AU5349400A

AU5349400A - Epoxy-steroidal aldosterone antagonist and angiotensin II antagonist combination therapy for the treatment of congestive heart failure

Info

Publication number: AU5349400A
Application number: AU53494/00A
Authority: AU
Inventors: John C. Alexander; Richard J. Gorczynski; Joseph R. Schuh
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1995-06-07
Filing date: 2000-08-18
Publication date: 2000-10-26
Also published as: AU2003202486B2

Description

AUSTRALIA

PATENTS ACT 1990 REGULATION 3.2 Name of Applicant: Actual Inventor/s: G. D. SEARLE CO.

JOHN C. ALEXANDER, JOSEPH R. SCHUH and RICHARD J. GORCZYNSKI.

Address for Service: E.F. WELLINGTON CO., Patent and Trade Mark Attorneys, 312 St. Kilda Road, Melbourne, Southbank, Victoria, 3006.

Invention Title: "EPOXY-STEROIDAL ALDOSTERONE ANTAGONIST AND ANGIOTENSIN II ANTAGONIST COMBINATION THERAPY FOR THE TREATMENT OF CONGESTIVE HEART FAILURE" Details of Associated Provisional Applications Nos: The following statement is a full description of this invention including the best method of performing it known to us.

SA

EPOXY-STEROIDAL ALDOSTERONE ANTAGONIST AND ANGIOTENSIN II ANTAGONIST COMBINATION THERAPY FOR TREATMENT OF CONGESTIVE HEART FAILURE Field of the Invention Combinations of an epoxy-steroidal 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, cardiac hypertrophy, cirrhosis and ascites. Of particular interest are therapies using an epoxy-containing steroidal aldosterone receptor 15 antagonist compound such as epoxymexrenone in combination *with an angiotensin II receptor antagonist compound.

Background of the Invention 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.

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 excretion, relative to dietary Na 4 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.

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

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.

Multiple factors regulate ALDO synthesis and metabolism, many of which are operative in the patient with myocardial failure. These include renin as well as nonrenin-dependent factors (such as K, ACTH) that promote ALDO synthesis. Hepatic blood flow, by regulating the clearance of circulating ALDO, helps determine its plasma S 25 concentration, an important factor in heart failure characterized by reduction in cardiac output and hepatic blood flow.

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-angiotensinaldosterone 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.

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 angioten'sin II antagonists Saralasin) have a significant residual agonist activity which further limit their therapeutic application.

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-l-(2chlorobenzyl)imidazole-5-acetic acid which has specific 25 competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests C. Wong et al, J. Pharmacol. Exo. Ther,, 247(1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-l- 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 T. Chiu et al, European J. Pharmacol., 157, 31-21 (1988)]. A family of derivatives has been shown to have competitive angiotensin II antagonist properties T. Chiu et al, J. Pharmacol.

Exp. Ther., 250(3), 867-874 (1989)]. U.S. Patent No.

4,816,463 to Blankey et al describes a family of 4,5,6,7tetrahydro-1H-imidazo(4,5-c)-tetrahydro-pyridine derivatives C-2S19 4 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 January 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, 15 biphenylmethyl-l,2,3-triazoles and biphenylmethyl 4substituted-4H-l,2,4-triazoles, including the compound dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-4H-1, 2,4triazole. U.S. Patent 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.

e Many aldosterone receptor blocking drugs are known. For example, spironolactone is a drug which acts at 25 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 Mantero et al, Clin. Sci. Mol. Med., (Suppl 2 19s-224s (1973)]. Spironolactone is also used commonly in the treatment of other hyperaldosteronerelated diseases such as liver cirrhosis and congestive heart failure Saunders et al, Aldactone; SDironolactone: A Comprehensive Review, Searle, New York (1978)]. Progressively-increasing doses of spironolactone from 1 mg to 400 mg per day 1 mg/day, 5 mg/day, mg/day] were administered to a spironolactone-intolerant patient to treat cirrhosis-related ascites Greenberger et al, N. Enc. Rea. Allercr Proc., 343-345 (Jul-Aug, 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 Klug et al, Am. J.

Cardiol., 71 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 Brilla et al, J. Mol. Cell.

Cardiol., 25(5), 563-575 (1993)]. Spironolactone at a dosage ranging from 25 mg to 100 mg daily is used to treat diuretic-induced hypokalemia, when orally-administered potassium supplements or other potassium-sparing regimens are considered inappropriate (Physicians' Desk Reference, 46th Edn., p. 2153, Medical Economics Company Inc., Montvale, N.J. (1992)].

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 25 hypertension. While ACE inhibitors may effectively control hypertension, side effects are common including chronic cough, skin rash, loss of taste sense, proteinuria and neutropenia.

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 Staessen et al, J. Endocrinol., 91, 457-465 (1981)]. A similar effect has been observed for patients with myocardial infarction receiving zofenopril Borghi C-2819 6 et al, J. Clin. Pharmacol., 31, 40-45 (1993)]. This phenomenon has been termed "aldosterone escape".

Another series of steroidal-type aldosterone receptor antagonists is exemplified by epoxy-containing spironolactone derivatives. For example, U.S. Patent No.

4,559,332 issued to Grob et al describes 9a,lla-epoxycontaining spironolactone derivatives as aldosterone antagonists useful as diuretics. These 9a,lla-epoxy steroids have been evaluated for endocrine effects in comparison to spironolactone de Gasparo et al, J. Pharm.

Exp. Ther., 240(2), 650-656 (1987)].

*e* 0* Combinations of an aldosterone antagonist and an ACE 15 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 Saldosterone 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.

25 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 Poncelet et al, Am. J.

CardiL., 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 Dahlstrom et al, Am.

J. Cardiol., 71, 29A-33A (21 Jan 1993)]. Spironolactone coadministered with an ACE inhibitor was reported to be highly effective in 13 of 16 patients afflicted with congestive heart failure van Vliet et al, Am. J.

Cardio, 21, 21A-28A (21 Jan 1993)]. Clinical improvements have been reported for patients receiving a co-therapy of spironolactone and the ACE inhibitor enalapril, although this report mentions that control.led trials are needed to determine the lowest effective doses and to identify which patients wduld benefit most from combined therapy [F.

Zannad, Am. J. Cardiol., 11(3), 34A-39A (1993)].

Combinations of an angiotensin II receptor antagonist and aldosterone receptor antagonist, are known.

For example, PCT Application No. US91/09362 published June 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 In a first aspect, the present invention provides a combination comprising a therapeutically-effective amount of an angiotensin II receptor antagonist and a therapeuticallyeffective amount of an epoxy-steroidal aldosterone receptor antagonist.

In a second aspect, the present invention provides a method of treating a patient afflicted with or susceptible to circulatory disorders, including a cardiovascular disorder or multiple cardiovascular disorders such as one or more of hypertension, congestive heart failure, cardiac hypertrophy, cirrhosis and ascites, by administration to the patient by combination therapy (as hereinafter described) of an effective amount of the combination of the first aspect of the invention.

In a preferred embodiment of the present invention, said epoxy-steroidal aldosterone receptor antagonist of the combination is selected from epoxy-containing compounds, more preferably said epoxy-containing compound has an epoxy moiety fused to the ring of the steroidal nucleus of a spiroxane compound, still more preferably said compound is characterized by the presence of a 9 11 substituted epoxy moiety.

In another preferred embodiment of the present invention said epoxy-containing compound of the combination is selected from the group consisting of pregn-4-efle- 7 2 l -dicarboxylic acid, 9,1 1-epoxy- 17-hydroxy-3-oXOy-lactofle, methyl ester, (7a,l1 ac,l1 7 pregn-4-ene- 7 2 l -dicarboxylic acid, 9,11 -epoxy- 1 7-hydroxy-3-oxo-dimlethyl ester, (7a, 1 1A, 1 7aL)-; 3'H-cyclopropa(6, 7 pregna-4,6-diele-21-carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-lactofle,( 6

I

3 7 pl 13, 1 7p3)-; 0. 10 pregn-4-ene-7,21 -dicarboxylic acid,9,11 epoxy-i 7-hyd roxy-3-oxo-,7-(l1-methylethyl) ester, 9* 99** pregn-4-ene-7,21 -dicarboxylic acid,9, 11,-epoxy- 909 1 7-hydroxy-3-oxo-,7-methyl ester, monopotassium salt, (7a,11 ac, 1 7c)-; 3'H-cyclopropa[6,7]pregna-1 ,4,6-triene-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-Iactone(6ct,7a, 11 3'H-cyclopropal6 ,7]pregna-4,6-diene-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,methyl ester, (6cz,7a, 11c, 1 7a)-; 3'H-cyclopropa[6,7]pregfla-4,6-diefle-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-, monopotassium salt, (6ct,7a,11 a,17x)-; 3'H-cyclopropa[6,7]pregfla-4,6-diefle-2 1 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,ylactone, (6cx,7c,11cc., 17ax)-; pregn-4-ene-7,2l -dicarboxylic acid, 9,11 -epoxy- 1 7-hydroxy-3-oxo-,y-lactofle, ethyl ester, (7cx, 11 cc, 1 7cx)-; and pregn-4-ene-7, 2 1 -dicarboxylic acid, 9,11 -epoxy- 1 7-hyd roxy-3-oxo-,y-lactofle, 1 -methylethyl ester, (7x,11 x,l17x)-.

In another preferred embodiment of the present invention, said angiotensin II receptor antagonist is 5-[2-[5-[(3,5-dibutyl-1 H-i ,2,4-triazol-1 -yl)methyl]-2-pyridinyIlphenyl-1 H-tetrazole or a 0% 0 pharmaceutically-acceptable salt thereof and said epoxy-steroidal aldosterone receptor :i0 antagonist is 9ct-,1 1la-epoxy-7ca-methoxycarboflyl- 2 -spirox- 4 -efe- 3 2 l-diofle or a 0pharmaceutically-acceptable salt thereof.

In another preferred embodiment of the present invention, said angiotensin II receptor antagonist of the oo ocombination is selected from the group consisting of o: 15 saralasin acetate, candesartan cilexetil, CGP-63170, .00. EMD-66397, KT3-671, LR-B/081, valsartan, A-8 1282, .0BIBR-363, BIBS-222, BMS-1 84698, candesartan, CV-1 1194, EXP-31 74, KW-3433, .0 L-161177, L-162154, LR-B/057, 0. 0: LY-235656, P0-1 '50304, U-96849, U-9701 8, U P-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-41 77, EMD-73495, eprosartan, HN-6502 1, irbesartan, L-159282, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-1 59689, L-1 62234, L-1 62441, L-1 63007, PD-i 23177, A-81 988, BMS-1 80560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-1 67, EXP-063, EXP-6155, EXP-6803, EXP-771 1, EXP-9270, FK-739, HR-720, lCl-D6888, lCI-D7155, ICI-D8731, isoteoline, KRI-1 177, L-1 58809, L-1 58978, L-1 59874, LR 6087, LY-285434, LY-302289, LY-315995, RG-1 3647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, VVK-1 360, X-6803, ZD-6888, ZD-7155, ZD-8731, 81BS39, 01-996, DMP-81 1, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319, more preferably said angiotensin II receptor antagonist is selected from the group consisting of: 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, 10 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.

In further preferred embodiments of the invention, the combination is characterized by said angiotensin II receptor antagonist and said epoxy-steroidal aldosterone 15 receptor antagonist being present in said combination in a weight ratio range from about one-to-one to about twenty-to-one of said angiotensin II receptor antagonist to said aldosterone receptor antagonist, more preferably said weight ratio range is from about five-to-one to about fifteen-to-one, still more preferably said weight ratio range is about ten-to-one.

8 Thus, the present invention provides a combination therapy comprising a therapeutically-effective amount of an epoxysteroidal aldosterone receptor antagonist and a therapeuticallyeffective amount of an angiotensin II receptor antagonist, useful to treat circulatory disorders, including cardiovascular disorders such as hypertension, congestive heart failure, cirrhosis and ascites.

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 eo. biological functions or events such as vasoconstriction or 15 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" "surmountable") or as being "insurmountable". These terms, "competitive" and *I "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.

The phrase "epoxy-steroidal aldosterone receptor antagonist" is intended to embrace one or more agents or compounds characterized by a steroid-type nucleus and having an epoxy moiety attached to the nucleus and which agent or compound binds to the aldosterone receptor, as a competitive inhibitor of the action of aldosterone itself at the receptor site, so as to modulate the receptor-mediated 0 9 activity of aldosterone.

The phrase "combination therapy", in defining use of an angiotensin II antagonist and an epoxy-steroidal 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.

The phrase "therapeutically-effective" is intended 15 to qualify the amount of each antagonist agent for use in the combination therapy which will achieve the goal of Sreduction of hypertension with improvement in cardiac sufficiency by reducing or preventing, for example, the progression of congestive heart failure.

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

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).

C-2819 Detailed Description of the Invention Epoxy-steroidal aldosterone receptor antagonist compounds suitable for use in the combination therapy consist of these compounds having a steroidal nucleus substituted with an epoxy-type moiety. The term "epoxytype" moiety is intended to embrace any moiety characterized in having an oxygen atom as a bridge between two carbon atoms, examples of which include the following moieties: 0 0 0 CH\

CH-

epoxyethyl 1,3-epoxypropyl 1, 2 -epoxypropyl The term "steroidal", as used in the phrase "epoxysteroidal", denotes a nucleus provided by a 15 cyclopentenophenanthrene moiety, having the conventional and rings. The epoxy-type moiety may be attached to the cyclopentenophenanthrene nucleus at any attachable or substitutable positions, that is, fused to one of the rings of the steroidal nucleus or the moiety may be substituted on a ring member of the ring system. The phrase "epoxy-steroidal" is intended to embrace a steroidal nucleus having one or a plurality of epoxy-type moieties attached thereto.

9 Epoxy-steroidal aldosterone receptor antagonists suitable for use in combination therapy include a family of compounds having an epoxy moiety fused to the ring of the steroidal nucleus. Especially preferred are spiroxane compounds characterized by the presence of a 9 a,lla-substituted epoxy moiety. Table I, below, describes a series of 9 a,lla-epoxy-steroidal compounds which may be used in the combination therapy. These epoxy steroids may be prepared by procedures described in U.S. Patent No.

4,559,332 to Grob et al issued 17 December 1985.

S. 9*4 0 0** 0** ~0 ~0 .0 00 0. Do 0* TABLE I: Aldosterone Receptor Antagonist Compound #I Structure Name Pregn-4-ene-7,21-dicarboxylic acid, 9 ,11-epoxyl 7 -hydroxy-3-oxo-,y-lactone, methyl ester, 11. 17(x) Pregn-4-ene-7,21-djcarboxylic acid, 9,11-epoxyl 7 -hydroxy-3-oxo-dimethyl ester, (7Qx,11h, 17x) TABLE I: Aldosterone Receptor Antagonist Compound ff Structure Name 3 'H-cyclopropa[6,7] pregna-4,6-diene-21carboxylic acid, 9 ,11-epoxy-6,7-dihydro-17hydroxy-3-oxo-,y-lactone, (613,73,1113,17f3)- Pregii-4-ene-7,21-dicarboxylic acid,9,11epoxy-l 7 -hydroxy-3-oxo-7.(lmethylethyl) ester, monopotassium salt, 7 a,lla,17a)- 0 0 0 0e 0** 0 *0 **0 0 0 0 0* 00 0 TABLE

I:

Aldosterone Receptor Antagonist Compound

#I

Structure Na me Preg-4-ne-,21-icaboxlicacid, 9 ,ll,-epoxyl 7 -hydroxy-3-oxo-7methyl ester, monopotassium salt, (7a,lla,17a)- 3 'H-cyclopropa[6,7]pregna14,6triene-21 carboxylic acid, 9 ,ll-epoxy-6,7-dihydro-17hyrx--x-glcoe6,al~) .0.

0 S. 0 0 0 000 S *0

I

*000 0 000 000 0 0 S 00 000 00 0 00 0.00 0 000 00 000 0 0 0 0 00 00 0 *0 TABLE I: Aldosterone Receptor Antagonist Compound 11 Structure Name acid, 9 ,ll-epoxy-6,7-dihydro-17.hydroxy-3-oxomethyl ester, 6 a,7a,lla,17a)acid, 9 ,ll-epoxy-6,7-dihydro-17hydroy-.oxomonopotassium salt, 6 a,7a,lla,17a)- 0* 9Oe 0 0** 0** 0** 0** *e 0: '0 00 0 o 0f** TABLE

I:

Aldosterone Receptor Antagonist Compound If Structure Name acid, 9 ,ll-epoxy-67-dihydro17hydroxy3oxo-,glactone, 6 a,7a,lla.,17a)- Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxyl 7 -hydroxy-3-oxo-,g.1actone, ethyl ester, (7a, 11a, 17a) 0 TABLE I: Aldosterone Receptor Antagonist Compound Structure Name P r e g -4 n e 2 1 i c a b o x l i c a c i d 9 1 1 e p o x y 17hdoy3ox-glcoe l-methylethyl ester, 7 a, lla, 17a) C-28i 17 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-alkvl moiety, or a mono-heteroaryl-alkyl moiety, or a biheteroaryl-alkyl moiety. A second portion constitutes a heterocyclic moiety or an open chain hetero-atom-containing moiety.

Typically, the first-portion mono/biaryl/heteroaryl-alkyl moiety is attached to the second portion heterocyclic/open-chain moiety through the alkyl group of the mono/bi-aryl/heterdaryl-alkyl moiety to any substitutable position on the heterocyclic/open-chain moiety second portion. Suitable first-portion mono/biaryl/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)

25 Ar-L-Het-Alk-L Het-L-Alk-L wherein the abbreviated notation used in the moieties of Formula I is defined as follows: "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".

"Het" means a monocyclic or bicyclic fused ring C-2819 18 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.

"Alk" means an alkyl radical or alkylene chain, linear or branched, containing from one to about five carbon atoms. Typically, "Alk" means "methylene", -CH2-.

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

15 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: C-2819 19

X

wherein each of X 1 through X 6 is selected from -CR2-, too 1 5 0, and S, with the proviso that at least one of X1 through X 6 in each of Formula ha and Formula hIb must be too a hetero atom. The heterocyclic moiety of Formula Iha or hIb may be attached through a bond from any ring member of the Formula Iha or hIb heterocyclic moiety having a substitutable or a bond-forming position.

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

Examples of bicyclic heterocyclic moieties of Formula IIb include benzolb]thienyl, isobenzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, thieno[2,3-blfuranyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d[1,2]oxazinyl, 1H-pyrazolol4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, cyclopenta[b]pyranyl, 4 H-[1,3]oxathiolo-[5,4-b]pyrrolyl, 0:06 Ge "thienol2,3-b]furanyl, imidazo[l,2-b] l,2,4itriazinyl and *0O6 00 S 15 4 H-1,3-dioxolo[4,5-dlimidazolyl.

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 55*5 S20 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:

25 -UnA

(III)

a oe 00 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.

The phrase "acidic group selected to contain at least one acidic hydrogen atom", as used to define the -UnA C-2819 21 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 protonreceiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I-IIa/b has a pKa in a range from about one to about twelve. More typically, the Formula I-IIa/b compound would have a pKa in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is Scarboxyl group (-COOH). Where n is zero and A is -COOH, in 15 the -UnA moiety, such carboxyl group would be attached directly to one of the Formula I-IIa/b positions. The Formula I-IIa/b compound may have one -UnA moiety attached at one of the Formula I-IIa/b positions, or may have a plurality of such -UnA moieties attached at more than one of the Formula I-IIa/b positions. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as "bioisosteres of carboxylic acid" or referred to as "acidic 25 bioisosteres". Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I-IIa/b may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I-IIa/b compound as conferred by the -UnA moiety be in a range from about two to about seven. The -UnA moiety may be attached to one of the Formula I-IIa/b positions through any portion of the -UnA moiety which results in a Formula I-IIa/b compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the -UnA acid moiety is tetrazole, the tetrazole is typically attached at C-2S19 22 the tetrazole ring carbon atom.

For any of the moieties embraced by Formula I and Formula II, such moieties may be substituted at any substitutable position by one or more radicals selected from hydrido, hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, i haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, 15 arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula W 2

W

-C-R1 -N and -NC-R 4 R3

*K

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

/R

7

-N

R8 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

R

9 W R1 W -N II/ II Rl0 -CN and -NC-R 13 R12

I

R14 wherein W is oxygen atom or sulfur atom; wherein each of R 9

R

10 RlI, 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 0" 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 20 unsaturated; wherein each of R2 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.

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 C-2819 24 therapy may be used in combination with other drugs, such as a diuretic, to aid in treatment of hypertension.

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.

9 9 *oo*oo C-2819 TABLE II: Angiotensin II Antagonists Compound Structure

CH

2 S C0 2

CH

3 Source zub. :4 9, *e

CH

2 coij.

WO t 91/17148 pub. 14 Nov 91 ,4 ~9 1/17 14 8 pub. 14d Nov 91 N- N

SN

H

C-2819 26 TABLE 11: Angiotensin II Antagonists Compound Structure Source

CH

2

CN-NH

2 a. a.

a a

N

C"

2 %j0

C--NS-F

NI A11 WO T9 1 17148 Pub-. 114 Nov 91 WO~-0#2/_1 7148 Pub. -4 N'\ov 91 a a.

a a.

a.

a

CI

N-

CM

2 C0 2

H

C-2819 27 TABLE II: Angiotensin II Antagonists Compound Structure Source

CI

CH.

N- N

N

NH

NN

CH

2 N C

IIL

pub. 4 N~v '4 '1/74 pab. 14 Nqov 91 WO "191/17148 Pub. 14 LNIOV 91 C-2819 28 TABLE 11: Angiotensin II Antagonists Compound Structure Source F

F

N-

~N~N N

CH,

N- N N. H 77 "0 7148 pub. -4 Nov 91 WO '191/17148 Pub. 2.4 Nov 91

A.

S

N

WO -"91/17148 pub. 14 Nov 9j.

*N

H

C-2819 29 TABLE 13:: Angiotensin II Antagonists Compound Structure Source N

CH

2

N-N

N

CHH

N--

N-

N

H

WO '191/17148 Pub* 14 Nov 91 *9 WO "-91/17148 Pub. 14 Nov 91 C-28619 TABLE II: Angiotenisin II Antagonists Compound Structure

N

Source Pun. A Nov 91

S

*5

S

S.

S

N

5*

S

5 0

N-

.'N

H

pub. ':-9Nov714 Pub. 1-4 Nov 91 C -2 819 31 TAB3LE 11: Angiotensin II Antagonists Compound

IQ

Structure Source '191/2.7148 PU..b :4 Nov 91 *WO ";91/17148 Pub. 14 Nov 91

N'

N'A

N' H 110 ="91/17148 pub. 14 Nov 91 C- 2 819 32 TABLE II: Angiotensin II Antagonists Compound Structure Source N- N

~N"

H

PUM. 4 N~ov 91 9 9e *9 9

N-

CH3C)

I

N,

N

WO 91/17148 Pub- 1.4 Nov 9.1 OCH3

N

1

H

WO :-91/17148 Pub. 14 Nov 91 C-2819 .33 TABLE II: Angiotensin II Antagonists Compound Structure Source N

N

NO

a 4* a ub* 91,/17148 Nov 01 '1o '191/17148 pub. 14 Nov 91 N IN

'H

a a.

*c

NN"

N

H

.10 091/17148 pub. 14 Nov 91 34 TABLE II: Angiotensin II Antagonists Compound Structure Source J rl

N

N- N

N

H

pub. -4 Nov 91 0 000* *000 0000 0 00 0 0

N

N. N

N/

H

WO "91/17148 pub. 74 Nov 91 *000 00 0 0 WO ;91/1148 pub. 14 Nov 91 C-2 819 TABLE 11: Angiotensin II Antagonists Compound 31 Structure Source 790 =91/17148 pub. 'Tv9

H

S

0**O 0O*O 0*S* be SS 0

C

SCO

0* SC S S

C

0@ 0 S

S

6600

S

0096

N

WO "91/17148 publ. 14 Nov 91

S

@500

SS

S

0@ lk

N

V

Wa#9/114 Pubh. 14 Nov 91 C-2819 36 TABLE II: Angiotensin II Antagonists Compound Structure Source* 0*

N

H

"qO 1/17148 pub. .4 Nov 91 WO 91/17148 pub. 14 Nov 91 0 NN

H

N

'N H

N-

N N-N N N N H WO :91/17148 pub. 14 Nov 91 C-28619 TABLE 11: Angioterisin II Antagonists Compound Structure Source Pun. 1 Nov 9j.

a a.

pub.91148v9 pub. 14 Nov 91 TABLE 11: Angiotensin II Antagonists Compound Structure Source

N

1 -7 p14 8 PU.D4 NOV 9 0 Pub. 1.4 Nov 91

-N

N

H

WO :-91/-17148 pub. 14 Nov 91

H

C-2 819 9* 39 TABLE 11: Angiotensin II Antagonists Compound 4 3 Structure Source ;1 "1/17148 Pub. 14 'I\OV 0, WJO '"91/17148 Pub. 14 Nov '91 'I91/17148 Pub. 124 Nov 91 44

H

C-2819 TABLE II: Angioterisin II Antagonists Compound 4 6 47 Structure Source

N"'

Pub. *4 Nqov 91

H

0 0.

0 09

F

Pub. 14 Nov 91 WO #91/17148 Pub. 14 Nov 91 41.

TABLE 11: Angiotensin II Antagonists Compound Structure Source 0 t -N N. 4H ~4Nov 91 pub 14 Nov 914 pu. 114 Nov 91 C-28619 42 TABLE II: Angiotensin II Antagonists Compound 7- Structure Source 0 N9 N' N I I

H

pub. 4 ovC 4*44 .4 4 4* 4 4 44 4 WO '19117148 pub. 14 Nov 91 WO #91/1 7148 pub. 14 Nov 91

N

C-2819 43 TABLE 11: Angiotensin II Antagonists Compound Structure Source

N

H

p:ub. -4 N ov 91

S

S S

S

S.

S

55*5

S

SS

S

WO 191/17148 Pub. 14 Nov 91

NN-

N

Pub. 14 Nov 91 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure '140 N H pu

N-N

N

H

59 N OON pub

N-N

NN

0 ource :91/17148 14 Nov 91 91/17148 14 Nov 91 F Nc, cub.

C-isi TABLE 1I: Angiotensin II Antagonists Compound Structure Source 9 .9 9 9 9.

9 9.

99 00 4000 00 N

N

NN

H

N-N

'N H 0 WO ;-1/7714 pun. 14 Nov 91 pub. :1 N.ov 91 WO "91/17148 pub. 14 Nov 91 WO 'Tr'9/17148 pub. 14 INov 91 C-2819 46 TABLE 11: Angiotensin II Antagonists Compound Structure Source 0

HO

WO 91/:!7148 pub. -A NOV 91 WqO :!91/17148 Puib- 14 Nov 91 6* 0

S

S. *S S S

S

S.

S S *5O 0

CH

2

N

N.

H

OS

0 0 *0 *554 54.5 5S S S 5S WO 'ru91/17148 Pub. 14 Nov 91 C-2 819 47 TABLE 11: Angiotensin II Antagonists Compound Structure Source

HN

N

N'

N

0

NHH

N'

N-N

N

H

C

2

FS

-f-91/17148 pub. :A Nov 91 WO ;.91/17148 pub. 14 Nov 91 WO '#91/17148 Pub. 1.4 Nov 91 N- N N'

N

I-

H

48 TABLE II: Angiotensin II Antagonists Compound Structure Source N-

C

3 F7(n)

N

O #9/,7148 pub. 14 Nov 91 '40 #91/17148 Pub. 14 Nov 91

N--

NK2 N eN

I

C-2819 49 TAB3LE 11: Angiotensin II Antagonists Compound 73 Structure Source

N

pun. LA Nov 91

H

a 0 a

ICH

2 Wa7 "91/17148 Pub. 1-4 Nov 91 WO -91/17148 Pub. 14 Nov 91

N'

CH

2

CO

2

H

C-2819 TABLE II: Aig iotensin II Antagonists Compound I Structure Source

NJN

CH2, S C0 2

H

40O '/1714 8 cpub. o

S.

S

N

CH

2

SCO

2

H

WO0 4#91/1714a Pub. 14 Nov 91

S

S.

S S

S.

C -28919 TABLE 11: Angiotensin II Antagonists Compound Structure Source

NO

2 0 'go "91/18888 pub.

WO #91/18888 pub WO '#91/18888 pub.

YI

0 Big 52 TAB3LE II: Angiotensin Il Antagonists Compound Structure Source N" Ph

N

CH,

:qo ;11/18888 wa #91/18888 Pub.

#-91/18888 pub.

NN

W Ri F C-2819 53 TABLE II: Argiotensin II Antagonists Compound I- Structure Source a a.

a N- H 0

CH

2 0

N-N

N- N--C0 2

CH

2 0

N-NH

0

N,

I'r

ON

WO "91/18888 pub.

WO #91118888 pub.

WO #91/18888 pub.

C-2619 54 TABLE 11: Angiotensjn II Antagonists Compound Structure Source N- N"NC02H CH 2 Wa 91/18888 pub.

,P

a.

a. a. a.

*o a a.

a a a 9 a a.

a a.

Wa 9/88 pub.

wa 91/18g888 pub.

N

CH 2 N-N0H TABLE 11: Angiotenrsin 11 Antagonists Compound Structure Source

CH,

WO §91/18888 H pub.

N

a.

A.

A

0 OPh

C

2

N

C H 2 WO r#91/18888 pub.

A A

A.

A

A..

A.

wa 91/18888 pub.

N-M-

H

f.i TABLE II: Angiotensin II Antagonists Compound 93 Structure Source pub.

NH

Cs e.g.

C. 5 5

C.

S

Ph N- N l Ph 00

N

I

wo 9/88 pub.

C C 55

C

S*

0 N~N~A~0 WO M91/18888 pub.

N

C-281g 57 TABLE 11: Arigiotensin II Antagonists Compound 96 Structure Source r~o -F0= -8 pub.

9 9999 9999 99 9.

9 9 9 .9 9 9 9 9 9 9 99 9 9 .9 999.

9 99 9. 9 99 999999

CH

2 0

H

N-N0 0 )0 04 tnl pub .91/18888 *wo F1/18888 pub.

TABLE 11: Angiotensin II Antagonists Compound Structure Source

N~

Wo 91/18888 Pub.

N- Wir

CO

2

CH

3 N 11 1 100 WO0 "91/18888 Pub.

be 101 WO -7791/18888 Pub.

C-2 819 TABLE 11: Compound Angiotensin 11 Antagonists Structure Source 102

CH

2 Wa0 '191/18888 Pub.

n.e C. CC C C

C

CC

C C

C

CC..

C

*C

C C

S*

CCC.

C

CC..

C C

CCC...

C

103 N-N

H

SN

Wa0 91/18888 Pub.

WO 1188 Pub.

104

N

C-2 819 TABLE II: Angiotensin II Antagonists Compound i0s Structure ;:h Source Pub.

*fl.

0 *0e 0 *0*0 0 0

S.

0 *0 0 0

S.

~00O@* 0 106 '0

C

II CH 2 Pub.-

N-

N 0Ph ~COE

N

2.07 WO gl/8888 Puba.

N-

N"H

N',

C--2 819 61 TABLE II: Angiotensin II Antagonists Compound '108 Structure Source '170 =O1/19715 Pub. 2-6 Dec 91 *see 0O 109 0-)H WO .91/19715 Pub. 26 Dec 91 WO 91/19715 Pub. 26 Dec 91 110 N N 62 TABLE 11: Angiotensin II Antagonists Compound Structure source

OH

Oil NN ill Pu- 10 Dec 91 0* 112

N

O 2

H

5

N=N

NH

WO #91/19715 Pub. 26 Dec 91 WaO 'I91/19715 Pub. 26 Dec 91 113 C-2819 63 TABLE II: Angioterjsjn II Antagonists Compound 114 Structure Source nC 4 Ha"

C..

Pub, 26 Dec 91

NH

N

flC4H. 11.5

N-N

H

Wo '=91/19715 pub 26 Dec 91 wa #91/19715 Pub. 26 Dec 91 nl-C 4

H

116

N-N

11 C-2819g 64 TABL E 11: Angiotensin II Antagonists Compound 117 Structure Source ~91/71,5 Pub. 26 Dec 91 flCfl

N-N

9 9 9 9 118 nN r WO ;E1/19715 pub. 26 Dec 91 0

'C-C{(CH

3 2 119

N

flC4H 9 WO E91/1971.

Pub. 26 Dec 91 -TABLE II: Angiotensjn 11 Antagonists Compound 120 Structure flC 4i Ha( Source Pub. 26 Dec 9o.

9 a a 0* a.

a

S

OH

O-CC (CH 3 3 I~YJO0 121 WO 911/19715 Pub. 2-6 Dec 91 a C-C (CH 3 3 122 wo 1/ 75 pub. 26 Dec a1

N-N

H

TABLE 11: Arigiotensin II Antagonists Compound 123 Structure Source 0 nC 4 H

(CH.)

r/1 9715 Pubo 26' Dec 91 4 a a a a a.

a a.

4 a.

124

N

Pub. 26 Dec 91 Pub. 26 Dec 91 125 TABLE 11: Compound 126 Angiotensin II Antagonists Structure Source pi jH- C07H Waq '-;92105161 pub.* 2 Apr 92

S..

S.

S S

S.

0 S S

S

127 WO #792/56 Pub.- 2 A-pr 92 WO -9/56 Pub. 2 A-pr 92 128 68 TABLE 11: Angiotensin Il Antagonists Compound 129 Structure Source wo"192/105161 Pub. 2 ApOr 92 R-i 0* 130

N_

N-!q I

N

Pub.- 2 Apr 92 .9 9* 131 yN~Q N~ N Cli,

N-N

I

N

I

Ii Pub. 2 Apr 92 C-2819 69 TABLE II: Angiotensin II Antagonists Compound Structure Source N 0 132

N

N- N 0 N H

N'N

I N N h' WO 192/07834 pub. 14 May 92 WO 192/07834 pub. 14 May 92 133 134 N 0

N-N

N HN

N

WO :92/07834 pub. 14 May 92 C -2 8 1 TABLE 11: Angiotensjn II Antagonists Compound 135 Structure Source NC 0

CH?

11O 492/07834 Pub, -14 IMaY 92 oat.

0 00 09..*9 N 0 C1 2.36 N- N it to 137 N 0 1CH, WO 92/07834 Pub* 14 MIav 92 WO IF92/07834 Pub. 14 MaY 92 C-2819 71 TABLE II: Angiotensin II Antagonists Compound Structure Source 138

N-N

pO "a92/07834 Pub- 14 May 92 139

N~N

N.

WO *92/11255 pub. 9 Jul 92 WO *f92/11255 pub. 9 Jul 92 *r 140 72 TABLE II: Angiotensjn II Antagonists Compound '41 Structure

N

Source -:2/11255 Pub. 3 jul 921 9* 142

N.

N

Cl WO 492/11255 pub. 9 Jul 92 WO #92/11255 pub. 9 Jul 92 000* 00 0 000000 0 143 C-2 819 73 TABLE II: Angiotens in II Antagonists Compound 144 Structure Source

N..

pub. z Jul 92 CF3 9 9 9.

9 9 999 9 9* 9 9* 145 wa -;92/11255 Pub. 90 Jul 92 '1792/1125.5 Pub. 9 Jul 92 9* 9 9 *9 999999 9 146

F

C-2819 TABLE 11: Angiotensin II Antagonists Compound Structure Source c 4 -4 ~q Cl 1.47 '110 492/15377 pub. 27 Sep 92 WO #t92/15577 Pub. 17 Sep) 92 148 N Cl nC 4 H:4 N Hq O 0 0 CH,Ohj IC1 149 WO -492/15577 Pub. 1-7 Sep) 92 2819 TABLE 11: Angiotensin II Anitagonists Compound Structure Source 150

N.

N-N

I

I i~r WO ;-9/62 Pub. 1 Oct 92

S.

5

S.

CH.)

151 WO #:92/16523 Pub. 1 Oct 92 WO #92/16523 pub. 1 Oct 92 152

Y

I

N

C-28 1 9 TABLE II: Angiotensin II Antagonists Compound Structure Source 153

N-N

N'

WO192/ 1 6 5 2 3 pub. Oct 92 *000 5@ 5* 0 0 0

S.

S

@500 0

S

N N N.N~ N 154

N\

H

WO =92/16523 pub. 1 Oct 92 N N 155

N

H

WO 92/16523 pub. 1 Oct 92 C-2 819 77 TABLE 11: Angiotensin II Antagonists Compound i56 Structure Source

CI-

WO =92/16523 Pub. 1 Oct 92 4 7 157 WO #92/16,523 Pub. 1I Oct 92 Ci.

158 WO -r9/62 Pub- 1. Oct. 92 -TABLE II: Angiotensjin II Antagonists -Structure Source Compound Oh..

4~ 1.

159 NUo 992116523 Pub. 1 Oct 92 9 9.

9 9@ 9 9 99 0 SO0 WO #92116523 Pub. 1 Oct 92 y 161 wo 092/16523 Pub. I. Oct 92 TABLE 11: Angiotens in Il Antagonists Comnpound ure Source 2.62 WO "::_2/10523 Pl.b Oct 92

N

H

9 a 163

II-

N-bN a.

a a.

WO"92116523 Pub. 1 Oct 92 "0 E92/16,523 Pub. 1 Oct 92 164 C-28 1 9 TABLE I: Angiotensin II Antagonists Compound Structure Source

CHI

150 i92/16523 pun. 1 Oct 92

NT

NNN'b

F

16 y" C:I7WO "92/16523 6 0 00 000.9 .ub 0 ct F F 167 6 YCH wO =92/16523 pub. 1 Oct 92

NN

N-

00' 0 0 00 C-2819 81 TABLE II: Argiotensin II Antagonists Compound 168 Structure Source

N

N-N

N

NJ H AiO F92/16523 pub. 1 Oct 92 a a.

9 a.

4* a a

F

N~

I~c 169 WO"92/16523 pub. 1 Oct 92

N

FF

NyN 170 WO ;92/16523 pub. 1 Oct 92

N-N

TABLE 11: Angiotensin II Antagonists Compound _;5t 1,-u-

C

ource 0

N-

C%'H7 171 qo :l92/16523 pub. 1 Oct 92

N-N

I,

S

S.

5 0

SS

OSSO

a 0050 0 0 N- e

H

HI

172 WO 2/16523 Pub. 1 Oct 92

CH

2 173 WO '*9/62 Pub. 1 Oct 92 2819 83 TABLE 11: Angiotensin II Antagonists Compound Structure Source -74

NNN

N.N

H

WO =*:92/16523 pub. 2. Oct 92

OCHI

OCH3 N AN pub. 2 01ct 22 H-t

OC,H:

0C 2

H

5 s Y 170 WO #u92/16523 Pub. 1 Oct 92 C-28 1 9 84 TABLE II: Angiotensin II Antagonists Compound

C--

Structure Source CHR3 177 '9 !;O'2/62 Pub- 1 Oct 92 9* S. S S. S S

S

S.

0CM (CH- 3 2 OCR (CM- 3 2 178 WO~ "r92/16523 pub. 1 Oct 92

S

SS

S

SS

S S

*S

<CHO

179

N-N

I/

N

H

WO -02/16523 Pub. Oct 92 C-2i 89 TABLE 11: Angiotensin II Antagonists Compound 180 Structure Source N%~Ny

N*

v7O 79/62 pub. 1 Oct 92 Cl1 3 181 WOA*i9/62 Pub. 1 Oct 92 N-

N'

C"1 3 0OCZ1 182 WO '492/152 Pub. 1 Oct 92 C-2819 TABLE I: Angiotensin II Antagonists Compound Structure Source 9112 183 WO 92/16523 pub. Oct 92 N- N

II

*0

S

CR

2 H2 184

N

WO #92/16523 pub. I Oct 92 WO #92/17469 pub. 15 Oct 92 185 N 0 CH2

N-N

N

-2819 87 TABLE II: Angiotensin II Antagonists Compound Structure Source 186

N

N-N1

N'"

N~ H WO '1192/17469 pub. 15 Oct 92 a. .a a a.

a a.

a. a a.

N 0o 187 WO ;92/17469 pub. 15 Oct 92

H

N0

CH-,

N

N-N

N H 188 WO =92/17469 pub. 15 Oct 92 TABLE II: Angiotensin II Antagonists Compound ur eLU~ Source N

C

189 N 0 190 WO -92/17469 pub. 1 Oct 92 WO T'-92/17469 Pub 15 Oct 92 WO #92/17469 pub- 15 Oct 92 00 9 N 0 1E 191

N-N

TABLE 11: Angiotensin II Anitagonists Compound Structure Source 192

H

tiO Dub. 2.5 Oct 92 t.* 0:*0*

N/

193 WO B92/17469 Pub..15. Oct 92 WO r--92/17469 Pub. 15 Oct 92 N 0 194 TABLE 11: Angiotensin II Antagonists Compound Structure Source 1,01 CH-) w o Dub.

N-

N, 0

CH

196

PU

CHI

19 N N 2 N' b 91.

TABLE 11: Angiotensin II Antagonists Compound 198 Structure N0 Source WO :".92/17469 pulb. 15 Oct 92 9 *9

JOG

N-N

N0

CI

N 0 WO 7-92/17460 pub. 15 Oct'92 wa 1192/17469 Pub. 15 Oct 92 200 TABLE 11: Angiotensin II Antagonists Compound Structure Source 201 2010 'O1192/17469 pub. 15 Oct 92

N-N

I

A

N

202 WO #92/17469 pub. 15 Oct 92

N-N

H

N 0

N

ON

H

203 WO *!92/17469 pub. 15 Oct 92 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source 204 a a. a CHa 2

N

LIT

N-

N 0

NN

N-N

N

205 WO #i92/17469 pub. 5 Oct 92 WO "92/17469 pub. 15 Oct 92 WO #92/17469 pub. 15 Oct 92 a 206 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source N'0D 2:07 WO #192/17469 Pub. 15 Oct 92 N-bl 'Ir

*:I

208

N-

wa t 92/17469 pub. 125 Oct 92 4%

S.

N>~O

CE,

-4%

N-N

1 .3 209 Wal~ #92 /1 746!9 92 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source 210

S

*6

N-N

qlNN

N-N

H

'140 2 17469 pub. 15 Oct 92 211 r7 92/17469 pub. 15 Oct 92

NN-N

N

212 WO 92/17469 pub. 15 Oct 92 C-2819 96 TABLE 11: Angiotensin II Antagonists Compound Structure Source 233 0 0*0* 0 0* 0 N 0

IHO

N- N

NNN

NL

WO '-.-92/17469 Pub. 15 Oct 92 #92/17469 Cub. 15 Oct 92 214 .0 0 215 N 0 N- N WO #92/17469 Pub. 1.5 Oct 92 C-2 819 97 TABLE 11: Angiotensin II Antagonists Compound 216 Structure Source

N

IC

-K

WO -;92/17469 Pub. !5 Oct 92 0* 217

NN

N- N

I

N

92/17469 pub. 2.5 Oct 92 p p p N I~O

OCH,

CH

2

I

218 WO 9/76 Pub. 15 Oct 92 C-2 819 TABLE 11: Angiotensin II Antagonists Compound Structure Source 2 19 S. S S. S

S.

S

S.

*SSS

S

S S .N 0

CH{

2

I

N H

ICHI

U-N

N

WO 92/17469 Oct 92 220 WO 92/17469 Dub. 15 Oct 92 22 1 WO "92/17469 pub. 15 Oct 92 C-2 819 99 TABLE II: Angiotensin II Antagonists Compound 222 Structure Source N 0 WO "792/17469 pub. Oct 92

IN

N

223 N 0

N

N H WO #92/17469 pub. 2.5 Oct 92 N 0

N-N

NI

N

224 WO =-:92/17469 Pub. 15 Oct 92 C-2819 100 TABLE II: Arigiotensin II Antagonists Compound Structure Source 225

N

HH

N'N

N-

NI

7KO "-92/17469 Pub- 15 Oct 92 WO #92/17469 pub. 15 Oct 92 @0 0 000 0 0 0 00 0 0000 000000 226 227

N

N> 0

CH

2

N'N

N-

WO #92/17469 Pub. 15 Oct 92 C-2819 101 TABLE II: Angiotensin II Antagonists StructureC Compound ource 228

II

N

N-

a..

229

N

230

H

3

CO

N Ik,0

OCM

3 4 CM1 2

NNN

C-2819 102 TABLE II: Angiotensin II Antagonists Compound Structure Source

C'

Ni

I

SC

C

.RC.

C. CR S C

C

C.

C

C.

C C

C.

C

C C S RC

C

232 233

N-N

N

C-2 819 103 TABLE 11: Angiotensii II Antagonists Compound -Structure Source 234

IN

N-N

066 609 0*S0 *236 C-2 819 104 TABLE 11: Angioterisin II Antagonists Compound Structure Source

NT

237CH

CH-)

H

N

H

N

OKN

CH

2 238 *N-N W 9/89 *N Z.I T .C-2819 105 TABLE II: Angiotensin II Antagonists Structure Source Compound 240

CH,

SCN

C0 H WO =92/18092 pub. 29 Oct 92 A. A

A

A A

N

241 WO #92/18092 Pub. 29 Oct 92

A

N.N

N-N

H H 242 WO #92/18092 pub. 29 Oct 92 C-2819 106 TABLE II: Angiotensin II Antagonists Compound Structure Source

N

CH.:

N' N N H 243 W0 792/18092 PUD. 29 Oct 92 9S 9

N'

244 WO -92/18092 Pub. 29 Oct 92 245

N

CH2 N -N N H WO =92/18092 pub. 29 Oct 92 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source

N

246 71.92/18092 Pub- 29 Oct 92

N

a a a a.

a a N'

N

I

H

247 WO 2/8 2 pub. 29 Oct 92 248 WO '#92/18092 pub. 29 Oct 92 C-2819 108 TABLE 11: Angiotensin II Antagonists Compound Structure Source

N

249 ;O 92/18092 Pub. 29 Oct 902 N-q

'I"

N

S.

S

S.

S S 555 S e

S

S S 5SSS

*SSS

250

IN

C F- 2 N- M

H

'40 T#92/18092 pub. 29 Oct 92 251 WO -r92/18092 pub. 290 Oct 902 C-2819 109 TABLE 11: Angiotensin II Antagonists Compound Structure Source

'I

252 NT D

H

WO #9/89 Pub. 29 Oct 92 a a a a a.

a a. a.

a.

a a.

N

253 WO ':9/89 Pub. 29 Oct 92 N- u

N-N~

N.

N

I

CE,

254 WO 1 92/18092 Pub. 29 Oct 92 C-28619 110 TABLE 11: Angiotensin II Antagonists Compound Structure Source 255

N-N

HIC

IN

0 CEj 2 WaO 92/18092 Pub. 29 Oct 92 WO :E92/18092 pub. 29 Oct 92 256 257 0

HI

NlN-

N

I

N-

WO '-.92/18092 Pub. 29 Oct 92 TABLE 11: Angiotensin II Antagonists Compound Structure source

C

0 r 258 WO '#92/18092 nub. 29 Oct 92 M- N 2590 WO '#92/18092 pub. 29 Oct 92 0O

N-N

II

H

N.N

N-N

N

I

260 WO #92/18092 pub. 29 Oct 92 C-2819 112 TABLE II: Angiotensin II Antagonists Compound Structure Source

N

CH

261 :O792/180 9 2 pub. 29 Oct 92 WO #92/18092 pub. 29 Oct 92 0*

CH-N

262

N-N

N

H

263

N

CH

2

IH

N-N

N*

N

A/

WO 492/18092 pub. 29 Oct 92 C-28619 113 TABLE II-. Angioterisin II Antagonists Compound Structure

;CH)

Source WO 92/18092 pub. 29 Oct 92 264 9* 9 9. 99 9 9 0 9.

9 265 9.

9 9.

9 .9 0 .9

N-N

(1: WO '7792/18092 Pub. 29 Oct 92 'k*

N

li-N

N

266 WO #-92/18092 Pub. 29 Oct 92 C-2819 114- TABLE II: Angiotensin II Antagonists Compound Structure Source <i 267 268 C 1 N-

CHI

~N-N

CE,

N-N

NN

WO =92/18092 pub. 29 Oct 92 WO T92/18092 pub. 29 Oct 92 WO #92/18092 pub. 29 Oct 92 9O 269 -p

N

CE1 2

N-N

N

I

c-2819 115 Angiotensin II Antagonists TABLE II: Compound 270 Source Structure rXT

N

%%N

N-N

AH

N. K Wao *92/18092 pub. 29 Oct 92

CC..

be

C

C C

C

271 N- N

N

N'

PCT/US5/02156 filed 8 Mar 94

C

CC

C

C.

N

CE

2 272 PCT/US94/02156 filed 8 Mar 94 C-2 819 TABLE II: Angiotensin II Antagonists Compound Structure Source 273

S

S.

S

S.

S

HI~CO

N- N

I..C

HCC

CH,

N 0

NN

?CT,'1J594 /02156 filed 8 Mar 904 PCT?/US94/0 2 3 156 filed 8 Mar 94 274 275 N 0

NN

PCT/US94/0 2 1 5 6 filed 8 Mar 94 C-2 819 117 -TABLE 11: Angiotensin II Antagonists Compound Structure Source 276

OOS*

CS

S

S. 55 S S 0 65

S

COOS

C

tee.

*0SO

S

CS..

C.

5 S

S.

S

5*55 0S C S 55 0 6 277

NO

N 0 PCT/tJS94/ 0 2 1 5 6 filed 8 Mar 94 PCT/US94/0 2156 filed 8 Mar 94 PCT/US94/02 1 5 6 filed 8 Mar 94 278 C-2 819 -TABLE 11: Angiotensin II Antagonists Structure Source Compound 279 a. a a.

a a a a a a a

N

c 2 PCT/US94/021 5 6 filed 8 Mar. 94 WO #91/17148 pub. 14 Nov 91 280 C-2819 119 TABLE II: Angiotensin II Antagonists Compound Hl1 Structure Source 7EP1 =d5,:o06 Pub. 18 Mar 92

N

S. p

S

55.5 .555 S S 5* *5 282 28.3 WO ;-93/18035 Pub. 2.6 Sep 93 ,40 93/17628 Pub. Sep 93 Wa0 't93/17681 pub. 16 Sep 93 1 N,

N

284 HON HN N C-2 819 120 TABLE 11: Angiotensin II Antagonists Compound Structure Source 285 Pub. a NL\ov 9 2 9 9 9.

9 286

HCHC

EP L#535,463 pub. 07 Apr 93 pub.7 37,Akpr 93 287 C-2 819 121 TABLE II: Angiotensin II Antagonists Compound 288 Structure Source EP "539,713 pub. 05 May 93 0i~ 289 EP #542,059 pub. 1.9 May 93 EP *05 557,843 pub. 01 Sep 93

COOH

290

COOH

C-2819 122 -TABLE II: Angiotensin II Antagonists Compound 291 Structure Source 0

~C~L

EP 7563,70 pub. 06 Oct 103 a.

a a a a.

a a a.

a a a a 292 H 0 0 1/ 0 Nl EP #562,261 pub. 29 Sep 93 EP '#05 557,843 pub. 2.5 Sep 93 293 C-2819 123 .TABLE II: Angiotensin II Antagonis Compound Structure ;ts Source EP 560, 163.

Pub. 15 Sep 93 294 295 EP F564, 788 pub. 13 ODct 93 EP '-'565,986 pub. 20 Oct 93 296 C-2819 124 -TABLE 11: Angiotensin II Antagonists Compound -Structure source EP O#0, 569, 795 pub. 18 Nov 93 297 9 9 9 298 EP '"7,569,794 Pub.- 1-8 Nov 9 3 a H,C OR 299 EP -';O,578,002 pub. 12 Jan 94 C-2 819 125 -TABLE II: Angiotensin II Antagonists Compound 300 Structure

-C

Source EP '!:;581,003 Pub. 02 Feb 94 9. 9.

9 9 9 9.

9 9 9 9 9 9 .9 9 9.

9 9 9.

9 9 301

CH

2 EP #392,317 a H N N NPub. 17 Oct g0 CH3 a NK H.NANN 1 Cl coiic EP 392,317 pub. 17 Oct 302 C-2 819 126 TALE II: Angiotensjin II Antagonists Compound Structure Source 303 EP Tiu502,314 pub.) 09 Sep 92 304 EP #1468,740 Pub. 29 Jan 92 EP #470,543 pub. 12 Feb 92 305 looli C-2 819 127 T~kLE 11: Angiotensin II Antagonists Compound 306

LI,

Structure Source 7P ';502,-'14 Pun. 09 SeD 92 9**9 ~9 .9 9 *999 9. 9* 9 9 9 9 9 9 9999 9 9*99 9 9.99 9. 9 9.99 9 9.9.

99 99 999999 307 308 E P F"5 29, 23 Pub. 03 m~ar 93 pub. 20' may 93 E:P *552,76.5 Pub. 28 Jul 93 309 C-2 819 128 TABLE II: Angiotensin II Antagonists Compound Structure 0 310 0 311 6066@

C.

04 0* et 3ource P '-:555,825 ib. 18 Aug 93 #556, 789 D. 25 Aug 93 E560, 330 .15 Sep 93

EP

pu~

EP

pub.

312 C-2819 129 TABLE II: Angiotensin II Antagonists Compound -Structure Source 313 N I'- N EP56020 N Pub. 20 Oct 93 314 EP =-581,166 pub. 02 Feb 94 WO #94/01436 pub. 20 Jan 94 315 C-2819 130 -TABLE 11: Angiotensin II Antagonists Compound Structure Source EP 2 53, 310 Pub- 20 jan 88 316 N $p ~N~f to..

0 317 EP E324,377 pub. 2.9 Jul 89 318

U

9 S T-*5,043,3 49 41sued 27 Aug 91.

WO :!91/00281 Pub. 10 Jan 91 319 C-2B19 131 -TABLE II: Angiotensin II Antagonists Compound Structure Source I CIL H-C

N

320 L0 OY p~ub. 4~ ma N' N-H 321l N CO N-

C

2

H

(n)H7C3~ c N

/H

0

HO

F WO 'r 02/00977 **322 NPub. 23 Jan 92 a., 323 H-N N ClC0 2 H N_:N H2

C

4

H

9 q(n) C-2 819 132 TABLE II: Angiotensin II Antagonists Compound Structure Source N 0 324 01:'\S 0WO O' 0/0A94 Pub. 04 Mar 93 325 WO 793/10106 Pub. 27 May 93 us E5,219,856 Pub.' 5 Jun 93 326 *C-2819 133 TABLE II: Angiotensin II Antagonists Compound Structure Source US ';5,260,325 Pub. 09 Nov 93 327 328 US 7-5,264, 581 Pub. 23 Nov 93 EP #-400,974 pub. 05 Dec 329 C-2819 134 -TABLE II: Angiotensin II Antagonists Compound Structure Source 330 331 EP E411,766 Pub. 06 Feb 91.

EP~12, 59 4 pub. 1 3 Feb 91 EP #419,048 Pub. 27 Mar 91 332 C-2819 135 ~TABLE II: Angiotensin II Antagonisi Compound -Structure 333 334 335

NN

1 N 0

OH

0

F

Source '91/12,001 Pub. 2-2 Aug 91 ;a 91/11,999 pub. 22 Aug 91 Wa #91/11,909 pub. 22 Aug 91 336 WO '::91/12,002 Pub. 22 Aug 91 C-2819 136 TABLE 11: Angiotensin II Antagoni~ Compound Structure 337 338 3ts Source US '15,053,329 Pub. 01 Oct 92.

US 45,057,522 pub 15 Oct 91

S

339 WO E91/15,479 Pub. 17 Oct 91 C-2819 137 TABLE II: Angiotensii II Antagonist Compound Structure s Source EP *4 56, 5 pub. 13 Nov 92.

340 0O 341 EP 467,715 pub. 272 Jan 92 US =15,087,702 pub. 2.2 Feb 92 342 C-2819 .138 -TABLE II: Angiotensin II Antagonist Compound Structure Source EP :--479,479 Pub. 08 Apr 92 343 CH3 344 345 ED *L481,614 pub. 22 APr 92 C-2819 139 -TABLE 11: Angioterisin II Antagonists Compound 3146 Structure 0 Source EP 490,587 Pub. 17 Jun 92 0* 347 0e US 5,2,2 Pub. 07 Jul 92 US :75, '32,216 Pub. 21 Jul 92 348 C-2819 140 -TAkBLE 11: Angiotensin II Antagonists Compound -Structure Source N 349 EP 47-l Pub. 05 Aug 92

S

S.

S

S.

5

SS

S

S. S 55 350 EP #N'502,725 pub. 09 Sep 92 EP #,:502,575 pub. 09 Sep 92 351 C-2819 -141 TAkBLE 11: Angiotensin II Antagonists Compound Structure 352

EP

PUj ;ource .503, 838 b. 2 .Seip 92 9O 9* 9 9 9*9 353 9* 9* 9 9* 9 EP Pub. 23 Sep 92 E:P "505,098 pub. 23 Sep 92 354 C-2 819 142 -TABLE II: Angiotensin II Antagonists Compound Strucrtource 355 507,594 pun. 07 Oct 92 *0O@

SS

0@ S

S

SS S S

S

S.

S S

S

SL

S S *0

S

S*

S SO 356 EP :158,723 pub. 2-4 Oct 92 357

N-H

N

NN-OH

2

C

4 1- 9 (n) C-2819 143 Angiotensin II Antagonists -TABLE 11: Compound Structure Source 358 o EP -7512,675 Pub. L.I NTov 9 2 359 EP t 512,676 pub. .1 LVOV 92 EP '*512,870 Pub. -NOV 9 2 360 r

CF

F..C

HHC 0 C-2819 144 -TABLE 11: Angiotensjn II Antagonis Compound Structure *ts Source EP 1513,979 Pub. 19 NOV 92 361 9 362 0 cl 4 0 r9 2 2 0 6 6 0 Pub. 26 NOV 92 WaO "92,20,661 /Pub. 26 Nov 92 363 C-2819 145 TABLE II: Angioterisin II Antagonists Compound Structure Source 364 0

N

WAK" O>?S 1a '192/20,662 pub. 2I No 365 4* 9 Wa1 A#92/20,687 pub. 26 NOV 92 EP 7''-517,357 Pub. 09 Dec 92 366 HO N 0 C-2 819 146 TABLE II: Angiotensjn II Antagonists Compound Stucur

ID

;ource 367 0.

0 368 Pub. 21. Jan 93 Pub. 2.6 Feb 93 Pub- 30 Mar 93 369 C-2 819 147 T'ABLE 11: Angiotensjn II Antagonists Compound Structure Source 370 Tr ~5202,322 pub. 13 A-or 93 EP "r537, 93 pub. 21 A-pr 93 US #L5,217,882 Pub. 08 Jun 93 372 C-2 819 148 -TABLE II: Angiotensin II Antagonists Compound Structure Source

HO

Nl 3-73 US t;5,214,153 Pub- 25 May 93 Us #5218,125 pub. 08 Jun 93 374

LL%>

NH

375 US r#5,236,928 Pub. 17 Aug 93 C-2 819 149 TABLE 11: Angiotensin II Antagonists Compound uz e Source US #5240,938 Pub- ;1 Aug 93 376 37-7 GB #2 264,709 Pub. 08 Sep 93 GB #"2,264,710 Pub* 08 Sep 93 378 C-2 819 TABLE 11: COMPOund 379 150 Angioterin II Antagonists Structure Source 0 US 5,256 667 pub. 276 Oct 93 ::0:0 0 0 00 0 380 US 1;5,=25574 pub. 22 Oct 93 o 0

C

0 381 WO 4#93/23,399 Pub. 25 NOV 93 C-2819.

151 TABLE II: Angiotensin II Antagonists Compound l ure Source US z5,262,412 pub. 6 Nqov 93 382 383 US -a5 264,447 Pub- 23 NOV 93 384 us #L5,266,583 Pub- 01 Sep 92 C-2819 152 TABLE 11: Angiotensin II Antagonists Compound Structure Source 385 pub). 04 Jan 94

OH

S.

S*

S.

386

H,,

H,C

US '7l5,278,068 Pub. 11 Jan 94 C-2819 153 TABLE 11: Angiotensin II Antagonists Compound Lucture 387 Source Pub. 03 Feb 94 '1O :L-94/02467 Pub. 03 Feb 94 0 388 389 EP Ad 0 3,159 Pub. 19 Dec C -2 819 154 -TABLE IIT: Aflgiotenisin Il Antagonists Compound Structure Source EP #2 1 Pub. 1J2 lay 91 390 9* .9 9 *99* *9*9 .9 9.

9 9 9 9.

9 9 9 9 9 .9 9 9

B.

9 9 9 9.

9 9 391 ,Cooli EP "427, 463 Pub M5~ay 91 WO u02'06 Pub. 39 Jan 92 392 C-2819 155 -TIABLE II: Angiotens'n II Antagonists Compound Structure Source

OK

0 393 y S Nl_ C 394 *:me ease 00 0 0.0 4 ease a0000 be of see* 9099 so 00 Cl 0

O

So L:9202,510 Z:Uz- 20 Feb 92 WO '#92/09278 pub- 11 Jun 92 ;1 792/10181 pub- 25 Jun 92 395 396 Cl C02H N N-H

N-CH

C4Hn) C-2 819 156 TABLE IIT: Angiotensjin II Antagonists Copud#Structure Source cl CONH 2 397

NC

N N 0

C

2

H

5 S2F 39 N

*-H

3982 N

-CH

2 N. N C-2819 157 TA13LE 11: Angiotensin II Antagonists Compound Structure Source 400 N ,N

N-H

N-

H

5

C

2 I

CH

3 0

S

S S

S

*5*S

S.

S

401 0N

N-H

N-CH 2

C

4

H

9 (n) 402 N t 0-C 2

H

5

-C.N-

N' N C-2 819 158 TABLE 11: Angiotensin II Antagonists Compound Structure Source 3 pub. 25 Jun 92 0

CF

3 N z.N.

N -4C0 2 H N -H N. N CH 2

C

4

H

9 (n) 405 0 11

,C

5

NH-C-NH-CH

3 H0 2

C

N NNC-C

C

4 Hq 0 159 TABLE II: Angiotensin II Antagonists Compound Structure Source

N-N

406 a 407 WO -?-92/20651 pub. 26 NOV 92 WO 9/31 Ptub. 18 Feb 93 408 C-2 819 160 .TABLE II: Angiotensin II Antagonists Compound uc ture Source Weo =94100120 Pub. 06 Jan 94 409 a 410 EP TIl4591 Pub. 04 Dec 91 2P :1#4 11, 5 07 Pub. 05 Feb 91 411 cl C-2819 161 TABLE 11: Angiotensin II Antagonists Compound Structure

COXM

Source "P 425, 921 Pub. 08 May 91 412 413

CIL

0 N

NN

0

N

HN I

I

EP =430,300 pub. 05 Jun 91 EP :E434,038 pub. 26 Jun 91 414 162 TABLE 11: Angiotensjn II Antagonists Compound Structure Source H~c 415 E:P 'LLd42,473 Pub* 21 Aug 91

S

S.

S*

S

S S

S.

416 EP:E4,6 Pub. 28 Aug 91 EP #459,136 Pub. 04 Dec 91 477 C-2819 163 TABLE II: Angiotensin II Antagonists Compound 418 Structure Stru ureSource EP '483,683 Pub. 05 lMay 92 9999 9 9 9 9 9 9 9 9 9 99 *99999 419

RN

EP :"518, 033 pub. 16 Dec 92 EP ;520,423 Pub. 30 Dec 92 0 0 420 C-2819 164 TABLE II: Angiotens in II Antagonists Compound L- ure

X

Source pub. 16 Jun 93 421

COOH~

422 ,10 ii93/00341 pub. 07 Jan 93 WO #92/O6og1 Pub. 16 A-pr 92

HO

N a C7 c -2 8 1 165 TABLE 11: Angiotensin II Antagonists Compound ure Source *93/00341 pub. 07 Jan c 424 a.

a a a a a a.

a a a a.

a a 425 US ':71,210,20e4 pub. 11 IMaY 93 426 EP i 343, 654 pub. 29 Nov 89 C-2819 166 TABLE II: Angiotensin II Antagonist Compound Structure

S

Source Pub. 08 Jrul 93 427

OSSS

S.

S. S

S

*0 S S a

S.

5 09* S

F;

428 *5 S S

S.

S

0 WO0 #u93/15734 Pub. 19 Aug 93 US -5,246,943 Pub. 21 Sep 93 429 Fsc

-I

C-2819 167 The term "hydrido" denotes a single hydrogen atom 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

CH-

to form a group; or, as another example, two hydrido atoms may be attached to a carbon atom to form a -CH2- group. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The 15 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 20 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 168 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 carboncarbon 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 15 or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The "alkoxy" or "alkoxyalkyl" radicals may be further substi-tuted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term "alkylthio" embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. Preferred aryl groups are those consisting of one, two, or three benzene rings. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl and biphenyl. The term "aralkyl" embraces arylsubstituted 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", C-2819 169 "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 15 alkanoyl" is an example of a more prefered sub-class of S acyl. The term "amido" denotes a radical consisting of S 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 S. 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 25 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 C-2819 170 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.

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.

Also included in the combination of the invention 15 are the isomeric forms of the above-described angiotensin II Sreceptor compounds and the epoxy-steroidal aldosterone Sreceptor 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, 171 cyclohexylaminosulfonic, stearic, algenic, P-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with such compound.

ft 172 BIOLOGICAL EVALUATION Human congestive heart failure (CHF) is a complex condition usually initiated by vascular hypertension or a myocardial infarction In order 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 through the angiotensin II receptor antagonist profiles were determined for many of the compounds described in Table II, herein. In Assays and there are described methods for evaluating a combination therapy of the invention, namely, an angiotensin 15 II receptor antagonist of Table II and an epoxy-steroidal aldosterone receptor antagonist of Table I. The efficacy of the individual drugs, epoxymexrenone 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.

Assay A: Antiotensin II Bindina Activity 2Compounds 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 [Endocrinolocr, 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 173 centrifuged at 1500 x g for 20 min., and the supernatant was recentrifuged at 100,000 x g for 60 min. The pellet was resuspended in buffer consisting of 2 mM EDTA and 50 mM Tris-HC1 (pH 7.5) to a final protein concentration of 4 mg/ml. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgCl2, 2 mM EDTA, 0.5% bovine serum albumin, mM Tris-HC1, pH 7.5 and 125 I-AII (approximately 105 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 0 C for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter weie washed with ice-cold buffer. Filters were S* 15 assayed for radioactivity in a Micromedic gamma counter.

Nonspecific binding was defined as binding in the presence of 10 JM of unlabelled AII. Specific binding was calculated as total binding minus nonspecific binding. The receptor binding affinity of an AII antagonist compound was indicated by the concentration (IC50) of the tested AII antagonist which gives 50% displacement of the total specifically bound 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.

Assay B: In Vitro Vascular Smooth Muscle-Response for AII 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 0 C, between moveable and fixed ends of a 174 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 130 NaCl, NaHC03, 15 KC1, 1.2 NaH2P04, 1.2 MgS04, 2.5 CaC12, 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 X 10-1 0 to 1 X 10- 5 Each concentration of AII was allowed to elicit its maximal contraction, and then AII was washed out repeatedly for minutes before rechallenging with a higher concentration of AII. Aorta rings were exposed to the test antagonist at 5 M for 5 minutes before challenging with AII. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H.O. Schild [Br. J. Pharmacol. Chemother., Z,189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for AII by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table III.

Assay C: In Vivo Intracastric Pressor Assay Response for All Antagonists Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with methohexital (30 mg/kg, 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 175 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 ng/kg bolus via the venous catheter delivered in a 50 gl 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 15 bolus injections were given at 30, 45, 60, 75, 120, 150, and S. 180 minutes after gavage. The pressor response to AII was measured at each time point. The rats were then returned to 000 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] X 100. Results are shown in Table

III.

Assav Hvyertensive Rat Model 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, epoxymexrenone alone, and combinations of AII antagonist and epoxymexrenone at various doses: C-281 176 AII Antagonist (ma/ka/dav) 3 Epoxymexrenone (mo/ka/dav) 5 100 200 5 100 200 5 20 100 200 Combination of All Antagonist Epoxymexrenone (ma/ka/day) (mo/ka/day) 3 3 3 3 100 3 200 10 10 10 10 100 10 200 30 30 30 30 100 30 200

C

a.

0

C

a.

a 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 epoxymexrenone components, as compared to rats treated with either component alone, will show improvements in cardiac performance.

Assay Mvocardial Infarction Rat Model: 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 C-2819 177 animals have the suture passed through without ligation.

One week prior to the surgery, animals to undergo infarction are divided into separate groups and drug treatment is begun. Groups of animals are administered vehicle, AII antagonist alone, epoxymexrenone alone, and combinations of AII antagonist and epoxymexrenone, at various doses, as follow:

C

C.

C C AII Antagonist (m/kq/day) 3 30 Epoxymexrenone (mg/kq/day) 5 20 100 200 5 100 200 5 50 100 200 Combination of All Antagonist Epoxymexrenone (mq/ko/day) (ma/ka/dav) 3 3 3 3 100 3 200 10 10 10 10 100 10 200 30 30 30 30 100 30 200

C

CC

C.

After six 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 epoxymexrenone components, as compared to rats treated with either component alone, will show improvements in cardiac performance.

C -2819 178 TABLE III In Vivo and In Vitro Anajotensin II Activity of Comnounds of the invention Test lAssay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Example (nM) (ma/ko) M% (min.) 6%.

a a.

1 2 3 4 15 5 6 7 8 9 11 12 13 14 16 17 18 19

NT

95 5.4

NT

200 1300 84 17, 000 700 4.9 160 6.0 17 7.2 16 6.4 4.0 970 12,000

NT

7.37/7.59 8.70 0.2

NT

7.48/6.91 6.55/6.82 8.01/8.05

NT

6.67/6.12 8.19/7 .59 6.45/6.77 8.66/8. 59 8.70/8.85 8.84/8.71 8.31/8.30 8.95/9.24 8.64/8.40 6.14/6.09 5.18/5.35

NT

10 10 30

NT

30 100 30

NT

30 100 3 30

NT

95 98 50 100

NT

38 90 90

NT

80 100 86 100

NT

9 0-120 >180 200+

NT

20-3 0 120 130

NT

130 100 240

NT

179 Test lAssay A Assay B 3 Assay Compound IC 50 pA 2 Dose Inhibition Exampole 4 (riM) (ma/ko)M 0 *000 0 a 0* 0 20 21 22 23 24 25 26 27 28 29 15 30 31 32 33 34 35 36 37 38 39 25 40 41 42 43 44 45 46 78,000 87 460 430 10 480 3.2 180 570 160 22 14 16 630 640 41 1400 340 10 10 83 3700 370 19 16 4-4 110 5.89/5.99 7.71.7.21 6.60/6.46 6.48/7 .15 7.56/7.73 6.80/6.73 9.83/9.66

NT

5.57/6.00

NT

7.73/7 .88

NT

7.68/7.29 6.73/6.36 5.34/5.69 7 .25/7.47 5.92/5.68 6.90/6.85 7 .82 /8.3 6 7.88/7.84 7.94/7.61 5.68/5.96 6.56/6.26 8.97/8.61 8.23/7.70 8.41/8.24 6.80/6.64 100

NT

10

NT

30

NT

10

NT

50

NT

50

NT

C

Duration (min.)

NT

>180

NT

>180

NT

c-2819 180 Test lAssay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Examole (nM) (ma/ka) M% (min.) 0 00 00* 0*0.0* 47 48 49 51.

52 53 54 56 57 58 59 61 20 62 63 64 66 67 68 69 71 72 73 21 680 120 54 8.7 100 65 3100 80 5.0 2300 140 120 2200 110 26 61 54 23 12 3100 8.6 15 44 12,000 83 790 7 .85/7 .58 6.27/6.75 7 .06/7 .07 7.71/7.89 8.39/8.51 8.14/8 .12 7 .56/7 .83 6.-02 6.56/7 .13 9 .04/8 6.00 6 .45/6 .57 7.23/7 .59 6.40/6.03 7.29/7.70 8.69/8.61 7.77/7 .67 7.00/6.77 7.85/7.75 9 .34/8.58 5.88/5.78 8.19/8.65 7.80/8.28 7.71/8.05 6.11/6.10 7 .65/7 .46 C-2 819 Test lAssay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Exarnole (nl4) (rnQ/kc) M% (min.) foot V..o *see 4.000 0..

74 76 77 78 79 81 82 83 84 86 87 88 89 91 92 93 94 96 97 98 99 100 101 6.5 570 5400 15,000 101 4.9 25 18 7.9 3.6 16 8 7 9 91 50 18 5.6 30 35 480 5, 800 66 21 280 22 280 4.4 36 8.1 8.0 8.5 8.3 7.1 8.9 7.8 7.8 7.7 7.9 9.0 8.6 7.9

NT

8.2 8.0 7.7 8.1 6.5 9.4 7.8 8.56/8.39 6.00/5.45 5.52/5.78 5.77 7.0 9.2

NT

60 -100 >200 >180

NT

180 180 >180

NT

>180

NT

C- 2819 182 Test lAssay A 2 Assay B 3 ASsay C Compound IC 50 pA 2 Dose Inhibition Duration Exarnole (rim) (ino/ka) M% (min.) *9*e p.

S. p

S

*5*p 9 9

S

*5

S

59 S S

*SSS

9* 9* S

S.

5 102 103 104 105 106 107 108 109 110 ill 15 112 113 114 115 116 117 118 119 120 121 25 122 123 124 125 43 12 15 290 48 180 720 250 590 4S 2000 12 400 11 230 170 37 16 25 46 46 50 40 40 7.7 8.0 8.0 6.6 7.7 8.3 5.3 7.3 6.4 9.0 5.2 8.4 6.4 8.2 6.5 6.5 9.21/9.17 9.21/9.00 9.05/8.77

NT

9.42/9.12 9.25/8.80 100 30 30 10 3 10 10 3 3

NT

45 50

NT

87

NT

60

NT

40

NT

70 20 80

NT

35

NT

160

NT

180 >24 0 120 240 >180 >240 C-2 819 183 Tetlsay A Assay B 3Assay Compound IC 50 pA 2 Dose Inhibition Duration Exarnole (nM) (rncr ka) (min.)

S

OS..

5O55 5555 S S S. S

S

eso.

SeeS S* SO 0 5

S

*0 S 0 126 127 128 129 130 131 132 133 134 15 135 136 137 138 139 140 141 142 143 144 25 145 146 240 12,000 16 6,700 40 9.5 12 10 22 16 220 130 0.270 0.031 0.110 2.000 0 .052 0 .088 0.480 0 .072 7.20/7.05 4.96 8.63/8.40 5.30 8.10/7.94 7.53/8.2S 8.6 8.7 180 90 -120 180 >180 9.3 8.5

NT

8.3 8.2 6.3 8.1 8.02

NA

7.7 7.7 6.7 6.4

S@

0 oq 0@@O 0 0000 0@ 0 0 00

S

050000 0 100

NT

85 50

NT

160

NT

125

NT

c-2819 184 Test Compound Examprle 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 lAs say A

IC

5 0 (nLM) 5.8 0.87 1.1 17 150 13 97 86 78 530 54 21 64 28 380 420 1700 410 2 ASsay B pA 2 5.6 5.8 6.1 8.03/7 .80 7.76/7.97 7 .46/7 .23 8.30/7 .69 8.19/8.38 7.60/7.14 8.03/7.66 /6.22 8.23/8.14 7 .92/7 .56 7.87/7.71 6.21/6 7.42/6.75 Dose (jrnr/ka) 3 3 3 3 3 3 3 3 Assay C Inhibition Duration M% (min.) 74 5-10 92 20-30 NT

NT

25 >180 15 180 10 140 25 >180 >180 150 6.90/7 .18 C-281 9 Test compound lAs saY

ICS(

A 2 Assay B 3 Assay

C

pA 2 Dose Inhibit ion Duration 9* 9 9 Examnole (nM) (ma/ka) M% (min.

166 160 7.57/7.74

N

167 370 7.08/7.11

N

168 420 7.69/7.58

NA

169 150 '7.78/7.58 3 15 180 170 26 7.08/7.77 3 40 >180 171 28 7.52/7.11 3 0 NA 0 172 70 7.15/7.04

N

173 90 7.49/6.92

NA

174 180 7.29/7.02 NA 0 175 27 NA300 15 176 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

N

184 1100 6.78/

NA

C-2 819 186 Test lAssay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Example (rim) (mr c/ ka) M(min.) 9 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 25 205 206 207 208 209 210 211 212 213 214 215 216 6.5 38 770 140 29 10 81 140 11 47 34 31 14 7.6 10 20 17 12 9.2 16 20 5.4 99 22 5.0 3 .6 18 23 51 65 45 5.4 8.82/8.53 8.13/7 .40 7.46/6.95 7.72/7.09 8.64/8.23 7.87/7.89 7.75/7.76 9.27/8.87 7.64/7.35 8 .44/8.03 7.68/8.26 8.03/8.60 8.76/8.64 8.79/8.85 8.42/8.77 8.78/8.63 8.79/8.64 8.43/8.36 9.17/8.86 9.14/9.15 8.75/8.89 9.04/8.60 9.19/8.69 9.41/9.16 8.36/8.44 8.74/8.67 8.85/8.25

NA

8.80/9.04 180 180 180 180 180 180 180 180 >180 180 180 180 180 180 180 180 180 187 Test lsaA Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Exainle 4 (rim) (ma/ka) M% (min.)

S

S.

S

217 218 219 220 221 222 223 224 225 226 227 228 229 230 20 231 232 233 234 235 25 236 237 238 239 240 241 242 243 244 245 246 247

NA

7 .45/7 .87

NA

7 .55/7 .67 9.17/8.25

NT

8.23/8.69

NT

8.59/8.89 8.51/8.78 8.49/9 .00 7.14/7.07

NC

NT

7.88/8.01

NA

8.57/8.24 7 .11/6.60

NA

7 .17/7 .17 6.64/7 .04 7.46/7.59 8.26/8.41 120 180 180 180 >180 >180 >180 >180 >180 >180 >180 >180 >180 C-2 819

I

Test Compound Examnle 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 25 269 270 271 272 273 274 275 276 277 278 279 280 20 4.4 43 25 13 2.6 72 12 4.1 160 350 54 220 18 53U 57 11 110 290 25 520 9.7 21 14 97 9.8 13 6.3 33 190 30 270 480 7.68/7.50

NA

7.61/7.46 8.43/7.78 6.63/6.68 6.84/6.84

NA

-/6.22

NA

N C 8.53/8.61 9.06/8.85 9.07/ 8.71/8.64 /6.54 8.49/8.51 8.06/8.25 6.41/6.35 >180 >180 >180 188 1 Assay A 2 Assay B 3 Assay C

IC

50 pA 2 Dose Inhibition Duration (rdA) (ma/ka) M% (min.) >180 70% 25% 35% 40% >180 >180 >180 >180 min.

min.

miun.

nmin.

>180 min.

C-2619 189 NT NOT TESTED NC Non-Competitive antagonist *Antagonist Activity not observed up to 10 p-M of test compound.

lAssay A: 2Assay B: 3Assay C: Angiotensin II Binding Activity In Vitro Vascular Smooth Muscle Response In vivo Pressor Response Test Compounds administered intragastrically, except for compounds of examples #27-#29, #30-#79, #108-#109, #111, i118 and #139-#149 which were given intraduodenally.

4 *9 a C-2819 190 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 pharmaceuticallyacceptable carriers or diluents, or a binder such as gelatin or hydroxypropyl-methyl cellulose, together with one or more 15 of a lubricant, preservative, surface-active or dispersing agent.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, S. 20 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.

S"Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of each active 25 ingredient from about 1 to 250 mg, preferably from about 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.

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 C-2819 191 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.

In combination therapy, the aldosterone receptor antagonist may be present in an amount in a range from about 20 .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.

25 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 mg to about 600 mg, which represents aldosterone antagonist-to-AII antagonist ratios ranging from about 40:1 to about 1:60.

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 mg to about 400 mg, which represents aldosterone C-2819 192 antagonist-to-AII antagonist ratios ranging from about 10:1 to about 1:20.

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.

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 20 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.

C-2819 193 Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

With reference to the use of the word(s) "comprise" or "comprises" or "comprising" in the foregoing description and/or in the following claims, we note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that we intend each of those words to be so interpreted in construing the foregoing description and/or the following claims.

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Claims

1. A combination comprising a therapeutically-effective amount of an angiotensin II receptor antagonist and a therapeutically-effective amount of an epoxy-steroidal aldosterone receptor antagonist.

2. The combination of Claim 1 wherein said epoxy-steroidal aldosterone receptor antagonist is selected from epoxy-containing compounds.

3. The combination of Claim 2 wherein said epoxy-containing compound has an epoxy moiety fused to the ring of the steroidal nucleus of a compound. 10

4. The combination of Claim 3 wherein said 20-spiroxane compound is characterized by the presence of a 9c-,11 a-substituted epoxy moiety. The combination of Claim 2 wherein said epoxy-containing compound is selected from the group consisting of pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy- S 15 17-hydroxy-3-oxo,y-lactone, methyl ester, (7a, 11lca,17a)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-

17-hydroxy-3-oxo-dimethyl ester,(7a,11a,17a)-; 3'H-cyclopropa[6,7] pregna-4,6-diene-21-carboxylic acid, 9,11 -epoxy-6,7-dihydro-17-hydroxy-3-oxo-,y-lactone,(6p,7p,1 1 3,173)-; pregn-4-ene-7,21-dicarboxylic acid,9,1 1- epoxy-17-hydroxy-3-oxo-,7-(1 -methylethyl) ester, monopotassium salt,(7ca,11 a, 17a)-; pregn-4-ene-7,21-dicarboxylic acid,9,11,-epoxy- 195 1 7-hyd roxy-3-oxo-, 7-m ethyl ester, monopotassium salt, (7a,11ca, 1 7a)-; 3'H-cyclopropa[6,7llpregna-1 ,4,6-triene-2 1 -carboxylic acid, 9,1 1-epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-actone(6c,7c,1 3'H-cyclopropa[6,7]pregna-4,6-diene-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,methyl ester, (6cc,7cc, 11ca, 17cc)-;l 3'H-cyclopropa(6,7]pregna-4,6-diene-21 -carboxylic ~acid, 9,11 -epoxy-6 ,7-d ihydro- 17-hyd roxy-3-oxo-, monopotassium salt, (6cc,7cc, 11cc, 17cc)-; 3'H-cyclopropa[j6,7]pregna-4,6-diefle-21 -carboxylic acid, 9,11 -epoxy-6 ,7-dihydro- 17-hyd roxy-3-oxo-,y- lactone, (6cc,7c,11 ac.,l17ac)-; pregn-4-ene-7,21 -dicarboxylic acid, 9,11 -epoxy- 17-hydroxy-3-oxo-,y-lactone, ethyl ester, (7a,11cc,l17ac)-; and pregn-4-ene-7,21 -dicarboxylic acid, 9,11 -epoxy- 17-hyd roxy-3-oxo-,y-lactone, 1 -methylethyl ester, (7cc,11 ac,17cc)-. 6. The combination of Claim 1 wherein said angiotensin 11 receptor antagonist is 5-[2-[5-[(3,5-dibutyl-1 H-i ,2,4-triazol-1 -yl)methyll-2-pyridiflyl]phenyll1 H-tetrazole or a pharmaceutically-acceptable salt thereof and said epoxy-steroidal aldosterofle receptor antagonist is 9cc-, 11 cc-epoxy7cc-methoxycarbonyly205pirox-4ee- 3 2 1 -diorie or a pharmaceutically-acceptable salt thereof. 196 7. The combination of any one of Claims 1 to wherein said angiotensin II receptor antagonist is selected from the group consisting of: saralasin acetate, candesartan cilex etil, CGP-631 EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-1 84698, candesartan, CV-1 1194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, P0-150304, U-96849, U-97018, UP-275-22, WAY-i 26227, WK-1 492.2K, YM-31 472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, Li159282, ME-3221, SL-91 .0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-1 59689, L-162234, L-162441, L-163007, PD-i 23177, A-81988, BMS-1 80560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-i 67, :EXP-063, EXP-6155, EXP-6803, EXP-771 1, EXP-9270, FK-739, HR-720, 10-06888, 10I-0D7i55, ICI-D8731, isoteoline, KRI-1 177, L-i 58809, L-1i58978, L-1 59874, LR B087, LY-285434, LY-302289, LY-315995, RG-i 3647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1 360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, 01-996, DMP-81 1, DuP-532, EXP-929, L-1 63017, LY-301875, XH-148, XR-5i0, zolasartan and PD-i 23319. 8 The combination of Claim 7 wherein said angiotensin 11 receptor antagonist is selected from the group consisting of: saralasin acetate, candesartan cilexetil, CGP-63 170, EM 0-66397, KT3-671, LR-B/081, valsartan, A-8 1282, BIBR-363, BIBS-222, BMS-1 84698, candesartan, CV-ii1194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, P0-150304, U-96849, U-9701 8, UP-275-22, WAY-i 26227, WK-1492.2K, YM-31472, losartan potassium, E-41 77, EMD-73495, eprosartan, HN-65021, irbesartan, L-1 59282, ME-322i, SL-91.0i02, Tasosartan, Telmnisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-1 62441, L-163007 and P0-123177. 197 9. The combination of any one of Claims 1 to 8 further characterized by said angiotensin II receptor antagonist and said epoxy-steroidal aldosterone receptor antagonist being present in said combination in a weight ratio range from about one-to-one to about twenty-to-one of said angiotensin II receptor antagonist to said aldosterone receptor antagonist. The combination of Claim 9 wherein said weight ratio range is from about five-to-one to about fifteen-to- one. 11. The combination of Claim 10 wherein said weight ,ratio range is about ten-to-one. 12. A method of treating circulatory disorders in a patient afflicted with or susceptible to circulatory disorders, by administration to the patient by combination therapy (as hereinbefore described), of an effective amount of the combination of any one of Claims 1 to 11. 13. The method of Claim 12 wherein said circulatory disorder is a cardiovascular disorder. 20 14. The method of Claim 12 or 13 wherein said patient is afflicted with or susceptible to multiple cardiovascular disorders. The method of any one of Claims 12 to 14 wherein said patient is afflicted with or susceptible to hypertension. 16. The method of any one of Claims 12 to 14 wherein said patient is afflicted with or susceptible to congestive heart failure. 198 17. The method of any one of Claims 12 to 14 wherein said patient is afflicted with or susceptible to cardiac hypertrophy.

18. The method of any one of Claims 12 to 14 wherein said patient is afflicted with or susceptible to cirrhosis. 18. The method of any one of Claims 12 to 14 wherein said patient is afflicted with or susceptible to ascites. 0 0060 0660 1 00;0 0@ 0 6 *006 S4 S. S 5566 6*5 1 5.55

19. Use of the combination of any one of Claims 1 to 11 in the preparation of a medicament, said medicament being in a form suitable for treating circulatory disorders in a patient.

20. Use according to Claim 19 wherein said circulatory disorder is a cardiovascular disorder.

21. Use according to Claim 20 wherein said cardiovascular disorder is hypertension, congestive heart failure, cardiac hypertrophy, cirrhosis, or ascites. DATED this day of August 2000 G. D. SEARLE CO., By its Patent Attorneys, F. WELLINGTON 0O., (Bruce A/KA/4319