Abstract:
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 is described for treatment of circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites. 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]    Combinations of a spirolactone-type aldosterone receptor antagonist and an angiotensin II receptor antagonist are described for use in treatment of circulatory disorders, including cardiovascular diseases such as hypertension, congestive heart failure, cirrhosis and ascites. 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&#39;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 (Mg 2+ ) 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. Exo. 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 12 July 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: A 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. Ena. 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&#39; 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.,  65(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, i 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 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 is useful to treat circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites.  
           [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 achieve the goal of reduction of hypertension with improvement in cardiac sufficiency by reducing or preventing, for example, hypertension and/or the progression of congestive heart failure.  
           [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: 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-315995, 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.  
         [0027]    A second group of AII antagonists of interest consists of the following compounds: 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 and PD-123177.  
         [0028]    A family of spirolactone-type compounds of interest for use in the combination therapy is defined by Formula A  
                         
 
         [0029]    wherein R is lower alkyl of up to 5 carbon atoms, and  
                         
 
         [0030]    Lower alkyl residues include branched and un-branched groups, preferably methyl, ethyl and n-propyl.  
         [0031]    Specific compounds of interest within Formula A are the following:  
         [0032]    7α-Aceylythio-3-oxo-4,15-androstadiene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0033]    3-Oxo-7α-propionylthio-4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0034]    6β,7β-Methylene-3-oxo4,15-androstadiene-[17((β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0035]    15α,16α-Methylene-3-oxo-4,7α-propionylthio-4-androstene[17(β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0036]    6β,7β,15α,16α-Dimethylene-3-oxo-4-androstene [17(β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0037]    7α-Aceylythio-15β,16β-Methylene-3-oxo-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one;  
         [0038]    15β,16β-Methylene-3-oxo-7β-propionylthio-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one; and  
         [0039]    6β,7β,15β,16β-Dimethylene-3-oxo-4-androstene-[17(β-1′)-spiro-5′]perhydrofuran-2′-one.  
         [0040]    Methods to make compounds of Formula A are described in U.S. Pat. No. 4,129,554 to wiechart et al issued on Dec. 12, 1978.  
         [0041]    A second family of spirolactone-type compounds of interest for use in the combination therapy is defined by Formula B:  
                         
 
         [0042]    wherein  
         [0043]    R 1  is C 1-3 -alkyl or C 1-3  acyl and R 2  is hydrogen or C 1-3 -alkyl.  
         [0044]    Specific compounds of interest within Formula B are the following:  
         [0045]    1α-Acetylthio-15β,16β-methylene-7α-methylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone; and  
         [0046]    15β,16β-Methylene-1α,7α-dimethylthio-3-oxo-17α-pregn-4-ene-21,17-carbolactone.  
         [0047]    Methods to make the compounds of Formula B are decribed in U.S. Pat. No. 4,789,668 to Nickisch et al which issued Dec. 6, 19888.  
         [0048]    A third family of spirolactone-type compounds of interest for use in the combination therapy is defined by a structure of Formula C:  
                         
 
         [0049]    Specific compounds of interest include:  
         [0050]    7α-Acylthio-21-hydroxy-3-oxo-17α-pregn-4-ene-17-carboxylic acid lactones; and  
         [0051]    21-hydroxy-3-oxo-17α-pregn-1,4-diene-17-carboxylic acid lactone.  
         [0052]    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:  
                         
 
         [0053]    “spironolactone”: 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate  
         [0054]    Spironolactone is sold by G. D. Searle &amp; Co., Skokie, Ill., under the trademark “ALDACTONE”, in tablet dosage form at doses of 25 mg, 50 mg and 100 mg per tablet.  
         [0055]    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.  
         [0056]    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.  
         [0057]    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  (I) 
         Ar-L-Het-Alk-L 
         Het-L-Alk-L 
         [0058]    wherein the abbreviated notation used in the moieties of Formula I is defined as follows:  
         [0059]    “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”.  
         [0060]    “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.  
         [0061]    “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., —CH 2 —.  
         [0062]    “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.  
         [0063]    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:  
                         
 
         [0064]    wherein each of X 1  through X 6  is selected from —CH═, —CH 2 —, —N═, —NH—, O, and S, with the proviso that at least one of X l  through X 6  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.  
         [0065]    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.  
         [0066]    Examples of bicyclic heterocyclic moieties of Formula IIb include benzo[b]thienyl, isobenzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, auinolizinyl, 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.  
         [0067]    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: 
         —U n A  (III) 
         [0068]    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.  
         [0069]    The phrase “acidic group selected to contain at least one acidic hydrogen atom”, as used to define the —U n A 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 pK a  in a range from about one to about twelve. More typically, the Formula I-IIa/b compound would have a pK a  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 —U n A 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 —U n A moiety attached at one of the Formula I-IIa/b positions, or may have a plurality of such —U n A 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 pK a  values. It is preferred, however, that at least one of these pK a  values of the Formula I-IIa/b compound as conferred by the —U n A moiety be in a range from about two to about seven. The —U n A moiety may be attached to one of the Formula I-IIa/b positions through any portion of the —U n A 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 pK a  criteria. For example, where the —U n A acid moiety is tetrazole, the tetrazole is typically attached at the tetrazole ring carbon atom.  
         [0070]    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, arkynyl, 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, alkylsulfinyl, 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  
                         
 
         [0071]    wherein W is oxygen atom or sulfur atom; wherein each of R 1  through R 5  is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, YR 6  and  
                         
 
         [0072]    wherein Y is selected from oxygen atom and sulfur atom and R 6  is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 7  and R 8  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 R 1 , R 2 , R 3 , R 4 , R 5 , R 7  and R 8  is further independently selected from amino and amido radicals of the formula  
                         
 
         [0073]    wherein W is oxygen atom or sulfur atom; wherein each of R 9 , R 10 , R 11 , R 12 , R 13  and R 14  is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 2  and R 3  taken together and each of R 4  and R 5  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 R 2  and R 3  taken together and each of R 7  and R 8  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.  
         [0074]    The combination therapy of the invention would be useful in treating a variety of circulatory disorders, including cardiovascular disorders, such as hypertension, congestive heart failure, myocardial fibrosis and cardiac 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.  
         [0075]    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                                 WO #91/17148 pub. 14 Nov. 1991               2                                 WO #91/17148 pub. 14 Nov. 1991               3                                 WO #91/17148 pub. 14 Nov. 1991               4                                 WO #91/17148 pub. 14 Nov. 1991               5                                 WO #91/17148 pub. 14 Nov. 1991               6                                 WO #91/17148 pub. 14 Nov. 1991               7                                 WO #91/17148 pub. 14 Nov. 1991               8                                 WO #91/17148 pub. 14 Nov. 1991               9                                 WO #91/17148 pub. 14 Nov. 1991               10                                 WO #91/17148 pub. 14 Nov. 1991               11                                 WO #91/17148 pub. 14 Nov. 1991               12                                 WO #91/17148 pub. 14 Nov. 1991               13                                 WO #91/17148 pub. 14 Nov. 1991               14                                 WO #91/17148 pub. 14 Nov. 1991               15                                 WO #91/17148 pub. 14 Nov. 1991               16                                 WO #91/17148 pub. 14 Nov. 1991               17                                 WO #91/17148 pub. 14 Nov. 1991               18                                 WO #91/17148 pub. 14 Nov. 1991               19                                 WO #91/17148 pub. 14 Nov. 1991               20                                 WO #91/17148 pub. 14 Nov. 1991               21                                 WO #91/17148 pub. 14 Nov. 1991               22                                 WO #91/17148 pub. 14 Nov. 1991               23                                 WO #91/17148 pub. 14 Nov. 1991               24                                 WO #91/17148 pub. 14 Nov. 1991               25                                 WO #91/17148 pub. 14 Nov. 1991               26                                 WO #91/17148 pub. 14 Nov. 1991               27                                 WO #91/17148 pub. 14 Nov. 1991               28                                 WO #91/17148 pub. 14 Nov. 1991               29                                 WO #91/17148 pub. 14 Nov. 1991               30                                 WO #91/17148 pub. 14 Nov. 1991               31                                 WO #91/17148 pub. 14 Nov. 1991               32                                 WO #91/17148 pub. 14 Nov. 1991               33                                 WO #91/17148 pub. 14 Nov. 1991               34                                 WO #91/17148 pub. 14 Nov. 1991               35                                 WO #91/17148 pub. 14 Nov. 1991               36                                 WO #91/17148 pub. 14 Nov. 1991               37                                 WO #91/17148 pub. 14 Nov. 1991               38                                 WO #91/17148 pub. 14 Nov. 1991               39                                 WO #91/17148 pub. 14 Nov. 1991               40                                 WO #91/17148 pub. 14 Nov. 1991               41                                 WO #91/17148 pub. 14 Nov. 1991               42                                 WO #91/17148 pub. 14 Nov. 1991               43                                 WO #91/17148 pub. 14 Nov. 1991               44                                 WO #91/17148 pub. 14 Nov. 1991               45                                 WO #91/17148 pub. 14 Nov. 1991               46                                 WO #91/17148 pub. 14 Nov. 1991               47                                 WO #91/17148 pub. 14 Nov. 1991               48                                 WO #91/17148 pub. 14 Nov. 1991               49                                 WO #91/17148 pub. 14 Nov. 1991               50                                 WO #91/17148 pub. 14 Nov. 1991               51                                 WO #91/17148 pub. 14 Nov. 1991               52                                 WO #91/17148 pub. 14 Nov. 1991               53                                 WO #91/17148 pub. 14 Nov. 1991               54                                 WO #91/17148 pub. 14 Nov. 1991               55                                 WO #91/17148 pub. 14 Nov. 1991               56                                 WO #91/17148 pub. 14 Nov. 1991               57                                 WO #91/17148 pub. 14 Nov. 1991               58                                 WO #91/17148 pub. 14 Nov. 1991               59                                 WO #91/17148 pub. 14 Nov. 1991               60                                 WO #91/17148 pub. 14 Nov. 1991               61                                 WO #91/17148 pub. 14 Nov. 1991               62                                 WO #91/17148 pub. 14 Nov. 1991               63                                 WO #91/17148 pub. 14 Nov. 1991               64                                 WO #91/17148 pub. 14 Nov. 1991               65                                 WO #91/17148 pub. 14 Nov. 1991               66                                 WO #91/17148 pub. 14 Nov. 1991               67                                 WO #91/17148 pub. 14 Nov. 1991               68                                 WO #91/17148 pub. 14 Nov. 1991               69                                 WO #91/17148 pub. 14 Nov. 1991               70                                 WO #91/17148 pub. 14 Nov. 1991               71                                 WO #91/17148 pub. 14 Nov. 1991               72                                 WO #91/17148 pub. 14 Nov. 1991               73                                 WO #91/17148 pub. 14 Nov. 1991               74                                 WO #91/17148 pub. 14 Nov. 1991               75                                 WO #91/17148 pub. 14 Nov. 1991               76                                 WO #91/17148 pub. 14 Nov. 1991               77                                 WO #91/17148 pub. 14 Nov. 1991               78                                 WO #91/18888 pub.               79                                 WO #91/18888 pub.               80                                 WO #91/18888 pub.               81                                 WO #91/18888 pub.               82                                 WO #91/18888 pub.               83                                 WO #91/18888 pub.               84                                 WO #91/18888 pub.               85                                 WO #91/18888 pub.               86                                 WO #91/18888 pub.               87                                 WO #91/18888 pub.               88                                 WO #91/18888 pub.               89                                 WO #91/18888 pub.               90                                 WO #91/18888 pub.               91                                 WO #91/18888 pub.               92                                 WO #91/18888 pub.               93                                 WO #91/18888 pub.               94                                 WO #91/18888 pub.               95                                 WO #91/18888 pub.               96                                 WO #91/18888 pub.               97                                 WO #91/18888 pub.               98                                 WO #91/18888 pub.               99                                 WO #91/18888 pub.               100                                 WO #91/18888 pub.               101                                 WO #91/18888 pub.               102                                 WO #91/18888 pub.               103                                 WO #91/18888 pub.               104                                 WO #91/18888 pub.               105                                 WO #91/18888 pub.               106                                 WO #91/18888 pub.               107                                 WO #91/18888 pub.               108                                 WO #91/19715 pub. 26 Dec. 1991               109                                 WO #91/19715 pub. 26 Dec. 1991               110                                 WO #91/19715 pub. 26 Dec. 1991               111                                 WO #91/19715 pub. 26 Dec. 1991               112                                 WO #91/19715 pub. 26 Dec. 1991               113                                 WO #91/19715 pub. 26 Dec. 1991               114                                 WO #91/19715 pub. 26 Dec. 1991               115                                 WO #91/19715 pub. 26 Dec. 1991               116                                 WO #91/19715 pub. 26 Dec. 1991               117                                 WO #91/19715 pub. 26 Dec. 1991               118                                 WO #91/19715 pub. 26 Dec. 1991               119                                 WO #91/19715 pub. 26 Dec. 1991               120                                 WO #91/19715 pub. 26 Dec. 1991               121                                 WO #91/19715 pub. 26 Dec. 1991               122                                 WO #91/19715 pub. 26 Dec. 1991               123                                 WO #91/19715 pub. 26 Dec. 1991               124                                 WO #91/19715 pub. 26 Dec. 1991               125                                 WO #91/19715 pub. 26 Dec. 1991               126                                 WO #92/05161 pub. 2 Apr. 1992               128                                 WO #92/05161 pub. 2 Apr. 1992               129                                 WO #92/05161 pub. 2 Apr. 1992               130                                 WO #92/05161 pub. 2 Apr. 1992               131                                 WO #92/05161 pub. 2 Apr. 1992               132                                 WO #92/07834 pub. 14 May 1992               133                                 WO #92/07834 pub. 14 May 1992               134                                 WO #92/07834 pub. 14 May 1992               135                                 WO #92/07834 pub. 14 May 1992               136                                 WO #92/07834 pub. 14 May 1992               137                                 WO #92/07834 pub. 14 May 1992               138                                 WO #92/07834 pub. 14 May 1992               139                                 WO #92/11255 pub. 9 Jul. 1992               140                                 WO #92/11255 pub. 9 Jul. 1992               141                                 WO #92/11255 pub. 9 Jul. 19921               142                                 WO #92/11255 pub. 9 Jul. 1992               143                                 WO #92/11255 pub. 9 Jul. 1992               144                                 WO #92/11255 pub. 9 Jul. 1992               145                                 WO #92/11255 pub. 9 Jul. 1992               146                                 WO #92/11255 pub. 9 Jul. 1992               147                                 WO #92/15577 pub. 17 Sep. 1992               148                                 WO #92/15577 pub. 17 Sep. 1992               149                                 WO #92/15577 pub. 17 Sep. 1992               150                                 WO #92/16523 pub. 1 Oct. 1992               151                                 WO #92/16523 pub. 1 Oct. 1992               152                                 WO #92/16523 pub. 1 Oct. 1992               153                                 WO #92/16523 pub. 1 Oct. 1992               154                                 WO #92/16523 pub. 1 Oct. 1992               155                                 WO #92/16523 pub. 1 Oct. 1992               156                                 WO #92/16523 pub. 1 Oct. 1992               157                                 WO #92/16523 pub. 1 Oct. 1992               158                                 WO #92/16523 pub. 1 Oct. 1992               159                                 WO #92/16523 pub. 1 Oct. 1992               160                                 WO #92/16523 pub. 1 Oct. 1992               161                                 WO #92/16523 pub. 1 Oct. 1992               162                                 WO #92/16523 pub. 1 Oct. 1992               163                                 WO #92/16523 pub. 1 Oct. 1992               164                                 WO #92/16523 pub. 1 Oct. 1992               165                                 WO #92/16523 pub. 1 Oct. 1992               166                                 WO #92/16523 pub. 1 Oct. 1992               167                                 WO #92/16523 pub. 1 Oct. 1992               168                                 WO #92/16523 pub. 1 Oct. 1992               169                                 WO #92/16523 pub. 1 Oct. 1992               170                                 WO #92/16523 pub. 1 Oct. 1992               171                                 WO #92/16523 pub. 1 Oct. 1992               172                                 WO #92/16523 pub. 1 Oct. 1992               173                                 WO #92/16523 pub. 1 Oct. 1992               174                                 WO #92/16523 pub. 1 Oct. 1992               175                                 WO #92/16523 pub. 1 Oct. 1992               176                                 WO #92/16523 pub. 1 Oct. 1992               177                                 WO #92/16523 pub. 1 Oct. 1992               178                                 WO #92/16523 pub. 1 Oct. 1992               179                                 WO #92/16523 pub. 1 Oct. 1992               180                                 WO #92/16523 pub. 1 Oct. 1992               181                                 WO #92/16523 pub. 1 Oct. 1992               182                                 WO #92/16523 pub. 1 Oct. 1992               183                                 WO #92/16523 pub. 1 Oct. 1992               184                                 WO #92/16523 pub. 1 Oct. 1992               185                                 WO #92/17469 pub. 15 Oct. 1992               186                                 WO #92/17469 pub. 15 Oct. 1992               187                                 WO #92/17469 pub. 15 Oct. 1992               188                                 WO #92/17469 pub. 15 Oct. 1992               189                                 WO #92/17469 pub. 15 Oct. 1992               190                                 WO #92/17469 pub. 15 Oct. 1992               191                                 WO #92/17469 pub. 15 Oct. 1992               192                                 WO #92/17469 pub. 15 Oct. 1992               193                                 WO #92/17469 pub. 15 Oct. 1992               194                                 WO #92/17469 pub. 15 Oct. 1992               195                                 WO #92/17469 pub. 15 Oct. 1992               196                                 WO #92/17469 pub. 15 Oct. 1992               197                                 WO #92/17469 pub. 15 Oct. 1992               198                                 WO #92/17469 pub. 15 Oct. 1992               199                                 WO #92/17469 pub. 15 Oct. 1992               200                                 WO #92/17469 pub. 15 Oct. 1992               201                                 WO #92/17469 pub. 15 Oct. 1992               202                                 WO #92/17469 pub. 15 Oct. 1992               203                                 WO #92/17469 pub. 15 Oct. 1992               204                                 WO #92/17469 pub. 15 Oct. 1992               205                                 WO #92/17469 pub. 15 Oct. 1992               206                                 WO #92/17469 pub. 15 Oct. 1992               207                                 WO #92/17469 pub. 15 Oct. 1992               208                                 WO #92/17469 pub. 15 Oct. 1992               209                                 WO #92/17469 pub. 15 Oct. 1992               210                                 WO #92/17469 pub. 15 Oct. 1992               211                                 WO #92/17469 pub. 15 Oct. 1992               212                                 WO #92/17469 pub. 15 Oct. 1992               213                                 WO #92/17469 pub. 15 Oct. 1992               214                                 WO #92/17469 pub. 15 Oct. 1992               215                                 WO #92/17469 pub. 15 Oct. 1992               216                                 WO #92/17469 pub. 15 Oct. 1992               217                                 WO #92/17469 pub. 15 Oct. 1992               218                                 WO #92/17469 pub. 15 Oct. 1992               219                                 WO #92/17469 pub. 15 Oct. 1992               220                                 WO #92/17469 pub. 15 Oct. 1992               221                                 WO #92/17469 pub. 15 Oct. 1992               222                                 WO #92/17469 pub. 15 Oct. 1992               223                                 WO #92/17469 pub. 15 Oct. 1992               224                                 WO #92/17469 pub. 15 Oct. 1992               225                                 WO #92/17469 pub. 15 Oct. 1992               226                                 WO #92/17469 pub. 15 Oct. 1992               227                                 WO #92/17469 pub. 15 Oct. 1992               228                                             229                                             230                                             231                                             232                                             233                                             234                                             235                                             236                                             237                                             238                                             239                                 WO #92/18092 pub. 29 Oct. 1992               240                                 WO #92/18092 pub. 29 Oct. 1992               241                                 WO #92/18092 pub. 29 Oct. 1992               242                                 WO #92/18092 pub. 29 Oct. 1992               243                                 WO #92/18092 pub. 29 Oct. 1992               244                                 WO #92/18092 pub. 29 Oct. 1992               245                                 WO #92/18092 pub. 29 Oct. 1992               246                                 WO #92/18092 pub. 29 Oct. 1992               247                                 WO #92/18092 pub. 29 Oct. 1992               248                                 WO #92/18092 pub. 29 Oct. 1992               249                                 WO #92/18092 pub. 29 Oct. 1992               250                                 WO #92/18092 pub. 29 Oct. 1992               251                                 WO #92/18092 pub. 29 Oct. 1992               252                                 WO #92/18092 pub. 29 Oct. 1992               253                                 WO #92/18092 pub. 29 Oct. 1992               254                                 WO #92/18092 pub. 29 Oct. 1992               255                                 WO #92/18092 pub. 29 Oct. 1992               256                                 WO #92/18092 pub. 29 Oct. 1992               257                                 WO #92/18092 pub. 29 Oct. 1992               258                                 WO #92/18092 pub. 29 Oct. 1992               259                                 WO #92/18092 pub. 29 Oct. 1992               260                                 WO #92/18092 pub. 29 Oct. 1992               261                                 WO #92/18092 pub. 29 Oct. 1992               262                                 WO #92/18092 pub. 29 Oct. 1992               263                                 WO #92/18092 pub. 29 Oct. 1992               264                                 WO #92/18092 pub. 29 Oct. 1992               265                                 WO #92/18092 pub. 29 Oct. 1992               266                                 WO #92/18092 pub. 29 Oct. 1992               267                                 WO #92/18092 pub. 29 Oct. 1992               268                                 WO #92/18092 pub. 29 Oct. 1992               269                                 WO #92/18092 pub. 29 Oct. 1992               270                                 WO #92/18092 pub. 29 Oct. 1992               271                                 PCT/US95/02156 filed 8 Mar. 1994               272                                 PCT/US94/02156 filed 8 Mar. 1994               273                                 PCT/US94/02156 filed 8 Mar. 1994               274                                 PCT/US94/02156 filed 8 Mar. 1994               275                                 PCT/US94/02156 filed 8 Mar. 1994               276                                 PCT/US94/02156 filed 8 Mar. 1994               277                                 PCT/US94/02156 filed 8 Mar. 1994               278                                 PCT/US94/02156 filed 8 Mar. 1994               279                                 PCT/US94/02156 filed 8 Mar. 1994               280                                 WO #91/17148 pub. 14 Nov. 1991               281                                 EP #475,206 pub. 18 Mar. 1992               282                                 WO #93/18035 pub. 16 Sep. 1993               283                                 WO #93/17628 pub. 16 Sep. 1993               284                                 WO #93/17681 pub. 16 Sep. 1993               285                                 EP #515,533 pub. 19 Nov. 1992               286                                 EP #535,463 pub. 07 Apr. 1993               287                                 EP #535,465 pub. 07 Apr. 1993               288                                 EP #539,713 pub. 05 May 1993               289                                 EP #542,059 pub. 19 May 1993               290                                 EP #05 557,843 pub. 01 Sep. 1993               291                                 EP #563,705 pub. 06 Oct. 1993               292                                 EP #562,261 pub. 29 Sep. 1993               293                                 EP #05 557,843 pub. 15 Sep. 1993               294                                 EP 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No. 5,278,068 pub. 11 Jan. 1994               387                                 WO #94/02142 pub. 03 Feb. 1994               388                                 WO #44/02467 pub. 03 Feb. 1994               389                                 EP #403,159 pub. 19 Dec. 1990               390                                 EP #425,211 pub. 02 May 1991               391                                 EP #427,463 pub. 15 May 1991               392                                 WO #92/00068 pub. 09 Jan. 1992               393                                 WO #92/02,510 pub. 20 Feb. 1992               394                                 WO #92/09278 pub. 11 Jun. 1992               395                                 WO #92/10181 pub. 25 Jun. 1992               396                                             397                                             398                                             399                                             400                                             401                                             402                                             403                                 WO #92/100097 pub. 25 Jun. 1992               404                                             405                                             406                                             407                                 WO #92/20651 pub. 26 Nov. 1992               408                                 WO #93/03018 pub. 18 Feb. 1993               409                                 WO #94/00120 pub. 06 Jan. 1994               410                                 EP #459,136 pub. 04 Dec. 1991               411                                 EP #411,507 pub. 05 Feb. 1991               412                                 EP #425,921 pub. 08 May 1991               413                                 EP #430,300 pub. 05 Jun. 1991               414                                 EP #434,038 pub. 26 Jun. 1991               415                                 EP #442,473 pub. 21 Aug. 1991               416                                 EP #443,568 pub. 28 Aug. 1991               417                                 EP #459,136 pub. 04 Dec. 1991               418                                 EP #483,683 pub. 05 May 1992               419                                 EP #518,033 pub. 16 Dec. 1992               420                                 EP #520,423 pub. 30 Dec. 1992               421                                 EP #546,358 pub. 16 Jun. 1993               422                                 EP #93/00341 pub. 07 Jan. 1993               423                                 EP #92/06081 pub. 16 Apr. 1992               424                                 WO #93/00341 pub. 07 Jan. 1993               425                                 U.S Pat. No. 5,210,204 pub. 11 May 1993               426                                 EP #343,654 pub. 29 Nov. 1989               427                                 WO #93/13077 pub. 08 Jul. 1993               428                                 WO #93/15734 pub. 19 Aug. 1993               429                                 U.S Pat. No. 5,246,943 pub. 21 Sep. 1993                  
 
         [0076]    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  
                         
 
         [0077]    group; or, as another example, two hydrido atoms may be attached to a carbon atom to form a —CH 2 — group. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “hydroxyalkyl”, the term “alkyla” 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 “alkoxy” 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 “aralky” 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 which are phenoxy and phenylthio. The terms “sulfinyl” and “sulfonyl”, whether used alone or linked to other terms, denotes, respectively, divalent radicals SO and SO 2 . 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.  
         [0078]    Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, 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.  
         [0079]    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, chioroprocaine, 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  
       [0080]    Human congestive heart failure (CHF) is a complex condition usually initiated by vascular hypertension or a myocardial infarction (MI). In o der to determine the probable effectiveness of a combination therapy for CHF, 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 Assays “D” and “E”, there are described methods 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 the individual drugs, spironolactone and the angiotensin II receptor blocker, and of these drugs given together at various doses, are evaluated in rodent models of hypertension and CHF using surgical alterations to induce either hypertension or an MI. The methods and results of such assays are described below.  
         [0081]    Assay A: Antiotensin II Binding Activity  
         [0082]    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.  125 I-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 MgCl 2 , 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and  125 I-AII (approximately 10 5  cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated 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 (IC 50 ) of the tested AII antagonist which gives 50% displacement of the total specifically bound  125 I-AII from the angiotensin II AT 1  receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table III.  
         [0083]    Assay B: In Vitro Vascular Smooth Muscle-Response for AII  
         [0084]    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 NaHCO 3 , 15 KCl, 1.2 NaH 2 PO 4 , 1.2 MgSO 4 , 2.5 CaCl 2 , 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 pA 2  values and were calculated according to H. O. Schild [ Br. J. Pharmacol. Chemother.,  2, 189-206 (1947)]. The pA 2  value is the concentration of the antagonist which increases the EC 50  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.  
         [0085]    Assay C: In Vivo Intracrastric Pressor Assay Response for All Antagonists  
         [0086]    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.  
         [0087]    Assay “D”: Hypertensive Rat Model  
         [0088]    Male rats are made hypertensive by placing a silver clip with an aperture of 240 microns on the left renal artery, leaving the contralateral kidney untouched. Sham controls undergo the same procedure but without attachment of the clip. One week prior to the surgery, animals to be made hypertensive are divided into separate groups and drug treatment is begun. Groups of animals are administered vehicle, AII antagonist alone, spironolactone alone, and combinations of AII antagonist and spironolactone, at various doses, as follow:  
                                                                                   Combination of       AII Antagonist   Spironolactone   AII Antagonist &amp; Spironolactone            (mg/kg/day)   (mg/kg/day)   (mg/kg/day)   (mg/kg/day)                    3   5   3   5           20   3   20           50   3   50           100   3   100           200   3   200       10   5   10   5           20   10   20           50   10   50           100   10   100           200   10   200       30   5   30   5           20   30   20           50   30   50           100   30   100           200   30   200                  
 
         [0089]    After 12 to 24 weeks, systolic and diastolic blood pressure, left ventricular end diastolic pressure, left ventricular dP/dt, and heart rate are evaluated. The hearts are removed, weighed, measured and fixed in formalin. Collagen content of heart sections are evaluated using computerized image analysis of picrosirius stained sections. It would be expected that rats treated with a combination therapy of AII antagonist and spironolactone components, as compared to rats treated with either component alone, will show improvements in cardiac performance.  
         [0090]    Assay “E”: Myocardial Infarction Rat Model:  
         [0091]    Male rats are anesthetized and the heart is exteriorized following a left sided thoracotomy. The left anterior descending coronary artery is ligated with a suture. The thorax is closed and the animal recovers. Sham animals have the suture passed through without ligation. One week prior to the surgery, animals to undergo infarction are divided into separte groups and drug treatment is begun. Groups of animals are administered vehicle, AII antagonist alone, spironolactone alone, and combinations of AII antagonist and spironolactone, at various doses, as follow:  
                                                                                   Combination of       AII Antagonist   Spironolactone   AII Antagonist &amp; Spironolactone            (mg/kg/day)   (mg/kg/day)   (mg/kg/day)   (mg/kg/day)                    3   5   3   5           20   3   20           50   3   50           100   3   100           200   3   200       10   5   10   5           20   10   20           50   10   50           100   10   100           200   10   200       30   5   30   5           20   30   20           50   30   50           100   30   100           200   30   200                  
 
         [0092]    After six weeks, systolic and diastolic blood pressure, left ventricular end diastolic pressure, left ventricular dP/dt, and heart rate evaluated. The hearts are removed, weighed, measured and fixed in formalin. Collagen content of heart sections are evaluated using computerized image analysis of picrosirius stained sections. It would be expected that rats treated with a combination therapy of AII antagonist and spironolactone components, as compared to rats treated with either component alone, will show improvements in cardiac performance.  
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               TABLE III                           In Vivo and In Vitro Angiotensin II Activity       of Compounds of the Invention            Test           Com-                pound     1 Assay A         3 Assay C            Exam-   IC 50       2 Assay B   Dose   Inhibition   Duration       ple #   (nM)   pA 2     (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   &gt;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   87   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   &gt;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   &gt;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   &gt;200                       50   &gt;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   &gt;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   &gt;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   &gt;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   &gt;180       125   40   9.25/8.80   3   35   &gt;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   &gt;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   &gt;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   &gt;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   &gt;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   &gt;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            185   6.5   8.82/8.53   3   50   &gt;180       186   38   8.13/7.40   3   25   18            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   &gt;180       199   10   8.79/8.85   3   60   &gt;180       200   20   8.42/8.77   3   45   &gt;180       201   17   8.78/8.63   3   10   180       202   12   8.79/8.64   3   65   &gt;180       203   9.2   8.43/8.36   3   50   &gt;180       204   16   9.17/8.86   3   75   &gt;180       205   20   9.14/9.15   3   40   &gt;180       206   5.4   8.75/8.89   3   30   &gt;180            207   99   9.04/8.60       NA            208   22   9.19/8.69   3   50   &gt;180       209   5.0   9.41/9.16   3   25   &gt;180       210   3.6   8.36/8.44   3   15   180       211   18   8.74/8.67   3   35   &gt;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   &gt;180       217   9.4   NA   3   65   &gt;180            218   9.0   NA       NA       219   14   NA       NA            220   7.0   NA   3   75   120       221   4.8   NA   3   25   &gt;180            222   5.0   NA       NA            223   14   7.45/7.87   3   20   &gt;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   &gt;180       229   19   NT   3   40   &gt;180       230   2.6   8.23/8.69   3   25   &gt;180       231   3.6   NT   3   75   &gt;180       232   4.4   8.59/8.89   3   70   &gt;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   &gt;180            237   3.6   NT       NT            238   1.7   NT   3   15   &gt;180       239   6.8   7.88/8.01   3   20   &gt;180            240   120   NA       NA            241   6.9   8.57/8.24   3   40   &gt;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   &gt;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   &gt;180       256   4.1   8.43/7.78   3   30   &gt;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   &gt;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%   &gt;180 min.       273   9.8   8.53/8.61   3   25%   &gt;180 min.       274   13   9.06/8.85   3   35%   &gt;180 min.       275   6.3   9.07/-         3   40%   &gt;180 min.       276   33   8.71/8.64   3   &lt;20%             277   190        -/6.54       NT            278   30   8.49/8.51   3   50%   &gt;180 min.            279   270   8.06/8.25       NT            280   480   6.41/6.35   NT   NT   NT                                                                       # #139-#149 which were given intraduodenally.           
 
         [0093]    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.  
         [0094]    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.  
         [0095]    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.  
         [0096]    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.  
         [0097]    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.  
         [0098]    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.  
         [0099]    The dosage regimen for treating 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.  
         [0100]    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.  
         [0101]    Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.