10	180
191	81	7.75/7.76	3	10	180
192	140			NA
193	11	9.27/8.87	3	10	180
194	47	7.64/7.35		NA
195	34	8.44/8.03		NA
196	31	7.68/8.26		NA
197	14	8.03/8.60		NA
198	7.6	8.76/8.64	3	35	>180
199	10	8.79/8.85	3	60	>180
200	20	8.42/8.77	3	45	>180
201	17	8.78/8.63	3	10	180
202	12	8.79/8.64	3	65	>180
203	9.2	8.43/8.36	3	50	>180
204	16	9.17/8.86	3	75	>180
205	20	9.14/9.15	3	40	>180
206	5.4	8.75/8.89	3	30	>180
207	99	9.04/8.60		NA
208	22	9.19/8.69	3	50	>180
209	5.0	9.41/9.16	3	25	>180
210	3.6	8.36/8.44	3	15	180
211	18	8.74/8.67	3	35	>180
212	23	8.85/8.25	3	15	180
213	51	NA		NA
214	65	NA		NA
215	45	NA		NA
216	5.4	8.80/9.04	3	50	>180
217	9.4	NA	3	65	>180
218	9.0	NA		NA
219	14	NA		NA
220	7.0	NA	3	75	120
221	4.8	NA	3	25	>180
222	5.0	NA		NA
223	14	7.45/7.87	3	20	>180
224	91	NA		NA
225	160	NA		NA
226	93	NA		NA
227	89	7.55/7.67		NA
228	4.5	9.17/8.25	3	80	>180
229	19	NT	3	40	>180
230	2.6	8.23/8.69	3	25	>180
231	3.6	NT	3	75	>180
232	4.4	8.59/8.89	3	70	>180
233	84	8.51/8.78		NT
234	5.0	8.49/9.00	3	20	—
235	34	7.14/7.07		NT
236	4.9	NC	3	70	>180
237	3.6	NT		NT
238	1.7	NT	3	15	>180
239	6.8	7.88/8.01	3	20	>180
240	120	NA		NA
241	6.9	8.57/8.24	3	40	>180
242	110	7.11/6.60		NA
243	250	NA		NA
244	150	7.17/7.17		NA
245	98	6.64/7.04		NA
246	72	7.46/7.59		NA
247	9.4	8.26/8.41	3	20	180
248	20	7.68/7.50	3	10	—
249	4.4	NA	3	20	>180
250	43	NA	3	0	—
251	25	NA		NA
252	13	NA		NA
253	2.6	NA		NA
254	72	NA		NA
255	12	7.61/7.46	3	20	>180
256	4.1	8.43/7.78	3	30	>180
257	160	6.63/6.68		NA
258	350	6.84/6.84		NA
259	54	NA		NA
260	220	NA		NA
261	18	NA		NA
262	530	−/6.22		NA
263	57	NA		NA
264	11	NA		NA
265	110	NA		NA
266	290	NA		NA
267	25	NA	3	25	>180
268	520	NA	3	0	—
269	9.7	NA		NA
270	21	NA		NA
271	14	NC	3	20%	—
272	97	NC	3	70%	>180 min.
273	9.8	8.53/8.61	3	25%	>180 min.
274	13	9.06/8.85	3	35%	>180 min.
275	6.3	9.07/−	3	40%	>180 min.
276	33	8.71/8.64	3	<20%
277	190	−/6.54		NT
278	30	8.49/8.51	3	50%	>180 min.
279	270	8.06/8.25		NT
280	480	6.41/6.35	NT	NT	NT

[0093] NT=NOT TESTED

[0094] NC=Non-Competitive antagonist

[0095] *Antagonist Activity not observed up to 10 μM of test compound.

[0096] 1Assay A: Angiotensin II Binding Activity

[0097] 2Assay B: In vitro Vascular Smooth Muscle Response

[0098] 3Assay C: In vivo Pressor Response

[0099] Test Compounds administered intragastrically, except for compounds of examples #1-#2, #4-#25, #27-#29, #30-#79, #108-#109, #111, #118 and #139-#149 which were given intraduodenally.

[0100] Administration of the angiotensin II receptor antagonist and the aldosterone receptor antagonist may take place sequentially in separate formulations, or may be accomplished by simultaneous administration in a single formulation or separate formulations. Administration may be accomplished by oral route, or by intravenous, intramuscular or subcutaneous injections. The formulation may be in the form of a bolus, or in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more pharmaceutically-acceptable carriers or diluents, or a binder such as gelatin or hydroxypropyl-methyl cellulose, together with one or more of a lubricant, preservative, surface-active or dispersing agent.

[0101] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of each active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.01 to 30 mg/kg body weight, particularly from about 1 to 15 mg/kg body weight, may be appropriate.

[0102] The active ingredients may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. A suitable daily dose of each active component is from about 0.01 to 15 mg/kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 10 mg/kg body weight. Compounds indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about 15 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 15 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 10 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.

[0103] In combination therapy, the aldosterone receptor antagonist may be present in an amount in a range from about 5 mg to about 400 mg, and the AII antagonist may be present in an amount in a range from about 1 mg to about 800 mg, which represents aldosterone antagonist-to-AII antagonist ratios ranging from about 400:1 to about 1:160.

[0104] In a preferred combination therapy, the aldosterone receptor antagonist may be present in an amount in a range from about 10 mg to about 200 mg, and the AII antagonist may be present in an amount in a range from about 5 mg to about 600 mg, which represents aldosterone antagonist-to-AII antagonist ratios ranging from about 40:1 to about 1:60.

[0105] In a more preferred combination therapy, the aldosterone receptor antagonist may be present in an amount in a range from about 20 mg to about 100 mg, and the AII antagonist may be present in an amount in a range from about 10 mg to about 400 mg, which represents aldosterone antagonist-to-AII antagonist ratios ranging from about 10:1 to about 1:20.

[0106] The dosage regimen for creating a disease condition with the combination therapy of this invention is selected in Accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.

[0107] For therapeutic purposes, the active components of this combination therapy invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the components may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These 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 formulations 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 and widely known in the pharmaceutical art.

[0108] Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

Claims

1. A method to treat a subject susceptible to or afflicted with cardiofibrosis or cardiac hypertrophy, which method comprises administering a combination of drug agents comprising a therapeutically-effective amount of an angiotensin II receptor antagonist and a therapeutically-effective amount of an epoxy-free spirolactone-type aldosterone receptor antagonist.

2. The method of claim 1 wherein said aldosterone receptor antagonist is 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate or a pharmaceutically-acceptable salt thereof.

3. The method of claim 1 wherein said angiotensin II receptor antagonist is selected from compounds consisting of a first portion and a second portion, wherein said first portion is selected from a fragment of Formula I:

4. The method of claim 3 wherein said monocyclic heterocyclic moiety of Formula IIa is selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, soxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, turanyl, thiophenyl, isopyrrolyl, 3-isopyrrolyl, 2-isoimidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, oxazolyl, thiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, 1,2-pyronyl, 1,4-pyronyl, pyridinyl, piperazinyl, s-triazinyl, as-triazinyl, v-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyl, 1,3,5,2-oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.

5. The method of claim 4 wherein said bicyclic heterocyclic moiety of Formula IIb is selected from benzo[b]thienyl, isobenzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d][1,2]oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, cyclopenta[b]pyranyl, 4H-[1,3]oxathiolo-[5,4-b]pyrrolyl, thieno[2,3-b]furanyl, imidazo[1,2-b][1,2,4]triazinyl and 4H-1,3-dioxolo[4,5-d]imidazolyl.

6. The method of claim 5 wherein said angiotensin II receptor antagonist compound having said first-and-second-portion moieties of Formula I and II is further characterized by having an acidic moiety attached to either of said first-and-second-portion moieties.

7. The method of claim 6 wherein said acidic moiety is attached to the first-portion moiety of Formula I and is defined by Formula III:

8. The method of claim 7 wherein said acidic moiety is selected from carboxyl moiety and tetrazolyl moiety.

9. The method of claim 7 wherein any of the moieties of Formula I and Formula II may be substituted at any substitutable position by one or more radicals selected from hydrido, hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula

10. The method of claim 9 wherein said angiotensin II receptor antagonist is 5-[2-[5-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl]-2-pyridinyl]phenyl-1H-tetrazole or a pharmaceutically-acceptable salt thereof and said aldosterone receptor antagonist is 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate or a pharmaceutically-acceptable salt thereof.

11. The method of claim 10 further characterized by said angiotensin II receptor antagonist and said aldosterone receptor antagonist being present in said combination in a weight ratio range from about one-to-one to about twenty-to-one of said angiotensin II receptor antagonist to said aldosterone receptor antagonist.

12. The method of claim 11 wherein said weight ratio range is from about five-to-one to about fifteen-to-one.

13. The method of claim 12 wherein said weight ratio range is about ten-to-one.

14. The method of claim 1 wherein said angiotensin II receptor antagonist is selected from the group consisting of

15. The method of claim 14 wherein said angiotensin II receptor antagonist is selected from the group consisting of

16. The method of claim 1 comprising administering said combination to treat or prevent the progression of cardiofibrosis.

17. The method of claim 1 comprising administering said combination to treat or prevent the progression of cardiac hypertrophy.

18. The method of claim 1 wherein said epoxy-free spirolactone-type aldosterone receptor antagonist is spironolactone which is administered in a non-diuretic-effective amount.