AU757071B2 - Method of treating heart failure with endothelin antagonists - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT(S): Banyu Pharmaceutical Co., Ltd.

ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Method of treating heart failure with endothelin antagonists" The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\MKR\GENERAL\723351-div.doc 22111/00 Ct I P:\OPERkMKRSPECI7233S I-div.doC-22/I 1/00 -1- METHOD OF TREATING HEART FAILURE WITH ENDOTHELIN ANTAGONISTS This is a divisional of patent No. 723,351 (22025/97), the disclosure of which is included herein in its entirety.

FIELD OF THE INVENTION The present invention is concerned with prevention and/or treatment of heart failure with compounds that are endothelin antagonists.

BACKGROUND OF THE INVENTION Endothelin is a 21-amino acid peptide produced by endothelial cells. The peptide is secreted not only by vascular endothelial cells but also by tracheal epithelial cells or from kidney cells. Endothelin (ET-1) has a potent vasoconstrictor effect. The vasoconstricting effect is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells.'-3 Endothelin-1 (ET-1) is one of three recently identified potent vasoconstricting peptides which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3) whose sequences differ from ET-1 by two and six amino acids, respectively.

4 Increased levels of endothelin are found in the blood of patients with essential 20 hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease or atherosclerosis or in the washing fluids of the respiratory tract of patients with asthma compared to normal levels.

5 8 An experimental model of cerebral vasospasm and a second model of acute renal failure have led to the conclusion that endothelin is one of the mediators causing cerebral 25 vasospasm following a subarachnoid hemorrhage, and renal failure.9 10 Endothelin was also found to control the release of many physiological substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A 2 ,1 4 prostacyclin, norepinephrine, angiotensin II and substance P.

11 -16 Further, endothelin causes contraction of the smooth muscle of the gastrointestinal tract and the uterine smooth muscle.

7 1 9 Endothelin has also been shown to promote the growth of rat vascular smooth 2 muscle cells which would suggest a possible relevance to arterial Endothelin receptors are present in high concentration in the peripheral tissues and also in the central nervous system, and cerebral administration of endothelin has been shown to induce behavioral changes in animals, suggesting that endothelin may play an important role in controlling neural functions.

2 1 Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelin is an important mediator for endotoxin-induced diseases.

22 23 A study has shown that cyclosporin added to a renal cell culture, increased endothelin secretion.

24 Another study has shown that administration of cyclosporin to rats, led to a decrease in the glomerular filtration rate and an increase in the blood pressure, in association with 1s a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the administration of anti-endothelin antibody.

25 These studies suggest that endothelin is significantly involved in the pathogenesis of cyclosporininduced renal disease.

20 A recent study in patients with congestive heart failure demonstrated a good correlation between the elevated levels of *endothelin in the plasma and the severity of the disease.

26 Endothelin is an endogenous substance which directly or indirectly (through the controlled release of various other endogenous substances) induces sustained contraction of vascular or non-vascular smooth muscles. Its excess production or excess secretion is believed to be one of the factors responsible for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, acute renal failure, myocardial infarction, angina pectoris, arteriosclerosis, cerebral vasospasm and cerebral infarction. See A. M. Doherty, Endothelin:.A New Challenge J. Med. Chem., 5 1493-1508 (1992).

Substances which specifically inhibit the binding of endothelin to its receptor are believed to block the physiological effects of endothelin and are useful in treating patients with endothelin related disorders.

The novel compounds of the present invention are useful as a non-peptidic endothelin antagonists, and have not been disclosed in any issued patents or published patent applications. Among the published patent applications disclosing linear and cyclic peptidic compounds as endothelin antagonists are the following: Fujisawa in European Patent Application EP-457,195 and Patent Cooperation Treaty (PCT) International Application No. WO 93/l14, Banyu in EP-436,189 and 460,679, I~munopharmaceutics Inc. in WO 93/225580, Warner Lambert Co. WO 92/20706 and Takeda Chemical Ind. in EP-528,3 12, EP-543,425, EP-547,317 and WO) 91/13089.

Fujisawa, has also disclosed two nonpeptidic endothelin.

antagonist compounds: atrqione derivatives produced by a process using S=tmye sp. No. 89009 in EP-405,421and U.S. Patent No. 5,187,195; and a 4-phenoxyphenol derivative produced by a fermentation process using Penicillium citreonigrm F- 12880 in a UK Patent Application GB 2259450. Shionogi and Co. has also disclosed nonpeptidic endothelin antagonist triterpene compounds were produced by a fermentation process using Mydca cerifem 0~ in WO 92/12991.

:Amon thenon-peptidic endotbelin. Aantagonis compounds imon inthe ptn ieaue w~~icl am: nw nth aetlteaueae 1) a series. of substituted 44fiolinoxy)methylbiphenylcarboxylic acids disclosed by Roussel- 810fin EP-498,723; 2) a series of of N-(4-pyrimidinyl)benzenesulfonamides with different substitution patterns from Hoffmann-La Roche published in EP-510,526, EP-526,708 and EP-601,386; 3) a series of naphthalenesulfonarnides and enenesulfonamides disclosed by E.R. Squibb Sons in EP-558,258 and EP-569,193, respectively-, 4) a series of compounds represented by 3-(3-indolylmethyl)-1,4-diaza-2,5o dioxobicyclo[4.3.Olnonane-9-carboxylic acid from 0 ImmunoPharmaceutics Inc. in WO 93/23404; 5) a'series of fused [1,2,4]tbiadiazoles substituted with an irninosulfonyl substituent from Takeda Chemical Id. has been disclosed in EP-562, 599; and 6) a series of indane and indene derivatives from SmithKline Beecham Corp.

disclosed in WO 93/08779; and a series of related phenylalkyl derivatives from SmithKline Beecham disclosed in WO 94/02474.

REFERENCES

1 Nature, 411-415 (1988).

2 FEBS Letters, 2M, 440-444 (1988).

3. Biochem. Biophys. Res. Commun. 14, 868-875 (1988).

4 TPS, 103-108, March 1992.

Japan J. Hypertension 12, 79 (1989).

6 J. Vascular Medicine Biology, 2, 207 (1990).

7 J. Am. Med. Association, 24, 2868 (1990).

8 The Lancet, ii, 207 (1990) and The Lancet, ii, 747-748 (1989).

9 Japan. Soc. Cereb. Blood Flow Metabol. .L 73 (1989).

J. Clin. Invest, D, 1762-1767 (1989).

11 Biochem. Biophys. Res. Comm. 152, 1164-1168 (1988).

12 Biochem. Biophys. Res. Comm. 1, 167-172 (1989).

13 Proc. Natl. Acad. Sci. USA, B. 9797-9800 (1989).

*2 o 14 J. Cardiovasc. Pharmacol., 11, 589-592 (1989).

15 Japan. J. Hypertension 12, 76 (1989).

16 Neuroscience Letters, 1&Z, 179-184 (1989).

17 FEBS Letters, 242. 337-340 (1989).

18 Eur. J. Pharmacol. 154., 227-228 (1988).

19 Biochem. Biophys. Res. Commun., I52 317-323 (1989).

Atherosclerosis, 12L 225-228 (1989).

21 Neuroscience Letters, M2 276-279 (1989).

22 Biochem. Biophys. Res. Commun. 6L., 1220-1227 (1989).

23 Acta. Physiol. Scand., 112 317-318 (1989).

3o 24 Eur. J. Pharmacol., 180, 191-192 (1990).

KidneyInt. 1487-1491 (1990).

26 Mayo Clinic Proc., aL 719-724 (1992).

fI P:\OPER\MKR\SPECI\723351-div.do.22 1/00 SUMMARY OF THE INVENTION The present invention is concerned with the prevention and/or treatment of heart failure and ventricular dysfunction with endothelin antagonists.

According to one embodiment of the invention there is provided an endothelin antagonist selected from the group consisting of: 6S, 7S)-2-butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine; 6S, 7S)-2-butyl-6-carboxy-7-[(S)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3,4-methylenedioxyphenyl)cyclopenteno[ 1,2-b]pyridine; (5S, 6R, 7R)-2-butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine; and 6R, 7R)-2-butyl-6-carboxy-7-[(S)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine.

According to another embodiment of the invention there is provided a pharmaceutical composition comprising an endothelin antagonist as outlined above, or a pharmaceutically acceptable salt thereof, and an excipient or carrier.

According to a further embodiment of the invention there is provided use of an endothelin antagonist as defined above in preparation of a pharmaceutical composition for preventing and/or treating heart failure and ventricular dysfunction in a warm blooded 20 animal.

BRIEF DESCRIPTION OF THE FIGURES Figure 1.

Measurements of LV dP/dt, mean left atrial pressure, mean arterial pressure and heart rate 25 made in the same conscious pigs before and after development of heart failure, and 60 min after injection of Compound 1 (0.5 mg/kg, during the heart failure stage. Data are mean SE and the number of animals studied is in parenthesis.

o* P\OPER\MKR\SPECI\723351-div.doc-22/ /00 Figure 2.

Measurements of cardiac index, stroke volume, total peripheral resistance and LV velocity of circumferential fibre shortening (Vcf) made in the same conscious pigs before and after development of heart failure, and 60 min after injection of Compound 1 (0.5 mg/kg, i.v.) during the heart failure stage. Data are mean± SE and the number of animals studied is in parenthesis.

Figure 3.

Effects of Compound 1 (0.5 mg/kg, on mean arterial pressure, mean left atrial pressure, cardiac index and total peripheral resistance in conscious pigs after development of heart failure. Values are expressed as the percent changes from baseline levels, except mean left atrial pressure which is change from baseline value in mmHg. Data are mean± SE and the number of animals studied is in parenthesis.

ooooo* Figure Effects of Compound 1(0.5 mg/kg, and Compound 2 (1 mg/kg and 4 mg/kg, on total peripheral resistance in conscious pigs after development of heart failure. Values are expressed as the percent changes from baseline levels. Data are mean±SE and the number of animals studied is in parenthesis.

Figure 6.

Comparison of the mean arterial pressure (MAP), LV dP/dt, cardiac output (CO) and total peripheral resistance (TPR) responses at 60 min after injection of Compound 1 (0.5 mg/kg, or Compound 2 (1 mg/kg and 4 mg/kg, in conscious pigs after development of heart failure. Values are expressed as the percent chances from baseline levels. Data are mean*SE and the number of animals studied is in parenthesis.

Figure 7.

Effects of endothelin-1 (ET-1, 0.1 to 0.5 gg/kg, on mean arterial pressure, mean left arterial pressure, total peripheral resistance and heart rate in conscious pigs after development of heart failure with and without Compound 1 (0.5 mg/kg, Values are expressed as the percent changes from baseline levels, except mean left aterial pressure which is change from baseline value in mmHg. Data are mean±SE and the number of animals studied is in parenthesis.

Figure 8.

Chronically instrumented heart failure model.

DESCRIPTION OF THE INVENTION The present invention involves a method of preventing and/or treating heart failure and ventricular dysfunction in a warm blooded animal which comprises administering to the warm blooded animal in need of such treatment a therapeutically effective amount of an 7 endothelin antagonist of the formula: Ar' A

(I)

S Y

R

3 Ar 2 or a pharmaceutically acceptable salt thereof wherein each of Arl and Ar 2 is independently a phenyl group, a thienyl group, a pyridyl group, an indolyl group, a benzofuranyl group or a dihydrobenzofuranyl group wherein an optional hydrogen atom(s) on the aromatic ring may be replaced with 1 to 4 groups selected from the group consisting of a halogen atom, a hydroxyl is group, an amino group, a carboxyl group, a C1-Cg alkoxycarbonyl group, a mono- or di- CI-C 6 alkylaminocarbonyl group, a carbamoyl group, a group, a methylenedioxy group, a C 1

-C

6 alkoxy group, a

C-C

6 alkenyloxy group, a mono- or di- C 1 alkylamino 20 group, a C 1

-C

6 alkyl group, a C 2

-C

6 alkenyl group and a

C

2

-C

6 alkynyl group (provided that the C 1 -Cg alkoxy group, C 2

-C

6 alkenyloxy group, mono- or di- CI-C 6 alkylamino group, C 1

-C

6 alkyl group, C 2

-C

6 alkenyl group and C 2 alkynyl group may be substituted by 1 to 3 25 groups selected from the group consisting of a phenyl group, a pyridyl group, an imidazolyl group, a hydroxyl group, a C 1

-C

6 alkoxy group, an amino group, a mono- or -8 di- c 1

-C

6 alkylamino group, a hydroxy C 1 -c 6 alkylcarbonyl group, a C 1

-C

6 acyloxy C 1

-C

6 alkyicarbonyl group, a carboxy C 1

-C

6 alkoxycarbonyl group, a carboxy c 1 -c 6 alkoxycarbonyl

C

1

-C

6 alkoxycarbonyl group, a C 1

-C

6 s alkoxycarbonyl group, a mono- or di- c,-C 6 alkylaminocarbonyl group, a carbamoyl group, a 16 alkylsulfonylaminocarbonyl group, a carbonyl group, a carboxyl. group, SO3H, P0 3

H

2 1 a group, a 2 -oxo- 3 H-l,2,3,5-oxathiadiazol-4-yl group and a 5-oxo- 4 H-1,2,4-oxadiazol.3.yl group (provided that when a hydroxyl group and a carboxyl. group are selected as substituents, they may together form a lactone ring)); each of R 1

R

2 and R 3 is independently a hydrogen atom, isa hydroxyl group or a C 1

-C

6 alkyl group, or R 1 and R 2 or R 2 and R 3 together form a single. bond; Y is a group of -CO-R 4 (wherein R4 is a hydroxyl group,.

an amino group, a C 1

-C

6 alkoxy group, a mono- or -di-

C

1

-C

6 alkylamino group, a C 1

-C

6 alkylsulfonylamino group, or an arylsulfonylamino group or aryl c1-c 6 alkylsulfonylamino group wherein an optional hydrogen atom(s) on the aryl ring may be replaced with aC alkyl. group), SO 3 H, P0 3 a tetrazol-5-yl group, a .2-oxo-3H-1,2,3, 5-oxathiadiazol-4-yl group or a 5-oxo-4H-l,2,4-oxadiazol-3-yl group; and A is a group which forms together with the adjacent carbon-carbon double bond a 5- or 6- membered 9 heteroaromatic ring including 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (provided that optional 1 or 2 hydrogen atoms on the heteroaromatic ring may be replaced with a hydroxyl group, an amino group, a C -C 6 alkoxy group, a Ci-C 6 alkylthio group, a halogen atom, a cyano group, a nitro group, a mono- or di- C -C 6 alkylamino group which may be substituted by a hydroxyl group at the alkyl moiety, a C3-Cg cycloalkylamino group which. may be substituted by a hydroxyl group at the alkyl or alkylene moiety, a C 3

-C

8 cycloalkyl C -C 6 alkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(Cl-C.

alkyl)-N-(C 3

-C

8 cycloalkyl)amino group which may be is substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(C 1

-C

6 alkyl)-N-(aroyl)amino group which may be substituted by a hydroxyl group at the alkyl moiety, a C 4

-C

7 cyclic imino group which may be substituted by a hydroxyl group at the alkylene moiety, 20 a carboxyl group, a C 1

-C

6 alkoxycarbonyl group, a formyl group, a C 2

-C

6 alkanoyl group, an aroyl group, or a

C

1

-C

6 alkyl group, C 3

-C

8 cycloalkyl group, C 3

-C

8 S* cycloalkyl C 1

-C

6 alkyl group, C 2

-C

6 alkenyl group or

C

2

-C

6 alkynyl group which may be substituted by 1 to 3 25 substituents selected from the group consisting of a hydroxyl group, an amino group, a CI-C 6 alkoxy group and a mono- or di- Ci-C 6 alkylamino group, and when the 10 heteroaromatic ring includes one or more nitrogen atoms, the nitrogen atom(s) may be oxidized to form an N-oxide group) or a pharmaceutically acceptable salt thereof.

Now, this invention will be described in more s detail with reference to specific examples for the various symbols used in the formula Each of Arl and Ar 2 is independently a phenyl group, a thienyl group, a pyridyl group, an indolyl group, a benzofuranyl group or a dihydrobenzofuranyl group wherein an optional hydrogen atom(s) on the aromatic ring may be replaced with 1 to 4 groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a carboxyl group, a

C

1

-C

6 alkoxycarbonyl group, a mono- or di- C1-C is alkylaminocarbonyl group, a carbamoyl group, a tetrazol-5-yl group, a methylenedioxy group, a C1-C 6 alkoxy group, a C 2

-C

6 alkenyloxy group, a mono- or di-

C

1

-C

6 alkylamino group, a C 1

-C

6 alkyl group, a C2-C 6 alkenyl group and a C 2

-C

6 alkynyl group (provided that 20 the CI-C 6 alkoxy group, C 2

-C

6 alkenyloxy group, mono- or di- C 1 -Cg alkylamino group, C 1

-C

6 alkyl group, C 2

-C

6 alkenyl group and C 2

-C

6 alkynyl group may be substituted by 1 to 3 groups selected from the group consisting of a phenyl group, a pyridyl group, an imidazolyl group, a 25 hydroxyl group, a C 1 -Cg alkoxy group, an amino group, a mono- or di- C 1 -Cg alkylamino group, a hydroxy C 1

-C

6 alkylcarbonyl group, a C 1

-C

6 acyloxy C 1

-C

6 alkylcarbonyl 11 group, a carboxy C 1

-C

6 alkoxycarbony. group, a carboxy

C

1

-C

6 alkoxycarbonyl C 1

-C

6 alkoxycarbonyl group, a cIC alkoxycarbonyl group, a mono- or di- C 1

-C

6 alkylaminocarbonyl group, a carbamoyl group, a 16 alkylsulfonylaminocarbolyl group, a tetrazol-S-ylaminocarbonyl group, a carboxyl group, S0 3 H, P0 3

H

2 a group, a 2-oxo-3H-1,2,3,5-oxathiadiazol-4.-yl group and a 5-oxo-4H-1,2,4--oxadiazol-3-yl group (provided that when a hydroxyl group and a carboxyl group are selected as substituents, they may together form a lactone ring)).

The halogen atom means a fluorine, chlorine, bromine or iodine atom.

The C 1

-C

6 alkoxycarbonyl group means an alkoxycarbonyl group having a linear or branched 1C alkoxy group such as a meihoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butyloxycarbonyl isobutyloxycarbonyl, tert butyloxycarbonyl pentyloxycarbonyl, isopentyloxycarbonyl or hexyloxycarbonyl .20 group.

The mono or di C 1 alkylaminocarbonyl group means an alkylaminocarbonyl group having I. or 2 linear or branched C 1

-C

6 alkyl groups at the nitrogen atom *:*:such as a methylaminocarbolyl, ethylaminocarbonyl, *:25 propylaminocarbolyl, isopropylaminocarbonyl, buylaminocarbonyl, isobutylaminocarbolyl, tert buylaminocarbonyl, pentylatuitocarbonyl, isopentylamiriocarbonyl 12 group, hexylaminocarbonyl, dimethylaminocarbonyl group, ethylmethylaminocarbonyl group, diethylaminocarbonyl,_ isopropylmethylaminocarbonyl, dipropylami.

nocarbonyl, ethylisopropylaminocarbonyl, s diisopropylaminocarbonyl, dibutylaminocarbonyl, diisobutylaminocarbonyl di tert butylaminocarbonyl, dipentylaminocarbonyl, ethylpentylaminocarbonyl, diisopentylaminocarbonyl or ethylhexylaminocarbonyl group.

The C 1

-C

6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy, ethoxy, propoxyp isopropoxy, butoxy, isobutoxy, sec-butoxy, .tert-butoxy, pentyloxy or hexyloxy group.

e~g. The C 2

-C

6 alkenyloxy group means an alkenyloxy group having a linear or branched C 2

-C

6 alkenyl group such as a vinyloxy, allyloxy, 1. 7 propenyloxy, isopro- 0009S* penyloxy, 2- butenyloxy, 3- butenyloxy, 2 -pentenyloxy, 3methyl 3 butenyloxy or 2 -hexenyloxy group.

0..**The mono or di C 1

-C

6 alkylamino group means an alkylamino group having I or 2 linear or branched C_ alkyl. groups at the nitrogen atom such as a methylamino, see:* ethylamino, propylamino, isopropylamino, butylamino, 0isobutylamino, tert-butylamino, pentylamino, isopentylamino, hexylamino, dimethylamino, ethylmethylamino, :25 diethylamino, dipropylamino, propylmethylamino, ethylpropylamino, diisopropylamino, diisobutylamino, ethylisobutylamino, di tert-butylamino, dipentylamino, di 13 isopentylamino, isopentylmethylamino or dihexylamino group, The C 1

-C

6 alkyl group means a linear or branched alkyl group having 1. to 6 carbon atoms such as a methyl, s ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2 -dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1 ,2-dimethylbutyl, 2,2-dimethylbutyl, I-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2 2 -trimethylpropyl, 1-ethyl-2-methylpropyl or I-ethyl-l-methylpropyl group.

The C,-C 6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms such as a vinyl, allyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, I-butenyl, 1-methyl-2-;propeiyl, 1-methyl-l-propenyl, 1-ethyl-l-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl or 4-pentenyl group.

The C 2 alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms such as an ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl or 1-pentynyl group.

The hydroxy C,-c 6 alkylcarbonyl group means a linear or branched hydroxyalkylcarbonyl group having 2 to 7 carbon atoms such as a hydroxyme-thylcarbonyl, 1 14 hydroxye thy Icarbony 1, 1 hydroxypropyl-carbonyl, 1 hydroxybutylcarbonyl, 1 hydroxypentylcarbonyl, 1 hydroxyhexylcarbonyl, 2 hydroxyethytcarbonyl, 3hydroxypropylcarbonyl, 2 -hydroxybutylcarbonyl, 4 hys droxypentylcarbonyl, 3 -hydroxyhexylcarbonyl or 2 hydroxy 2 methyipropylcarbonyl group.

The C 1

-C

6 acyloxy C 1

-C

6 alkylcarbonyl group means an acyloxy C 1

-C

6 alkylcarbonyl group having a aliphatic or aromatic acyloxy group such as an acetyloxymethylcarbony 1, 1 acetyloxyethylcarbonyl., 2 acetyloxyethylcarbonyl, 1 acetyloxypropylcarbonyl., 1 acetyloxybutylcarbonyl, 1 acetyloxypentylcarbonyl, 1Iacetyloxyhexylcarbonyl, 2 acetytoxypropylcarbonyl, propionyloxymethylcarbonyl, 1 propionyloxyethylcarbonyl, is butylyloxymethyicarbonyl, pentanoyloxymethylcarbonyl, 0 00 0 0hexanoyloxymethylcarbonyl, benzoyloxymethylcarbonyl, 1 benzoyloxyethyicarbonyi, 2 benzoyloxyethylcarbonyl, othienylcarbonyloxymethylcarbonyl, furfuryloxymethylcarbonyl, pyridylcarbonyloxymethylcarbonyI or 0:20 imidazo lylcarbony loxymethylcarbony I group.

TecrxyC- 6 alkoxycarbonyl group means a linear or branched carboxy C 1

-C

6 alkoxycarbonyl group 0.

**having 3 to 10 carbon atoms such as a carboxymethoxycarbonyl, 1 carboxyethoxycarbonyl 1 carboxypropoxycarbonyl, 1 carboxybutoxycarbonyl, 2 carboxyethoxycarbonyl, 2 carboxybutoxycarbonyl, 2 carboxypentoxycarbonyl, 3 carboxypropoxycarbonyl, 3 car- 15 boxybutoxycarbonyl, 4- carboxypentoxycarboflyl, 3- carboxyhexyloxycarbonyl or 2 carboxy 2 methylpropyloxycarbonyl group.

The carboxy C 1

-C

6 alkoxycarbonyl c 1 -c 6 alkoxycarbonyl group means a linear or branched carboxy

C

1

-C

6 alkoxycarbonyl Cl-C 6 alkoxycarbonyl group having 3 to 16 carbon atoms such as a carboxymethoxycarbonylmethoxycarbonll 1 carboxyethoxycarbonylmethoxycarbonyl, 1 carboxypropoxycarbonylmethoxycarbonyl, 1 carboxybuoxycarbonylmethoxycarbonll 2 carboxyethoxycarbonymethoCycarbofll 2 carboxybutoxycarbonylethoxycarbonll 2 carboxypentoxycarboflylethoxycarbonyl, is 3 carboxypropoxycarbonylethoxycarbonyl, 3 carboxybutoxycarbolylethoxycarbonll 4 carboxypentoxycarboflylethoxycarbonyl, 3 carboxyhexyloxycarbonylmethoxYcarboflyI or 2 carboxy 2 methylpropylo'Cycarboflylmethoxycarbonyl group.

The C,-C 6 alkylsulfonylaminocarbonyl group means an alkylsulfonylaminocarboflyl group having a linear or branched C 1

-C

6 alkyl group such as a methylsul-fonylaminocarbonyl, ethylsulfonylamlitlocarbonyl, propylsulfonylaminocarbonyl, isopropylsulfonylamiiocarbofll butylsulfonylaminocarbonyl, isobutylsulfonylaminocarbonyl, tert butylsulfonylaminocarbonyl, pen- 16 tylsulfonylaminocarbonyl, isopentylsulfonylaminocarbonyl or hexylsulfonyLaMinocarbonyl group. Preferred compounds useful in the present invention are those wherein Arl and Ar 2 are independently a phenyl group, a thienyl group or a dihydrobenzofiiranyl group wherein an optional hydrogen atom(s) on the aromatic ring may be replaced with I to 4groups selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, a rnethylenedioxy group, a C,-C 6 alkoxy group, a C 2

-C

6 alkenyloxy group, a mono- or di- CI-C 6 alkylamnino group, a C,-C 6 alkyl group, a C0,-C 6 alkenyl group and a C 2

-C

6 alkynyl group (provided that the said C I-C 6 alkoxy group, C0,-C 6 alkenyloxy group, mono- or di- Cl1-C 6 alkyiainino group, CX- 6 alkyl group, C,-_C 6 alkenyl group and 0,-C 6 alkynyl group may be substituted by 1 to 3 groups selected from the group consisting of a phenyl group, a pyridyl group, an iniidazolyl group, a hydroxyl group, a C I-C, alkoxy group, an amino group, a mono- or di- C I C 6 alkylamino group, a hydroxy C I-C 6 alkylcarbonyl group, a C I-C 6 acyloxy oo~oC 1

-C

6 alkYlcarbonyl group, a carboxy C 1

-C

6 alkoxycarbonyl group, a carboxy CX- 6 alkoxycarbonyl CX- 6 alkoxycarbonyl group, a CX- 6 alkoxycarbonyl group, a mono- or di- 0 0 a a 0C I-Cs alkylaminocarbonyl group, a carbamoyl group, a C I-.C 6 alkylsulfonylamninocarbonylI group, a tetrazol-5-ylaminocarbonyl group, a carboxyl group, a tetrazol-5-yl group, a 2oxo-3H-l,2,3,5-oxathiadiazol-4-yl group and a SUBSTITUTE SHEET (RULE 26) 17 5-oxo-4H-1,2,4-oxadiazo-3-yl group (provided that when a hydroxyl group and a carboxyl group are selected as the substituents, they may together form a lactone ring)).

Each of R, R 2 and R 2 is independently a hydrogen atom, a hydroxyl group or a Cl-C 6 alkyl group, or RI and R 2 or R 2 and R 3 together form a single bond.

The C 1

-C

6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, 1-ethylpropyl, hexyl., isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1,1,2-trimethylpropyl, l,2,2-trimethylpropyl, 1-ethyl-2-methylpropyl or 1-ethyl-l-methylpropyl group.

*When R 1 and R or R 2 and R 3 together form a ::*single bond, compounds of the general formula(I) are compounds of the general formula or(I) Ar' Ar' R' 25

R

3 [1 [b Ar 1 Ar, A, R 1 and Rare as defined above.

18 Y is a group of -CO-R 4 (wherein R 4 is a hydroxyl group, an amino group, a C 1

-C

6 alkoxy group, a mono- or di- C 1

-C

6 alkylamino group, a C 1

-C

6 alkylsulfonylamino group, or an arylsulfonylamino group or aryl c.-c 6 alkylsulfonylamino group wherein an optional hydrogen atom(s) on the aryl ring may be replaced with a iC alkyl group), SO 3 H, PO3H 2 a tetrazol-5-yl group, a 2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl group or a 5-oxo-4H-1,2,4-oxadiazol-3-yl group.

The C 1

-C

6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy group.

15 The mono or di C,-C 6 alkylamino group means an alkylamino group having 1 or 2 linear or branched

C

1

-C

6 alkyl groups at the nit rogen atom such as a metbylamino, etkiylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino, hexylamino, dimethylamino, ethylmethylamino, diethylamino, dipropylamino, propylmethylamino, ethyipropylamino, diisopropylamino, diisobu- .:tylamino, ethylisobutylamino, d! tert-butylamino, di pentylamino, diisopentylamino, isopentylmethylamino or dihexylamino group, The C 1

-C

6 alkylsulfonylamino group means an alkylsulfonylamino group having a linear or branched 19

C

1

-C

6 alkyl group such as a methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, tert butylsulfonylamino, pentylsulfonylamino, isopens tylsulfonylamino or hexylsulfonylamino group.

The arylsulfonylamino group wherein an optional hydrogen atom(s) on the aryl ring may be replaced with a

C

1

C

6 alkyl group means an arylsulfonylamino group having a C 6

C

14 aromatic hydrocarbon ring or heteroaromatic ring including 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, wherein an optional hydrogen atom(s) on the aryl ring may be replaced with a

C

1

C

6 alkyl group, such as a phenylsulfonylamino, s naphthylsulfonylamino, thienylsulfonylamino, pyridylsulfonylamino or furylsulfonylamino group, or said groups having a C 1

C

6 alkyl group on the aromatic ring.

The aryl C 1

C

6 alkylsulfonylamino group wherein an optional hydrogen atom(s) on the aryl ring may be replaced with a C 1

C

6 alkyl group means an arylalkylsulfonylamino group having, at the alkyl moiety of the above defined C 1

C

6 alkylsulfonylamino group, a C 6

C

14 aromatic hydrocarbon ring or heteroaromatic ring including 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, wherein an optional hydrogen atom(s) on the aryl ring may be replaced with a. C 1

C

6 alkyl 20 group, such as a benzylsulfonylamino, phenylethyl.

sulfonylamino, phenylpropylsulfonylamino, 1 methyl 2 -phenylethylsulfonylamino, phenylbutylsulfonylamino, phenylpentylsulfonylamino, phenylhexylsulfonylamino, naphthylmethylsulfonylamino, naphthylethylsulfonylamino, naphthylpropylsulfonylamino, thienylmethylsulfonylamino, pyridylmethylsulfonylamino, furylmethylsulfonylamino, thienylethylsulfonylamino, pyridylethylsulfonylamino, furylethylsulfonylamino, thienyipropylsulfonylamino, pyridylbutylsulfonylamino, furylpentylsulfonylamino or thienylhexylsulfonylamino group, or said groups having a

C

1

-C

6 alkyl group on the aromatic ring.

A is a group which f orms together with the adjacent carbon-carbon double bond a 5- or 6- membered *is heteroaromatic ring including 1 to 4 hetero atoms *...selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (provided that optional 1 or 2 hydrogen atoms on the heteroaromatic ring may be replaced with a hydroxyl group, an amino group, a l.

alkoxy group, a C 1

-C

6 alkylthio group, a halogen atom, _a cyano group, a nitro group, a mono- or di- I6 alkylamino group which may be substituted by a hydroxyl group at the alkyl moiety, a C-C 8 cycloalkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, a C 3

-C

8 cycloalkyl C 1

-C

6 alkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(C 1

-C.

21 alkyl)-N-(C 3

-C

8 cycloalkyl)amino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(C 1 -Cg alkyl)-N-(aroyl)amino group which may be substituted by a hydroxyl group at the alkyl moiety, a C 4

-C

7 cyclic imino group which may be substituted by a hydroxyl group at the alkylene moiety, a carboxyl group, a C 1

-C

6 alkoxycarbonyl group, a formyl group, a C 2

-C

6 alkanoyl group, an aroyl group, or a

C

1

-C

6 alkyl group, C 3

-C

8 cycloalkyl group, C 3

-C

8 cycloalkyl C 1

-C

6 alkyl group, C 2

-C

6 alkenyl group or

C

2

-C

6 alkynyl group which may be substituted by 1 to 3 substituents selected from the group consisting of a hydroxyl group, an amino group, a C 1

-C

6 alkoxy group and a mono- or di- C 1

-C

6 alkylamino group, and when the :is* I heteroaromatic ring includes one or more nitrogen atoms, the nitrogen atom(s) may be oxidized to form an N-oxide group).

The C -C 6 alkoxy group means a linear or tihanched alkoxy group having 1 to 6 carbon atoms such as a: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy group.

The C 1 -Cg alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms such as a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec isobutylthio, tert butylthio, pentylthio or hexylthio group.

22 The halogen atom means a fluorine, chlorine, bromine or iodine atom.

The mono or di alkylamino group wherein an optional hydrogen atom(s) at the alkyl moiety may be s replaced with a hydroxyl group means a linear or branched alkylamino group having, at the nitrogen atom, 1 or 2 linear or branched alkyl groups which may be substituted by a hydroxyl group, such as a methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, isopentylamino, hexylamino, dimethylamino, ethylmethylamino, diethylamino, dipropylamino, propylmethylamino, ethylpropylamino, diisopropylamino, diisobutylamino, ethylisobutylamino, di tert-butylamino, dipentylamino, di is isopentylamino, isopentylmethylamino or dihexylamino group.

The C 3

C

8 cycloalkylamino group wherein an optional hydrogen atom(s) at the alkyl or alkylene moiety may be replaced with a hydroxyl group means a C 3 20 C 8 cycloalkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, such as a cyclopropylamino, cyclobutylamino, cyclopen- S. tylamino, cyclohexylamino, cyclooctylamino, 2 methylcyclopropylamino, 1 methylcyclobutylamino, 2 methylcyclopentylamino or 2,2 dimethylcyclohexylamino.

The C 3

C

8 cycloalkyl C 1

-C

6 alkylamino group wherein an optional hydrogen atom(s) at the alkyl or 23 alkylene moiety may be replaced with a hydroxyl group means a C 3 c 8 cycloalkyl

C

1

-C

6 alkylamino group which has 4 to 14 carbon atoms and may be substituted by a hydroxyl group at the alkyl or alkylene moiety, such as s a cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, cyc loheptylmethylamino, cyclooctylmethylamilo, 1 cyclopropylethylamino, 2 cyclopropylethylamfino ,3 cyclopropylpropylaliflo f 2 cyclobutylethylamino or 2 cyclopentylethylamino group.

The N (C 1

-C

6 alkyl) N (C 3

C

8 cycloalkyl.

l)amino group wherein an optional hydrogen atom(s) at the alkyl or alkylene moiety may be replaced with a hydroxyl group means an N (Cl-C. alkyl) N (C 3

CS

cycloalkyl) amino group which has 4 to 15 carbon atoms *and may be substituted by a hydroxyl group at the **~*alkyl. or alkylene moiety, such as an N methyl N cyclop;opylamilo, N methyl N cyclobutylamilo, N 1~tht- N--cyclopenty-aminfo, N. methyl. N cyclohexy3.amino, N methyl- N cyclooctylalUifo, N ethyl N cyclopropylamilo, N butyl N -cyclopropylamiino, N pentyl. N cyclopropylamino, N -hexyl N cyclopropylamilo, N ethyl N cyclobutylainfo, N ethyl N cyclopentylamino, N propyl N cyclobutylamilo, N 5:25 pentyl N cyclopentylamino group.

The N (C 1

-C

6 alkyl) N (aroyl)amiflo group wherein an optional hydrogen atom(s) at the alkyl moiety 24 may be replaced with a hydroxyl group means an N

(C

1

-C

6 alkyl) N (aroyl)amirlo group which has 6 to 12 carbon atoms and may be substituted by a hydroxyl group at the alkyl moiety, such as an N methyl -Ns benzoylamilo, N (1 ethyl) N benzoylamino, N propyl) N benzoylamilo, N (1 butyl) N benzoylamino, N (1 pentyl N benzoylamino, N (2 ethyl) N benzoylamilo, N (2 propyl) N benzoylamino, N (3 butyl N benzoylamiflo, N (4 pentyl) N benzoylamino, N methyl N naphthoylamino, N methyl -N thienylcarboflylamino, N methyl -N furylamino, N methyl N pyridylamilo or N -methyl N imidazoylamino group.

The C 4

C

7 cyclic imino group wherein an is optional hydrogen atom(s) may be replaced with a hydroxyl group means a cyclic imino group which has 4 *to 7 carbon atoms and may be substituted by a hydroxyl group at the alkylene moiety, such as a 1 pyrrolidinyl, 2 methylpyrrolidino, 2,5 dimethylpyrrolidino, piperidino, 2 methylpiperidino, 2,6 dimethylpiperidilo, morpholino, thiomorpholio, piperazino, 4 methylpiperazilo or hexamethylefleimino, group.

The C -C 6 alkoxycarbolyl group means an *1 6 alkoxycarbonyl group having a linear or branched Ci-C 6 *:25 alkoxy group such as a methoxycarbolyl, ethoxycarbolyl, **propoxycarbonyl, isopropoxycarbonylt butyloxycarbonyl isobutyloxycarbonyl, tert butyloxycarbonyl pentylox- 25 ycarbonyl, isopentyloxycarbonyl or hexyloxycarbonyl group.

The C 2

C

6 alkanoyl group means a linear or branched alkanoyl group having 2 to 6 carbon atoms such as an acetyl, propanoyl, butylyl, isobutylyl, isopropanoyl, isobutylyl, pentanoyl or hexanoyl group.

The aroyl group means an aroyl group having mono -,bi or tri cyclic aromatic hydrocarbon ring or heteroaromatic ring including 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, such as a benzoyl, naphthoyl, pyridylcarbonyl, thienylcarbonyl, furylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolylcarbonyl or quinolylcarbonyl group.

The C 1

-C

6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,. neoperityl, tert-pentyl, *1.4uethylbutyl, 2-methylbutyl, 1, 2-dimethyipropyl, 1-ethyipropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1-ethylbutyl, 1, 1,2-trimethyJlpropyl, 1,2,2-trimethyipropyl, 1-ethyl-2-methylpropyl or *:25 1-ethyl-1-methylpropyl group.

:The

C

3

C

8 cycloalkyl. group means a cycloalkyl group having 3 to 8 carbon atoms such, as a cyclopropyl, 26 cyclobutyl, cyclopentyl, cyc3lohexyi, cycloheptyl or cyclooctyl group.

The C 2 -C6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms such as a vinyl, allyl, 2-propelyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1-methyl-I-propenyl, 1-ethyl-l-ethelYl, 2-methyl-2-propenyl, 2-methyl-i-propel or 4-pentenyl group.

The C 3

C

8 cycloalkyl Cl-C 6 alkyl group means a C 1

-C

6 alkyl group substituted by a C 3

C

8 cycloalkyl group such as a cyclopropylmethyl, 1 cyclopropylethyl, 2 cyclopropylethyl, 2 cyclopropylpropyl, 3 cyclopropylpropyl, 4 cyclopropylbutyl, 5 cyclopropylpenyl, 6 cyclopropylhexyl, cyclobutylmethyl, 1 cyclobutylethyl, 2 cyclobutyJlethyl, cyc lope ntylImethyl1, *:so cyclohexylmethyl, cycloheptylmethyl or cyclooctylmethyl group.

a The C 2

-C

6 alkynyl group means a linear or branched alkyny. group having 2 to 6 carbon atoms such as a ethynyl, 1-propyrlyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1mty--rPf~ r1pnyy group.

A is a group which forms together with the adjacent carbon carbon double bond a 5 or 6 *:25 membered heteroaromatic ring including 1 to 4 hetero as,. atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and examples of 27 the 5- or 6- membered heteroaromatic ring are a furan ring, a pyrrole ring, a thiophene ring, a diazole ring, a thiazole ring, an oxazole ring, a pyridine ring, a diazine ring, a triazine ring, etc..

Preferred compounds useful in the present invention are those wherein A is a group which forms together with the adjacent carbon-carbon double bond a 5- or 6- membered nitrogen-containing aromatic ring or the corresponding N-oxide ring (provided that optional 1 or 2 hydrogen atoms on the heteroaromatic ring may be replaced with a hydroxyl group, an amino group, a C,-C 6 alkoxy group, a Ci-C 6 alkylthio group, a mono- or di- alkylamino group which may be substituted by a hydroxyl group at the alkyl moiety, a C 3

-C,

cycloalkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, a C 3

-C

8 cycloalkyl Ci-C 6 alkylamino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(C,-C 6 alkyl)-N-(C3-Cg cycloalkyl)amino group which may be substituted by a hydroxyl group at the alkyl or alkylene moiety, an N-(C,-C 6 alkyl)-N-(aroyl)amino group which may be substituted by a hydroxyl group at the alkyl S*e.

moiety, a C 4

-C

7 cyclic imino group which may be substituted by a hydroxyl group at the 8 alkylene moiety, or a alkyl group, C 3 cycloalkyl group, C 3 cycloalkyl C,-C 6 alkyl group, C,-C 6 alkenyl group or C,-C 6 alkynyl group which may be substituted by 1 to 3

SS@*

SUBSTITUTE SHEET (RULE 26) groups selected from the group consisting of a hydroxyl group, an amino group, a IC alkoxy group and a mono- or di- CX- 6 alkylamino group).

Specific examples of the endothelin antagonists useful in the present invention include 6-Ethocarbonyl-5-(3 ,4-methylenedioxyphenyl)-7-(4methoxyphenyl)cyclopenteno[ 1,2-b]pyridine, (5RS,6SR,7SR)-6-Carboxy-5,-(3 ,4-methylenedioxyphenyl)-7-(4-methoxyphenyl)cyclopenteno[ 1,2-b]pyridine, 6-Ethoxycarbonyl-5,7-diphenyicyclopenteno-[ I ,2-b]pyridine, RS,6SR,7SR)-6-Carboxy-5 ,7-diphenylcyclopenteno[ 1 ,2-b]pyridine, ,7-di(4-methoxyphenyl)cyclopenteno[ 1 ,2-b]pyridine, (5RS,6SR,7SR)-6-Carboxy-5 ,7-di(4-methoxyphenyl)cyclopenteno[ 1 ,2-blpyridine, 6 -Ethoxyqarbonyl-5,7-di(3,4-methylenedioxyphenyl)cyclopenten[ 1 ,2-blpyridine, (5RS,6SR,7SR)-6-Carboxy-5,7-di(3 4 -methylenedioxyphenyl)cyclopenteno[ 1,2bipyridine, 6-Ethoxycarbonyl-7-(3 .4-methylenedioxyphenyl)-5-(4-methoxyphenyl)7(3 ,4methylenedioxyphenyl)cyclopenteno[ I ,2-blpyridine, (5 RS,6SR ,7SR)-6-Carboxy-7-(3 ,4-methylenedioxyphenyl)-5-(4.

methoxyphenyl)cyclopenteno( 1,2-blpyridine, SUSITT SHE*RL 6 29 7 (4-methoxyphenyl)cyclopeltelo( 1,2-b]pyridile, 6SR, 7SR) -6--Carboxy-5-pherlyl-7- (4-metho~xyphenyl)cyclopeltelorI1,2-b~pyridile, 6-EthoxycarbonyI-7-phelyl-5- (4-methoxyphenyl )cyclopelteflof1,2-b jpyridine, (5RS,6SR,7SR)-6-Carboxy-7-phenyI-5-(4-methoxyphenyl )cyclopenteno 2-b] pyridine, 7 4-methylenedioxyphenyl)cyclopeltelo[1,2-b]pyridine, 6SR, 7SR) -6-Carboxy-5-phelyl- 7 4-methylenedioxyphenyl )cyclopentelo 1,2-b] pyridine, 6-Ethoxycarbonyl-7-phelyl-5- 4-methylenedioxyphenyl)cyclopeltelot1,2-b]pyridile, (5RS ,6SR, 7SR) -6-Carboxy-7-pheflYl-5- 4-methylenedioxyphenyl )cyclopenteno pyridine, Vooo.(5RS,6SR,7SR)-6-Carboxy-7-(3,4-methylenedioxyphenyl) (4-methoxyphel)cyclopetelo( 1,2-c ]pyridine, (5RS,6SR,7SR)-6-Carboxy-5-(3,4-methylenedioxyphenyl)-7-(4-methoxyphlenyl)cyclopenteno( 1,2-c ]pyridine, -:Soo:lenedioxyphenyl)-7-(4-methoxyphenyl)cyclopenteno( 1,2-b]- :25 pyridine, (5RS ,6SR, 7SR) -6-Carboxy-2-methyl-5- 4-methylenedioxyphenyl) (4-methoxyphel)cycIopetelo( 1,2-b] 30 pyridine, (5RS,6SR,7SR)-6-Carboxy-2-butyl-5-(3,4-methylenedioxypheflyl)-7-(4-methoxyphelyl)cycIopeltelo( 1 2-blp yridine, (5RS, 6SR, 7SR) -6-Carboxy-2-ethylami- 4-methylefledioxyphey 1) (4-methoxyphenyl)cyclopeltelo( 1, 2-b]pyridine, 6SR, 7SR) -6-Carboxy-5- 4-methylenedioxyphenyl)-7-(4-methoxypheyl)cyclopetelo(1, 2-b pyridine, N-oxide 6SR, 7SR) -6-Carbamoy 1-5- 4-methylenedioxy phenyl) methoxyphenyl)cyclopelteo( 1, 2-b ]pyr.idine, ,6SR, 7SR) -6 -methanesulfolylamiflocarboflis 5- 4-methylenedioxyphenyl) 4-methoxyphenyI) cyclopentenof 1, 2-blpyridile, ,6SR, 7SR) (4-Isopropylbenzelesulfofl- ~aminocarbonyl) 3, 4-methylenedioxypheli) (4-niethoxyphenyl)cyclopeltelo( 1 ,2-b~pyridine, 6-Carboxy-5-hydroxy-5-( 3,4-methylenedioxyphenyl)-7-(4-methoxyphel)cyclopet-lI 4-dieri of1, 2-blpyridine, ,6SR, 7SR) -6-Carboxy-7- (2-carboxymethoxy-4- *methoxyphenyl1) 5- 3, 4 -methy lenedioxyp hely 1) cyc lopenteno 2S (1,2-b]pyridine, (5RS ,6SR, 7RS) -6-carboxy-5- (2-carboxymethoxy-4methoxyphenyl) 4-methylenedioxyphelyl)cyclopetelo- 31 (1,2-c]pyridine, 6SR, 7SR) -6-carboxy-7- (2-hydroxy-4-rnethoxyphenyl)-5-(3 4methylefledioxyphel)cyclopeteflo- [1,2-blpyridile, (5RS,6SR,7SR)-6-carboxy-7-[2-(2-hydroxyethoxy) -4-metboxyphelyl 1-5- 4-methylefledioxypheflyl )cyclopenteno( 1, 2-blpyridile, (5RS,6SR,7SR)-6-carboxy-7-2-(2-methylaminoethoxy) -4-methoxypheflyl 1-5- 4-methylenedioxyphenyl) cyclo-pentelot1,2-b]pyridine, (5RS,6SR,7SR)-6-Carboxy-2-ethoxymethyl-7- (4-methoxyphenyl) 4-methylenedioxyphelyl )cyclopenteno[ 1, 2-b]pyridine, (5RS,6SR,7SR)-6-Carboxy-7-(4-methoxypheflyl)- 5-(3 ,4-methylenedioxyphel)-2-propylcyclopeltelo- 1, 2-blpyridile, (5RS,6SR,7SR)-6-Carboxy-2-isobutyl- 7 4 -methoxyphenyl) 3, 4-methylenedioxyphely1)cyclopetelo- El, 2-blpyridile, 6-Carboxy-7-hydroxy- 7 4-methoxyphelyl) (3,4methylenedioxyphenyl)cyclopeflt-,3-dielo( 1 2 -b]pyridine, 7 (4-rnethoxypheflyl) (3,4methylenedioxyphelyl) -2-propylcyclopelt-1, 3-dieno- 1-blpyridile, (5RS,6SR,7RS)-6-Carboxy-5-hydroxy- 7 -(4-methoxyphenyl) -5-(3,4-methyleledioxyphelyl)cyclopefteno( 1,2-b]pyridine, 32 (5RS,6SR,7SR)-6-Carboxy-7-(4-hydroxyphenyI)- 3, 4-methylenedioxyphel)cyc]lopetelo( 1, 2-b]pyridine, 6SR, 7RS )-6-Carboxy-7- (2-hydroxyethoxy) phenyI]-5-(3,4-methylefedioxyphenyl)cyclopenteno(,2bP s pyridine, (5RS,6SR,7SR)-6-Carboxy-7(4(2methylamilo- 3 e 4-methylenedioxyphefl3cyclopenteno[ 1,2-b]-pyridile, ,6SR, 7SR) -6-Carboxy-7- (4-hydroxymethylpheny1)-5-(3,4-mfethylefedioxyphefl)cyclopenteno- 2-blpyridine, ,6SR, 7SR) -6-Carboxy-5- 4-methyl.enedioxyphenyl)-7-(3-thienl)cyclopefltelo(1, 2 -b]pyridine, (5RS,6SR,7RS)-7-(4-Methoxyphenl)-5-(3,4-methylenedioxypheny)-6(2oxo-3H-1,2,3,5-oxathiadiazoI -4-yl)cyclopeltelo( 1,2-b]pyridile, 6SR,7SR) 6-(5 -xo -4H 1, 24 -xadiazolI-3 -yl) 5 (3,4 methylenedioxyphelyl) 7 (4 methoxyp henyl)cyclopelteloE1,2 b]pyridine, (5RS,6SR,7SR)- 6- (Tetrazol- 5-yi)- 5- methylenedioxyphenyl) 7 (4 methoxyphenl) cyclopetelot 2 blpyridine, 6SR, 7SR) -5 3 ,4 -methy leledioxyphely 1) -6 methoxycarbony- 7 (4 methoxyphel]) cyclopeteo 1, 2 bjpyridine, (5RS,6SR,7SR)- 7- Ethoxycarbonylmethoxy- 4- methoxyphenyl) 6- carboxy- 5- methylenedioxyphenyl )cy- 33 clopenteno(1,2 bjpyridine, 6SR, 7SR) Carboxy- 7- (tetrazolI- 5- yiaminocarbonylmethoxy)- 4- methoxyphefly I] 5- methylendioxyphenyl)cyclopeltelo[1,2 b]pyridine, (5RS,6SR,7SR)- 7- Carbamoylmethoxy- 4- me thoxyphenyl) 6- carboxy 5 3, 4 methylerldioxyphenyi) cyc lopenterio[1,2- blpyridile, (5RS,6SR,7SR) 6 Carboxy 7 (2 methanesulf onyl.-aminocarboflylmethoxy 4 methoxyphenyl) 5 4 methylenedioxypheny)cyc]lopetelo( 1,2 b~pyridine, 6SR, 7SR) 6- Carboxy- 7 (2 (tetrazol 5 ylmethoxy) 4 methoxyphenyl] 5 (3,4 methylenedioxyphenyl)cyclopeltelo( 1,2 bipyridine, 6SR, 7SR) 6 -Carboxy -7 is bonyipropoxy) 4 methoxyphenyl] 5 (3,4 dioxyphenyl)cyclopentelot1,2 blpyridine, 6SR, 7SR) 6- Carboxy 7- (2 1 bonylipropoxy) 4 methoxyphenyl] 5 (3,4 dioxyphenyl)cyclopeltelot1,2 b]pyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2 propoxy) 4 methoxyphenyl] 5 (3,4 dioxyphenyl)cyciopentelo(1,2 b]pyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2 methoxycarmethylenemethoxycarmethylene- (1 carboxymethylene- (1 carboxypropoxy) 4 methoxyphenyll 5 (3,4 methylendioxyphenyl)cyciopentenof 1,2 blpyridiie, 6SR, 7SR) 7- 2- 1- ethoxycarbonylethoxy) 4 methoxyphenyll 6 carboxy 5 methylene- 34 dioxyphenyl)cyclopentelo(1,2 bjpyraidine, (5RS,6SR,7SR) 6 Carboxy -7 (2 (1 carboxyethoxy) 4 methoxyphenyl] 5- (3,4 methylene.

dioxyphenyl)cyclopenteno[ 1,2 b]pyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2 (2 carboxyethoxy) 4 methoxyphenyl] 5 methylenedioxyphenyl)cyclopeltelo( 1,2 b]pyridine, 6SR, 7SR) 6-Carboxy 7 2 -carboxyethoxycarbonyl) ethoxy 4- methoxyphenyl])- 5- 4- methylenedioxyphenyl)cyclopentelo[1,2 b]pyridine, 6SR, 7SR) Carboxy- 7- 2- 2- carboxyethoxycarbonyl ethox-ycarbonyl 3 ethoxy 4 methoxyphenyl 5- 4 methylenedioxypheny) cyclopeltelo(C1,f2 b ]pyridine, 15(5RS, 6SR, 7SR) -6 -Carboxy -bezl~yoxy I -met hoxyc arbony lethoxy) 4 methoxyphenyl]- 5- (3,f4- methylenedioxyphenyl)cyclopeltelo( 1,2 b~pyridine, 6SR, 7SR) 6 Carboxy- 7 2- methoxycarbonylethenyloxy) 4 methoxyphenyl- 5 (3f4 methylenedioxyphenyl)cyclopenteno( 1,2 blpyridine, o 6SR, 7SR) 6- Carboxy 7- 2- (2 hydroxy -1 00 methoxycarbonylethoxy) 4 methoxyphenyl 5 5- 4 methylenedioxyphenyl)cyclopentelo[1,2 b pyridine, 6SR, 7SR) 6- Carboxy 7- 2- (1 carboxy -2 hydroxyethoxy) 4 methoxyphenyl] 5 (3,4 methylene- 0*0.:dioxyphenyl)cyclopenteno( 1,2 bjpyridine, 6SR, 7SR) 6 Carboxy 7 2 1 carboxye- 35 thenyloxy) 4 methoxyphelyl] 5 (3,4 methylenedioxyphenyl)cyc-opeltelo(1, 2 b]pyridine, 6SR, 7SR) 6 Carboxy 2 hydroxymethyl. 5 (3,4 methylenedioxyphel) 7 (4 methoxypherlyl)cyclopentenoil, 2 -b]pyridile, 6SR, 7SR) 2 Ethoxymethyl 6 carboxy 7 (2 carboxymethoxy 4 rnethoxyphenly) 5 (3,4 methylenedioxypheny)cyc]lopetelo(1,2 b~pyridine, (5RS,6SR,7SR)- 7- Ethylamiflocarboflylmethoxy- 4 methoxyphenyl) 2 ethylaminomethy- 6 carboxy 5 (3 ,4 -mtethylenedioxyphel)cyc]lopentenot 1,2 b]pyridine, 6SR, 7SR) 2 Ethylamiflomethyl 6 carboxy 7 carboxymethoxy- 4- methoxyphelyl) 5- methylenedioxyphenyl)cyclopeltelo( 1,2 b]pyridile, (5RS, 6SR, 7SR) 6 -Carboxy 7 (2 carboxylmethoxy -4 methoxyphenyl) 2 -propoxy 5 (3,4 -methylenedioxyphenyl)cyc]-opetelo( 1,2 b~pyridile, (5RS,6SR,7SR)- 2- Ethyl- 6- carboxy- 5 methylenedioxyphelyl) 7 (4 methoxyphel)cycJlopeteflot, 2 b~pyridine, 6SR, 7SR) -6 Carboxy -2 -cyclopropyl -5 4 -methylenedioyphel) 7 (4 methoxyphel)cyc3lopenteno(1,2 blpyridile, (SRS, 6SR,7SR) 6 Carboxy -2 -pentyl-5 4 -methylenedioxyphelyl) 7 (4 methoxyphel)cyclpenteno(1,2 blpyridile, 6 6 Carboxy5 -hydroxy-2 -butenyl) -5 3 4 methylenedioxyphenyl)-7-(4-methoxyphenyD~cyclopent 1,3 dieno[2, I -bipyridine, (5RS.6SR, 7SR)-6-Carboxv-2- butenyl)-5-(3 ,4-methylenedioxyphenyl)-7- (4methoxyphenyl)cyciopenteno[1 .2 -b]pyridine, (SRS, 6SR, 7SR)-6-Carboxy-2-propylthio-5-(3, 4-methylenedioxyphenyl methoxyphenyl)cyclopenteno[ 1,2 -blpyridine, 6SR, 7SR)-6-carboxy-2'-propylamnino-5-(3, 4 methylenedioxypheny)-7-(4methoxyphenyl)cyclopenteno( 1.2 -blpyridine, RS, 6SR, 7SR)-6-carboxy-2-piperidino-5-(3, 4-methylenedioxyphenyl)-7- (4methoxyphenvi)cyclopenteno( 1,2 -bjpyridine, RS,6SR,7SR)-2-butyl-6-Carboxy-7- (2 carboxyrnethoxy-4- rnethoxyphenyl)5- (3,4 -methylene-dioxyphenyl)cyclopenteno[ 1,2-bjpyridine, 6SR, 7SR)- 6-Carboxy-7-(2-carboxyniethoxy-4-methoxyphenyl)-2propylaniino-5-(3 ,4methylene-dioxyphenyl)cyclopenteno[ 1,2- blpyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2-carboxymethylamino 4 methoxyphenyl) (3,4-methylenedioxyphenyl)cyclopenteno[ 1,2- blpyridine, (5RS,7SR) 6 Ethoxycarbonyl 7 (2-carboxymethylamino- (3 ,4-methylenedioxyphenyl)cyclopenteno[ 1,2 -b]pyridine, (5RS,6SR,7SR)-6-Carboxy-7-(2-pyridyl)-5-(3 ,4 37 methylenediaxyphenyl)cyclopenteno[1,2 b~pyridine, 6SR, 7SR) -6 -Carboxy 5-(3 -f luorophenyl)- 7 (4 methoxyphenyl)cyclopentenof 1,2 bipyridine, 6SR, 7SR) 6 Cziboxy 5 (3 -methoxyphenyl) 7 methoxyphenyl) cyclopenteno( 1, 2 b pyridine, 6SR, 7SR) 6 Carboxy 7 (4 f luorophenyl) 4 methylenedioxyphenyl) cyclopenteno 2 b )pyridine, 6SR, 7SR)- 6 -Carboxy- 5-C(2 -methoxyphenyl) 7 methoxyphenyl) cyc2.openteno C1, 2 b )pyridine,.

6SR, 7SR) 7 -C2 -(50 x-4H 1 2, 4 -oxadiazol 3- ylmethoxy)- 4 -methoxyphenyl)- 6 -carboxy -5 (3,f4 -methylenedioxyphenyl) cyclopenteno 1, 2 b )pyridine, 6 Carboxy -5 hydroxy 5 4 methyleneis dioxyphenyl) 7 (4 -methoxyphenyl) cyclopent 1,f3 dieno(2,1 dipyrimidine 6- Carboxy- 5- hydroxy- 2- butyl- 5- (3,f4- methylenedioxyphenyl) 7- (methoxyphenyi) cyc lopent I1f3 dieno C 2,f1 djpyrimidine (5RS,6SR,7SR) 6 Carboxy 7 (2 (1 carboxypentyloxy) 4 methoxyphenyl) 5 (3,4 methylenedioxyphenyl)cyclopenteno( 1,2 b]pyridine, 5RS, 6S R f7 SR) 6- C arbo xy 7 2- (E -2 c ar box yethenyl] 4 methoxyphenyl] 5 (3,4A methylenedioxyphenyl)cyclopenteno(1,2 b]pyridine, .:(5RS,6SR,7SR) 6 Carboxy 5 (3,4 -methylene- :dioxyphenyl) 7- 2- (2 methoxyc ar bony lethyl1) 4- methoxy- 38 phenyI~cyclopeltelo(1, 2 b]pyridile, (5RS,6SR,7SR -6-Carboxy- 7 carboxyethyl) -4 -methoxyphelyl] 5 (3,4 methylefledioxyphelyl)cyclopenteno(l, 2 blpyridine, (5RS,6SR,7SR) 6 Carboxy 5 (3,4 methylenedioxyphelyl) 7 (2 (2 methoxycarbofllpropy]) 4 methoxyphenyllcyclopeltelot1,2 blpyridile, 6SR, 7SR) 6 Carboxy 7 2 (2 carboxypropyl) 4 methoxyphelyl] 5 (3,4 methylenedioxyphenyl)cyclopeltelo( 1,2- blpyridile, (5RS,6SR,7SR) 6 Carboxy 5 (3,4 methylenedioxyphenyl) 7 2 (2 carboxy 2 propenly) -4 methoxyphenyllcyc.opeltelot1,2 b]pyridile, 6SR, 7SR) 6 Carboxy 7 C(2 (2 -carboxy 2 is propeny.) 4 methoxyphelyl] 5 (3,4 -methylenedioxyphenyl)cyclopelteloE1,2 blpyridile, 6SR, 7SR) 6- Carboxy 7 2- dihydroxy methoxycarbonylethy]l) 4- methoxyphel I 5 4 methylenedioxyphenli)cyclopetelo( 1,2 blpyridine, (5RS, 6SR, 7SR) 6 -Carboxy -7 2- (2 -carboxy 2 -dihydroxyethy]-) 4 methoxyphelylI 5 (3 4 methylenedioxyphenyl)cyclopeltelo( 1,2 bipyridile, 6SR, 7SR) -6 -Carbo -72 (3 -hydroxy -1 propyny.) 4 methoxyphenyll 5 (3,4 methyleledioxyphelyl)cyclopeltelo( 1,2 blpyridile, **(5RS,6SR,7SR) 6Carboxy-7(2( -hydroxy -1 propenly) 4 methoxypheflyll 5 (3,4 methylenle- 39 dioxyphenyl)cyclopenteno(l, 2 bipyridine, (5RS,6SR,7SR) 6- Carboxy- 7 (3 -hydroxy 1 propenyl) 4 methoxyphelyl 5- 4 methylenedioxyphenyl)cyclopentelo(l, 2 b]pyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2 (3 hydroxypropyl) 4 methoxyphenyl] 5 (3,4 methylenedioxyphenyl)cyclopeltelo( 1,2 b]pyridine, 6SR, 7SR) 6 Carboxy -7 1, 2 dihydroxyethyl) 4 methoxyphenyl] 5 methylenedioxyphenyl)cyclopentelo( ,2 b]pyridine, 6SR, 7SR) 6 Carboxy (2 1,3 dihydroxypropyl) 4 methoxypheny] 5 methylenedioxyphenyl)cyclopentelo[l, 2 b]pyridine, 6SR, 7SR) 6 Carboxy -7 2 3 dihydroxis ypropy.) 4 rethoxypheny] 5 (3,4 methylenedioxyphenyl)cyclopenteno( 1,2 blpyridine, 6SR, 7SR) 6 Carboxy -7 [2 1,2, 3 trihy- -droxypropyl) 4 methoxypheny 5- 4 methylenedioxyphenyl~cyclopentelo(l, 2 blpyridine, (5RS, 6SR, 7SR) 6 Carboxy 2 1,2, 3 trihydroxypropyl) 4 methoxyphenyl -5 methylenedioxyphenyl~cyclopeltelot1,2 b]pyridine, 6SR, 7SR)- 6 -Carboxy -7 -C2 carboxy 2 hydroxyethoxy) 4 methoxyphelyl]I 2 propylamino 5 4 methylenedioxyphelyl)cyc].opeteflotv 2 blpyridine, .:(5RS,6SR,7SR) 6 Carboxy 7 (2 (I carboxye- *thenyloxy) 4 -methoxyphelyl]I 2- propylamino 5 4- me- 40 thylenedioxyphenyl)cyclopentelo( 1,2 b]pyridine, 6SR, 7SR) 7 (2 Ethoxycarbonylmethoxy- 4 -methoxyphenyl) 6 carboxy 2 (N propyl N methylamino) (3,4 methylenedioxyphenyl)cycIopeltelo(,2 b]pyridine, 6SR, 7SR) 6 -Carboxy 7 (2 -carboxymethoxy 4 -methoxyphenyl) -2 -propy N -methylamilo) -5 -(3,4 methylenedioxyphenyl)cyclopeltelo(1,2 bipyridine, 6SR, 7SR) -6 Carboxy 7 (2 carboxymethoxy 4 methoxyphenyl) 2 -methylamiio) 5 (3,4 methylenedioxyphenyl)cyclopentenof 12 b]pyridine, 6SR, 7SR) 6 -Carboxy- 7 (2 -carboxymethoxy 4 -methoxyphenyl) 2-(NfN -dimethyiamilo) 5 3,4 -methylenedioxyphenyl)cyclopeltelo( 1,2 b]pyridine, (5RS, 6SR, 7SR) 6 -Carboxy 7 (2 -carboxymethoxy eec. 5 tert butyl 4 methoxyphelyl) 2 methylamino 5 (3 4 methylenedioxyphenyl)cyc1.opentelot1,2 b]pyridine, 6SR, 7SR) 2- Amino- 6- carboxy- 7- carboxy- *...methoxy 4 methoxyphenyl) 5 (3,4 methylenedioxyphenyl)cyclopentenof 1,2 blpyridine, 6SR, 7SR) 6 -Carboxy 7 (2 -carboxymethoxy 4 iethoxyphenyl) 2 benzoyl) 3 hydroxyp ropy Iamino] 5- (3,f4 methylenedioxyphel) cyclopetelo[ 1, 2 bi]pyridine, 2S (5RS, 6SR, 7SR) 6 -Carboxy 7 (2 carboxymethoxy 4 4- methoxyphenyl) 2- 3- hydroxypropy Iaminlo) 5 4- methy le nedioxyphely 1) cyclope ntelo,( 1, 2 blpyridine, 41 6SR, 7SR) carboxy -7 (2 -carboxymethoxy 4 methoxyphelyl) 2 (2 kiydroxyethylamilo 5 4 methylenedioxypheflyl)cyclopenteno[ 1,2 blpyridine, (5RS,6SR,7SR) 6 Carboxy 5 (3,5 dimethoxyphenyl) 7 (4 methoxyphefly)cyclopefteno[1, 2 b]pyridine, 6SR, 7SR) 6 Carboxy -5 3-propoxy thoxyphelyl) 7- (4 -methoxyphenlY) cyclopentelo 1, 2 -b Ipyridine, ~(5RS, 6SR, 7SR) -6 -Carboxy 5 4 -methylefledioxy 5- methoxyphel) 7 methoxyphel) cyclopeflteno C1, 2 blpyridile, 6 SR, 7S 6 Carboxy5 (3 -benzyloxy 4 -methoxyphenly) 7- (4 methoxypheflyl) cyclopenteno([ 1, 2- b pyis ridine, 6 SR 7SR) -6 -Carbo -5 3 hydroxy 4 -methoxyphel) 7- (4 methoxyphely) cyclopenteno 1, 2 b pyridine, 6 SR 7SR) 5 (4 Indoy-6 carboxy 7 4 20 methoxyphel)cyc3-opetenli12 b]pyridile, 6 SR, 7SR)7 (5 Indoy)6 carboxy 5-( 3 4 methy lenedioxyp hely 1)C clopenteno 1, 2 b I pyr id ine, 6SR, 7SR) 7 4 -Ethoxypheny) -6 carboxy 4- methyJlenedioxyphel) cycopentelo 1, 2- b pyridinle, (SRS, 6SR, 7SR) 7 C 2 (4 imidazolylmethoxy) 4 methoxyphel) 6 carboxy 5 (3,4 methylerie- .:dioxyphel]) cyclopenteno(C 1, 2 b )pyridin.fe, 42 (5RS,6SR,7SR) 7 (2 Oxo 4,5 dihydrof uryloxy) 4- methoxyphenyl] carboxy 5 4 -rethylenedioxyphenyl)cyclopeltelo( 1,2 bipyridine, 6SR,7SR)- 6 -Carboxy 7-(2 1- carboxy -3 hydroxypropoxy) 4 methoxyphenyl] 5 4 methylenedioxyphenyl)cyclopeltelo(1, 2 b]pyridine, (5RS,6SR,7SR) 7 (2 Acetoxymethylcarbonylmethoxy 4 methoxyphenyl 6 carboxy 5 4- methylenedioxyphenyl)cyclopentelo( 1,2 b]pyridine, ~(5RS, 6SR, 7SR) 2 Isopropylamino 6 carboxy 5 (3,4 methylenedioxyphenyl 7 (4 methoxyphenyl)cyclopenteno[1,2 b~pyridine, 6 Carboxy 5 (3 ,4 methylenedioxyphenyl 7 (4 methoxyphenyl) cyc lopent 1, 2 -dieno 2 b ]pyr idine, 6 -Carboxy 5 4 -methylenedioxyphenyl 7 (4 -methoxyphenyl) cyclopeit 1, 2 dieno C2, 1 b ]pyridine, 6SR, 7SR) 6 Carboxy 2, 7 dimethyl 5- 4 -methylenedioxyphenyl 7 (4 methoxyphenyl)cyclopenteno(l.2 blpyridine, (5RS, 6SR, 7SR) -6 -Carboxy -2 -pyrrolidilo 5 f4 -methylenedioxyphenyl 7 (4 methoxyphenyl)cyclopenteno(1,2 -blpyridine, (5RS,6SR,7SR)-6-Carboxy- 7 (2,3-dihydro- zofuranyl) 5 (3,4 methylenedioxypheny].)cyclopenteno(1,2 -b]pyridine, (5RS,6SR,7SR) 6 Carboxy 7 (2 (2 hydroxyethoxy) 4 methoxyphelyl 2 2- (N methyl 3 hydroxypro- 43 pylIamino) 5 4 -m rnthy lenedioxypheny I) cyc lope nteno (1,2 bipyridine, 6SR, 7SR) 6 Carboxy 2 cyclopropylamino- 3, 4 methylenedioxyphenyl) 7 4 rnethoxpheny1) penteno[1,2 -bipyridine, (5RS,6SR,7SR) 6 Carboxy 2 (N -methylisopropylamino) 5 (3,4 methylenedioxyphenyl) -7 (4 methoxphenyl) cyclopenteno C 1, 2 b ]pyridine, (5RS,6SR,7SR) 6 Carboxy 2 (N methylcyclopropylamino) 5 (3,4 methylenedioxyphenyl) 7 (4 methoxphenyl)cyclopenteno[ 1,2 b]pyridine, (5RS,6SR,7SR) -2 -Ethylamino- 6- carboxy- 7- f2- (2 carboxyethyl 4 methoxyphenyl) 5 (3,4 methylenedioxyphenyl)cyclopenteno[1,2 b]pyridine, 6SR, 7SR) -6 -Carboxy 7-(2 -carboxy -2 propenyl) 4 methoxypheiyl 2 propylamino 5 4 methylenedioxyphenyl)cyclopenteno( 1,2 b~pyridine, 6SR, 7SR) 6 -Carboxy 7 2 (2 carboxyp ropyl1) 4- me tboxyp heny] 2- prop ylIamino 5 3, 4- me thy lenedioxyphenyl)cyclopenteno( 1,2 b]pyridine, (5RS,6SR,7SR) -6 -Carboxy 5 (3,4 methylenedioxyphenyl) 7 (2 -methoxypropyl) 4 methoxyphexy I] cyc lopenteno 2 b pyridine, (SRS,6SR,7SR) 7 (2 (2 Acetoxymethylcarbonylethyl) 4- methoxyphenyl 6- carboxy 5- 4 -methy lenedioxyphenyl) cyc lopenteno 1, 2 b]pyridine, 6SR, 7SR) 6 Carboxy 7 2 hdoye 44 thy IcarboriylethylI) 4- methoxyphelylI] 5 methylenedioxyphenyl)cyclopeltelo(li2 b]pyridile, 6SR, 7SR) 6 -Carboxy 7 2 (3 carboxypropyl) 4 rnethoxypheflyl] 5 (3,4 -methylenedioxypheny)cycJlopetelof1,2 b]pyridile, 6SR, 7SR) 6 Carboxy 7 [2 (3 -carboxy 2 propylmethyl) 4 methoxyphelyl] 5 methylenedioxyphenyl)cycIopelteno(lt 2 b]pyridine, (5RS,6SR,7SR) 6 -Carboxy 7 [2 (2 carboxypropyl) 4 methoxypheflyl] 2 isopropylamino 5 4 methylenedioxypheflyl)cyclopenteno( 1,2 b]pyridine, 6SR, 7SR) 6 Carboxy 7 [2 (2 carboxy 3 hydroxypropyl) 4 methoxypheriyll 2 2- propylamino 5 (3,4 methylenedioxyPhelyl) cyclopelteflo(l 12 b b]pyridine, is(5RS,6SR, 7SR) 2 Ethyamino- 6 carboxy- 7 2 -(2 carboxypropyl) 4 methoxyphelI 5 4 methylenedioxyphenyl)cyclopeltelo[1,2 blpyridile, 6SR, 7SR) 2 -Isobuty]-mino6 carboxy -7 C2 carboxypropy-) 4 methoxyphel 5 4 -methylenedioxypheny)cyclopeltelo( 1,2 b]pyridile, (5RS,6SR,7SR) 6 -Carboxy 7 (2 (2 carboxypropy.) 4 methoxyphelyl] 2 cyclopelty-amilo 5 4 methylenedioxyphelyl) cyclopeitelo 1, 2 b Ipyridinle, (5RS,6SR,7SR) 6 -Carboxy 7 (2 (2 carboxypropyl) 4 methoxyphenyil 2 2- (N (methyl) propylamilo] methy le nedioxyphely 1)cyc lope rte no( 1, 2- b~pyridile, 6SR, 7SR) 6 Carboxy 7 (2 (2 carboxy- 45 propyl) 4- methoxypheflyl 2- (N (methyl) isOPropylamino]I 5- 4 methylenedioxyphel) cyclopenteno 1, 2 b Ipyridine, (5RS,6SR,7SR) 6 -Carboxy 7 [2 (2 carboxypropyl) 4- methoxyphel (methyl) ethylamino -5 4 iethylenedioxypheflyl) cyclopefteno([ 1 2 b I pyridine, 6SR, 7SR) 6 Carboxy 7 2 (2 -carboxy 2 hydroxypropy-) 4 methoxyphel)] 2 (methyl)propylamino]I 5- 4 methylefledioxypheflyl)C ccopefteno C 2 bl.pyridine, 6SR, 7SR) -6 -Carboxy- 7 2 -carboxyethyl) 4 -methoxyphefyl 2 N-diethy-amfilo) 5 4 -methylenedioxyphel)cyc3lopefteno( 1,2 blpyridile, (SRS, 6SR, 7SR) -6 -Carboxy- 7 2 -carboxyethyl) is 4- methoxyphefl I- 2- N- (ethyl) propy-amilo 5- 4- methylenedioxyphefl)cyclopenteno(lI 2 b]pyridine, (5RS,6SR,7SR) 6 -Carboxy -7 (2 (2 carboxypropy 4 methoxyphefl l 2 N -diethylamilo) 5- 4 mdth. y-lenedioxyphefl) cyc openteno 1, 2 b pyridine, (5RS,6SR,7SR) 6 -Carboxy 7 (2 (2 carboxypropyl) 4 -methoxyphenl- -2 (N (ethyl) propylamilo]I -5 4 methylenedio'Cyphel) cyclopenteno [l1, 2 b Ipyridine, (5RS,6SR,7SR) 6 -Carboxy 7 (2 (2 carboxypropyl) 4- methoxyphenl] 2 pyrrolidilo -5 4- methy- 25 lenedioxypheflyl)cyclopeflteno(1,2 b~pyridine, 6SR, 7SR) 2 -Hydroxybutylamino)5 3

,I

4 *-methylefledioxyphenyl) 6- methoxycarbofl 7 (2 me- 46 thoxycarboflpropyl 4 methoxyphel IcycIopeltelo 1, 2 b ]pyridine, 6SR, 7SR) -2 -isobuty 6-carboxy 7 (2 carboxypropyl) 4 methoxypheny-] 5 (3,4 -methylenedioxypheny)cyc1lopetelo[l, 2 b]pyridile, 6SR,7SR) -2 -Buty- 6 -carboxy- 7 2 -carboxypropyl) 4 methoxyphelyll 5 (3,4 methylenedioxyphenyl)cyciopeltelo[li2 b]pyridine, 6SR, 7SR) 6 Carboxy 7 (2 (2 carboxypropyl) -4-methoxypheflyl]- 2- cyclopentyl 5- methylenedioxyphel)cyclopetelo( 1,2 b]pyridine, (5RS,6SR,7SR 6 Carboxy 7 [2 (2 carboxypropyl) 4- methoxyphelyl] 2- (methyl)isopropylamilo] (3,4 methylenedioxyphelyl)cyclopeflteno( 1 2 b]pyriis dine, (5RS,6SR,7SR) 6 -Carboxy 7 (2 (2 carboxypropyl) 4 methoxyphelyl] 2 N (ethyl) isopropylamilo] 4 methylenedioxyphel) cyc3openteno 1, 2 b Ipyridine, (5RS, 6SR, 7SR) 7 7- [2 (2 Carboxypropyl) 4 methoxyphenyll 5 4 -methylefledioxyphelyl) 6 6- methoxy- ~carbonylcyclopeltelo(1,2 b ]pyridile, (5RS,6SR,7SR) Carboxy 7 2 (2 -carboxy 3 hydroxypropyl) 4 rnethoxypheflyl 2 2- propylamino 5 4 me th y Ien e d ioxyphely I)cyc I open t eno( 1, 2 b Ipy r id i ne, 6SR, 7SR) Carboxy 7 C(2 (2 carboxy 3 hydroxypropyl) 4 methoxyphel 2 (methyl)propy- 47 Ilamino I 5- (3,4 -met hylenedioxyphely I)cycIopeltelo[ 1,2 b 1pyridine, 6SR, 7SR) 6- Carboxy- 7- carboxyethyl) 4 -methoxyphenl 2 N- (methyl) ethylamilo 5 4- methylenedioxyphelyl)cyclopeflteno( 1,2 b]pyridine, 6SR, 7SR) 2 Sec butylamino 6 carboxy 7 carboxypropyl) methoxyphenyl 5- methylenedioxyphenyl)cyclopentelot1,2 b]pyridine, 6SR,7SR) 6 -Carboxy -7 2 3 -carboxy 2 methyipropyl) 4 methoxyphelyl] 2 propylamiio 5 4 methylenedioxyphelyl)cyclopelteno( 1,2 b]pyridine, 6SR, 7SR) 6 Tert butoxycarboflyl 7 2 (2 methoxycarboflyl 2 propenyl) 4- methoxyphenyl I 5- 4 methylenedioxyphel) 5- (3,4 methylenedioxyphenyl) cyclopenteno[1, 2 -b]pyridile, 6SR, 7SR) Ethylpropylamilo) carboxy 7 2-croyrpl ehxpey 3 methylenedioxypheflyl )cyclopeitelo (1,2 b Ipyridin (SRS, 6SR, 7SR) 6 -Carboxy 7 2 (2 carboxypropyl) 4 methoxyphenyl- 2 2- tert buty3.amiflo 5 (3,4 methyienedioxyphel) cycJopefteno C 1, 2 b Ipyridinle, 6SR, 7SR) 6- Carboxy 7- (2 carboxy 2 propenyl) -4 methoxyphenly]- 2 isopropylamilo 5 4 methylenedioxypheflyl) cyclopenteno 1, 2 bpyridile, (5RS, 6SR, 7SR) 6 Carboxy 7 2 (2 carboxyp ropy 1) -4 me thoxyp he ny II 2 cyc lohe xy lamilo 5 4 -me :thylenedioxyphelyl)cycIopeflteno( 1,2 b~pyridine, and 48 isomerically pure compounds and pharmaceutically acceptable salts thereof.

Preferred are (5RS, 6SR. 7 SR)-2-butvl-6-carboxy-7-[2-(2-caboxypropy)-4methoxyphenyl] (3,4 methylenedioxyphenyl)cyclopenteno[ 1,2 bjpyridine, (5RS,6S R,7SR)-2-isopropylamnino-6-carboxy-7-[2-(2-carboxypropyl)-4-methoxyphenyl (3 ,4-methylenedioxyphenyl)cyclopentno[ I,2-b]pyridine, and isomerically pure compounds thereof.

Especially preferred are most potent endothelin antagonistic isomers selected from the group consisting of (5R,6S,7S)-2-butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl-4methoxypheyl]-5-(3 ,4-methylenedioxyphenyl)cyclopenteno[ 1,2 -b]pyridine, (5R,6S,7S)-2butyl-6-carboxy-7 carboxypropyl)-4-methoxpheny]-5-(3 ,4methylenedioxyphenyl )cyclopenteno[l ,2-b~pyridine, (5 S.6R,7R )-2-butyl-6-carboxy-7-[ (2-carboxypropyl)-4-methoxyphenyl]-5-(3 ,4-methylenedioxyphenyl)cyciopenteno[ 1,2b]pyridine,(5S,6R,7R)-2-butyl-6-carboxy-7-( (S)-2-(2-caboxypropyl)-4-methoxyphphenyl)-5- 4- methylenedioxyphenyl)cyclopenteno[l,2-b]pyridine, (5R,6S,7S)-2-isopropylamino-6carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyll-5-(3 ,4-methylenedioxyphenyI)cyclopenteno[ 1,2-blpyridine, (5R,6S,7S)-2-isopropylamino,-6- carboxy-7-[(S)-2-(2-carboxypropyl) -4-methoxyphenyl-5(3 ,4-methvlenedioxyphenyl)cyclopenteno[ 1,2-b]pyridine, (5 S,6R,7R)-2isopropylamino-6-carboxy-7-[(R)- SUSITT SHET(RLE26 49 2- carboxypropyl) 4- methoxyphenyl] 5- methylenedioxyphenyl)cyclopenteno(1,2 b]pyridine and (5S,6R,7R)- 2- isopropylamino- 6- carboxy- 2 (2carboxypropyl) 4 methoxyphenyl] 5 (3,4 methylenedioxyphenyl)cyclopenteno[1,2 b]pyridine.

The above-described compounds form salts with various inorganic and organic acids and bases and these salts are also within the scope of the invention. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like calcium and magnesium salts, salts with organic bases; dicyclohexylamine salts, Nmethyl-D-glucamine, salts with amino acids like arginine, lysine and the like. Also, salts with organic and inorganic acids may be prepared: HC1, HBr, H 2 SO,, HPO,, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.

The compounds described above are disclosed in W095/05374, the disclosure of which is incorpoared herein by reference, and can be prepared by the methods described therein. Isomerically pure compounds thereof can be prepared from the corresponding isomeri.c mixture, for example, by means of chromatography using chiral column.

t ft ft f f f .f ft ft ft--- The above endothelin antagonist compounds of Formula I, including their pharmaceutically acceptable salts are effective in the prevention and/or treatment of heart failure congestive heart failure) and veritricular dysfunction (symptomatic and asymptomatic). Among the compounds of Formula I useful in the treatment of heart failure and ventricular dysfunction is an isomeric mixture of (5RS, 6SR, 7SR)-2-butyl-6-carboxy-7-[2-(2carboxypropyl)-4-methoxyphenyl]-5-(3,4methylenedioxyphenyl)-cyclopenteno[ 1,2-b]pyridine.

This isomeric mixture was chromatographed using a chiral column and the most active isomer, 6R*, 7R*)-2-butyl-6-carboxy-7-[2-(2-carboxypropyl)-4methoxyphenyll-5-(3,4methylenedioxyphenvl)cyclopenteno[ 1,2b]pyridine, hereinafter referred to as Compound 1, was identified and isolated. See Example 1.

The instant invention relates to a method of preventing and/or treating heart failure and ventricular dysfunction, including but not limited to congestive heart failure, in a warm blooded animal which comprises administering to the warm blooded animal in need of such treatment a therapeutically effective amount of a compound of Formula 1. Additionally, the administration of an endothelin antagonist for the treatment of heart failure and ventricular dysfunction a) may cause regression reversal) of heart failure and ventricular dysfunction; b) may prevent histologic/morphologic changes in end organs, such as heart, vasculature and Vee kidney associated with heart failure and ventricular dysfunction; and c) may also manage secondarily any of the following conditions renal failure, atrial flutter, atrial fibrillation and ventricular arrhythmia.

For the purposes of this disclosure, a warm blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism, and includes mammals and birds. Preferably the warm blooded animal is man. A therapeutically effective amount, for the purposes of this disclosure, is an amount effective to improve cardiac function and/or reduce the hemodynamic •o 50/1 burden on the heart and/or alleviate other pathophysiologic manifestations of heart failure and ventricular dysfunction.

e eee ooeoo: °oeee oeoe oo oe e e 51 The endothelin antagonistic substances above described may be used in the form of drug formulations suitable for parenteral administration, oral administration or external administration by mixing them with s solid or liquid excipient carriers known in this field.

The drug formulations include a liquid formulation such as an injection formulation, an inhalant formulation, a syrup formulation or an emulsion, a solid formulation such as tablets, capsules or granules, and an external drug such as an ointment or a suppository. Further, these drug formulations may contain additives which are commonly employed, such as an adjuvant, a stabilizer, a wetting agent, an emulsifier, an absorption-promoting agent or a surfactant, as the case requires. As the 15 additives, distilled water for injection, physiological saline, Ringer's solution, glucose, sugar syrup, gelatin, vegetable oil, cacao butter, ethylene glycol, hydroxypropyl cellulose, lactose, sucrose, corn starch, magnesium stearate and talc may be mentioned.

The dose of an endothelin antagonist varies depending upon the manner of administration, the age and body weight of the patient and the condition of the "patient to be treated. However, a typical administration method for an adult is oral administration or 25 parenteral administration. The daily dose in the case of oral administration to an adult patient is from 0.1 to 100 mg/kg body weight, and the daily dose in the case 52 of parenteral administration is from 0.01 to 10 mg/kg body weight.

The following Examples illustrate the present invention more specifically. It should be understood that the present invention is not limited to these examples alone.

Example 1 6R*, 7R*)-2-butyl-6-carboxy-7-[2-(2carboxypropyl)-4-methoxyphenyl]-5-(3,4methylenedioxyphenyl)cyclopenteno[l,2-b]pyridine Separation of and compound obtained in Example 186 of WO 95/05374 was done by a HPLC column (Daicel chiralpack AD); retention time for 39-58 min, HPLC data: column chiralpak AD (Daicel), 50 mm diameter, 500 mm length; solvent hexane:isopropanol:TFA (90:10:0.1); flow rate 100 ml/min; injection 1.1 g of racemate in isopropanol; detection UV=260 nm *o The above separation was repeated eight times and the fractions containing the desired compound were combined and evaporated to dryness. To the residue were added AcOEt and water.

The aqueous phase was adjusted to pH 4 with 3N NaOH. The organic phase was washed with water, brine, and dried over Na 2

SO

4 The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (Wako Gel* C-300, eluent; hexane(2)/AcOEt(1) AcCEt) to give a glassy solid (2.91 The solid was triturated in water to afford a title compound as white amorphous powder (2.24g).

'H-NMR (300 MHz, CDC1,, 6 ppm); 0.84 (3H, t, J=7.3Hz), 1.18-1.35 (2H, 1.31 (3H, d, J=6.3Hz), 1.40-1.56(2H, 2.55-2.72 (3H, 2.88-3.02 (1H, 3.36 (1H, dd, J=5.6Hz, 13.1Hz), 3.60 (1H, t, J=9.7Hz), 3.75 (3H, 4.58 (1H, d, J=9.7Hz)m, 4.99 (1H, d, J=9.7Hz), 6.00 (2H, br 6.70 .53- (1H, d, J=2.7Hz), 6.775 (1H, d, J=1.4Hz), 6.785 (1Hi, dd, J=2.7HZ, 8.6 Hz), 6.81 (1H, dd, J=1.4Hz, 7.9Hz), 6.84 (1H, d, J=7.9Hz), 6.94 (1H, d, J=8.6Hz),7.06 (1H, d, .1=7.9Hz), 7.33 (1H, d, .1=7.9Hz)

D

2 0 46.,0 c=1, CH3OH) Rf value: 0.40 Merck, Kieselgel 60 F 24/chloroform) The isocmerically pure compound is hereinafter designated as Compound 1.

Exapl 2 54 Step A: Implantation of Instrumentation Five farm pigs of either of sex and weighing 34.5±2.5 kg were sedated with ketamine hydrochloride (25 mg/kg, and xylazine (6 mg/kg, After tracheal intubation, general anesthesia was maintained with isoflurane (1.5-2.0 vol% in oxygen). Using sterile surgical technique, a left thoracotomy was performed at the fifth intercostal space. Catheters made of Tygon tubing (Norton Performance Plastics Co., Akron, OH) were implanted in the descending aorta, left and right atria for measurement of pressures. A solid-state miniature pressure gauge (Konigsberg Instruments Inc., Pasadena. CA) was implanted in the left ventricular (LV) chamber to obtain LV pressure and the rate of change of LV pressure (LV dP/dt). A flow probe (Transonic System Inc., Ithaca, NY) was placed around the main pulmonary artery for measurement of blood flow. One pair of piezoelectric ultrasonic dimension crystals were implanted on opposing anterior and posterior endocardial regions of the LV to measure the short-axis internal diameter. Proper alignment of the endocardial crystals was achieved during surgical implantation by positioning the crystals so as to obtain a signal with the greatest amplitude and shortest transit time. A pacing lead (model 5069, Medtronic Inc..

Minneapolis, MN) was attached to the right ventricular free wall, and stainless steel pacing leads were attached to the left atrial appendage. The left circumflex coronary artery was isolated and two hydraulic occluders, made of Tygon tubing, were implanted proximally and distally to the first *obtuse marginal branch. The wires and catheters were externalized between the scapulae, the incision was closed in layers, and air was evacuated from the chest cavity. See Figure 8.

Step B: Experimental Measurements Hemodynamic recordings were made using a data tape recorder (RD-130TE. TEAC, Montebello, CA) and a multiple-channel oscillograph (MT95K2, Astro-Med, West Warwick, RI). Aortic and left atrial pressures were measured using strain gauge manometers (Statham Instruments. Oxnard, CA), which were calibrated in vitro using a mercury manometer, connected to the fluid-filled catheters. The solid-state LV pressure gauge was cross-calibrated with aortic and left atrial pressure measurements. LV dP/dt was obtained by electronically differentiating the LV pressure signal. Blood flow was measured using a volume flow meter (T208, Transonic System Inc., Ithaca, NY). Mean arterial pressure, left atrial pressures, and pulmonary blood flow (cardiac output) were measured using an amplifier filter. Stroke volume was calculated as the quotient of cardiac output and heart rate. Cardiac output was normalized by body weight to yield cardiac index. LV dimension was measured with an ultrasonic transit-time dimension gauge (Model 203, Triton Technology Inc., San Diego, CA). Total peripheral resistance was calculated as the quotient of mean arterial pressure and cardiac output. LV short-axis enddiastolic dimension (EDD) was measured at the beginning of the upstroke of the LV dP/dt signal. LV end-systolic dimension (ESD) was measured at the time of maximum negative dP/dt. The percent shortening of LV internal diameter was calculated as (EDD-ESD)/EDD*100. LV mean velocity of circumferential fibre shortening (Vcf) was calculated from the dimension measurements using the following formula:(EDD- ESD)/EDD/Ejection time Ejection time was measured as the interval between maximum and minimum LV dP/dt. A cardiotachometer triggered by the LV pressure pulse provided instantaneous and continuous records of heart rate.

Step C: Heart Failure Model Experiments were initiated 10-14 days after surgery, when the pigs were fully recovered from surgery. During the post-operative period, the pigs were introduced to a sling for training. Heart failure was produced by progressive myocardial ischemia induced by two coronary artery occlusions followed by intermittent ventricular pacing. Briefly, after post-surgical hemodynamic control monitoring was performed, the left circumflex coronary artery was occluded by inflating the distally implanted hydraulic occluder. Approximately 48 hrs after the first occlusion, the proximal coronary artery occluder was inflated. One to two -56 days following the second myocardial infarction, the right ventricle was paced at a rate of 190-210 beats/min using a programmable external cardiac pacemaker (model EV4543, Pace Medical, Waltham, MA). Pacing was continued for 1 week and then terminated for 3 days. This procedure was repeated another 1-2 cycles, until heart failure was evident and the hemodynamic parameters were stable.

Step D: Experimental Protocols Hemodynamic experiments were performed after 2 cycles of tachycardic pacing in the presence of myocardial ischemia injury, after the animal had achieved a stable state of heart failure. During the experiments, the pigs were conscious and quietly restrained in a sling. The test compound is dissolved in saturated NaHCO, (10% by Vol) and 0.9% saline (90% by Vol) at a concentration of 2 mg/ml, was studied in four conscious pigs with heart failure. A dose of 0.5 mg/kg was injected intravenously over a period of 2 minutes, and hemodynamics were continuously recorded before and 90 minutes following injection of the test compound in all 4 pigs. In two of these pigs, recording continued until 3 hours following injection of the test compound. The vehicle was tested on separate days. The effects of 0.1 to 0.5 gg/kg cumulative bolus doses in 0.1 Lg/kg steps of endothelin-1 (Peptide Institute, Inc., Osaka, Japan) were also examined on separate days before and 90 minutes after injection of the test compound in three pigs during development of heart failure to characterize the extent of endothelin block by the test compound. ET-1 was dissolved in 0.1 N NaHCO, (95% by Vol) and 0.9% saline (95% by Vol) at a concentration of 20 ptg/ml.

Step E: Data Analysis SAll data were stored on an AST 4/d computer. Data before and after development of heart failure were compared using Student's t-test for paired data. The data at baseline and after injection of the test compound also were compared using Student's t-test for paired data with a o Bonferroni correction. All values are expressed as the mean S.E.

Statistical significance was accepted at the p<0.05 level.

-57- Experimental protocol using an endothelin antagonist: Compound 1 Step A: Hemodynamic study with Compound 1 Hemodynamic experiments were performed after 2 cycles of tachycardic pacing in the presence of myocardial ischemia injury, after the animal had achieved a stable state of heart failure. During the experiments, the pigs were conscious and quietly restrained in a sling.

Compound 1, dissolved in saturated NaHCO, (10% by Vol) and 0.9% saline by Vol) at a concentration of 2 mg/ml, was studied in four conscious pigs with heart failure. A dose of 0.5 mg/kg was injected intravenously over a period of 2 minutes, and hemodynamics were continuously recorded before and 90 minutes following injection of Compound I in all 4 pigs. In two of these pigs, recording continued until 3 hours following injection of Compound 1. The vehicle was tested on separate days. The effects of 0.1 to 0.5 g/kg cumulative bolus doses in 0.1 jig/kg steps of endothelin- (Peptide Institute, Inc., Osaka, Japan) were also examined on separate days before and 90 minutes after injection of Compound I in three pigs during development of heart failure to characterize the extent of ET block by Compound 1. ET-I was dissolved in 0.1 N NaHCO 3 (95% by Vol) and 0.9% saline (95% by Vol) at a concentration of 20 p.g/ml.

For comparative purpose, the effects of intravenous injection of Compound 2 (enalaprilat), at doses of 1 mg/kg and 4 mg/kg, were studied on different days in three of the pigs that were used to study Compound 2 and in one additional pig. Compound 2 was dissolved in 0.9% saline.

Step- B: Baseline Hemodynamics Before and After Development of Heart Failure Tables I and 2 summarize the baseline LV function and systemic vascular dynamics before post surgical control) and after heart failure induced by serial myocardial infarctions in combination with intermittent tachycardic stress in conscious pigs. Heart failure resulting from at least 2 cycles of tachycardic pacing in the presence of myocardial injury was manifested by significant increases in LV end-diastolic (+10.7+0.4 mm from 40.2+3.6 mm) and end-systolic diameters (+14.6+1.1 mm from 31.2+2.7 mm) and in mean left atrial pressure (+19+3 mmHg from 4±2 mmHg). LV dP/dt, LV fractional shortening, Vcf, and cardiac 58 index significantly decreased by 45+4, 54+6, 46+1 and 29+8%, respectively. Also, total peripheral resistance increased significantly while mean arterial pressure and heart rate were unchanged.

In addition to these hemodynamic changes, which are shown in Figures 1 and 2, heart failure, particularly at the advanced stages, was characterized by anorexia, peripheral and pulmonary edema, and reduced activity.

Table 1: Baseline Left Ventricular Function in Controls and Con. cious Pigs with Heart Failure.

Control Heart Failure LV End-Diastolic Diameter (mm) 40.2+3.6 50.9+3.5* LV End-Systolic Diameter (mm) 31.2+2.7 45.8+3.6* LV Fractional Shortening 22.3+1.5 10.3+1.3* Vcf 1. 1+0. 1 0.6+0.0* LV dP/dt (mmHg/sec) 3012±153 1681+184* Significantly different from control, p<0.05.

Data are mean SE with n=3, except that LV dP/dt n=4.

Table 2: Baseline Cardiac and Systemic Hemodynamics in Controls and Conscious Pigs with Heart Failure.

Control Mean Arterial Pressure (mmHg) 90+3 Mean Left Atrial Pressure (mmHg) 4+2 Cardiac Index (ml/min/kg) 123+11 Total Peripheral Resistance 0.73+0.06 (mmHg/ml/min/kg) Heart Rate (beat/min) 139+4 Significantly different from control, p<0.05.

Data are mean SE with n=4.

Heart Failure 88+5 23+3* 86+9* 1.04+0.09* 143+15 59 Ste C: Effects of Compound I on Hemodvnamics in Heart Failure The time course of hemodynamic changes following intravenous administration of Compound I (0.5 mg/kg) are shown in Figures 3 and 4. Tables 3 and 4 summarize LV function and systemic hemodynamic responses to Compound I at 15 minutes and 60 minutes after administration of Compound 1. Figures 1 and 2 illustrate the cardiac and systemic dynamic measurements made before and after development of heart failure, as well as 60 minutes after administration of Compound I during the heart failure stage.

Compound I mainly induced a sustained increase in cardiac index, and prolonged decreases in mean arterial pressure and total peripheral resistance. For example, at 60 minutes after administration of Compound 1, mean arterial pressure was significantly decreased by 10±2% and cardiac index was increased by 17+4%. Thus, total peripheral resistance was significantly decreased by 22+3% with Compound 1. which basically constitutes a complete restoration of the elevated vascular resistance of heart failure back to pre-heart failure control values (Figure Although Compound I also decreased left atrial pressure and increased heart rate, these changes were not statistically significant. Vcf was increased by 12±2%, while LV dP/dt, LV end-diastolic and systolic diameter, and LV fraction shortening were not affected by Compound 1.

o*o*o *oooo *oo o* oo** *•oo *o 60 The vehicle did not induce any significant changes throughout 180 minutes of observation (Figures 3 and 4).

The salutary effects of acute administration of Compound I in this heart failure model were predominantly due to the reversal of elevated vascular resistance.

Table 3: Effects of Intravenous Injection of Compound 1 (0.5 mg/kg) on LV Function in Conscious Pigs with Heart Failure.

Change from Baseline Baseline 15 min 60 min LV End-Diastolic Diameter (mm) 50.9+3.5 +0.1+0.2 +0.2+0.3 LV End-Systolic Diameter (mm) 45.8+3.6 -0.3+0.3 -0.2+0.3 LV Fractional Shortening 10.3+1.3 +0.6+0.2 +0.7+0.2 Vcf (sec') 0.60+0.04 0.05+0.01* +0.07+0.02* LV dP/dt (mmHg/sec) 1681+184 +25+40 56+65 Significantly different from baseline. p<0.02 5 Data are mean SE with n=3, except that LV dP/dt n=4.

*i 61 Table 4: Effects of Intravenous Injection of Compound 1 (0-5 mg/kg) on Cardiac and Systemic Hemodynamics in Conscious Pigs with Heart Failure.

Change from Baseline Baseline 15 min 60 min Left Atrial Pressure 23±3 -4±2 -2±2 (mmHg) Mean Arterial Pressure (mmHg) 88±5 -10±1* -8±1 Cardiac Index (ml/min/kg) 86±9 +14±2* +13±2* Total Peripheral Resistance 1.04±0.09 -0.25±0.03* -0.024±0.05 Heart Rate (beat/min) 143±15 +5±5 *Significantly different from baseline, p<0/025.

Data are mean SE with n=4.

Step D: Effects of Compound 1 compared with Compound 2 in Heart Failure Figure 5 compares the effects of the intravenous aministration of Compound 1 mg/kg) and Compound 2 (enalaprilat) with (1 mg/kg or 4 mg/kg) on total peripheral resistance in conscious pigs with heart failure. While the effects were not dose-dependent, suggesting maximal effect, both doses of Compound 2 did significantly reduce the total peripheral resistance to a similar level throughout 90-minute observation period. The reduction in total peripheral resistance by administration of Compound 1 (0.5 mg/kg) was greater than that induced by either dose of Compound 2. Figure 6 compares the changes in mean arteriall pressure, LV dP/dt, cardiac output and total peripheral resistance at 60 minutes after administration of Compound 1 or Compound 2.

-62- Step E: Effects of ET-1 in the Absence and Presence of Compound 1 in Heart Failure Figure 7 shows the effects of cumulative intravenous bolus injections of ET-1 I (total dose of 0.5 btg/kg) on mean arterial pressure, mean left atrial pressure, total peripheral resistance and heart rate before and after intravenous administration of Compound 1 at a dose of 0.5 mg/kg. ET-1 induced significant dose-dependent increases in mean arterial pressure, mean left atrial pressure and total peripheral resistance. Heart rate decreased, but not dose-dependently. The hemodynamic responses to ET-1 were markedly attenuated after administration of Compound 1, suggesting the 0.5 mg/kg, i.v. dose of Compound 1 to be capable of significant blocking the effects of exogenous ET-1.

Compound 1, at a dose of 0.5 mg/kg, i.v. reduced the elevated vascular resistance but did not affect myocardial contractility in conscious pigs with heart failure. This acute effect of Compound 1 was greater than that of 1 mg/kg or 4 mg/kg, i.v. Compound 2. The salutary effects of Compound 1 in this heart failure model were attributed to ET receptor antagonism since the hemodynamic responses to an ET-1 challenge were markedly -•attenuated by the same dose of Compound 1.

°•o.oi Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or •steps.

The reference to any prior art in this specification is not, and should not be taken 25 as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

Claims (6)

1. An endothelin antagonist selected from the group consisting of: 6S, 7S)-2-butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyl] (3 ,4-methylenedioxyphenyl)cyclopenteno[ 1,2-b]pyridine; 6S, 7S)-2-butyl-6-carboxy-7-[(S)-2-(2-carboxypropyl)-4-methoxyphenyl] (3,4-methylenedioxyphenyl)cyclopenteno[ 1,2-b]pyridine; 6R, 7R)-2-butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3 ,4-methylenedioxyphenyl)cyclopenteno [1 ,2-bjpyridine; and (5S, 6R, 7R)-2-butyl-6-carboxy-7-[(S)-2-(2-carboxypropyl)-4-methoxyphenyl]-5- (3 ,4-methylenedioxyphenyl)cyclopenteno[ 1,2-b]pyridine.

2. The endothelin antagonist of claim 1, wherein said antagonist is (5R,65,75)-2- butyl-6-carboxy-7-[(R)-2-(2-carboxypropyl)-4-methoxyphenyl] ,4- 15methylenedioxyphenyl)cyclopenteno[ 1 ,2-b]pyridine. 02

3. The endothelin antagonist of claim 1, wherein said antagonist is (5S, 6S, 7R)-2- butyl-6-carboxy-7-[(S)-2-(2-carboxypropyl)-4-methoxyphenyl]-5-(3,4- methylenedioxyphenyl)cyclopenteno[ 1 ,2-b]pyridine.

4. T hraetclcmoito opiiga endothelin antagonist of clai 1,e whrioadatgnstif5,6,7)2 tclam61,2,arbo7r)2or(a-parmaoeuticaly)accetablosathereof5-(,4da- xcpeto carier P:OPER\MKR\SPECI\72335I-div.doc-2I 100 -64-

7. Use of an endothelin antagonist according to any one of claims 1 to 5 in preparation of a pharmaceutical composition for preventing and/or treating heart failure and ventricular dysfunction in a warm blooded animal.

8. An endothelin antagonist according to claim 1, substantially as hereinbefore described with reference to the examples. DATED this 22nd day of November, 2000 Banyu Pharmaceutical Co., Ltd. By DAVIES COLLISON CAVE Patent Attorneys for the Applicant S. o S S o