ENDOTHELIN RECEPTOR ANTAGONISTS

Abstract: Novel pyrroles, pyrazoles and triazoles, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists are described.

Description: ENDOTHELIN RECEPTOR ANTAGONISTS FIELD OF INVENTION The present invention relates to novel pyrroles, pyrazoles and triazoles, pharmaceutical compositions containing these compounds and their use as endothelin receptor antagonists. Endothelin (ET) is a highly potent vasoconstrictor peptide synthesized and released by the vascular endothelium. Endothelin exists as three isoforms, ET-1, ET-2 and ET-3. [Unless otherwise stated "endothelin" shall mean any or all of the isoforms of endothelin]. Endothelin has profound effects on the cardiovascular system, and in particular, the coronary, renal and cerebral circulation. Elevated or abnormal release of endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of cardiovascular, cerebrovascular, respiratory and renal pathophysiology. Elevated levels of endothelin have been reported in plasma from patients with essential hypertension, acute myocardial infarction, subarachnoid hemorrhage, atherosclerosis, and patients with uraemia undergoing dialysis. In vivo, endothelin has pronounced effects on blood pressure and cardiac output. An intravenous bolus injection of ET (0.1 to 3 nmol/kg) in rats causes a transient, dose-related depressor response (lasting 0.5 to 2 minutes) followed by a sustained, dose-dependent rise in arterial blood pressure which can remain elevated for 2 to 3 hours following dosing. Doses above 3 nmol/kg in a rat often prove fatal. Endothelin appears to produce a preferential effect in the renal vascular bed. It produces a marked, long-lasting decrease in renal blood flow, accompanied by a significant decrease in GFR, urine volume, urinary sodium and potassium excretion. Endothelin produces a sustained antinatriuretic effect, despite significant elevations in atrial natriuretic peptide. Endothelin also stimulates plasma renin activity. These findings suggest that ET is involved in the regulation of renal function and is involved in a variety of renal disorders including acute renal failure, cyclosporine nephrotoxicity, radio contrast induced renal failure and chronic renal failure. Studies have shown that in vivo, the cerebral vasculature is highly sensitive to both the vasodilator and vasoconstrictor effects of endothelin. Therefore, ET may be an important mediator of cerebral vasospasm, a frequent and often fatal consequence of subarachnoid hemorrhage. ET also exhibits direct central nervous system effects such as severe apnea and ischemic lesions which suggests that ET may contribute to the development of cerebral infarcts and neuronal death. ET has also been implicated in myocardial ischemia (Nichols et al. Br. J. Pharm. 99: 597-601, 1989 and Clozel and Clozel, Circ. Res.. 65: 1193-1200, 1989) coronary vasospasm (Fukuda et al.. Eur. J. Pharm. 165: 301-304, 1989 and Lϋscher, Circ. 83: 701, 1991) heart failure, proliferation of vascular smooth muscle cells, (Takagi. Biochem & Biophvs. Res. Commun.: 168: 537-543, 1990, Bobek eLa , Am. J. Phvsiol. 258:408-C415, 1990) and atherosclerosis, (Nakaki et al.. Biochem. & Biophvs. Res. Commun. 158: 880-881, 1989, and Lerman et al.. New Eng. J. of Med. 325: 997-1001, 1991). Increased levels of endothelin have been shown after coronary balloon angioplasty (Kadel et al.. No. 2491 Circ. 82: 627, 1990). Further, endothelin has been found to be a potent constrictor of isolated mammalian airway tissue including human bronchus (Uchida et al.. Eur J. of Pharm. 154: 227-228 1988, LaGente, Clin. Exp. Allergy 20: 343-348, 1990; and Springall et al.. Lancet. 337: 697-701, 1991). Endothelin may play a role in the pathogenesis of interstitial pulmonary fibrosis and associated pulmonary hypertension, Glard et al.. Third International Conference on Endothelin, 1993, p. 34 and ARDS (Adult Respiratory Distress Syndrome), Sanai et ah, Supra, p. 112. Endothelin has been associated with the induction of hemorrhagic and necrotic damage in the gastric mucosa (Whittle et al.. Br. J. Pharm. 95: 1011-1013, 1988); Raynaud's phenomenon, Cinniniello et al.. Lancet 337: 114-115, 1991); Crohn's Disease and ulcerative colitis, Munch et al.. Lancet. Vol. 339, p. 381; Migraine (Edmeads, Headache, Feb. 1991 p 127); Sepsis (Weitzberg et al.. Circ. Shock 33: 222-227, 1991: Pittet et al.. Ann. Surg. 213: 262-264, 1991), Cyclosporin-induced renal failure or hypertension (Eur. J. Pharmacol .. 180: 191- 192, 1990. Kidney Int. 37: 1487-1491, 1990) and endotoxin shock and other endotoxin induced diseases (Biochem. Biophvs. Res. Commun.. 161: 1220-1227, 1989, Acta Phvsiol. Scand. 137: 317-318, 1989) and inflammatory skin diseases. (Clin Res. 41:451 and 484, 1993). Endothelin has also been implicated in preclampsia of pregnancy. Clark et ah, Am. J. Obstet. Gvnecol. March 1992, p. 962-968; Kamor et al.. N. Eng. J. of Med.. Nov 22, 1990, p. 1486-1487; Dekker e Eur J. Ob. and Gvn. and Rep. Bio. 40 (1991) 215-220; Schiff e ah, Am. J. Ostet. Gvnecol. Feb 1992, p. 624-628; diabetes mellitus, Takahashi et al.. Diabetologia (1990) 33:306-310; and acute vascular rejection following kidney transplant, Watschinger et al.. Transplantation Vol. 52, No. 4, pp. 743-746. Endothelin stimulates both bone resorption and anabolism and may have a role in the coupling of bone remodeling. Tatrai et al. Endocrinology. Vol. 131, p. 603-607. Endothelin has been reported to stimulate the transport of sperm in the uterine cavity, Casey et al.. J. Clin. Endo and Metabolism. Vol. 74, No. 1, p. 223- 225, therefore endothelin antagonists may be useful as male contraceptives. Endothelin modulates the ovarian/menstrual cycle, Kenegsberg, J. of Clin. Endo. and Met.. Vol. 74, No. 1, p. 12, and may also play a role in the regulation of penile vascular tone in man, Lau et al.. Asia Pacific J. of Pharm.. 1991, 6:287-292 and Tejada et al.. J. Amer. Phvsio. Soc. 1991, H1078-H1085. Endothelin also mediates a potent contraction of human prostatic smooth muscle, Langenstroer et al.. J. Urology. Vol. 149, p. 495-499. Thus, endothelin receptor antagonists would offer a unique approach toward the pharmacotherapy of hypertension, acute and chronic renal failure, ischemia induced renal failure, sepsis-endotoxin induced renal failure, prophylaxis and/or treatment of radio-contrast induced renal failure, acute and chronic cyclosporin induced renal failure, cerebrovascular disease, cerebrovascular spasm, subarachnoid hemorrhage, myocardial ischemia, angina, congestive heart failure, acute coronary syndrome, myocardial salvage, unstable angina, asthma, primary pulmonary hypertension, pulmonary hypertension secondary to intrinsic pulmonary disease, atherosclerosis, Raynaud's phenomenon, ulcers, sepsis, migraine, glaucoma, endotoxin shock, endotoxin induced multiple organ failure or disseminated intravascular coagulation, cyclosporin-induced renal failure and as an adjunct in angioplasty for prevention of restenosis, diabetes, diabetic retinopathy, retinopathy, diabetic nephropathy, diabetic macrovascular disease, atherosclerosis, preclampsia of pregnancy, bone remodeling, kidney transplant, male contraceptives, infertility and priaprism and benign prostatic hypertrophy. SUMMARY OF THE INVENTION This invention comprises compounds represented by Formula (I) and pharmaceutical compositions containing these compounds, and their use as endothelin receptor antagonists which are useful in the treatment of a variety of cardiovascular and renal diseases including but not limited to: hypertension, acute and chronic renal failure, cyclosporine induced nephrotoxicity, benign prostatic hypertrophy, pulmonary hypertension, migraine, stroke, subarachnoid hemorrhage, cerebrovascular vasospasm, myocardial ischemia, angina, congestive heart failure, atherosclerosis, diabetic nephropathy, diabetic retinopathy, retinopathy, diabetic macrovascular disease, atherosclerosis and as an adjunct in angioplasty for prevention of restenosis. This invention further constitutes a method for antagonizing endothelin receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I). This invention also constitutes intermediates represented by Formula (II). In a further aspect the present invention provides a process for the preparation of a compound of Formula (I)(d). DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are represented by structural Formula (I): (CH 2 ) n I FL (I) wherein (Z) is (d) (e) ( ) (g) P is tetrazol-5-yl, CO2R6 or C(O)N(R 6 )S(O) q Rιo; R a is independently hydrogen or Ci .galkyl; Rt is independently hydrogen, Ar, C^ .galkyl or Cj.g alkoxy; R2 is Ar, C 2.galkyl, C(O)Ri4 or (c) R3 and R 5 are independently R13OH, C^galkoxy, S(O) q R! 1 ? N(R 6 ) 2 , NO2, Br, F, I, Cl, CF3, NHCOR 6 , R 13 CO 2 R 7 , -X-R9-Y, -X(C(R 6 ) 2 )OR 6 , -(CH 2 ) m X , Rg or - X(CH2) n R8 wherein each methylene group within -X(CH2) n Rg may be unsubstituted or substituted by one or two -(CH2) n Ar groups; R 4 is independently Ri 1 , OH, C^alkoxy, S(O) q R! 1 , N(R 6 ) 2 , Br, F, I, Cl or NHCOR 6 , wherein the C^alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; Rg is independently hydrogen or C 1.galkyl; R7 is independently hydrogen, Cι _ιoalkyl, C2-i()alkenyl or C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(Rg)2, CO2R j 2 > halogen or XCi _ιoalkyl; or R7 is (CH2) n Ar; Rg is independently R n , CO2R7, CO 2 C(R! ι ) 2 O(CO)XR 7 , PO3(R 7 ) 2) SO2NR 7 Ri NR 7 SO 2 Rι 1, CONR 7 SO 2 Rι !, SO 3 R 7 , SO 2 R 7 , P(O)(OR 7 )R 7 , CN, CO 2 (CH 2 ) m C(O)N(R 6 ) 2 , C(Rι ι) 2 N(R 7 ) 2 , C(O)N(R 6 ) 2 , NR 7 C(O)NR 7 SO 2 Rn, ORg, or tetrazole which is substituted or unsubstituted by Cj. galkyl; R9 is independently a bond, lOalkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(Rg)2, COOH or halogen; RlO is independently Cι_ιoalkyl, N(Rg)2 or Ar; Rl 1 is independently hydrogen, Ar, C\_ galkyl, C2_galkenyl, C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(Rg)2 or halogen; Rl2 is independently hydrogen, Cj .galkyl, C2_galkenyl or C2- alkynyl; Rj3 is independently divalent Ar, Ci.jøalkylene, C _ιøalkylidene, C2_ιoalkenylene, all of which may be unsubstituted or substituted by one or two OH, CH2OH, N(Rg)2 or halogen; R14 is independently hydrogen, CJ.J galkyl, XCi.iøalkyl, Ar or XAr; Rl5 is independently hydrogen, Ar, C\. galkyl, or XAr; Rig is independently Ci -galkyl or phenyl substituted by one ortwo Ci .galkyl, OH, Cι_ 5 alkoxy, S(O) q Rg, N(Rg) 2 , Br, F, I, Cl, CF3 or NHCORg; X is independently (CH2) n . O, NRg or S(O) q ; X' is independently O, NRg or S(O) q ; Y is independently CH3 or X(CH2)nAr; Ar is: (a) (b) naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or two Zi or Z2 groups; A is independently C=O, or (C(Rg)2) ; B is independently -CH2- or -O-; Zi and Z2 are independently hydrogen, XRg, Ci .galkyl, (CH2) q CO2Rg, C(O)N(Rg)2, CN, (CH 2 ) n OH, NO 2 , F, Cl, Br, I, N(Rg) 2 , NHC(O)Rg, O(CH 2 ) m C(O)NR a SO 2 Rιg, (CH 2 )mOC(O)NR a SO2Rig, O(CH2) m NR a C(O)NR a SO2Rig or tetrazolyl which may be substituted or unsubstituted by one or two Ci .galkyl, CF3 or C(O)Rg; m is independently 1 to 3; n is independently 0 to 6; q is independently 0, 1 or 2; provided R3 R4 and R5 are not O-O(CH2)nAπ and further provided that R2 is not dihydrobenzofuran; or a pharmaceutically acceptable salt thereof. All alkyl, alkenyl, alkynyl and alkoxy groups may be straight or branched. Halogen may be Br, Cl, F or I. The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and diastereoisomers are contemplated to be within the scope of the present invention. Preferred compounds are those wherein: P is CO2Rg; more preferably P is CO2H. Rl is hydrogen. R2 is Ar, cyclohexyl or Cj galkyl. More preferably R2 is a group Ar wherein Ar is a group (a) or (b). In said group (a) or (b) Zi and Z2 are independently hydrogen, CO2R , (CH2) n OH, Ci galkyl or C g alkoxy, e.g. methoxy; A is preferably CH2, both Bs are preferably O. R3 and R5 are independently hydrogen, CO2Rg, OH, Ci.galkoxy, Ci.galkyl, N(Rg) 2 , NO 2 , Br, F, Cl, I, R 13 CO 2 R 7 , X(CH 2 ) n Rg, (CH 2 )mX'R , or X(C(Rg) 2 ) m ORg; In the context of the group R3 and R5 preferably do not represent hydrogen. In particular in the group R3 preferably represents Br, Cl, Ci.galkoxy e.g. methoxy; X(CH2) n R8> wherein X preferably represents O, n is 0, 1, or 2, and Rg is preferably selected from: CO2Rg wherein Rg is preferably hydrogen; ORg wherein Rg is preferably H; tetrazolyl optionally substituted by Ci.galkyl e.g. ethyl; CONR 7 SO2Ri i wherein R 7 is H or Ci .galkyl e.g. methyl, Ri preferably is C .galkyl (e.g. methyl, isopryl, or t-butyl) or phenyl optionally substituted by Br, Cl, F, Ci.galkyl e.g. methyl; or Rg is phenyl or pyridyl substituted by one or more Br, Cl, CO2H, CH2OH. R5 is Ci.galkoxy e.g. methoxy, or N(Rg)2 wherein Rg preferably is H or methyl. R4 is hydrogen, OH, C^alkoxy, N(Rg)2, Br, F, Cl, I, NHCOCH3, or s (°)q Cj. salkyl wherein the C galkyl may be unsubstituted or substituted by OH, methoxy or halogen. R4 is more preferably hydrogen; Rg is hydrogen or Ci.galkyl e.g. methyl and ethyl; R 7 is hydrogen, Cι_ιoalkyl, C2-ioalkenyl or C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(Rg)2, CO2R12, halogen, or R 7 is (CH2) n Ar. When R 7 is (CH2) n r, n is preferably zero or 1 and Ar is preferably phenyl substituted or unsubstituted by halogen or C _ζ alkoxy. Rl l is hydrogen, phenyl, pyridyl wherein the phenyl and pyridyl may be substituted or unsubstituted by one or two Ci^alkyl groups; Ci.galkyl, C2-galkenyl, C2-galkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(Rg)2_ or halogen; R12 is hydrogen or Ci.galkyl. Rl3 is phenyl, pyridyl, or C2-ioalkylene, all of which may be unsubstituted or substituted by one or more CO2Rg, OH, CH2OH, N(Rg)2, or halogen; R15 is preferably hydrogen or Ci.galkyl e.g. ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylethyl. (Z) is preferrably (d). Preferred compounds are: (E)-alpha-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-l-ethyl-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Allyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[ 1 -Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-chlorophenyl]- lH-pyrazol- 4-yl]methylene]-6-methoxy-l,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Butyl-5-[4-methoxy-2-[[N- (phenylsulfonyl)]carboxamidomethoxy]phenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-3-[ 1 -Butyl-5-[2-[2-carboxyphenyl)methoxy]-4-methoxyphenyl]- 1 H-pyrazol-4- yl]-2-[(2,5-dimethoxyphenyl)methyl]-prop-2-enoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-hydroxymethylphenyl)methoxy]-4-methoxyphenyl]- 1 H-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-7 -methoxy- 1 ,4-benzodioxan-6-propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-l- cyclopropylmethyl- lH-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5- propanoic acid; (E)-alpha-[[ 1 -(3-Butenyl)-5-[2-[(2-hydroxymethylphenyl)methoxy]-4- methoxyphenyl]- lH-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5- propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-l- cyclopropylethyl-lH-pyrazol-4-yl]methylene]-6-methoxy-l,3-benzodioxole-5- propanoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-carboxyphenoxy]methyl)-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid. The present invention provides compounds of Formula (I), which may be made by methods similar to those given below. Compounds of the Formula (Id) can be prepared by alkylating a ketone of Formula (2) in dimethyl carbonate in the presence of sodium hydride to provide a β-keto ester of Formula (3). Condensation of a β-keto ester of Formula (3) with dimethyl formate dimethyl acetal in a suitable solvent such as toluene at approximately 95 °C affords a compound of Formula (4). Treatment of a compound of Formula (4) with a hydrazine derivative of the Formula (5) wherein R15 is Cμgalkyl; in suitable solvents such as methanol and water in the presence of sodium acetate provides a pyrazole of Formula (6). Reduction of an ester of Formula (6) with a reducing agent such as diisobutylalluminum hydride in a solvent such as dichloromethane followed by oxidation with an oxidant such as Jones reagent in acetone affords an aldehyde of Formula (7). Knoevenagel condensation of an aldehyde of Formula (7) with a half acid of Formula (8), wherein Rig is Cι_8 alkyl R2 ( 8 ) in a solvent such as benzene at reflux, in the presence of piperidinium acetate with azeotropic removal of water using a Dean-Stark apparatus to afford an ester of Formula (9). Followed if necessary and desired by: 1) deprotection and alkylation and hydrolysis of the R3, R4, R5, R 5, R g, Zi and Z2 groups as required and; 2) salt formation. Aldehyde condensation may also be effectuated by heating in the presence of pyridine and acetic acid. Conversion of an ester of formula (9) into an acid may be carried out using conventional deprotection techniques and hydrolysis. A half acid of Formula (8), HQ_C^CQ>Ri6 Wherein n=l, R is (b), A=CH2, B=O and Rig is C g alkyl, may be prepared by reacting a compound of Formula (10) with methyl iodide in the presence of sodium hydride in a solvent such as dimethyl formamide to provide a compound of Formula (11). Treament of a compound of Formula (11) with POCI3 in dimethyl formamide affords an aldehyde of Formula (12). Condensation of an aldehyde of Formula (12) with a dialkyl malonate of Formula (13) R 16 0 2 C > R 16 0 2 C (13) in the presence of piperidine and acetic acid in benzene provides a α,β-unsatuated ester of Formula (14). Reduction of a α,β-unsatuated ester of Formula (14) with sodium borohydride in a solvent such as ethanol gives a compound of Formula of (15) Monosaponification of a diester of Formula (15) with a base such as potasium hydroxide in a mixture of ethanol and water followed by acidic work up provides a half acid of Formula (8). Other compounds of formula (Id) may be prepared by methods well known in the art. The invention also is a process for preparing compounds of Formula (Id) by: (a) Reaction of a compound of Formula (II) or a protected form or precursor thereof (as defined hereinafter) with a compound of Formula (8) (wherein R2 and Rjg are as defined for Formula (Id) hereinabove); followed if necessary or desired by: (b) conversion of one compound of Formula (Id) into a different compound of Formula (Id) e.g. (i) when Formula (Id) contains a group CO2Rg, CO2R 7 or CO2R12 wherein Rg, R 7 or R12 is alkyl, conversion to a corresponding compound where Rg, R 7 or R 2 represents hydrogen; (ii) when Formula (Id) contains a hydroxy group (e.g. in R3, R4 or R5) conversion to a different group, e.g. a group (CH2)Ar where Ar is optionally substituted phenyl, by method well known in the art; and/or (c) salt formation. It will be appreciated by those skilled in the art that the substitutents R3, R4, R5' R 5 and Zi and Z2 may be introduced at any appropriate stage of the synthesis, preferably at an early stage, using methods well known in the art. In some of the reactions depicted above, particularly those in the early stages of the overall synthesis, one or more of the substitutents may therefore represent a precursor for the eventual substituent. A precursor for any of the substitutents means a group which may be derivatised or converted into the desired group. It will be further appreciated that it may be necessary or desirable to protect certain of these substitutents(or their precursors) at various stages in the reaction sequence. Suitable precursors and protecting groups are well known to those skilled in the art, as are methods for their conversion or removal respectively. In another aspect the invention provides for an intermediate of the formula (II) wherein R15, R3, R4, R5 and R a are as described for Formula (I) Compounds of Formula (Ii) can be prepared starting by commercially available ketones of Formula (17) by reaction with diethyl oxalate of Formula (18) (18) in the presence of a base such as sodium ethoxide in a solvent such as ethanol to produce a diketone of Formula (19). (19) Reaction of a diketone of Formula (19) with hydrazine derivative of Formula (20) R_. ^NH 2 ' H (20) in a suitable solvent such as ethanol at reflux provides a pyrazole of Formula (21). Saponification of an ester of Formula (21) using lithium hydroxide in a solvent such as aqueous methanol affords, after acidification an acid of the Formula (22), which can be subsequently converted to the corresponding N-methoxy-N- methylamide of Formula (23) by treatment with methyl chloroformate followed by N,O-dimethylhydroxylamine hydrochloride in the presence of a base such as N-methylpiperidine. Compound of Formula (23) can be treated with an organometallic reagent Ra-M wherein Ra is C g alkyl and m is Li or MgCl; to provide a compound of Formula (24), wherein R a is Ci -galkyl. Reaction of compound of Formula (24) with the the lithium enolate of an ester of Formula (25) provides an alcohol of Formula (26) Dehydration of compound of Formula (26) with acetic anhydride followed by treatment with a base such as l,8-diazabicyclo[5.4.0]undec-7-ene provides a compound of Formula (27) Alternatively, reaction of compound (24), wherein R a is Ci^alkyl, with Lawesson's reagent in a suitable solvent such as tetrahydrofuran affords a thione of Formula (28), which can be treated with diazoester (29) in refluxing tetrahydrofuran to provide a thiirane of Formula (30). Treatment of a thiirane of Formula (30) with trimethylphosphite at reflux in a solvent such as chloroform provides compounds of Formula (27), wherein R a is C j _ 6 alkyl. Saponification of an ester of Formula (27) using lithium hydroxide in a solvent such as aqueous methanol affords, after acidification with acetic acid, an acid of the Formula (Ii), wherein P is CO 2 H. Compounds of the Formula (Ie) can be prepared following the steps outlined in the following Scheme (32) starting from an aryl ester of Formula (31), wherein Rig is Ci-g alkyl, to provide a pyrrole of Formula (32). Compound of Formula (32) can be subsequently converted to compounds of Formula (Ie) following the same sequence of steps as the one described above for the conversions of compound (6) and compound (21) to compounds (Id) and compound (Ii), respectively. Compounds of Formula (Ih) may be prepared starting from a boronic acid of Formula (33) with a triazole of Formula (34), wherein X is Cr or Br; under standard Suzuki coupling conditions to provide an ester of Formula (35) A compound of Formula (33) may be prepared by reaction of a corresponding organometallic derivative (eg lithium or Grignard) with a trialkyl borate followed by hydrolysis. A compound of Formula (34) may be prepared starting from dimethyl malonate with p-acetaminobenzenesulfonyl azide in a solvent such as acetonitrile in the of a base such as triethyl amine to provide dimethyl diazomalonate (36). Treatment of diazomalonate of Formula (36) with an amine of Formula (37) R— NH 2 (3?) followed by acidic work up provides a triazole of Formula (38) Reaction of a compound of Formula (38) with PX5, whereas X is Br or Cl, in the presence of potassium carbonate in dimethylformamide affords a compound of Formula (34). Compounds of Formula (Ij) may be prepared starting from an analine of Formula (39) with a diketone of Formula of (40) in a suitable solvent such as ethyl alcohol at reflux to provide a pyrrole of Formula (41). A diketone of Formula of (40) might be prepared by reacting of α,β-unsatuated ketone of Formula (42) with a silyl enol ether of Formula (43) Me-SiO OSiMe, EtO OEt (43) in the presence of Lewis acid such as zinc chloride in a suitable solvent such as dichloromethane followed by acidic hydrolysis. Compounds of Formula (35) and compounds of Formula (41) can be subsequently converted to compounds of Formula (Ih) and compounds of Formula (Ij), respectively, following the same sequence of steps as the one described above for the conversions of compound (6), compound (21) and compound (32) to compounds (Id), compound (Ii) and compound (Ie), respectively. In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration. Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavouring or colouring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell. Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, poly vinylpyrrolidone, lecithin, arachis oil, or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues. Typical transdermal formulations comprise a conventional aqueous or non¬ aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane. Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose. Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I). The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. The biological activity of the compounds of Formula (I) are demonstrated by the following tests: I. Binding Assay A) CHO cell membrane preparation. CHO cells stably transfected with human ET^ and ETg receptors were grown in 245 mm x 245 mm tissue culture plates in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. The confluent cells were washed with Dulbecco's phosphate-buffered saline containing a protease inhibitor cocktail (5 mM EDTA, 0.5 mM PMSF, 5 ug/ml of leupeptin and 0.1 U/ml of aprotinin) and scraped in the same buffer. After centrifugation at 800 x g, the cells were lysed by freezing in liquid nitrogen and thawing on ice followed by homogenization (30 times using a glass dounce homogenizer) in lysis buffer containing 20 mM Tris HCl, pH 7.5, and the protease inhibitor cocktail. After an initial centrifugation at 800 x g for 10 min to remove unbroken cells and nuclei, the supernatants were centrifuged at 40,000 x g for 15 min and the pellet was resuspended in 50 mM Tris HCl, pH 7.5, and 10 mM MgCl2 and stored in small aliquots at -70°C after freezing in liquid N2. Protein was determined by using the BCA method and BSA as the standard. (B) Binding studies. [125i]ET-l binding to membranes prepared from CHO cells was performed following the procedure of Elshourbagy et al. (1993). Briefly, the assay was initiated in a 100 ul volume by adding 25 ul of [ 125 I]ET-1 (0.2-0.3 nM) in 0.05% BSA to membranes in the absence (total binding) or presence (nonspecific binding) of 100 nM unlabeled ET-1. The concentrations of membrane proteins were 0.5 and 0.05 ug per assay tube for ET^ and ETg receptors, respectively. The incubations (30°C, 60 min) were stopped by dilution with cold buffer (20 mM Tris HCl, pH 7.6, and 10 mM MgCl2) and filtering through Whatman GF/C filters (Clifton, NJ) presoaked in 0.1% BSA. The filters were washed 3 times (5 ml each time) with the same buffer by using a Brandel cell harvester and were counted by using a gamma counter at 75% efficiency. The following examples are illustrative and are not limiting of the compounds of this invention. EXAMPLE 1 (E)-α/p/tfl-rri-n-Butyl-5-r2-r ( 2-carboxyphenyl)methoxy1-4-methoxyphenyl]-lH- pyrazol-4-yllmethylenel-6-methoxy- 1.3-benzodioxole-5-propanoic acid a) (£)-Ethyl 6-Methoxy-α//?Λα-[(7-methoxy-4-oxo-4H-l-benzopyran-3- yl)methylene]- 1 ,3-benzodioxole-5-propanoate A solution of 3-formyl-7-methoxychromone (0.67 g, 3.3 mmol) and ethyl hydrogen 2-[(6-methoxy-3,4-methylenedioxy)benzyl]malonate (0.89 g, 3.0 mmol) in benzene (30 mL) was treated with piperidine (0.15 mL, 1.5 mmol) followed by acetic acid (0.085 mL, 1.5 mmol). The reaction was stirred at reflux equipped with a Dean Stark apparatus for 2 h. The mixture was cooled then extracted with EtOAc (200 mL). The organic extract was washed successively with saturated NaHCO β and brine, dried (MgSO 4 ) and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, EtOAc/hexane, gradient 75:25 to 70:30) to afford a material consisting of a 1.2 : 1 mixture of E:Z enoates as an oil (1.02 g, 78%). Recrystallization of this material from ethanol affords the title compound as the E-isomer, exclusively. Data for the the E-isomer: mp 140-141°C; MS (ESI) m/z 439 (M+H)+. Anal. Calcd for C 24 H 2 2θ 8 : C, 65.75; H, 5.06. Found: C, 65.56; H, 4.99. b) (E)-Ethyl α//?Λα-[[l-Butyl-5-(2-hydroxy-4-methoxyphenyl)-lH-pyrazol-4- yl]methylene]-6-methoxy-l,3-benzodioxole-5-propanoate and (E)-Ethyl α/pΛα-[[l- Butyl-3-(2-hydroxy-4-methoxyphenyl)-lH-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoate A solution of the compound of Example 1(a) (0.679 g, 1.55 mmol), butylhydrazine oxalate (0.552 g, 3.1 mmol) and sodium acetate trihydrate (1.265 g, 9.3 mmol) in a mixture of 9: 1 EtOH:H 2 O (31 mL) was stirred at reflux for 1 h. The reaction mixture was cooled and subsequently partitioned between EtOAc (300 mL) and aqueous pH 7 buffer. The organic extract was washed with brine, dried (Na 2 SO4) and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, EtOAc/hexane, 60:40) to afford the 1,3,4- pyrazole (340 mg, 43%) followed by the isomeric 1,4,5-pyrazole (361 mg, 46%). Data for the 1,4,5-pyrazole: R/ (70:30 hexane:ethyl acetate) 0.14; 1 H NMR (400 MHz, CDC1 3 ) δ 0.79 (t, J= 7.3 Hz, 3 H), 1.12-1.21 (m, 2 H), 1.20 (t, J = 7.2 Hz, 3 H), 1.67 (quintet, 7 = 7.4 Hz, 2 H), 3.79 (s, 3 H), 3.83 (s, 3 H), 3.86-3.95 (m, 4 H), 4.14 (q, J = 7.2 Hz, 2 H), 5.84 (s, 2 H), 6.53 (s, 1 H), 6.54 (s, 1 H), 6.56 (d, J = 2.4 Hz, 1 H), 6.61 (dd, J= 8.5, 2.4 Hz, 1 H), 7.03 (d, J= 8.5 Hz, 1 H), 7.39 (s, 1 H), 7.60 (s, 1 H); MS (ESI) m/z 509 (M+H) + . Data for 1,3,4-pyrazole: Rf (70:30 hexane:ethyl acetate) 0.41; lH NMR (400 MHz, CDCI3) δ 0.91 (t, J - 7.3 Hz, 3 H), 1.22- 1.25 (m, 2 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.80 (quintet, J - 7.4 Hz, 2 H), 3.76-3.81 (m, 2 H), 3.77 (s, 3 H), 3.78 (s, 2 H), 4.04 (t, J = 7.1 Hz, 2 H), 4.24 (q, J = 7.2 Hz, 2 H), 5.88 (s, 2 H), 6.49-6.54 (m, 1 H), 6.55 (s, 2 H), 6.61 (d, J = 2.5 Hz, 1 H), 7.32 (s, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.92 (s, 1 H), 10.5 (s, 1 H); MS (ESI) m/z 509 (M+H) + . c) (£)-Ethyl α//>Λα-[[l-Butyl-5-[4-methoxy-2-[[2- (methoxycarbonyl)phenyl]methoxy]phenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy- 1 ,3-benzodioxole-5-propanoate A solution of the 1,4,5-pyrazole of Example 1(b) (0.34 g, 0.67 mmol) in DMF (2.0 mL) was added dropwise to a slurry of NaH (0.024 g, 1.0 mmol) in DMF (1.3 mL) at room temperature. The reaction was stirred for 3 min at which time was added methyl 2-(bromomethyl)benzoate (0.23 g, 1.0 mmol) and stirring continued for 1 h at room temperature. The mixture was quenched with aqueous pH 7 buffer, then diluted with EtOAc. The organic extract was washed with brine, dried (Na SO 4 ) and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, gradient hexane/Et 2 O, 60:40 to 50:50) to afford the title compound (396 mg, 90%). Rf (70:30 hexane:ethyl acetate) 0.23; MS (EST) m/z 657 (M+H)+ d) (E)-α pΛα-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic Acid To a solution of the ester of Example 1(c) (0.396 g, 0.60 mmol) in MeOH (16.2 mL) was added aqueous LiOH » H 2 O (0.253 g, 6.0 mmol, in 1.8 mL H 2 O), and the reaction was heated at reflux for 4 h. After cooling to room temperature, acetic acid (2.5 mL) was added followed by H 2 O (15 mL) at which time a precipitate formed. Most of the methanol was removed under reduced pressure, and the resulting aqueous solution was cooled to 0°C. The mixture was filtered and the precipitate was recrystallized from EtOAc (-20 °C) to give the title compound as white crystals (0.27 g). The mother liquors were purified by column chromatography (silica gel, gradient CH2C12/hexane/EtOAC/HOAc 40:40:20:1 to 40:30:30: 1) to afford an additional 86 mg of title compound (356 mg, 96% overall): mp 213-214°C; Rf (50:50: 1 hexane:ethyl acetate: acetic acid) 0.43; l U NMR (400 MHz, CDC1 3 ) δ 0.80 (t, 7 = 7.3 Hz, 3 H), 1.21-1.26 (m, 2 H), 1.69-1.77 (m, 2 H), 3.59 (s, 2 H), 3.81 (s, 3 H), 3.86 (s, 3 H), 3.97-4.02 (m, 2 H), 5.53 (s, 2 H), 5.82 (s, 2 H), 6.47 (s, 1 H), 6.52 (s, 1 H), 6.67 (dd, 7= 8.4, 2.2 Hz, 1 H), 6.70 (d, 7= 2.2 Hz, 1 H), 7.12 (d 7 = 8.4 Hz, 1 H), 7.32-7.36 (m, 2 H), 7.48 (t, 7 = 7.6 Hz, 1 H), 7.52 (s, 1 H), 7.54 (s, 1 H), , 8.08 (d, 7 = 7.4 Hz, 1 H); MS (ESI) m/z 613 (M-H)\ Anal. Calcd for C3 4 H34N2O9. • 0.25 H 2 O: C, 65.96; H, 5.62; N, 4.52. Found: C, 65.94; H, 5.44; N, 4.44. Alternately l-butyl-5-[2-(2-carboxyphenyl)methoxy]-4-methoxyphenylpyrazole-4- carboxy aldehyde may be prepared as follows. a) (E)-Methyl 2-[[2-(3-hydroxy-l-oxo-2-propenyl)-5- methoxyphenoxy]methyl]benzoate To a 12 L round bottomed flask, was added 60% sodium hydride (50.9 g, 1.27 mol, 2 equivalents). Toluene (600 mL) was added and the resulting solution was stirred. Methyl 2-[(2-acetyl-5-methoxyphenoxy)methyl]benzoate (200.0 g, 0.636 mol) dissolved in toluene (2.0 L) was added slowly over a period of 20 minutes. After the addition was complete, the solution was stirred for a period of 15 minutes. Methyl formate (229.1 g, 235 mL, 3.82 mol) was added over 20 minutes. The mixture was stirred for 1 hour at ambient temperature. Sodium methoxide (34.3 g, 0.636 mol) was added in three equal portions over 30 minutes. The mixture was stirred at ambient for 16 hours. HPLC of the reaction mixture showed the absence of starting material. Hexane (6 L) was added and the reaction mixture was stirred for 1 hour. The solids were filtered and washed with 2 L of hexane and dried under vacuum (0.5 mTorr) to afford (E)-methyl 2-[[2-(3-hydroxy-l-oxo-2- propenyl)-5-methoxyphenoxy]methyl]benzoate, monosodium salt (303.9 g). The (E)-methyl 2-[[2-(3-hydroxy- l-oxo-2-proρenyl)-5- methoxyphenoxy]methyl]benzoate, monosodium salt was slurried in water (3 L) and toluene (4 L) was added. A solution of 10% citric acid (2.5 L) was added and the solution stirred for 1 hour. The layers were separated, and the aqueous layer was extracted with 2 L of toluene. The combined toluene layers were washed with brine solution (2 x 2 L) and dried (magnesium sulfate), filtered and concentrated to a solid which was triturated with hexane (2 L). The solid was filtered and dried to afford the title compound (188.4 g, 86.6% yield) as a light yellow solid: ! H NMR (300 MHz, CDC1 3 ) δ 8.20 (IH, d), 8.05 (IH, d), 7.95 (IH, m), 7.70 (IH, d), 7.65 (IH, m), 7.45 (IH, m), 6.50 (2H, m), 5.65 (2H, m), 5.3 (IH, br s), 3.90 (3H, s), 3.80 (3H, s). b) (E)-Methyl 2-[[2-[3-(diethylamino)-l-oxo-2-propenyl]-5- methoxyphenoxy]methyl]benzoate To a 2 L round bottomed flask was added (E)-methyl 2-[[2-(3-hydroxy-l- oxo-2-propenyl)-5-methoxyphenoxy]methyl]benzoate (104 g, 0.304 mol) and 1 L of toluene. After complete dissolution, diethylamine (28.3g, 40 mL, 0.39 mol) was rapidly added under nitrogen via an addition funnel into the stirred solution. The reaction mixture was stirred under nitrogen for 1 h and it was then concentrated under reduced pressure to give approximately 120 g (100% yield) of the title compound as an orange solid: ! H NMR (300 MHz, CDC1 3 ) δ 8.02 (IH, d), 7.84(1H, d) 7.67 (2H, bd) 7.51 (IH, t) 7.35 (IH, t), 6.54 (2H, m), 5.75 (IH, d), 5.52 (2H, s), 3.80 (3H, s), 3.23 (4h, br), 1.14 (6H, br). c) l-Butyl-5-[2-(2-methoxycarbonylphenylmethoxy)-4-methoxyphenyl-lH- pyrazole To a 5 L round bottomed flask was added (E)-methyl 2-[[2-[3- (diethylamino)- 1 -oxo-2-propenyl]-5-methoxyphenoxy]methyl]benzoate ( 150 g, 0.37 mol), 2.9 L of methanol and 0.45 L of water. After complete dissolution, a premixed quantity of sodium acetate (294 g, 3.58 mol) and n-butylhydrazine oxalate salt (133 g, 0.746 mol) was added via a powder funnel in rapid portions over a period of 20 minutes. The reaction mixture was blanketed with nitrogen during the reaction period. After 20 hours the reaction mixture was partitioned between 3 L of ethyl acetate and 3 L of water. The aqueous was removed and poured into 2 L of ethyl acetate and the aqueous was separated once again. This operation was repeated once more with 1.2 L of ethyl acetate (a total of 6 L of ethyl acetate used in total). The combined organic extracts were dried (magnesium sulfate) and concentrated under reduced pressure to 187 g of a thick oil. Flash chromatography (50% TBME/Hex) afforded the title compound (153 g, 73% yield) as a colourless oil which slowly solidified on standing: l H NMR (300 MHz, CDCI3) δ 8.02 (IH, d), 7.6 (IH, d), 7.52-7.22 (3H, m), 7.12 (IH, d), 6.64 (IH, d), 6.54 (IH, dd), 6.20 (IH, s), 5.48 (2H, s), 4.01 (2H, t), 3.89 (s 3H), 3.76 (3H, s), 1.7-1.5 (2H, m), 1.2-1.05 (2H, m), 0.7 (3H, t). d) l-Butyl-5-[2-(2-methoxycarbonylphenylmethoxy)-4-methoxyphenyl-lH- pyrazole-4-carboxyaldehyde To a 2 L round bottomed flask was added 235 mL of DMF, followed by phosphorous oxychloride (125.0 g, 75 mL, 0.81 mol) under nitrogen. The temperature of the reaction mixture rose to 40 °C during the addition. The mixture was then allowed to cool to room temperature and then was poured into a separate flask containing 235 mL of DMF and l-butyl-5-[2-(2- methoxycarbonylphenylmethoxy)-4-methoxyphenyl-lH-pyrazole (145 g, 0.36 mol). The resulting mixture was warmed to 95 °C under nitrogen; it was then allowed to cool and was poured into 1 L of water containing sodium acetate (lOOg, 1.13 mol). TBME (1.5 L) was added and the organic phase was separated. An additional 1.5 L of TBME was added. The combined organic phases were dried with magnesium sulfate , filtered and concentrated to 200 g of crude product as a dark oil. Flash chromatography (30% TBME/hexane to 60% hex/TBME) afforded 100 g of solid which was recrystallized (TBME/ Hex) to give the title compound (91.3g, 58% yield) as a white solid: J H NMR (300 MHz, CDC1 3 ) δ 9.54 (IH, s), 8.1 (IH, s), 8.02 (IH, d), 7.45 (IH, t), 7.31 (IH, t), 7.29-7.261 (IH, m), 7.20 (IH, d), 6.71 (IH, s), 6.55 (IH, d), 5.5 (2H, s), 4.0 (2H, t), 3.92 (3H,s), 1.82-1.64 (2H, m), 1.22-1.08 (2H, m), 0.8 (3H, t). e) l-Butyl-5-[2-(2-carboxyphenyl)methoxy]-4-methoxyphenylpyrazole-4- carboxyaldehyde To a 2 L round bottomed flask equipped with an air driven stirrer and condenser was added l-butyl-5-[2-(2-methoxycarbonylphenylmethoxy)-4- methoxyphenyl-lH-pyrazole-4-carboxyaldehyde (92 g, 0.218 mol), 0.883 L of methanol and lithium hydroxide (14.1 g, 0.336 moles, 1.54 eq). The mixture was warmed to 70 °C and 0.222 L of water was added and the resultant light yellow mixture was maintained at 65 °C for 2 hours under nitrogen atmosphere. The solution was allowed to cool and then was concentrated under reduced pressure to give a thick oil. The oil was sequentially treated with citric acid (60 g, 0.285 moles, 1.3 eq) predissolved in 1.0 L of water and 1 L of dichloromethane. The organic layer was removed and the aqueous layer was washed with 0.5 L of dichloromethane. The organic layers were combined, dried (magnesium sulfate), filtered through a pad of celite, and then concentrated under reduced pressure. This oil was redissolved in 0.8 L of toluene and placed in a -20 °C freezer for 12 hours. The solid formed was filtered, washed with 500 mL of toluene and placed in an oven and dried to constant weight (1.0 Torr @ 50°C) to afford the title compound (72 g, 81% yield) as a white solid: *H NMR (300 MHz, CDC1 3 ) δ 9.55 (IH, s), 8.15-8.10 (2H, m), 7.51 (IH, t), 7.35 (IH, t), 7.28 (IH, d), 7.20 (IH, d), 6.70 (IH, s), 6.52 (lH,dd), 5.51 (2H, s), 4.1-3.90 (2H, m), 3.85 (3H, s), 1.82-1.64 (2H, m), 1.22-1.08 (2H, m), 0.8 (3H, t). EXAMPLE 2 (E)-fl/p/zQ-rri-n-Butyl-3-f2-r(2-carboxyphenyl)methoxy1-4-methoxyphenyl1-lH- pyrazol-4-yl1methylenel-6-methoxy- 1.3-benzodioxole-5-propanoic acid a) (E)-Εthyl α/p/zα-[[l-Butyl-3-[4-methoxy-2-[[2- (methoxycarbonyl)phenyl]methoxy]phenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy- 1 ,3-benzodioxole-5-propanoate To a solution of the 1,3,4-pyrazole of Example 1(b) (0.23 g, 0.45 mmol) in DMF (5 mL) was added NaH (0.04 g, 1.83 mmol) at 0°C. The reaction stirred for 3 min at which time was added methyl 2-(bromomethyl)benzoate (0.22 g, 0.80 mmol) and stirring continued for 1.5 h at room temperature. The mixture was partitioned with EtOAc and 2% HCl, the resulting organic layer was then washed with water (2X). The aqueous layer was then neutralized with NaHCO 3 to pH 7 and then partitioned with EtOAc. The combined organic extract was washed with brine, dried (MgSO4) and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, gradient hexane/Et O, 67:33 to 65:35) to afford the title compound as an oil (0.25 g, 81%). J H NMR (400 MHz, CDC1 3 ) δ 0.91 (t, 7 = 7.4 Hz, 3 H), 1.13 (t, 7 = 7.1 Hz, 3 H), 1.30 (sextet, 7= 7.4 Hz, 2 H), 1.83 (quintet, 7 = 7.4 Hz, 2 H), 3.73 (s, 2 H), 3.85 (s, 3 H), 3.86 (s, 3 H), 3.89 (s, 3 H), 4.07 (q, 7 = 7.1 Hz, 2 H), 4.08 (t, 7 = 7.4 Hz, 2 H), 5.51 (s, 2 H), 5.87 (s, 2 H), 6.49 (s, 1 H), 6.59 (s, 1 H), 6.61 (dd, 7= 8.4, 2.2 Hz, 1 H), 6.69 (d, 7 = 2.2 Hz, 1 H), 7.31 (t, 7 = 7.8 Hz, 1 H), 7.34 (d, 7 = 8.4 Hz, 1 H), 7.39 (s, 1 H), 7.46 (t, 7 = 7.7 Hz, 1 H), 7.61 (d, 7 = 7.8 Hz, 1 H), 7.70 (s, 1 H), 7.99 (d, 7 = 7.8 Hz, 1 H). b) (E)-fl/pΛα-[[l-Butyl-3-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic Acid To a solution of the ester of example 2(a) (0.21 g, 0.33 mmol) in MeOH (13.5 mL) was added aqueous LiOH (0.13 g, 3.0 mmol, in 1.5 mL H 2 O), and the reaction was heated at reflux for 5 h. To the mixture was added acetic acid (1 mL) and most of the solvent was removed under reduced pressure. The residue was partitioned between ΕtOAc and brine. The organic layer was dried (MgSO ) and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel, CH 2 Cl 2 /ΕtOAc/hexane/HOAc, 40:30:30: 1) to give a white solid, which was recrystallized from EtOAc to afford the title compound (0.175 g, 86%): mp 226-227 °C; *H NMR (400 MHz, CDC1 3 ) δ 0.94 (t, 7 = 7.3 Hz, 3 H), 1.33 (sextet, 7= 7.3 Hz, 2 H), 1.85 (quintet, 7 = 7.3 Hz, 2 H), 3.44 (s, 2 H), 3.82 (s, 3 H), 3.85 (s, 3 H), 4.10 (t, 7 = 7.2 Hz, 2 H), 5.65 (s, 2 H), 5.85 (s, 2 H), 6.47 (s, 1 H), 6.57 (s, 1 H), 6.62 (dd, 7 = 8.4, 2.1 Hz, 1 H), 6.67 (d, 7 = 2.1 Hz, 1 H), 7.32-7.37 (m, 2 H), 7.43 (d 7 = 8.4 Hz, 1 H), 7.48-7.52 (m, 2 H), 7.76 (s, 1 H), 8.12 (d, 7 = 7.9 Hz, 1 H); MS (ESI) m/z 615 (M+H) + . Anal. Calcd for C 34 H34N 2 O9 • 0.25 H 2 O: C, 65.97; H, 5.62; N, 4.52. Found: C, 65.84; H, 5.46; N, 4.31. EXAMPLE 3 (E)-α/p zQ-rri-n-Butyl-5-r2-r('2-carboxyphenyπmethoxyl-5-chloro-4- methylphenyll- 1 H-pyrazol-4-vπmethylene1-6-methoxy- 1.3-benzodioxole-5- propanoic acid a) (E)-Εthyl 6-Methoxy-α/p/ια-[(6-chloro-7-methyl-4-oxo-4H-l-benzopyran-3- yl)methylene]- 1 ,3-benzodioxole-5-propanoate Following the procedure of Example 1(a), except substituting 6-chloro-3- formyl-7-methylchromone for 3-formyl-7-methoxychromone, the title compound was prepared in 38% yield: mp (hexane/ethyl acetate) 134-135 °C. b) (E)-Ethyl α/ Λα-[[l-Butyl-5-(5-chloro-2-hydroxy-4-methylphenyl)-lH-pyrazol- 4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoate Following the procedure of Example 1 (b), except substituting the compound of Example 3(a) for (£)-ethyl 6-methoxy- /p ι -[(7-methoxy-4-oxo-4H-l- benzopyran-3-yl)methylene] - 1 ,3-benzodioxole-5-propanoate, the title compound was prepared in 41% yield: MS (ESI) m/z 527 (M+H)+. c) (£)-Ethyl α/p/ια-[[l-Butyl-5-[5-chloro-2-[[2- (methoxycarbonyl)phenyl]methoxy]-4-methylphenyl]-lH-pyrazol-4-yl]methylene]- 6-methoxy- 1 ,3-benzodioxole-5-propanoate Following the procedure of Example 1(c), except substituting the compound of Example 3(b) for (E)-ethyl α/pΛα-[[l-butyl-5-(2-hydroxy-4-methoxyphenyl)-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propenoate, the title compound was prepared in 90% yield: MS (ΕSI) m/z 675 (M+H) + . d) (E)-α/p ifl-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-5-chloro-4- methylphenyl]- 1 H-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5- propanoic Acid Following the procedure of Example 1(d), except substituting the compound of Example 3(c) for (E)-ethyl α/ /ια-[[l-butyl-5-[4-methoxy-2-[[2- (methoxycarbonyl)phenyl]methoxy]phenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy-l,3-benzodioxole-5-propanoate, the title compound was prepared in 83% yield, mp 114-116°C. EXAMPLE 4 (E)-alpha-rri-n-Butyl-5-r2-r(2-carboxyphenyl)methoxyl-4-chlorophenyl1-lH- pyrazol-4-yl1methylenel-6-methoxy- 1.3-benzodioxole-5-propanoic acid 110°C (dec) EXAMPLE 5 f ZValpha- IT 1 -n-Butyl-5-f2- r( " 2-carboxyphenyl)methoxyl-4-methoxyphenvπ- 1 H- pyrazol-4-vnmethylenel-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid 188-189°C EXAMPLE 6 (E -alpha-lT 1 -Hvdro-(3-r(2-Carboxyphenyl)methoxy1-4-methoxyphenyl " l- 1H- pyrazol-4-yllmethylene1-6-methoxy- 1 ,3-benzodioxole-5-propionic acid EXAMPLE 7 (E)-alpha-rri-Ethylf5-r(2-carboxyphenyl)methoxyl-4-methoxyphenyll-lH-pyrazol- 4-yl1methylene1-6-methoxy- 1.3-benzodioxole-5-propionic acid EXAMPLE 8 (E)-alpha-fπ-Allyl-r5-(2-carboxyphenyl)methoxy1-4-methoxyphenyll-lH-pyrazol-4- yllmethylenel-6-methoxy- 1.3-benzodioxole-5-propionic acid EXAMPLE 9 (E)-alpha-rri-n-Butyl-5-f2-r(2-carboxyphenyl)methoxy1-4.5-dichlorophenyn-lH- pyrazol-4-vnmethylene1-6-methoxy- 1.3-benzodioxole-5-propanoic acid 226-228°C EXAMPLE 10 (E)-alpha-rfl-n-Butyl-r3-r4-methoxy-2-rrN-(phenylsulfonyl)lcarboxamido- methoxy1phenvn-lH-pyrazol-4-yllmethylenel-6-methoxy-1.3-benzodioxole propionic acid EXAMPLE 11 (E)-3-ri-n-Butyl-5-r2-r(2-carboxyphenyl)methoxyl-4-methoxyphenyl1-lH-pyrazol- 4-yl1-2-r(3.5-dimethoxyphenyl)methyll-prop-2-enoic acid EXAMPLE 12 (E)-alpha-rri-n-Butyl-5-r4-methoxy-2-rrN-(phenylsulfonyl)1carboxamido- methoxylphenyl1-lH-pyrazol-4-yl1methylenel-6-methoxy-l,3-benzodioxole-5- propanoic acid EXAMPLE 13 (E)-3-ri-n-Butyl-5-r2-r2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- yl1-2-r(2.3-dimethoxyphenyl)methyll-prop-2-enoic acid 188-189°C EXAMPLE 14 (E)-3-[l-M-Butyl-5-r2-r2-carboxyphenyl)methoxy]-4-methoxyphenyl1-lH-pyrazol-4- yH-2-r(2,5-dimethoxyphenyl)methyl]-prop-2-enoic acid 192-194°C EXAMPLE 15 (E)-alpha-rri-Benzyl-5-[2-r(2-carboxyphenyl)methoxyl-4-methoxyphenvn-lH- pyrazol-4-vnmethylene1-6-methoxy- 1.3-benzodioxole-5-propanoic acid EXAMPLE 16 (E)-3-ri-Ai-Butyl-5-r2-r2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- yll-2-r(2.6-dimethoxyphenyl)methyll-prop-2-enoic acid EXAMPLE 17 (E)-3-ri-n-Butyl-5-r2-r2-carboxyphenyl)methoxy1-4-methoxyphenyll-lH- pyrazol-4-vH-2-r(2,5-dichlorophenyl)methyπ-ρrop-2-enoic acid 177-179°C EXAMPLE 18 (E)-alpha-rri-^-Butyl-5-r2-r(2-hvdroxymethylphenyl)methoxy1-4-methoxyphenyll- 1 H-pyrazol-4-yl1methylene]-6-methoxy- 1.3-benzodioxole-5-propanoic acid EXAMPLE 19 (E)-alpha-rri-n-Butyl-5-r2-r(2-carboxyphenyl)methoxyl-4-methoxyphenyl1-lH- pyrazol-4-yl1methylene1-6-methoxy- 1.3-benzodioxan-5-propanoic acid 124-126°C EXAMPLE 20 (E)-alpha-ir5-r2-r(2-Carboxyphenyl)methoxy1-4-methoxyphenyll-l-cvclopropyl- methyl- 1 H-pyrazol-4-vπmethylene1-6-methoxy- 1.3-benzodioxole-5-propanoic acid EXAMPLE 21 (E)-3-ri-»-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- yll-2-r(2-methoxy-5-chlorophenyl)1-prop-2-enoic acid 202-203°C EXAMPLE 22 (E)-3-ri-n-Butyl-5-r2-(2-carboxyphenyl)methoxyl-4-methoxyphenyll-lH-pyrazol-4- yll-2- r2-chloro-5-methoxyphenyn-prop-2-enoic acid 141-143°C EXAMPLE 23 (E)-alpha-ril-n-ButvI-5-r2-r(2-Carboxyphenyl)methoxyl-4-methoχyphenyll-lH- pyrazol-4-vnmethylene-2-chloro-5-thiophene propanoic acid EXAMPLE 24 (E)-alpha-rri-n-Butyl-5-r2-r(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH- pyrazol-4-yl1methylene-3-indolepropanoic acid EXAMPLE 25 (E)-3-ri- -Butyl-5-r2-r2-(carboxyphenyl)methoxy1-4-methoxyphenyl1-lH-pyrazol- 4-yll-2-r(2.4-dmethoxyphenyl)methyn-prop-2-enoic acid 197-199°C EXAMPLE 26 (E)-3-ri-n-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- yl1-2-r(5-fluoro-2-methoxyphenyl)methyll-prop-2-enoic acid 200-20 c EXAMPLE 27 (E)-3-ri-n-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- vn-2-r(2-methoxy-5-nitrophenyl)methyll-prop-2-enoic acid 239-241°C EXAMPLE 28 (E)-3-ri-»-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoχyphenyll-lH-pyrazol-4- yl1-2-r(2-methoxyphenyl)methyl1-prop-2-enoic acid 182-183°C EXAMPLE 29 (E)-3-ll-n-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH-pyrazol-4- vn-2-r5-benzyloxy-2-methoxyphenyl)methvn-prop-2-enoic acid 180-183°C EXAMPLE 30 (E)-3-ri-n-Butyl-5-r2-(2-carboxyphenyl)methoxy1-4-methoxyphenyll-lH-pyrazol-4- yl1-2-r(2-methoxyphenyl-5-methylthio)methyl1-prop-2-enoic acid 158-160°C EXAMPLE 31 (E)-alpha-rri-?ι-Butyl-5-r2-r(2-carboxyphenyl)methoxy1-4-methoxyphenvn-lH- pyrazol-4-yllmethylene1-2.4-dibromo-5-methoxybenzenepropanoic acid EXAMPLE 32 (E)-alpha-iri-«-Butyl-5-r2-r(2-carboxyphenyl)methoxyl-4-methoxyphenyll-lH- pyrazol-4-yllmethylene1-4-chloro-2.5-dimethoxybenzenepropanoic acid EXAMPLE 33 (E)-alpha-rfl-(3-Butenyl)-5-r2-r(2-carboxyphenyl)methoxyl-4-methoxyphenyll-lH- pyrazol-4-vnmethylene1-6-methoxy- 1.3-benzodioxole-5- propanoic acid EXAMPLE 34 (E)-alpha-rr5-r2-r(2-Carboxyphenyl)methoxyl-4-methoxyphenvn-l-cvclopropyl- ethyl- 1 H-pyrazol-4-yllmethylenel-6-methoxy- 1.3-benzodioxole-5-propanoic acid EXAMPLE 35 (E)-alpha-fπ-n-Butyl-5-r2-rN-(phenylsulfonyl)-(N-methyl)methylureal-4-methoχy- phenyll- lH-pyrazol-4-vn-methyIenel-6-methoxy- 1.3-benzodioxan-5- propanoic acid trifluoroacetate salt 58-60°C EXAMPLE 36 (E)-alpha-rri-n-Butyl-5-r2-(2-carboxyphenylmethylether)-4-methoxyphenvn-lH- pyrazol-4-vnmethylene1-6-methoxy- 1.3-benzodioxan-5-propanoic acid 185-187°C EXAMPLE 37 (ΕVS-ri-n-Butyl-S-r∑-r∑-carboxyphenyπmethoxy^-methoxyphenyn-l^J-triazol- 4-yn-2-r(2-methoxy-4.5-methylenedioxy ' )phenylmethyll-prop-2-enoic acid m.p. 195°C. EXAMPLE 38 (E1-3-r 1 -n-Butyl-5-r2-(2-hvdroxymethyl)phenylmethoxy-4-methoxyphenvn- 1.2.3- triazol-4-yl1-2-r(2-methoxy-4.5-methylenedioxy)phenylmethvn-prop-2-enoic acid m.p. 134-137°C. EXAMPLE 39 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below. Inhalant Formulation A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use. Tablets/Ingredients Per Tablet 1. Active ingredient 40 mg (Cpd of Form. I) 2. Corn Starch 20 mg Tablets/Ingredients Per Tablet 3. Alginic acid 20 mg 4. Sodium Alginate 20 mg 5. Mg stearate 1.3 mg 2.3 mg Procedure for tablets: Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender. Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules. Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen. Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry. Step 5 The dry granules are lubricated with ingredient No. 5. Step 6 The lubricated granules are compressed on a suitable tablet press. Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then steriled by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

Claims: CLAIMS: 1. A compound of Formula (I) : (CH 2 ) n (I) wherein (Z) is P is tetrazol-5-yl, CO2Rg or C(O)N(Rg)S(O) q Rιo; R a is independently hydrogen or Ci.galkyl; Rl is independently hydrogen, Ar, Ci.galkyl, or C g alkoxy; R2 is Ar, Ci.galkyl, C(O)Ri4 or (C) R 3 and R5 are independently R13OH, C^galkoxy, S(O) q Rι , N(Rg) , NO 2 , Br, F, I, Cl, CF3, NHCORg, R13CO2R7, -X-R9-Y. -X(C(Rg) 2 )ORg, -(CH 2 )mX'Rg or - X(CH2) n R8 wherein each methylene group within -X(CH2) n Rg may be unsubstituted or substituted by one or two -(CH2) n Ar groups; R4 is independently Ri 1, OH, Ci^alkoxy, S(O) q Rι j, N(Rg) 2 , Br, F, I, Cl or NHCORg, wherein the C 1.5 alkoxy may be unsubstituted or substituted by OH, methoxy or halogen; Rg is independently hydrogen or Ci.galkyl; R7 is independently hydrogen, Cι_ιoalkyl, C2-ioalkenyl or C2_galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(Rg)2, CO2R12, halogen or XCj.ioalkyl; or R7 is (CH2) n Ar; Rg is independently R 1, CO2R7, CO 2 C(Rι ι) O(CO)XR 7 , PO 3 (R 7 )2, SO NR 7 Rι l , NR 7 SO Rι 1, CONR 7 SO 2 Rι 1, SO3R7, SO2R7, P(O)(OR 7 )R 7 , CN, CO 2 (CH 2 ) m C(O)N(Rg)2, C(Rι ι) 2 N(R 7 )2, C(O)N(Rg) 2 , NR7C(0)NR 7 S0 2 Rι ι, ORg, or tetrazole which is substituted or unsubstituted by Ci.galkyl; R9 is independently a bond, Cι_ιoalkylene, Ci.ioalkenylene, Cι_ιoalkylidene, C\_ løalkynylene, all of which may be linear or branched, or phenylene, all of which may be unsubstituted or substituted by one of more OH, N(Rg)2, COOH or halogen; RlO is independently Cj.ioalkyl, N(Rg)2 or Ar; Rl l is independently hydrogen, Ar, Ci.galkyl, C2-galkenyl, C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(Rg)2 or halogen; Rl2 is independently hydrogen, Ci.galkyl, C2-galkenyl or C2-7alkynyl; R 3 is independently divalent Ar, Cι_ιoalkylene, Cι_ιoalkylidene, C2-ioalkenylene, all of which may be unsubstituted or substituted by one or more OH, CH2OH, N(Rg)2 or halogen; Rl4 is independently hydrogen, Cι_ιoalkyl, XCι_ιoalkyl, Ar or XAr; Rl5 is independently hydrogen, Ar, Ci.galkyl, or XAr; R is independently Ci.galkyl or phenyl substituted by one or more Ci.galkyl, OH, Cι. 5 alkoxy, S(O) q Rg, N(Rg) 2 , Br, F, I, Cl, CF3 or NHCORg; X is independently (CH2) n . O, NRg or S(O) q ; X' is independently O, NRg or S(O) q ; Y is independently CH3 or X(CH2) n Ar; Ar is: naphthyl, indolyl, pyridyl, thienyl, oxazolidinyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrimidyl; all of which may be unsubstituted or substituted by one or more Zi or Z2 groups; A is independently C=O, or (C(Rg)2)m'> B is independently -CH2- or -O-; Z and Z2 are independently hydrogen, XRg, Ci.galkyl, (CH2) q CO2R , C(O)N(Rg)2, CN, (CH 2 ) n OH, NO 2 , F, Cl, Br, I, N(Rg) 2 , NHC(O)Rg, O(CH 2 ) m C(O)NR a SO 2 Rιg, (CH2) m OC(O)NR a SO 2 Rιg, O(CH2) m NR a C(O)NR a SO2Rig or tetrazolyl which may be substituted or unsubstituted by Ci .galkyl, CF3 or C(O)Rg; m is independently 1 to 3; n is independently 0 to 6; q is independently 0, 1 or 2; provided R3 ( R4 and R5 are not O-O(CH2) n Ar or O-O Rg; and further provided that R2 is not dihydrobenzofuran; or a pharmaceutically acceptable salt thereof. 2. A compound of Formula (I) wherein P is CO2Rg; Ri is hydrogen; R2 is Ar, cyclohexyl or C galkyl; R3 and R5 are independently hydrogen, CO2Rg, OH, Ci.galkoxy, Ci.galkyl, N(R ) 2 , NO 2 , Br, F, Cl, I, R13CO2R7, X(CH 2 ) n R8- (CH 2 )mX'Rg, or X(C(Rg)2) m ORg; R4 is hydrogen, OH, Cι_ 5 alkoxy, N(Rg) , Br, F, Cl, I, NHCOCH3, or S(O) q C^alkyl wherein the C^alkyl may be unsubstituted or substituted by OH, methoxy or halogen; Rg is hydrogen, methyl or ethyl; R7 is hydrogen, Cι_ιoalkyl, C2-io l enyl or C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(Rg)2, CO2Ri2» halogen, or R7 is (CH2) n Ar wherein n is zero or 1 and Ar is substituted phenyl; R j j is hydrogen, phenyl, pyridyl all of which may be substituted or unsubstituted by one or two Ci galkyl groups; Ci.galkyl, C2-galkenyl, C2-galkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(Rg)2, or halogen; R12 is hydrogen or Ci.galkyl; R13 is phenyl, pyridyl, or C2-ioalkylene, all of which may be unsubstituted or substituted by one or more CO2Rg, OH, CH2OH, N(Rg)2, or halogen; R15 is hydrogen or Ci.galkyl; and (Z) is (d). 3. A compound of claim 2 wherein P is CO2H; Ri is hydrogen; R2 is a group Ar wherein Ar is a group (a) or (b) and in said group (a) or (b), Zi and Z2 are independently hydrogen, CO2Rg, (CH2) n OH, C galkyl or C g alkoxy and A is CH2, and both Bs are O; R3 is Br, Cl, Ci.galkoxy or X(CH2) n Rg, wherein X is O, n is 0, 1, or 2, and Rg is selected from: CO2H, OH, tetrazolyl optionally substituted by C galkyl; CONR7SO2R11 wherein R7 is H or .galkyl, Ri 1 is Ci .galkyl or phenyl optionally substituted by Br, Cl, F, Ci.galkyl; or Rg is phenyl or pyridyl substituted by one or more Br, Cl, CO2H, CH2OH; R5 is methoxy or N(Rg)2 wherein Rg is H or methyl; R4 is hydrogen; Rg is hydrogen, methyl or ethyl; R7 is hydrogen, Ci.iøalkyl, C2-ioalkenyl or C2-galkynyl, all of which may be unsubstituted or substituted by one or more OH, N(Rg)2, CO2R12' halogen, or R7 is (CH2) n r wherein R7 is (CH2) n Ar and n is zero or 1 and Ar is phenyl substituted or unsubstituted by halogen or C .5 alkoxy; Ri 1 is hydrogen, phenyl, pyridyl wherein the phenyl or pyridyl be substituted or unsubstituted by one or two Ci galkyl groups; Ci .galkyl, C2-galkenyl, C2-galkynyl, all of which may be substituted or unsubstituted by one or more OH, CH2OH, N(Rg)2, or halogen; R12 is hydrogen or Ci.galkyl; R13 is phenyl, pyridyl, or C2-io lkylene, all of which may be unsubstituted or substituted by one or more CO2Rg, OH, CH2OH, N(Rg)2, or halogen; R15 is hydrogen, ethyl, isopropyl, n-butyl, cyclopropylmethyl or cyclopropylethyl; and (Z) is (d). 4. A compound of claim 1 selected from: (E)-alpha-[[5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-l-ethyl-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Allyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-chlorophenyl]-lH-pyrazol- 4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Butyl-5-[4-methoxy-2-[[N- (phenylsulfonyl)]carboxamidomethoxy]phenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy- l,3-benzodioxole-5-propanoic acid; (E)-3-[l-Butyl-5-[2-[2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH-pyrazol-4- yl]-2-[(2,5-dimethoxyphenyl)methyl]-prop-2-enoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-hydroxymethylphenyl)methoxy]-4-methoxyphenyl]- lH-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid; (E)-alpha-[[l-Butyl-5-[2-[(2-carboxyphenyl)methoxy]-4-methoxyphenyl]-lH- pyrazol-4-yl]methylene]-7-methoxy- 1 ,4-benzodioxan-6-propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-l- cyclopropylmethyl- lH-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5- propanoic acid; (E)-alpha-[[l-(3-Butenyl)-5-[2-[(2-hydroxymethylρhenyl)methoxy]-4- methoxyphenyl]- 1 H-pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5- propanoic acid; (E)-alpha-[[5-[2-[(2-Carboxyphenyl)methoxy]-4-methoxyphenyl]-l- cyclopropylethyl-lH-pyrazol-4-yl]methylene]-6-methoxy-l,3-benzodioxole-5- propanoic acid; (E)-alpha- [[ 1 -Butyl-5- [2- [(2-carboxyphenoxy]methyl)-4-methoxyphenyl]- 1 H- pyrazol-4-yl]methylene]-6-methoxy- 1 ,3-benzodioxole-5-propanoic acid. 5. A compound of claim 1 which is (E)-alpha-[[l-Butyl-5-[2-[(2- carboxyphenyl)methoxy]-4-methoxyphenyl]-lH-pyrazol-4-yl]methylene]-6- methoxy- 1 ,3-benzodioxole-5-propanoic acid. 6. A compound of Claim 5 which is the disodium salt thereof. 7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 8. A compound of claim 1 for use as an endothelin receptor antagonist. 9. A method of treatment of diseases caused by an excess of endothelin comprising administering to a subject in need thereof, an effective amount of an endothelin receptor antagonist of Claim 1. 10. A method of treating renal failure or cerebrovascular disease which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 11. A method for the prophylaxis and treatment of radiocontrast induced renal failure which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 12. A method of treatment of congestive heart failure which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 13. A method of treatment of unstable angina, coronary vasospasm and myocardial salvage which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 14. A method of preventing or treating restenosis which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 15. A method of treatment of pulmonary hypertension which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 16. A method of treatment of stroke or subarachnoid hemorrhage which comprises administering to a subject in need thereof, an effective amount of a compound of Claim 1. 17. A process for preparing a compound of Formula (Id) by: (a) Reaction of a compound of Formula (II) or a protected form or precursor thereof with a compound of Formula (8) «<H 2 ) n R2 (8) (wherein R2 and Rig are as defined in claim 1 for Formula (Id) hereinabove); followed if necessary or desired by: (b) conversion of one compound of Formula (Id) into a different compound of Formula (Id) e.g. (i) when Formula (Id) contains a group CO2Rg, CO2R7 or CO2R12 wherein Rg, R7 or R12 is alkyl, conversion to a corresponding compound where Rg, R7 or R12 represents hydrogen; (ii) when Formula (Id) contains a hydroxy group (e.g. in R3, R4 or R5) conversion to a different group, e.g. a group (CH2)Ar where Ar is optionally substituted phenyl, by a method well known in the art; and/or (c) salt formation.

Inventors: ELLIOTT JOHN DUNCAN, LUENGO JUAN IGNACIO, XIANG JIA-NING, ELLIOTT, JOHN, DUNCAN, LUENGO, JUAN IGNACIO, XIANG, JIA-NING
Applicants: ELLIOTT JOHN DUNCAN, LUENGO JUAN IGNACIO, SMITHKLINE BEECHAM CORP, XIANG JIA NING, ELLIOTT, JOHN, DUNCAN, LUENGO, JUAN IGNACIO, SMITHKLINE BEECHAM CORPORATION, XIANG, JIA-NING
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P13, A61P43, C07D231, C07D403, C07D405, C07D409