SUBSTITUTED BENZOYLBENZENE-, BIPHENYL- AND 2-OXAZOLE- ALKANOIC ACID DERIVATIVES AS INHIBITORS OF PLA2 AND LIPOXYGENASE

Abstract: There are disclosed compounds of the formula: A(CH2)nO-B, wherein A is phenoxyethyl, phenoxyphenyl or a group having formula (a), wherein X is -N- or (b); Z is (c), (d), (e), (f), -S- or -O-; R<1> is hydrogen, lower alkyl or phenyl; R<2> is hydrogen or lower alkyl; or R<1> and R<2> taken together form a benzene ring; R<3> is hydrogen or lower alkyl; n is 1 -2; B is (g), (h), (i) or (j), wherein R<4> and R<5> are each, independently, hydrogen or lower alkyl; R<6> is halo or nitro; R<7> is (k) or (l); R<8> is lower alkyl; m is 0-3; and the pharmacologically acceptable salts thereof, and their use in the treatment of inflammatory conditions, such as rheumatoid arthritis, ulcerative colitis, psoriasis and other immediate hypersensitivity reactions; in the treatment of leukotriene-mediated naso-bronchial obstructive air-passageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like; and as gastric cytoprotective agents.

Description: SUBSTITUTED BENZOYLBENZENE-, BIPHENYL- AND 2-OXAZOLE- ALKANOIC ACID DERIVATIVES AS INHIBITORS OF PLA 2 AND LIPOXYGENASE This invention relates to novel substituted benzoylbenzene-, biphenyl- and 2 oxazole- " alkanoic acid derivatives possessing lipoxygenase inhibitory, phospholipase A inhibitory and leukotriene antagonist activity, which are useful as anti-inflammatory, anti allergic and cytoprotective agents. It is now well-established that arachidonic acid (AA) is metabolized in mammal by two distinct pathways. The metabolism of arachidonic acid by cyclooxygenase enzyme results in the production of prostaglandins and thromboxanes. The physiological activity of th prostaglandins has already been amply elucidated in recent years. It is now known tha prostaglandins arise from the endoperoxides PGG2 and PGH2 by the cyclooxygenase pathwa of arachidonic acid metabolism. These endoperoxides are also the precursors of the throm boxanes (Tx) A and B2. TxA2 is a vasoconstrictor which stimulates platelet aggregation. I the normal situation, the vasoconstrictive and platelet aggregating properties of the thrombox anes are balanced by another product arising from the endoperoxides in the cyclooxygenas pathway, prostacyclin (PGI2), which is a vasodilator with platelet aggregation inhibitor activity. In the event prostacyclin synthesis is impaired and/or platelet activation is enhanced then thrombosis and vasoconstriction is favored. The role of prostanoids in haemostasis an thrombosis are reviewed by RJ. Gryglewski, CRC Crit. Rev. Biochem.. 7. 291 (1980) and J B. Smith, Am. J. Pathol., 99. 743 (1980). Cyclooxygenase metabolites are known to partici pate directly in the inflammatory response [see Higgs et al., Annals of Clinical Research, Jj5 287-299 (1984)]. This is through their vasodepressor activities, participation in pain and feve augmentation of peptide mediator vascular permeability and edema forming properties Finally, various aspects of cell mediated immunity are influenced by cyclooxygenase products. The other pathway of AA metabolism involves lipoxygenase enzymes an results in the production of a number of oxidative products called leukotrienes. The latter ar designated by the T nomenclature system, and the most significant products of the lipoxy genase metabolic pathway are the leukotrienes B 4 , C4 and D 4 . The substance denominate slow-reacting substance of anaphylaxis (SRS-A) has been shown to consist of a mixture o leukotrienes, with LTC4 and LTD 4 as the primary products and having varying amounts o other leukotriene metabolites [see Bach et al., J. Immun.. 215. 115-118 (1980); Biochem Biophvs. Res. Commun.. 93, 1121-1126 (1980)]. The significance of these leukotrienes is that a great deal of evidence has bee accumulated showing that leukotrienes participate in inflammatory reactions, exhibit chemo tactic activities, stimulate lysosomal enzyme release and act as important factors in the immedi¬ ate hypersensitivity reaction. It has been shown that LTC4 and LTD4 are potent bronchocon- strictors of the human bronchi [see Dahlen et al., Nature.288. 484-486 (1980) and Piper, Int. Arch. Appl. Immunol.. 76. suppl. 1, 43 (1985)] which stimulate the release of mucus from airways in vitro [Marom et al., Am. Rev. Resp. Pis.. 126. 449 (1982)], are potent vaso¬ dilators in skin [see Bisgaard et al., Prostaglandins. 23.797 (1982)], and produce a wheal and flare response [Camp et al., Br. J. Pharmacol.. 80, 497 (1983)]. The nonpeptide leukotriene, LTB4, is a powerful chemotactic factor for leukocytes [see A. W. Ford-Hutchinson, J. Roy. Soc. Med.. 74. 831-833 (1981), which stimulates cell accumulation and affects vascular smooth muscle [see Bray, Br. Med. Bull..29, 249 (1983)]. The activity of leukotrienes as mediators of inflammation and hypersensitivity is extensively reviewed in Bailey and Casey, Ann. Reports Med. Chem.. 19, 87 (1986). Phospholipase A2 (PLA2) is the critical rate limiting enzyme in the arachidonic acid (AA) cascade since it is responsible for the hydrolysis of esterified AA from the C-2 position of membrane phospholipids. This reaction generates two products (1) free A A which is then available for subsequent metabolism by either the cyclooxygenase or lipoxygenase enzymes and (2) lysophospholipid. When alkyl-arachidonoyl-glycerophosphatidylcholine is acted upon by the PLA2 the generation of platelet activating factor (PAF) is initiated; PAF is pro-inflammatory in its own right [see Wedmore et al., Br. J. Pharmacol.. 74, 916-917 (1981)]. In this regard it may be noted that the anti-inflammatory steroids are thought to inhibit eicosanoid synthesis by inducing the synthesis of a PLA2 inhibitory protein denominated macrocortin or lipomodulin [see Flower et al., Nature. London, 27 , 456 (1979) and Hirata et al., Proc. Natn. Acad. Sci. U.S.A.. 77, 2533 (1980)]. As the initial step leading to subsequent conversion of AA to the various eicosanoids by the cyclooxygenase and lipoxygenase pathways, the PLA2-mediated release of AA from membrane phospholipids is a critical event in attempting to deal with the various physiological manifestations which are based on the activity of the eicosanoids and/or PAF. Thus, while PLA2 has been shown to be required for platelet aggregation [Pickett et al., Biochem. J.. 160. 405 (1976)], cardiac contraction and excitation [Geisler et al., Pharm. Res. Commun..2, 117 (1977)], as well as prostaglandin synthesis [Vogt, Adv. Prostagl. Thromb. Res.. , 89 (1978)], the inhibition of PLA2 is indicated in the therapeutic treatment of both PAF induced or cyclooxygenase and/or lipoxygenase pathway product-mediated physiological conditions. There is also evidence that products of the cyclooxygenase/lipoxygenase pathways play key roles in both the pathogenesis of gastric mucosal damage due to extra¬ cellular (gastric and intestinal contents, microorganisms, and the like) or intracellular (ischemia, viruses, etc.) agents, as well as in cytoprotection against such damage. Thus, on the one han prostaglandins exert a cytoprotective effect on the gastric mucosa [see Robert, Gastro enterology. 77. 761-767 (1979)] and this action of the prostaglandins, especially of the series, is considered to be of importance in the treatment of gastro-intestinal ulceration [se Isselbacher, Drugs.23 (suppl.), 38-46 (1987)]. On the other hand, ex vivo experiments hav shown that gastric mucosal tissue from ethanol-pretreated rats is capable of LTC4 generatio and that this LTC4 production is quantitatively related to the severity of the ethanol damage [se Lange et al., Naunvn-Schmiedeberg's Arch. Pharmacol. Suppl.. 330. R27, (1985)]. It ha also been demonstrated that LTC4 can induce vasoconstriction in both venous and arteriol vessels in the rat submucosa [see Whittle, IUPHAR Ninth Int. Cong, of Pharm.. S30- London, England (1984)]. This is significant since ethanol-induced lesion formation in gastri mucosa may be multifactorial with, for example, stasis of gastric blood flow contributin significantly to the development of the hemorrhagic necrotic aspects of the tissue injury [se Guth et al., Gastroenterology. 87. 1083-90 (1984)]. Moreover, in the anesthetized ca exogenous LTD4 evokes both increased pepsin secretion and decreased transgastric potenti [Pendleton et al., Eur. J. Pharmacol. 125. 297-99 (1986)]. A particularly significant rece finding in this regard is that 5-lipoxygenase inhibitors and some leukotriene antagonists prote the gastric mucosa against lesions induced by the oral or parenteral administration of mo nonsteroidal anti-inflammatory drugs [see Rainsford, Agents and Actions. 21, 316-31 (1987)]. Platelet activating factor (PAF) is also implicated as a mediator of gastrointestin damage, and it has been recently shown that 5-lipoxygenase inhibitors inhibit PAF-induce gastric mucosal damage (Gastroenterology. 96, A55, A434, 1989). Accordingly, a significa body of evidence implicates the involvement of lipoxygenase products in the development pathological features associated with gastric mucosal lesions, such as for example, thos induced by ethanol exposure and administration of non-steroidal anti-inflammatory drug Thus, compounds which inhibit the biological effects of leukotrienes and PAF and/or whic control the biosynthesis of these substances, as by inhibiting 5-lipoxygenase, are considered t be of value as cytoprotective agents. Accordingly, the biological activity of the leukotrienes and SRS's, and lipoxygenase as the enzyme leading to the metabolism of AA to leukotrienes, indicates that rational approach to drug therapy to prevent, remove or ameliorate the symptoms of allergie anaphylaxis, asthma and inflammation and for gastric cytoprotection must focus on eith blocking the release of mediators of these conditions or antagonizing their effects. Thu compounds which inhibit the biological effects of the leukotrienes and SRS's and/or whic control the biosynthesis of these substances, as by inhibiting the PLA2-mediated release o arachidonic acid from membrane phospholipids, or by inhibiting lipoxygenase, are considere to be of value in treating such conditions as allergic bronchial asthma, allergic rhinitis, as wel as in other immediate hypersensitivity reactions and in providing gastric cytoprotection. It has now been found that certain novel substituted benzoylbenzene-, biphenyl and 2-oxazole- alkanoic acid derivatives inhibit PLA2 and lipoxygenase, and antagoniz products of the lipoxygenase pathway, and so are useful as anti-inflammatory, anti-allergic an cytoprotective agents. The present invention provides novel compounds having the followin formula: A(CH 2 ) n O-B wherein A is phenoxyethyl, phenoxyphenyl or a group having the formula wherei R 3 R 3 R3 R 3 R 3 I I I I f Z is -C= C- , -C=N- , -N=C- , -N- , -S- or -O- R 1 is hydrogen, lower alkyl or phenyl; R 2 is hydrogen .or lower alkyl; or R 1 and R 2 taken together form a benzene ring; R 3 is hydrogen or lower alkyl; n is i - 2; B is wherein R 4 and R 5 are each, independently, hydrogen or lower alkyl; R6 is halo or nitro; O R4 7 H β - I 5 R 7 is -C-R 8 or -CHCOOR 5 ; R 8 is lower alkyl; m is 0 - 3 ; and the pharmacologically acceptable salts thereof. The term "lower alkyl" refers to moieties having 1 - 6 carbon atoms in th carbon chain. The term "halo" refers to fluoro, chloro or bromo. The grouping A embraces, inter alia. 5- or 6- membered unsaturated nitroge sulfur or oxygen containing mono- or benzofused-heterocycles, optionally substituted wit lower alkyl or phenyl. The foregoing definition embraces the following heterocyclic moietie furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, benz furanyl, benzothienyl, benzothiazolyl, indolyl, benzoxazolyl, quinolinyl, quinazolinyl, benz imidazolyl, quinoxalinyl, quinazolinyl and the like. Especially preferred are quinoliny benzothiazolyl, and benzimidazolyl. The compounds of the invention can form pharmacologically acceptable salt from pharmacologically acceptable organic and inorganic acids such as hydrochloric, hydr bromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoi succinic, methanesulfonic, acetic, propionic, tartaric, citric, lactic, malic, mandelic, cinnami palmitic, itaconic and benzenesulfonic. The compounds which are carboxylic acids are capabl of forming alkali metal and alkaline earth carboxylates and carboxylates of pharmacologicall acceptable cations derived from ammonia or a basic amine. Examples of the latter include b are not limited to cations such as ammonium, mono-, di-, and trimethylammonium, mono-, d and triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethy ammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzy ammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidiniu 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, 1-n-butyl-pipe dinium, 2-methylpiperidinium, 1 -ethyl- 2-methylpiperidinium, mono-, di- and triethanolamm nium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methy ammonium, phenylmonoethanolammonium, and the like. The compounds of the invention can be prepared by the following reactio schemes. When it is desired to prepare compounds having the formula 4-methoxybenzonitrile, for example, is reacted with 3-bromotoluene, followed by reaction with bromine in ethylene bromide to yield the intermediate 3-bromomethyl-[4'-methoxy]benzo- phenone. The bromo intermediate is reacted with sodium cyanide to yield the cyano intermediate, which is hydrolyzed in the presence of base to yield the carboxylic acid, which in turn is demethylated to yield the hyd oxy carboxylic acid intermediate: The hydroxy carboxylic acid intermediate is converted to the methyl ester with methanol in th presence of p-toluenesulfonic acid followed by reaction with an appropriate haloalkyl-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product as the methyl ester. The ester can be hydrolyzed by conventional methods to yield the desired final product in fre carboxylic acid form. Compounds of the invention having the formula can be prepared by several routes: Compounds in which R 6 is nitro and R 7 is the -C-R 8 moiety can be prepared as follows; for example: 4-bromo-3-nitroacetophenone is reacted with 4-iodoanisole in the presence of copper bronze, to yield the intermediate methoxy-containing biphenyl, which is demethylated with aluminum bromide to yield the hydroxy intermediate The latter is then reacted with an appropriate haloalkyl-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product. Compounds in which R 6 is halo and R 7 is the -CHCOOR 5 moiety can be prepared by a process which utilizes the 4-methoxy-biphenyl intermediate of the preceding scheme. Thus, the 4-acetyl-4-methoxy-2-nitrobiphenyl intermediate of the previous scheme is subjected to reduction with stannous chloride to yield the intermediate amino derivative, which is then subjected to replacement of the amino group with a halo group. For example, the amino group can be replaced with fluorine via a diazonium fluoroborate transitory intermediate prepared from the amino intermediate using sodium nitrite and tetrafluoroboric acid. The resulting acetyl-fluoro-methoxy biphenyl intermediate is converted to the corresponding carboxylic aci followed by demethylation with hydrogen bromide to yield the 2-fluoro-4'-hydroxy-[l, biphenyl]-4-acetic acid intermediate: The latter carboxylic acid intermediate is esterified with methanol in the presence of p-toluene¬ sulfonic acid and the latter is reacted with an appropriate haloalkyl-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product as the methyl ester. 18-crown-6 The ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form. Compounds of the invention having the formula can be prepared as follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to yield 4- methoxybenzoin, which is converted to the hemisuccinate by reaction with succinic anhydride. The latter is reacted with urea and acetic acid to yield the intermediate 4-(4-methoxyphenyl)-5- phenyl-2-oxazole-propionic acid. The latter intermediate is demethylated with bromide and esterified with methanol yield the corresponding hydroxy methyl ester intermediate, which is then reacted with appropriate haloalky-A compound, where A is as defined hereinbefore and hal is halo, to yie the desired final product as the methyl ester. K 2 C0 3 / The ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form. The conventional starting materials used in the reaction sequences outlined above are available commercially or can be prepared by methods known in the art. Thus, for example, the intermediate compound 2-bromomethylquinoline can be prepared by the following reaction sequence: The benzo-fused heterocyclic compounds used in the above reaction sequences are also either commercially available or can be prepared by methods conventional in the art. Thus, for example, such intermediates as l-methyl-2-chloromethylbenzimidazole, 2-chloromethylbenz- thiazole and 2-chloromethylbenzoxazole can be prepared by the following reaction scheme wherein X is O, S or NCH3. The reaction is preferably carried out at a controlled low temperature in an organic solvent, such as methylene chloride. The compounds of the invention, by virtue of their ability to inhibit the activity of PLA2 enzyme, as well as that of lipoxygenase enzyme and to antagonize mediators arising from the enzymatic pathway, are useful in the treatment of conditions mediated by products of the oxidation of arachidonic acid. Accordingly, the compounds are indicated in the treatment such diseases as rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, tendiniti bursitis, psoriasis (and related skin inflammation) and similar conditions involving inflamm tion. Moreover, by virtue of their ability to antagonize the effect of LTC4, LTD4 and LTE which are the constituents of SRS-A, they are useful for the inhibition of symptoms induced these leukotrienes. Accordingly, the compounds are indicated in the prevention and treatme of those disease states in which LTC4, LTD4 and LTE4 are causative factors, for examp allergic rhinitis, allergic bronchial asthma and other leukotriene mediated naso-bronchi obstructive air-passageway conditions, as well as in other immediate hypersensitivity reaction such as allergic conjunctivitis. The compounds are especially valuable in the prevention a treatment of allergic bronchial asthma. The compounds of the invention are cytoprotective agents and are consider especially useful when administered with conventional non-steroidal anti-inflammatory drug whose major side effect is gastrointestinal irritation. The cytoprotective effect of t compounds of the invention significantly reduces the gastroirritant impact of conventional an inflammatory drugs. This effect is based not only on the ability of the compounds of t invention to inhibit the biological effects of leukotrienes and/or control the biosynthesis of the substances, as by inhibiting lipoxygenase, but also by a shunting effect, whereby the control the lipoxygenase pathway "shunts" the oxidation of arachidonic acid into the cyclooxygena pathway, giving rise to an increase in the formation of cytoprotective prostaglandins. The biological effects make the compounds of the invention especially useful in treating su conditions as erosive esophagitis, inflammatory bowel disease and induced hemorrhag lesions such as those induced by alcohol or non-steroidal anti-inflammatory drugs (NSAJD' hepatic ischemia, noxious agent induced damage or necrosis of hepatic, pancreatic, renal myocardial tissue; liver parenchymal damage caused by hepatotoxic agents such as carb tetrachloride and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bi salt-induced pancreatic or gastric damage; trauma or stress-induced cell damage; and glycero induced renal failure. When the compounds of the invention are employed in the treatment of allerg airway disorders, as anti-inflammatory agents and/or as cytoprotective agents, they can formulated into oral dosage forms such as tablets, capsules and the like. The compounds c be administered alone or by combining them with conventional carriers, such as magnesiu carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacant methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the lik Diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, table disintegrating agents and the like may be employed. The compounds may be encapsulated wi or without other carriers. In all cases, the proportion of active ingredients in said compositions both solid and liquid will-be at least to impart the desired activity thereto on oral administration. The compounds may also be injected parenterally, in which case they are used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. For administration by inhalation or insufflation, the compounds may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until the optimum effect under the circumstances is reached. In general, the compounds of the invention are most desirably administered at a concentration that will generally afford effective results without causing any harmful or deleterious side effects, and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits administered at suitable times throughout the day. The PLA2 and lipoxygenase inhibitory and leukotriene antagonist effects, as well as the anti-inflammatory and potential gastroirritant effects of the compounds of the invention, may be demonstrated by standard pharmacological procedures which are described more full in the examples given hereinafter. These procedures, inter alia, determine the specificity of action of the compounds of the invention as PLA2 inhibitors as measured by their ability to inhibit the synthesis of LTB 4 and PGE2 by rat glycogen-elicited polymorphonuclear leukocytes, as well as measure their ability to inhibit arachidonic acid release mediated by human source PLA2. The pharmacological testing additionally demonstrates the ability of the compounds of the invention to inhibit, in vivo, the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism. The following examples show the preparation and pharmacological testing of compounds within the invention. Example 1 l-r2-Nitro-4'-f2-αuinolinvlmethoxv -ri .l '-hinhenvn4-vnethanone A. 4-Acetyl-4'-methoxy-2-nitro biphenyl . A stirred mixture of 4-iodoanisole (43.65 g, 0.187 mole), 4-bromo-3-nitro acetophenone (40.6 g, ' 0.166 mole) and copper powder (copper bronze, 36 g, Θ.567 mole) kept under nitrogen is placed in an oil bath heated at 80°C. The temperature is slowly raised to 110°C and the mixture is kept at this temperature for 5 days (TLC, 8:2 hexane-ethyl acetate). Upon cooling the mixture is dissolved in dichloromethane and filtered through a Celite pad. The filtrate and washings are evaporated and the residual thick, dark brown oil (58.4 g) is flash chromatographed (on silica Merck 60, preabsorbed in dichloromethane, eluted with 9:1 hexane-ethyl acetate to remove the impurities and 8:2 hexane-ethyl acetate to recover the main product) to provide 16.2 g (32%) of the title compound (yellow solid, m.p. 124-126°C). NMR (CDC1 3 , 400 MHz): δ 2.67 (s, 3H, COCH 3 ), 3.85 (s, 3H, OCH 3 ), 6.97 (d, 2H, J 8.74 Hz, ArH), 7.27 (d, 2H, J 8.74 Hz, ArH), 7.56 (d, IH, J 8 Hz, ArH), 8.15 ( d, 1 H, J 8 Hz, ArH), 8.34 (s, IH, ArH) MS (El, m/z): 271 (M) \+ B. 4- Acetyl-4'-hydroxy-2-nitro biphenyl To a stirred solution of AlBr 3 (12.6 g, 47.4 mmole) in benzene (45 mL) is added dropwise under nitrogen a solution of the methylether (5 g, 18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours. (TLC, 8:2 hexane-ethyl acetate). The mixture is cooled in an ice bath and the complex is decomposed by the dropwise addition of 6N-HC1 (ca. 37 mL). The organic layer is separated and the aqueous phase is reextracted with ether (3x). The combined extracts are concentrated to a small volume and extracted again with 2.5N-NaOH (2x50 mL + 1x10 L). The basic extracts are cooled and acidified with concentrated HC1 (to pH 2). The solid is collected and dried (4.27 g, 90%). It is used in the next step without further purification. NMR (CDC1 3 , 400 MHz): δ 2.67 (s, 3H, COCH 3 ), 5.03 (broad, IH, OH), 6.91 (d, 2H, J 8.56 Hz, ArH), 7.23 (d, 2H, J 8.57 Hz, ArH), 7.55 (d, IH, J 7.9 Hz, ArH), 8.15 (d, IH, J 8.1 Hz, ArH), 8.34 (s, IH, ArH). MS (El, m/z): 257 (b.p., M) + C. 1 -r2-Nitro-4'-f 2-quinolinvDr 1.1 '-biphenyl-4-vnethanone A mixture of the phenol (4.4 g, 17.12 mmole) of Step B, powdered anhy¬ drous potassium carbonate (2.37 g, 17.12 mmole), 18-crown-6 (0.453 g, 1.71 mmole) and acetonitrile (38 mL) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloro- methylquinoline (3.34 g, 18.83 mmole, free base freshly prepared from the hydrochloride salt) is added and the mixture is refluxed for 10 hours. (TLC, 7:3 hexane-ethyl acetate). A 10% excess of potassium carbonate, 18-crown-6 and the chloromethylquinoline is added and reflux continued for another 4 hours ■ The solvent is removed and the residue is diluted with water and extracted with ethyl acetate (3x). The extracts are washed and dried (MgSO 4 ). The residue is flash chromatographed. (on silica Merck 60, preabsorbed in dichloromethane and eluted in order of increasing polarity with 7:3, 1:1 and 1:3 hexane-ethyl acetate followed by pure ethyl acetate) to provide the pure title compound (2.59 g). Reciystallization from toluene yields a yellow solid, m.p. 160-162°C (2.05 g, 30%). NMR (CDC1 3 , 400 MHz): δ 2.66 (s, 3H, COCH 3 ), 5.43 (s, 2H, OCH 2 Ar), 7.10 (d, 2H, J 8.7 Hz, ArH), 7.27 (d, 2H, J 8.7 Hz, ArH), 7.56 (m, 2H, ArH), 7.68 (d, IH, J 8.49 Hz, ArH), 7.75 (dt, IH, ArH), 7.84 (d, IH, J 8.1 Hz, ArH), 8.09 (d, IH, J 8.5 Hz, ArH), 8.14 (dd, IH, ArH), 8.22 (d, IH, J 8.49 Hz, ArH), 8.34 (s, IH, ArH) MS (El, m/z): 398 (M) + , 256, 158, 142 (b.p.) Analysis for: C 24 H 18 N 2 O 4 Calculated: C, 72.35; H, 4.55; N, 7.03 Found: C, 71.96; H, 4.75; N, 6.80. Example 2 l-Fluoro^'-Q-quinolinvImethoxv l '-hiphenvM^-acetic acid A. 4-Acetyl-4'-methoxy-2-amino biphenyl To a stirred, warm solution of tin (II) chloride (49.4 g, 218.9 mmole) in a mixture of concentrated HC1 (72 mL) and ethanol (99 mL) is added over a period of 45 minutes the nitro derivative (10.7 g, 39.5 mmole) of Example 1A. The resulting yellow solution is refluxed for 3.5 hours (TLC, 1:1 hexane-ethyl acetate). The ethanol is removed and the residue is poured into a mixture of 50% NaOH (360 mL) and ice. The resulting . solid is extracted (dichloromethane, 3x), the extracts are washed with water and dried (Na 2 S0 4 ). Removal of the solvent provides a yellow solid (9.31 g, 97.8%), m.p. 152- 154°C. NMR (CDC1 3 , 400 MHz): δ 2.59 (s, 3H, COCH 3 ), 3.80 (s, 3H, OCH 3 ), 6.97 (d, 2H, J 8.7 Hz, ArH), 7.23 (d, IH, J 7.4 Hz, ArH), 7.40 (d, 2H, J 8.7 Hz, * ArH), 7.48 (d, IH, J 7.3 Hz, ArH), 7.49 (s, IH, ArH). MS (El, m/z): 241 (b.p., M) + , 226 (M-CH 3 ) + , 198 (M-COCH 3 ) + , 83. B. 4- Acetyl-4'-methoxy-2-fluoro biphenyl To a stirred, ice cold mixture of the aniline (9.2 g,- 38.2 mmole) in tetrahydro¬ furan (26 mL), water (9.8 mL) and HBF 4 (48%, 35.1 mL) is slowly added a solution of sodium nitrite (2.82 g, 40.85 mmole) in water (5 mL). The internal temperature is kept below 5°C during the addition. The mixture is then stirred for an additional 20 minutes at 0-5°C. The diazonium fluoroborate is filtered off and washed with 10% HBF 4 and 10% methanol in ether and dried in vacuo. The salt is decomposed by heating at 70°C in xylene (95 mL). When the decomposition subsides, the mixture is refluxed for another 2.5 hours (TLC, 1:1 hexane-ethyl acetate, UV). The xylene is removed and the residue is extracted with ethyl acetate (3x) and ether. The combined extracts are washed with 10% sodium carbonate and brine and dried (MgSO 4 ). Removal of the solvent provides an amber oil (6.03 g) which is purified by flash chromatography (on silica Merck 60, preabsorbed in dichloromethane and eluted with 95:5 hexane-ethyl acetate). The title compound is obtained as a yellow solid 3.12-4.75 g, (33-51% depending on the run); m.p. 100-101°C. NMR (CDC1 3 , 400 MHz): δ 2.62 (s, 3H, COCH 3 ), 3.86 (s, 3H, OCH 3 ), 7.00 (d, 2H, J 8.9 Hz, ArH), 7.50-7.80 (m, 5H, ArH). MS (El, m z): 244 (M) + , 229 (b.p., M-CH3) + C. 2-Fluoro-4'-methoxy- fl.l '-biphenyll -4-acetic acid A mixture of sulfur (0.468 g, 14.6 mmole), morpholine (2.57 mL) and the ketone (3.95 g, 16.2 mmole) of Step A is refluxed for 17 hours (TLC, acid treated silica plate, 8:2 hexane-ethyl acetate). Upon cooling, glacial acetic acid (9.9 mL), sulfuric acid (1.6 mL) and water (4 mL) are added and the reflux resumed for 30 hours. Water is then added and the mixture is extracted with ether (3x). The combined extracts are concentrated to a smaller volume and extracted with 10% sodium carbonate. The basic extracts are carefully acidified in the cold with concentrated HC1 (to pH 2). The title acid is extracted with ether (3x) and the extracts are washed and dried (MgSU 4 ). Removal of the solvent provides a tan to brown solid (2.37 g, 56.3%) melting at 140-142°C. NMR (CDC1 3 , 400 MHz): δ 3.68 (s, 2H, CH 2 COO), 3.85 (s, 3H, OCH 3 ), 6.96-7.50 (m, 7H, ArH). MS (El, m/z): 260 (M) + , 215 (b.p., M-COOH) + . D. 2-Fluoro-4'-hydroxy-r 1.1 '-biphenyll -4-acetic acid To a solution ofthe methylether (1.31 g, 5.04 mmole) of Step C in glacial acetic acid (17 mL) is added dropwise 48% HBr in acetic acid (25 mL) and the mixture is refluxed for 4.5 hours (TLC, 7:3 hexane-ethyl acetate). A little water is added and the mix¬ ture is extracted with ether (3x). The extracts are washed and dried (MgSO 4 ). Removal of the solvent provides the title compound as a tan solid (1.13 g, 92%), m.p. 208-210°C. NMR (DMSO-d 6 , 400 MHz): δ 3.61 (s, 2H, CH 2 COO), 6.83 (d, 2H, J 8.64 Hz, ArH), 7.1-7.42 (m, 5H, ArH), 9.61 (s, IH, COOH). ' MS ( C I, m/z)f 246 (M) + , 201 (b.p., M-COOH) + - E. 2-Fluoro-4'-hydroxy-[ 1.1 '-biphenyl] -4-acetic acid methylester A solution ofthe acid (1.1 g, 4.47 mmole) of Step D in methanol (10 mL) containing p-toluenesulfonic acid ■ H 2 0 (0.159 g) is refluxed for 1.5 hours (TLC, acid treated silica plate, hexane-ethyl acetate 7:3). The solvent is removed, the residue is dissolved in ethyl acetate, washed with brine and dried (MgSO 4 ). The tan solid (1.16 g, m.p. 115-118°C, quantitative yield) is used as such in the next step. NMR (CDC1 3 , 400 MHz): δ 3.65 (s, 2H, CH 2 COO), 3.73 (s, 3H, COOCH 3 ), 6.88 (d, 2H, J 8.8 Hz, ArH), 7.10 (m, 2H, ArH), 7.32-7.44 (m, 3H, ArH). MS (El, m/z): 260 (M) + , 201 (b.p., M-COOCH 3 ) + . F. 2-Fluoro-4'-f2-quinolinylmethoxyVri.r-biphenyl1-4-acetic acid methylester A stirred mixture of the phenol (1.16 g, 4.46 mmole) of Step E, powdered anhydrous potassium carbonate (0.616 g, 4.46 mmole), 18-crown-6 (0.118 g, 0.445 mmole) and acetonitrile (10 mL) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloromethylquinoline (0.871 g, 4.9 mmole, free base freshly prepared from the hydro- chloride salt) is then added and the mixture is placed in an oil bath heated at 65°C for 5 hours. A 10% excess of potassium carbonate, 18-crown-6 and the chloromethylquinoline is added and the heating continued for another 6 hours (TLC, 19:1 dichloromethane-methanol or 7:3 hexane-ethyl acetate). The solvent is removed and the residue is diluted with water and extracted with ethyl acetate (3x). The extracts are washed and dried (MgSO 4 ). Removal of the solvent provides a tan solid which is purified by flash chromatography (on silica Merck 60, preabsorbed with dichloromethane, eluted with 7:3 hexane-ethyl acetate). The title com¬ pound thus obtained (1.55 g, 87%) is recrystallized from methanol. The off-white solid melts at 99-101°C. NMR (CDC1 3 , 400 MHz): δ 3.64 (s, 2H, CH 2 COO), 3.72 (s, 3H, COOCH 3 ), 5.43 (s, 2H, OCH 2 Ar), 7.1 (m, 4H, ArH), 7.35 (t, IH, ArH), 7.47 (d, 2H, ArH), 7.55 (t, IH, ArH), 7.69 (d, IH, ArH), 7.74 (t, IH, ArH), 7.84 (d, IH, ArH), 8.09 (d, IH, ArH), 8.20 (d, IH, ArH). MS (El, m z): 401 (M) + , 142, 114 (b.p.) Analysis for: C 25 H 20 FNO 3 Calculated: C, 74.80; H, 5.02; N, 3.49. Found: C, 74.68; H, 4.65; N, 3.49. G. 2-Huoro-4'-(2-quinoh^ylmethoxyVri.r-biphenyl " l -4-acetic acid A solution of the ester (1.69 g, 4.21 mmole) of Step F, in dry tetrahydrofuran (20 mL) is treated dropwise under nitrogen with lN-LiOH (12.6 mL) and the mixture is stirred for 3 hours at room temperature (TLC, 19:1 dichloromethane-methanol or 1:1 hexane- ethyl acetate). The solvent is removed, the residue is treated with water and neutralized (to pH 6.5) with 10% acetic acid. The acid is extracted with ethyl acetate (large volume needed) and the extracts are dried (MgSO 4 ) anc l evaporated to dryness to yield an off-white solid (1.65 g, quantitative yield, m.p. 190-193°C, dec.). Recrystallization from ethyl acetate pro¬ vides a white solid (1.32 g, 80%, m.p. 195-196°C dec.). The analytical sample is dried in. vacuo at 40°C. NMR (DMSO-dg, 400 MHz): δ 3.62 (s, 2H, CH 2 COO), 5.41 (s, 2H, CH 2 OAr), 7.15 (m, 4H, ArH), 7.41 (t, IH, J 8 Hz, ArH), 7.48 (d, 2H, ArH), 7.61 (t, IH, ArH), 7.69 (d, IH, ArH), 7.78 (dt, IH, ArH), 8.01 (m, 2H, ArH), 8.42 (d, IH, ArH), 12.42 (s, COOH). MS (+ FAB, m/z): 388 (M) + - Analysis for: C 24 H 18 FNO 3 Calculated: C, 74.41; H, 4.68; N, 3.62. Found: C, 74.28; H, 4.48; H, 3.69. Exampte 3 3.r4-f2.Quinolinvlτnethoxv,henzovπbenzene acetic acid A. 3-Methyl-[4'-methoχy]-benzophenone ■ A 3-neck flask equipped with a condenser, mechanical stirrer and dropping funnel is charged under nitrogen with 1.925 g (79.19 g.a.) of magnesium turnings and enough ether to cover the turnings. A few drops of a solution of 3-bromotoluene (15.79 g, 92.28 mmole) in ether (40 mL) is then added along with a crystal of iodine to initiate the reaction. The remainder of the solution is then added dropwise and the mixture is refluxed until most of the magnesium has disappeared. After cooling, a solution of 4-methoxybenzo- o nitrile (10 g, 75.1 mmole, dried in vacuo over P 2 O 5 ) is added in one portion. The mixture is refluxed for 2 hours (TLC, no starting material present), cooled (ice bath) and slowly treated with cold water (130 mL) followed by dilute H 2 SO 4 (1: 1, v/v, 25 mL). The decom¬ position of the complex is completed by refluxing the mixture for 4 hours (followed by TLC, 8:2 ether-ethyl acetate). Following stirring overnight at room temperature, the layers are 5 separated and extracted with ether (3x). The extracts are washed with 5% NaHCO 3 , dried (MgSO 4 ) and evaporated to dryness. The crude material (amber oil, 13.93 g) is purified by flash chromatography (on silica Merck-60, eluted with 8:2 petrolether-ethyl acetate) to pro¬ vide the title compound as a light yellow oil (12.5 g, 73.5%). NMR (CDC1 3 , 400 MHz): δ 2.4 (s, 3H, CH 3 ), 3.9 (s, 3H, OCH 3 ), 6.96 (d, J 8.8 Hz, 0 2H, ArH), 7.38 (m, 2H, ArH), 7.53 (d, J 6.9 Hz,lH, ArH), 7.57 (s, IH, ArH), 7.82 (d, J 8.7 Hz,2H, ArH). MS (El, m/z): 226 (M) + , 135 (b.p.), 91. B. 3-Bromomethyl-r4'-methoxy1-benzophenone A solution of the benzophenone (17.5 g, 77.4 mmole) of Step A in ethylene bromide (26.5 mL) (containing a small amount of benzoyl peroxide) is heated at reflux. A solution of bromine (12.7 g, 79.6 mmole) in ethylene bromide (15 mL) is added dropwise over 30 minutes while the mixture is irradiated with a Photolamp (300 W). Reflux is con¬ tinued for 17 hours (TLC, 9:1 petrolether-ethylacetate, traces of starting material still present). The solvent is removed in vacuo and the residue (brown oil, 39.22 g) is purified by flash chromatography (on silica Merck-60, preabsorbed in dichloromethane, eluted with 9:1 petrol- ether-ethyl acetate) to give unreacted starring material (2.59 g, ca. 15%) along with the desired product (14.36 g, 61% or 71.5% based on recovered unreacted starting material) and some mixed fractions (ca. 5.20 g). The light yellow solid melts at 58-61°C and it is used as such in the next step. NMR (CDC1 3 , 400 MHz): δ 3.88 (s, 3H, OCH 3 ), 4.52 (s, 2H, CH 2 Br), 6.96 (d, J 8.8 Hz, 2H, ArH) 7.44 (t, J 7.6 Hz, IH, ArH), 7.58 (d, J 7.8 Hz, IH, ArH), 7.66 (d, J 7.6 Hz, IH, ArH), 7.76 (s, IH, ArH), 7.81 (d, J 8.8 Hz, IH, ArH). MS (El, m/z): 306/304 (1 bromine, M) + , 225, 135 (b.p.). Trace of dibromo at 386/384/382 (possibly ) C. 3-Cyanomethyl-r4'-methoxyl-benzophenone The bromo compound (14 g, 45.9 mmole) of Step B, is dissolved in dioxane (30 mL) and a solution of NaCN (7 g) in water (28.5 mL) is added. The mixture is refluxed for 6 hours (TLC, petrolether-ethyl acetate 8:2), charcoalized if needed and extracted with ether (3x). The extracts are dried (MgS0 ) and evaporated to dryness to yield a brown oil (13.44 g). The crude product is purified by flash chromatography (on silica Merck-60, pre¬ absorbed in dichloromethane, eluted with 6:4 hexane-ethyl acetate) to provide the pure product (10.69 g, 92%) as a light yellow oil that sets up upon standing. The nearly colorless solid melts at 70-71°C. NMR (CDCI 3 , 400 MHz): δ 3.80 (s, 2H, CH 2 CN), 3.87 (s, 3H, OCH 3 ), 6.95 (d, J 8.6 Hz, 2H, ArH), 7.48 (t, J 7.7 Hz, IH, ArH), 7.54 (d, J 7.6 Hz, IH, ArH), 7.68 ( s+d, J 7.6 Hz, 2H, ArH), 7.79 (d, J 8.6 Hz, 2H, ArH). MS (El, m/z): 251 (M) + , 135 (b.p.). D. 3-[4-Methoxybenzoyl1-phenylacetic acid The nitrile (4 g, 15.9 mmole) of Step C, is dissolved in 40% NaOH (40 mL) and the solution is heated at reflux under nitrogen for 7 hours (TLC, toluene-methanol 9:1). Water is added while cooling in an ice bath. The solution is washed with ethyl acetate and then acidified in the cold with concentrated HCl (to pH 2). The acid is extracted with ethyl acetate (3x) and the extracts are dried (MgS0 4 ) and evaporated to dryness to yield the crude product (yellow solid, 3.56 g, 82%), m.p. 138-140°C. NMR (CDC1 3 , 400 MHz): δ 3.72 (s, 2H, CH 2 COO), 3.88 (s, 3H, OCH 3 ), 6.95 (d, J 8.8 Hz, 2H, ArH), 7.43 (t, IH, ArH), 7.48 (d, IH, ArH), 7.65 (d. IH, ArH), 7.68 (s, IH, ArH), 7.81 (d, J 8.6 Hz, 2H, ArH). MS (El, m/z): 270 (M) + , 211 (M-CH 2 COOH) + , 135 (b.p.), 107. E. 3-r4-Hydroxybenzoyl1-phenylacetic acid An intimate mixture of the acid (8.1 g, 0.030 mole) of Step D, and pyridine hydrochloride (13.87 g, 0.120 mole) is stirred under nitrogen in an oil bath heated at 200- 210°C for 7 hours (TLC, toluene-methanol 9:1, dichloromethane-methanol 9:1). After cooling, the mixture is dissolved in dichloromethane. The solution is extracted with 1N- NaOH, the extract acidified in the cold with concentrated HCl and extracted with ethyl acetate (3x). After drying (MgS0 4 ) the solvent is removed to provide the crude title compound as a tan solid (7.61 g, quantitative yield), m. p. 147-149°C. NMR (DMSO-d 6 , 400 MHz): δ 3.67 (s, 2H, CH 2 COO), 6.88 (d, J 8.84 Hz, 2H, ArH), ca. 7.5 (m, 4H, ArH), 7.65 (d, J 8.8 Hz, 2H, ArH), 10.4 (s, IH, OH), ca. 12.3 (s, IH, COOH). MS (m/z): 257 (M+H) + , 217, 131, 91 (b.p.). F. 3-[4-Hvdroxybenzoyl1-phenylacetic acid methylester A mixture of the acid (8.56 g, 33.4 mmole) of Step E and p-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70 mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanol is evaporated and the residue is dissolved in ethyl acetate and washed with brine. After drying (MgSO 4 ) the solvent is removed to yield a tan solid (8.68 g, 96.2%, m.p. 111-113°C). The crude product is used as such in the next step. NMR (CDC1 3 , 400 MHz): δ 3.69 (s, 2H, CH 2 COO), 3.69 (s, 3H, COOCH 3 ), 6.86 (d, J 8.4 Hz, 2H, ArH), 7.41 (t, IH, 7.58 Hz, IH, ArH), 7.47 (d, J 7.56 Hz, IH, ArH), 7.62 (d, J 7.4 Hz, IH, ArH), 7.64 (s, IH, ArH), 7.74 (d, 2H, J 8.4 Hz, ArH). MS (m/z): 271(M+H) + , 217, 131, 91 (b.p.). G. 3-[4-(2-Ouinohnylmethoxy)benzoyl]benzene acetic acid methylester A mixture ' of the phenol (4 g,14.8 mmole) of Step F, powdered anhydrous K 2 CO 3 (2.05 g, 14.8 mmole) and 18-crown-6 (0.4 g, 1.48 mmole) in acetonitrile (35 mL) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloromethylquinoline (2.9 g, 16.28 mmole, freshly prepared from the hydrochloride salt) is added in one portion and the mixture is heated in an oil bath kept at 65-70°C for 8 hours (TLC, toluene-methanol 9:1). A 10 % excess of K 2 CO 3 , crown ether and chloromethylquinoline is added and the heating is continued for another 8 hours. The acetonitrile is evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is dried (MgSO 4 ) and evaporated to yield a tan solid (6.57 g). The crude product is purified by flash chromatography (on silica Merck-60, preabsorbed in dichloromethane, eluted with petrolether-ethyl acetate 7:3) to give the title compound as a light yellow solid (5.03 g, 82.7%) m.p. 93-95°C. NMR (CDC1 3 , 400 MHz): δ 3.67 (s,5H, CH 2 COO + OCH 3 ), 5.45 (s, 2H, ArCH 2 0), 7.08 (d, J 8.8 Hz, 2H, ArH), 7.40 (t, J 7.8 Hz, IH, ArH), 7.46 (d. J 7.7 Hz, IH, ArH), 7.55 (t, J 7.3 Hz, IH, ArH), 7.6-7.66 (m, 3H, ArH), 7.7-7.82 (m, 4H, ArH), 8.07 (d, IH, ArH), 8.20 (d, J 8.4 Hz, IH, ArH). MS (El, m z): 411 (M) + , 142, 121 (b.p.). H. 3-r4-f2-Ouinolinylmethoxy ' .benzoyl1benzene acetic acid To a solution of the ester (5 g, 12.16 mmole) of Step G, in dry tetrahydro¬ furan (66 mL) is added lN-LiOH (37 mL, 37 mmole) and the mixture is stirred under nitrogen at room temperature for 2.5 hours (TLC, toluene-MeOH 9:1). The tetrahydrofuran is evaporated and the residue is diluted with water, acidified (to pH 6.5) with 10% acetic acid and extracted with ethyl acetate (3x). The extracts are washed with brine, dried (MgSO 4 ) and evaporated to dryness. The crude product (4.94 g, pale yellow solid) is recrystallized from ethyl acetate to provide 3.65 g (75%) ofthe pure title compound (white solid, m.p. 146-147°C). NMR (DMSO-d 6 , 400 MHz): δ 3.68 (s, 2H, CH 2 COO), 5.48 (s, 2H, ArCH 2 O), 7.22 (d, 2H, J 8.8 Hz, ArH), 7.47 (m, IH, ArH), 7.53 (m, 2H, ArH), 7.62 (m, 2H, ArH), 7.69 (d, J 8.4 Hz, IH, ArH) 7.74-7.82 (m, 3H, ArH), 8.2 (m, 2H, ArH), 8.43 (d, J 8.5 Hz, IH, ArH), 12.39 ( IH, COOH). MS (El, m/z): 397 (b.p., M) + , 380 (M-OH) + , 142 . Analysis for: C 25 H 19 N0 4 Calculated: C, 75.57; H, 4.78; N, 3.53. Found: C, 75.22; H, 4.76; N, 3.39. Example 4 3-r4-f2-Naphthalenvlmethoxv)henzovπhenzene acetic acid A. 3-r4-(2-Naphthalenylmethoxy')benzovπbenzene acetic acid methylester A mixture of the phenol (1 g, 3.7 mmole) of Example 3F, powdered anhhy- drous K 2 CO 3 (0.48 g, 3.7 mmole), 18-crown-6 (0.098 g, 0.37 mmole) and acetonitrile (10 mL) is stirred under nitrogen for 15 minutes. 2-Bromomethylnaphthalene (0.496 g, 4.07 mmole) is added and the mixture is placed in an oil bath heated at 65-70°C for 10 hours (TLC, dichloromethane-ethyl acetate 8:2). A 10% excess of K 2 CO 3 , crown ether and bromo- methylnaphthalene is added and the heating is continued for another 4 hours. The acetonitrile is evaporated and the residue dissolved in water and extracted with ethyl acetate (3x). The extracts are washed with lN-NaOH and brine, dried (MgSO 4 ) and evaporated to dryness. The crude product (1.49 g, waxy solid) is used as such in the next step. NMR (CDC1 3 , 400 MHz): δ 3.7 (s, 5H, OCH 3 + CH 2 COO), 5.32 (s, 2H, ArCH 2 O), 7.08 (d, J 8.7 Hz, 2H, ArH), 7.4-7.56 (m, 5H, ArH), 7.63-7.68 (m, 2H, ArH), 7.82-7.92 (m, 6H, ArH). MS (m/z): 410 (M) + , 141 (b.p.). B. 3-r4-(2-Naphthalenylmethoxy>benzovnbenzene acetic acid A solution of the ester (1.29 g, 3.15 mmole) of Step A, is treated dropwise with IN-LiOH and the mixture is stiired under nitrogen overnight The solvent is evaporated and the residue is dissolved in water, acidified in the cold with 10% acetic acid (to pH 3) and extracted with ethyl acetate (3x). The extracts are dried (MgS0 ) and evaporated to dryness. The residue (1.24 g, quantitative yield) is recrystallized by dissolving it in a relatively large volume of warm ethyl acetate-dichloromethane followed by concentrating to half volume. The precipitate is collected and dried at 45°C in vacuo (0.610 g, 48.8%), m.p. 150-152°C. NMR (DMSO-dg, 400 MHz): δ 3.70 (s, 2H, CH 2 COO), 5.40 (s, 2H, ArCH 2 ), 7.20 (d, 2H, ArH), 7.45-7.60 (m, 7H, ArH), 7.75 (d, 2H, ArH), 7.95 (m, 3H, ArH), 8.02 (s, IH, ArH), 12.47 (broad s, IH, COOH). MS (+FAB, m z): 397 (M+H) + , 217, 141. Analysis for: C 26 H 20 O 4 Calculated: C, 78.78; H, 5.09. Found: C, 78.12; H, 5.13. Example 5 5-Phenyl-4-r4-f2-Ouinolinylmethoxy)-phenvπ-2-oxazole propanoic acid A. 4-Methoxybenzoin To a solution of KCN (5 g) in water (35 mL) is added 4-methoxybenzalde- hyde (27.2 g, 0.2 mole), benzaldehyde (21.2 g, 0.2 mole) and 95% ethanol (70 mL). The mixture is refluxed under nitrogen for 4.5 hours and the ethanol removed in vacuo. Water (200 mL) is added to the residue and then distilled off at reduced pressure (to remove remaining unreacted bezaldehyde). The procedure is repeated twice and the residual water azeotroped with ethanol. The crude product (56.3 g, orange semi-solid) is purified by flash- chromatography (on silica Merck-60, preabsorbed in dichloromethane-ethyl acetate and eluted with hexane-ethyl acetate 8:2) to yield a light yellow solid (20.1 g, 41.5%), m.p. 99-101°C. NMR (CDC1 3 , 400 MHz): δ 3.82 (s, 3H, OCH 3 ), 4.62 (broad s, IH, OH), 5.88 (s, IH, CHOH), 6.86 (d, 2H, J 8.94Hz, ArH), 7.22-7.38 (m, 5H, ArH), 7.91 (d, 2H, J 8.94Hz, ArH). MS ( C I, m/z): 243 (b.p., M+H) + , 225, 197, 137 (M-PhCO) + B. 4-Methoxybenzoin hemisuccinate A mixture of 4-methoxybenzoin (20 g, 0.083 mole) and succinic anhydride (9.1 g, 0.091 mole) in toluene (6 mL) is heated for 7 hours under nitrogen at 135°C (internal temp.). The solution is poured into 0.5N-NaHCO 3 , the organic layer was separated and re- extracted with 0.5N-NaHCO 3 . The combined extracts are washed with ether and then acidified in the cold with concentrated HCl. The liberated oil is extracted with ethyl acetate ' (3x), the extracts washed with water and dried (MgSO 4 ). Removal of the solvent yields a yellow solid (20.89 g, 73.8%), m.p. 104-108°C. It is used in the next step without further purification. NMR (CDC1 3 , 400 MHz): δ 2.72-2.82 (mm, 4H, CH 2 CH 2 COO), 3.82 (s, 3H, OCH 3 ), 6.86 (d, 2H, J 9.1Hz, ArH), 7.34-7.46 (m, 5H, ArH), 7.92 (d, 2H, J 9.1Hz, ArH). MS (EL m/z): 342 (M) + , 135 (b.p.). C. 4-(4-Methoxyphenyl ' )-5-phenyl-2-oxazole-propanoic acid A mixture of the crude 4-methoxybenzoin hemisuccinate (20.8 g, 0.061 mole) of Step B, urea (8.7 g, 0.146 mole) and acetic acid (60 mL) is heated at reflux under nitrogen for 5.5 hours. The mixture is cooled and poured into ice water. The liberated oil is extracted with ethyl acetate (3x). The extracts are washed with water until neutral and then extracted with saturated sodium carbonate. The combined aqueous extracts are carefully acidified in the cold with concentrated HCl and extracted with ethyl acetate. The organic extract is dried (MgSO 4 ) and evaporated to dryness to provide a waxy yellow oil (19.6 g). Purification of the residue by flash chromatography (on silica Merck-60, eluant: dichloro¬ methane-ethyl acetate 8:2) yields a pale yellow solid (14.3 g, 72.7%), m.p. 100-101°C. NMR (CDC1 3 , 400 MHz): δ 2.96 (t, 2H, CH 2 C), 3.20 (t, 2H, CH 2 COO), 3.83 (s, 3H, OCH 3) , 6.90 (d, 2H, ArH), 7.28-7.38 (m, 3H, ArH), 7.54-7.62 (m, 4H, ArH). MS (El, m/z): 323 (M) + , 278 (b.p., M-COOH) + , 152, 77. D. 4-(4-Hvdroxyphenyl)-5-phenyl-2-oxazole-propanoic acid To a solution ofthe methoxyacid (5.6 g, 17.3 mmole) of Step C, in acetic acid (55 mL) is added 48% HBr (84 mL) and the mixture is heated at reflux under nitrogen for 8 hours (TLC, 1:1 hexane-ethyl acetate). After cooling, water is added and the solution extracted with ethyl acetate (3x). The extract is dried (MgSO ) and evaporated to dryness. The residue (brown waxy oil, 5.25 g, 99%) is used in the next step without further purification. For analytical characterization a small sample is flash-chromatographed (on silica Merck-60, eluant: dichloromethane -methanol 98:2 and 95:5). NMR (DMSO-de, 400 MHz): δ 2.75 (t, 2H, J 7.14Hz, CH 2 C), 3.02 (t, 2H, J 7.1Hz, CH 2 COO), 6.77 (d, 2H, J 8.7Hz, ArH), 7.35 (d, 2H, J 8.55Hz, ArH), 7.41 (t, 3H, J 7.12Hz, ArH), 7.50 (d, 2H, J 7Hz, ArH), 9.64 (broad s, exchangeable). MS (El, m/z): 309 (M) + , 264 (M-COOH) + , 121, 105, 77. E. 5-Phenyl-4-(4-hydroxyphenyl -2-oxazole propanoic acid methylester A solution of the crude acid (5 g, 16.18 mmole) of Step D, in methanol (40 mL), containing a small amount of p-toluenesulfonic acid " H 2 O (0.58 g) is refluxed for 2.5 hours. The methanol is evaporated and the residue is partitioned between ethyl acetate and 20% NaCl. The extracts are washed, dried (MgSO 4 ) and evaporated to yield a thick oil (ca. 4.8 g). The residue is flash-chromatographed (on silica Merck-60, preabsorbed in dichloro¬ methane, eluted with a dichloromethane-ethyl acetate gradient from 90:10 to 75:25) to yield a white solid (3.56 g, 68%), m.p. 115-116°C. NMR (CDC1 3 , 400 MHz): δ 2.92 (t, 2H, J 7.4 Hz, CH 2 C), 3.20 (t, 2H, J 7.4Hz, CH 2 COO), 3.71 (s, 3H, OCH 3 ), 6.74 (d, 2H, J 8.59 Hz, ArH), 7.26-7.36 (m, 3H, ArH), 7.40 (d, 2H, J 8.7Hz, ArH), 7.54 (d, 2H, J 7.56Hz, ArH). MS (El, m/z): 323 (M) + , 264 (M-COOCH 3 ) + , 105, 77 (b.p.). F. 5-Phenyl-4- [ 4- ( 2-quinolmylmethoxy.phenyπ-2-oxazole propanoic acid methylester A mixture of the ester (2.46 g, 7.61 mmole) of Step E, powdered anhydrous K 2 CO 3 (1.05 g, 7.60 mmole), 18-crown-6 (0.223 g, 0.843 mmole) and acetonitrile (33 mL, ex-sieves) is stirred at room temperature under nitrogen for 15 minutes. 2-Chloromethyl- quinoline (free base, freshly prepared from the hydrochloride salt, 1.35 g, 7.60 mmole) is added and the mixture is placed in an oil bath heated at 65°C for 10 hours (N.B. A 10% excess of the chloromethylquinoline, 18-crown-6 and K 2 CO 3 is added after 6 hours). The solvent is removed and the residue is partitioned between ethyl acetate and water. The extracts are washed (brine), dried (MgSO ) and evaporated to yield a yellow solid. The crude product is flash chromatographed (on silica Merck-60, eluant: toluene and then toluene- methanol 97.5:2.5) to provide the title compound (3.5 g, quantitative yield). NMR (CDC1 3 , 400 MHz): δ 2.90 (t, 2H, J ca. 7.2Hz, CH 2 C), 3.16 (t, 2H, J 7.2 Hz, CH 2 COO), 3.72 (s, 3H, OCH 3 ), 5.41 (s, 2H, ArCH 2 O), 7.02 (d, 2H, J 8.8Hz, ArH), 7.29-7.36 (m, ca. 4H, ArH), 7.54-7.84 (m, ca. 6H, ArH), 7.83 (d, IH, J 8.1Hz, ArH), 8.08 (t, IH, J 8.5Hz, ArH), 8.19 (d, IH, J 8.5Hz, ArH). MS (+FAB, m z): 487 (M+Na) + , 465 (M+H) + G. 5-Phenyl-4-r4-(2-quinolinylmethoxy ' )phenyl]-2-oxazole propanoic acid A solution of the ester (3.4 g, 7.32 mmole) of Step F, in dry tetrahydrofuran (37 mL) is treated dropwise under nitrogen with IN-LiOH (21.98 mL, 3 equiv.) and stirred at room temperature for 3 hours (TLC, dichloromethane-methanol 97:3 or toluene-methanol 95:5). The solvent is evaporated, the residue is dissolved in water, neutralized in the cold with 10% acetic acid (to pH 5.5-6) and extracted with ethyl acetate. The extracts are washed with brine, dried (MgSO 4 ) and evaporated to yield a pale yellow solid (3.18 g, quantitative yield). The crude product is recrystallized from warm ethyl acetate (containing enough dichloromethane to obtain a clear solution) to yield a first crop of crystals (2.63 g, m.p. dec. 192-194°C). A second crop is obtained by concentrating the mother liquors (0.327 g, m.p. dec. 192-193°C). The combined yield is 85.8%. ■ IR (KBr, cm "1 ): 1720 (CO). NMR (DMSO-d 6 , 400 MHz): δ 2.76 (t, 2H, J 7Hz, CH 2 C), 3.03 (t, 2H, J 7Hz, CH 2 COO), 5.38 (s, 2H, ArCH 2 O), 7.11 (d, 2H, J 8.8Hz, ArH), 7.36-7.56 (m, 7H, ArH), 7.61* (t, IH, ArH), 7.69 (d, IH, J 8.5Hz, ArH), 7.78 (t, IH, ArH), 8.00 (t, J 7.9Hz, 2H, ArH), 8.42 (d, IH, J 8.5Hz, ArH). MS (El or C I, m/z): 451 (M+H) + , 310 (b.p.). Analysis for: C 28 H N 2 O 4 Calculated: C, 74.65; H, 4.92; N, 6.22. Found: C, 74.20; H, 4.86; N, 6.00. Exampte 6 4-r4-r2-Naphthalenvlmeth()xv1phenvll-5-phenvl.2-oxazole propanoic acid A. 4-r4-[2-Naphthalenylmethoxy]phenyl1-5-phenyl-2-oxazole propanoic acid methylester A mixture of the hydroxyester (1.5 g, 4.6 mmole) of Example 5E, powdered anhydrous K 2 CO 3 (0.636 g,4.6 mmole), 18-crown-6 (0.123 g, 0.46 mmole) and acetonitrile (18 mL) is stirred at room temperature under nitrogen, for 15 minutes. 2-Bromo- methylnaphthalene (1.13 g, 5.1 mmole) is added and the mixture is placed in an oil bath heated at 70°C for 8-9 hours (TLC, hexane-ethyl acetate 9:1 or dichloromethane-methanol 9:1). The solvent is evaporated and the residue dissolved in water and extracted with ethyl acetate. The extracts are washed and dried (MgS0 4 ). Removal of the solvent yields a tan solid (2.17 g, quantitative yield). A sample is recrystallized from methanol (containing enough dichloromethane to obtain a clear solution) by concentrating to small volume and cooling in an ice bath. The white solid is collected and dried overnight in vacuo. m.p.134- 135°C. IR (KBr, cm "1 ): 1740 (CO). NMR (CDCl 3 -400 MHz): δ 2.89 (t, 2H, J 7.5Hz, CH 2 C), 3.16 (t, 2H, J 7.5Hz, CH 2 COO), 3.71 (s, 3H, OCH 3 ), 5.2 (s, 2H, ArCH 2 0), 7.00 (d, 2H, J 8.6Hz, ArH), 7.25-7.35 (m, 3H, ArH), 7.46-7.58 (m, 7H, ArH), 7.8-7.9 (m, 4H, ArH). MS (CI, m/z): 464 (M+H) + , 324. Analysis for: C 3 QH- 25 N0 4 Calculated: C, 77.73; H, 5.44; N, 3.02. Found: C, 77.44; H, 5.36; N, 3.03. B . 4-r4-(2-Naphthalenylmethoxy'>phenyll-5-phenyl-2-oxazole propanoic acid A solution of the ester (1.49 g, 3.21 mmole) of Step A, in dry tetrahydrofuran (18mL) containing IN-LiOH (9.6 mL) is stirred under nitrogen overnight at room temperature (TLC, 75:25 hexane-ethyl acetate). The solvent is evaporated, the residue dissolved in water and acidified (to pH 5) with dilute HCl. The mixture is extracted with ethyl acetate, the extracts are dried (MgSO ) and evaporated to yield the crude product (1.39 g, m.p. 145- 150°C). For purification, it is dissolved in hot ethyl acetate (containing enough dichloro¬ methane to obtain a clear solution), concentrated to half volume and precipitated with ether. The white solid melts at 151-152°C (1.07 g, 58%). IR (KBr, cm "1 ): 1720 (CO). NMR (DMSO-d f i, 400 MHz): δ 2.78 (t, 2H, CH 2 C), 3.03 (t, 2H, J 7Hz, CH 2 COO), 5.29 (s, 2H, ArCH 2 O), 7.10 (d, 2H, J 8.9Hz, ArH), 7.34-7.60 (m, 10H, ArH), 7.90-8.00 (m, 4H, ArH), 12.28 (s, IH, COOH). MS (El, m/z): 450 (M+H) + , 310. Analysis for: C 29 H 23 NO 4 Calculated: C, 77.48; H, 5.15; N, 3.11. Found: C, 76.40; H, 5.16; N, 3.04. Example 7 4-r4-rα-Methvl-l H-henzimidazol-2-vnmethoxvl- Dhenvn-5-phenvI-2-oxazole propanoic acid A. 4-r4-[fl -Methyl- 1 H-benzimidazol-2-yl)methoxy1phenyri-5-phenyl-2-oxazole propanoic acid methylester A mixture ofthe ester (0.5 g, 1.55 mmole) of Example 5E, powdered anhy¬ drous K 2 C0 3 (0.214 g, 1.55 mmole), 18-crown-6 (0.0416 g, 0.155 mmole) and acetonitrile (6 mL) is stirred under nitrogen at room temperature for 15 minutes. 2-Chloromethyl-l- methylbenzimidazole (0.307 g, 1.7 mmole) is added and the mixture is placed in an oil bath heated at 65-70°C for 4 hours (TLC, dichloromethane-ethyl acetate 9: 1, iodine visualization). A 10% excess of K 2 C0 3 , 2-chloromethyl-l-methyl-benzimidazole and 18-crown-6 is added at this point and the heating continued for another 10 hours. The solvent is evaporated, the residue dissolved in water and extracted with ethyl acetate. The extracts are washed, dried (MgS0 ) and evaporated to dryness. The residue (1.64 g) is purified by flash-chromato graphy (on silica Merck-60, preabsorbed in dichloromethane containing a small amount of methanol, eluted with dichloromethane-ethyl acetate 8:2) to yield 1.03 g (71.2%) of a light yellow solid, m.p. 142-144°C (dec). NMR (CDC1 3 , 400 MHz): δ 2.87 (t, 2H, J 7.1Hz, CH 2 C), 3.16 (t, 2H, J 7.8Hz, CH 2 COO), 3.72 (s, 3H, COOCH 3 ), 3.90 (s, 3H, NCH 3 ), 5.41 (s, 2H, . ArCH 2 0), 7.07 (d, 2H, J 8.8Hz, ArH), 7.25-7.40 (m, 7H, ArH), 7.5-7.6 (m, 3H, ArH), 7.78 (d, IH, ArH). MS (+C I, m/z): 468 (M+H) + , 324, 293, 147. B . 4- [4- [( " 1 -Methyl- 1 H-benzimidazol-2-vDmethoxy ~ l-5-phenyl-2-oxazole propanoic acid A solution of the ester (1 g, 2.14 mmole) of Step A, in tetrahydrofuran (13 mL) containing IN-LiOH (6.42 mL) is stirred under nitrogen at room temperature for 1 hour (TLC, dichlσromethane-ethanol 9:1). The solvent is evaporated, water added and the pH adjusted to 6.5 with 10% acetic acid. The light yellow precipitate is collected, washed with water and dried in vacuo. It is redissolved in hot ethyl acetate (containing enough methanol to obtain a clear solution), concentrated to a smaller volume and cooled in an ice bath. The crystals are collected and dried (0.642 g, 66.2%, m.p.222-224°C). NMR (DMSO-d 6 , 400 MHz): δ 2.76 (t, 2H, J 7Hz, CH 2 C), 3.03 (t, 2H, J 7Hz, CH 2 COO), 3.86 (s, 3H, NCH 3 ), 5.43 (s, 2H, ArCH 2 O), 7.14-7.66 (m, 13H, ArH). MS (Cl, πo/z): 454 (M+H) + , 147 (b.p.). Analysis for: C 27 H 23 N 3 0 4 Calculated: C, 71.51; H, 5.11; N, 9.27. Found: C, 71.62; H, 5.17; N, 9.40. Example 8 The compounds 5- and 12-hydroxyeicosatetraenoic acid (5-HETE and 12- HETE) and LTB 4 are early arachidonic acid-oxidation products in the lipoxygenase cascade, which have been shown 'to mediate several aspects of inflammatory and allergic response. This is especially true with respect to 5,12-diHETE, which is also denoted as LTB4 [see Ford- Hitchinson, J. Rov. Soc. Med.. 74. 831 (1981)]. Compounds which inhibit the PLA2- mediated release of arachidonic acid thereby effectively prevent the oxidation of arachidonic acid to the various leukotriene products via the lipoxygenase cascade. Accordingly, the specificity of action of PLA2 inhibitors can be determined by the activity of test compounds in this assay, which measures the ability of compounds to inhibit the synthesis of LTB4 by rat glycogen-elicited polymorphonuclear leukocytes (PMN) in the presence of exogenous substrate. The assay is carried out as follows: Rat polymorphonuclear leukocytes (PMNs) are obtained from female Wistar rats (150- 200 g) which receive an injection of 6% glycogen (10 ml i.p.). Rats are sacrificed 18-24 hours post injection by CO2 asphyxiation and the elicited cells are harvested by peritoneal lavage using physiological saline (0.9% NaCl). The exudate is centrifuged at 400 xg for 10 minutes. The supernatant fluid is discarded and the cell pellet is resuspended to a concentration of 2.0 x 10 7 cells/mL in HBSS containing Ca-*-*- and Mg++ and 10 μM L-cysteine. To 1 mL aliquots of cell suspension, test drugs or vehicle are added, then preincubated at 37"C for 10 minutes. A23187 (1 μM), [3H]-AA (3.0 μCi/mL) and unlabeled AA (1 μM) are then added and the samples are further incubated for 10 minutes. The reaction is terminated by centrifugation and pelleting cells. Supernatants are then analyzed by HPLC analysis on a 15 cm x 4.6 mm ID supelcosil LC-18 (Supelco)(3M) column, using a two solvent system at a flow rate of 1.4 mL total flow as follows: Solvent A: 70:30 17.4 mM H PO 4 :CH 3 CN Solvent B. CH3CN Gradient: (system is equilibrated with Solvent A) Time Percent A Percent B 0 100 0 15.0 100 0 20.0 65 35 40.0 65 35 42.0 10 90 50.0 10 90 50.1 100 * 0 Percent solvent changes are accomplished in a linear fashion. Injections: 140 μL of each supernatant is injected directly onto column and 3 H .arachidonic acid metabolites are monitored using an on-line radioactivity detector (Ramona, IN/US, Fairfield, NJ). Standards: 10 4 - 2.0 x 10 4 dpm of eicosanoids of interest are injected in 90 μL EtOH cocktail. Co-chromatography with standard [ 3 H] leukotriene B4 (LTB4) in medium of stimulate PMN exposed to drug is compared to that found in medium of stimulated cells exposed to n drug, generating percent inhibition. Results are expressed as percent inhibition at a given compound dose or as an IC50 value. Testing compounds ofthe invention in this assay gave the following results: Table I * a negative value denotes potentiation of cyclooxygenase (PGE2 synthesis) Example 9 The procedure of Example 8 is also employed for the determination of the extent to which compounds of the invention inhibit the synthesis of the arachidonic acid cyclooxygenase oxidation product PGE 2 . * * In this assay, the procedure of Example 8 is carried out as described. However, in order to determine cyclooxygenase activity, the samples are co-chromatographed with authentic reference [ 3 H]-PGE2. The results are calculated as in Example 8 and presented below: Table π A 2 assay to determine the ability of the test compounds to inhibit the release of arachidonic aci from an arachidonic acid-containing substrate by the action of phospholipase A2 enzyme fro human and non-human sources. This assay is carried out as follows: Into a 15 mL polypropylene tube are added the following: Agent Volume. μL Final Cone. 3 H-AA E. coli substrate * 25 5 nmoles PL CaCl 2 (0.1M) 2 5 5 mM Tris-HCl (0.5M) pH 7.5 3 20 100 mM Water 4 25 Drug vehicle 5 1 50 μM PLA 2 25 Volume yielding 12% hydrolysis in 10 min. 100 * pre-incubate at room temperature 30 min prior to substrate addition. 1 Prepared by adding 2 mL deionized and distilled water to 2 mL 3H-arachidonat labeled E. coli (lower count), to which is added 1 mL of 3H-arachidonate labeled E. col (higher count) to yield a total of 5 m substrate (containing 1000 nmoles phospholipid). 2 Stock 0.1 m CaCl2, required for enzyme activity. 3 Stock 0.5 m Trisma-Base. Stock 0.5 M Trisma-HCl. Adjust pH to 7.5 (optimum for enzyme). Deionized and distilled water. 5 Stock 10 mM prepared in dimethyl sulfoxide. Make 1:2 dilution with dimethyl sulfoxide and add 1 μL to 100 μL assay tube. 6 Two human PLA2 enzymes are used: a) Semi-purified human platelet acid extract PLA2 (in 10 mM sodium acetate buffer, pH 4.5). Remove protein precipitate by centrifugation at about 2200 rpm for 10 minutes. b) Purified human synovial fluid. Incubate the lOOμL reaction mixture for 10 minutes at 37°C in a shaking water bath. The reaction is terminated by the addition of 2 mL tetrahydrofuran, followed by vortexing. NH2 columns (100 μg mL - Analytichem International) are conditioned with 0.5 mL tetrahydrofuran followed by 0.5 mL tetrahydrofuran/water (2 mL:0.1 mL, v v). The sample is loaded onto the columns and slowly drawn through them. The hydrolyzed arachidonic acid retained in the columns is eluted therefrom with 1 mL tetrahydrofuran/glacial acetic acid (2%). The arachidonic acid is transferred to scintillation vials and quantitated by β-counting analysis. A "total counts" sample is prepared by pipetting 25 μL 3 H-arachidonate E. coli directly into a scintillation vial to which is added 1 mL tetrahydrofuran. 10 mL aquasol (scintillation cocktail) is added to all samples. Calculations: [3H]AA dpm (sample) - [3H] AA dpm (nonspecific hydrolysis) % hydrolysis = x 100 total counts dpm vehicle dpm - drug dpm % change = x 100 vehicle dpm Activity of Standard Drugs: I-Os o (μ M) Human Synovial Drug PLA Arachidonic Acid 3.2 Monoalide 0.14 When tested in this assay, the compounds of the invention gave the followin results: ** negative values denote a potentiation of HSF Example 11 The compounds of the invention are evaluated for their ability to inhibit t lipoxygenase and/or cyclooxygenase pathways of arachidonic acid metabolism in the in vi murine zymosan peritonitis assay. This assay is carried out as follows: Male CD-I mice (8 weeks old) are placed in plastic boxes in groups of six. Anima are injected with 1 mL i.p. of either 1% zymosan in pyrogen free 0.9% saline or sali (unstimulated control). Compounds are dosed orally 1 hour prior to zymosan injectio Twenty minutes after zymosan injection, the mice are asphyxiated by CO2 inhalation and t peritoneal cavity is lavaged with 2 mL ice cold Hanks Balanced Salt Solution (HBSS) witho CaCl2, MgS04 • 7H2O and MgCl2 • 6H2O. Peritoneal lavage fluid from each mouse removed by syringe and placed in 5 mL plastic test tubes put on ice and volume is note Preparation of samples for evaluation by ELISA is as follows: Samples are centrifuged at 8 xg for 15 minutes; 1 mL of the supernatant is added to 8 mL ice cold methanol and kept a 70°C overnight to precipitate protein; and samples are then centrifuged at 800 xg for 1 minutes, followed by a drying procedure in a Savant speed vac concentrator. The samples a reconstituted with 1 mL ice cold ELISA buffer and stored at -70 β C until assayed. The ass for eicosanoids (LTC4 and 6-keto-PGFι α ) is performed according to conventional ELIS procedures. Compounds to be tested orally are suspended in 0.5% Tween 80. Compoun to be tested intraperitoneally are suspended in 0.5% methylcellulose in 0.9% saline. The total metabolite level in lavage fluid/mouse is calculated and the significan is determined by a one-way analysis of variance with LSD comparisons to control (p < 0.05 Drug effects are expressed as a percent change from control values. The activity of standard drugs in this assay is as follows: When tested in this assay a compound of the invention and the anti- inflammatory compound etodolac gave the following results: • Table VI Compound of Dose % Inhibition Example No. mg/kg LTC _ 6-keto-PGF 5 10 (i.p.) * 86 -27 ** * intraperitoneally administered ** negative values denote potentiation The results show that the compound of the invention exerts a potent inhibitory effect on the lipoxygenase pathway but not on the cyclooxygenase pathway.

Claims: WHAT IS CLAIMED TS: 1. A compound having the formula A(CH 2 ) n σB wherein A is phenoxyethyl, phenoxyphenyl or a group having the formula wherein R 3 X is -N- or -C- ; Z is , -S- or -O- R 1 is hydrogen, lower alkyl or phenyl; R 2 is hydrogen or lower alkyl; or R 1 and R 2 taken together form a. benzene ring; R 3 is hydrogen or lower alkyl; n is 1 - 2; B is wherein R 4 and R 5 are each, independently, hydrogen or lower alkyl; R 6 is halo or nitro; O R4 R 7 is -C-R 8 or -CHCOOR 5 ; R 8 is lower alkyl; m is 0 - 3 ; and the pharmacologically acceptable salts thereof. 2. The compound of Claim 1, having the name l-[2-nitro-4'-(2-quino- linylmethoxy)-[l,l'-biphenyl]4-yl]ethanone. 3. The compound of Claim 1, having the name 2-fluoro-4'-(2-quinolinyl- methoxy-[l,l'-biphenyl]-4-acetic acid. 4. The compound of Claim 1, having the name 3-[4-(2-quinolinyl- methoxy)benzoyl]benzene acetic acid. 5. The compound of Claim 1, having the name 3-[4-(2-naphthalenyl- methoxy)benzoyl]benzene acetic acid. 6. The compound of Claim 1, having the name 5-phenyl-4-[4-(2-quino- linylmethoxy)-phenyl]-2-oxazole propanoic acid. 7. The compound of Claim 1, having the name 4-[4-[2-naphthalenyl- methoxy]phenyl]-5-phenyl-2-oxazole propanoic aeid. 8. The compound of Claim 1, having the name 4-[4-[2-naphthalenyl- methoxy]phenyl]-5-phenyl-2-oxazole propanoic acid methylester. 9. The compound of Claim 1, having the name 4-[4-[(l-methyl-l H-benz- imidazol-2-yl)methoxy]phenyl]-5-phenyl-2-oxazole propanoic acid. 10. A process for preparing a compound of Claim 1 comprising an ester function; with a compound of formula A(CH 2 ) n -X where A and n are as defined above and X is a leaving group, and, if necessary, hydrolyzing the product, to give a product wherein R 5 is hydrogen or lower alkyl; or b) hydrolyzing a compound of formula I, II, IH or IV which contains the -COOR 5 moiety, wherein R-5 is lower alkoxy, to give a compound wherein R 5 is hydrogen or a pharmacologically acceptable salt thereof; c) converting a compound of formula I, II, III or IV to a pharmacologically acceptable salt. 11. A process as claimed in Claim 10 substantially as hereinbefore described and illustrated in any one of Examples IC, 2F, 2G, 3G, 3H, 4A, 4B, 5F, 5G, 6A, 6B, 7A and 7B.

Inventors: FAILLI AMEDEO ARTURO, KREFT ANTHONY FRANK III, MUSSER JOHN HENRY, FAILLI, AMEDEO, ARTURO, KREFT, ANTHONY, FRANK, III, MUSSER, JOHN, HENRY
Applicants: AMERICAN HOME PROD, AMERICAN HOME PRODUCTS CORPORATION
Application year: 1990
Main classification: C07D215
IPC codes: A61K31, A61P29, A61P37, A61P43, C07C45, C07C49, C07C51, C07C59, C07C67, C07C69, C07C205, C07C255, C07D209, C07D215, C07D263, C07D413