|||||IIIUSOO57673 10A United States Patent (19) 11 Patent Number: 5,767,310 Bagley et al. 45 Date of Patent: Jun. 16, 1998

(54) PHENOXYPHENYLACETIC ACD 2259 540 3/993 United Kingdom. DERVATIVES WO 92 O0952 1/992 WIPO WO 92 12991 6/992 WIPO (75) Inventors: Scott W. Bagley, Groten. Conn.; WO 92/15321 9/1992 WIPO Theodore P. Broten, Ambler, Pa.; WO 92/2O706 11|1992 WIPO WO 93 08799 5/1993 WIPO : Prasun K. Chakravarty. Edison, N.J.; WO 93 O144 5/1993 WIPO Daljit S. Dhanoa, La Jolla, Calif.; WO 93 13052 7/1993 WIPO Kenneth J. Fitch, Cranford, N.J.; WO 93 13069 7/1993 WIPO William J. Greenlee, Teaneck, N.J.; WO 93 23.404 11/1993 WIPO Nancy Jo Kevin, Clifton, N.J.; Douglas WO 94 14796 12/1993 WIPO J. Pettibone. Chalfont, Pa.; Ralph A. WO 94 O2474 2/1994 WIPO Rivero, North Wales, Pa.; James R. WO 94. 14434 7/1994 WIPO. Tata, Westfield; Thomas F. Walsh. Watchung, both of N.J.; David L. OTHER PUBLICATIONS Williams, Jr., Telford, Pa, "Endothelin: A New Challenge", Doherty, A.M., J. Med. Chem. vol. 35. No. 9, (1992), pp. 1493-1508. 73) Assignee: Merck & Co., Inc.. Rahway, N.J. "Studies on the Chemical Constituents of Rutaceous 21 Appl. No.: 507,492 Plants. ''). Development of a Versatile Method for the Synthesis of Antitumor-Active Benzoic phenanthridine (22 PCT Filled: Mar 17, 1994 Alkaloids. (2)' Preparation of 2-Aryl-1-tetralone Deriva 86) PCT No.: PCT/US94/02871 tives', Ishii, H. et al. Chem. Pharm. Bulletin, vol. 31, No. 9, (1983) pp. 3039-3055. S371 Date: Nov. 8, 1995 “Synthesis with ot-Heterosubstituted Phosphonate Carban ions. 12." X-ray Structure Determination of (RS)-Diphenyl S 102(e) Date: Nov. 8, 1995 1-(4-bromoanilino)-1(4.5-methylenedioxy-2-nitrophbe 87 PCT Pub. No.: WO94/21590 nyl)methanephosphonate", Crenshaw, M.D., et al. J. Org. Chem... vol. 47. (1982), pp. 101-104. PCT Pub. Date: Sep. 29, 1994 "Antihypertensive Effects of the Endothelin Receptor Antagonist BQ-123 in Conscious Spontaneously Hypeten Related U.S. Application Data sive Rats' E. H. Ohlstein, et al. Journal of Cardiovascular 63) Continuation-in-part of Ser. No. 34,455, Mar. 19, 1993, Pharmacology, vol. 22, (Suppl. 8), 1993, pp. S321-S324. abandoned. "Direct and Sympathetically Mediated Vasoconstriction in Essential Hypertension” W. G. Haynes, et al. J. Clin. Invest. 51 Int. Clar. CO7C 59/40 vol. 94, Oct. 1994, pp. 1359–1364. (52) U.S. Cl...... 562/469:562/.466; 562/471; "Role of Endothelin in Hypertension” B.K. Krämer, et al. 514/569; 514/570; 548/253 Clin. Investig., vol. 72. (1994), pp. 88-93. 58) Field of Search ...... 562/469, 466, "Potential Role of Endothelin in Hypertension" T. F. Lis 562/471; 548/253; 514/569. 570 cher, et al. Hypertension, vol. 21. No. 6. Part 1, Jun. 1993, pp. 752-757. 56) References Cited "BQ123, An ET(A) Receptor Antagonist. Attenuates U.S. PATENT DOCUMENTS Hypoxic Pulmonary-Hypertension in Rats" Bonvallet, S.T., et al. American Journal of Physiology, vol. 266. No. 4. (Apr. 3.499,008 3/1970 Talet et al. . 1994), pp. H1327-H1331. 4,748.272 5/1988 Youssefyeh . 5,082,838 1/1992 Naka et al. . "Protection from Pulmonary Hypertension with an Orally 5,114,918 5/1992 Ishikawa et al. . Active Endothelin Receptor Antagonist in Hypoxic Rats" 5,187,195 2/1993 Oohata et al. . American Journal of Physiology-Heart and Circulatory Physiology, vol. 37. No. 2. (Feb. 1995), pp. H828-H835. FOREIGN PATENT DOCUMENTS (List continued on next page.) 436189 A1 7/1990 European Pat. 405 421A2 1/1991 European Pat. Primary Examiner-Paul J. Killos 460 679 A2 12/1991 European Pat. Attorney, Agent, or Firm-Valerie J. Camara; Mark R. 496 452A1 7/1992 European Pat. : Daniel 510526A1 10/1992 European Pat, 457 195A2 1/1992 European Pat. 57 ABSTRACT 526 642 A 2/1993 European Pat. 526 708 A 2/1993 Phenoxyphenylacetic acids and derivatives of general struc 528 312 A2 2A1993 tural formula (I) have endothelin antagonist activity and are 534. 539 A1 3/1993 ropean E. useful in treating cardiovascular disorders, such as 543. 425A1 5/1993 European Pat. hypertension, postischemic renal failure, vasospasm, cere 54.737 A1 6/1993 European Pat. 558 258A1 9/1993 European Pat. bral and cardiac ischemia, myocardial infarction, endoxic 562 599 A1 9/1993 European Pat. shock, benign prostatic hyperplasia, inflammatory diseases 569 93A 11/1993 European Pat. including Raynaud's disease and asthma. 601 386A1 6/1994 06122625 6/1994 3 Claims, No Drawings 5,767,310 Page 2

OTHER PUBLICATIONS "Localization of Endothelin-1 and Its Binding-Sites in "Endothelin-A Receptor Antagonist Prevents Acute Scleroderma Skin' Vancheeswaran, R., et al. Journal of Hypoxia-Induced Pulmonary-Hypertension in the Rat' Rheumatology, vol. 21. No. 7, (Jul. 1994), pp. 1268-1276. Oparil, S., et al. American Journal of Physiology-Lung "Increased Endothelin-1 Production in Fibroblasts Derived Cellular and Molecular Physiology, vol. 12. No. 1. (Jan. from Patients with Systemic-Sclerosis" Kawaguchi, Y. et 1995), pp. L95-L100. al. Annals of the Rheumatic Diseases, vol. 53. No. 8. (Aug. Endothelial Dysfunction and Remodeling of the Pulmonary 1994), pp. 506-510. Ciculation in Chronic Hypoxic Pulmonary-Hypertension "Characterization of Endothelin-Binding Sites in Human Dinh Xuan. A.T. et al. ACP-Applied Cardiopulmonary Skin and Their Regulation in Primary Raynauds-Phenom Pathophysiology, vol. 5. No. 2. (1994), pp. 93-99. enon and Systemic-Sclerosis' Knock G.A., et al. Journal of "Cyclosporine-Induced Elevation in Circulating Endothe Investigative Dermatology, vol. 101, No. 1. (Jul. 1993). pp. lin-1 in Patients with Solid-Organ Transplants" Grieff. M. 73-78. et al. Transplantation vol. 54, No. 4, (Oct. 1993), pp. "Raynaud Phenomenon" Coffman. J.D., et al. Current Opin 880-884. ion in Cardiology, vol. 8, No. 5. (Sep. 1993), pp. 821-828. "Cyclosporine-Induced Hypertension. After Transplanta "Parameters of Vascular Function in Idiopathic and Silic tion"Textor, S.C.. et al. Mayo Clinical Proceedings. vol. 69. a-Induced Systemic-Sclerosis" Haustein. U.F., et al. Hau (1994), pp. 1182-1193. tarzt. vol. 44, No. 11. (Nov. 1993). pp. 717-722. "A Role for Endogenous Endothelin-1 in Neointimal For "Circulating Endothelin-1 Levels in Systemic-Sclerosis mation. After Rat Carotid Artery Balloon Angioplasty" Dou Subsets-A Marker of Fibrosis or Vascular Dysfunction" glas S. A. et al. Circulation Research. vol. 75. (1994), pp. Vancheeswaran. R. et al. Journal of Rheumatology, vol. 21. 190-197. No. 10, (Oct. 1994), pp. 1838-1844. 125I-Endothelin-1 Binding to Vasa Vasorum and Regions of Neovascularization in Human and Porcine Blood Wessels: "Endothelin and Collagen Vascular Disease: A Review with A Possible Role for Endothelin in Intimal Hyperplasia and Special Reference to Raynauds-Phenomenon and Systemic Atheroscelerosis Dashwood, M.R., et al. Journal of Cardio Sclerosis' Yamane, K. Internal Medicine, vol. 33, No. 10. vascular Pharmacology, vol. 22. (Suppl. 8). (1993), pp. (Oct. 1994), pp. 579-582. S343-S347. "A Pathogenic Role for Endothelin in Raynauds-Phenom "The Endothelin-1 Receptor Antagonist BQ-123 Reduces enon" Bottomley, W., et al. Acta Dermato-Venereologica, Infarct Size in a Canine Model of Coronary Occlusion and vol. 74, No. 6, (Nov. 1994), pp. 433-434. Reperfusion" Grover, G. J.. et al. Cardiovascular Research, "BQ 123, A Peptidic Endothelin ETA Receptor Antagonist. vol. 75. No. 9, (Sep. 1993). pp. 1613-1618. Prevents the Early Cerebral Vasospasm Following Sub "The Effects of the Endothelin ETa Receptor Antagonist, arachnoid Hemorrhage. After Interacisternal but not Intrave FR139317, on Infarct Size in a Rabbit Model of Acute nous-Injection" Clozel, M. et al. Life Sciences. vol. 52. No. Myocardial Ischemia and Reperfusion" McMurdo, L., et al. 9. (1993), pp. 825–834. British Journal of Pharmacology, (1994), vol. 112, pp. "An Endothelin ET(A) Receptor Antagonist, FR139317. 75-80. Ameliorates Cerebral Vasospasm in Dogs" Nirei. H. et al. "Vasodilator Effects of the Endothelin-1 Receptor Antago Life Sciences, vol. 52, No. 23. (1993), pp. 1869-1874. nist Bosentan in Patients with Severe Chronic Heart Failure' "Reversal of Subarachnoid Hemorrhage-Induced Vasocon Kiowski, W., et al. Journal Am. College of Cardiology, Feb. striction with an Endothelin Receptor Antagonist" Foley, 1995, p. 296A, abstract No. 779-1. P.L. et al. Neurosurgery, vol. 34. No. 1. (Jan. 1994), pp. "Nonpeptide Endothelin Receptor Antagonists. III. Effect of 108-113. SB 209670 and BQ123 on Acute Renal Failure in Anesthe tized Dogs" Brooks. D. P. et al. Journal of Pharmacology "Endothelin Levels Increase in Rat Focal and Global-Is and Experimental Therapeutics, vol. 271, (1994), pp. chemia' Barone F.C.. et al. Journal of Cerebral Blood Flow 769-775. and Metabolism, vol. 14. No. 2. (Mar. 1994), pp. 337-342. "Reversal of Postischemic Acute Renal Failure with a Selec "Endothelin ET(A) and ET(B) Receptors in Subarachnoid tive Endothelin a Receptor Antagonist in the Rat" Gellai, Hemorrhage-Induced Cerebral Vasospasm" Zuccarello, M., M. et al. Journal of Clinical Investigator, vol. 93. (1994), pp. et al. European Journal of Pharmacology, vol. 259, No. 1, 900-906. (Jun. 23 1994), pp. R1-R2. "Effects of BQ-123 on Renal-Function and Acute "Changes of Endothelin Concentration in Cerebrospi Cyclosporine Induced Renal Dysfunction". Kivlighn, S.D. nal-Fluid and Plasma of Patients with Aneurysmal Sub et al. Kidney International, vol. 45, No. 1. (Jan. 1994), pp. arachnoid Hemorrhage" Shirakami, G. et al. Acta Anaes 131-136. thesiologica Scandinavica, vol. 38, No. 5, (Jul. 1994), pp. "Endotoxin-Mediated Changes In Plasma Endothelin Con 457-461. centrations. Renal Endothelin Receptor And Renal-Func "Prevention of Delayed Vasospasm by an Endothelin ET(A) tion”. Nambi. P. et al., vol. 48. No. 3. (Mar. 1994), pp. Receptor Antagonist. BQ-123-Change of ET(A) Receptor 147-156. Messenger-RNA Expression in a Canine Subarachnoid "Effect of Total-Body Cold-Exposure on Plasma-Concen Hemorrhage Model” Itoh. S. et al. Journal of Neurosurgery. trations of Vonwillebrand-Factor, Endothelin-1 and Throm vol. 81, No. 5. (Nov. 1994), pp. 759-764. bomodulin in Systemic Lupus-Erythematosus Patients with Safrole as Starting Material for the Synthesis of 7-Meth or without Raynauds-Phenomeon". Matsuda, J., et al. Acta oxy-3',4'-Methylenedioxyisoflavanone, Saraiva, M.C., et Haematologica, vol. 88, No. 4. (1992), pp. 189-193. al., Chem. Abst. vol. 114. (1990), AB. No. 191:185076t. 5,767,310 Page 3

"Preparation of N-alkadienyl N-E-2-arylthenylcarbamates "Endothelin Concentrations in Patients with Aneurysmal Via Sulfoxide Elimination in a Synthetic Approach to Lyco Subarachnoid Hemorrhage-Correlation with Cerebral rine ''", Jung, M.E. et al., Heterocycles, vol. 30. No. 2. Vasospasm, Delayed Ischemic Neurological Deficits, and (1990), pp. 839-853. Volume of Hematoma" Seifert W., et al. Journal of Neuro "A Novel Synthesis of N-Substituted Amino Acids”, Naim. surgery, vol. 82. No. 1, (Jan. 1995), pp.55-62. S.S. et al., Indian Journal of Chemistry, vol. 19B. (1980), Chemical Abstracts vol. 64, 5003 a (Neth. Appl 6,503.523 pp. 622-623. 21 Sep. 1964). 5,767,310 1 2 PHENOXYPHENYLACETIC ACID been shown to promote the growth of rat vascular smooth DERVATIVES muscle cells which would suggest a possible relevance to arterial hypertrophy.' RELATED APPLICATIONS 11 Biochem. Biophys. Res. Comm. 157, 1164-1168 (1988). 12 Biochem. Biophys. Res. Comm. 155, 167-172 (1989). The present application is a continuation in part applica 13 Proc. Natl. Acad. Sci. USA, 85,9797-9800 (1989). tion of U.S. Ser. No. 08/034455 filed on Mar. 19, 1993, now 14 J. Cardiovasc. Pharmacol., 13,589-592 (1989). 15 Japan. J. Hypertension 12, 76 (1989). abandoned. 16 Neuroscience Letters, O2, 179-184 (1989). 17 FEBS Letters, 247, 337-340 (1989). SUMMARY OF THE INVENTION 18 Eur. J. Pharmacol. 154, 227-228 (1988). 10 19 Biochem. Biophys. Res. Commun., 159, 317-323 (1989). This invention is concerned with non-peptidic endothelin 20 Atherosclerosis, 78, 225-228 (1989). receptor antagonists represented by the compound of For Endothelin receptors are present in high concentration in mula I, pharmaceutical compositions containing these the peripheral tissues and also in the central nervous system, compounds, as well as combination therapies which include and cerebral administration of endothelin has been shown to a compound of the present invention. The compounds of the induce behavioral changes in animals, suggesting that endot present invention are therapeutic agents particularly useful 15 helin may play an important role in controlling neural for the treatment of asthma, hypertension, pulmonary functions.' hypertension, arteriosclerosis, congestive heart failure, renal 21 Neuroscience Letters, 97, 276-279 (1989). failure, particularly post-ischemic renal failure, cyclosporin Endotoxin has been shown to promote the release of nephrotoxicity, vasospasm, vascular restenosis. cerebral and endothelin. This finding has suggested that endothelin is an 20 important mediator for endotoxin-induced diseases.** cardiac ischemia and other ischemic states, myocardial 22 Biochem. Biophys. Res. Commun. 161, 1220-1227 (1989). infarction. Raynaud's disease, benign prostatic hyperplasia, 23 Acta. Physiol. Scand., 137, 317-318 (1989). inflammatory bowel diseases, including Crohn's disease and A study has shown that cyclosporin added to a renal cell ulcerative colitis, as well as other inflammatory diseases, or culture-, increased endothelin secretion. Another study has endotoxic shock caused by or associated with endothelin. 25 shown that administration of cyclosporin to rats, led to a This invention further constitutes a method for antago decrease in the glomerular filtration rate and an increase in nizing endothelin receptors in a mammal, including humans. the blood pressure, in association with a remarkable increase which comprises administering to a mammal in need of such in the circulating endothelin level. This cyclosporin-induced treatment an effective amount of a compound of Formula I. renal failure can be suppressed by the administration of anti-endothelin antibody.” These studies suggest that endot BACKGROUND OF THE INVENTION 30 helin is significantly involved in the pathogenesis of Endothelin is a 21-amino acid peptide produced by endot cyclosporin-induced renal disease. 24 Eur. J. Pharmacol., 180, 191-192 (1990). helial cells. The peptide is secreted not only by endothelial 25 Kidney int. 31, 1487-1491 (1990). cells but also by tracheal epithelial cells or from kidney A recent study in patients with congestive heart failure cells. Endothelin (ET-1) has a potent vasoconstrictor effect. 35 demonstrated a good correlation between the elevated levels The vasoconstricting effect is caused by the binding of of endothelin in the plasma and the severity of the disease.' endothelin to its receptor on the vascular smooth muscle 26 Mayo Clinic Proc., 67, 719-724 (1992). cells." Endothelin is an endogenous substance which directly or 1 Nature, 332, 411-415 (1988). 2 FEBS Letters, 231, 440-444 (1988). indirectly (through the controlled release of various other 3 Biochem. Biophys. Res. Commun. 154,868-875 (1988). endogenous substances) induces sustained contraction of Endothelin-1 (ET-1) is one of three recently identified vascular or non-vascular smooth muscles. Its excess pro potent vasoconstricting peptides which also includes endot duction or excess secretion is believed to be one of the helin-2 (ET-2) and endothelin-3 (ET-3) whose sequences factors responsible for hypertension, pulmonary hyperten differ from ET-1 by two and six amino acids, respectively.' sion, Raynaud's disease, bronchial asthma. acute renal fail 4 TPS, 13, 103-108, March 1992. 45 ure, myocardial infarction, angina pectoris, arteriosclerosis, Increased levels of endothelin are found in the blood of cerebral vasospasm and cerebral infarction. See A. M. patients with essential hypertension, acute myocardial inf Doherty. Endothelin: A New Challenge. J. Med. Chem., 35. arction, pulmonary hypertension. Raynaud's disease or ath 1493-1508 (1992). erosclerosis or in the washing fluids of the respiratory tract Substances which specifically inhibit the binding of of patients with asthma compared to normal levels. 50 endothelin to its receptor are believed to block the physi 5 Japan J. Hypertension 12, 79 (1989). ological effects of endothelin and are useful in treating 6 J. Vascular Medicine Biology, 2, 207 (1990). 7 J. Am. Med. Association, 264, 2868 (1990). patients with endothelin related disorders. 8. The Lancet, ii, 207 (1990) and The Lancet, ii, 747-748 (1989). The novel compounds of the present invention are useful An experimental model of cerebral vasospasm and a as a non-peptidic endothelin antagonists, and have not been second model of acute renal failure have led to the conclu 55 disclosed in any issued patents or published patent applica sion that endothelin is one of the mediators causing cerebral tions. Among the published patent applications disclosing vasospasm following a subarachnoid hemorrhage, and renal linear and cyclic peptidic compounds as endothelin antago failure. nists are the following: Fujisawa in European Patent Appli 9 Japan. Soc. Cereb. Blood Flow & Metabol. 1, 73 (1989). cation EP-457.195 and Patent Cooperation Treaty (PCT) 10 J. Clin. Invest., 83, 1762-1767 (1989). International Application No. WO 93/10144, Banyu in Endothelin was also found to control the release of many EP-436.189 and 460,679. Immunopharmaceutics Inc. in physiological substances such as renin, atrial natriuretic WO 93/225580, Warner Lambert Co. WO 92/20706 and peptide, endothelium-derived relaxing factor (EDRF), Takeda Chemical Ind. in EP-528.312, EP-543,425, EP-547, thromboxane A'. prostacyclin, norepinephrine, angio 317 and WO 91/13089. tensin II and substance P.'" Further, endothelin causes 65 Fujisawa has also disclosed two nonpeptidic endothelin contraction of the smooth muscle of the gastrointestinal tract antagonist compounds: anthraquinone derivatives produced and the uterine smooth muscle.''' Endothelin has also by a fermentation process using Streptomyces sp. No. 89009 5,767,310 3 4 in EP-405.421 and U.S. Pat. No. 5.187, 195; and a 4-phe 24 Eur. J. Pharmacol., 180, 191-192 (1990). noxyphenol derivative produced by a fermentation process 25 Kidney Int. 31, 1487-1491 (1990). using Penicillium citreonigrum F-12880 in a UK Patent Application GB 2259450. Shionogi and Co. has also dis 26 Mayo Clinic Proc. 67, 719-724 (1992). closed nonpeptidic endothelin antagonist triterpene com pounds which were produced by a fermentation process DETALED DESCRIPTION OF THE using Myrica cerifera in WO92/12991. INVENTION Among the non-peptidic endothelin antagonist com pounds which are known in the patent literature are: 1) a This invention is concerned with novel compounds of series of substituted (1.4-quinolinoxy)methylbiphenylcar O structural formula I: boxylic acids disclosed by Roussel-Uclaf in EP-498.723; 2) a series of N-(4-pyrimidinyl)benzene-sulfonamides with dif R2 I ferent substitution patterns from Hoffmann-La Roche pub lished in EP-510,526 and EP-526.708; 3) a series of naph R9 R10 thalenesulfonamides and benzenesulfonamides disclosed by 5 E.R. Squibb & Sons in EP-558.258 and EP-569,193, respec tively; 4) a series of compounds represented by 3-(3-indolyl methyl)-1,4-diaza-2,5-dioxobicyclo4.3.0nonane-9-car boxylic acid from Immunopharmaceutics Inc. in WO 93/23404; 5) a series of fused 1.2.4thiadiazole substituted with an iminosulfonyl substituent from Takeda Chemical Ind. has been disclosed in EP-562. 599; and 6) a series of indane and indene derivatives from Smith-Kline Beecham Corp. disclosed in WO 93/08779. Youssefyeh. et al. U.S. Pat. No. 4,748.272 discloses 25 or a pharmaceutically acceptable salt thereof, wherein: phenoxyphenylacetates as useful lipoxygenase inhibitors for R. R. Ra and Rb are independently: the treatment of inflammatory conditions and allergic (a) H. responses. (b) F. Cl, Br, or I, Talet, et al. U.S. Pat. No. 3,499,008 discloses bispheny (c) -NO. lacetate derivatives as useful as herbicides, fungicides, and 30 (d) -NH. bacterocides, also as an ingredient in thermosetting acrylic (e) -NH(C-C)-alkyl, paints or as a starting material for the preparation of epoxy (f) -N (C-C)-alkyll. CSS. (g) -SONHR'. (h) -CF. REFERENCES 35 (i) (CC)-alkyl, (j) -OR'. 1 Nature, 332, 411-415 (1988). (k) --S (O)-(C-C)-alkyl, 2 FEBS Letters. 231. 440-444 (1988). (l) -NHCO-(C-C)-alkyl. 3 Biochem. Biophys. Res. Commun. 154, 868-875 (m) -NHCO-O(C-C)-alkyl, (1988). 40 (n) -CHO-(C-C)-alkyl. 4 TPS, 13, 103-108, March 1992. (o)(p) -9-CONR'R''. CH-OR’. 5 Japan J. Hypertension 12, 79 (1989). (q) -COOR. or 6 J. Vascular Medicine Biology, 2, 207 (1990). (r) -phenyl: 7 J. Am. Med. Association, 264, 2868 (1990). 5 R" and R on adjacent carbon atoms can be joined 8The Lancet, ii. 207 (1990) and The Lancet, ii. 747-748 together to form a ring structure: (1989). 9 Japan. Soc. Cereb. Blood Flow & Metabol. 1.73 (1989). -N 10 J. Clin. Invest. 83, 1762-1767 (1989). A 11 Biochem. Biophys. Res. Comm. 157. 1164-1168 50 (1988). N 12 Biochem. Biophys. Res. Comm. 155, 167-172 (1989). 13 Proc. Natl. Acad. Sci. USA, 85, 9797-9800 (1989). 14 J. Cardiovasc. Pharmacol., 13. 589-592 (1989). 55 15 Japan. J. Hypertension 12, 76 (1989). 16 Neuroscience Letters, 102. 179-184 (1989). 17 FEBS Letters, 247, 337-340 (1989). 18 Eur. J. Pharmacol. 154, 227-228 (1988). 19 Biochem. Biophys. Res. Commun., 159, 317-323 (1989). 20 Atherosclerosis, 78, 225-228 (1989). 21 Neuroscience Letters, 97.276-279 (1989). 22 Biochem. Biophys. Res. Commun. 161, 1220-1227 65 (1989). 23 Acta. Physiol. Scand. 137, 317-318 (1989). Y is -O-, -S(O)- and NR': 5,767,310 5 6 R and Rare independently: (i) phenyl. (a) H. (j) (C-C)-alkyl-S(O)-(CH2)-, (b) (C-C)-alkyl or (C-C)-alkenyl each of which is (k) hydroxy-(C-C)-alkyl, unsubstituted or substituted with one or two substitu (l) -CF. ents selected from the group consisting of: 5 i) -OH, (m) -COR". ii) -O-(C-C)-alkyl. (n) -OH, iii) -S(O)-(C-C)-alkyl, iv) -NR'-(C-C)-alkyl. v) -NHR'. vi) -COOR. O (r)-(CH2)-SO13 (R'). vii) -CONHR'. (s) -NR'CO-(C-C)-alkyl, or viii) -OCOR', or (t) -CONCR): ix) -CONR'R'', RandR' on adjacent carbons can join together to form (c) (C-C)-cycloalkyl. a fused phenyl ring, unsubstituted or substituted with a (d) F. Cl. Br. I. 15 substituent selected from the group consisting of: (e) CF. (C-C)-alkyl, (C-C)-alkoxy, (C-C)-cycloalkyl (f) -COOR.". and (C-C)-alkyl-(C-C)-cycloalkyl, (g) -CONR'R''. R is (h)-NR'R'', (a) (C-C)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i)(j)-NRCOOR', -NRCONR'R''. 20 i) -OR". (k) -SO.NR'R'', ii) -NIR) (l) -O-(C-C)-alkyl. iii) -NH. (m) -S(O)-(C-C)-alkyl, or iv) -COOR. or (n)-NHSOR': 25 v)-NICHCHQ; R is: (b) aryl, wherein aryl is defined as phenyl or naphthyl (a) H. which is unsubstituted or substituted with one or two (b) (C-C)-alkyl unsubstituted or substituted with one substituents selected from the group consisting of: of the following substituents: i) (C-C)-alkyl, i) -OH, ii) -O-(C-C)-alkyl, ii) -NR'R''. 30 iii) -CONR7 2. iii) -COOR.". iv) F, Cl, Br or I. iv) -CONHR'. or v) -COOR, vi) -NH. R is: vii) -NH(C-C)-alkyll. (a) H. 35 viii) -N (C-C)-alkyl or (b) (C-C)-alkyl, ix) -CONCHCHQ; (c) phenyl, (c) -(C-C)-alkylaryl, wherein aryl is as defined (d) (C-C)-alkylphenyl, or above, (e) (C-C)-cycloalkyl; (d) (C-C)-cycloalkyl, R is: 40 (a) H. (e) (b) (C-C)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) -phenyl, (ii) -(C-C)-cycloalkyl. 45 (iii) -NR'R'', (iv) -morpholin-4-yl. (v) -OH, (vi) -COR", or R" and R' on the same nitrogen atom they can join (vii) -CONCR), 50 together to form a ring selected from the group con (c) phenyl, unsubstituted or substituted with a substitu sisting of: morpholinyl, piperazinyl, or pyrrolyl, or ent selected from the group consisting of: Q is O.S or -NR': i) (C-C)-alkyl R? is ii) –9 (CC)-alkyl iii) -CONR'R''. (a) H. 55 (b) (C-C)-alkyl, unsubstituted or substituted with one iv) F. Cl, Br or I, or or two substituents selected from the group consist w) -COOR; ing of: R and R' are independently: i) -OH, (a) H, ii) -O-(C-C)-alkyl, (b) (C-C)-alkyl, unsubstituted or substituted with iii) -O-(C-C)-cycloalkyl. (C-C)-cycloalkyl or -COR'. 60 iv) - S(9)-(C -C)-alkyl. (c) (C-C)-alkenyl, w) -NR'R'', (d) (C-C)-alkynyl, vi) -COOR. (e) Cl, Br, F, I, vii) -CONHR'. (f) (C-C)-alkoxy, viii) --OCOR'', (g) perfluoro-(C-C)-alkyl. 65 ix) - CONR'R''. (h) (C-C)-cycloalkyl, unsubstituted or substituted x) -NR'CONR'R'', with (C-C)-alkyl, xi) --NRCOOR'. 5,767,310 7 8 (h)-tetrazol-5-yl, xii) -COR)(OH)-C(R)(R')(OH), or (i) -CONHSO-heteroaryl, wherein heteroaryl is xiii) -SONR'R''. defined as carbazolyl, furyl, thienyl, pyrrolyl, (d)(c) (CC,-OR, )-cycloalkyl, isothiazolyl, imidazolyl. isoxazolyl, thiazolyl, (e) -COOR. 5. Oxazolyl, pyrazolyl, pyrazinyl. pyridyl, pyrinidyl, (f) -CONH purinyl or quinolinyl, which is unsubstituted or sub (g) CONRR11, stituted with one or two substituents selected from (h) -CONRCOR". the group consisting of: (i)(j)-NR'R''. -NH i)ii)-9 (C.C.)-alkyl (CS)-alkyl, -NR7 7 i O iii) -CONR'R''. st-SSR". iv) FC B,or I. (m) - CR9H-C(R')(R')(OH). My SoNR'R'' and (n) Scori vii) -NRCOOR'; 8 38 SSS 5 (j) SQNHCO-aryl. wherein aryl is defined in Z(d) (q) - SQNRCONR'R''.4. (k)a)OW -SONHCO-(C-C)-alkyl, wherein the alkyl (r)s: NSSR'sCONSORF 11 (SöNHCO-C-C-periorally.group is unsubstituted or substituted as defined in (u) -CO-amino acid. wherein amino acid is defined as 20 (m) -SONHCO-heteroaryl, wherein heteroaryl is as al L-or D- amino acid selected from the group defined in Z(g) above. consisting of Ala, Ile. Phe, Asp. Pro and Val and (n) -SONHCONOR') wherein the R' groups are which can be further substituted as a (C 1-C8)-alkyl the same or different, ester or an amide, or (o)-PO(OR), wherein the R'groups are the same or 25 different, or (v) (p) -PO(R')OR; R R"13 is: N YN (a)by (C-C)-alkyl.CHROCORI, -( l; (c) CH2CH2-N (C-C2)-alkyl). N (d) CHCH-NICH2CH2O. N 1. (e) (CHCHO)-O-(C-C)-alkyl). whereiny is 1 or 2. X is (f) phenyl, naphthyl, CH2-phenyl or CH-naphthyl, (a) -O-, 35 where phenyl or naphthyl is substituted or unsubsti (b) -S(O)-. tuted with CO-(C-C)-alkyl. (c) -NR'-. (d) -CHO- (g) 8 S9. -CH CH3 (g) - Oil - 40 )=( (h) SS: O O , (i)(j) -S(O)CH-,-single Soni. or Z is: (a) -COH, 45 (h) (b) -COR', (c) -CONH-(tetrazol-5-yl). (d) -CONHSOOR'. O, (e) -CONHSO-aryl, wherein aryl is defined as phe nyl or naphthyl which is unsubstituted or substituted 50 with one or two substituents selected from the group (i) consisting of: i) (C-C)-alkyl, ii) -O-(C-C)-alkyl, , or iii) -CONR'R''. 55 iv) F. Cl, Br or I. v) -COOR. (j) vi) -NH2, vii) -NHI (C-C)-alkyl). -CH2 viii) -N (C-C)-alkyl 60 )- ix) -phenyl, x) -OH, O O; xi) -OCHCHOH, x xii) -CF; (f) -CONHSO-(C-C)-alkyl, wherein the alkyl group is unsubstituted or substituted as defined in 65 R'' and R' independently are (C-C)-alkyl or phenyl. R(b). An embodiment of the invention is the compound of (g) -CONHSO-(C-C)-perfluoroalkyl, structural formula II:

5,767,310 11 12 (t) -CONCR); (i) -NH2, R and R' on adjacent carbons can join together to (j) -NRR, form a fused phenyl ring unsubstituted or substi (k) --NR'CONR'R'', tuted with a substituent selected from the group (1)-NRCOOR'', consisting of: (C-C)-alkyl. (C-C)-alkoxy. (C-C)-cycloalkyl and (C-C)-alkyl-(C-C)- (n) -SONR'R''. cycloalkyl. R is (a) (C-C)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: 10 (r) -NHSOR', i) -OR’. (s) -NR'SONR'R''. ii) -NR'2. (t) -CONHSOR'. iii) -NH. (u) -CO-amino acid, wherein amino acid is defined as iv) -COOR, or an L-or D- amino acid selected from the group v) -NCHCHQ; consisting of Ala. Ile. Phe, Asp, Pro and Val and (b) aryl, wherein aryl is defined as phenyl or naphthyl which can be further substituted as a (C-C)-alkyl which is unsubstituted or substituted with one or two ester or an amide, or substituents selected from the group consisting of: i) (C-C)-alkyl, (v) ii) -O-(C-C)-alkyl, iii) -CONR), iv) F. Cl, Br or I, v) -COOR. vi) -NH2. vii) -NH. (C-C)-alkyl). 25 viii) -N (C-C)-alkyll, or ix) -CONCHCHQ; X is (c) -(C-C)-alkylaryl, wherein aryl is as defined (a) -O-, above, (b) -S(O)-, (d) (C-C)-cycloalkyl, 30 (c) -NR'-. (d) -CHO-. (e) (e) -CHS(O)-. (f) -CHNR'-. (g) -OCH-, 35 (h)-N(R)CH-. (i) -S(O)CH-, or (j) -single bond; Z is: (a) -CO2H. R” and R' on the same nitrogen atom they can join (b) -COR". together to form a ring selected from the group con (c) -CONH-(tetrazol-5-yl). sisting of: morpholinyl, piperazinyl, or pyrrolyl, or (d) -CONHSOOR', Q is O. S or -NR': (e) -CONHSO-aryl, wherein aryl is defined as phe R? is nyl or naphthyl which is unsubstituted or substituted (a) H. 45 with one or two substituents selected from the group (b) (C-C)-alkyl, unsubstituted or substituted with one consisting of: or two substituents selected from the group consist i) (C-C)-alkyl. ing of: ii) -O-(C-C)-alkyl, i) -OH, iii) -CONR'R'', ii) -O-(C-C)-alkyl, 50 iv) F, Cl, Br or I, iii) -O-(C-C)-cycloalkyl, v) -COOR’. iv) -S(O)-(C-C)-alkyl, vi) -NH. v)-NR'R''. vii) -NH(C-C)-alkyll. vi) -COOR7, viii) -N (C-C)-alkyl vii) -CONHR'. 55 ix) -phenyl, viii) --OCOR', X) -OH, ix) -CONR'R''. xi) OCHCH-OH, x)-NRCONR'R'', xii) CF; xi)-NR7COOR, (f) -CONHSO-(C-C)-alkyl, wherein the alkyl xii) -C(R)(OH)-C(R)(R')(OH), or group is unsubstituted or substituted as defined in xiii) -SONR'R''. R(b), (c) (C-C)-cycloalkyl, (g) -CONHSO-(C-C)-perfluoroalkyl, (d) -OR. (h)-tetrazol-5-yl, (e) -COOR. (i) -CONHSO-heteroaryl, wherein heteroaryl is (f) -CONH2, 65 defined as carbazolyl, furyl, thienyl pyrrolyl, (g) -CONR'R''. isothiazolyl. imidazolyl, isoxazolyl, thiazolyl, (h) -CONRCOR’. oxazolyl pyrazolyl pyrazinyl pyridyl pyrimidyl,

5,767,310 16 (c) phenyl, or xii) -C(R)(OH)-C(R)(R')(OH), or (d) benzyl; xiii) -SONR'R''. R is: (c) -COOR’. (a) H. (d) -CONH2. (b) (C-C)-alkyl, or 5 (e) -CONR'R''. (c) phenyl: (f) -CONRCOR. Rand R' are independently: (g) -COR)(OH)-C(R)(R')(OH), or (a) H. (h) -CONHSOR''. (b) (C-C)-alkyl, unsubstituted or substituted with (i) -SONR'R''. (C-C)-cycloalkyl. 1O (j)-NR'SONR'R'', (c) Cl, Br, F, I, (k) -CO-amino acid, wherein amino acid is defined as (d) (C-C)-alkoxy, or an L-or D- amino acid selected from the group (e) hydroxy-(C-C)-alkyl consisting of Ala. Ile. Phe. Asp, Pro and Val and R is 5 which can be further substituted as a (C-C)-alkyl (a) (C-C)-alkyl, unsubstituted or substituted with a ester or an amide, or substituent selected from the group consisting of: i) -OR”. (l) ii) -NIR), iii) -NH2, iv) -COOR, or 2O n v) -NCHCHQ; -( I (b) aryl, wherein aryl is defined as phenyl or naphthyl 1 which is unsubstituted or substituted with one or two N substituents selected from the group consisting of: i) (C-C)-alkyl, X is ii) -O-(C-C)-alkyl, (a) -O-, iii) -CONR), (b) -NR'-, or iv) F. Cl, Br or I, (c) -single bond; v) -COOR. 30 vi) -NH Z is: vii) -NHI (C-C)-alkyl). (a) -C9H, viii) -N (C-C)-alkyll, or (b) -COR". ix) -CONCHCHQ: (c) -CONH-(tetrazol-5-yl). (c) -(C-C)-alkylaryl, wherein aryl is as defined 35 (d) -CONHSO-aryl, wherein aryl is defined as phe above, nyl or naphthyl which is unsubstituted or substituted (d) (C-C)-cycloalkyl, with one or two substituents selected from the group consisting of: (e) i) (C-C)-alkyl, R7 40 ii) -O-(C-C)-alkyl, N iii) -CONR'R''. YN iv) F. Cl, Br or I, v) -COOR. -( vi) -NH2, N 1 vii) -NH (C-C)-alkyl). 45 viii) -NH(C-C)-alkyl). R” and R' on the same nitrogen atom they can join ix) -phenyl; together to form a ring selected from the group con (e) -CONHSO-(C-C)-alkyl, wherein alkyl is sisting of: morpholinyl, piperazinyl, or pyrrolyl, or unsubstituted or substituted as defined in R(b). (f) -CONHSO-heteroaryl, wherein heteroaryl is Q is O.S or -NR': 50 defined as carbazolyl. furyl, thienyl, pyrrolyl. R is isothiazolyl. imidazolyl, isoxazolyl, thiazolyl, (a) H. (b) (C-C)-alkyl, wherein alkyl is defined as unsub oxazolyl, pyrazolyl pyrazinyl, pyridyl, pyrimidyl, stituted or substituted with one or two substituents purinyl, or quinolinyl, which is unsubstituted or selected from the group consisting of: 55 substituted with one or two substituents selected ii)i) -OH,-O-(C-C)-alkyl, i)f (C-C)-alkyl. gonising of: iii) -O-(C-C)-cycloalkyl, ii)-O (CC)-alkyl, iv) -S(O)-(C-C)-alkyl, iii) -CONR'R''. iv) -NR'-(C-C)-alkyl, 60 iv) F. Cl, Br or I, v)-NR'R''. v) -COOR, vi) -COOR. vi) -NRCONR'R'', and vii) -CONHR'. vii) -NRCOOR'; viii) -OCOR', (g) -tetrazol-5-yl; and ix) -CONR'R'', 65 R' is: (C-C)-alkyl. x) -NR7CONR'R'', A subclass of the compounds of Formula III are the xi) -NRCOOR'. compounds of Formula IV: 5,767,310 17 18 (d) (C-C)-alkoxy, or R12 (e) hydroxy-(C-C)-alkyl; R is (a) (C-C)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: R9 i) -OR, ii) -NIR', X Z iii) -NH2, iv) -COOR. or v) -NCHCHQ. (b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two substituents selected from the group consisting of: c R1 i) (C-C)-alkyl, R2 15 ii) -O-(C-C)-alkyl. or a pharmaceutically acceptable salt thereof, wherein: iii) -COINR, R" and R taken together form the ring structure: iv) F. Cl, Br or I. w) -COOR.". vi) -NH2, vii) -NH. (C-C)-alkyll, s viii) -N (C-C)-alkyll, or N ix) -CONCHCHQ; (c)-(-)-alkylaryl, wherein aryl is as defined above. (d) (C-C)-cycloalkyl, A represents: 25 a)-Y-IC(R)(R)-Y-, or (e) b) -COR")=C(R)-C(R)=C(R)-; s is 1 or 2; Y is -O-; Ra is: 30 (a) H. (b) F, Cl, Br, or I. (c) (C-C)-alkyl, (d) -OR. R’ and R' on the same nitrogen atom they can join (e) -O-(CH2)-OR". 35 together to form a ring selected from the group con (f) -CONR'R'', or sisting of: morpholinyl, piperazinyl, or pyrrolyl, or (g) -COOR; Q is O.S or -NR'; m is 2, 3 or 4; R2 is R" and Rare independently: (a) H. (a) H. (b) (C-C)-alkyl, wherein alkyl is defined as unsub (b) (C-C)-alkyl, stituted or substituted with one or two substituents (c) (C-C)-cycloalkyl. selected from the group consisting of (d) F. Cl, Br, I, i) -OH, (e) -NRCOOR'', ii) -O-(C-C)-alkyl, (f) -SONR'R''. 45 iii) -O-(C-C)-cycloalkyl. (g) -O-(C1-C4)-alkyl, iv) -S (O)-(C-C)-alkyl, (h) -S(O)-(C-C)-alkyl, or iv)-NR’-(C-C)-alkyl, (i) -NHSOR'; v)-NR'R''. n is 0, 1 or 2, vi) -COOR”. R is: 50 vii) -CONHR'. (a) H. or viii) --OCOR', (b) (C-C)-alkyl; ix) - CONR'R''. R7 is: x)-NR'CONR'R''. (a) H. xi) -NRCOOR', (b) (C-C)-alkyl. 55 xii) -C(R)(OH)-C(R)(R')(OH), or (c) phenyl, or (c)xiii) -COOR'. SQNR'R''. (d) benzyl; (d) -CONH2. R is: (e) -CONR'R''. (a) H. (f) -CONR'COR. (b) (C-C)-alkyl, or (g) -C(R)(OH)-C(R)(R)(OH), or (c) phenyl; (h) -CONHSOR', R is: (i) -SONR'R''. (a) H., (j) -NR'SONR'R'', (b) (C-C)-alkyl, unsubstituted or substituted with 65 (k) -CO-amino acid, wherein amino acid is defined as (C-C)-cycloalkyl. an L-or D- amino acid selected from the group (c) CI. Br. F. I. consisting of Ala, lie, Phe, Asp, Pro and Val and 5,767,310 19 20 which can be further substituted as a (C-C)-alkyl (a) H, ester or an amide, or (b) F. Cl, Br, or I, (c) -NO. (l) (d) (C-C)-alkyl, (e) -OR. (f) -NHCO-(C-C)-alkyl. (g) -NHCO-O(C-C)-alkyl, (h) -O-(CH2)-OR’. (i) -CONR'R'', or O (j) -COOR; X is m is 2.3 or 4. (a) -O-, R" and R are independently: (b) -NR'-, or (a) H. (c) -single bond; 15 (b) (C-C)-alkyl, Z is: (c) (C-C)-cycloalkyl. (a) -CO2H. (d) F. Cl, Br, I. (b) -COR". (c) -CONH-(tetrazol-5-yl). (e) -NRCOOR'', (d) -CONHSO-aryl, wherein aryl is defined as phe (f) -SONR'R''. nyl or naphthyl which is unsubstituted or substituted (g) -O-(C-C)-alkyl, with one or two substituents selected from the group (h) -S(O)-(C-C)-alkyl, or consisting of: (i) -NHSOR"; i) (C-C)-alkyl, n is 0, 1 or 2. ii) -O-(C-C)-alkyl, 25 R is: iii) -CONR'R''. (a) H. iv) F, Cl, Br or I. (b) (C-C)-alkyl, v) -COOR.". R’ is: vi) -NH2, (a) H. vii) -NHI(C-C)-alkyl. 30 viii) -N (C-C)-alkyl). (b) (C-C)-alkyl, ix) -phenyl; (c) phenyl, or (e) -CONHSO-(C-C)-alkyl, wherein alkyl is (d) benzyl: unsubstituted or substituted as defined in R'(b). R is: (f) -CONHSO-heteroaryl, wherein heteroaryl is (a) H. defined as carbazolyl, furyl, thienyl pyrrolyl. (b) (C-C)-alkyl, or isothiazolyl, imidazolyl isoxazolyl, thiazolyl, (c) phenyl: oxazolyl pyrazolyl pyrazinyl, pyridyl pyrimidyl, R and R' are independently: purinyl, or quinolinyl, which is unsubstituted or (a) H. substituted with one or two substituents selected 40 (b) (C-C)-alkyl, unsubstituted or substituted with from the group consisting of: (C-C)-cycloalkyl, i) (-)-alkyl. (c) Cl, Br. F. I. ii) -O-(C-C)-alkyl, (d) (C-C)-alkoxy, or iii) -CONR'R''. (e) hydroxy-(C-C)-alkyl; iv) F. Cl, Br or I, v) -COOR". 45 R' is vi) --NR'CONR'R'', and (a) (C-C)-alkyl, unsubstituted or substituted with a vii) -NRCOOR'', or substituent selected from the group consisting of: (g) -tetrazol-5-yl; and i) -OR'. R" is: (C-C)-alkyl. 50 ii) -NIR'), A second embodiment of the compounds of Formula II iii) -NH. are the compounds of Formula V: iv) -COOR. or v) -NICHCHQ; R12 (b) aryl, wherein aryl is defined as phenyl or naphthyl 55 which is unsubstituted or substituted with one or two substituents selected from the group consisting of: i) (C-C)-alkyl. ii) -O-(C-C)-alkyl, iii) -CONR), iv) F, Cl, Br or I, w) -COOR, vi) -NH. R38 vii) -NH (C-C)-alkyl). viii) -N (C-C)-alkyl, or 65 ix) -CONCHCHQ; or a pharmaceutically acceptable salt thereof, wherein: (c) -(C-C)-alkylaryl, wherein aryl is as defined R". R. Ra and Rb are independently: above, 5,767.310 21 22 iii) -CONR'R'', (e) iv) F, Cl, Br or I, R7 w) -COOR, vi) -NH. YN 5 vii) -NH(C-C)-alkyl). -( viii) -N (C-C)-alkyll, or N 1 ix) -phenyl; (e) -CONHSO-(C-C)-alkyl, wherein alkyl is unsubstituted or substituted as defined in R(b). R" and R' on the same nitrogen atom they can join 10 (f) -CONHSO-heteroaryl. wherein heteroaryl is together to form a ring selected from the group con defined as carbazolyl, furyl, thienyl, pyrrolyl. sisting of: morpholinyl, piperazinyl, or pyrrolyi, or isothiazolyl, imidazolyl, isoxazolyl. thiazolyl, Q is oxazolyl pyrazolyl pyrazinyl pyridyl, pyrimidyl, R’ is (a) H, purinyl, or quinolinyl, which is unsubstituted or (b) (C-C)-alkyl, wherein alkyl is defined as unsub 15 substituted with one or two substituents selected stituted or substituted with one or two substituents from the group consisting of: selected from the group consisting of: i) (C-C)-alkyl, i) -OH, ii) -O-(C-C)-alkyl, ii) -O-(C-C)-alkyl, iii) -CONR'R'', iii) -O-(C-C)-cycloalkyl. 2O iv) F. Cl, Br or I. iv) -SCO)-(C-C)-alkyl. w) -COOR.". iv) -NR'-(C-C)-alkyl, vi) --NR'CONR'R'', and v)-NR'R''. vii) -NRCOOR'', or vi) -COOR7. (g) -tetrazol-5-yl; and vii) -CONHR'. 25 R' is: (C-C)-alkyl. viii) -OCOR', A third embodiment of compounds of Formula II are the ix) -CONR'R''. compounds of Formula VI: x)-NR7CONR'R'', xi) --NRCOOR.". R12 WI xii) -COR)(OH)-C(R)(R)(OH), or 30 xiii) -SONR'R''. (c) -COOR, (d) -CONH. R9 Rio (e) -CONR'R'', (f) -CONR'COR7. 35 X Z. (g) -C(R)(OH)-C(R)(R')(OH), or (h) -CONHSOR". Ri (i) -SONR'R''. 3. (j) -NR'SONR'R''. R (k) -CO-amino acid, wherein amino acid is defined as 40 R2 an L-or D- amino acid selected from the group R3a. consisting of Ala, Ile, Phe, Asp, Pro and Val and which can be further substituted as a (C-C)-alkyl or a pharmaceutically acceptable salt thereof, wherein: ester or an amide, or R" and Rare represented by the following ring structure: 45 (l) R7 -N A n N -( Nl; 50 N 1 A represents: a)-Y-C(R)(R)-Y-, or (a) -O-, 55 s is 1 or 2. (b) -NR'-, or Y is -O-, -S- and NR; (c) -single bond; Ra and Rb are independently: Z is: (a) H. (a) -CO2H. (b) F, Cl, Br, or I, (b) -COR', 60 (c) -NO. (c) -CONH-(tetrazol-5-yl). (d) (C-C)-alkyl. (d) -CONHSO-aryl, wherein aryl is defined as phe- (e) -OR’. nyl or naphthyl which is unsubstituted or substituted (f) -NHCO-(C-C)-alkyl. with one or two substituents selected from the group (g) -NHCOO(CC)-alkyl, consisting of: 65 (h) -O-(CH2)-OR', i) (C-C)-alkyl, (i) - CONR'R'', or ii) -O-(C-C)-alkyl, (j) -COOR: 5,767,310 23 24 m is 2, 3 or 4, Q is O. S or -NR'; R and Rare independently: R1 is (a) H. (a) H. (b) (C-C)-alkyl, (b) (C-C)-alkyl, wherein alkyl is defined as unsub (c) (C-C)-cycloalkyl, 5 stituted or substituted with one or two substituents (d) F. Cl, Br, I, selected from the group consisting of: (e) -NRCOOR'', i) -OH, (f) -SONR'R'', ii) --O-(C-C)-alkyl, (g) -O-(C-C)-alkyl. iii) -O-(C-C)-cycloalkyl, (h) -S(O)-(C-C)-alkyl, or 10 iv) -S(O)-(C-C)-alkyl. (i) -NHSOR'; iv) -NR'-(C-C)-alkyl, o v)-NR'R''. Rn isis: 0, 1 or 2, vi) -COOR,7 (a) H., or 15 viii)vii) -2S R. (b) (C-C)-alkyl; ix) - CONR'R''.

R ch h X)xi) -NRONR'R''.-NR7COOR'. (b) (C-C)-alkyl, xii) -C(R)(OH)-C(R)(R)(OH), or (c) phenyl, or 20 xiii) -SONR'R'', (d) benzyl; (c) -COOR. R is: (d) -CONH2. (a) H. R conRR11, (b) (C-C)-alkyl, or (f) -CONRCOR’. (c) phenyl; 25 (g) -C(R)(OH)-C(R)(R')(OH), or R and R'' are independently: (h) -CONHSOR'', (a) H. (i) -SO2NR'R''. (b) (C-C)-alkyl, unsubstituted or substituted with (j) -NRSONR'R''. (C-C)-cycloalkyl. (k) -CO-amino acid, wherein amino acid is defined as (c) Cl, Br. F. I. 30 an L-or D- amino acid selected from the group (d) (C-C)-alkoxy, or consisting of Ala, Ile, Phe, Asp, Pro and Val and (e) hydroxy-(C-C)-alkyl; which can be further substituted as a (C-C)-alkyl R is ester or an amide, or (a) (C-C)-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: 35 R7 i) -OR’. ii) -NIR' NN iii) -NH2, (1) -( iv) -COOR’, or N; v) -NCHCHQ, 40 N (b) aryl, wherein aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one or two X is substituents selected from the group consisting of: (a) -O-, i) (-)-alkyl. (b) -NR'-, or ii) -O-(C-C)-alkyl, 45 (c) -single bond; iii) -COINR). Z is: iv) F. Cl, Br or I. (a) -COH, v) -COOR’. (b) -COR', vi) -NH. (c) -CONH-(tetrazol-5-yl). vii) -NHI(C-C)-alkyl. 50 (d) -CONHSO-aryl, wherein aryl is defined as phe viii) -N (C-C)-alkyll, or nyl or naphthyl which is unsubstituted or substituted ix) -CONCHCHQ; with one or two substituents selected from the group (c) -(C-C)-alkylaryl. wherein aryl is as defined consisting of: above, i) (C-C)-alkyl, (d) (C-C)-cycloalkyl. 55 ii) -O-(C-C)-alkyl, iii) -CONR'R''. (e) iv) F, Cl, Br or I, R v) -COOR. N vi) -NH2, YN 60 vii) -NH (C-C)-alkyll. -( l; viii) -N (C-C)-alkyl). 1. ix) -phenyl; (e) -CONHSO-(C-C)-alkyl, wherein alkyl is unsubstituted or substituted as defined in R'(b). R" and R'I on the same nitrogen atom they can join 65 (f) -CONHSO-heteroaryl, wherein heteroaryi is together to form a ring selected from the group con- defined as carbazolyl, fury. thienyl pyrrolyl, sisting of: morpholinyl, piperazinyl, or pyrrolyl, or isothiazolyl. imidazolyl. isoxazolyl, thiazolyl.

5,767,310 29 30 Cycloalkyl denotes rings composed of 3 to 8 methylene in the text, the alkyl and aryl groups represent unfunction groups, each of which may be substituted or unsubstituted alized or functionalized derivatives as described before. The with other hydrocarbon substituents, and include for leaving group Q present in the alkylating agents is either example cyclopropyl. cyclopentyl, cyclohexyl and chloro, bromo, iodo, methanesulfonate, p-toluenesulfonate 4-methylcyclohexyl, or triflate.

Scheme 1 R12 R12 Q R9 R10 Rio + Ar Zi Base ^ Zl XH Ar 2 3

R12

R1, R3, A or R9 R10

R2 R3a ^ Z. Ar III,V or VI R3a

A. Q = Cl, Br, I, OMs, OTs or OTf Z= a precursor to Z.

40 The alkoxy substituent represents an alkyl group as More specifically, the compounds of Formula III, V or VI described above attached through an oxygen bridge. The heteroaryl is defined as carbazolyl, furyl, thienyl, (where X is oxygen, sulphur or appropriately substituted pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, nitrogen) can be synthesized as outlined in Scheme 1. The oxazolyl pyrazolyl pyrazinyl, pyridyl, pyrimidyl, purinyl or 45 substituted compound 1 may be reacted with the alkylating quinolinyl. agent 2 in an appropriate solvent such as alcohols (methanol, Although the reaction schemes described below are rea ethanol, isopropanol and like), dimethylformamide (DMF). sonably general. it will be understood by those skilled in the dimethylsulfoxide (DMSO), tetrahydrofuran (THF) and art of organic synthesis that one or more functional groups acetone in the presence of an alkali metal salt such as present in a given compound of Formula I may render the 50 alkoxides. carbonates, hydroxides and hydrides, or organic molecule incompatible with a particular synthetic sequence. bases such as trialkylamines or alkyl lithiums to provide In such a case an alternative synthetic route, an altered order compound 3. The Z" group present in compound 3 may then of steps, or a strategy of protection and deprotection may be be further transformed to provide the appropriate com employed. In all cases the particular reaction conditions. pounds of Formula III, V or VI. including reagents, solvent, temperature and time, should be 55 In general, the alkylating agent 2 can be prepared using chosen so that they are consistent with the nature of the methods and techniques outlined in U.S. Pat. No. 5.177,095. functionality present in the molecule. More specifically, compound 2 (where Z is COOR and Q The compounds of Formula I and specifically compounds is Br) can be synthesized from the substituted arylacetic of Formula DII can be synthesized using the reactions and acids 4 as outlined in Scheme 2. The substituted arylacetic techniques described for the synthesis of the non acid 4 is converted to the corresponding ester either by heterocyclic components in the patent application WO91/ refluxing the acid in an appropriate alcohol in the presence 11999 (Merck & Co.; published on Aug. 22.1991 under the of a catalytic amount of conc. sulfuric acid, or using other Patent Cooperation Treaty) and also U.S. Pat. No. 5,177,095 conventional methods of esterification. The resulting ester is (Merck & Co.; Jan. 5, 1993). then refluxed in carbon tetrachloride with The reaction schemes described below have been gener 65 N-bromosuccinimide and a catalytic amount of a radical alized for simplicity. It is further to be understood that in the initiator (e.g., AIBN or benzoylperoxide) to provide the generalized schemes below, unless specified more narrowly 2-bromo-arylacetic acid ester 5. 5,767,310 31 -continued Scheme 2 Scheme 4 Br 1. ROH, H 1. A1N COOH 2. NBS, ABN Air COOR CCL R3b OH 4 5 COOH Alternatively, the ester 5 may also be prepared from - Ge. appropriate aryl aldehydes (Scheme 3). The aldehyde 6 can 10 N be reacted with trimethylsilyl cyanide and catalytic amounts bo. R3a. of KCN and 18-crown-6 to provide the corresponding trimethylsilyl cyanohydrin 7. which upon further treatment 11 with the gaseous HCl and alcohol affords the 2-hydroxy ester 8. The ester 8 is treated with triphenylphosphine and 15 R3b Br carbon tetrabromide in methylene chloride to give the 2-bromoarylacetate derivatives 5. / COOMe

Scheme 3 N OTMS bo. R3a Ar-CHO - Ge. -N CN - b > 12 a. (i) DIBALH, Toluene; (ii) Boc2O, DMAP, CH2Cl2 6 7 b. (i) CHCl, KOH, DMF, 0° C.; (ii) NaOH, DME/HO 25 c. (i) CHN; (ii) CBr/Ph3P. CHCl2 OH Br scoe -G -> COOEt A typical synthesis of alkylating agents bearing a substi 8 5 tuted benzoxazole or benzthiazole ring is outlined in Scheme 30 5. The substituted benzoxazole 14 is prepared from the a. TMSCN, Cat. KCN, CH2Cl2, 18-Crown-6; corresponding o-aminophenol 13 by the reaction of an b. HCl(g), EtOH; c. CBr, PhP, CHCl2 appropriate orthoester under refluxing conditions (for other methods of synthesis of benzoxazoles see. S. A. Lang and Y. Scheme 4 illustrates a typical synthesis of an alkylating 35 Lin, Comprehensive Heterocyclic Chemistry, Vol. 6, 1-130, agent 12 (where Ar represents a heterocycle such as an Ed. C. W. Rees; and references cited therein). Reduction of indole). The appropriately substituted cyanoindole 9 (for a 14 with NaBH provides the alcohol 15 which is then general synthesis of substituted indoles refer to, R. K. subjected to pyridinium dichromate (PDC) oxidation to Brown, Indoles, Part One, Ed. W. J. Houlihan, Vol. 25, yield the corresponding aldehyde 16. Further elaboration of Chapter II, Wiley-Interscience. New York, 1972) is reduced 16 as outlined provides the key intermediate 17. Similarly, with DIBAL-H to provide the corresponding aldehyde. the benzothiazole 19 can also be prepared form the appro which is then converted into the N-Boc derivative 10. priately substituted o-aminothiophenol 18. Reaction of 10 with the trichloromethide anion generated from KOH and CHCl; J. M. Wyvratt et al. J. Org. Chem, 5, 944-945 (1987) followed by treatment with aqueous 45 Scheme 5 NaOH in DMF provides the alcohol 11. Treatment of 11 with diazomethane followed by the reaction with CBr/Ph3P R36 R3b yields the alkylating agent 12. NH2 COOH N COOH Scheme 4 50 - Ge. ( - b > R3b HO O R3a Ra / CN 13 14 - Ge. 55 N R3b R3b H Ra N CH2OH N CHO 9

R3b (O - >{ O d / CHO R3a R3a b G 15 16 N ho R3a. 65 10 5,767,310 33 -continued -continued Scheme 5 Scheme 6 R35 Br

N 5 R3b R3b ( COOMe O CHO O tek a. CH(OEt)3, EtOH, reflux 17 10 R3a R3a b.(i) CCOOEt, EtsN, THF; (ii) NaBH, THF-HO c. Pyridinium dichromate, CH2Cl2 21 22 d.(i) CHCl, KOH, DMF, 0° C.; (ii) NaOH, DME/HO; (iii) HC/MeOH; (iv) CBra/Ph3P, CHCl, d c R3 R36 Br 15 R3b R3b Br NH COOH N COOMe O O ( COOMe COOMe HS S R3a R3a 2O R3a. R3a. 23 18 19 24 b a.ZnCl2 Scheme 6 illustrates the synthesis of benzofuran and C b.DBALH, toluene dihydrobenzofuran alkylating agents 23 and 25. The benzo c.(i) CHCl3, KOH, DMF, O C.; 25 R3b Br (ii) NaOH, DME/HO: furan 21 can be prepared from the o-phenoxy carbonyl (iii) HCl/MeOH; compound 20 via a ring closure reaction Stoermer and O coole (iv) CBr/Ph3P, CH2Cl2: Wehlin. Chem. Ber, 35.3549 (1902) (for general methods of d. Ra-Ni/H2 synthesis of benzofurans and dihydrobenzofurans see. R. C. Elderfield and V. B. Meyer. Heterocyclic Compounds, Vol. 3O 25 2, Chapter 1, Ed. R. C. Elderfield, Wiley; and references R34 cited therein). The ester 21 is reduced to provide the alde hyde 22 which is then transformed into the corresponding alkylating agent 23. The dihydrobenzofuran ester 24, R35 R3b obtained by catalytic reduction of 21. can also be trans 35 / CHO COOMe formed into the corresponding alkylating agent 25 using the sequence of reactions outlined in Scheme 6. HOOC Benzothiophene 26 may be synthesized from the corre S S sponding aldehyde 26b in a manner similar to that outlined R3a H R3a in Scheme 6 for benzofuran 23. Benzothiophene 26b can be prepared by the oxidative cyclization (using an alkaline 40 26b 26a solution of potassium ferricyanide) of appropriately substi tuted o-mercaptocinnamic acid 26a C. Chmelewsky and P. R3b Br Friedlander. Chem. Ber, 46, 1903 (1913). (For general methods of synthesis of benzothiophene, See. E. Cham COOMe paigne in Comprehensive Heterocyclic Chemistry, vol. 4, 45 Chapter 3-15; Eds. A. Katritzky and C. W. Rees.) S Scheme 7 outlines a typical synthesis of ot-bromoaryl acetates, 30 and 32, bearing appropriately substituted meth R3a ylenedioxy or 1,4-dioxane rings. The substituted catechol 26 derivative 27 is treated with an appropriate dibromide 50 (where m is 1 or 2) in the presence of cesium carbonate in dimethylformamide to provide 28. Treatment of 28 with DIBALH yields the aldehyde 29 which is then transformed Scheme 7 into the desired alkyl bromide as described. 55 R3b R3b Scheme 6 HO COOMe COOMe 3 G (CH2)m b (EtO)2.HClo COOMe HO O 60 R3a. R3a 20 27 28 R3a

65 5,767.310 35 36 -continued New York London. 1975, Ch. 31, pp. 306–326, H. Ferres, Scheme 7 Drugs of Today, Vol 19,499-538 (1983) and J. Med. Chem, 18, 172 (1975)). Examples of such prodrugs include the R3b physiologically acceptable and metabolically labile ester O CHO derivatives, such as lower alkyl (e.g. methyl or ethyl esters). aryl (e.g. 5-indanyl esters), alkenyl (e.g. vinyl esters), ch alkoxyalkyl (e.g. methoxymethyl esters), alkylthioalkyl (e.g. methylthiomethyl esters), alkanoyloxyalkyl (e.g. pivaloy O loxymethyl esters), and substituted or unsubstituted amino 29 R3a. ethyl esters (e.g. 2-dimethylaminoethyl esters). Additionally, O any physiologically acceptable equivalents of the com pounds of general Formula I, similar to the metabolically V labile esters, which are capable of producing the parent R3b R3b Br compounds of general Formula I in vivo, are within the fO CHCOOt Me A.O COOMe scope of this invention. 15 It will be further appreciated that the majority of com (CH2)m. - Ge. (Chim pounds of general Formula I claimed herein are asymmetric O O and are produced as racemic mixtures of enantiomers and that both the racemic compounds and the resolved individual R3a. R3a enantiomers are considered to be within the scope of this 31 30 invention. The racemic compounds of this invention may be a. Br-(CH2)-Br, Cs2CO3, DMF resolved to provide individual enantiomers utilizing meth b.DBALH, toluene ods known to those skilled in the art of organic synthesis. c. (i) CHCla. KOH, DMF, 0° C.; (ii) NaOH, DME/HO: For example, diastereoisomeric salts, esters or imides may (iii)HC/MeOH; (iv) CBr/Ph3P. CHCl2: d.NBS, ABN, CCI be obtained from a racemic compound of general Formula I 25 and a suitable optically active amine. amino acid, alcohol or R3b Br the like. The diastereoisomeric salts, esters or imides are separated and purified, the optically active enantiomers are R12 O COOMe regenerated and the preferred enantiomer is the more potent isomer. The resolved enantiomers of the compounds of X. 30 general Formula I, their pharmaceutically acceptable salts R3a 32 and their prodrug forms are also included within the scope of this invention. The reactions are performed in a solvent appropriate to Endothelin (ET-1), and two closely related bioactive the reagents and materials employed and suitable for the peptides. ET-2 and ET-3. are widely distributed in mamma transformation being effected. It is understood by those 35 lian tissues, and they can induce numerous biological skilled in the art of organic synthesis that the functionality responses in non-vascular as well as vascular tissues by present on the heterocycle and in the reactants being binding to at least two distinct endothelin receptor subtypes. employed should be consistent with the chemical transfor In addition to cardiovascular smooth muscle, neural and mations being conducted. Depending upon the reactions and atrial sites, endothelin receptors may also be found in techniques employed, optimal yields may require changing gastrointestinal, kidney, lung, urogenital. uteral and placen the order of synthetic steps or use of protecting groups tal tissues. followed by deprotection. Endothelin is a potent vasoconstrictor peptide and thus The compounds useful in the novel method treatment of plays a role in vivo in arterial pressure-volume homeostasis. this invention form salts with various inorganic and organic Not only peripheral, but coronary vascular resistance as acids and bases which are also within the scope of the 45 well, is increased by endothelin; cardiac output is decreased, invention. Such salts include ammonium salts, alkali metal while plasma renin activity is increased. There is a reduction salts like sodium and potassium salts, alkaline earth metal in renal blood flow and glomerular filtration rate, while salts like the calcium and magnesium salts, salts with levels of atrial matriuretic factor, vasopressin, and aldoster organic bases; e.g. dicyclohexylamine salts, N-methyl-D- one become elevated. glucamine, salts with amino acids like arginine, lysine, and 50 It is also considered, in accordance with the present the like. Also, salts with organic and inorganic acids may be invention, that antagonists for the endothelin receptor may prepared; e.g., HCl, HBr, HSO, HPO, methanesulfonic. be useful in preventing or reducing restenosis subsequent to toluenesulfonic, maleic, fumaric, camphorsulfonic. denudation following angioplasty. Such denudation results The salts can be formed by conventional means, such as in myointimal thickening following angioplasty, due to by reacting the free acid or free base forms of the product 55 increased endothelin release. Endothelin acts as a growth with one or more equivalents of the appropriate base or acid factor with respect to smooth muscle and fibroblastic cells, in a solvent or medium in which the salt is insoluble, or in and possibly other types of cells, as well. a solvent such as water which is then removed in vacuo or Endothelin is also a neuropeptide, acting on the posterior by freeze-drying or by exchanging the cations of an existing pituitary, where it modulates the release of the neurosecre salt for another cation on a suitable ion exchange resin. tory hormones vasopressin and oxytocin. Endothelin It will be appreciated that the compounds of general released from the posterior pituitary also acts as a circulating Formula I in this invention may be derivatised at functional hormone, having a wide range of actions as discussed further groups to provide prodrug derivatives which are capable of above. This includes effects on the endocrine system, espe conversion back to the parent compounds in vivo. The cially the adrenal glands. Endothelin increases plasma levels concept of prodrug administration has been extensively 65 of epinephrine. reviewed (e.g. A. A. Sinkula in Annual Reports in Medicinal Consequently, the novel compounds of the present Chemistry, Vol 10. R. V. Heinzelman, Ed. Academic Press, invention, which are receptor antagonists of endothelin. 5,767,310 37 38 have therapeutic usefulness in preventing, decreasing or protease inhibitors. Hippocampi were homogenized using a modulating the various physiological effects of endothelin Dounce (glass-glass) homogenizer with type A pestle, with discussed above, by wholly or partially blocking access of homogenizer in ice. Tissue homogenate was centrifuged at endothelin to its receptor. 750xg for 10 min at 4°C. Supernatant was filtered through dampened cheesecloth, and centrifuged again at 48,000xg Endothelin Receptor Binding Assays for 30 min at 4° C. Pellets were resuspended in sucrose The binding of the novel compounds of this invention to buffer with protease inhibitors. Aliquots of this preparation the endothelin receptor was determined in accordance with were quick frozen and stored at -70° C. until use. Mem the assay described in detail immediately below. It is similar branes were diluted into 50 mM KPi, 5 mM EDTA pH 7.5 to the assay described in Ambar et al. (1989) Biochem. 10 containing 0.01% human serum albumin. Assays were done Biophys. Res. Commun, 158. 195-201; and Khoog et al. in triplicate. Test compounds and 25pM 'I-endothelin-1 (1989) FEBS Letters, 253, 199-202. (2000-2200 Ci/mmole. obtained from New England The endothelins (ETs) have a number of potent effects on Nuclear or Amersham) were placed in a tube containing this a variety of cells, and exert their action by interacting with buffer. and the membranes prepared above were added last. specific receptors present on cell membranes. The com 15 The samples were incubated for 60 min at 37° C. At the end pounds described in the present invention act as antagonists of this incubation, samples were filtered onto prewetted of ET at the receptors. In order to identify ET antagonists (with 2% BSA in water) glass fiber filter pads and washed with 150 mM. NaCl, 0.1% BSA. The filters were assayed for and determine their efficacy in vitro, the following three 'I radioactivity in a gamma counter. Nondisplaceable ligand receptor assays were established. binding of 'I)-endothelin-1 is measured in the presence of Receptor binding assay using cow aorta membrane 100 nM unlabelled endothelin-1 Endothelin-1 (ET-1) was preparation purchased from Peptides International (Louisville, Ky.). 'I-ET-1 (2000 Ci/mMol) was purchased from Amersham Thoracic aortae were obtained from freshly slaughtered (Arlington Heights, Ill.)). Specific binding is total binding calves and brought to the lab on wet ice. The adventitia were 25 minus nondisplaceable binding. removed. and the aorta was opened up lengthwise. The lumenal surface of the tissue was scrubbed with cheesecloth The inhibitory concentration (IC) which gives 50% to remove the endothelial layer. The tissue was ground in a displacement of the total specifically bound 'I)- meat grinder, and suspended in ice-cold 0.25M sucrose, 5 endothelin-1 was presented as a measure of the efficacy of mM tris-HCl, pH 7.4, containing 0.5 mg/mL leupeptin and 7 such compounds as endothelin antagonists. mg/mL pepstatin A. Tissue was homogenized twice and then 30 centrifuged for 10 minutes at 750xg at 4°C. The supernatant Receptor binding assay using cloned human ET was filtered through cheesecloth and centrifuged again for receptors expressed in Chinese Hamster Ovary 30 minutes at 48,000xg at 4°C. The pellet thus obtained was Cells resuspended in the buffer solution described above 35 Both endothelin receptor subtypes were cloned from a (including the protease inhibitors), and aliquots were quick human cDNA library and were individually expressed in frozen and stored at -70° C. until use. Membranes were Chinese Hamster Ovary cells. Cells were harvested by diluted into 50 mM KPi. 5 mM EDTA pH 7.5 containing addition of 126 mM NaCl, 5 mM KC, 2 mM EDTA, 1 mM 0.01% human serum albumin. Assays were done in tripli NaHPO, 15 mM glucose, 10 mM tris/HEPES pH 7.4 Cells cate. Test compounds and 100 pM 'I)-endothelin-1 were centrifuged at 250xg for 5 minutes. The supernatant (2000-2200 Ci/mmole, obtained from New England was aspirated off, and the cells were resuspended in the 50 Nuclear or Amersham) were placed in a tube containing this mM KPi, 5 mM EDTA pH 7.5 containing 0.01% human buffer, and the membranes prepared above were added last. serum albumin. Assays were done in triplicate. Test com The samples were incubated for 60 min at 37° C. At the end pounds and 25-100 pM 'I'-endothelin-1 (2000–2200 of this incubation, samples were filtered onto prewetted 45 Ci/mmole. obtained from New England Nuclear or (with 2% BSA in water) glass fiber filter pads and washed Amersham) were placed in a tube containing 50 mM KPi. 5 with 150 mM NaCl, 0.1% BSA. The filters were assayed for mM EDTA pH 7.5 containing 0.01% human serum albumin, 'I radioactivity in a gamma counter. Nondisplaceable and the cells prepared above were added last. The samples binding of ''Il-endothelin-1 is measured in the presence of were incubated for 60 min at 37° C. At the end of this 100 nM unlabelled endothelin-1 Endothelin-1 (ET-1) was SO incubation, samples were filtered onto prewetted (with 2% purchased from Peptides International (Louisville, Ky.). BSA in water) glass fiber filter pads and washed with 150 'I-ET-1 (2000 CilmMol) was purchased from Amersham mM NaCl, 0.1% BSA. (Arlington Heights, Ill.)). Specific binding is total binding The filters were assayed for 'I radioactivity in a gamma minus nondisplaceable 30 binding. The inhibitory concen counter. Nondisplaceable binding of 'I)-endothelin-1 is tration (ICs) which gives 50% displacement of the total 55 measured in the presence of 100 nM unlabelled endothelin-1 specifically bound 'Il-endothelin-1 was presented as a Endothelin-1 (ET-1) was purchased from Peptides Interna measure of the efficacy of such compounds as ET antago tional (Louisville, Ky.). 'T-ET-1 (2000 CilmMol) was nists. purchased from Amersham (Arlington Heights, Ill.). Spe cific binding is total binding minus nondisplaceable binding. Receptor binding assay using rat hippocampal The inhibitory concentration (IC) which gives 50% dis membrane preparation placement of the total specifically bound . 1 Rat hippocampi were obtained from freshly sacrificed was presented as a measure of the efficacy of such com male Sprague-Dawley rats and placed in ice cold 0.25M pounds as endothelin antagonists. sucrose, 5 mM tris-HCl, pH 7.4 containing 0.5 mg/mL The binding assays described above were used to evaluate leupeptin. 7 mg/mL pepstatin A. Hippocampi were weighed the potency of interaction of representative compounds of and placed in a Dounce homogenizer with 25 volumes (wet the invention with endothelin receptors. To determine weight to volume) ice-cold sucrose buffer in the presence of whether these compounds were endothelin antagonists, 5,767.310 39 40 assays which measure the ability of the compounds to inhibit roacetic acid to 6% concentration. Samples were sonicated endothelin-stimulated phosphatidylinositol hydrolysis were for 10 min, centrifuged 20 min, then trichloroacetic acid was established. Rat uterus contains predominantly one of the extracted with water-saturated ethyl ether. An aliquot of each known endothelin receptor subtypes (ETA). sample was neutralized and diluted by addition of 50 mM tris-HCl pH 7.4. A 100 mL aliquot of this solution was Phosphatidylinositol hydrolysis assays using rat assayed for radioactivity in a beta counter. The diluted uterine slices neutralized sample was applied to DoweX 1X8-formate Diethylstilbestrol primed female Sprague-Dawley rats columns, washed with water, then washed with 60 mM were sacrificed and their uteri were collected, dissected of ammonium formate. 5 mM sodium tetraborate. Samples fat and connective tissue and minced. Minced tissue was were eluted with 200 mM ammonium formate, 5 mM added to oxygenated (95% O. 5% CO) 127 mM NaCl. 25 sodium tetraborate. The radioactivity of each eluted sample mM NaHCO. 10 mM Glucose, 2.5 mM KCI, 1.2 mM was measured in a beta counter. Radioactivity was normal KHPO, 1.2 mM MgSO 1.8 mM CaCl. To the tissue ized by dividing radioactivity in post column sample by mince. 1.2 mM myo-H-inositol (Amersham) was added. radioactivity in precolumn sample. Control values (100% The mince was incubated 90 min at 37° C., with constant 15 stimulated) are values in the presence of sarafotoxin minus oxygenation. After incubation, the loaded tissue mince was the values in the absence of sarafotoxin (basal). Test sample washed five times with the same oxygenated buffer to values are the values in the presence of sarafotoxin and test remove excess radiolabelled inositol. The tissue mince was sample minus basal. Inhibitory concentration (IC) is the resuspended in the above buffer, containing 10 mM LiCl, concentration of test compound required to give a sample aliquotted into tubes, and 3 nM endothelin-1 with and activity of 50% of control value. without test compounds was added to start the assay. Assays were done in quadruplicate. Samples were incubated at 37 Phosphatidylinositol hydrolysis assays using cloned C. under blowing O in a hooded water bath for 30 minutes. human endothelin receptors expressed in Chinese Reaction was stopped by addition of trichloroacetic acid to Hamster Ovary cells 6% concentration. Samples were sonicated for 10 min. centrifuged 20 min, then trichloroacetic acid was extracted Endothelin receptors of both receptor subtypes were with water-saturated ethyl ether. An aliquot of each sample cloned from a human cDNA library and were individually was neutralized and diluted by addition of 50 mM tris-HCl expressed in Chinese Hamster Ovary cells. Cells were pH 7.4. A 100 mL aliquot of this solution was assayed for loaded overnight by the addition of 1.2 M myo-H- radioactivity in a beta counter. The diluted neutralized 30 inositol to their growth medium. Cells were harvested by sample was applied to Dowex 1X8-formate columns. addition of 126 mM NaCl, 5 mM KCl 2 mM EDTA 1 mM washed with water, then washed with 60 mM ammonium NaHPO, 15 mM glucose, 10 mM tris/HEPES pH 7.4. formate, 5 mM sodium tetraborate. Samples were eluted Cells were washed five times by centrifugation at 250Xg for with 200 mM ammonium formate, 5 mM sodium tetrabo 5 minutes to remove excess radiolabelled inositol. The rate. The radioactivity of each eluted sample was measured 35 supernatant was aspirated off, and the cells were resus in a beta counter. Radioactivity was normalized by dividing pended in the same oxygenated (95% O2, 5% CO) buffer radioactivity in post column sample by radioactivity in containing 10 mM LiCl, aliquotted into tubes, and 0.3 nM precolumn sample. Control values (100% stimulated) are endothelin-1 with and without test compounds was added to values in the presence of endothelin minus the values in the start the assay. Assays were done in quadruplicate. Samples absence of endothelin (basal). Test sample values are the 40 were incubated at 37° C. under blowing O in a hooded values in the presence of endothelin and test sample minus water bath for 30 minutes. Reaction was stopped by addition basal. Inhibitory concentration (IC.so) is the concentration of of 0.5 mL 18% trichloroacetic acid to 6% concentration. test compound required to give a sample activity of 50% of Samples were sonicated for 10 min, centrifuged 20min, then control value. trichloroacetic acid was extracted with water-saturated ethyl 45 ether. An aliquot of each sample was neutralized and diluted Sarafotoxin S6c is a member of the endothelin family by addition of 50 mM tris-HCl pH 7.4. A 100 mL aliquot of which binds preferentially to one of the known endothelin this solution was assayed for radioactivity in a beta counter. receptor subtypes (ET). The diluted neutralized sample was applied to Dowex 1x8 Phosphatidylinositol hydrolysis assays using rat formate columns, washed with water, then washed with 60 lung slices 50 mMammonium formate.5 mM sodium tetraborate. Samples were eluted with 200 mM ammonium formate, 5 mM Male Sprague-Dawley rats were sacrificed and their lungs sodium tetraborate. The radioactivity of each eluted sample were collected, dissected of fat and connective tissue and was measured in a beta counter. Radioactivity was normal minced. Minced tissue was added to oxygenated (95% O. ized by dividing radioactivity in post column sample by 5% CO) 127 mM NaCl, 25 mM NaHCO. 10 mM glucose. 55 radioactivity in precolumn sample. Control values (100% 2.5 mM KCl. 1.2 mM KHPO, 1.2 mM MgSO, 1.8 mM stimulated) are values in the presence of endothelin minus CaCl2. To the tissue mince, 1.2 M myo-H-inositol was the values in the absence of endothelin (basal). Test sample added. The mince was incubated 60 min at 37° C., with values are the values in the presence of endothelin and test constant oxygenation. After incubation, loaded tissue mince sample minus basal. Inhibitory concentration (ICs) is the was washed five times with the same oxygenated buffer to concentration of test compound required to give a sample remove excess radiolabelled inositol. Tissue mince was resuspended in the above buffer, containing 10 mM LiCl, activity of 50% of control value. aliquotted into tubes, and 3 nM sarafotoxin S6c with and Using the methodology described above, representative without test compounds was added to start the assay. Assays compounds of the invention were evaluated and found to were done in quadruplicate. Samples were incubated at 37 65 exhibit ICso values of at least<50M thereby demonstrating C. under blowing O in a hooded water bath for 30 minutes. and confirming the utility of the compounds of the invention Reaction was stopped by addition of 0.5 mL 18% trichlo as effective endothelin antagonists. 5,767,310 41 42 Intravenous Effect of Endothelin-1 Antagonist, N (4-iso-propylbenzene-sulfonyl)-O-(4-carboxy-2-n- The drugs utilized in the experiment described above propylphenoxy)-3.4-methylenedioxyphenyl Were: acetamide dipotassium salt Example 58 on 1) Phenylephrine. HCl (PE) (Sigma Chemical, Co.) was Endothelin 1-Induced Changes in Diastolic and 5 given at a volume of 0.05 mL/kg: Urethral Pressures in the Anesthetized Male Dog 2) Endothelin-1 (ET-1) (Human, Porcine. Canine, Rat. Methodology for determining whether an ET-1 Mouse. Bovine) (Peninsula Laboratories, Inc.) was given selective antagonist could inhibit the ET-1 mediated at a volume of 0.05 mL/kg; prostatic urethral contractions in a mongrel dog 3) ET-1 selective antagonist, such as the compound of model 10 Example 58.N-(4-iso-propylbenzene-sulfonyl)-O-(4- On separate days, two fasted male mongrel dogs (HRP, car box y - 2 - n - propyl phen ox y ) - 3 - 4 - Inc.) weighing 11.0 and 12.4 kg, were anesthetized with methylenedioxyphenylacetamide dipotassium salt, was Sodium Pentobarbital (Steris Laboratories. Inc.) at 35 mg/kg given at a volume of 0.3 mL/kg. (i.v.) to effect, followed by 4 mg/kg/hr (i.v.) infusion. A 15 All drugs were dissolved in isotonic saline solution. cuffed endotracheal tube was inserted and each animal was ventilated with room air using a positive displacement large animal ventilator (Harvard Apparatus) at a rate of 18 Results breaths/minute and an average tidal volume of 18 ml/kg body weight. Body temperature was maintained with a ET-1 elicited an initial depressor effect followed by a heating pad and heat lamp using a temperature controller longer pressor effect. In one dog, the pressor effect was (YSI) and esophageal probe. Two catheters (PE 260) were biphasic. The decrease in DBP in both dogs averaged 13 placed in the aorta via the femoral arteries (one in each mmHg, while the peak pressor effect averaged 26 mmHg. artery) for administration of endothelin or phenylephrine The average ET-1 induced increase in IUP was 15 mmHg. and for continuous direct monitoring of blood pressure and 25 heart rate using a Statham blood pressure transducer Ten to 14 minutes after administration of N-(4-iso (Spectramed) and a computer system (Modular instruments, propylbenzene-sulfonyl)-O-(4-carboxy-2-n-propylphenoxy) Inc.). Two other catheters (PE 260) were placed in the vena -3.4-methylenedioxyphenyl-acetamide dipotassium salt cava via the femoral veins (one catheter in each vein) for Example 58), the dogs were challenged with ET-1 again and administration of pentobarbital and N-(4-iso 30 the depressor and pressor effects on DBP were inhibited propylbenzene-sulfonyl)-O-(4-carboxy-2-n-propylphenoxy) 69% and 76%. respectively. The pressor effect on IUP was -3.4-methylenedioxyphenyl-acetamide dipotassium salt inhibited 93% (Table 1). Intra-arterial PE-induced increases Example 58). A supra-pubic incision approximately one in DBP and IUP did not change significantly after admin half inch lateral to the penis was made to expose the ureters, istration of N-(4-iso-propylbenzene-sulfonyl)-O-(4- urinary bladder, prostate, and urethra. The dome of the 35 carboxy-2-n-propylphenoxy)-3.4-methylenedioxyphenyl bladder was retracted to facilitate dissection of the ureters. acetamide dipotassium salt Example 58 in the one dog The ureters were cannulated with PE 90 and tied off to the studied. Increases in DBP and IUP were inhibited 35 and bladder. Umbilical tape was passed beneath the urethra at the 13%. respectively (Table 2). bladder neck and another piece of tape was placed approxi mately 1-2 cm. distal to the prostate. The bladder dome was 40 incised and a Micro-tip6) catheter transducer (Millar TABLE 1. Instruments, Inc.) was advanced into the urethra. The neck Effects of ET-1Antagonist, N-(4-iso-propylbenzene of the bladder was ligated with the umbilical tape to hold the sulfonyl)-c-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenyl transducer. The bladder incision was sutured with 3-0 silk acetamide dipotassium salt Example 58, on ET-1 induced Changes in (purse string suture). The transducer was withdrawn until it 45 DBP and IUP in Anesthetized Male Dogs (n = 2) was positioned in the prostatic urethra. The position of the CHANGE Micro-tip6) catheter was verified by gently squeezing the CHANGE IN DBP NUP prostate and noting the large change in urethral pressure (minHg) (mmHg) prior to ligating the distal urethra. DOG DEPRESSOR PRESSOR PRESSOR Experimental Protocol 50 ET-1 (i.a.) Phenylephrine (PE) (10 pg/kg, intra-arterial) was admin HGFMJC -IO 19 18 istered and pressor effects on diastolic blood pressure (DBP) HGFMHK -15 33 11 and intra-urethral pressure (IUP) were noted. When blood MEAN -13 26 15 pressure returned to baseline, endothelin-1 (ET-1) (1 nmole? 55 SEM 3 7 4 kg. intra-arterial) was administered. Changes in DBP and ET-1 + Example 58 IUP were monitored for one hour and an ET-1 selective HGFMJC -3 8 endothelin antagonist, such as the compound of Example 58, HGFMHK -5 2 1 N-(4-iso-propylbenzene-sulfonyl)-O-(4-carboxy-2-n- MEAN -4 5 1. propylphenoxy)-3.4-methylenedioxyphenyl-acetamide SEM 1. 3 O dipotassium salt (30 mg/g, intra-venous) was administered. % INHIBITION Ten to fifteen minutes later when blood pressure had HGFMJC 70 58 94 stabilized, ET-1 was administered again, and inhibition of HGFMHK 67 94 9. ET-1 induced effects were noted. PE was administered at the MEAN 69 76 93 end of the experiment to verify specificity for ET-1 block 65 SEM 2 18 2 ade. The dogs were euthanized with an overdose of pento barbital followed by saturated KCl. 5,767,310 43 44 propylbenzene-sulfonyl)-O-(4-carboxy-2-n-propylphenoxy) TABLE 2 -3.4-methylenedioxyphenylacetamide dipotassium salt was demonstrated to cause a specific inhibition of ET-1 to Effects of ET-1Antagonist, N-(4-iso-propylbenzene sulfonyl)-o-(4-carboxy-2-n-propylphenoxy)-3,4- contract the prostate and will be useful in the treatment of methylenedioxyphenylacetamide dipotassium salt Example urinary obstruction in benign prostatic hyperplasia. 58, on PE-Induced Changes in DBP and IUP in Accordingly the novel compounds of the present inven Anesthetized Male Dog # HGFMJC tion are useful in human therapy for treating asthma, hypertension, renal failure particularly post-ischemic renal INCREASE IN DBP INCREASE IN UP failure, cyclosporin nephrotoxicity, vasospasm, cerebral and TREATMENT (mmHg) (minHg) cardiac ischemia, myocardial infarction, or endotoxin shock Phenylephrine 17 31 caused by or associated with endothelin, by administration Phenylephrine 11 27 to a patient in need of such treatment of a therapeutically -- effective amount thereof. Example 58 In the management of hypertension and the clinical con %. Inhibition of Control 35 13 ditions noted above, the compounds of this invention may be 15 utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal Conclusions administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The ET-1 causes constriction of the prostatic urethra, as well compounds of this invention can be administered to patients as a complex hemodynamic response comprised of an initial (animals and human) in need of such treatment in dosages depressor and subsequent pressor response in anesthetized that will provide optimal pharmaceutical efficacy. Although dogs. The hemodynamic and prostatic urethral responses to the dose will vary from patient to patient depending upon the ET-1 were specifically inhibited by N-(4-iso nature and severity of disease, the patient's weight, special propylbenzenesulfonyl)-O-(4-carboxy-2-n-propylphenoxy)- diets then being followed by a patient, concurrent 3.4-methylenedioxyphenylacetamide dipotassium salt. The 25 medication, and other factors which those skilled in the art efficacy of the N-(4-iso-propylbenzenesulfonyl)-O-(4- will recognize. the dosage range will generally be about 0.5 carb oxy - 2 - n - p r opy l - phen oxy) - 3, 4 - mg to 1.0 g. per patient per day which can be administered methylenedioxyphenylacetamide dipotassium salt in inhib in single or multiple doses. Preferably, the dosage range will iting the prostatic urethral pressor effect of ET-1 suggests be about 0.5 mg to 500 mg. per patient per day; more that selective antagonists of ET-1 will be useful in the 30 preferably about 0.5 mg to 200 mg. per patient per day. treatment of urinary obstruction in benign prostatic hyper The compounds of this invention can also be administered plasia. in combination with A-adrenosine receptor agonists. O-adrenergic antagonists, angiotensin II antagonists, angio In Situ Rat Prostate tensin converting enzyme inhibitors, B-adrenergic Male Sprague-Dawley rats (Taconic Farms) weighing 35 antagonists. atriopeptidase inhibitors (alone or with ANP), 300-400 grams were anesthetized with urethane (1.75 g/kg. calcium channel blockers, diuretics, potassium channel ip), a tracheal cannula was inserted, and the femoral artery agonists, renin inhibitors. Sertonin antagonists, sym was cannulated. Core body temperature was maintained at patholytic agents, as well as other antihypertensive agents. 37+0.5° C. A 4-5 cm midline abdominal incision was made For example. the compounds of this invention can be given to expose the bladder and prostate. The prostate was sepa 40 in combination with such compounds as A-69729, FK906, rated from the bladder and surrounding capsule by blunt FK 744, UK-73900, CSG 22492C, amiloride, atenolol, dissection with a forcep. A length of surgical silk was gently atriopeptin. bendroflumethiazide, chlorothalidone, secured around the anterior tips of the prostate lobes. A chlorothiazide, clonidine, cromakalin, cryptenamine second length of surgical silk attached to an atraumatic acetates and cryptenamine tannates, deserpidine, diazoxide, needle was passed through and tied to the base of the 45 doxazosin, guanabenz, guanethidine, guanethidine sulfate, prostate approximately 10-12 mm posterior to the first tie. hydralazine hydrochloride, hydrochlorothiazide. isradipine, The posterior ligature was secured to an anchor post whereas ketanserin, losartan, metolazone, metoprolol, metoprolol the anterior ligature was connected to a Grass FTO3 trans tartate, methyclothiazide, methyldopa, methyldopate ducer (Grass Instruments. Quincy, Mass.) and maintained at hydrochloride, minoxidil. nadolol, pargyline hydrochloride, a tension of 1 g. Signals from the transducer were amplified 50 pinacidil, pindolol, polythiazide, prazosin, propranolol, rau and recorded on a polygraph (Hewlett-Packard 8805B wolfia serpentina, rescinnamine, reserpine. sodium amplifiers and 7758A recorder. Palo Alto, Calif.). After nitroprusside, spironolactone, terazosin, timolol maleate, equilibrating for approximately 15 min, the rats were admin trichlormethiazide, trimethophan camsylate, verapamil. istered pretreatment drugs (atropine 1 mg/kg. (+) propra benzthiazide, quinethazone, ticry nafan, triamterene, nolol 1 mg/kg) 10 min apart through the intra-arterial (IA) 55 acetazolarinide, aminophylline, cyclothiazide, ethacrynic cannula. Thirty minutes later, ET-1 (0.3 nmoles/kg) was acid, furosemide, merethoxyline procaine, sodium injected intra-arterial every thirty minutes for a total of three ethacrynate, captopril, delapril hydrochloride, enalapril, times. Five minutes before the third injection of ET-1. enalaprilat, fosinopril sodium, lisinopril, pentopril, vehicle with or without an endothelin antagonist was quinapril, quinapril hydrochloride, ramapril, teprotide, injected IA. The response of the prostate to ET-1 was zofenopril, zofenopril calcium, diffusinal, diltiazem, quantified by measuring the change (A) from baseline felodipine, nicardipine, nifedipine, niludipine, nimodipine. tension to the peak of the response during the 5-minute nisoldipine, nitrendipine, and the like, as well as admixtures period after the third ET-1 injection. and combinations thereof. Combinations useful in the man The in situ rat postate protocol has been utilized to agement of congestive heart failure include, in addition, determine the antagonist activity and potency of compounds 65 compounds of this invention with cardiac stimulants such as of this invention to block the direct contractile effects of dobutamine and Xamoterol and phosphodiesterase inhibitors ET-1 on the rat prostate in vivo. In this protocol, N-(4-iso including amrinone and milrinone. 5,767,310 45 46 Typically, the individual daily dosages for these combi The following examples illustrate the preparation of the nations can range from about one-fifth of the minimum compounds of Formula I and their incorporation into phar recommended clinical dosages to the maximum recom maceutical compositions and as such are not to be consid mended levels for those entities given singly. To illustrate ered as limiting the invention set forth in the claims these combinations, one of the endothelin antagonists of this appended hereto. invention effective clinically at a given daily dose range can be effectively combined, at levels which are less than that EXAMPLE 1. daily dose range, with the following compounds at the 2-(2,6-Dipropyl-4-hydroxymethyl) indicated per day dose range: hydrochlorothiazide (6-100 phenoxyphenylacetic acids mg), chlorothiazide (125-500 mg), furosemide (5-80 mg). Step A: Preparation of Alkyl 2-bromo-2-phenylacetates ethacrynic acid (5-200 mg), amiloride (5-20 mg), diltiazem 10 Method. A (30-540 mg), felodipine (1-20 mg), nifedipine (5-120 mg). Substituted phenylacetic acid is convered to the corre nitrendipine (5-60 mg), timolol maleate (1-20 mg), pro sponding methyl ester by refluxing the acid in methanol in panolol (10-480 mg), and methyldopa (125-2000 mg). In the presence of a catalytic amount of conc. sulfuric acid. The addition triple drug combinations of hydrochlorothiazide ester thus obtained is then refluxed in carbon tetrachloride (6-100 mg) plus amiloride (5-20 mg) plus endothelin 5 with N-bromosuccinimide (1.1 equiv) and AIBN (0.05-0.1 antagonists of this invention, or hydrochlorothiazide (6-100 equiv). Upon completion of the reaction, the resulting prod mg) plus timolol maleate (1-20mg) plus endothelin antago uct is purified by flash column chromatography using silica nists of this invention, or hydrochlorothiazide (6-100 mg) gel and ethyl acetate in hexane as eluent to provide the plus nifedipine (5-60mg) plus endothelin antagonists of this desired alkyl bromide. invention are effective combinations to control blood pres 2 Method B sure in hypertensive patients. Naturally, these dose ranges An arylaldehyde is reacted overnight with trimethylsilyl can be adjusted on a unit basis as necessary to permit divided cyanide in the presence of catalytic amounts of KCN and daily dosage and the dose will vary depending on the nature 18-crown-6 in methylene chloride. The reaction mixture is and severity of the disease, weight of the patient, special quenched with water and extracted with CHCl/ethyl diets and other factors. 25 acetate/ether (1/2/2) mixture. The organic phase is washed The present invention also relates to pharmaceutical com with saturated aq. NaHCO solution. After drying and positions for treating asthma, hypertension, renal failure, concentration of the organic phase, the resulting trimethyl particularly post-ischemic renal failure, cyclosporin silyl cyanohydrin is hydrolyzed to give the corresponding nephrotoxicity, vasospasm, cerebral and cardiac ischemia, hydroxy acid. Treatment with gaseous HCl in methanol or benign prostatic hyperplasia, myocardial infarction, or ethanol at 0° C. for 0.5 h and then overnight at room endotoxin shock caused by or associated with endothelin. temperature affords the crude 2-hydroxy ester. The ester is comprising a therapeutically effective amount of the novel then treated with triphenylphosphine and carbon tetrabro compound of this invention together with a pharmaceuti mide in methylene chloride at 0° C. overnight, Methylene cally acceptable carrier therefor. chloride is removed and flash column chromatography of the crude product using silica gel and ethyl acetate?hexane as About 0.5 mg to 1.0 g of compound or mixture of 35 eluent gives the desired 2-bromophenylacetates. compounds of Formula I or a physiologically acceptable salt Step B: Alkylation of the phenol is compounded with a physiologically acceptable vehicle. (2,6-Dipropyl-4-hydroxymethyl)phenol (prepared as carrier, excipient, binder, preservative, stabilizer, flavor, etc. described in patent application WO 91/11999) is alkylated in a unit dosage form as called for by accepted pharmaceu with 2-bromo-2-aryl esters in DMF using either cesium tical practice. The amount of active substance in these carbonate (CsCO), or potassium carbonate (KCO). or compositions or preparations is such that a suitable dosage sodium hydride (NaH). The alkylated product is purified by in the range indicated is obtained. flash column chromatography using silica gel and ethyl Illustrative of the adjuvants which can be incorporated in acetate?hexane mixture as eluent to provide the desired tablets, capsules and the like are the following: a binder such substituted 2-phenoxy-2-phenylacetic acid esters. as gum tragacanth, acacia, corn starch or gelatin; an excipi 45 Step C: General procedure for ester hydrolysis ent such as microcrystalline cellulose; a disintegrating agent The product of Step C is dissolved in methanol or ethanol such as corn starch, pregelatinized starch, alginic acid and and reacted with aqueous NaOH or LiOH, or KOH solution the like; a lubricant such as magnesium stearate; a sweet at room temperature for 1-6 hours. neutralized to pH 7 with ening agent such as sucrose. lactose or saccharin; a flavoring 1N HCl and then concentrated in vacuo. The residue is agent such as peppermint, oil of wintergreen or cherry. 50 purified on a silica gel flash chromatography column to When the dosage uniform is a capsule, it may contain, in afford the corresponding carboxylic acid. addition to materials of the above type. a liquid carrier such The following phenoxyphenylacetic acid derivatives were as fatty oil. Various other materials may be present as prepared using the general procedures outlined in Example coatings or to otherwise modify the physical form of the 1. dosage unit. For instance, tablets may be coated with shellac, 55 EXAMPLE 2 sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and 2-(2,6-Dipropyl-4-hydroxymethyl)phenoxy-2-(3- propyl parabens as preservatives, a dye and a flavoring such methylphenyl)acetic acid as cherry or orange flavor. "H NMR (400 MHz, CDOH, ppm): 87.15-6.95 (m, 4H). Sterile compositions for injection can be formulated 6.86 (s. 2H). 4.92 (br s. 1H), 4.5 (s. 2H), 2.3–2. 1 (m, 4H). according to conventional pharmaceutical practice by dis 2.2 (s.3H), 1.5-1.35 (m. 2H), 1.32-1.18 (m. 2H). 0.7 (t. 6H). solving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like EXAMPLE 3 sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a 2-(2,6-Dipropyl-4-hydroxymethyl)phenoxyl-2-(4- synthetic fatty vehicle like ethyl oleate or the like. Buffers, 65 phenoxyphenyl)-acetic acid preservatives, antioxidants and the like can be incorporated "H NMR (400 MHz, CDOH, ppm): 87.42 (d. 2H. J=8.4 as required. Hz). 7.33 (dd, 2H. J-7.4 Hz, 8.5), 7.09 (t, 1H, J=7.4 Hz).

5,767,310 49 50 STEP C: t-Butyldimethylsilyloxy-2,6-dipropyl-4-(2- hydroxyethyl)-benzene 4.99 (s.1H), 3.79 (s.3H), 3.68 (t, 2H.J=7.1 Hz). 2.70 (t, 2H, To a solution of 475 mg (1.48 mmol) of the product of J=7.1 Hz), 2.34 (t, 4H, J=8.0 Hz). 1.54-1.40 (m, 4H), 0.80 Step B in 3 mL of THF at 0° C. was added 1.6 mL (1.62 (t. 3H, J=7.3 Hz). mmol) of a 1N borane/THF solution. After 1 hour TLC FAB-MS me=387 (M+1) indicated that the starting material had been consumed. The reaction mixture was quenched with 3 drops of methanol EXAMPLE 17 and then 0.70 mL (6.22 mmol) of 30% sodium peroxide and 6.2 mL (6.2 mmol) of 1N sodium hydroxide were added. 2-(2,6-Dipropyl-4(1,2-dihydroxyethyl)phenoxy)-2- After two hours the reaction mixture was diluted with ethyl (2-naphthyl)acetic acid acetate and washed with water and brine. The organic layer O STEPA; 2,6-dipropyl-4-vinylphenol was then dried over sodium sulfate, filtered and concen The title compound was prepared from t-butyldimethyl trated. Flash chromatography (silica gel, hexane/ethyl silyloxy-2,6-dipropyl-4-vinylbenzene (Step B. Example 14) acetate 4:1) gave 265 mg of the title compound as a clear oil. by treatment with tetrabutylammonium fluoride in THF for "H NMR (400 MHz. CDC1, ppm): 86.79 (s. 2H), 3.79 a few hours. It was poured into ether?ethyl acetate mixture (m. 2H), 2.75–2.72 (m. 2H), 2.51-2.48 (m, 4H), 1.58-1.51 and washed with brine. After removal of the solvent the (m, 6H). 0.99 (s.9 H), 0.90 (t. J=7.33, 6H), 0.16 (s, 6H). 15 STEP D: 2,6-Dipropyl-4-(2-hydroxyethyl)phenol crude product was purified by flash column chromatography To a solution of 1.0 g (2.98 mmol) of the product of Step using ethyl acetate/hexane as eluent. Cin 3.0 mL of THF was added 3.57 mL (3.57 mmol) of 1.0N "H NMR (400 MHz. CDC. ppm): 87.01 (s. 2H), 6.55 solution of tetrabutylammonium fluoride in THF. After 15 (dd, J-17.6. J=11.0 Hz, 1H), 5.55 (d. J=17.6 Hz, 1H), 5.06 minutes TLC indicated that the reaction was complete. The (d, J-11.0 Hz, 1H). 2.64 (t. J=7.7 Hz, 4H), 1.65-1.60 (m. reaction mixture was concentrated and then purified by flash 4H). 0.96 (t. J=7.2 Hz 6H). chromatography (silica gel, hexane/ethyl acetate 3:1) to give STEP B: Methyl 2-(2,6-dipropyl-4-vinyl)phenoxy-2-(2- 1.13 g of the title compound. naphthyl)-acetate "H NMR (400 MHz, CDC1, ppm): 86.8 (s.2H), 3.78 (t. The title compound was prepared by alkylation of 2.6- J=6.5 Hz, 2H), 2.73 (t. J=6.5 Hz, 2H), 2.54-2.50 (m, 4H), dipropyl-4-vinyl phenol (Step A) with methyl 2-bromo-2- 1.66-1.56 (m, 4H), 0.96 (t. J=7.3 Hz, 6H). 25 (2-naphthyl)acetate using the procedure for alkylation STEP E: Methyl 2-(2,6-dipropyl-4-(2-hydroxyethyl) phenoxy-2-(2-naphthyl)acetate described in Step B of Example 1. The title compound was prepared from 2.6-dipropyl-4- "H NMR (400 MHz. CDC1, ppm): 87.9–7.8 (m, 4H). (2-hydroxyethyl)phenol (Step D) by alkylating with methyl 7.68 (d. J=6.7 Hz, 1H), 7.50-7.48 (m. 2H), 7.02 (s. 2H), 6.57 2-bromo-2-(2-naphthyl)acetate using cesium carbonate or (dd J=18.4, 10.8 Hz. 1H), 5.61 (d. J= 18.4, 1H). 5.26 (s. 1H). potassium carbonate in DMF. The reaction mixture was 5.14 (d. J=10.8, 1H). 3.73 (s. 1H). 2.38-2.34 (m, 4H). filtered through Celite and the filter cake was washed with 1.54-1.43 (m, 4H), 0.74 (t, J=7.33 Hz. 6H). methylene chloride. The filtrate was concentrated and the STEP C: Methyl 2-(2,6-dipropyl-4-(1,2-dihydroxyethyl) resultant material was purified by flash column chromatog phenoxyl-2-(2-naphthyl)acetate raphy to yield the titled ester. 35 To a solution of 6 mg (0.024 mmol) of OsO and 31 mg "H NMR (400 MHz. CDC. ppm): 87.90–7.82 (m, 4H). (0.263 mmol) of N-methylmorpholine-N-oxide (NMO) in 3 7.69-7.67 (m. 1H), 7.49–7.47 (m. 2H), 6.8 (s. 2H), 2.74 (t, mL of acetone and 2 drops of water was added 96 mg (0.239 J-6.2 Hz. 2H), 2.36-2.32 (m, 4H), 1.49-141 (m, 4H), 0.72 mmol) of the product of Step B. After 90 minutes the (t. J=7.3, 6H). reaction mixture was poured into a mixture of ether and STEP F: 2-(2,6-Dipropyl-4-(2-hydroxyethyl)phenoxy-2- water. The layers were separated and the aqueous layer was (2-naphthyl)acetic acid extracted twice with ether. The combined aqueous layers The title compound was prepared from the product of were washed with saturated sodium chloride, dried over Step E by saponification with IN aqueous KOH in methanol anhydrous magnesium sulfate, filtered and concentrated. as outlined in Step C of Example 1. Purification by flash chromatography (silica gel, hexane/ "H NMR (400 MHz. CDOH, ppm) 87.84-7.7 (m, 4H), ethyl acetate 1:1) gave 63 mg of the title compound. 7.73 (d.J-6.8 Hz, 1H), 7.45-743 (m. 2H), 6.79 (s. 2H), 5.01 45 (s. 2H), 3.66 (t, J-7.2 Hz, 2H). 2.68 (t. J-7.2 Hz, 2H), "H NMR (400 MHz, CDC1, ppm): 87.89-7.80 (m, 4H), 2.33-2.29 (m, 4H), 1.55-1.45 (m. 2H). 1.40-1.28 (M. 2H), 7.67 (d. J=8.4 Hz, 1H), 7.50-7.48 (m. 2H), 6.9 (s. 2H). 5.25 0.69 (t, J-7.3, 6H). (s, 1H), 4.75-4.68 (m. 1H), 3.72 (s.3H), 3.75-3.61 (m. 2H), FAB-MS: me=445 (M+K), 429 (M+Na), 407 (M+1). 2.38-2.34 (m, 4H), 1.53-1.46 (m, 4H), 0.75-0.71 (m, 6H). The following phenoxyphenylacetic acid derivatives were 50 STEP D: 2-(2,6-Dipropyl-4-(1,2-dihydroxyethyl)phenoxy prepared using the general procedures outlined in Example -2-(2-naphthyl)acetic acid 14. The title compound was prepared from the product of Step C by saponification with IN aqueous KOH solution as EXAMPLE 1.5 described above. 2-(2,6-Dipropyl-4-(2-hydroxyethyl)phenoxy-2-(3. 55 "H NMR (400 MHz, CD,OH, ppm): 87.84-7.71 (m, 5H). 4-methylenedioxy-phenyl)acetic acid 7.46–7.42 (m. 2H), 6.96 (s. 2H). 5.03 (s. 1H). 4.55 (t, J=7.2 "H NMR (200 MHz, CD,OH, ppm): 87.03 (s, 1H), 6.83 Hz, 1H), 3.54 (d. J-7.2 Hz, 2H), 2.34 (t, J-7.9 Hz, 4H). (m, 3H), 6.72 (d. 1H, J=7.8 Hz), 5.93 (s. 2H), 4.80 (s. 1H). 1.51-1.30 (m, 4H), 0.70 (t. J=7.3 Hz, 6H). 3.68 (t, 2H, J=7.1 Hz). 2.69 (t, 2H. J=7.1 Hz), 2.35 (t, 4H, J=7.9 Hz), 1.42 (m, 4H), 0.83 (t. 6H. J-7.3 Hz). EXAMPLE 18 FAB-MS m/e=401 (M-1) 2-(2,6-Dipropyl-4-(1-hydroxypentyl)phenoxy)-2-(2- naphthyl)acetic acid EXAMPLE 16 STEPA: Methyl 2-(2,6-dipropyl-4-formyl)phenoxy-2-(2- 2-(2,6-Dipropyl-4-(2-hydroxyethyl)phenoxy-2-(3- naphthyl)acetate methoxyphenyl)-acetic acid 65 To a solution of 262 mg (0.645 mmol) of methyl 2-(2. H NMR (400 MHz. CDOH, ppm): 87.28 (t, 1H, J=7.9 6-dipropyl-4-hydroxymethyl)phenoxy-2-(2-naphthyl) Hz), 7.07 (m. 1H), 7.15 (m. 1H), 6.94 (m. 1H), 6.84 (s. 2H), acetate in 2 mL of methylene chloride was added 404 mg 5,767,310 51 52 (0.968 mmol) of PDC. After 4 hours the reaction mixture with 3 mL of trifluoroacetic acid (TFA) in methylene chlo was diluted with 20 mL of ether and filtered through a pad ride for 2 h. The volatiles were removed to give the titled of florisill/celite and concentrated to give 235 mg of the title compound (90 mg). compound. "H NMR (400 MHz, CDOH. ppm): 87.67 (s, 2H), "H NMR (400 MHz, CDC1. ppm): 89.86 (s. H). 7.463-744 (m. 2H), 7.387-7.362 (m. 3H), 5.177 (s. 1H). 7.89-7.80 (m, 4H), 7.65 (m. 1H), 7.52-7.49 (m, 4H), 5.35 (s. 3.856 (s.3H), 2.377 (t, 4H), 1.6-1.366 (m, 4H). 0.773 (t, 1H), 3.73 (s.3H), 2.47-2.43 (m, 4H), 1.54-1.43 (m, 4H). 6H). 0.77 (t. J=7.3 Hz, 6H). STEP D: 2-(4-Carboxy-2,6-dipropyl)phenoxyl-2- STEP B: Methyl 2-(2,6-dipropyl-4-(1-hydroxypentyl) phenylacetic acid phenoxy-2-(2-naphthyl)acetate O The product of Step C (70 mg 0.19 mmol) was treated To a solution of 56 mg (0.143 mmol) of the product of with 1N aqueous solution of LiOH in methanol. The reaction Step A in 1 mL of THF at -78° C. was added 0.075 mL was monitored by TLC. When the starting material was (2.0M in THF, 0.150 mmol) of n-butyl magnesium chloride. completely consumed, the mixture was acidified at 0°C. to TLC analysis showed that the starting material remained pH 5 by addition of 1N HCl. The aqueous phase was unconsumed so 0.020 mL of n-butyl magnesium chloride 15 extracted with ethyl acetate, dried over anhydrous magne was added. After 1 h the reaction mixture was diluted with sium sulfate and filtered. The filtrate was concentrated to saturated aqueous ammonium chloride solution and then yield the titled compound (25 mg). extracted twice with ethyl acetate. The organic layers were "H NMR (400 MHz. CDOH, ppm): 57.68 (s. 2H), dried over anhydrous sodium sulfate. filtered and concen 7.52-7.45 (m. 2H), 7.43-7.365 (m, 3H). 5.175 (s, 1H), 2.43 trated. Purification by flash column chromatography (silica (t, 4H), 1.64-1.4 (m, 4H). 0.83 (t. 6H). gel, hexane/ethyl acetate 6:1) gave 32 mg of the title compound. EXAMPLE 20 "H NMR (400 MHz. CDC1, ppm): 87.89-7.82 (m, 4H). 7.67 (m. 1H), 7.49-7.47 (m. 2H), 6.9 (s. 2H), 5.26 (s, 1H). 2-(4-Carboxy-2,6-dipropyl)phenoxy-2-(3.4- 2.36 (t, J=8.0 Hz, 4H), 1.75-1.2 (m, 8H), 0.86 (t. J=7.2 Hz, 25 dichlorophenyl)acetic acid 3H), 0.72 (t, J=7.3 Hz. 6H). The titled compound was prepared using procedures STEP C: 2-(2,6-Dipropyl-4-(1-hydroxypentyl)phenoxy)- similar to that described in Example 19. 2-naphthylacetic acid "H NMR (200 MHz. CDOH. ppm): 87.72 (d. 1H. J=2.0 The title compound was prepared from the product of Hz) 7.69 (s. 2H), 7.56 (d. 1H, J=8.3 Hz), 7.43 (dd. 1H, J=8.3, Step B by saponification with aqueous 1H KOH in methanol 30 as described above. 1.9 Hz), 5.18 (s, 1H), 2.45 (m, 4H). 1.58-1.43 (m, 4H). 0.84 "H NMR (400 MHz, CDOH, ppm): 87.84-7.72 (m.5H), (t, 6H. J-7.3 Hz). 7.45-7.43 (m, 2H), 6.91 (s. 2H), 5.03 (s.1H), 4.45 (t, 1H). FAB-MS m/e=426 (M+1) 2.36-2.32 (m, 4H), 1.75-1.45 (m, 4H), 1.35-1.29 (m. 4H). EXAMPLE 21 0.87 (t, J-7.2 Hz, 3H), 0.70 (t. J=7.2 Hz. 6H). 35 FAB-MS : m/e=487 (M--K), 469 (M-Na). 2-(4-Carboxy-2,6-dipropyl)phenoxy-2-(3- EXAMPLE 19 bromophenyl)acetic acid 2-(4-Carboxy-2,6-dipropyl)phenoxy-2- The titled compound was prepared using procedures phenylacetic acid 40 similar to that described in Example 19. STEP A: t-Butyl 2-(4-carbomethoxy-2,6-dipropyl) "H NMR (200 MHz. CDOH, ppm): 87.73 (d. 1H. J-1.8 phenoxy-2-phenylacetate Hz). 7.69 (s. 2H), 7.56 (dd. 1H, J=7.8, 1.9 Hz), 7.46 (d. 1H, Methyl 2,6-dipropyl-4-hydroxybenzoate (1.5 g. 6.383 J=7.9 Hz), 7.32 (t, 1H, J=7.8 Hz). 5.19 (s. 1H). 2.44 (t, 4H, mmol) was refluxed with KCO (1.5 equiv) and t-butyl J=7.6 Hz). 1.70-1.34 (m, 4H). 0.84 (t. 6H. J-7.3 Hz). o-bromophenylacetate (2.4 g., 8.856 mmol) in acetone for 16 45 h. The reaction mixture was filtered through Celite, the filter FAB-MS me=436 (M-1) cake was washed with acetone and the combined filtrate and EXAMPLE 22 washings were concentrated. The resulting crude oil was chromatographed (flash column) using silica gel and 10% 2-(4-Carboxy-2,6-dipropyl)phenoxy-2-34 ethyl acetate in hexane to give the titled compound (2.7 g). SO methylenedioxyphenyl acetic acid "H NMR (400 MHz. CDOH, ppm): 57.665 (s. 2H), 7.443 (dd. 2H), 7.345 (dd. 3H). 5.019 (s., 1H), 3.851 (s.3H). The titled compound was prepared using procedures 2.49–2.335 (m, 4H), 1.63-1.4 (m, 4H), 1.364 (s.9H). 0.803 similar to that described in Example 19. (t, 6H). "H NMR (200 MHz. CDOH. ppm): 87.68 (s. 2H), 7.02 STEP B: t-Butyl 2-(4-carboxy-2,6-dipropyl)phenoxy-2- 55 (d. 1H, J=1.6 Hz). 6.84 (m. 2H), 5.98 (s. 2H). 5.08 (s, 1H). phenyl acetate 2.44 (t, 4H. J-7.9 Hz). 1.52 (m, 4H), 0.86 (t. 6H, J=7.3 Hz). Saponification of the above t-butyl 2-(4-carbomethoxy 2,6-dipropyl)phenoxy-2-phenylacetate (200 mg, 0.47 FAB-MS me=401 (M+1) mmol) with 1N aqueous solution of LiOH in methanol gave EXAMPLE 23 the titled compound (125 mg). "H NMR (400 MHz. CDOH. ppm): 57.66 (s. 2H). 2-(4-Carboxy-2,6-dipropyl)phenoxy-2-(3- 7.5-7.4 (dd. 2H), 7.43-7.36 (dd. 3H) 4.88 (s. 1H), 2.5-2.35 methoxyphenyl)acetic acid (m. 4H), 1.63-1.33 (m, 4H). 1.38 (t, 9H), 0.83 (t. 6H). STEP C: 2-(4-Carbomethoxy-2,6-dipropyl)phenoxy-2- The titled compound was prepared using procedures phenylacetic acid 65 similar to that described in Example 19. t-Butyl 2-(4-carbomethoxy-2,6-dipropyl)phenoxyl-2- "H NMR (200 MHz. CDOH. ppm) 87.68 (s.2H), 7.29 (t. phenylacetate (Step A) (125 mg. 0.293 mmol) was treated 1H, J-7.9 Hz), 7.08 (d. H. J=2.3 Hz), 7.03 (d. 1H, J=7.7 5,767,310 53 S4 Hz), 6.95 (dd. 1H, J=09, 8.3 Hz), 5.14 (s, 1H).3.79 (s.3H). then with brine, dried over MgSO filtered and the solvent 2.43 (t, 4H.J-7.9 Hz), 1.58-1.42 (m, 4H), 0.82 (t, 6H, J=7.3 removed. Hz). The sulfonamide precursors used in the preparation of the FAB-MS me=387 (M+1) compounds of Examples 28, 29.31, 32.37.38, and 39 were prepared from the corresponding sulfonyl chlorides utilizing EXAMPLE 24 the procedure described above. The sulfonamide precursors (N-Benzenesulfonyl)-2-(4-(N-benzenesulfonyl) used in the preparation of the compounds of Examples 26 carboxamido-2,6-dipropylphenoxy-2-(3- and 33-36 are commercially available. bromophenyl)acetamide. The sulfonamide precursors used in Examples 27.30 and 32, whose sulfonyl chlorides are not commercially available, The titled compound was prepared using the procedure were prepared using standard chemistry: described for the synthesis of N-sulfonylcarboxamides in U.S. Pat. No. 5.177,095. The diacid 2-(4-carboxy-2,6- Preparation of precursor sulfonamide for Example 27 dipropyl)phenoxy-2-(3-bromophenyl)acetic acid (200 mg. S The t-butylsulfonamide of 4-bromobenzenesulfonyl chlo 0.46 mmol; from Example 21) was refluxed with carbonyl ride was prepared using the procedure described above. The diimidazole (1.5 equiv) in THF for 3–4 h. At room t-butylsulfonamide was then coupled to phenylboronic acid temperature, a mixture of 1.5 equiv of benzenesulfonamide in a palladium catalyzed cross-coupling reaction with and 1.5 equiv DBU in THF was added to the above reaction NaOH, EtOH, toluene, and Pd(PPh) at 100° C. to afford mixture, and the mixture was stirred overnight. The reaction 20 the biphenylsulfonamide. Deprotection of the mixture was diluted with ethyl acetate and washed with 5% t-butylsulfonamide with TFA and anisole yielded the free aq. solution of citric acid. The solvent was removed and the crude product was purified by flash column chromatography sulfonamide. to provide 238 mg of the titled compound. Preparation of precursor sulfonamide for Example 30 "HNMR (400 MHz. CDOH, ppm): 88.07 (dd, 2H.J=1.4. 25 The t-butylsulfonamide of 2-thiophenesulfonyl chloride 7.2 Hz), 7.91-7.88 (m. 2H), 7.67-749 (m.8H), 7.46 (s, 2H), was prepared using the procedure described above. Treat 7.28–7.25 (m. 2H), 5.01 (s. 1H), 2.28-2.23 (m, 4H). ment of the t-butylsulfonamide with BuLi then isobutyl 1.49-1.29 (m, 4H); 0.71 (t, 6H. J=7.4 Hz). iodide afforded the 5-isobutyl-2-thiophene-t- 30 butylsulfonamide which was then deprotected with TFA and FAB-MS me=713 (M+1). anisole to yield the free sulfonamide. EXAMPLE 25 Preparation of precursor sulfonamide for Example 32 The t-butylsulfonamide of p-nitrobenzenesulfonyl chlo N-(4-t-butylbenzenesulfonyl)-2-(4- ride was prepared using the procedure described above. methoxycarbonyl-2-propyl-phenoxy)-2-(3.4- 35 Reduction of the nitro group to the amine was accomplished methylenedioxyphenyl)acetamide with hydrogen in MeOH over Pd-C. Treatment of the free Step A: Preparation of 2-(4-carbomethoxy-2- amine with LiBr and (MeO)PO and then NaOH afforded propylphenoxy)-3.4-methylenedioxyphenylacetic acid the dimethylamine and the t-butylsulfonamide was depro To ethyl 2-(4-carbomethoxy-2-propylphenoxy)-34 tected with TFA and anisole to yield the free sulfonamide. methylenedioxyphenylacetate (Step A of Example 56) (2.04 40 Step C: Preparation of N-(4-t-butylbenzenesulfonyl)-2-(4- g, 5.10 mmol) in MeOH (40 mL) was added 5N NaOH (8 carbo methoxy-2-propyl phen oxy) - 3, 4 mL). The rapid reaction was followed immediately by TLC methylenedioxyphenyl-acetamide to monitor mono deesterification. The reaction was quenched with 9N HCl (4.5 mL) after loss of the ethyl ester To the product of Step A (57.2 mg. 0.154 mmol) in dry and before methyl ester saponification. A saturated solution 45 THF (0.75 mL) was added CDI (76.0 mg. 0.469 mmol) and of NaHCO was added to the reaction until it was basic and the reaction heated to 50° C. for 2.5 hr. To this solution was the MeOH was removed in vacuo. The residue was parti added a solution of p-t-butylphenyl-sulfonamide (131.7 mg. tioned between Et2O and water collecting the product in the 0.618 mmol) and DBU (92.1 L, 0.594 mmol) in dry THF aqueous phase and removing impurities with the organic (0.75 mL). The reaction continued to be stirred at 50° C. phase. The aqueous phase was then acidified with 9N HCl SO monitoring by thin layer chromatography until all of the (pH=1) and the product extracted into EtOAc. The solution mono-acid was consumed (approx. 3 hr). The reaction was was dried over MgSO filtered and the solvent removed. concentrated in vacuo and the residue was taken up in Yield=1.78 g (4.78 nmole, 94%) rf=0.16 (80:10:11 50:50/EtO:EtOAc. The organic phase was washed with CHCl:MeoH:NHOH). 10% citric acid (2x), water and brine then dried over Step B: Preparation of the precursor sulfonamide 55 MgSO filtered and the solvent removed. Purification was To a dichloromethane solution of the sulfonyl chloride (1 accomplished by radial chromatography eluting with 3:2/ eq) cooled to 0°C. was added t-butylamine (3 eq). After 3-5 Hex:EtOAc. Yield=74.3 mg (0.131 mmol. 85%) rf=0.32 hrs the CHCl was removed and replaced with EtOAc. The (80:10:1/CHCl:MeoH:NHOH) FAB mass spectrum, m/e reaction solution was washed with NHCl water, 1NNaOH 590.0 (M+Na calculated for CHNSO 590). See and brine. The resulting solution was dried over MgSO, and Drummond, J. T.; Johnson, G. Tetrahedron Lett. 1988, 29. filtered. The solvent was removed. To the resulting solid was 1653. added a couple of drops of anisole and then TFA to remove the t-butyl group. After all of the sulfonamide had been EXAMPLES 26-39 deprotected, the TFA was removed in vacuo and the residue 65 taken up in EtOAc/Et2O. The solution was washed with Examples 26 through 39 were prepared following the saturated NaHCO solution to remove any residual TFA. procedures described above in Example 25.

5,767,310 57 58 1H). 6.66 (d. 1H), 6.71 (d. 1H), 6.87 (dd. H). 7.34 (dd. 1H), for an additional 30 minutes at which point TLC analysis 7.58 (dd. 1H), 7.68 (m. 2H), 8.20 (dd. 1H), 8.39 (dd. 1H). (CH.Cl-MeOH-NHOH 90:10:1) indicated that the starting 8.47 (dd. 1H). 8.83 (dd, 1H). material had been consumed. The reaction mixture was adjusted to pH-4 with 6N HCl, and the bulk of the organic EXAMPLE 55 solvent was removed in vacuo. The precipitated organic product and the aqueous layer were next partitioned between N-(8-quinolinesulfonyl)-2-(4-carboxamido-2- CHCl (1 L) and water (1 L) which produced a copious propylphenoxy)-2-(3.4-methylenedioxyphenyl) emulsion. The reaction mixture was then aged overnight in acetamide a refrigerator which resulted in crystallization of the organic To N-(8-quinolinesulfonyl)-2-(4-carboxy-2-propyl 10 product. The crystalline solid was separated from the two phenoxy)-2-(3.4-methylenedioxyphenyl)acetamide, phase mixture by filtration and washed with CHCl2. The Example 54, (25.8 mg. 0.047 mmol) in dry DMF (0.5 mL) solid was slurried again in diethylether, filtered, washed with was added 1 - (3-dimethylamino-propyl)-3- hexane, and then dried in a vacuum to afford 65 g (94%) of ethylcarbodiimide hydrochloride, also referred to as EDC, the title compound as a white crystalline solid. (18.4 mg. 0.096 mmol), NHCl (6.7 mg, 0.125 mmol), and 15 'H-NMR (400 MHz. CDOH. ppm): 80.93 (t. J=7.20 Hz, TEA (17.5 mL. 0.125 mmol). Reaction was followed by thin 3H), 1.62-1.75 (m. 2H). 2.63-2.70 (m. 1H). 2.77-2.81 (m. layer chromatography (100:15:1.5/CHCl:MeoH:HOAc). 1H), 3.84 (s.3H), 5.54 (s, 1H). 5.94 (s. 2H), 6.81 (d. J=7.60 When the reaction was completed the DMF was removed in Hz, 1H), 6.89 (d. J-9.20 Hz, 1H), 7.08 (d. J=1.60 Hz, 1H). vacuo and the residue taken up in EtO/EtOAc. The solution 7.11 (brs, 1H), 7.78-7.81 (m. 2H). was washed with 10% citric acid, water and brine then dried 20 over MgSO filtered and the solvent removed. The product EXAMPLE 57 was purified by chromatography eluting with 200:5:1.5/ N-(4-iso-propylbenzenesulfonyl)-O-(4- CHC 1: Me OH: HOA c. rf=0.35 (100:5:1.5/ carbomethoxy-2-n-propyl-phenoxy)-34 CHCl:MeoH:HOAc) FAB mass spectrum. m/e 548.0 methylenedioxyphenylacetamide 25 Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-O- (M+1 calculated for CHNSO, 548). (4-carbomethoxy-2-n-propylphenoxy)-3.4-methylenedioxy EXAMPLE 56 phenylacetamide An oven dried three-necked 24/40 1 L round-bottom flask O-(4-carbomethoxy-2-n-propylphenoxy)-34 was equipped with a mechanical stirrer, a nitrogen inlet, and methylenedioxy-phenyl)acetic acid 30 a septum. The flask was flushed with nitrogen, then charged Step A: Preparation of ethyl O-(4-carbomethoxy-2-n-propyl with 20.06 g (53.9 mmol) of the product of Example 56.400 phenoxy)-3.4-methylenedioxylphenylacetate mL of anhydrous THF, and 9.76 mL (70.0 mmol) of triethy To a 2 L three necked 24/40 round bottom flask equipped lamine. The flask and its contents were stirred and cooled to with a mechanical stirrer, a nitrogen inlet and a dropping -78°C. with an external dry ice-acetone bath and then 7.30 funnel was first added a solution of 36.0 g (0.185 mol) of 35 mL (59.3 mmol) of trimethylacetyl chloride was added methyl 4-hydroxy-3-in-propylbenzoate dissolved in 700 mL slowly via a syringe. After the addition was complete, the of anhydrous DMF followed by 66.4 g (0.204 mol) of dry ice-acetone bath was replaced with an ice-water bath and cesium carbonate. The flask was purged with nitrogen and the reaction was stirred at 0°C. for 1 hour. A separate oven the reaction mixture was stirred at room temperature for 2 dried 3 necked 24/402 L round-bottom flask was equipped hours. A solution of 58.5 g (0.204 mol) of ethyl d-bromo with a mechanical stirrer, a septum and a nitrogen inlet. The 3.4-methylenedioxyphenylacetate dissolved in 100 mL of flask was flushed with nitrogen then charged with 16.102 g DMF was then added via an addition funnel over a 15 (80.8 mmol) of 4-iso-propylbenzenesulfonamide and 300 minute period. The reaction mixture was stirred an addi mL of anhydrous methyl sulfoxide. The stirrer was started tional 1 hour at room temperature then quenched by addition and a 162 mL of a 1.0M solution of lithium bis to 5 L of a 5% aqueous citric acid solution. The organic 45 (trimethylsilylamide) in THF was slowly (mildly product was extracted into diethylether (2x4 L), the organic exothermic) added via a syringe through the septum. After layers were separated, washed with saturated aqueous NaCl, the addition was complete, the reaction mixture was stirred dried (MgSO), filtered, and evaporated. The residue was at room temperature for an additional 30 minutes. The applied to a silica gel (2 kg; 70-230 mesh) column equili contents of the first reaction mixture including a fine white brated in 10% CHC1-hexane. The column was then eluted 50 precipitate that was suspended in the reaction mixture were successively with 12 L of 10% CH-Cl-hexane, 12 L of 5% then slowly transferred to the stirred solution of the depro EtOAc-hexane, 4 L of 7.5% EtOAc-hexane, 12 L of 10% tonated sulfonamide in the second flask via a wide diameter EtOAc-hexane, and finally 8 L of 20% EtOAc-hexane. cannula. The combined reaction mixture was then stirred for Combination of the purified fractions and evaporation in an additional 14 hours under a nitrogen atmosphere. The vacuo afforded 76.3 g (74.2 theoretical) of the title com 55 reaction was the quenched with 1.0N HCl and the majority pound as a pale yellow oil which was used without further of the volatile solvents were removed in vacuo. The residue purification in the next step. was partitioned between EtOAc and 1.0N HCl, then organic Step B: Preparation of ot-(4-carbomethoxy-2-n- layer was separated, washed with saturated aqueous NaCl, propylphenoxy)-34-methylenedioxyphenylacetic acid dried (MgSO), filtered and evaporated in vacuo. The resi A 1 L 3 necked 24/40 round bottom flask equipped with due was purified on a silica gel (3 kg; 70-230 mesh) a mechanical stirrer, a dropping funnel. and a nitrogen inlet chromatography column (15 cmx150 cm) eluted with was charged with a solution of 76.3 g 0.185 mol) of the (90:10:1 CHCl-MeOH-NHOH). Combination of the semi-purified product of Step A dissolved in 500 mL of purified fractions and evaporation in vacuo afforded 18.367 methanol. The flask was purged with nitrogen, the stirrer g (62%) of the title compound. was started, and 37 mL of a 5.0Naqueous solution of sodium 65 "H-NMR (400 MHz. CDOH. ppm): 80.88 (t. J=7.60 Hz, hydroxide was added over a 30 minute period via an addition 3H), 1.24 (d. J=7.00 Hz, 3H), 1.25 (t. J=7.00 Hz, 3H). funnel. The reaction mixture was stirred at room temperature 1.55-1.60 (m. 2H), 2.59-2.66 (m. 2H), 2.97 (sept, J=7.00 5,767,310 59 60 Hz, 1H), 3.83 (s.3H), 5.52 (s. 1H), 5.97 (s. 2H), 6.50 (d. fied on a silica gel flash chromatography column eluted with J=8.80 Hz, 1H), 6.80 (d. J=8.00 Hz, 1H), 6.89 (d. J=1.60 Hz. 10% EtOAc-hexane; combination of the purified fractions 1H), 6.94 (dd, J-2.00, 8.00 Hz, 1H).7.14 (d.J-8.80 Hz, 2H), and drying in vacuo afforded 1.518 g (76%) of the title 7.59 (dd.J=2.20, 8.80 Hz, 1H), 7.75 (d. J=2.20, 1H), 7.79 (d. compound as an amorphous powder. J=8.80 Hz. 2H). 5 'H-NMR (400 MHz, CDClippm): 80.90 (d. J=6.60 Hz, 3H). 0.94 (d. J=6.60 Hz, 3H), 1.17 (t. J=7.20 Hz, 3H). EXAMPLE 58 2.02-2.08 (m. 1H), 2.55 (dd, J=7.20, 13.20 Hz, 1H), 2.64 (dd, J-7.20. 13.20 Hz, 1H), 3.85 (s.3H). 4.11-4.19 (m. 2H), N-(4-iso-propylbenzenesulfonyl)-O-(4-carboxy-2-n 5.56 (s. 1H), 5.96 (s. 2H), 6.70 (d. J=9.20 Hz, 1H), 6.68 (d. -propylphenoxy)-34 10 J=7.60 Hz, 1H), 7.02 (dd, J=1.60, 8.00 Hz, 1H), 7.05 (d. methylenedioxyphenylacetamide dipotassium salt J=2.00 Hz, 1H), 7.78-7.81 (m. 2H). Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-O- Step B: Preparation of O-(2-iso-butyl-4- ( 4 - carboxy-2-n - propyl phen oxy) - 3. 4 - carbomethoxyphenoxy)-3.4-methylenedioxyphenylacetic methylenedioxyphenyl-acetamide dipotassium salt acid To a solution of 18.367 g (33.2 mmol) of the product of 15 To a solution of 1.518 g (3.66 mmol) of the product of Example 57 dissolved in 100 mL of methanol was added a Step A dissolved in 8.0 mL of methanol was added 1.0 mL solution of 6.56 g (116.9 mmol) of potassium hydroxide in of a 5.0M solution of aqueous sodium hydroxide. The 25 mL of water and the reaction mixture was stirred at 60° reaction was stirred at room temperature and monitored by C. under a nitrogen atmosphere. After 6 hours TLC analysis TLC (80:15:1 CHCi-MeOH-NHOH). After 1.5 hours (80:15:1 CHC-MeOH-NHOH) indicated that ester the reaction was judged to be complete and the reaction hydrolysis was complete. The reaction mixture was cooled mixture was adjusted to pH-5 with 1.0N HCl. The reaction to room temperature, diluted with 100 mL water, filtered mixture was then partitioned between EtOAc and water. through a 0.45 micron filter and then divided into two equal separated, dried (MgSO), filtered, and evaporated. The volume portions. The fractions were individually desalted residue was purified on a silica gel flash chromatography and purified on a Waters Millipore Delta Prep 3000 liquid 25 column eluted with CHCl-MeOH-NHOH (80:15:1): chromatograph equipped with an M1000 Prep-Pak module evaporation of the purified fractions and drying in vacuo containing a 47x300mm Delta-Pak Cs sum 100A column afforded the title compound as an amorphous foam. cartridge. Two solvent reservoirs were employed: solvent "H-NMR (400 MHz, CDOH, ppm): 80.86 (d. J=6.80 Hz. system A (95-5 water-acetonitrile), and solvent system B 3H), 0.89 (d. J=6.80 Hz, 3H), 1.96-2.04 (m. 1H), 2.49 (dd. (5-95 water-acetonitrile), and the column effluent was moni 30 J=7.20, 12.80 Hz, 1H). 2.69 (dd. J=7.20, 12.80 Hz. 1H), 3.84 tored simultaneously at 210 and 280 nm with a Waters (s.3H). 5.49 (s.1H). 5.92 (d.J=1.20 Hz, 1H).5.93 (d. J= 1.20 model 490 UV-visible detector. Each fraction was pump Hz, 1H), 6.79 (d. J=8.00 Hz, 1H), 6.89 (d. J=8.80 Hz, 1H), injected onto the column and desalted by elution (50 7.08 (dd, J-1.60.8.00 Hz, 1H), 7.11 (d.J-1.60 Hz, 1H).7.74 mL/min) with several column volumes of solvent system A. (d. J=2.40 Hz, 1H). 7.78 (dd, J=2.40, 8.80 Hz, 1H). A gradient elution was then begun which had as initial 35 CI-MS m/e=386.2 (M). conditions 100% solvent system.A-0% solvent system B and reached after 30 minutes 50% solvent system.A-50% solvent EXAMPLE 60 system B, and the fractions were collected with an ISCO N-(4-iso -propylbenzenesulfonyl)-O-(2-iso-butyl-4- Foxy 200 fraction collector. The purified fractions were carbomethoxy-phenoxy)-34 combined in round bottom flasks, frozen in a -78° C. dry methylenedioxyphenylacetamide ice-acetone bath, and lyophilized. Combination of the puri Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- fied product afforded 18.719 g (92%) of the title compound (2- is o-butyl-4-carbo methoxyphenoxy)-3,4- as a white lyophilized powder. methylenedioxyphenyl-acetamide "H-NMR (400 MHz. CDOH, ppm): 80.88 (t. J=7.20 Hz. To a solution of 0.727 g (1.88 mmol) of the product of 3H), 1.21 (d. J-7.00 Hz, 3H), 1.22 (d, J-7.00 Hz, 3H). 45 Step B in Example 58 dissolved in 4 mL of anhydrous THF 1.56-1.63 (m. 2H). 2.52-2.59 (m. 1H), 2.67-2.74 (m. 1H). was added 0.458 g (2.82 mmol) of 1.1'-carbonyldiimidazole 2.91 (sept, J=7.00 Hz, 1H), 5.33 (s, 1H), 5.92 (d. J-1.20 Hz, and the mixture was magnetically stirred and refluxed for 2 1H), 5.93 (d. J=1.20 Hz, 1H), 6.72 (d. J=8.50 Hz, 1H), 6.76 hours. The reaction mixture was then cooled to room (d, J=8.50 Hz, 1H), 7.04 (d. J=7.50 Hz, 1H), 7.05 (s. 1H), temperature, and 0.562 g (2.82 mmol) of 4-iso 7.21 (d.J-8.50 Hz.2H). 7.64 (dd, J-2.00, 8.50 Hz, 1H), 7.67 50 propylbenzenesulfonamide and 0.42 mL (2.82 mmol) of (d. J=8.50 Hz, 2H), 7.73 (d. J=2.00 Hz, 1H). 1,8-diazabicyclo[5.4.0]undec-7-ene were added. The reac Microanalysis for CHNSOK.H.O. Calc'd: tion mixture was stirred an additional 3 hours at room C=53.06; H=4.61; N-2.21; K=12.34. Found: C=52.81; temperature, then was evaporated in vacuo. The residue was H-4.56: N=2.17; K=12.02. partitioned between EtOAc and 1.0N HCl and extracted. 55 The organic layer was separated, dried (MgSO), filtered, EXAMPLE 59 and evaporated and the residue was purified on a silica gel C-(2-iso-butyl-4-carbomethoxyphenoxy)-3,4- flash chromatography column eluted with CHCl methylenedioxy-phenylacetic acid MeOH-NHOH (80:15:1). Evaporation of the purified Step A: Preparation of ethyl ot-(2-iso-butyl-4- fractions and drying in vacuo afforded 0.666 g (63%) of the carbomethoxy-phenoxy)-3.4-methylenedioxyphenylacetate title compound. To a solution of 1.008 g (4.84 mmol) of methyl 3-iso 1H-NMR (400MHz, CDOH. ppm): 80.81 (d. J=6.80 Hz, butyl-4-hydroxybenzoate and 1.737 g (6.05 mmol) of ethyl 3H). 0.84 (d. J-6.80 Hz, 3H), 1.23 (d. J=6.80 Hz. 3H), 1.24 o-bromo-3.4-methylenedioxyphenylacetate in 10 mL of (d. J=6.80 Hz, 3H), 1.88-1.94 (m. 1H). 2.45 (dd, J=7.00, acetone was added 1.338 g (10 mmol) of finely powdered 13.00 Hz, 1H). 2.58 (dd, J=7.00, 13.00 Hz, 1H), 2.95 (sept, potassium carbonate. The reaction mixture was magnetically 65 J-6.80 Hz, 1H), 3.84 (s.3 H). 5.46 (s. 1H). 5.95 (d. J=1.20 stirred and refluxed for 4 hours, then cooled to room Hz, 1H), 5.96 (d. J=1.20 Hz, 1H). 6.59 (d. J=8.60 Hz, 1H). temperature, filtered and evaporated. The residue was puri 6.79 (d. J=8.00 Hz, 1H), 6.98 (brs, 1H), 6.99 (dd, J-1.60, 5,767,310 61 62 8.00 Hz, 1H), 7.30 (d.J-8.40 Hz, 2H), 7.60 (dd, J-2.00, 8.60 EXAMPLE 63 Hz, 1H), 7.70 (d. J=2.00 Hz, 1H), 7.72 (d, J-8.40 Hz, 2H). N-(4-iso-propylbenzenesulfonyl)-O-(2-n-propyl-4- EXAMPLE 61 carboxyphenoxy)-O-methyl-3,4- methylenedioxyphenylacetamide dipotassium salt N-(4-iso-propylbenzenesulfonyl)-O-(2-iso-butyl-4- Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- carboxyphenoxy)-3,4- (2-n-propyl-4-carboxyphenoxy)-O-methyl-3,4- methylenedioxyphenylacetamide methylenedioxy-phenylacetamide dipotassium salt Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-O- To a solution of 0.293 g (0.52 mmol) of the product of (2 - is o-butyl - 4 - carboxyphen oxy)-3. 4 O Example 62 dissolved in 2.0 mL of methanol was added a methylenedioxyphenyl-acetamide solution of 0.143 g (2.54 mmol) of potassium hydroxide To a solution of 0.294 g (0.52 mmol) of the product of dissolved in 1.0 mL of water. The reaction mixture was Example 60 dissolved in 3.0 mL of methanol was added 1.0 magnetically stirred at 60° C. for 4 hours until TLC analysis mL of a 5.0N aqueous solution of sodium hydroxide. The (CHCl-MeOH-NHOH 80:15:1) indicated complete reaction mixture was magnetically stirred at 60° C. After 3 15 hydrolysis of the starting material. The reaction mixture was hours TLC analysis (CHCl-MeOH-NHOH 80:15:1) then cooled to room temperature, diluted with 5.0 mL of indicated complete hydrolysis of the ester. The reaction was water and filtered through a 0.45 micron filter. The filtrate cooled to room temperature. adjusted to pH=5 with dropwise was then purified on a Waters Millipore Delta Prep 3000 addition of 1.0N HCl, then partitioned between EtOAc and liquid chromatograph equipped with two DuPont Zorbax(6) water. The organic layer was separated, washed with satu 20 21.2 mmx25 cm ODS reversed phase HPLC columns con rated aqueous NaCl, dried (MgSO), filtered and evaporated. nected in series. Two solvent reservoirs were employed: The residue was dried in vacuo to afford 0.238 g (83%) of solvent system A (95-5 water-acetonitrile). and solvent sys the title compound as an amorphous powder. ten B (5-95 water-acetonitrile), and the column effluent was 'H-NMR (400 MHz. CDOH, ppm): 80.82 (d. J=6.80 Hz, monitored simultaneously at 210 and 280 nm with a Waters 3H), 0.85 (d. J=6.80 Hz, 3H), 1.24 (d. J-7.20 Hz, 3H), 1.25 25 model 490 UV-visible detector. The reaction mixture was (d. J=7.20 Hz, 3H), 1.91 (sept, J=6.80 Hz, 1H). 2.48 (dd. injected onto the column and desalted by elution (50 J=7.20, 13.20 Hz, 1H), 2.56 (dd.J-7.20. 13.20 Hz, 1H), 2.97 mL/min) with approximately 1 L of solvent system A. A (sept, J-7.20 Hz, 1H), 5.51 (s, 1H). 5.97 (s. 1H), 6.50 (d. gradient elution was then begun which had as initial con J=8.40 Hz, 1H), 6.81 (d. J=8.00 Hz, 1H), 6.91 (d.J-1.60 Hz, ditions 100% solvent system A-0% solvent system B and 1H). 6.95 (dd.J-1.60, 8.00 Hz. 1H), 7.36 (d.J-8.40 Hz, 2H), 30 reached after 30 minutes 50% solvent system A-50% solvent 7.62 (dd.J=2.20.8.40 Hz, 1H), 7.72 (d, J=2.20 Hz, 1H), 7.79 system B, and the fractions were collected with an ISCO (d. J=8.40 Hz, 2H). Foxy 200 fraction collector. The purified fractions were FAB-MS me=554 (M+1). combined in round bottom flasks, frozen in a -78°C. dry ice acetone bath, and lyophilized. Combination of the purified EXAMPLE 62 35 product afforded 0.273 g (84%) of the title compound as a white lyophilized powder. N-(4-iso-propylbenzenesulfonyl)-O-(2-n-propyl-4- 1H-NMR (400 MHz. CDOH, ppm): 80.96 (t. J=720 Hz, methoxycarbonyl-phenoxy)-O-methyl-3,4- 3H), 1.25 (d. J=7.20 Hz. 3H), 1.26 (d. J-7.20 Hz. 3H), methylenedioxyphenylacetamide 1.64-1.71 (m. 2H), 1.67 (s, 3H). 2.58-2.65 (m. 1H). Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-O- 2.74-2.82 (m. 1H). 2.96 (sept, J-7.20 Hz, 1H), 5.91 (d. (2-n-20 propyl-4-methoxycarbonylphenoxy)-O-methyl-3,4- J= 1.20 Hz, 1H). 5.92 (d.J-1.20 Hz, 1H), 6.52 (d. J=8.40 Hz. methylenedioxylhenylacetamide 1H), 6.72 (d. J=8.00 Hz, 1H), 7.12 (dd, J-1.80, 8.00 Hz, 1H), To a solution of 0.516 g (0.93 mmol) of the product of 7.17 (d. J-2.00 Hz, 1H), 7.28 (d. J=8.80 Hz, 2H), 7.50 (dd. Example 57 dissolved in 1.0 mL of anhydrous THF was J=2.20, 8.40 Hz. 1H). 7.72 (d. J=8.80 Hz, 2H), 7.74 (d. added 2.80 mL (2.80 mmol) of a 1.OM solution of lithium 45 =2.00 Hz, 1H). bis(trimethylsilylamide) in THF at -78°C. under a nitrogen FAB-MS m/e=591.6 (M+K+). atmosphere. The reaction mixture was magnetically stirred at -78° C. for 1 hour, then 174 L (2.80 mmol) of EXAMPLE 64 iodomethane was added via syringe. The reaction was N-(4-iso-propylbenzenesulfonyl)-O-(2-n-propyl-4- allowed to warm to room temperature and was stirred an 50 carboxamido-phenoxy)-3,4- additional 14 hours. The reaction was next quenched with methylenedioxyphenylacetamide excess 10% aqueous NaHSO and partitioned between Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- EtOAc and water. The organic layer was washed with (2-n-propyl-4-carboxamidophenoxy)-34-methylenedioxy saturated aqueous NaCl, dried (MgSO), filtered and evapo phenylacetamide rated. The residue was purified on a silica gel flash chro 55 matography column eluted with CHCl-MeOH-NHOH propylbenzenesulfonyl)-O-(4-carboxy-2-n-propylphenoxy)-To a solution of 0.162 g (0.30 mmol) of N-(4-iso (90:10:1). Evaporation of the purified fractions and drying in 3.4-methylenedioxyphenylacetamide (free acidic form of vacuo afforded 0.293 g (55%) of the title compound as an the product of Example 58) dissolved in 1.5 mL of anhy amorphous solid. drous THF was added 0.073 g (0.45 mmol) of 1,1'- "H-NMR (400 MHz. CDOH, ppm): 80.99 (t, J=7.20 Hz, carbonyldiimidazole and the resulting mixture was magneti 3H), 1.31 (d, J-6.80 Hz. 6H), 1.64-1.72 (m. 2H), 1.66 (s, cally stirred and refluxed for 50 minutes. The reaction 3H). 2.64-2.73 (m. 1H), 2.81-2.88 (m. 1H), 3.02 (sept, mixture was cooled to room temperature, and then added at J=6.80 Hz, 1H), 3.85 (s.3H), 5.96 (s. 2H), 6.36 (d. J-8.40, 0° C. to excess THF that had been previously saturated with 1H), 6.77 (d. J=8.40 Hz, 2H), 6.99 (m. 1H), 7.05 (brs. 1H). anhydrous gaseous ammonia. The reaction mixture was 7.37 (d. J=7.60 Hz, 1H), 7.43 (dd, J=2.40, 8.60 Hz, 1H), 7.76 65 sealed and then stirred at room temperature for 14 hours. The (d. J=8.40 Hz, 2H), 7.81 (brs. 1H). reaction mixture was then poured into water (70 mL) and FAB-MS me=568 (M+1). extracted with EtOAc (150 mL). The organic layer was 5,767,310 63 64 separated, washed with saturated aqueous NaCl, dried then completely evaporated and dried in vacuo to afford the (MgSO), filtered, and evaporated in vacuo to afford the title crude product which was used directly in the next step. compound as an amorphous solid. FAB-MS me=481 (M+Na". "H-NMR (400 MHz, CDOH, ppm): 50.88 (t. J=7.60 Hz, Step D: Preparation of N-(4-iso-propylbenzenesulfonyl)-O- 3H). 1.21 (d. J-6.80 Hz, 6H), 1.55-1.66 (m. 2H), 2.54-2.62 (4-tert-butylidimethylsilyloxymethyl-2-n-propylphenoxy)-3. (m. 1H), 2.70-2.77 (m. 1H). 2.89 (sept, J=6.80 Hz, 1H).5.36 4-methylenedioxyphenylacetamide (s. 1H), 5.93 (d. J-1.20 Hz, 1H), 5.94 (d. J=1.20 Hz. 1H). To a solution of 3.30 g (7.21 mmol) of the crude product 6.75 (d. J=8.40 Hz, 1H), 6.78 (d.J-8.80 Hz, 1H), 7.02-7.04 from Step C dissolved in 40 mL of anhydrous THF was (m. 2H), 7.06 (brs. 2H), 7.20 (d. J=8.40 Hz, 2H), 7.55 (dd. added 1.75 g (10.8 mmol) of 1.1'-carbonyldiimidazole and J=2.20, 8.60 Hz, 1H), 7.62-7.66 (m. 2H), 7.71 (s. 1H). the reaction mixture was magnetically stirred and heated at FAB-MS m/e-539 (M+1). reflux for 10 minutes. The reaction was then cooled to room temperature, 2.15 g (10.8 mmol) of 4-iso EXAMPLE 65 propylbenzenesulfonamide and 1.61 mL (10.8 mmol) of 1.8-diazabicyclo[5.4.0]undec-7-ene were added and the N-(4-iso-propylbenzenesulfonyl)-O-(2-n-propyl-4- 15 reaction was stirred for an additional 30 minutes at room hydroxymethyl-phenoxy)-3,4- temperature. The mixture was then diluted with EtOAc (80 methylenedioxyphenylacetamide mL), washed with 10% aqueous citric acid, saturated aque Step A: Preparation of methyl o-(4-hydroxymethyl-2-n- ous NaCl, dried (MgSO), filtered and evaporated. The propyl-phenoxy)-3.4-methylenedioxyphenylacetate residue was partially purified on a silica gel flash chroma To a solution of 3.84 g (23.13 nmole) of 4-hydroxy-3-in tography column eluted with CHCl-MeOH-NHOH propylbenzyl alcohol dissolved in 70 mL of anhydrous DMF (92:8:0.5). The semi-purified material was combined and was added 9.04 g (27.7 mmol) of cesium carbonate and the repurified on a second silica gel flash chromatography reaction mixture was magnetically stirred at room tempera column eluted initially with 35%. EtOAc-hexane, later with ture for 15 minutes. Methyl o-bromo-3,4- 50% EtOAc-hexane, and finally with 70% EtOAc-hexane. methylenedioxyphenylacetate (7.58 g; 27.7 mmol) was 25 Combination of the purified fractions and evaporation added and the reaction mixture was then stirred for an afforded 3.20 g (69%) of the title compound as a yellow oil. additional 14 hours at room temperature under a nitrogen FAB-MS me=678 (M--K). atmosphere. The reaction was then partitioned between 5% Step E: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- aqueous citric acid (700 mL) and EtOAc (100 mL) and (4-hydroxymethyl-2-n - propyl phenoxy)-3,4- extracted. The organic layer was separated, washed with 30 methylenedioxy-phenylacetamide saturated aqueous NaCl. dried (MgSO), filtered and evapo To a solution of 3.20 g (5.01 mmol) of the product of Step rated. The residue was purified on a silica gel flash chro D dissolved in 5.0 mL of anhydrous THF was added 5.06 mL matography column eluted with 40% EtOAc-hexane. The (5.06 mmol) of a 1.0M solution of tetrabutylammonium purified fractions were combined, evaporated, and dried in fluoride in Th and the reaction mixture was stirred at room vacuo to afford 6.74 g (81%) of the title compound as a 35 temperature under a nitrogen atmosphere. After 2.5 hours yellow oil. 1.0 mL additional tetrabutylammonium fluoride in THFP 'H-NMR (200 MHz. CDC1ppm): 80.97 (t, J=7.60 Hz. was added and the reaction mixture was stirred for an 3H). 2.55-2.75 (m. 2H), 2.71 (t, J=7.20 Hz, 2H), 3.71 (s. additional 14 hours. The reaction mixture was then concen 3H), 4.59 (s. 2H), 5.55 (s. 1H), 5.97 (s. 2H), 6.69 (d, J-8.20 trated in vacuo and applied to a silica gel flash chromatog Hz, 1H), 6.82 (d. J-7.80 Hz, 1H), 7.02-7.28 (m, 4H). 40 raphy column and eluted with 60% EtOAc-hexane. Combi FAB-MS me=359 (M-1). nation of the purified fractions and drying in vacuo afforded Step B: Preparation of methyl O-(4-tert 0.691 g (26%) of the title compound as an amorphous butyldimethylsilyloxy-10 methyl-2-n-propylphenoxy)-3,4- powder. methylenedioxyphenyl-acetate "H-NMR (400 MHz. CDOH, ppm): 80.87 (t. J=7.60 Hz, To a solution of 2.50 g (6.98 mmol) of the product of Step 45 3H), 1.26 (d. J-6.80 Hz, 3H), 1.27 (d. J-6.80 Hz, 3H), A dissolved in 20 mL of dichloromethane was added 1.95 1.51-1.63 (m. 2H), 2.54-2.68 (m. 2H), 2.98 (sept, J=6.80 mL (14.0 mmol) of triethylamine. 1.26 g (8.38 mmol) of Hz, 1H). 4.46 (s. 2H), 5.37 (s. 1H), 5.95 (s. 1H), 6.51 (d. tert-butyldimethylchlorosilane. 85 mg (0.1 eq) of J=8.40 Hz, 1H). 6.77 (d.J-8.00 Hz, 1H), 6.88-6.95 (m, 3H). 4-dimethylaminopyridine and the reaction mixture was 7.10 (d, J=2.00 Hz, 1H), 7.36 (d. J=840 Hz, 2H), 7.77 (d. stirred at room temperature for 30 minutes under a nitrogen 50 J=8.40 Hz, 2H). atmosphere. The reaction was then diluted with 100 mL FAB-MS me=548 (M--Na"). EtOAc, washed with water, 1.0N HCl, saturated aqueous NaHCO, saturated NaCl. dried (MgSO), filtered and EXAMPLE 66 evaporated in vacuo to afford 3.20 g (97%) of the title N-(4-iso-propylbenzenesulfonyl)-D-(4-formyl-2-n- compound. 55 propylphenoxy)-3,4- EI-MS me=472 (M). methylenedioxyphenylacetamide Step C: Preparation of O-(4-tert-butyldimethyl Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- silyl oxy methyl-2-n - propyl phen oxy)-3,4- (4-formyl-2-n-propylphenoxy)-3.4-methylenedioxyphenyl methylenedioxyphenylacetic acid acetamide To a solution of 3.20 g (6.78 mmol) of the product of Step To a solution of 0.573 g (1.09 mmol) of the product of B dissolved in 10 mL of methanol and 3 mL of dichlo Example 65 dissolved in 5.0 mL of dichloromethane was romethane was added 1.42 mL (7.12 mmol) of a 5.0N added 2.86 g (32.9 mmol) of manganese dioxide and 1.15g aqueous solution of sodium hydroxide and the reaction of finely powdered 3A molecular sieves and the reaction mixture was magnetically stirred at room temperature. After mixture was magnetically stirred at room temperature for 14 4 hours TLC analysis (CHCl-MeOH-NHOH 80:15:1) 65 hours. The reaction mixture was then filtered through a bed indicated complete hydrolysis and the reaction mixture was of celite and MgSO and the filtrate was evaporated in adjusted to pH=4 with 1.0N HCl. The reaction mixture was vacuo. The residue was dissolved in dichloromethane and 5,767,310 65 66 applied to a silica gel flash chromatography column and then with 6.0N HCl. The mixture was then evaporated in vacuo eluted with 3% MeOH-CHCl, Evaporation of the puri and the residue was purified on a silica gel flash chroma fied fractions and drying in vacuo afforded 0.149 g (26%) of tography column eluted with CHCl-MeOH-NHOH the title compound. (80:15:1). Evaporation of the purified fractions and drying in "H-NMR (400 MHz. CDOH. ppm): 80.89 (t, J=7.60 Hz. vacuo afforded 0.416 g (78%) of the title compound. 3H), 1.24 (d, J-7.20 Hz, 3H), 1.25 (d. J-7.20 Hz. 3H). H-NMR (400 MHz. CDOH. ppm): 80.94 (t, J=7.60 Hz, 1.57-1.68 (m. 2H), 2.63-2.74 (m. 2H), 2.96 (sept, J=7.20 3H), 1.62-1.70 (m. 2H), 2.53 (s.3H), 2.61-2.69 (m. 1H), Hz, 1H), 5.56 (s.1H), 5.97 (s. 2H), 6.70 (d. J=8.40 Hz, 1H), 2.80-2.889m, 1H), 5.39 (s, 1H). 5.93 (d. J=1.20 Hz, 1H), 6.80 (d. J-8.00 Hz, 1H), 6.91 (d. J=1.60 Hz, 1H), 6.96 (dd, 5.94 (d, J=1.20 Hz, 1H), 6.79 (d, J-8.00 Hz, 1H), 6.91 (d. J=1.60, 8.00 Hz, 1H), 7.34 (d. J=8.40 Hz, 2H), 7.53 (dd. 1) J=8.80 Hz, 1H), 7.10 (dd. J= 1.60, 8.00 Hz, 1H). 7.15 (d. J=2.00, 8.40 Hz, 1H), 7.66 (d. J=2.00 Hz, 1H). 7.76 (d. J=1.60 Hz, 1H), 7.78 (d. J=2.40 Hz, 1H), 7.81 (dd. J=2.40, J=8.40 Hz, 2H), 9.77 (s. 1H). 8.80 Hz, 1H). FAB-MS m/e=546 (M+Na"). EXAMPLE 67 EXAMPLE 68 O-(4-acetyl-2-n-propylphenoxy)-3,4- 15 N-(4-iso-propylbenzenesulfonyl)-O-(4-acetyl-2-n- methylenedioxyphenylacetic acid propylphenoxy)-3,4- Step A: Preparation of 4-hydroxy-2-n-propylacetophenone methylenedioxyphenylacetamide A Parr hydrogenation apparatus flask was charged with a Step A: Preparation of N-(4-iso-propylbenzenesulfonyl)-o- solution of 2.00 g (11.36 mmol) of 3-ally 14 (4-acetyl-2-n-propylphenoxy)-3,4-methylenedioxyphenyl hydroxyacetophenone dissolved in 10 mL of ethanol and acetamide 200 mg of a 10% palladium on carbon catalyst. The flask To a solution of 0.181 g (0.51 mmol) of the product of was mounted in the Parr apparatus and shaken under a 46 Example 67 dissolved in 2.5 mL of anhydrous DMF was psig hydrogen atmosphere for 15 minutes. At the end of this added 0.248 g (1.53 mmol) of 1.1'-carbonyldiimidazole and period TLC analysis (15% EtOAc-hexane) indicated that the 25 the reaction mixture was magnetically stirred and heated at starting material had been completely consumed, and the 80° C. under a nitrogen atmosphere in an oil bath. After 20 reaction mixture was filtered and evaporated. The residue minutes the reaction mixture was cooled to room tempera was purified on a silica gel flash chromatography column ture and 0.152 g (0.77 mmol) of 4-iso-propylbenzene eluted with 25% EtOAc-hexane. Evaporation of the purified sulfonamide and 381 pil (2.55 mmol) was added. The fractions and drying in vacuo afforded 1.83 g (91%) of the 30 reaction mixture was heated at 80° C. for an additional 10 title compound. minutes then cooled again to room temperature and parti 'H-NMR (200 MHz, CDC1, ppm): 80.98 (t, J=7.40 Hz, tioned between EtOAc and 10% aqueous citric acid. The 3H). 1.56-1.78 (m. 2H), 2.57 (s.3H), 2.63 (t, J=7.20 Hz, organic layer was separated. washed with saturated aqueous 2H), 6.08 (bris, 1H), 6.84 (d. J=8.20 Hz, 1H), 7.74 (dd. NaHCO, saturated aqueous NaCl, dried (MgSO), filtered J=2.20, 8.20 Hz, 1H), 7.79 (d, J-2.20 Hz, 1H). 35 and evaporated. The residue was purified on a silica gel flash FAB-MS me=178 (M). chromatography column eluted with CHCl-MeOH Step B: Preparation of methyl o-(4-acetyl-2-n- NH4OH (80:15:1); evaporation of the purified fractions and propylphenoxy)-3.4-methylenedioxyphenylacetate drying in vacuo afforded 0.128 g (47%) of the title com To a solution of 0.250 g (1.40 mmol) of the product of pound as an amorphous solid. Step A dissolved in 3.0 mL of DMF was added 0.504 g (1.54 "H-NMR (400 MHz. CDOH, ppm): 80.88 (t, J=7.60 Hz, immol) of cesium carbonate and the reaction mixture was 3H), 1.21 (d. J=6.80 Hz, 3H), 1.22 (d. J=6.80 Hz, 3H), magnetically stirred at room temperature under a nitrogen 1.55-1.65 (m. 2H), 2.51 (s, 3H), 2.54-2.64 (m. 1H), atmosphere for 15 minutes. Methyl ot-bromo-3,4- 2.67-2.75 (m. 1H). 2.92 (sept. J=6.80 Hz, 1H), 5.43 (s, 1H). methylenedioxyphenylacetate (0.422 g. 1.54 mmol) was 5.94 (s. 2H), 6.75 (d. J=8.80 Hz, 1H). 6.77 (d. J=8.40 Hz, then added and the resulting mixture was stirred at room 45 1H), 7.01-7.03 (m. 2H), 7.23 (d, J=8.40 Hz, 2H), 7.66 (dd. temperature for an additional 24 hours. The reaction mixture J=2.40, 8.80 Hz, 1H), 7.67 (d. J-8.40 Hz, 2H), 7.73 (d. was then partitioned between 10% aqueous citric acid and J=2.40 Hz, 1H). EtOAc. The organic layer was washed with saturated aque FAB-MS me=538 (M+1). ous NaHCO, saturated aqueous NaCl, dried (MgSO), EXAMPLE 69 filtered and evaporated in vacuo to afford the title com 50 pound. O-(2-n-propylphenoxy)-34 "H-NMR (300 MHz, CDC1, ppm): 80.96 (t, J=7.50 Hz, methylenedioxyphenylacetic acid 3H), 1.62-1.74 (m, 2H), 2.52 (s, 3H), 2.68-2.75 (m, 2H), 3.71 (s.3H). 5.61 (s, 1H). 5.98 (s. 2H), 6.71 (d. J=8.60 Hz, FAB-MS for CHOs: me=337 (M+Na"). 1H), 6.81 (d. J=8.20 Hz, 1H).7.02 (dd, J=1.80, 8.20 Hz, 1H), 55 7.04 (d. J=1.80 Hz, 1H), 7.73 (dd, J=2.20, 8.60Hz, 1H), 7.79 EXAMPLE 70 (d. J-2.20 Hz, 1H). FAB-MS me =371 (M-1). N-(4-iso-propylbenzenesulfonyl)-O-(2-n- Step C: Preparation of O-(4-acetyl-2-n-propylphenoxy)-34 propylphenoxy)-3,4- methylenedioxyphenylacetic acid methylenedioxyphenylacetamide To a solution of 0.556 g (1.50 mmol) of the product of FAB-MS for CHNSOs: me=534 (M+K'). Step B dissolved in 4.0 mL of methanol was added 0.45 mL (2.25 mmol) of a 5.0N aqueous solution of sodium hydrox EXAMPLE 71 ide. The reaction mixture was stirred at room temperature and monitored by TLC (CHCI-MeOH-NH4OH 65 O-(3-methoxyphenoxy)-34 80:15:1). After 4 hours the reaction was judged to be methylenedioxyphenylacetic acid complete and the reaction mixture was adjusted to pH=7 EI-MS for CHOs: me=302 (M"). 5,767.310 67 68 EXAMPLE 72 4.15 (m. 2H); 3.84 (s.3H); 3.83 (s.3H); 2.68 (m. 2H); 1.69 (m. 2H); 1.20 (t, 3H, J=7.4 Hz); 0.90 (t, 3H, J-74 Hz). O-(2-(2-hydroxyethyl)phenoxy)-3,4- Step B: 2-(4-carbomethoxy-2-n-propylphenoxy)-2-(5- methylenedioxyphenylacetic acid methoxy-3.4-methylenedioxyphenyl)acetic acid To a solution of the product of Step A (4.3 g. 12 mmol) FAB-MS for CHOs: me=317 (M-1). in methanol (25 mL) was added aqueous 2N NaOH (10 mL) and the reaction mixture was stirred at room temperature. EXAMPLE 73 The rapid progress of mono-deesterification was monitored O-(-(-carbomethoxyethyl)phenoxy)-34 by TLC analysis using CHC1-MeOH-NHOH: O (80:15:1). After 15 min, the reaction mixture was cooled to methylenedioxyphenylacetic acid 0° C. and neutralized with aqueous 2N HCl. Methanol was CI-MS for CHO: me=359 (M+1). removed in vacuo and the resulting mixture was acidified with aqueous 2N HCl. The oily product which precipitated EXAMPLE 74 was extracted into methylene chloride (3x40 mL) and the 15 combined organic phase was washed with water, brine and O-(4-hydroxymethyl-2-n-propylphenoxy)-34 then dried over MgSO. Removal of the solvent in vacuo methylenedioxyphenyl-acetic acid afforded the crude product which was then purified by flash-chromatography on silica gel using CHCl-MeOH CI-MS for CHO: me=326 (M*-HO). NHOH:(80:10:1) to give desired product as the ammonium EXAMPLE 75 salt. The salt was treated with aqueous 1N HCl (20 mL) to 20 provide the titled compound as a white solid (3.4 g). oc-(4-(2-hydroxyethyl)-2-n-propylphenoxy)-34 "H NMR (200 MHz. CDOH. ppm) 87.78 (m. 2H), 6.77 methylenedioxyphenyl-acetic acid (m, 3H), 6.61 (d. 1 H. J-1.5 Hz), 5.93 (s. 2H), 5.54 (s. 1H). 3.84 (s.3H). 3.83 (s.3H). 2.68 (m. 2H), 1.69 (m. 2H), 0.90 CI-MS for CHOs: me=359 (M+1). (t. 3H, J=7.4 Hz). 25 Step C: N-(4-iso-Propylbenzene sulfonyl)-2-(4- EXAMPLE 76 carbomethoxy-2-n-propylphenoxy)-2-(5-methoxy-3,4- N-(4-iso-propylbenzenesulfonyl)-O-(2-(2- methylenedioxyphenyl)-acetamide carbomethoxyethyl)phenoxy)-3,4- To the product of Step B (0.12 g. 0.30 mmol) in dry THF methylenedioxyphenylacetamide (1.5 mL) was added 1.1'-carbonyldiimidazole (0.1 g. 0.61 mmol) and the reaction stirred at 50° C. for 3 hr. To this ESI-MS for CHNSOs: m/e=540 (M-1). solution was added a solution of 4-iso propylbenezenesulfonamide (0.17 g. 0.9 mmol) and DBU EXAMPLE 77 (0.14 mL, 0.94 mmol) in dry THF (1.5 mL), and the reaction N-(4-iso-propylbenzenesulfonyl)-O-(2-(2- 35 continued at 50° C. for 4 hr. The reaction was diluted with carboxyethyl)phenoxy)-34 ice water and acidified with aqueous 1N HCl. The precipi methylenedioxyphenylacetamide tated material was taken up in EtOAc and the organic phase was washed with water, brine, and then dried over MgSO. CI-MS for CHNSOs: me=526 (M-1). filtered and the solvent removed. The product was purified by flash-chromatography on silica-gel using EXAMPLE 78 CHCl:MeOH:NHOH (80:10:1) as the eluting solvent to o-(2-(2-carboxyethyl)phenoxy)-3,4- yield the titled product as the ammonium salt. Acidification methylenedioxyphenylacetic acid of the ammonium salt afforded the titled product as a white solid (0.14 g). CI-MS for CHO,; me=345 (M+1). 45 "H NMR (400 MHz, CDOH, ppm): 87.78 (d. 2H, J=8.4 Hz), 7.76 (d. 1H, J=2.3 Hz), 7.62 (dd. 1H, J=8.6. 2.2 Hz). EXAMPLE 79 7.37 (d. 2H, J=8.4 Hz), 6.70 (d. 1H,J-1.4 Hz), 6.61 (d. 1H, N-(4-iso-propylbenzenesulfonyl)-2-(4- J-1.5 Hz). 5.97 (s. 2H), 5.49 (s. 1H). 3.84 (s.3H), 3.83 (s. carbomethoxy-2-n-propyl-phenoxy)-2-(5-methoxy 3H). 2.98 (sept, 1H. J=6.9 Hz). 2.65 (m. 2H), 1.59 (m. 2H), 3.4-methylenedioxyphenyl)acetamide 50 1.25 (dd, 6H. J-7.0, 2.5 Hz), 0.90 (t, 3H, J=7.4 Hz). Step A: Ethyl 2-(4-carbomethoxy-2-n-propylphenoxy)-2-(5- CHNON: Calc: C 59.50 H 5.33N 2.31. Found: C methoxy-3.4-methylenedioxyphenyl)acetate 59.60 H 5.34N 2.59 To a mixture of methyl 4-hydroxy-3-n-propylbenzoate EXAMPLE 80 (3.0 g. 15.46 mmol) and CSCO (5.1 g. 16 mmol) in dry N-(4-iso-propylbenzenesulfonyl)-2-(4-carboxy-2- dimethylformamide (50 mL) was added ethyl 2-bromo-2- 55 (5-methoxy-3.4-methylenedioxy)phenylacetate (4.3 g. propylphenoxy)-2-(5-methoxy-3,4- 15.56 mmol), and the resulting mixture was stirred at room methylenedioxyphenyl)acetamide temperature for 6 h. At the end of this period, the reaction To the product of Example 79 (0.6 g. 1.02 nmole) in mixture was diluted with ice water (300 mL) and extracted MeOH (15 mL) was added aqueous 2N NaOH (5 mL) and with ethyl acetate (3x60 mL). The combined organic phase the reaction was stirred at 600° C. for 3 h. When the reaction was washed with water and brine, and then dried over was complete the MeOH was removed in vacuo and the anhydrous MgSO, filtered and solvent removed to give the aqueous phase was acidified with 2N HCl. The product crude product. Purification of the crude product by silica-gel precipitated was extracted into methylene chloride (3x50 flash column chromatography using ethyl acetate-hexane mL) and the combined organic phase was washed with brine (1:9) afforded the titled product as an oil (5.1 g). 65 then dried over MgSO filtered and the solvent removed. "H NMR (200 MHz, CDC. ppm) 87.82 (m. 2H); 6.75 The residue upon trituration with ether provided the titled (m. 3H); 6.61 (d. 1H, J=1.5 Hz); 5.93 (s. 2H); 5.54 (s, 1H): product as a white solid (0.45 g).

5,767,310 75 76 (m. 1H), 2.82 (m. 1H), 2.54 (m. 2H), 1.69 (m. 2H), 1.26 (dd. partitioned between EtOAc (80 mL) and 10% aqueous citric 6H, J=7.0.2.5 Hz), 1.15 (dd. 6H, J=7.0, 2.5 Hz), 0.90 (t,3H, acid (300 mL). The organic layer was separated, washed J=7.4 Hz). with saturated aqueous NaHCO. saturated aqueous NaCl, FAB-MS: me 596 (M-1). dried (MgSO), filtered and evaporated. The residue was dried in vacuo to afford 5.90 g (5.79 theoretical) of the title EXAMPLE 100 compound which was used in the next step without further ot-(2-n-propyl-4-methylaminosulfonylphenoxy)-3,4- purification. methylenedioxy-phenylacetic acid "H-NMR (400 MHz. CDOH, ppm): 80.97 (t. J-7.20 Hz, Step A: Preparation of 3-allyl-4-hydroxybenzenesulfona 3H), 1.64-1.76 (m. 2H), 2.74 (t, J=7.20 Hz, 2H), 3.70 (s, mide O 3H), 5.87 (s.1H).5.97 (s.2H), 6.85 (d. J=8.00 Hz, 1H), 6.93 To a solution of 5.00 g (28.9 mmol) of (d. J=8.40 Hz, 1H), 7.03 (d. J= 1.60 Hz, 1H), 7.06 (dd. 4-hydroxybenzenesulfonamide dissolved in 30 mL of anhy J=1.60, 8.00 Hz, 1H). 7.65 (dd, J=2.40, 8.40 Hz, 1H), 7.69 drous DMF was added 10.36 g (31.8 mmol) of cesium (d, J=2.40 Hz, 1H). carbonate and the reaction mixture was magnetically stirred FAB-MS me=408 (M+1). at room temperature under a nitrogen atmosphere for 10 15 Step D: Preparation of methyl O-(2-n-propyl-4- minutes. Allyl bromide (2.75 mL. 31.8 mmol) was added methylamino-sulfonylphenoxy)-3.4-methylenedioxyphe and the reaction mixture was then stirred for an additional 14 nylacetate hours. The reaction mixture was then partitioned between To a solution of 2.19 g (5.38 mmol) of the product of Step EtOAc (60 mL) and 10% aqueous citric acid (200 mL) and C dissolved in 20 mL of anhydrous THF was added 2.41 mL extracted. The organic layer was separated, washed with (16.1 mmol) of 1.8-diazabicyclo5.4.0]undec-7-ene and the saturated aqueous NaHCO, saturated aqueous NaCl, dried reaction mixture was magnetically stirred under a nitrogen (MgSO), filtered, evaporated and dried in vacuo to afford atmosphere for 25 minutes at room temperature. 5.40 g (88%) of a yellow solid. The crude O-allyl ether Iodomethane (1.00 mL; 16.1 mmol) was added and the (5.36, 25.2 mmol) was then dissolved in 10 mL of 1.2- reaction mixture was stirred an additional 15 hours at room dichlorobenzene in a 50 mL round bottom flask and mag 25 temperature. The reaction mixture was diluted with EtOAc netically stirred at reflux under a nitrogen atmosphere for 15 and a precipitate formed which was redissolved by addition hours. The reaction mixture was then cooled to room tem of methanol. The mixture was further diluted with warm perature and diluted with methanol. The 1.2- EtOAc (150 mL total), refrigerated overnight and a solid dichlorobenzene was removed by extraction of the methanol separated which was removed by filtration. The filtrate was layer with hexane. the methanol layer was separated, then 30 evaporated in vacuo and the residue was purified on a silica evaporated. The residue was then purified on a silica gel gel flash chromatography column eluted with 5% EtOAc flash chromatography column eluted with 5% MeOH CHCl Combination of the purified fractions and evapora CHCl Combination of the purified fractions, evaporation tion in vacuo afforded 0.164 g of the title compound and a and drying in vacuo afforded 3.04 g (57%) of the title number of impure fractions which were reserved for repu compound. 35 rification. 'H-NMR (400 MHz. CDOH. ppm): 83.38 (d.J-6.40 Hz, "H-NMR (400 MHz. CDOH, ppm): 80.97 (t, J=7.20 Hz, 2H). 5.02-5.10 (m. 2H), 5.94-6.04 (m. 1H), 6.84 (d. J=8.40 3H), 1.65-1.77 (m. 2H), 2.48 (s, 3H), 2.74 (t, J=7.20 Hz, Hz, 1H), 7.58 (dd. J=2.40, 8.40 Hz, 1H), 7.61 (d. J=2.40 Hz, 2H), 3.71 (s.3H). 5.87 (s, 1H), 5.98 (s. 2H), 6.85 (d. J=8.00 1H). Hz. 1H), 6.96 (d. J-8.80 Hz, 1H), 7.04 (d, J-1.60 Hz, 1H), CI-MS me=213 (M). 7.07 (dd. J=1.60, 8.00 Hz. 1H), 7.58-7.61 (m. 2H). Step B: Preparation of 4-hydroxy-3-n-propylbenzenesul ESI-MS me=421 (M). fonamide Step E: Preparation of d-(2-n-propyl-4- AParr hydrogenation flask was charged with a solution of m ethyl a mino sulfonyl - phen oxy) - 3, 4 - 3.04 g (14.30 mmol) of the product of Step A dissolved in methylenedioxyphenylacetic acid 25 mL of ethanol and 0.300 g of a 10% palladium on carbon 45 To a solution of 0.372 g (0.884 mmol) of the product of catalyst was added. The flask was mounted in the hydroge Step D dissolved in 3.0 mL of methanol was added 212 ul nation apparatus, freed of air, pressurized with hydrogen (40 (1.06 mmol) of a 5.0N aqueous sodium hydroxide solution psig) and shaken for 15 minutes. At the end of this period which resulted in a cloudy suspension. The reaction was TLC analysis (3% MeOH-CHCl, 2 elutions) indicated warmed to assist solution, methanol (1 mL) was added that the reaction was complete and the reaction mixture was 50 followed by dichloromethane (0.5 mL), however a clear filtered and evaporated. The product was dried in vacuo to solution was not obtained. Additional 5N sodium hydroxide afford 3.06 g (99%) of the title compound. solution was added (212 ul), and finally 0.5 mL of THF was 1H-NMR (400 MHz, CDOH. ppm): 80.94 (t. J=7.20 Hz, added which resulted in a clear solution. After stirring an 3H). 1.58-1.68 (m. 2H), 2.01-2.62 (m. 2H), 6.82 (d. J=8.40 additional 15 hours at room temperature. TLC analysis Hz, 1H). 7.55 (dd. J-2.40, 8.40 Hz, 1H), 7.60 (d. J=2.40 Hz, 55 (CHCl-MeOH-NHOH 80:15:1) indicated complete 1H). hydrolysis of the starting material and the reaction was FAB-MS me=216 (M+1). adjusted to pH=7 with 6N HCl. The reaction mixture was Step C: Preparation of methyl O-(2-n-propyl-4- then concentrated in vacuo and the residue was purified on aminosulfonyl-phenoxy)-3.4-methylenedioxyphenylacetate a silica gel flash chromatography column eluted with To a solution of 3.06 g (14.23 mmol) of the product of CHCl-MeOH-HOAc (92:7:1). Combination of the puri Step B dissolved in 25 mL of anhydrous DMF was added fied fractions and drying in vacuo afforded 0.335 g (93%) of 4.87 g (15.0 mmol) of cesium carbonate and the reaction the title compound as an amorphous solid. mixture was magnetically stirred under a nitrogen atmo "H-NMR (400 MHz, CD,OH, ppm): 80.96 (t. J=720 Hz, sphere at room temperature for 15 minutes. Methyl 3H), 1.66-1.78 (m. 2H), 2.48 (s.3 H). 2.73-2.77 (m. 2H). O-bromo-3,4-methylenedioxyphenylacetate (4.08 g. 15.0 65 5.74 (s.1H). 5.97 (s. 2H), 6.85 (d. J=7.60 Hz, 1H), 6.98 (d. mmol) was then added and the reaction mixture was stirred J=9.20 Hz, 1H), 707-7.10 (m. 2H), 7.59-7.62 (m. 2H). for an additional 3 hours, The reaction mixture was then ESI-MS m/e=407 (M'.). 5,767,310 77 78 EXAMPLE 101 7.47 (dd, J-240, 8.80 Hz, 1H), 7.52 (d. J=2.40 Hz, 1H), 7.65 N-(4-iso-propylbenzenesulfonyl)-O-(2-n-propyl-4- (d. J=8.40 Hz, 2H). methylamino-sulfonylphenoxy)-34 ESI-MS me=627 (M+1). methylenedioxyphenylacetamide potassium salt What is claimed is: 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3-1. A compound selected from the group consisting of: To a solution of 0.298 g (0.73 mmol) of the product of methylphenyl)acetic acid; Example 100 dissolved in 4.0 mL of anhydrous THF was 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(4- added 0.237 g (1.46 mmol) of 1.1'-carbonyldiimidazole and phenoxyphenyl)acetic acid; the reaction mixture was magnetically stirred and refluxed 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(4- for 2 hours under a nitrogen atmosphere. The reaction 10 phenylphenyl)acetic acid; mixture was then cooled to room temperature, 0.219 g (1.10 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3- mmol) 4-iso-propylbenzenesulfonamide and 164 uL (1.10 carboxyphenyl)acetic acid; mmol) 1,8-diazabicyclo5.4.0]undec-7-ene were added and 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3,4- the reaction was stirred and heated at reflux for an additional ethylenedioxy-phenyl)acetic acid; 10 minutes. The reaction mixture was then cooled to room 15 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3.4.5- temperature, partitioned between 10% aqueous citric acid trimethoxy-phenyl)acetic acid; and EtOAc and extracted. The organic layer which separated 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3,4- was washed with saturated aqueous NaCl, dried (MgSO), dimethoxy-phenyl)acetic acid; filtered and evaporated. The residue was redissolved in 1.0 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3.5- mL of methanol and treated with 2.20 mL (3 eq) of a 1.1M dimethoxy-phenyl)acetic acid; aqueous solution of potassium hydroxide. The mixture was 2-((2,6-dipropyl-4-tetrazol-5-yl)phenoxy)-2-(3- then diluted with 5 mL of water and filtered through a 0.45 bromophenyl)acetic acid; micron filter. The filtrate was desalted and purified on a 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(3- Waters Millipore Delta Prep 3000 liquid chromatograph bromophenyl)acetic acid; 25 2-(2,6-dipropyl-4-hydroxymethyl)phenoxy-2-(2- equipped with an M1000 Prep-Pak module containing a naphthyl)acetic acid; 47x300mm Delta-Pak Cs sum 100A column cartridge. 2-(2,6-dipropyl-4-(2-hydroxyethyl)phenoxy-2-(2- Two solvent reservoirs were employed: solvent system A naphthyl)acetic acid; (95-5 water-acetonitrile), and solvent system B (5-95 water 2-(2,6-dipropyl-4-(2-hydroxyethyl)phenoxy-2-(3- acetonitrile), and the column effluent was monitored simul methoxyphenyl)acetic acid; taneously at 210 and 280 nm with a Waters model 490 30 2-(2,6-dipropyl-4-(1,2-dihydroxyethyl)phenoxy)-2-(2- UV-visible detector. The column was preequilibrated with naphthyl)acetic acid; solvent system A and the filtrate was injected. The product 2-(2,6-dipropyl-4-(1-hydroxypentyl)phenoxy-2-(2- was desalted by elution with 0.5 L of solvent system A (50 naphthyl)acetic acid; mL/min) then a gradient elution was begun which had as 2-(4-carboxy-2,6-dipropyl)phenoxy-2-phenylacetic acid; initial conditions 100% solvent system.A-0% solvent system 35 2-(4-carboxy-2,6-dipropyl)phenoxyl-2-(3.4- B and reached after 15 minutes 60% solvent system A% dichlorophenyl)acetic acid; solvent system B, and the fractions were collected with an 2-(4-carboxy-2,6-dipropyl)phenoxy-2-(3-bromophenyl) ISCO Foxy 200 fraction collector. The purified fractions acetic acid; and were combined in round bottom flasks, frozen in a -78° C. 2-(4-carboxy-2,6-dipropyl)phenoxy)-2-(3-methoxyphenyl) dry ice-acetone bath, and lyophilized. Combination of the acetic acid. purified product afforded 0.284 g (62%) of the title com 2. A pharmaceutical composition comprising a therapeu tically effective amount of the compound of claim 1 and a pound as a white lyophilized powder. pharmaceutically acceptable carrier. 'H-NMR (400 MHz. CDOH, ppm): 80.89 (t. J=7.60 Hz, 3. A pharmaceutical composition useful in the treatment 3H), 1.21 (d. J-6.80 Hz, 3H), 1.22 (d, J-6.80 Hz, 3H). 45 of hypertension which comprises a pharmaceutically accept 1.57-1.64 (m. 2H), 2.45 (s. 3H), 2.56-2.63 (m. 1H), able carrier and a pharmaceutically effective amount of a 2,70-2.76 (m. 1H), 5.37 (s, 1H). 5.93 (d. J=1.20 Hz, 1H). compound of claim 1. 5.94 (d. J=1.20 Hz, 1H), 6.76 (d. J-8.40 Hz, 1H), 6.85 (d. J=8.80 Hz, 1H), 7.02-7.04 (m. 2H), 7.21 (d. J-8.40 Hz, 2H), k ck k se k