AU2003202486B2 - Epoxy-steroidal aldosterone antagonist and angiotensin II antagonist combination therapy for the treatment of congestive heart failure - Google Patents

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.

-1- EPXY-STE ROIDL ADOSTE RNE ANTAG O TAND AN TENSN ANTAGONST COMBINATION THERAP

FO

TREATMENT OF CONGESTIVE HEART FAILUR 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 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 (Na excretion, relative to dietary Na* intake, and is importantly related to circulating levels of aldosterone (ALDO). An abnormal retention of Na' occurs via tubular epithelial cells throughout the nephron, including the later portion of the distal tubule and cortical collecting ducts, where ALDO receptor sites are present.

I

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 2 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 ACTH) that promote

ALDO

synthesis. Hepatic blood flow, by regulating the clearance of circulating ALDO, helps determine its plasma concentration, an important factor in heart failure characterized by reduction in cardiac output and hepatic blood flow.

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 angiotensin

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-(2acid which has specific 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. Exp. 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 inJ_ vi tests T. Chiu et al, European J. Pharmacol., 152, 31-21 (1988)]. A family of derivatives has been shown to have competitive angiotensin II antagonist properties T. Chiu et al, J. Pharmacol Ez. Ther, 250(3), 867-874 (1989)]. U.S. Patent No.

4,816,463 to Blankey et al describes a family of 4,5,6,7derivatives 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, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4substituted-4H-1, 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.

Many aldosterone receptor blocking drugs are known. For example, spironolactone is a drug which acts at the mineralocorticoid receptor level by competitively inhibiting aldosterone binding. This steroidal compound has been used for blocking aldosterone-dependent sodium transport in the distal tubule of the kidney in order to reduce edema and to treat essential hypertension and primary hyperaldosteronism Mantero et al, Clin_ Si. 1M-1. Med., (Suppl 219s-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, AldactoneL

S

Q

irnolaco. A Compreensive 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 C-2819 patient to treat cirrhosis-related ascites Greenberger et al, N. Ena Allery 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.

Cardial, 21 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 ec al, J. Mel. Cell.

Cadi_ 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 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,, 21, 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.

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

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

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__L Cardiol., 65(2), 33K-35K (1990)]. In a 90-patient study, a combination of captopril and spironolactone was administered and found effective to control refractory CHF without serious incidents of hyperkalemia Dahlstrom et al, AmL 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.

Cardiol., 71, 21A-28A (21 Jan 1993)]. Clinical improvements have been reported for patients receiving a co-therapy of spironolacone and the ACE inhibitor enalapril, although this report mentions that controlled trials are needed to determine the lowest effective doses and to identify which patients would benefit most from combined therapy [F.

*Zannad, Am. J. Cardiol., 21(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 spironolaccone.

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-ene-7,21 -dicarbox yfic acid, 9,1 1-epoxy- 1 7-hydroxy-3-oxo,y-lactone, methyl ester, (7cr, 11 1 7cx)-; pregn-4-ene-7,21 -dicarboxylic acid, 9,1 1-epoxy- 1 7-hydroxy-3-oxo-dimnethyl ester, (7a, 1 1la, 1 7ct)-i 3H-cyclopropa[6,7] pregna-4,6-diene-21 -carboxylic acid, 9,1 1-epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-factone,(6373, 113,1713)-; pregn-4-ene-7,21 dicarboxylic acid,9,1 1 epoxy-l1 7 -hydroxy3oxo-,7-(1 methylethyl) ester, monopotassium salt,(7az,11 cc,17ax)-; pregn-4-ene-7,2 1 dicarboxylic acid,9, 1 1,-epoxy- 1 7-h yd roxy-3-oxo-, 7-m ethyl ester, m onopotassium salt, (7a, 1a,l17a)-; 3'H-cyclopropa[6,7Jpregna-1 ,4,6-triene-2 1-carboxylic acid, 9,1 1-epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-Iactone(6a,7(, 3'H-cyclopropa[6, 7]pregna-4,6-diene-2 1 -carboxylic acid, 9, 11 -epoxy-6,7-dihydro-1 7-hyd roxy-3-oxo-,mrnethyl ester, (6c,7a, 11 aX, 1 7a)-; 3'H-cyclopropa[6,7]pregna.-4,6diene-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-, monopotassium salt, 6 a,7a,11 a, 17x)-; 3 H-cyclopropa[6 ,7]pregna-4, 6-diene-21 -carboxylic acid, 9, 11 -epoxy-6 ,7-dihydro-1 7-hydroxy-3-oxo-,ylactone, (6a, 7c,11 cc.,1I7ac)-; pregn-4-ene-7,2 1 -dicarboxyl ic acid, 9, 11 -epoxy- 17-hydroxy-3-oxo-,y-lactone, ethyl ester, (7a~,11 a,l17a)-; and pregn-4-ene-7,2 1 -dicarboxylic acid, 9,11 -epoxy- 1 7-hydroxy-3-oxo-,'y-lactone, 1 -methylethyl ester, (7a,11 ac, 17a~)-.

In another preferred embodiment of the present invention, said angiotensin II receptor antagonist is 5-dibutyl-1 H-i ,2,4-triazo!-1 -yI)methylj-2-pyridinyllphenyl-1 H-tetrazole or a p harm aceutica Ily-acceptab le salt thereof and said epoxy-steroidal aldosterone receptor antagonist is 9cr-, 11 a-epoxy-7ca-methoxycarbonyl-20-spirox4ene-3,21 -dione or a pharmaceutically-acceptable salt thereof.

In another preferred embodiment of the present invention, said angiotensin II receptor antagonist of the combination is selected from the group consisting of saralasin acetate, candesartan cilexetiil,CGP-63 170, EMD-66397, KT3-671, LR-B/081, valsartan, A-81282, EIBR-363, BIBS-222, 8MS-1 34698, candesartan, CV-11194, EXP-3174, KW-3433, L-161177, L-162154, LR-8/057, LY-235656, P0-150304, U-96849, U-97018, UP-275-22, WAY-i 26227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-1 59282, ME-3221, SL-9 1.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-1 59639, L-162234, L-1 62441, L-163007, PD-123177' A-8 1988, BMS-1 80560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-1 67, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, 101-06888, ICI-D7155, 01-08731, isoteoline, KRI-1177, L-158809, L-1 58978, L-159874, LR B087, LY-285434, LY-302289, LY-31 5995, RG-1 3647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-1360, X-6803, ZD-6888, ZD-7 155, ZD-8731, 818S39, 01-996, OMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-5 10, zolasartan and PD-123319, more preferably said angiotensin II receptor antagonist is selected from the group consisting of: saralasin acetate, candesartan cilexetil, CGP-631 EMD-66397, KT3-671, LR-B/08 1, valsartan, A-8 1282, BIBR-363, BIBS-222, BMS-1 84698, candesartan, CV-1 1194, EXP-3174, KW-3433, L-161177, L-1621 54, LR-B/057, LY-235656, PD-i 50304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-1 59282, 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 and P0-123177.

In further preferred embodiments of the invention, the combination is characterized by said angiotensin

II

receptor antagonist and-said epoxy-steroidal aldosterone receptor anatagonist 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.

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 biological functions or events such as vasoconstriction or vasorelaxation, kidney-mediated sodium and fluid retention, sympathetic nervous system activity, and in modulating secretion of various substances such as aldosterone, vasopressin and renin, to lower blood pressure in a subject susceptible to or afflicted with elevated blood pressure.

Interactions of such angiotensin II receptor antagonist with this receptor site may be characterized as being either "competitive" "surmountable") or as being "insurmountable". These terms, "competitive" and "insurmountable", characterize the relative rates, faster for the former term and slower for the latter term, at which the antagonist compound dissociates from binding with the receptor site.

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 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 to qualify the amount of each antagonist agent for use in the combination therapy which will achieve the goal of reduction of hypertension with improvement in cardiac sufficiency by reducing or preventing, for example, the progression of congestive heart failure.

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

For a combination of All 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 All 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) etilsi Decrpn of t Invenin 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: SCH2--

CH--

epoxyethyl 1,3-epoxypropyl 1, 2 -epoxypropyl The term "steroidal", as used in the phrase "epoxysteroidal", dtnotes a nucleus provided by a 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.

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 ca,lla-substituted epoxy moiety. Table I, below, describes a series of 9a,ll-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.

TABLE I: Aldosterone Receptor Antagonist Compound Structure Name Pregn-4-ene?,21-dicarboxy1ic acid, 9 1 1-epoxyl 7 -hydroxy-3-oxo-,T-1actone, methyl ester, 11. cc. 17(x) 2 ~Pregn-4-ene-7,21-dicarboxylic acid, 9 ,11-epoxyl 7 -hydroxy-3-oxo-dimethyl ester, (7cX,11a, 17a) TABLE I: Aldosterone Receptor Antagonist Compound Structure Name 3 'H-cyclopropa[6,7] pregna-4, 6-diene-21carboxylic acid, 9 ,1l-epoxy-6,7-dihydro17hyrx oo,-l oe (6p, 7P,110, 173) Pregn-4-ee721-dicarboxylic acid,9,l1epoxy- 7 hydrox3-oxo-,7-(methylethyl) ester, monopotassium salt, 7 a,lla,17a)- TABLE I: Aildosterone Receptor Antagonist Compound Structure Name Pregn-4-ene-7,21-dicarboxyljc acid,9,11,-epoxyl7-hydroxy--3-oxo-,7-methyl ester, monopotassium salt, (7a,lla,17a)-

I-.

3 'H-cyclopropa[6,7lpregna-1,4,6-triene-21carboxylic acid, 9,11-epoxy-6,7-dihydro-17hydroxy-3 -oxo-,g-lactone (6a, 7a,11. a) TABLE I: Aldosterone Receptor Antagonist Compound Structure Name 3 H-cyclopropaf6,7]pregna-4, 6 -diene-21-carboxylic acid, 9 ,ll-epoxy-6,7-dihydro17-hydroxy-3-oxomethyl ester, 6 a,7a,lla,17a)- 8 3 H-cyclopropa[6G7lpregna-4, 6 -diene-21-carboxylic acid, 9 ,ll-epoxy-67dihydro-17hydroxy-3-oxoronopotassium salt, (6a,7a,lla,17a)- TABLE I: Aldosterone Receptor Antagonist Compound fl Structure Name 3 H-cyclopropa[6,7lpregna-4,6-diene-21-carboxylic acid, 9,11-epoxy-6,7-dihydro-17-hydroxy-3-oxo-,glactone, (6a,7a,lla.,17a)- Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy- 17-hydroxy-3-oxo-,g-lactone, ethyl ester, (7a,11a, 17a) TABLE I: Aldosterone Receptor Antagonist Compound #i Structure Na me Pregn-4-ene-7,21dicarboxylic acid, 9 ,1l-epoxy- 17hdoy3ox-glcoe 1-methylethyl ester, 7 a,lla,17a)- C-2819 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-alkyl 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)

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.

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 X1 x 2 5 X 6 X1 I b x 4 x 2 wherein each of X1 through

X

6 is selected from -CH2-, 0, and S, with the proviso that at least one of X1 through X6 in each of Formula ha and Formula lIb must be a hetero atom. The heterocyclic moiety of Formula Iha or Ib may be attached through a bond from any ring member of the Formula a. or Ilb heterocyclic moiety having a substitutable or a bond-forming position.

Examples of monocyclic heterocyclic moieties of Formula ha include thienyl, furyl, pyranyl, pyrrolyl, irnidazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, furanyl, thiophenyl, isopyrrolyl, 3 -isopyrrolyl, 2 -isoimidazolyl, 1,2,3- 1, 2 3 -oxathiolyl, oxazolyl, thiazolyl, l, 2 ,3-oxadiazolyl, 1, 2 4 -oxadiazolyl, 1 2 ,S-oxadiazolyl, 1, 3 4 -oxadiazolyl, 1,2,3, 4 -oxatriazolyl, 1, 2 3 ,5-oxatriazolyl, 1,2,3dioxazolyl, l, 2 ,4-dioxazolyl, l, 3 ,2-dioxazolyl, 1,3,4dioxazolyl, l, 2 ,S-oxathiazoly1, l, 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, l, 4 -oxazinyl, D-isoxazinyl, .D-isoxazinyl, 1,2,5oxathiazinyl, l, 2 ,6-oxathiazinyl, 1, 4 2 -oxadiazinyl, C-2819 1,3,5, 2 -oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl and 1,2,4-diazepinyl.

Examples of bicyclic heterocyclic moieties of Formula IIb include benzo[b]thienyl, isobenzofuranyl, chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isochromanyl, chromanyl, thieno[2,3-b]furanyl, 2 H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d][1,2]oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, cyclopenta[b]pyranyl, 4 H-[1, 3 ]oxathiolo-[5,4-b]pyrrolyl, thieno[2,3-b]furanyl, imidazo[1,2-b]J1,2,4]triazinyl and 4 H-1,3-dioxolo[4,5-d]imidazolyl.

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

III:

-UnA

(III)

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 carboxyl group (-COOH). Where n is zero and A is -COOH, in the -UnA moiety, such carboxyl group would be attached directly to one of the Formula I-IIa/b positions. The Formula I-IIa/b compound may have one -UnA moiety attached at one of the Formula I-IIa/b positions, or may have a plurality of such -UnA moieties attached at more than one of the Formula I-IIa/b positions. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as "bioisosteres of carboxylic acid" or referred to as "acidic bioisosteres". Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I-IIa/b may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I-IIa/b compound as conferred by the -UnA moiety be in a range from about two to about seven. The -UnA moiety may be attached to one of the Formula I-IIa/b positions through any portion of the -UnA moiety which results in a Formula I-IIa/b compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the -UnA acid moiety is tetrazole, the tetrazole is typically attached at C-2919 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, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula

-C-R

1 -N 3 and -NC-R 4

I

R

3 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 R8 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, C-2819 23 arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R1, R2, 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 R W -N II

II

Rio -CN and -NC-R 13 R12

I

R2R4 wherein W is oxygen atom or sulfur atom; wherein each of R 9

R

1 0 Rll, R 1 2

R

13 and R 14 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 2 and R 3 taken together and each of R 4 and

R

5 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 2 and R 3 taken together and each of R 7 and R8 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

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 intreatment 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.

C-2819 TABLE II: Angiotens in II Antagonists Compound -Structure Source

N

N'

SCO..8

MN

I

HH

N N Pub- 14 Nov 91 f4Q. r#91 /17148 pub. 1.4 Niov 91 C-2819 26 TAB3LE 11: Angiotensin II Antagonists Compound .1 Structure Source WO 71 18 Wpub. o 2 0 11

H

N

CH

2 N 0 11 Cl

N'N

C14,

CO'H

Pub. -4 No 9 pub. :4 N\ov 91.

C-2819 27 TABLE II: Angiotens in II Antagonists Compound Structure Source

CH.,

N- N

N

Pub- 124g Wa u91/17148 pub.- 14 NcJv 91 WO 491/17148 Pub. 14 UaIv 91

N

"N

N H C-2819 28 TABLE II: Angiotensin II Antagonists Compound Structure Source 210 121 F F

N

CH,

N

0

N

N'

NN

H

N- N

N

N H

N

'-7~148 pub. 4 Nov 9j WO 91/17148 pub. 2.4 Nlov 91

N-

HN

N'

C-2819 29 TABLE 11: Arigiotensin Il Antagonists Compound Structure Source N

I

ICH

2

N-N

IN'

N

N'N

CHI

N-N

W

N

"I

H

"q 91/17148 Pub. 14 No-v 91 14 1s

CR

2 N- N 1rN

H

Pub. 14 Nov 91.

C-2 819 TABLE II nMgiotensin II Antagonists Compound Structure .Source 17 =z ±~:148 purL L 9io~.

N- N

H

NC\k

N

N-

N

H

N

00CH WO "91/17148 Pub. 14 Nov 91 'dO "91/-17148 Puz.- 2.4 Nov 91 C-je19 31 TABLE 11: Angiotensin II Antagonists Compound Structure LNyN Source "91-/17148 CZF7 N C3F 7

N

CH

o' Pub. 14 Nov 91

N'

N'

N' H 'dO 191174 pub. 14 N~ov 91 C-2819 32 TABLE 11: Angiotensin II Antagonists Compound 22 Structure Source ub. -4 Nov 9 CH3C)

N

W7O /7 Pub. 14 Nov 91 WO AP91/17148 Pub. 14 Nov 91

OCH

2 N OCH3

N'

H

(f-2819 33 TABLE 1I: Algiotensjn II Antagonists Compound Structure Source

N-

\A<1 Nsl

H

Vo =-Z1 17148 put. 1~~o 2 '191/17148 Pub. 1-4 N\ov 91

NH

N '10 q. .91/17148 Pub. 2.4 Nov 91.

H

C-2B19 34 TABLE 11: Angiotensin II Antagonists Compound Strcture Source

N-

N H pub.-4 Nv 91

N-

N H%

N'

~I

N. H rW1 -"91/17148 pub. 74 Nov 91 WO ?1111 1 14 pub- :4 Nov 91 C-12819 TABLE 1: Angiotensin II Antagonists Compound Structure Source

N-

N

N

vN

H

pu -a IXOV N6

N

N-N

N

N

H

WO 91/17148 Pub. 14 N~'ov 91

N

"0 ".91/17148 Pub- 14 Nay 91 N

H

C-2819 36 TABLE 11: An-gioterisjn II Antagonists Compound ,4 Structure Source 0 Pub- 14 Nqov 91

N

H

2 ~N N N H WC) "91/171.48 Pub. 14 Nov 91~ Pub. 7-4 Nov 91 C-2819 37 TABLE 11: Angiotensin Il Antagonists Compound Structure Source Pub. :4 N~ov 91

N

H

38 39 pu~b. 14 Nov 91 Pub- 14 Nov 91 C -2819 38 TABLE II: Angiotensin II Antagonists Compound Structure Source WO ~91/7148 0

NH

cv 41 42 pub.* -14 NYov 91 Pub, 14 Nov 91

N

H

C-2819 39 TABLE II: Angiotensin II Antagonists Compound If3 Structure Source pub. -4 LqTOV 91 44 WO #-91/17148 Pub. 14 Nov 91

N

IVO #"1/17148 PUb,. 14 Nov 91 C-281

TABLE

Compound 46 47 Angiotensin II Antagonists Structure Source .0 1 -N L- *7

N"

Pub. -4 27148 Nov al 1N

H

7 91/17148 Pub. 14 Niov 91 WO 91/17,l48 Pub. 14 Nov 91 N

H

C -2 819 TABLE 11: Angiotensin Il Antagonists Compound Structure Source "V 91/17148 91 51

H

Pub- 14 Nov 91 "91/17148 Pub. 14 Nov 91

H

C-2819 42 TABLE II: Angiotensin II Antagonists Compound Structure Source 0 N_

O

N-N

N. HN P uh WOiC s~91/1jga

N

WO .91/17148 pub. 14 Nov 91 WO 9/74 Pub. 14 Nov 91

N

N- N

N

H

C-28ig 43 TABLE 11: Angiotensin II Antagonists Compouind 33 Structure Source 714 pub. I4Nov 9 1 36 57

N

WOb "17148v9 Pub. 14 ov 91

H

C-2819 44 TABLE 11: Angiotensin II Antagonists Compound Structure Source .4 "91/17148 14 Nlov 91

H

NNJON

N N-N N

N

'4 491O74 Pub. 14 Nov 91 Pub. 14 NOcV 91

N

C -28919 TABLE 11: Angiotensin II Anta~gonists Compound 61 Structure Source

NN

rz pubi. 14 .qov 91 N- N \'x

N

H

N

Pub. 2-4 Nov 91 WO #i91/17148 Pub. 14 Nqov 91 0

CH

N

N H C-2819 46 TABLE 11: Angiotensin II Antagonists Compound Structure Source

HO

64 N'f I

SN

H

Pub. qov 91

CH

2 WO 91/17148 Pub- 14 Nov 91

H

CH

2

N'N

N

WO N91/17148 Pub- 14 Nov 91 C-2 819 47 TABLE 11: Angiotensin II Antagonists Compound Structure Source 67 68

CH

2

N

NI

H

pub. i4 ~INOV 91 orf Pub. 14 Nov 91 I- N

H

C

2

F

WO :.9/74 pub. 14 N'ov 91 C -2 919 TABLE 11: Angiotensin II Antagonists Compound Structure Source C3F7(n)

N'N

~-N

N.

H

pub. 24 U"ov 9i.

NH2-'N, /17 N

N

WO0 #91/17148 Pub, 14 Nov 91 WO0 u91/17148 Pub. 14 Nov 91.

~~J«~NH2 N

O

H

C-2819 49 TABLE I: Angiotensin II Antagonists Compound ~Structure Source 73 74

N

CH2 N- N

I

H

N

IH

CH2H c- 148 puzb. -4 -ov 91 WO"91/17148 pub. -4 Nov 91 WO "91/171 48 Pub. 14 Nov 91 C -2 819 TABLE I1: Angiotensjin Il Antagonists Compound Structure Source 77

N"

S C0 2

H.

AlN' Cit 2 S C0 2

H

WO 91/17148 Pub. 14 Nov 91 C-2819 51 TABLE II: Angiotensin II Antagonists Compound Structure Source 79 .eH

N

H

CHIN

i~O 9 1/2.aggg pub.

WO U91/18888 pu..

pub.

N--

I, rf C-2819 T-A-LE 11: Angiotensjn Il Antagonists Compound uuCure Source N-N Ph N 0 81.

82 a 3 7r.LD N- N"

H

Nd #7091/18888 Pub.

Dub.

C-2 819 TABLE II: Compound 84 Angiotensin Il Antagonists Structure Source wo pub.

86 wo"9/88 pub.

q-

N

N**

N- N CC El v o wo #91/18888 pub.

TABLE 11: Angiotensin II Antagonists COmPOUnd 87 Structure Source WO 1/88 pub- N-

N~H

il WO#9/88 pub.

Pub.

yNxo

N

?H

2 I/ 11 NI C-2819 TABLE 1I: Angiotensin Il Antagonists Compound Structure Source WO i 91g/18888 Pub.

9H2 wo U91/lg888 Pub.

WO #91/18888 Pub.

C-28iq 56 T'ABLE 11: Angiotens in II Antagonists Compound 93 Structure Source FF114 N-N Ph Fh IN a Fh CH2 pub.

N-

94

N

CH

2 0 N- N- O

N

0 pub.

Pub.

H

N

C-2 819 57 TABLE 11: Angiotensin Il Antagonists Compound Structure Source Pub.

WO0 .91/1g888 Pub.

N-.

CH

2 0 0t, wo Pub.

N

C -2 819 TABLE 11: Angiotensjn II Antagonists Compound Structure Source IdN-- 99 100o

N

pub.

C0 2

CH

3 w1o 9/8 8 pub.

N- r H wo 7L92./18888 Pub.

C-2819 59 TABLE 11: Angiotensin 11 Antagonists Structure

C

Compound ;ource 102 103 104

CH

2 0 N

N)=

9:H2 WO "91/18888 pub.

WOb pub.

N-N" H Ni~ N~I,-J2QV

N

WO P91/18 pub.

H

N

C-2919 TABLE 11: Angiotensin II Antagonists Compound _I-Structure Source 106 107 Pub.

Pub.

0

M

H

N-p

KC

2 Ef N Pub.

N- N-

H

v I N I

N

C-12819 TABLE 11: Angictensin IT Antagonists Compound Structure Source pub. -70 Dec 91.

109 110 WO :9/91 pu.b. 26 Dec 91.

wo F91/19715 pub. 26 Dec 91 C-2 819 TABLE IT: Compound 11of Angiotensin II Antagonists Structure Source Pub 206 Dec 91 J12

O

2

H

N N N

N

0 0,H 5

N

N

NH

Pub. 26 Dec 91 113 n-butyi Pub. 26 Dec 91 C -2 8 1 TABLE 11: Compound 114 Angiotensin II Antagonists Structure Source Pub. 26 Dec 91 flC 4 E HO 175 "O #91/19715 pub. 26 Dec 91

N-N

H

115

NO

-l-C4H WO u91/19715 pub .26 Dec 91 C-28i9 TABLE 11: Angiotensjn II Antagonists Compound Structure Source 117 nC 4i~. Pubo. 26 D~ec 91 0 C 4 H 9 rlC 4 HC WO: 91/19715 pub. 26 ]Dec 91 0 C-CH (C 3 )2 119 WO 1/92 Pub. 26 Dec 91.

C-2819 TABLE 11: Compound 12o Angiotensin II Antagonists Structure iC 4 zi Source "0 Pub. 26 Dec 91 121 122 0 0.

0- C N'C3 rN 9

I

HO

Wo i Pub. 26Dec 91

WO

Pub. 26 Dec 91 C-2819 TA-BL2 11: Angiotensjn II Antagonists Compound Structure Source 123 124 125 0 -0

NN

pFCC(H, Pub. 26 Dec 91 Wub.192/19715 Pub-26Dec 91 Puc. 26 Dec 91 ic 4

H

9 I'

*CF.

0 67 TABLE II: Angiotensin II Antagonists Compound Structure Source

N

126 yj6 pub. 2 Aar 92 C0 2

H

127 CH2 NI 07H S2r 92/5161 Pub. 2 A-or 92 128 m

N'

N-eq N

I

92/05161 pub. 2 Apr 92 -TABLE 1: Angiotensjn II Antagonists Comrpounrd -S triit-~ Source 2.29

C'

Pub. 2 A-Or 92

N'Z

I z i Pu~b. 2 A-Or 92

WO

Pub.- 2 Apr 92

N

U-N

C-2819 69 T'ABLE 11: Angioterisji II Antagonists Copud#Structure Source 132 Pub- 14 M~ay 92 zrN' -~0 133

N-N

II

N

El WO "92/07834 Pub- 14 May 92 134 ChF2

N'N

WO /Og3 Pub. 14 May 92 C-2819 TABLE 11: Angiotensin II Antagonists Compound x uc L-u.L e

C

source WO ==92/07834 pub. 14 May 92 136 137

NO

1CH, WIO 92/07834 Putb. 14 May 92 WO ?-92/07834 PUIO. 14 May 92

N

'I

H

C-28919 71 TABLE 11: Angiotensin II Antagonists Compound 138 Structure source WO T"92/07834 pub. 14 May 92

H

139 1.40

HO

N<N

WO #92/11255 pub. 9 Jul 92 a0 -792/11255 pub. 9 Jul 92 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source

-N

141

N'.

142

N*NN

'WO 92/11255 pub. 3 Jul 921 WO "92/11255 pub. 9 Jul 92 WO #92/11255 pub. 9 Jul 92

X

143 TABLE 11: Angiotensin II Antagonists Compound .144 Structure Source Pub- Jul 92 CF3 145 146

LN.

N02 WO -92/11255 pub. 9 Jul 92 WO~ '192/11255 pub. 9 Jul 92

N..

TABLE 11: Angiotensin Il Antagonists Compound 3ource c Il 47 148 149 "-9/157 pub. 27 Se-P 92 WO t92/15577 pub. 17 Se-P 92 WO 92/15577 Pub. 17 Se-p 92 -CHi 2

OH-

TABL II:Angiotensin II Antagonists Compo0und "'--L-ure Source is()

SI

pub'1 Oct 92 "O :192/16523 Pub. 1 Oct 92

V

152

CH

2 '1 E2162 Pub. 1 Oct 92 TABLE 11: Angiotensin II Antagonists Compound -ucture Source 753

U-N

wo# 92116523 Pub- 1 Oct 92 154

'S

1 .192/16523 Pub. 2. Oct 92 WO 92/16523 Pu-. Oct 92 -TABLE ii: Angiotensin Il Antagonists Compound Stucure1 Source WO#2/62 pub. I. Oct 92 156

N-N

N

7 157 W~O ;e92/16523 pub- I Oct 92

N

158

CF

2 I

I

WO#92/16523 pub- 1 Oct. 92 78 Compund~ TABLE 1:Angiotensin II Antagonists CO-on Structure Source i59

OE.

/R-

WO#L92116,523 Pub. 1 Oct 92 0 y 160 WqO 9162 Pub. 7. Oct 92 WO #92/16523 Pu~b- 1 Oct 92 161

F

CHi 2 Compound 12 2 TABLE 11: Angiotensin 11 Antagonists Ure Source

AT

y 9-i'l D%~2T =rCF2R

U,

y'~ Pub. 2 Oct 92 WO '.'9/62 Pub 1 Oct 92

F

164 wo0 p 92/16523 Pub. 1 Oct 92 -TABLE 11: Angiotensin Il Antagonists COM-Pound 7-C ture Source 165 166 Pub. 1 Oct 92

~NN~%N

W0 -77-92/16523 pub- 1 Oct 92 WO -':92/16523 Pub. 1 Oct 92 F F

J

167 ~1

N

Ii C-2 819 81 TABIL2 11: Angiotensin 11 Antagonists Compound OLructure Source i-i92/16523 pub 1 Oct 92 168

N

t i

F

169 w; "12162 Pub. 1 Oct 92

N-,N

's F F

N

170 Pub. 1 Oct 92

N-N

N

TABLE 11: Angiotensin 11 Antagonists Compound Structure Source 0

N=

y C

(CH.)

171 WO:"2162 Pub. 1. Oct 92

I,

J*

N

0

CH

Il 172

'I

N

Pub. 1 Oct 92 0 cHI 2 173 ;qO T92/2.6523 D Oct 92 83 TABLE II: Angiotensin I Antagonists Compound Structure Source :74

OC:

OC~s-

N--N

1

N

WO 92/16523 pub. I Oct 92

OCR.

OCH

3 9H2 175 WO ;92/16523 pub. I Oct 92

NOCH

0C'H 170- WO 492/16523 pub- 1 Oct 92 NI

N

H

COMPound TABLE li: Angiotensin II Antagon Iists Structure ~Ource 1.77

CC

3

C

N-N

WqO=2/62 Pub. 2. Oct 92 CCH (Cli

)I

P---r4ocli(C, 2

N

y 178 179 4O 92/16523 Pub. iOct 92 N~-NCliN WO '92/16523 Pub. Oct 92 C-2819 TABLE 11: COMPound iso 181 Angiotensjn II Antagonists Structure Source 0 WO -9162 pu.b. 1 Oct 92

'I

N

N

CH3 WO~ :E'92/16523 Pub. 1 Oct 92 C%~N

CJ

182 WO 92/16523 pub- 1 Oct 92

N-N

C-2819 86 TABLE II: Angiotensin II Antagonists Compound IfStructure Source

I

183 1.84 pub 2.Oct 92

WO

pub. I. Oct 92

CIH

2

N.%N

N H 185 N' N 1 O

CH

2 N H WO 92/17469 Pub.- 15 Oct 92 C- 2819 87 TABLE 11: Angiotensin II Antagonists Compound Structure Source KO 7 92/17469 Pu~b- 15 Oct 92

N

187 WC!792/1.7469 Pub '5 Oct 92

H

N 0 188 WO -=92/17469 Pub 15 Oct 92 C-2819 88 TABLE 11: Angiotensin II AntagonistS Compound '89 Structure Source WO F92/,'17469 pub. 15 Oct 92

N

El N 0 190 W!O #u92/17469 pub. 15 Oct 92 191 CIi

N

WO #92/17469 Pub. 1s Oct 92 C -2 819 89 TAB3LE 11: Angiotensin II Antagonists Compound Structure Source 192

DT-

N-N

pub. 15 Oct 92 N0 193 194 WO 1192/17469 pub. 15 Oct 92

H

0< WO 92/17469 pub. 15 Oct 92

N-

C-2819 TABLE 11: Angioterisin II Antagonists Compound -Structure Source .795 196 197 N 0 CH2

H

N 0

C

2 N- N WO 19/76 Pub. 15 Oct 92 WO #92/17469 Pub. 15 Oct 92 WO a=92/17469 Pub- 15 Oct 92 TABLE 11: TABL II:Angiotensin II Antagonists Compound Structure Source WO -92/17469 pub. is Oct 92 U, I

NX

199 200

N-F

WO 92/17469 Pub.' 15 Oct 92 Pub. 15 Oct 92

N

H

C-2 819 92 TABLE 11: Angiotensin II Antagonists Compound Structure Source N C 201 #92/17469 pub. 13 Oct 92

N-N

N

H

N0 202 qO ru-92/17469 Pub. 15 Oct 92

N-N

a

N

H

203 I -JK 0~

CI-

2 WO u92/17469 pub. 15 Oct 92 C-2819 TABLE II: Angiotensin II Antagonists Compound Structure Source 204 205

N.

CH

2

N

N-N

NH2 N 0 WO J92/17469 pub. :s Oct 92 WO #92/17469 pub. 15 Oct 92 PO #92/17469 pub. 15 Oct 92

I

206

N-N

$N.

H

C-2 819 94 TABLE II: Angiotensin II Antagonists Compound Structure Source 207 208

NC

NN

N-

~7 pub. 5 Oct 92 IWO t 92 /17469 Pub. 15 Oct 92

H

209 WO #u92/17469 pub. 15 Oct 92 C-2819 TABLE II: Angiotensin II Antagonists Compound q 5 ource 0N 210 211 WJO 92/17469 pub. 15 Oct 92

N

HND

NO,

Cm

N-N

N

H

WO 792/17469 pub. 15 Oct 92

NO

fl-N

NIN;

H

212 WO92/174G pub. 15 Oct -2 C-2819 96 TABLE II: Angiotensin II Antagonists Compound Structure Source 213 214 215 Cii?

NM

N-N

I

N

N

CI{~

NM

N-N

N'

H

WO. 2/17469 Pu'o. 15 Oct 92 WC 92/17469 pub. 15 Oct 92 N0

CH

W1O :#92/17469 Pub. 15 Oct 92 C -2 819 -TABLE 11: Angiotensjn 11 Antagonists Structure Source Compound 4 216

II

CF.,

N-N

NN

Pub. 2-5 Oct 92 217

CH

2 LI T' WO--.92/17469 pub. 15 Oct 92

CH

2 NI N 218 WO 4'92/17469 Pub. 15 Oct 92 C-28i9 TABLE 11: Angioterisin II Antagonists Compound Structure Source WOQ '-:92/17469 Pub. "5 Oct 92 N-Nq

NF

220 221 rW1 92/17469 Pub. 15 Oct 92 WO '192/17469 Pub. 15 Oct 92

N-N

II

N

H

C -2 819 99 TABLE 11: Angiotensin II Antagonists Compound Structure Source N 0 222 223 224 N0

CH-)

1

N

0

N

WO -"92/17469 Pub- 15 Oct 92 WO 92/17469 pub. 15 Oct 92 WO0 =#92/17469 Pub. 15 Oct 92 C-2 819 100 TABLE 11: Angioterisin II Antagoniists Compound Structure Source

N

N-N

225 74 .19/76 pub. 15 Oct 92 226 227

N'

N- N

IN.

NI

N H WO :9/76 pub. 15 Oct 92 WO -"92/17469 Pub. 15 Oct 92

N

CE

2 C -2 819 101.

TABLE II: Angiotensin II Antagonists Compound Structure Source 222 N -N

N-

I

N 0 CHi 2

N

N

229 0CE 230

CH

2

NN

C-28219 102 TABLE II: Angiotensin Il Antagonists Compound Structure Source

N

02.

D~T 0 232 C~I2

~T

I I 1'jI N H 233

N-N

N,-

C-2819 103 TABLE 11: Arigiotensin II Antagonists Compound -Structure Source 234

I

UNN

N

H

235

CH-)

N H N 0 236

CHE,

H

C-2819 104 TABLE 11: Angiotensin II Antagonists Compound -Structure Source 237 238

CHE

1

NN-

H

N~O

CH

2

NH

CE

2

N-N

2310 WO #92/18092 pub. 29 Oct 92 C-2819 105 TABLE 11: Angiotensin II Antagonists Compound Structure Source 240 241

N

CO-,H

WJO #92/18092 pub. 29 Oct 92 WO #92/18092 Pub. 29 Oct 92

N*

N

N

242 WO #92/18092 Pub. 29 Oct 92 C-2 819 106 TABLE II: Angiotensin II Antagonists Compound Structure Source 243

N-N

IN.

WO"T9/89 pubo. 29 Oct 92

NI

244

N-N

I,

N

H

WO 92/18092 pub. 29 Oct 92

N

CE

2 245

N-N

WO "=92/18092 pub. 29 Oct 92 C-2819 107 TABLE II: Angiotensin II Antagonists Compound Structure Source 246

M

CE,

N-N

N

H

'11O 92/18092 pub. 29 Oct 92

N'

H,

N

N-N

S 'I 247 WO :92/18092 pub. 29 Oct 92

N-(N~

N

N

N. N

N-N

I'

N

248 WO f92/18092 pub. 29 Oct 92 C-28i9 108 TABLE 11: Angiotensin II Antagonists Compound Structure Source

N

249 250 pubO. 29 Oct 92

N-N

CH

2

N

N I

I

W!O 92/18092 pub. 29 Oct 92

CH

2 251 WO 92/18092 pub. 29 Oct 92 C-2819 109 TABLE 11: Angiotensjn II Antagonists Compound Structure Source Na 252 W1O 9/89 pub. 29 Oct 92

H

NJ

N

C!i2 253

N-N

/1

N

pub. 29 Oct 92

N

254

N-N

WO 92/18092 pub. 29 Oct 92 C-28919 110 TABLE II:. Angiotensin II Antagonists Compound 255 Structure Source 0 N C- WO -=92/18092 Pub. 29 Oct 92

N-N

256 257 0 CH 2 WO iE92/18092 pub. 29 Oct 92

CE

N

wO ::,92/18092 pub. 29 Oct 92

N-N

H

C-28iq TABLE 11: Angiotensjn II Antagonists Compound Structure Source

-C

0 258 WO '7 92/18092 Pub- 29 Oct 92

N

259 WO 9/g9 pub. 29 Oct 92

H~

NA

CH,

N-N

H

260 WO u92/18092 Pub-. 29 Oct 92 C-2819 112 TABLE 11: Angiotensin Il Antagoni Compound -Structure 261 262 .Sts Source ,1 #92 /18 0 92 pub. 29 Oct 92 WO '92/18092 pub. 29 Oct 92

N-N

N

N-N

I,

N

N

H

263

N

CR

2

I

WO #-:92/18092 pub. 29 Oct 92 C-2 819 113 TABLE II: Angiotensin II Antagonists Compound Structure H ?C Source WO -9/89 Pub. 29 Oct 92 264

H

265 266

N-N

wO #-92/18092 Pub. 29 Oct 92 WO :E92/18092 pub. 29 Oct 92

N-N

I,

N

N

H

C-28B19 114 TABLE 11: Angiotensin II Antagonists Compound -Structure Source YN ci.

C 267 268 269 WO=9/89 ub. 29Oct 92 WO 792/18092 pub. 29 Oct 92 WO 4-92/18092 pub. 29 Oct 92

N

N-N

N I C-2819 115 TABLE II: Compound Angiotensin II Antagonists Structure Source 270 271 272 ,qO -92/18092 pub. 29 Oct 92

NN

H

0

CH.)

N'

I-

N j filed 8 Mar 94 0 filed 8 Mar 94 C-28is 116 TABLE 11: Compound 272 Angiotensin II Antagonists Structure Source rjled 8 M4ar 94 274 275 N0

&H,

HI

PCT7/US94/ 0 2 1 5 6 filed 8 Mar 94 PCT/US94/ 02156 filed 8 Mar 94 C-2819 117 TABLE 11: Angiotensin II Antagonists Structure Compound source 276 277 278 7'

N

C!1 2

N'

N-N

I

H

PCT/US94/ 0215 6 filed a Mar 94 PCT/Us94/ 021 s 6 filed 8 Mar 94 PCT/US94/0 215 6 filed 8 Mar 94

N

H

N 0 C-2 819 'ABLE II: Angiotensin Il Antagonists Compound 279 280 Structure Source

N'

N-N

N' PCT/JS9 4 /02156 filed 8 r.94 WO0 #91/17148 PUb. 14 'Vov 91 C-2 819 119 TABLE 11: Angiotensjin II Antagonists Structure Source Compound 282 283 284

NN

NNN 0

N

"P 0.=d 5, zL)6 D U :O .a 9 2

WO

pulD. 1S Sep 93 WO 7 93/17628 PU6. 2.6 Sep 93 WO 93/17681 pub. 16 Sep 93 HO 0FN F c C-2819 Compound 285 120 ABLE ii: Angiotensin II Antagonists Structure Source F=53, 553 pub. LNO 92 286 287 'EP #535,463 Pub. 07 Apr 93 EP #3,6 Pub. 07 Aar 9 C-2919 121 -TABLE 1:Angiotensjin li Antagoni~s Compound 6tructure Source 288 289 290 s E{ C 0 F539, 713 Pub. 05 '4ay 93 EP 542,059 pub. 1-9 M4aY 93 2EP #05 557,843 Pub. 01 Sep 93

COOH

.0 CC0OC C-2819 122 TABLE TI: Angioterisi II Antagonists Compound Structure Source 291 EPL563,705 pub. .36 Oct 93 i c 'ooooooooool 0- 292 Pu 562, 261 pu.29 Sep 93 293 EP :E'5 557,843 pub. 2.5 Sep 93 C-28i9 123 .TABLE 11: Angiotensin II Antagonists Compound 4 Structure Source 294 295 296 EP ;1560,163.

Pub. .5 Sem 93 0

N

EP a564, 788 Pub. 73 Oct 93 Pub. 20 ct 93 C-28.19 124 -TA&BLE Angiotensin 11 Antagonists COMPOund 297 Structure Source CTr, E P 6 ,9 298 E'p :"Q,c69,794 Pub. M ~OV 93 N y N7 H~c I C 299 EP#05700 Pub. 1.2 uan 94 C-28i9 125 -TABLE 1:Angioterisin II Antagonists Compound 300

C

N

O

OR

Source

CX.

5p 8 1, 00 3 Pub. 02 Feb 94 301 CH3 N EP :!392,317 N~raNPub" 17 Oct g0 302 zDP '77392,317 Pub. 17 Oct g0 C-2 819 126 -TABLE 11: Angiotensin II Ant.agonis Compound -Structure 303 'Cs Source EP ":502,314 pub. 09 Sep 92 EP 468,740 pub. 29 Jan 92 "204

NN

ICO N I

CDOH

EP i470,543 pub. 12 Feb 92 C-2 819 127 .T-BLE II: Angiotensii II Antagonists Compound Structure Source c.

X

307 308 30-9 j 0 £P 502, '14 Pub. 09 Sep 92 EP -7529,253 pub. 03 M~ar 93 EP 4 ,6 PUhc. 26' may 93 EP F552,765 Pub. 28 Jul 93 C-28919 128 TABLE II: Angiotensii II Antagonists Compound Structure 0 310

CC

311 I~ source ib. 1-8 Aug 93 L25 Aug 93 I

EP

put 312

'N

EP #560,330 Pub. 15 Sep 93 C-2819 129 TABLE 11: Angiotensin II Antagonis Compound Structure 313 ts Source -P "566, 020 Pub. 20 Oct 93 EP 581, 166 Pub. 02 Feb 94 314

OH

WO F.94/01436 Pub. 20 Jan 94 315 C-2819 130 TABLE II: Angioterisin II Antagon Compound Structure 316 317 378 319

X

ists Source -251,31.0 pub. 20 Tj-L 88 EP 4324,377 pub. 19 Jul 89 S-5,43, 349 27 Aug 91.

Pub 10 Jan 9 1 C-2 8i9 131 -TABLE II: Angiotensin II Antagonists Compound Structure Source 0 L 320 321 322 zpub. -4 Y-av92 I N

N

N-H

C02

H

r L- "N (n)H7\

CH/

WO~ 'L92/00977 Pub- 23 Janr 92 323 Cl

CO

2

H

N N-CH 2

C

4 H(n) C-2819 132 TABLE 11: Angiotensin II Antagonists ComPound Structure Source 0 F;C 0 324 325 226 WO F 93/04046 Pub. 04 Mar 93 *Pub. 27 May 93 US 5,219,856 pu. 5 Jun 93 C -2 819 133 TABLE 11: Angiotensjn II Antagonists Corn~structure IH 327 328 329 Source US F5,260,325 Pub- 09 NJov 93 US 5,264,581 Pub- 23 NOV 93 EP #4Q0,974 Pub. 05 Dec C-2819 134 -TABLE 11: Angiotensin II Antagonists Compound Structure Source 330 EP #411,766 Pub- 06 Feb 91 331 EP #412,594 zuD. 13 Feb 91 EP 4419,048 pub.. 27 I~far 91

HC

U N r' 332 C-2 819 135 -ABLE 11: Angiotensin II Antagonists Compound Structure Source 333 334 335 336 "0 '91/12,001 pOub. 22 Aug 91 pub. 22 Aug 9 1 rdO -1/11,9Q9 pub. 22 Aug 91 C-2 819 136 TABLE II: Angiotensin II Antagonist.s Structure Compound 3ource

HO

N N 3327 338 US '"5,053,329 pub. 01 Oct 91 US #5r,057,522 pub 15 Oct 91 WO #-91/15,479 Pub. 17 Oct 91 339 C-2819 137 TABLE 11: Angiotensin II Antagonists Compound Structure Source 340 341 342 EFp "456, 510 Pub- 7-3 Nov 91 EP p7.467,715 pub. 272 Jan 92

OH

US 5,8,0 pub. II Feb 92 C-2819 138 TABLE II: Angiotensin II Antagonists Compound 343 344 Structure Source EP "479,479 Pubo. 08 Apr 92 CH3

NN'

345 E F' 4 81, 614 Pubo. 22 Aar 92 C-2 819 139 -TABLE I I: Angiotensin II Antagonists Compound Structure Source 346 .347 348 EP '=490,587 Pub. 17 Jun 92 US 5,128,327 pub. 07 Jul 92 US -75,132,216 pub. 21 Jul 92 C-2819 140 -TABLE.II: Angiotensin Il Antagonis Compound -Structure ts Source FP 7-497,516 Pub. 05 Aug 92 349 350 FP -502,725 pub. 09 Sep 92 EP -4502,575 pub. 09 Sep 92 C-2 819 TAkBLE 11: Angiotensin II Antagonists Compound Structure Source 352 353 354 I c EP ~O,3 pub. 2.6 sep 92 EP 50,1 pub. 23 Sep 92 EP #-505, 09 pub. 23 Sep 92 C -2 819 142 -TAEBLE 11: Compound Angiotensin II Antagonists Structure Source Pub. 07 Oct 92 Nl 356 357 EP 1508,723 Pub. 7-4 Oct 92 N' *N-H

F

5

C

C

4 HS(n) C -2 819 143 -TABLE II: Angniotensin II Antagonists Compound Structure Source 358 N 0 EP #512,675 pub. INv9 0

N

359 0 EP ti5l2,676 pub. NLIV92 360

CIL

HN 0 EPF S12 pub. -jNOV 9 2 C -2 819 .144 .TABLE II: Angioteusin II Antagonis Compound 'Structure t s Source EP ":S13,979 pu'b. 19 Nov 92 361 362 0* 0; o WO92/20,6,50 Pub- 26 Nov 92 ~qou92,20,61 /pub. 26 Nov 92 363 C-2 819 145 Angiotensjn II Antagonists

TPABLE

Compound 364 -11: Structure Source WO "r92/20,662 pub. 26r-ov9 365 366 WO 92/20,687 pub. 26 Nov 92 EP #517,357 Pub- 09 Dec 92 C-2819 146 TABLE II: Angiotensjn II Antagonists Compound Q f-- "kJ- UL. e I C source 367 368 369 Pu-b. 2-1 Jan 93 US 5,1871, pub. 16 Feb 93 US* #5 ,198,438 pub- 20 Mlar 93 C -2 819 147 MABLE li: Angiotenin II Aritago Compound -Structure 370 371 372 fliSs Source pub. 13 Aar 93 EP -#537,937 Pub" 21 ApOr 93 us 4L5,217,882 Pub. 0 Jun 93 C-2819 148 -TABLE II: Angiotensin II Antagonists Compound uc ture

N

373 374 375 Source US 214,.53 Pub, 25 M"ay 93 Pub 08 JTunl 93 US 45,236,928 Pub. 17 Aug 93

NIH

C-2 819 149 .TABLE. 1I: Compound Angiotensin 11 Antagonists Structure Source

N

N

376 37,7 US 5,240,938 Pub- 31 Aug 93 TB#2 264,709 Pub* 68 Sep 93 378 GE #2,264,710 Pub. 08 Sep9 C-2819 150 TABLE 11: AngiOtensjin II Antagonists Compound 379 Structure Source US ~S5,667 pt-6b 26 Oc 9 0 380 0

S

N

381 0 "o~ 0 US 4;5,525,574 Pub. 12 Oct 93 WO 9i23g Pub, 25 -\rOV 93 C-2 819 151 -TABLE 11: .Angiotensin II Antagonists Compound

C

tLI.ucture Source US -5 E24j pub' -6 "40oV 93 382 383 384

?L;C

OH- US :05,264,447 Pub. 23 NOV 93 US #u-5,266,583 Pub. 01 Selo 92 C-2 81.9 152 -TABLE 11: Angiotensin II Antagonists Compound Structure Source :fO Lc 385 US =5,276,054 Pub- 04 Jan 94 Q

HO

I c

OH

F c 0

CIN

0 386 US -;5,278,o68 pu.11 Jan 94 C-2819 153 TABLE II: Angiotensjn II Antagonists Compound

C+

-IU LL ure 387 Source Pub. 03 Feb 94 WO :L94/02467 Pub. 03 Feb 94 0N f 388 389 EP Ld0,~ Pu Ib. 19 Dec go C-2819 154 TABLE II: Angiotens in II Antagonists Compound StrLucture Source 390 391 392 SP 425,271 Pub. *J2 M4ay 92 EP :!427,463 Pub 2.5 M'ay 91 Pub. 39 Jan 92 C-2819 155 -TABLE 11: Angiotensin II Antagonists Compound 393 Structure Source .;0o "92/02,Sio zub. 2)0 Feb 92 394 395 396

OH

WO:92/09278 Pub. 11 Jun, 92 5 JUn 92

C

4

H

9 (n) C-2 819 156 TABLE ii: Angiotensjn II Antagonists Compound #-Structure Source

CNH

2 3 9 N

H

NC N -N 38N 0 -CH 2

\/C

H

5

C

2

N,

N..NN-H

C -2 819 157 -TABLE II: Angiotensin II Antagonists Compound Structure Source 400 401 402 0

O-C

2

H-

5

N

N-H

/N

CH3 0 Ph-H C0 2

H

N -C H 2

O-C

2

H

5

!N

NN'N-H

C-28iq TA13LE 1I: 158 Angiotensin II Antagonists Compound 403 Structure Source 25 uln 92 404 405 0

CF

3 N

N.

N CO 2 HN

N-H.

N~ N -CH2- 0 1 CS

NH-C..NHCH,

H H0 2

C

N N-CH2

N-C

C,

4 Hg C-28j19 159 TABLE 1I: Angiotensjn II Antagonists Comnpound Structure Source

N-N

'c'K 406 407 408 WO'L-92/20651 Pub. 26 NOV 92 WO 93/03Oja Pub.- 18 Feb 93 C-2819 Compound 409 160 rABLE I: Angiotensjn II Antagonists Structure Source N HH 0 p1 =4/00120 Pub. 06 JTan 9 4 410 411 E:P "r459,136 Pub. 04 Dec 91 EP 4:411 507 Pub. 05 Feb 91

CHI

C-2819 161 TABLE 11: Angiotensin II Antagonists Compound I- 1U L ure

CO-H

412 413 414 Source zo 425,921 Pub. 08 may 91 EP 43 ,0 pub. 05 JTun 91 #P 434,038 pub. 26 Jun 91 C -2 819 162 TABLE II: Angiotensin Il Antagonists Compound Structure Source FCl

-N

I

I

N~

.N~

415 416 EP 7442,473 Pub. 21. Aug 91.

EP 1=443,568 Pub* 28 Aug 91 477 2P #5,3 Pub. 04 Dec 91.

C-2 819 163 -TABLE 11: Compound 418S Angiotensin II Antagonists Structur-e Source EP #-483, 683 Pub 05 M4aY 92 419 420 1 Pub. 16 Dec 92 EP ;--520,423 Pub. 30 Dec 92 C-2919 164 TABLE 11: Angiotensin II Antagonists Compound 421 Structure Source pu-b. 16 Jun 93 422 Nz WO -r93/00341 Pub. 07 Jan 93 WO #:92/06081 Pub- 16 Apr 92 422

HN

CH

C-2819 165 TABLE 11: Angiotensjn II Antagonists Compound Structure Source

X

424 0 1 =-9/130341 H~C Npubo. 07 Jan 93 0 N F

F

425 0 US =3,210,204 pub. 11 M4ay 93 I1sc 0 0 HO.Ic or 0

H

4 2 6 N iE P 3 4 3 6 5 4 0 0 0 OH pub. 29 Nov 89 C-2819 166 TABLE IT: Compound 0 4 27 Angiotensin II Antagonists Structure Source '14-3/13077 Pu.08 Jul 93

NC

NC

428 429 '10 im93/15734 Pub* 19 Aug 93 US #5,246 943 Pub. 21 Sep 93 0; 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- grdup. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The term "cycloalkyl" embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups.

A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2, 2 ,3,3-tetrafluoropropyl groups. The term "difluoroalkyl" embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The terms "alkylol" and "hydroxyalkyl" embrace linear or branched C-2819 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 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-2919 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 alkanoyl" is an example of a more prefered sub-class of acyl. The term "amido" denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein.

The term "monoalkylaminocarbonyl" is interchangeable with "N-alkylamido". The term "dialkylaminocarbonyl" is interchangeable with "N,N-dialkylamido". The term "alkenylalkyl" denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term "heteroaryl", where not otherwised defined before, embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity 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 are the isomeric forms of the above-described angiotensin II receptor compounds and the epoxy-steroidal aldosterone receptor compounds, including diastereoisomers, regioisomers and the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable.

Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.

Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2 -hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, C-2819 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.

C-2819 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 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 Binding Activity Compounds of the invention were tested for ability to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin II (AII) was purchased from Peninsula Labs. 12 5 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 (Endocrinoloc,, 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4 0 C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at pH 7.4 containing 5 mM EDTA. The homogenate was C-2819 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 MgC12, 2 mM EDTA, 0.5% bovine serum albumin, mM Tris-HC1, pH 7.5 and 1 25 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 250C 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 assayed for radioactivity in a Micromedic gamma counter.

Nonspecific binding was defined as binding in the presence of 10 4M 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 12 5 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 AIl 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 370C, between moveable and fixed ends of a C-2819 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 1.1.4 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., 2,189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for AII by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table III.

Assay C: In Vivo Intracastric Pressor Assay Response for All An taonists 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 C-2819 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 pl volume with a 0.2 ml saline flush. The pressor response in mm Hg was measured by the difference from pre-injection arterial pressure to the maximum pressure achieved. The AII injection was repeated every 10 minutes until three consecutive injections yielded responses within 4 mmHg of each other. These three responses were then averaged and represented the control response to AII. The test compound was suspended in 0.5% methylcellulose in water and was administered by gavage. The volume administered was 2 ml/kg body weight. The standard dose was 3 mg/kg. Angiotensin II bolus injections were given at 30, 45, 60, 75, 120, 150, and 180 minutes after gavage. The pressor response to AII was measured at each time point. The rats were then returned to their cage for future testing. A minimum of 3 days was allowed between tests. Percent inhibition was calculated for each time point following gavage by the following formula: [(Control Response Response at time point)/Control Response] X 100. Results are shown in Table

III.

Assay Hypertensive 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-2819 176 AII Antagonist (mg/kg/day) 3 Epoxymexrenone (mg/kg/day) 5 100 200 5 100 200 5 100 200 Combination of AII Antagonist Epoxymexrenone (mg/kg/dav) (ma/ka/day) 3 3 3 3 100 3 200 10 10 10 10 100 10 200 30 30 30 30 100 30 200 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: AII Antagonist (mcg/kg/day) 3 Epoxymexrenone (mg/kg/day) 5 100 200 5 100 200 5 100 200 Combination of AII Antagonist Epoxymexrenone (mg/kg/day) (mg/kg/day) 3 3 3 3 100 3 200 10 10 10 10 100 10 200 30 30 30 30 100 30 200 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 -2 819 178 TA BL E II I In Vivo and In Vitro Anaiot~ensin II Activity of Comnodunds of the Invention Test 'Assay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Example (nM) (mg/kg)

I

2 3 4 5 6 7 a 9 12 13 14 16 17 18 19

NT

95 5.4

NT

2 00r 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 8.9S/9.24.

8 .64/8.40 6. 14/6.09 5.18/5.35

NT

10 10

NT

30 100 30

NT

30 100 3

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

95 98 s0 100

NT

38 90 90 N T 80 100 86 100

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

90 -120 >180 200+

NT

20-30 120 130

NT

130 100 240

NT

NT

NT

NT

NT

NT

NT

NT

NT

C -2 819 179 Test 1 Assay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibit ion Duration Examole (rim) (rna/ka) M% (min.) 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 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 6.90/6.8S 7 .82/8 .36 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

NT

NT

NT

NT

10

NT

NT

NT

30

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

MT

10

NT

NT

NT

NT

NT

50

NT

NT

NT

50

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

>180

NT

NT

NT

>180

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

C -2 819 180 Test lAssay A 2 Assay B 3 Assay C Compound IC 50 pA 2 Dose Inhibition Duration Example 4 (nM) (ma/kq) (min.) 47 48 49 51 52 53 54 56 57 58 59 61 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 9.04/8.35 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 7.6S/7.46

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

MT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

C-2819 181 Test Compound Exainole 74 76 77 78 79 81 82 83 84 86 87 88 89 91 92 9 94 96 97 98 99 100 1013 'Assay

A

ICS

50 2 AssayB PA2 Dose Dose k W-4 6.5 570 5400 15, 000 101.

4.9 25 18 7.9 3 .6 16 8 7 9 91 s0 18 5. 6 30 35 480 5, 800 66 21 280 22 280 6 7 8.56/8.39 6.00/5.45 5.52/5.78 5.77 7.0 9.2 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

NT

8.2 8 .0 7.7 8.1 3 Assay

C

Inhibition Duration M% (min.) UT

NT

NT

NT

NT

NT

NT

NT

93 60-100 100 >200 50 >180 NT

NT

40 180 20 180 15 >180 20 NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

40 ->180 NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT

NT NT C- 28 19 182 Test 'Assay

A

Compound

ICS

0 Example (nM) 102 43 103 12 104 15 105 290 106 48 107 180 108 720 109 250 110 590 ill 45 112 2000 113 12 114 400 115 11 116 230 117 170 118 37 9..

119 16 9.: 120 25 9 121 46 122 46 123 so 124 40 9 .4 125 40 9 .2 2 Assay

B

pA 2 3 Assay c Inhibition Duration Dose 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 21/9.17 21/9 .00 O5/8.77

NT

NT

NJT

2/9 .12 5/8.80 100 30 30 10 3.

10 3 10 3 3

NT

NT

NT

NT

NT

NT

45 so

NT

87

NT

G0

NT

40

NT

NT

70 20 80

NT

HT

NT

45 35 (min.

NT

NT

NT

NT

NT

NT

NT

160

NT

180 -2 120 240 >180 >240 C-2 819, 183 Test Compound Example 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 1 As say A

IC

5 0 (nM) 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 2 Assay

B

pA 2 Dose ULLc KJa) 7.20/7.05 4 .96 8.63/8.40 5.30 8 .10/7.94 7.53/8.25 8.6 8.7 3 Assay

C

Inhibition Duration (min.)

NIT

NT

NT

NT

NT

180 90 -120 180 >180 9.3

NT

8.3 8.2 6.3 8.1 8 .02

NA

7.7 7.7 6.7 6.4 100

NT

NT

85 s0

NT

NT

160

NT

NT

125

NT

NT

C-2819 184 Test 'Assay A 2 Assay B Compound

IC

5 0 pA 2 Exaxnple 0 (rim) 147 5.8 5.6 148 0.87 5.8 149 1.1 6.1 150 1,i 8.03/7.80 151 17 7.76/7.97 152 ISO 7.46/7.23 153 13 8.30/7.69 154 97 8.19/8.38 155 86 7.60/7.14 156 78 8.03/7.66 157 530 /6.22 158 54 8.23/8.14 159 21 7.92/7.56 160 64 7.87/7.71 161 28 162 380 6.21/6.55 163 420 7.42/6.75 164 1700 165 410 6.90/7.18 Dose (mg/kg) 3 3 3 3 3 3 3 3 Assay

C

Inhibition Duration (min.) 74 5-10 92 20-30 NT

NT

25 >180 15 180 10 140 25 >180 >180 150 C- 28 19 185 Test Compound Example 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 1 Assay A 2 Assay B 3Assay

C

IC

50 pA 2 Dose Inhibition Duration L nM (ma/ka) M% (min.) 160 370 420 150 26 28 70 90 180 27 9.8 26 88 310 20 21 69 390 1100 7.57/7.74 7.08/7.11 7.69/7.58 7.78/7.58 7.08/7.77 7.S2/7.11 7.15/7.04 7.49/6.92 7.29/7.02

NA

7.69/7.55 7.41/7.85 7.54/7.47 6.67/ 7.56/7.15 7.70/7.12

NA

NA

6.78/

NA

NA

NA

180 >180 0 0 150 180 C -2 819 186 Test 'Assay A 2 Assay B 3 Assay 'C COmpound

ICS

0 p".Q Dose inhibition Duration Examle (nM) (inn/krTi (min.) 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 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 7.46/6.9S 7.72/7.09 8.64/8.23 7 .87/7.89 7.75/7.76 9.27/8.87 7 .64/7 8.44/8.03 7 .68/a8.26 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

NA

NA

NA

8.80/9.04 180 180 180 180 180 180 180 180 180 180 1> 180 180 180 180 180 180 >180 180 180 C-2819 187 Test 1 Assay A 2 Assay B 3 Assay C Compound

IC

50 pA 2 Dose Inhibition Duration Example (riM) (Inc/kg) W% (min.) 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 9.4 9 .0 14 7.0 4.8 5.0 14 91 160 93 89 4.5 19 2.6 3.6 4.4 84 5.0 34 4 .9 3. 6 1.7 6.8 120 6.9 110 250 150 98 72 9.4

NA

NA

NA

NA

NA

NA

7.45/7.87

NA

NA

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

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 8.26/8.41 180 120 180 *180 >180 >180 >180 >180 >180 >180 >180 >180 >180 C-28.1.9 188 Test iAssay A 2 Assay B 3 Assay

C

Compound IC5 0 pA 2 Dose Inhibition Duration Example (nM) (mg/kg) (min.) 248 20 7.68/7.50 3 10 249 4.4 NA 3 20 >180 250 43 NA 3 0 251 25 NA

NA

252 13 NA

NA

253 2.6 NA

NA

254 72 NA

NA

255 12 7.61/7.46 3 20 >180 256 4.1 8.43/7.78 3 30 >180 257 160 6.63/6.68

NA

258 350 6.84/6.84

NA

259 54 NA

NA

260 220 NA

NA

261 18 NA

NA

262 53U -/6.22

NA

263 57 NA

NA

264 11 NA

NA

265 110 NA

NA

266 290 NA

NA

267 25 NA 3 25 >180 268 520 NA 3 0 269 9.7 NA

NA

270 21 NA

NA

271 14 NC 3 20% 272 97 NC 3 70% >180 min.

273 9.8 8.53/8.61 3 25% >180 min.

274 13 9.06/8.85 3 35% >180 min.

275 6.3 9.07/ 3 40% >180 min.

276 33 8.71/8.64 3 277 190 /6.54

NT

278 30 8.49/8.51 3 50% >180 min.

279 270 8.06/8.25

NT

280 480 6.41/6.35 NT NT Xo C-2819 189 NT =NOT TESTED NC =Non-Competitive antagonist *Antagonist Activity not observed up to 10 im of testcompound.

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, #118 and #139-#149 which were given intraduodenally.

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 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, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.

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

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 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.

Claims (8)

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.

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-

17-hydroxy-3-oxo,y-lactone, methyl ester, (7a, 11 a, 17a)-; pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy- 17-hydroxy-3-oxo-dimethyl ester,(7a, 11 a, 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,73,11p,17p)-; pregn-4-ene-7,21-dicarboxylic acid,9,11- epoxy-17-hydroxy-3-oxo-,7-(1-methylethyl) ester, monopotassium salt,(7a,11 a,17a)-; pregn-4-ene-7,21-dicarboxylic acid,9,11,-epoxy- 195 1 7-hyd roxy-3-oxo-, 7-ml ethyl ester, monopotassium 3'H-cyclopropai6 ,7pregna-1 ,4,6-triene-21 -carboxylic acid, 9,11 -epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,y-lactofle( 6 aO(, 1li.cX)-; 3'H..cyclopropa6,7]pregna-4,6..diene- 2 l -carboxylic acid, 9,1 1-epoxy-6,7-dihydro-1 7-hydroxy-3-oxo-,mfethyl ester, (6cC,7t, 11aC, 1 7c)-; 3'H-cyclopropa[6 ,7]pregna-4,6-diefle- 2 I -carboxylic acid, 9,11 -epoxy-6,7-d ihyd ro-1 7-hyd roxy-3-oxo-, rnonopotassiurnl salt, (6cc, 7 cx, 11 a, 1 7ax)-; 3'-ylpoa67prga46dee2 -carboxylic acid, 9,11 -epoxy-6 ,7-dihyd ro-1 7-hydroxy-3-oxo-,7- pregn-4-ene-7, 2 l -dicarboxylic acid, 9,11 -epoxy- 1 7-hydroxy-3-oxo-,y-Iactofle, ethyl ester, (7x,l 11C, 1 7 and pregn-4-ene-7, 2 l -dicarboxylic acid, 9, 11 -epoxy- 1 7-hyd roxy-3-oxo-,y-lactofle, 1 -methylethyl ester, (7cx,l1 ct,l1 7 6. The combination of Claim 1 wherein said angiotensin 11 receptor antagonist is 5-dibutyl-1 H-i ,2,4-triazol-1 -yl)methyl1-2-pyridinyl]pheflyll H-tetrazole or a pharmaceutically-acceptable salt thereof and said epoxy-steroidal aldosterone receptor antagonist is 9Cx-, 11 Cxepoxy7Cx-methoxycarbnyl-2spirox 4 ene- 3 2 l-dione or a pharmaceutically-acceptable salt thereof. 196 7. The combination of any one of Claims 2. to wherein said angiotensin II receptor antagonist is selected from the group consisting of; saralasin acetate, candesartan cilex etil, CGP-63170, 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-B1057, LY-235656, PD-i 50304, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-3 1472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, P0-123177, A-81988, BMS-180560, CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, I0-06888, 10-07155, [CI-D8731,. isoteoline, KRI-1 177, L-1 58809, L-1 58978, L-1 59874, LR B087, LY-285434, LY-302289, LY-31 5995, RG-1 3647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan, saralasin, Sarmesin, WK-i 360, X-6803, ZD-6888, ZD-71 ZD-8731, 81BS39, 01-996, OMP-811, DuP-532, EXP-929, L-163017, LY-301875, XH-148, XR-510, zolasartan and P0D-123319. 8 .The combination of Claim 7 wherein said angiotensin 11 receptor antagonist is selected from the group consisting of: saralasin acetate, candesartan cilexetil, CGP-631 EMD-66397, KT3-671, LR-B/081, valsartan, A-8 1282, BIBR-363, BIBS-222, BMS-1 84698, candesartan, CV-1 1194, EXP-31 74, KW-3433, L-i161177, L-1 62154, LR-B/057, LY-235656, P0-i 50304, U-96849, U-9701 8, UP-275-22, WAY-i 26227, WK-1492.2K, YM-31472, losartan potassium, E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-1 59282, ME-322i, SL-9i.0102, Tasosartan, Telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-1 59689, L-162234, L-162441, L-1 63007 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. 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.

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. 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 26 day of March 2003 G. D. SEARLE CO., By its Patent Attorneys, SF. WELLINGTON CO., A/KA/4319