WO1991006538A1 - Derives d'acide alcanoiques benzoylbenzene, biphenyle et 2-oxazole substitues utilises comme inhibiteurs de la phospholipase a2(pla2) et de la lipoxygenase - Google Patents

Derives d'acide alcanoiques benzoylbenzene, biphenyle et 2-oxazole substitues utilises comme inhibiteurs de la phospholipase a2(pla2) et de la lipoxygenase Download PDF

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WO1991006538A1
WO1991006538A1 PCT/US1990/006252 US9006252W WO9106538A1 WO 1991006538 A1 WO1991006538 A1 WO 1991006538A1 US 9006252 W US9006252 W US 9006252W WO 9106538 A1 WO9106538 A1 WO 9106538A1
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arh
compound
phenyl
lower alkyl
ethyl acetate
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PCT/US1990/006252
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Amedeo Arturo Failli
Anthony Frank Kreft, Iii
John Henry Musser
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American Home Products Corporation
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Priority to AU67220/90A priority Critical patent/AU647425B2/en
Priority to KR1019920700970A priority patent/KR927003552A/ko
Priority to BR909007783A priority patent/BR9007783A/pt
Publication of WO1991006538A1 publication Critical patent/WO1991006538A1/fr
Priority to FI921864A priority patent/FI921864A/fi
Priority to SU925052050A priority patent/RU2037481C1/ru

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • 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.
  • arachidonic acid 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.
  • 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.
  • prostacyclin a vasodilator with platelet aggregation inhibitor activity.
  • prostacyclin a vasodilator with platelet aggregation inhibitor activity.
  • 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
  • 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..
  • 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 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.
  • AA arachidonic acid
  • PAF platelet activating factor
  • 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)].
  • PLA2 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.
  • 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.
  • 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)].
  • Platelet activating factor 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.
  • 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.
  • A is phenoxyethyl, phenoxyphenyl or a group having the formula
  • R 1 is hydrogen, lower alkyl or phenyl
  • R 2 is hydrogen .or lower alkyl
  • R 1 and R 2 taken together form a benzene ring
  • R 3 is hydrogen or lower alkyl; n is i - 2; B is
  • R 4 and R 5 are each, independently, hydrogen or lower alkyl
  • R6 is halo or nitro
  • R 7 is -C-R 8 or -CHCOOR 5 ;
  • R 8 is lower alkyl;
  • m is 0 - 3 ; and the pharmacologically acceptable salts thereof.
  • lower alkyl refers to moieties having 1 - 6 carbon atoms in th carbon chain.
  • 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
  • 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
  • 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.
  • R 6 is halo and R 7 is the -CHCOOR 5 moiety
  • R 7 is the -CHCOOR 5 moiety
  • 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.
  • 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 ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form.
  • the ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form.
  • the intermediate compound 2-bromomethylquinoline can be prepared by the following reaction sequence:
  • 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.
  • such intermediates as l-methyl-2-chloromethylbenzimidazole, 2-chloromethylbenz- thiazole and 2-chloromethylbenzoxazole can be prepared by the following reaction scheme
  • 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.
  • 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.
  • 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
  • the compounds of the invention 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.
  • 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.
  • 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.
  • 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.
  • PLA2 and lipoxygenase inhibitory and leukotriene antagonist effects may be demonstrated by standard pharmacological procedures which are described more full in the examples given hereinafter.
  • These procedures 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.
  • Example 1 l-r2-Nitro-4'-f2- ⁇ uinolinvlmethoxv -ri .l '-hinhenvn4-vnethanone
  • 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.
  • 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.
  • 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 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%).
  • 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.
  • Step C 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • PMN polymorphonuclear leukocytes
  • Rat polymorphonuclear leukocytes 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 ⁇ M L-cysteine.
  • PMNs Rat polymorphonuclear leukocytes
  • Percent solvent changes are accomplished in a linear fashion.
  • 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:
  • Example 8 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 .
  • Example 8 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.
  • 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.
  • reaction is terminated by the addition of 2 mL tetrahydrofuran, followed by vortexing.
  • 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 ⁇ -counting analysis.
  • a "total counts" sample is prepared by pipetting 25 ⁇ L 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.
  • % hydrolysis x 100 total counts dpm vehicle dpm - drug dpm
  • 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:
  • mice 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
  • mice 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
  • HBSS Hanks Balanced Salt Solution
  • 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:

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Abstract

L'invention se rapporte à des composés représentés par la formule: A(CH2)nO-B, où: A représente un phénoxyéthyle, un phénoxyphényle ou un groupe ayant la formule (a), où X représente -N- ou (b), Z représente (c), (d), (e), (f), -S- ou -O-, R1 représene l'hydrogène, un alkyle inférieur ou un phényle, R2 représente l'hydrogène ou un alkyle inférieur, ou R1 et R2 forment ensemble une chaîne fermée de benzène, R3 représente l'hydrogène ou un alkyle inférieur; n est égal à 1 ou à 2; B représente un groupe ayant la formule (g), (h), (i) ou (j), où R4 et R5 représentent chacun séparément l'hydrogène ou un alkyle inférieur, R6 représente un halo ou un nitro, R7 représente (k) ou (l), R8 représente un alkyle inférieur, et m est égal à un nombre compris entre 0 et 3; ainsi qu'aux sels pharmacologiquement acceptables de tels composés, et à leur utilisation dans le traitement d'états inflammatoires, tels que l'arthrite rhumatoïde, la colite ulcérative, le psoriasis et d'autres réactions d'hypersensibilité immédiate, dans le traitement d'états obstructifs des voies bronchonasales se développant par l'intermédiaire de la leukotriène, tels que la rhinite allergique, l'asthme bronchique allergique et similaires et comme agents cytoprotecteurs gastriques.
PCT/US1990/006252 1989-10-27 1990-10-27 Derives d'acide alcanoiques benzoylbenzene, biphenyle et 2-oxazole substitues utilises comme inhibiteurs de la phospholipase a2(pla2) et de la lipoxygenase WO1991006538A1 (fr)

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AU67220/90A AU647425B2 (en) 1989-10-27 1990-10-27 Substituted benzoylbenzene-, biphenyl- and 2-oxazole- alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
KR1019920700970A KR927003552A (ko) 1989-10-27 1990-10-27 Pla₂및 리폭시게나제 억제제로서의 치환된 벤조일 벤젠-, 비페닐- 및 2-옥사졸-알칸산 유도체
BR909007783A BR9007783A (pt) 1989-10-27 1990-10-27 Derivados de acido benzoilbenzeno-,bifenil-e 2-oxazol-alcanoico substituido como inibidores de pla2 e lipoxigenase
FI921864A FI921864A (fi) 1989-10-27 1992-04-24 Substituerade bensoylbenzen-, bifenyl- och 2-oxazolalkansyraderivat som inhibitorer av pla2 och lipoxigenas.
SU925052050A RU2037481C1 (ru) 1989-10-27 1992-04-24 Производные замещенной бензоилбензолбифенил- или 2-оксазолалкановой кислоты или их фармакологически приемлемые соли и способ их получения

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190968A (en) * 1991-09-30 1993-03-02 Merck Frosst Canada, Inc. (Polycyclic-arylmethoxy) indoles as inhibitors of leukotriene biosynthesis
WO1994001407A2 (fr) * 1992-07-10 1994-01-20 American Home Products Corporation Derives d'indole et d'indene utilises comme inhibiteurs de pla2 et de lipoxygenase
US5290798A (en) * 1991-09-30 1994-03-01 Merck Frosst Canada, Inc. (hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis
US5308850A (en) * 1991-09-30 1994-05-03 Merck Frosst Canada, Inc. (Bicyclic-hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis
US5374635A (en) * 1993-03-29 1994-12-20 Merck Frosst Canada, Inc. Furo[3,2-b]pyridines and thieno[3,2-b]pyridines as inhibitors of leukotriene biosynthesis
EP0675114A1 (fr) * 1993-10-15 1995-10-04 Shionogi & Co., Ltd. Derive d'oxazolinone presentant une activite inhibitrice de la phospholipase a 2? intracellulaire
EP1121129A1 (fr) * 1998-09-17 2001-08-08 Bristol-Myers Squibb Company Procede de traitement de diabetes a l'aide de l'inhibiteur ap2 et combinaison associee
EP1620089A1 (fr) * 2003-03-26 2006-02-01 CRC For Asthma Limited Compositions therapeutiques et prophylactiques et utilisations associees

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5021576A (en) * 1989-10-27 1991-06-04 American Home Products Corporation 2-Anilino phenylacetic acid derivatives

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GB220223A (en) * 1923-12-31 1924-08-14 Harry Ingram Improvements in closures for tumblers, jars and other containers
US3578671A (en) * 1967-11-06 1971-05-11 Wyeth John & Brother Ltd Oxazoles
US4659728A (en) * 1985-02-25 1987-04-21 American Home Products Corporation Hydroxy substituted 4,5-diphenyl-2-oxazole propanoic acid
EP0226342A1 (fr) * 1985-11-19 1987-06-24 American Home Products Corporation Dérivés de 5-phényl-2-oxyzole comme agents anti-inflammatoires et anti-allergiques
EP0315399A2 (fr) * 1987-11-03 1989-05-10 Rhone-Poulenc Rorer International (Holdings) Inc. Dérivés de la quinoléine, leur utilisation pour le traitement des maladies hypersensibles et compositions pharmaceutiques de ces composés
WO1989004303A1 (fr) * 1987-11-03 1989-05-18 Rorer International (Overseas) Inc. Derives de quinoline utilise comme antagonistes de leukotriene d4

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB220223A (en) * 1923-12-31 1924-08-14 Harry Ingram Improvements in closures for tumblers, jars and other containers
US3578671A (en) * 1967-11-06 1971-05-11 Wyeth John & Brother Ltd Oxazoles
US4659728A (en) * 1985-02-25 1987-04-21 American Home Products Corporation Hydroxy substituted 4,5-diphenyl-2-oxazole propanoic acid
EP0226342A1 (fr) * 1985-11-19 1987-06-24 American Home Products Corporation Dérivés de 5-phényl-2-oxyzole comme agents anti-inflammatoires et anti-allergiques
EP0315399A2 (fr) * 1987-11-03 1989-05-10 Rhone-Poulenc Rorer International (Holdings) Inc. Dérivés de la quinoléine, leur utilisation pour le traitement des maladies hypersensibles et compositions pharmaceutiques de ces composés
WO1989004303A1 (fr) * 1987-11-03 1989-05-18 Rorer International (Overseas) Inc. Derives de quinoline utilise comme antagonistes de leukotriene d4

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5190968A (en) * 1991-09-30 1993-03-02 Merck Frosst Canada, Inc. (Polycyclic-arylmethoxy) indoles as inhibitors of leukotriene biosynthesis
US5290798A (en) * 1991-09-30 1994-03-01 Merck Frosst Canada, Inc. (hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis
US5308850A (en) * 1991-09-30 1994-05-03 Merck Frosst Canada, Inc. (Bicyclic-hetero-arylmethoxy)indoles as inhibitors of leukotriene biosynthesis
WO1994001407A2 (fr) * 1992-07-10 1994-01-20 American Home Products Corporation Derives d'indole et d'indene utilises comme inhibiteurs de pla2 et de lipoxygenase
WO1994001407A3 (fr) * 1992-07-10 1994-03-03 American Home Prod Derives d'indole et d'indene utilises comme inhibiteurs de pla2 et de lipoxygenase
US5374635A (en) * 1993-03-29 1994-12-20 Merck Frosst Canada, Inc. Furo[3,2-b]pyridines and thieno[3,2-b]pyridines as inhibitors of leukotriene biosynthesis
EP0675114A1 (fr) * 1993-10-15 1995-10-04 Shionogi & Co., Ltd. Derive d'oxazolinone presentant une activite inhibitrice de la phospholipase a 2? intracellulaire
EP0675114A4 (fr) * 1993-10-15 1995-11-02
US5817826A (en) * 1993-10-15 1998-10-06 Shionogi & Co., Ltd. Oxazolinone derivatives having cytosolic phospholipase A2 inhibitory activity
EP1121129A1 (fr) * 1998-09-17 2001-08-08 Bristol-Myers Squibb Company Procede de traitement de diabetes a l'aide de l'inhibiteur ap2 et combinaison associee
EP1121129A4 (fr) * 1998-09-17 2002-10-16 Bristol Myers Squibb Co Procede de traitement de diabetes a l'aide de l'inhibiteur ap2 et combinaison associee
EP1620089A1 (fr) * 2003-03-26 2006-02-01 CRC For Asthma Limited Compositions therapeutiques et prophylactiques et utilisations associees
EP1620089A4 (fr) * 2003-03-26 2008-12-24 Crc For Asthma Ltd Compositions therapeutiques et prophylactiques et utilisations associees

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HUT64750A (en) 1994-02-28
JPH05502021A (ja) 1993-04-15
FI921864A0 (fi) 1992-04-24
EP0497888A1 (fr) 1992-08-12
CA2067138A1 (fr) 1991-04-28
FI921864A (fi) 1992-04-24
BR9007783A (pt) 1992-08-11
KR927003552A (ko) 1992-12-18
IE903874A1 (en) 1991-05-08
PT95690A (pt) 1991-09-13
AU647425B2 (en) 1994-03-24
AU6722090A (en) 1991-05-31
HU9201395D0 (en) 1992-07-28

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