MXPA99005071A - PHENYL GLYOXAMIDES AS sPLA2 - Google Patents

Abstract

A class of novel phenyl glyoxamides is disclosed together with the use of such compounds for inhibiting sPLA2 mediated release of fatty acids for treatment of conditions such as septic shock.

Description

FENIL GLIOXAMIDAS AS INHIBITORS OF THE SPLA FIELD OF THE INVENTION This invention relates to novel substituted phenyl glyoxamides employed to inhibit the mediated release of sPLA2 from fatty acids for conditions such as septic shock.

BACKGROUND OF THE INVENTION The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter referred to as "sPLA2") has been described in two articles, called "Cloning and Recombinant Expression of Phospholipase A2" presented in Rheumatoid Arthritic Synovial Fluid "by Seilhamer, Jeff ey J .; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A .; Kloss, Jean; and Jojnson, Lorin K .; The Journal of Biological Chemistry Vol. 264, No.10, Published on April 5, pp. 5335-5338, 1989; and "Structure and Properties of a Human Non-pancreatic Phospholipase A2" REF .: 30486 by Kramer, Ruth M .; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Published on April 5 pp, 5768-5775, 1989; descriptions of which are incorporated herein by reference.

It is believed that sPLA2 is an enzyme of limiting proportion in the arachidonic acid cascade which hydrolyzes the phospholipids of the membrane. Thus, it is important to develop compounds which inhibit the mediated release of sPLA2 from fatty acids (eg, arachidonic acid). Such compounds may be of value in the general treatment of conditions induced and / or maintained by overproduction of sPLA2; such as septic shock syndrome of respiratory distress in adult pancrea itis, trauma-induced trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, etc.

It is desirable to develop new compounds and treatments for conditions induced by sPLA2.

This invention provides compounds of the form T. i n where; X is -O- or - (CH2) m-, where m is 0 or 1; And it is -CC-2-, -P03-, -S03-; R is independently -H or -alkyl (C? -C4); R1 and R- are each independently -H, halo or -alkyl (C? -C4); R3 and R4 are each independently -H, alkyl (Cl-C4), alkoxy (C: -C4), alkylthio (C? ~ C4), halo, phenyl or phenyl substituted with halo; n is 1 -8; and P is 1 when Y is -C02- or -S03- and 1 or 2 when Y is -PO3-; or a pharmaceutically acceptable salt thereof. These phenyl glyoxamides are effective in inhibiting the release of human sPLA2 from fatty acids.

The present invention also provides novel intermediate intermediates of formula II. 9 (0 where: X is -0- or - (CH2) m-, where m is 0 or 1; R1 and R are each year independently -H, halo or alkyl (C? -C4) and R3 and R4 are each independently -H, (C1-C4) alkyl, -alkoxy (C1-C4), alkylthio (C1-C4), halo, phenyl or phenyl substituted with halo.

R T? Intermediary in the preparation of compounds of formula (I-Ii) rrio f? rmn l a T Tnnn p? pnl pahrií fnmri I.

This is also a formulation Pharmaceutical comprising a compound of formula I in association with one or more pharmaceutically acceptable diluents, carriers and excipients.

This invention is also a method for inhibiting e a1 sPLA: < which comprises administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of formula I.

In accordance with a further aspect of the present invention, there is provided a method of selectively inhibiting sPLA2 in a mammal in need of such treatment, which comprises administering to said mammal a therapeutically effective amount of a compound of formula I.

This invention also provides a method of alleviating the pathological effects of septic shock, respiratory distress syndrome in an adult, pancreatitis, stroke induced trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and related conditions which comprises administering to a mammal. in need of such treatment, a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit the mediated release of sPLA2 from fatty acids and thereby, inhibit or prevent the cascade of arachidonic acid and its harmful products.

Other characteristic objects? windows of the present invention will be apparent from the subsequent description and the appended claims. tm rrM t? i? Defi ict is <; same or as part of another substituent suggests less otherwise defined, a straight or branched chain monovalent hydrocarbon radical, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl and isobutyl. The term "halo" suggests chlorine, fluorine, bromine or iodine.

The term "(C 1 -C 4) alkoxy" denotes a straight or branched or straight chain alkyl having one to four carbon atoms attached to the rest of the molecule by an oxygen atom. Typical (C1-C4) alkoxy groups include, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and the like.

The term "(C1-C) alkylthio" defines straight-chain or branched-chain alkyl having from one to four carbon atoms attached to the rest of the molecule by a sulfur atom. Typical alkylthio (C1-C4) groups include methylthio, ethylthio, propylthio, butylthio and the like.

Salts of the above phenyl qlyoxamides are a further aspect of the invention. In these examples wherein the compounds of the invention possess acidic functional groups, they can be formed various salts which are more water soluble and physiologically suitable than the original compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. The salts are conveniently prepared from the free acid by treatment of the acid in a solution with a base or by exposure of the acid to an ion exchange resin.

Examples of pharmaceutically acceptable organic bases which can be used to prepare pharmaceutically acceptable salts include ammonia, amines such as triethanolamine, triethylamine, ethylamine and the like.

Preferred Compounds of the Invention Preferred substitute groups of compounds of formula (I) include the following: (a) X is 0; ib) X is CH :; (c) Y is -C02- or -PO3-; (d) R, R1 and R2 are -H; (e) R3 and R4 are each independently -H, - / n-(C1-C4) alkyl, -jn-(C1-C4) alkoxy, - / n-halo, - / n-alkylthio (C1-C4) , or m-phenyl substituted with halo; (f) R3 is independently -H, -o-alkyl (Ci- C4), -o-(C1-C4) alkoxy, o-halo, -o-alkylthio (C? -C4), o-phenyl or -o phenyl substituted with halo; (g) R3 and R4 are each independently -H or m-phenyl or -PI.-3-fluorophenyl; (h) R3 and R4 are each independently -H, o-phenyl or -o-3-fluorophenyl; and (i) n is 4-5 Preferred substituent groups of compounds of formula (II) include the following: (aa) R1 v R2 are -H; (bb) R3 and R4 are each independently -H, -m-alkyl (C? -C4), - / n-alkoxy (C-C4), -m-halo, -zn-alkyl (C? ~ C4), or m-phenyl substituted with halo; . { ce) R3 is independently -H, -o-alkyl (Cj-C4), -o-akoxy (C? -C4), o-halo, -o-alkylthio (C1-C4), o-phenyl oo-fe substi uido with halo; (dd) R3 and R4 are each independently -H or J? -phenyl or / O-3-fluorophenyl; and (ee) R3 and R4 are each independently -H, o-phenyl or -o-3-fluorophenyl. Additional typical examples of compounds of formula I which are employed in the present invention include: 2- (-ca boxi ex-1-yloxy) -4- (3-phenylphenoxy) -5- ethylphenylglyoxamide; 2- (8-carboxyoct-l-yloxy) - -benzyl-5-t-butyl-6-propylphenylglyoxamide sodium; 2- (4-earbocibut-l-eoxy) -4- (2-methylbenzyl) -6-chlorophenylglyoxamide; 2-hydroxy-4- (2-methoxybenzyl) -6-chlorophenoxyamide; 2- (3-carboxypropyl) -yloxy) -4- (2-ethylthio-6-fluorobenzyl) phenyl-1-oxoamide; 2- (4-carboxybutyl-1-yloxy) -4- (3, 5-diphenyl) benzyl) -6-phenylglyoxamide of potassium; 2- (3-carboxyprop-1-yloxy) -4- (3-fluoro-5-phenyl) phenyl-5-propylphepylglyoxamide; 2-hydroxy-4- (3-fluoro-5-phenyl) pheny1-5-pro ^ i Ifenglial amide; 2- (2-carboxyethoxy) -4-thiophenyl-5- fluorofeniIglioxamide; 2- (4-carboxybutyl-l-yloxy) -4- (2,6-dimethyl) phenyl-phenylqlioxamide of calcium; 2- (3-carboxyprop-1-yloxy) -4- (3,5-difluorobenzyl) phenylglyoxamide; 2- (2-carboxyethoxy) -4- (4- (4-chlorophenyl) encyl) -5-bromophenylglyoxamide; Magnesium 2- (3-carboxyprop-1-yloxy) -4- (3-ethylphenyl) -6-methylphenylglyoxamide; 2- (4-carboxybutyl-l-yloxy) -4- (2-ethyl-6-methoxy) benzyl-5,6-dimethylphenyl-xyloxamide; 2-hydroxy-4- (2-ethyl-6-methoxy) benzyl-5,6-dimethylphenylglyoxamide; 2- (2-carboxyethoxy) -4- (3-methy1thio-5-phenyl) benzyl-fer.i-l-xyloxamide; 2- (4-carboxybut-i-yloxy) -4- (3-propyl-5-chloro) ncyl-phenyl-1-oxoamide; 2- 3-carboxypropyl-1-yloxy-1-4-f-p-3-chlorophenyl) benzyl-1-phenylenediol; 2- (2-carboxyethoxy) -4- (3-phenyl-5-fluorobenzyl) phenylglyoxa ida; 2- (3-carboxyprop-1-yloxy) -4- (4-methyl) benzyl-1-phenylglyoxamide; - (-carboxyl-l-yloxy) -4- (2, 4-dimethyl) benzyl-fe iiojiic ar.ida * 2-hydroxy-4- (2,4-dimethyl) benzyl-phenylglyoxamide; 2- (carboxymethoxy) -4- (4-propyl) phenyl-5-methylphenylglyoxamide; 2- (2-carboxyethoxy) -4- (3- (3-fluorophenyl) benzy1-6-butylphenylglyoxamide lithium; 2- (3-carboxyprop-1-yloxy) -4- (3,5-diethoxy) benzyl-5 -ethylphenylglyoxamide; 2- ((3-dimethoxyphosphonyl) prop-1-yloxy) -4-phenoxyphene-1-yl-amide; 2- (2-phosphonoyl) -ethoxy-4-benzyl-5-methyl-6-fluorophenyl-glyoxamide; 2- (diethoxyphosphono) sodium ethoxy-4-benzylphenylglyoxamide; 2- ((3-phosphonoyl) prop-1-yloxy) -4- (2-methyl) benzylphenylglyoxamide; 2-hydroxy-4- (2-methyl) -pentylphenylglyoxamide; 2- (2- di-ethoxyphosphonoyl-ethoxy-4- (3, 5-dichlorophenylphenyl) phenylglyoxamide; 2- ((4-diethoxyphosphonoyl) but-l-yloxy) -4- (6-phenyl) phenylglyoxamide; 2- ((3-fesphonyl) propri- 1-yloxy) -4- (2-fluoro-4-phenyl) phenylglyoxamide; 2- (dimethoxyphosphonoyl) methoxy-4-pheny1-5-fluoro-6- and ylphenylphenyl; 2- ((4-phosphonoyl) but-l-yloxy) -4- (2,6- potassium dimethoxy) phenyl-5-methylphenylglyoxamide; 2- (phosphonoyl) ethoxy-4- (4-propyl) benzyl-5-fluorophenylglyoxamide; 2- ((4-diethoxyphosphonoyl) but-l-yl-oxy) -4- (3- (4-fluorophenyl) benzyl) -6-methylphenol-1-glyoxamide; 2- (dimethoxy phosphonoyl) methoxy-4- (2,6-diethylbenzyl) -5-met-il-phenylglyoxamide; 2- (methoxysulfonyl) methoxy-4- (3,5-diethyl) benzylphenylglyoxamide; 2-Sulfonyl-ethoxy-4- (3-methylthio-5-phenyl) -cyclic-phenyl-1-yl-ioxamide; 2-hidesoxy-4- (3-meth i thio-5-phenyl) benzyl-phenyl-1-oxoamide; 2- ((4-sulfonyl) but-l-yloxy) -4- (6-chloro) phenoxy-phenylglyoxamide calcium; 2- ((3-sulfonyl) prop-1-yloxy) -4-benzyl-phenyl-xyloxamide; 2-Sulfonyl-yl-4- (4- (4-fluorophenyl)) benzyl-phenyl-1-xyloxamide; 2- ((3-sulfoni) prop-1-yloxy) -4- (4-methyl) phenoxy-phenyl-1-ioxamide; 2- (methoxysulfonyl) methoxy-4- (2,4-dimethyl) benzyl-phenyl-1-ioxamide; 2- (-methoxysulfonyl) but-l-yloxy-4- (4-propyl) e cyl-5- et i1-phenyl glyoxal ida; 2- (2-ethoxysulfonyl) ethoxy-4- (3- (3-fluorophenyl) phenoxy-6-butylphenylglyoxamide; 2-hydroxy-4- (3- (3-fluorophenyl) phenoxy-6-butylphenylglyoxamide; 2- ((3 -methoxysulfonyl) prop-1-yloxy) -4- (3,5-diethoxy (magnesium benzyl-5-ethylphenylglyoxamide; 2- ((3-carboxymethoxy) prop-1-yloxy) -4-phenoxyphenylglyoxamide; -ethoxycarbonyl) ethoxy-4-benzyl-5-methyl-6-fluorophenylglyoxamide; 2- (propoxycarbonyl) methoxy-4-benzylphenylglyoxamide; 2- ((3-methoxycarbonyl) prop-1-yloxy) -4- (4-phenyl); phenoxy-phenylglyoxamide; 2- (ethoxycarbonyl) ethoxy-4- (2,6-difluorophenylphenyl) phenylglyoxamide; 2- ((4-methoxycarbonyl) but-l-yloxy) -4- (3-phenyl) phenoxy-5-methylphenylglyoxamide; 2- (3-propoxycarbonyl) prop-1-yloxy-4-phenyl-6-ethylphenylglyoxamide; 2- (methoxycarboyl) ethoxy-4-phenoxy-5-fluoro-6-methylphenylglyoxamide.

Synthesis Methods The compounds wherein R1, R2, R3 and R4 are H, and X, Y and n and p are as defined above, can be prepared according to the following scheme I.

Scheme I R 'is - (C1-C4) alkyl The reflux of (1) with oxalyl chloride in an alkyl halide solvent, such as chloroform, using 4-N, N'-diethylaminopyridine as a catalyst leads to the intermediate (2).

Under Friedel-Crafts conditions, using a suitable Lewis acid catalyst such as ammonium chloride, the compound (2) is cyclized internally to form the compound (3). The reaction is preferably carried out at temperatures of about 0 ° C at room temperature and allowed to proceed for about 24 hours.

The aminolysis of (3) to amide (4) can be conducted by treatment with concentrated ammonium hydroxide.

The alkylation of the hydroxyl of the compound (4) can be conducted rapidly by treatment with an appropriate alkylating agent, such as Br (CH2) nY, where Y is -C02R, -P03R2 or S03R and R is -alkyl (C1-C4) , to form the intermediary (5). The reaction is preferably conducted in a polar aprotic solvent, such as dimethylformamide, in the presence of potassium carbonate and a suitable catalyst, such as potassium iodide.

The conversion of (5) to the carboxylic or sulfonic acid or salt of the acid (6) can be conducted by treatment with an appropriate base, such as aqueous sodium hydroxide, in a protic polar solvent, such as methanol.

When n is 2, bromoacetal can be used as an alkylating agent to obtain the carboxylic acid (6). The alkylated portion (5) is then converted to acid (6) by oxidation with sodium dichromate under aqueous conditions.

When Y is -P03-, conversion to acid (6) is preferably conducted in an alkyl halide solvent, such as methylene chloride, using a dealkylating agent, such as trimethylsilyl bromide, and an excess of potassium carbonate. , followed by the methanol treatment.

When R1, R2, R3 or R4 are preferably hydrogen, the preparation process is as described in Scheme II on the next page.

Scheme II (9) (12) OJ > ? c R 'is as defined in Scheme I.

An appropriately substituted R1, R2 phenol (7) is converted to lactone (8) following the procedures described in Scheme I, steps (a-b) above.

The conversion to the intermediate (9) is completed by reacting it (2a) with an aqueous acid, such as hydrochloric acid which provides for the removal of the aluminum chloride from the reaction. The acid (9) is converted to the corresponding acid chloride using oxalyl chloride with dimethylformamide as a catalyst. The acid chloride is recycled to the alctone (10) with the removal of the solvent preferably under vacuum. The lactone (10) is converted to the glyoxamide (11) by treatment with an excess of ammonia as described in Scheme I, step (c) above.

The alkylation of (11) to prepare the ester (12), followed by the conversion to the acid is completed in accordance with the procedure listed in Scheme I, steps (d) and (e).

Alternatively, the conversion from (10) to (12) can be completed in a boiler process by the treatment of lactone (10) with sodium amide in an aprotic polar solvent, such as dimethylformamide, preferably at temperatures from about 0 ° C to 20 ° C, followed by alkylation with a suitable alkyl halide.

The intermediates and the final product can be isolated and purified by conventional techniques, for example, by the concentration of the solvents, followed by washing the residue with water, then purification by conventional techniques such as chromatography or recrystallization.

It will be readily appreciated by the person skilled in the art that the starting materials are any commercially available. For example, when X is oxygen, the initiating material (1) can be prepared rapidly by coupling an appropriately substituted phenol with a phenyl halide appropriately substituted to prepare the anisole, under Ullmann-type conditions, by refluxing the phenol and the feni i halide in the presence of an excess of potassium carbonate and cupric oxide in an aprotic polar solvent such as pyridine. The reaction is preferably conducted under a Oxygen blanket and is completed substantially from 1 to 48 hours.

The demethylation of the anisole is conducted by refluxing it for 1 to 24 hours using any cleavage reagent, such as 40% hydrogen bromide in acetic acid, in a protic polar solvent, such as acetic acid to prepare (1).

All other reagents used to prepare the compounds in the current invention are commercially available.

The following examples further illustrate the preparation of the compounds of this invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

The following abbreviations are used in Examples 1 to 13 below.

HOAc is acetic acid HBr is hydrogen bromide EtOAc is ethyl acetate aHC03 is sodium bicarbonate Na2S04 is sodium sulfate CHC13 is chloroform NH40H is ammonium hydroxide HCl is hydrochloric acid CuO is copper oxide (II) MgSO4 is magnesium sulfate DAP is diammonium phosphate A1C3 is aluminum chloride K? C03 is potassium carbonate CH2C12 is chloride methylene NH3 is ammonia DMF is dimethylformamide Kl is potassium iodide MeOH is methanol NaH is sodium hydride NaOH is sodium hydroxide DMAP is dimethylamino (pyridine; Example 1 - (5-carboxypent-l-yloxy) -4-phenoxyphenylglyoxamide Paration of 3-phenoxyanisole 3-methoxyphenol (287.4 g, 2.3 mol), 316.0 g (2.0 mol) of bromobenzene, 552 g (4.0 mol) of K2C03, 12.0 g (0.19 mol) of activated copper (prepared in accordance with Org. Syn. Coll. Vol. II, p.445-6), Cu (II) acetate hydrate 2.0 g (11 mMol), CuO powder (2.0 g, 25 mMol), and 2.0 g of copper sulfate (12 mMol) were combined in 1500 mL of dry pyridine. The resulting mixture was heated under reflux for three days. After cooling, the mixture was concentrated under reduced pressure, then treated with 6N HCl. The extraction was carried out with ether. The combined organics were washed with water, diluted with NaOH, and water, then concentrated under reduced pressure. The residue was distilled in vacuo to give 3-phenoxyanisole, distilling at 138/40 ° C / 2 mm pressure, 119 g (75% yield). XH NMR (CDC3) d: 3.81 (s, 3H), 6.61 (m, 2H), 6.68 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 8.3, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.37 (t, J = 7.8 Hz, 2H).

B. Preparation of 3-phenoxyphenol 3-phenoxyanisole (8.3 g) was added to a mixture of 50 mL of 40% HBr and 100 mL of glacial acetic acid. The resulting mixture was heated under reduced pressure. He The residue was taken up in EtOAc, washed with water, saturated NaHCO3, and brine. After drying with MgSO4, and at a concentration under reduced pressure, 3-phenoxyphenol was obtained and used without further purification.

C. Preparation of 3-phenoxyphenylglyoxylic acid lactone The 3-phenoxyphenol was combined with oxalyl chloride (6.5 mL, 2 equivalents) and 1.0 g of DMPA (catalytic), in 30 mL of CHC13. The mixture was heated under reflux for 10 hours, then cooled and concentrated under reduced pressure. The residue was dissolved in 20 mL of dichloromethane and added dropwise at room temperature to a suspension of A1C13 in 100 mL of dichloroethane. The mixture was allowed to stir overnight at room temperature, then carefully poured into water and allowed to stir for one hour to effect hydrolysis. The extraction was carried out without methylene chloride. The combined organics were washed with brine and dried over MgSO4. After concentration under reduced pressure, the product was obtained as a yellow solid (4.1 g). A sample was recrystallized from CH2Cl2 / ether for characterization. p.f. 137-139 ° C.

Elemental Analysis for Ci4H804 Calculated: C 70.00, H 3.36; Found: C 69.65, H 3.49; M / Z 240 (M +).

D. Preparation of 2-hydroxy-4-phenoxyphenylglyoxamide The compound of part C was combined with 30 mL of concentrated NH 4 OH and water, and stirred at room temperature. A homogenous yellow solution resulted after 30 minutes. The solution was treated with concentrated HCl until a tar residue was formed. The solution was decanted from the residue, and acidified to pH 1 by further addition of concentrated HCl. The product was collected by suction filtration and washed with fresh water. A sample was recrystallized with EtOAc / hexane for characterization. P.f. 144-146 ° C. XH NMR (CDC3) d: 5.81 (br s, 1H), 6.42 (s, 1H), 6.58 (d, J = 10.0 Hz, 1H), 7.06 (br s, 1H), 7.12 (d, J = 7.7 Hz , 2H), 7.27 (m, 1H), (t, J = 7.7 Hz, 2H), 8.68 (d, J = 9.2 Hz, 1H). M / Z 257 (M +).

E. Preparation of 2- (5-carboxypent-l-yloxy) -4-phenoxyphenylglyoxamide methyl ester 2-Hydroxy-4-phenoxyphenylglyoxamide (0.3 g, 1.2 mMol) was added to 60 mg of a 60% suspension of NaH in mineral oil in 20 mL of DMF. When the evolution of the gas stopped, 0.3 g of 6-methyl bromohexanate was added. The resulting solution was heated and stirred overnight while immersing in an oil bath maintained at 60-65 ° C. The mixture was poured into 100 mL of water and extracted with EtOAc. The combined organics were washed with brine, and dried over MgSO4. The product was isolated as a white crystalline solid (0.2 g, 43% yield) by means of pressure chromatography on silica gel, eluting with EtOAc / hexane: 6/4.

F. Preparation of 2- (5-carboxypent-l-yloxy) -4-phenoxypheniiglyoxamide The ester (0.2 g, 0.52 mMoL), prepared in the Step E, above, was combined with IN NaOH (0.52 mL) and 5 mL of methanol in an argon atmosphere. The resulting mixture it was stirred at room temperature for 7 days. The solvent was removed under reduced pressure. The residual solid, pale yellow foam was taken in water. The aqueous solution was extracted with ethyl acetate, then acidified to pH 1 with concentrated HCl. The product (35 mg, 18% yield) was isolated by suction filtration and washed with fresh water.

Elemental Analysis for C2oH2? N06: Calculated: C 64.68, H 5.70, N 3.77; Found: C 64.50, H 5.72, N 3.65. M / Z 371 (M +).

Example 2 2- (3-carboxyprop-l-yloxy) -4-phenoxyphenylglyoxamide The title compound was prepared as described in Example 1 above. Performance 9%. P.f. 170-172 ° C. XH NMR (DMSO-de): 1.97 (m, 2H), 2.49 (t, J = 7.2 Hz, 2H), 4. 07 (t, J = 6.0 Hz, 2H), 6.60 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 7.23 (m, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.55 (m, 2H), 7. 64 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 8.03 (s, 1H), 12.18 (s, 1H). M / Z 343 (M +).

Example 3 2- (5-carboxyhex-l-yloxy) -4-phenoxyphenylglyoxamide The title compound was prepared as described in Example 1, above; 69% yield P.f. 132-134 ° C.

Elemental Analysis for C2? H23N06 Calculated: C 65.44, H 6.02, N 3.63; Found: C 65.63, H 6.13, N 3.39.

Example 4 2- (^ -carboxyhept-l-yloxy) -4-phenoxyphenylglyoxamide The title compound was prepared as described in Example 1, above; 24% yield P.f. 119-121 ° C.

Analysis for C22H25N? 6 Calculated: C 66.15, H 6.31, N 3.51; Found: C 65.87, H 6.05, N 3.25.

Example 5 2- (4-carboxibut-l-yloxy) -4-phenoxyphenylglyoxamide The precursor ester of this acid was prepared by the general method listed in Example 1, Steps A-E, above. The ester (0.193 g, 0.52 mMol) was combined with 0.52 mL of IN NaOH in 5 mL of methanol under an argon atmosphere. The mixture was stirred at room temperature for 7 days, then concentrated under reduced pressure to give a pale yellow solid (0.170 g, 86% yield).

Analysis calculated for Ci9H? ßN06Na-H20: Calculated: C 57.43, H 5.07, N 3.52; Found: C 57.43, H 4.91, N 3.08. : H NMR (DMSO-de) d: 1.64 (br s, 4H), 1.90 (br t, 2H), 3.92 (br t, 2H), 6.50 (d, J = 8.50 Hz, 1H), 6.72 (s, 1H), 7.13 (d, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.46 (t, J = l .3 Hz, 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.7-8.4 (brs, 2H) Example 6 Sodium 2-carboxymethoxy-4-phenoxyphenylglyoxamide A. Preparation of 2-carboxymethoxy-4-phenoxyphenylglyoxamide To 25 mL of dry DMF was added 0.54 g (2 mmole) of 2-hydroxy-4-phenoxyphenylglyoxamide, the compound of Example 1, Step D, above, followed by 0.244 mL (2.2 mmole) of methyl bromoacetate, 0.304 g ( 2.2 mmole) K2C03, and 200 mg of Kl in dry powder form. The mixture was stirred 16 hours at room temperature and evaporated under vacuum. The product was redissolved in EtOAc and washed with brine. The solution was evaporated under vacuum, and the product was purified by chromatography on silica gel (30-40% EtOAc in hexanes), yielding 0.461 g (67%) of 2-carboxymethoxy-4-phenoxypheni-glyoxamide as an oil.

Mass Spectral Analysis (FD) m / z: 343.3 (M +).

B. Preparation of sodium 2-carboxymethoxy-4-phenoxyphenylglyoxamide.

In 25 mL of MeOH, 460 mg (1.34 mmole) of the intermediate glioxamide prepared above was dissolved. To the stirred solution was added 1.34 mL of IN NaOH, and hydrolysis was allowed to continue at room temperature for 24 hours. The solvent was removed under vacuum, leaving a residue, an oily residue, which, in addition of a few mL of EtOAc, gave 402 mg (89%) of the sodium 2-carboxymethoxy-4-phenoxyphenylglyoxamide, melting at 106 ° C. (d).

XH NMR (DMSO-de) d: 4.12 (s, 3H), 6.57 (d, 1H), 7.09 (d, 2H), 7.21 (t, 1H), 7.43 (t, 2H), 7.58 (d, 2H) , 8.16 (br s, 1H).

Example 7 2- (2-carboxy) ethoxy-4-phenoxyphenylglyoxamide A. Preparation of 2- (1,3-dioxolan-2-yl) ethoxy-4-phenoxy-phenyl-ioxamide To a stirred DMF solution (24 mL) containing 0. 448 g (1.74 mmole) of 2-hydroxy-4-phenoxyphenylglyoxamide, the compound of Example 1, Step D, above, was added 0.225 g (1.91 mmole) of 2- (2-bromoethyl) -1,3-dioxolan, 50 mg of Kl in dry powder form, and 92 mg (1.91 mmol) of NaH (50% in oil). The mixture was heated at 60 ° C for 16 hours. The reaction mixture was quenched with cold brine, and the resulting organic layer was washed with cold brine twice. After drying over Na 2 SO 4 and evaporation under vacuum, the product was purified on a preparative silica gel plate (75% EtOAc-25% hexane), giving 220 mg (35%) 2- (1,3-dioxolan) -2-yl) ethoxy-4-phenoxyphenylglyoxamide as an oil. aH NMR (CDC13) d: 2.14 (q, 2H), 3.88-3.98 (m, 4H), 4.12 (t, 2H), 5.08 (t, 1H), 5.51 (bd s, 1H), 6.39 (bd s, 1H), 6.57 (d, 1H), 6.58 (s, 1H), 7.09 (d, 1H), 7.23 (t, 1H), 7.42 (t, 2H), 7.73 (d, 1H).

B. Preparation of 2- (2-carboxyethoxy) -4-phenoxyphenylglyoxamide In 20 mL of acetone, 220 mg (0.62 mmcie) of the intermediate dioxolanylglyoxamide prepared arrioa was dissolved. The Jones oxidation reagent was added in drop form until the reddish color did not become extinct. The Most of the solvent was removed under vacuum, and the reaction mixture was extracted between EtOAc and cold water. The organic layer was shaken with dilute bicarbonate, and the resulting aqueous layer was acidified and extracted with EtOAc. The organic layer was dried over Na2SO4, and evaporated under vacuum. The product was redissolved in a mixture of acetone-CH2Cl2 solvent (1: 1) to give 15 mg (7.4%) of the crystalline 2-carboxyethoxy-4-phenoxyphenylglyoxamide, melting at 140 ° C (d).

Elemental Analysis for CpH? 5N? 6 Calculated: C, 62.01; H, 4.59; N, 4.25; Found: C, 61.74; N, 4.64; N, 4.11.

Example 8 2- (4-carboxibut-l-yloxy) -4- (2-phenylphenoxy) phenylglyoxamide A. Preparation of 3- (2-phenylphenoxy) anisole In 200 mL of pyridine were added 26.7 g (215 mmeles ^ of 3-phenoxyphenol, 50.0 g (215 mmoles) of 1-bromo-2-phenylbenzene, and 59.3 g (430 mmoles) of K2C03. the mixture was heated to 70 ° C, and 43.0 g (538 mmoles) of CuO were added in powder form. The mixture was then heated for 72 hours at reflux with vigorous stirring. After cooling and filtration, the reaction mixture was evaporated under vacuum. The residue was extracted between EtOAC and diluted in cold HCl 3 times. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum. The product was purified via flash chromatography on silica gel (0 to 50% EtOAc in hexanes), giving 50.9 g (86%) of 3- (2-phenyl) phenoxyanisole as a crystalline solid, melting at 52-54 ° C.

Elemental Analysis for C? 9H? 602: Calculated: C, 82.58; H, 5.84; O, 11.58; Found: C, 82.75; H, 5.88; OR 11.40.

B. Preparation of 3- (2-phenylenoxy) phenol To 200 mL of HOAc and 80 mL of 40% HBr was added 20 g (72.5 mmol) of the intermediate anisole prepared above. The mixture was heated to reflux for 6 hours. The majority of the solvent was removed under vacuum, and the residue was shaken between EtOAc and water. The organic layer is washed with saturated NaHCO3, dried over Na2SO4, and evaporated under vacuum to give 16 g (85%) of 3- (2-phenyl) phenoxyphenol) as an oil, which was used without further purification.

Spectral mass analysis (FD) m / z: 262 (M +).

C. Preparation of 2-hydroxy-4- (2-phenylphenoxy) phenylglyoxamide To 50 mL of CHC13 was added 2.62 g (10 mmol) of the intermediate phenol, 100 mg of DPA, and 2.1 mL (22 mmol) of oxalyl chloride. The mixture was refluxed for 16 hours. The solvent was removed under vacuum, yielding the condensation product of oxalyl chloride as an oil, which was used without further purification.

The condensation product of oxalyl chloride (approximately 10 mmole) was dissolved in 25 ml of 1,2-dichloroethane and added for 3 minutes to 3.99 g (30 mmole) of A1C13 dispersed in 25 ml of cooled 1,2-diclcroethane. in an ice bath. After 2 hours, the ice bath was removed, and the reaction was left continue for 1 hour. The reaction was placed in an ice bath, and 50 mL of concentrated NH4OH was added with vigorous shaking. After 1 hour, the reaction was diluted with water and filtered. The filtrate was further diluted with CH2C12 and taken into a separating flask. The organic layer was washed with dilute cold HCl, dried over NaSO 4, and evaporated under vacuum. The product was purified on silica gel (first, a gradient of 0-100% EtOAc in hexane, followed by 20-80% MeOH in EtOAc), giving 206 mg (7.8%) of 2-hydroxy-4- ( 2-phenyl) phenoxyphenyl-1-yl-glyoxamide. A crystalline analytical sample from CH2C12 melted at 100-103 ° C.

Elemental Analysis for C2oH? 5N? : Calculated: C, 72.06; H, 4.54; N, 4.20; Found: C, 72.06; H, 4.64; N, 3.94. Mass spectral analysis (FD) m / z: 333 (M +).

It was also obtained in the last fractions of the chromatography mentioned above, 1.14 g (34%) of 2-hydroxy-4- (2-phenyl) phenoxyphen-1-yl-glyoxylic acid as a crystalline solid, melting at 205 ° C ( d).

Mass Spectral Analysis (FD) m / z): 334 (M +).

The glyoxylic acid was converted to the most desired glyoxamide as follows: to 25 mL of CH2C12 0.8 g (2.4 mmol) of the intermediate glyoxylic acid was dissolved. The mixture was cooled by an ice bath, and then a catalytic amount of DMF was added, followed by 0.28 mL (2.9 mmole) of oxalyl chloride. After 1 hour, the ice bath was removed, and the reaction was allowed to warm to room temperature for 1 hour. The solvent was removed under vacuum, and the product was redissolved in 50 mL of CH2C12. From a reading bottle, NH3 was pumped over a period of 5 minutes with stirring. The reaction was shaken with cold diluted HCl, and the organic layer was dried over Na2SO4, and evaporated under vacuum. The crude product crystallized from CH2Cl2-hexanes, giving an additional 303 mg (38%) of 2-hydroxy-4- (2-phenyl) phenoxyphenylglyoxamide. (17%) P.F. 100-103 ° C.

Mass Spectral Analysis (FD) m / z: 333 (M +).

D. Preparation of 2- (-carboxymethoxybutyl-l-yloxy) -4- (2-phenyl) phenoxyphenylglyoxamide To 62.4 mg (1.3 mmol) of 50% NaH in mineral oil, which has been washed with hexanes, was added 50 mL of dry DMF, C.40 g (1.2 mmol) of 2-hydroxy-4- (2- phenyl) phenoxyphenylglyoxamide, and 100 mg of Kl in the form of a dry powder and 4-methyl bromobutane. The reaction mixture was stirred and heated 16 hours at 60 ° C, quenched with cold diluted HCl, and after further dilution with cold brine, extracted with EtOAc. The organic layer was washed with acidified brine twice, dried over Na 2 SO 4, evaporated under vacuum. When chromatographed on silica gel (20 to 80% EtOAc in hexanes), 254 mg (47%) 2- (4-carbomethoxy) butoxy-4- (2-phenyl) phenoxyphenylglyoxamide was prepared as an oil.

XH NMR (CDCL3) d: 1.7-1.9 (m, 4H), 2.39 (t, 2H), 3.69 (s, 3H), 3.93 (t, 2H), 5.84 (br s, 1H), 6.29 (br s, 1H), 6.46 (s, 1H), 6.49 (d, 1H), 7.12 (d, 1H), 7.3-7.5 (m, 8H), 7.65 (d, 1H); Mass Spectral Analysis (FD) m / z: 447 (m +).

E. Preparation of 2- (4-carboxibut-l-yloxy) -4- (2-phenyl) phenoxyphenylglyoxyl ida In 10 mL of MeOH they were dissolved with agitations, 254 mg (0.57 mmole) of the carbomethoxy intermediate prepared above, followed by the addition of 1.14 mL of 5N NaOH. The mixture was stirred 16 hours at room temperature. The solvent was removed under vacuum, and the residue was diluted with water and extracted with 4: 1 EtOAc: hexanes. The aqueous layer was acidified with dilute HCl, and shaken with EtOAc. The organic layer was dried over Na2SO4, and evaporated under vacuum. The crystalline 2- (4-carobxy (butoxy-4- (2-phenyl) phenoxyphenylglyoxamide, 181 mg (73%) was obtained, melting at PF = 118-20 ° C.

Elemental Analysis for C25H23N06: Calculated: C, 68.95; H, 5.79; N, 3.23; Found: C, 68.91; H, 5.58; N, 3.22; : H NMR (DMSO-de) d: 1.7-1.9 (m, 4H), 2.37 (t, 2H), 3.93 (t, 2H), 6.32 (br s, 1H), 6.44 (s, 1H), 6.45 (d, 1H), 6.47 (br s, 1H), "M2 (d, 1H), 7.3-7.5 (m, 8H), 7.65 (d, 1H); Mass spectral analysis (FD) m / z: 433 (M +).

Example 9 2- (4-carboxibut-l-yloxy) -4-phenoxy-5-methylphenylglyoxamide A. Preparation of 3-hydroxy-4-methylanisole To a solution of 10.0 g (65.8 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 50 mL of HOAc and 50 mL of concentrated HCl, 17.2 g (263.2 mg atoms) of zinc was added as a powder. The mixture was heated one hour at 85-90 ° C and then extracted three times between EtOAc and a saturated NaCl solution. The organic layer was washed with saturated NaHCO3, dried over Na2SO4, and evaporated under vacuum. The crude product was purified via flash chromatography on silica gel (0 to 20% EtOAc in hexanes), yielding 2.0 g (22.0%) of 3-hydroxy-4-methylanisole as an oil which crystallized permanently, melting 34-35 ° C.

B. Preparation of 4-methyl-3-phenoxyanisole Er. 50 L of pyridine, 4.14 g (30 mmol) of the hiaroxianisol prepared above, 3.48 mL were added. (33 immoles) of bromobenzene, and 4.8 g (60 mmol) of K2C03. Under argon, the mixture was heated to 70 ° C, and 4.87 g (33 mmoles) of bromobenzene, and 4.8 g (60 mmoles) of K2CO3. Under argon, the mixture was heated to 70 ° C, and 4.8 g (60 mmoles) of CuO in powder form. The mixture was then heated for 16 hours at reflux with vigorous stirring. An additional CuO (4.8 g, 60 mmol) and bromobenzene (3.5 mL, 60 mmol) was added, and the reaction mixture was heated at reflux for 16 hours. After cooling and filtration the reaction mixture was evaporated under vacuum. The residue was extracted between EtOAc and cold diluted HCl three times. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum. The product was purified via flash chromatography on silica gel (0 to 30% EtOAc in hexane) to give 3.32 g (51.7%) of 4-methyl-3-phenoxyanisole as an oil.

C. Preparation of 4-methyl-3-phenoxyphenol To 50 ml of HOAc and 20 ml of 40% HBr was added 3.2 g (15.0 mmoles) of the intermediate methylanisole prepared above, and the mixture was heated at reflux for 16 hours. The majority of solvent was removed under vacuum and the residue stirred between EtOAc and water. The product after drying over MgSO4 and evaporation under vacuum, was purified via flash chromatography on silica gel (0 to 30% EtOAc in hexane), giving 1.81 g (60%) of 4-methyl-3-phenoxyphenol as a oil.

D. Preparation of 2-hydroxy-5-methyl-4-phenoxyphenylglyoxylic acid To 100 ml of CHCl3 was added 1.70 g (8.5 mmol) of the intermediate methylphenol prepared above, 30 mg of DAP, and 1.79 ml (18.7 mmol) of oxalyl chloride. The mixture was refluxed for 16 hours. The solvent was removed under vacuum, yielding the condensation product of the oxalyl chloride as an oil, which was used without purification. The intermediate oxalyl chloride product was dissolved in 25 ml of 1,2-dichloroethane and added to 3.39 g (2.25 mmoles) of AICI-? For 5 minutes. dispersed in 100 ml of 1,2-dichloroethane cooled in an ice bath. After 1 hour, the ice bath was removed and the reaction was allowed to continue for 30 minutes. The reaction mixture was poured into 300 ml of a 3: 1 mixture of crushed ice and concentrated HCl with vigorous stirring. The Organic layer was separated and washed with cold diluted HCl and dilute K2CO3. The carbonate extract was acidified with dilute HCl and extracted with EtOAc. After drying over MgSO4 and evaporation under vacuum, 1.04 g (45%) of 2-hydroxy-5-methyl-4-phenoxyphenylglyoxylic acid was obtained as a crystalline solid, melting at 85-87 ° C.

E. Preparation of 2-hydroxy-5-methyl-4-phenoxyphenylglyoxamide To 25 ml of CHCI; containing a few drops of DMF, 0.80 g (4 mcls) of the glyoxylic acid intermediate prepared above was added. The mixture was cooled in an ice bath, and 0.46 ml of oxalyl chloride (4.8 mmol) was added. After 1 hour, the ice bath was removed and the reaction was allowed to continue for 1 hour. The solvent and excess oxalyl chloride were removed under vacuum, and the product was redissolved in 50 ml of CH 2 Cl 2 and cooled in an ice bath. Approximately 5 ml of liquid NH3 was added and the reaction was stirred for 1 hour. The reaction mixture was cooled rapidly with cold concentrated HCl, then diluting with brine and CH2Cl2, stirring in a separator funnel. The organic layer was washed with brine, dried over MgSO4, and concentrated to give 225 mg (21%) of 2-hydroxy-5-methyl-4-phenoxyphenylglyoxamide, melting at 158-60 ° C.

Elemental Analysis for C? 5Hi3 04: Calculated: C, 66.42; H, 4.83; N, 5.16; Found: C, 66.04; H, 4.75; N, 4.82.

F. Preparation of 2- (4-carboxymethoxy-l-yloxy) -4-phenoxy-5-methylphenylglyoxamide The compound was prepared as described in Example 8, step D above. Yield = 47%, oil.

H1 NMR (CDCli) d: 1.2-1.8 (m, 4H), 2.23 (s, 3H), 2.35 (t, 2H), 3.66 (s, 3 H), 3.81 (2, 2H), 6.11 (br s, 1H), 6.34 (s, 1H1, 6.40 (br s, 1H), 7.01 (d, 2H), 7.17 (t, 1H), 7.38 (t, 2H), 7.64 (s, 1H) G. Preparation of sodium 2- (4-carboxibut-l-yloxy) -4-phenoxy-5-methylphenylglyoxamide The title compound was prepared as described in Example 8, step D, above. Yield = 70%, PF = 206-9 ° C H1 NMR (DMSO-d6) d: 1.5-1.6 (m, 4H), 1.86 (t, 2H), 2.17 (s, 4H), 3.78 (t, 2H), 6.52 (s, 1H), 7.04 (d.2H), 7.18 (t, 1H), 7.43 (t, 2H), 7.64 (s, 1H), 7.83 (br s, 1H), 7.40 (br s, 1H).

Example 10 2- (3- (phosphonoyl disodium) prop-1-yloxy) -4-phenoxypheni Iglioxamide A. Preparation of 2- (3-dimethoxyphosphono) prop-1-yloxy-4-phenoxyphenylglyoxamide To 20 mL of dry DMF was added with stirring, 0.457 g (1.78 mmole) of 2-hydroxy-4-phenoxyphenylglyoxamide, 0.411 g (1.78 mmole 'of (3-bromoprop-1-yl) dimethylphosphonate, 100 mg of Kl in form of dry powder, and 57 mg (1.78 mmole) of 50% NaH dispersion in mineral oil. heated 16 hours at 6 ° C, cooled and cooled rapidly with cold diluted HCl, and stirred between EtOAc and brine. The organic layer was washed with brine twice, dried over Na 2 SO 4, and evaporated under vacuum. The product was chromatographed on silica gel (0 to 100% EtOAc in hexane), giving 0.353 g (49%) of 2- (3-dimethoxyphosphonoyl) prop-1-yloxy-4-phenoxyphenylglyoxamide as an oil.

Elemental Analysis for C19 H N 0: Calculated: C, 56.02; H, 5. ^ 3: N, 2.67; Found: C, 56.02; H, 5.44; N, 2.67; H1 NMR (CDCli) d: 2.0-2.2 (m, 4H), 3.77 (s, 3H), 3.81 (s, 3H, 4.00 (t, 2 H), 6.25 (Dr s, 1H), 6.56 (s, 1H), 6.59 (d, 1H), 7.09 (d, 2H), 7.23 (t, 1H), 7.40 (t , 2H), 7.78 (d, 1 HOUR); Mass Spectrum Analysis (FD) m / z: 407.

B. Preparation of 2- (3- (phosphonoyl disodium) prop-1-yloxy) -4-phenoxyphenylglyoxamide In 10 mL of CH2Cl2, 0.35 g of the intermediate dimethylphosphonate prepared above was added, 0. 95 g (6.88 mmole) of KC03, and 0.91 mL (6.88 mmole) of trimethylsilyl bromide. The reaction mixture was stirred 16 hours at room temperature. The reaction mixture was evaporated under vacuum and treated with 15 ml of MeOH at room temperature for 1 hour. The mixture was filtered and diluted with EtOAc to give a solid, which was chromatographed on an ionization column (5 to 30% acetonitrile in water). The fractions were lyophilized to give 140 mg (43%) of 2- (3-phosphonoyl disodium) propo-l-yloxy-4-phenoxyphenylglyoxamide as a solid.

H1 (DMSO-C-6.) D: 1.73 (m, 2H), 2.17 (m, 2H), 4.10 (t, 2H), 6.63 (d, 1H), 6.75 (s, 1H), 7.19 (d , 2H), 7.32 (t, 1H), 7.53 (t, 2H), 7.84 (d, 1H).

Example 11 2- (4-carboxybutyl-1-yloxy) -4- (3-phenylphenoxy) phenylglyoxamide A. Preparation of 3- (3-phenylphenoxy) anisole Under the Ullmann conditions used in Example 8, steps A and B, above, 13.3 g of 3-ethoxyphenol (107 mmole) were condensed with l-bromo-3-phenylbenzene, giving, after purification on silica gel (gradient 0 to 30% EtOAc in hexane), 17.8 g (60%) of 3- (3-phenylphenoxy) anisole as a crystalline solid, melting at 41-42 ° C.

Mass Spectral Analysis (FD) m / z: 276 (M +) B. Preparation of 3- (3-phenylphenoxy) phenol To the anisole derivative prepared above (17.7 g, 64 mmole), it was demethylated in 40% HOAc / HBr under the conditions of Example 8, step c, above and, after purification of the product on silica gel, (gradient EtOAc 0 30% in hexane), 12.2 g (72%) of 3- (3-phenylphenoxy) phenol was obtained as an oil.

Elemental Analysis for C ?? Hi4 O2: Calculated: C, 82.42; H, 5.38; O, 12.20; Found: C, 82.17; H, 5.38; 0, 12.42; C. Preparation of 2-hydroxy-4- (3-phenylphenoxy) phenylglyoxylic acid As in Example 8, step D above, the intermediate phenol prepared above (7.4 g, 31.4 mmole) was treated with oxalyl chloride, and after removing the solvent the product was subjected to A1C13. The reaction mixture was rapidly cooled in one liter of a 2: 1 mixture of h: - chopped and concentrated HCl with vigorous shaking. The organic layer was separated, washed with brine, diluted with EtOAc to obtain a clear solution, and dried over MgSO4. The product was concentrated under vacuum and purified by chromatography on silica gel (0 to 100% EtOAc in hexanes then 0 to 20% MeOH in EtOAc) to give 4.3 g (421) of 2-hydroxy-4- ( 3-phenylphenoxy) phenylglyoxylic acid as an oil.

Spectral mass analysis (FD) m / z: 334 (M D. Preparation of 2-hydroxy-4- (3-phenylphenoxy) phenylglyoxylic acid lactone In 150 ml of CH 2 Cl 2, 4.3 g (12.9 mmoles) of the glyoxylic acid prepared above were dissolved. After adding 10 drops of DMF and cooling the mixture with an ice bath, 1.48 ml of oxalyl chloride (15.5 mmol) was added to the stirred mixture in one portion. After 30 minutes the ice bath was removed and the reaction was allowed to continue for 1 hour. The reaction mixture was concentrated under vacuum and a solid formed, which was washed with 1: 1 hexane: CH 2 Cl 2, giving 3.5 g, of the 2-hydroxy-4- (3-phenylphenoxy) phenylglyoxylic acid lactone melting at 55 ° C. -58 ° C.

Mass Spectral Analysis (FD) m / z: 316 (M +).

E. Preparation of 2- (4-carboxymethoxybutyl-l-yloxy) -4- (3-phenylphenoxy) phenylglyoxamide To 50 mL of dry DMF, 1.58 g (5 mmole) of the 2-hydroxy-4- (3-phenylfenoxy) phenylglyoxylic acid lactone was added with stirring. The solution was cooled cor. an ice bath and 0.234 g (6.0 mmole) of sodium amide was added. After 15 minutes, 0.786 ml (5.5 mmole) of 5-bromovalerate was added. methyl, and the ice bath was removed, leaving the mixture to reach room temperature. The mixture was heated 16 hours at 60 ° C and then cooled rapidly with cold diluted HCl. The reaction mixture was stirred between EtOAc and cold diluted HCl. The organic layer was washed twice with cold diluted HCl, dried over Na2SO4 and concentrated in vacuo. The product was chromatographed on silica gel (0 to 70% EtOAc in hexane), giving 0.682 g (31%) of 2- (4-carbomethoxybutyl-1-yloxy) -4- (3-phenylphenoxy) -phenylglyoxamide as a oil.

H1 NMR (CDCl3) d: 1.8-1.9 (m, 4H), 2.40 (t, 2H), 3.6 (s, 3H), 4.00 (t, 2H), 5.77 (br s, 1H), 6.30 (br s, 1H), 6.60 (s, 1H), 6.61 (d, 1H), 7.06 (br s, 1H) 7.3-7.5 (m, 6H), 7.5Q (d, 2H), 7.74 (d, 1H).

F. Preparation of 2- (4-carooxibut-l-yloxy) -4- (3-phenyl) phenoxyphenylglyoxamide In 20 mL of MeOH, 0.682 g (1.53 mmole) of the glyoxamide intermediate prepared above was dissolved at room temperature. To the solution they were added 3. 0.5 mL of 0.5 N NaOH After stirring for 15 hours, the solvent was removed under vacuum and the residue was diluted with water and extracted with EtOAc. The crystals were filtered from the organic layer, giving 0.458 g (69%) of 2- (4-carboxy) butoxy-4- (3-phenyl) phenoxyphenylglyoxamide, melting at 97-98 ° C.

H1 NMR (CDC13) d: 1.6-1.8 (m, 4H), 2.28 (t, 2H), 4.02 (t, 2H), 6.61 (d, 1H), 6.86 (s, 1H), 7.15 (br s, 1H ), 7.4-7.6 (, 7H), 7.70 (d, 3H), 7.94 (br s, 1H), 12.02 (br s, 1H); Mass Spectrum Analysis (FD) m / z: 433 (M +).

Example 12 2- (4-carboxypent-l-yloxy) -4- (2-phenylphenoxy) phenylglyoxamide A. Preparation of 2- (4-carbomethoxypent-l-yloxy) -4- (2-phenylphenoxy) phenylglyoxamide The compound was prepared as described in Example 8, steps A-D, above. Yield = 63%, PF = 70 - 74 ° C Elemental Analysis for C2 H27 N 06: Calculated: C, 70.27; H, 5.90; N, 3.04; Found: C, 72.26; H, 6.31; N, 2.95; Mass Spectral Analysis (FD) m / z: 461 (M +).

B. Preparation of 2- (4-carboxy) pentoxy-4- (2-phenyl) phenoxyphenylglyoxamide The compound was prepared as described in Example 8, Step E, above. Yield = 42%, PF = 97 - 99 ° C Elemental Analysis for C26 H25 N 06: Calculated: C, 69.79; H, 5.53; N, 3.13; Found: c, 69.57; H, 5.62; N, 3.06; H1 NMR (DMS0d6) d: 1.39 (quint, 2H), 1.48 (quint, 2H), 1.63 (quint, 2H), 2.21 (t, 2H), 3.88 (t, 2H), 6.41 (d, 1H), 6. 63 (s, 1H), 7.17 (d, 1H), 7.3 - 7.6 (m, 8H), 7.88 (s, 1 HOUR); Mass Spectrum Analysis (FD) m / z: 447 (M +).

- - EXAMPLE 13 2- (4-carbuxibut-l-yloxy) -4-phenylphenylglyoxamide A. The preparation of the lactone of 2-hydroxy-4-phenylphenylglyoxylic acid.

The commercially available 3-phenylphenol was treated with oxalic chloride, and the resulting product was treated with AICI3 as described in Example 1, step c, described above. After quenching the reaction mixture from the treatment of the AlCli with water was dried over MgSO; and concentrated to give the crystalline 2-hydroxy-4-phenyl-phenylglyoxylic acid lactone (85 °), melted at 131-33 ° C.

Mass spectral analysis (FD) m / z: 224 (M +).

B. Preparation of 2-hydroxy-4-phenylphenylglyoxamide.

- - The lactone prepared above, (4.0 g, 17.9 moles), was dissolved in 200 L of CH2C12 and excess ammonia gas was bubbled for more than 5 minutes. The reaction mixture was stirred with brine, and dried over MgSO-, and concentrated. Upon cooling, the crystallized product gave 2-hydroxy-4-phenylphenylglyoxamide (93%), with a mp of 150 ° C (d).

Elementary analysis for u Hn 03: Calculated: C, 69.70; H, 4.60; N, 5.81; Found: C, 69.72; H, 4.59; N, 5.57. / Mass spectral analysis (FD) m / z: 241 (Mt) C. Preparation of 2- (4-carboxymethoxybutyl-1-yloxy) -4-phenylphenylglyoxamide The compound was prepared as described in example 8, step D, above.

Yield = 28 ° 0, PF = 119 - 20 ° CH NMR (DMSOd.) D: 1.6 - 1.8 (m, 4H), 2.39 (t, 2H), 3.58 ís, 3H'¡, 4.18 (t, 2H), 7.36 (d, 1H), 7.38 (s, 1H), 7.4-7.5 - - (, 3H), 7.58 (s, 1H), 7.70 (d, 1H), 7.38 (d, 2H), 8.00 (s, 1H); Mass spectral analysis (FD) m / z: 355 (M +).

D. Preparation of 2- [(4-carboxybutyl-l-yloxy] -4-phenyl-phenylglyoxamide.

The title compound was prepared in Example 8, Step E, above. Yield = 58%, MP = 157-158 ° C Elemental analysis for C: í H N, 4.10; Calculated: C, 66.85; H, 5.61; N, 4.10; Found: C, 66.81; H, 5.59; N, 4.14; H "NMR (DMSOds) d: 1.6 - 1.8 (m, 4H), 2.32 (t, 2H), 4.14 (t, 2H), 7.36 (d, 1H), 7.39 (s, 1H), 7.4-7.5 (m , 3H), 7.56 (s, 1H), 7.71 (d, 1H), 7.78 (d, tH), 8.00 (s, 1H), 12.02 (s, 1H); Mass spectral analysis (FD) m / z: 341 (M +).

- - Therapeutic use of phenylglyoxamides The phenylglyoxamide compounds described herein are believed to perform their beneficial therapeutic action mainly by the direct inhibition of human sPLA2, and not by the action of antagonists for arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, etc.

The method of the invention for the inhibition of sPLA; by the release of fatty acids comprises the contact of sPLA.- with a therapeutically effective amount of the compound of formula (I), or salts thereof.

The compounds of the invention can be used in a method of treating a mammal (eg, a human) to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, rhinitis allergic, and rheumatoid arthritis; wherein the method comprises administering to a mammal, a compound of formula (I) in a therapeutically effective amount. A The "therapeutically effective" amount is an amount sufficient to inhibit the mediated release of sPLA2 from fatty acids and thereby inhibit or prevent the cascade of arachidonic acid and its harmful products. The therapeutic amount of the compound of the invention necessary to inhibit SPL 2 can be determined quickly by taking a sample from a fluid body and assessing the content of SPLA2 by conventional methods.

Pharmaceutical Formulations of the Invention As noted previously, the compounds of this invention are employed to inhibit the mediated release of sPLA2 from fatty acids such as arachidonic acid. By the term "inhibition" is suggested the therapeutically significant reduction or prevention in the release of the fatty acids initiated by the SPL 2 of the compounds of the invention. By "pharmaceutically acceptable" it is suggested that the carrier, diluent or excipient may be compatible with the other ingredients of the formulation and not damage the container thereof.

- - In general, the compounds of the invention are most desirably administered at a concentration which will generally allow effective results without causing any serious side effects and can be administered either as single unit doses, or if desired the dose can be divided into conveniently administered subunits at appropriate times during the day.

The specific dose of a compound administered according to this invention, to obtain therapeutic or prophylactic effects, will of course be determined by the particular circumstances that round the case, including for example, the route of administration, age, weight and response individual's condition, the condition to be treated and the damage of the patient's symptoms. Typical daily doses will contain a non-toxic dosage level of about 0.01 mg / kg to an approximate 50 mg / kg body weight of an active compound of this invention.

Preferably the pharmaceutical formulation is in a unit dosage form. The way of - - unit dosage may be a capsule or likewise a tablet, or the appropriate number of any of these. The amount of the active ingredient in a unit dose of the composition may vary or adjust from about 0.1 to an approximate form of 1000 mg or more in accordance with the particular treatment involved. It can be appreciated that it may be necessary to make routine variations to the dosages depending on the age and condition of the patient. The dosage will depend on the route of administration.

A "chronic" condition suggests a deteriorating condition of slow progress and long continuity. As such, it is treated when it is diagnosed and continues through the course of the disease. An "acute" condition is an exacerbation of the short course followed by a period of remission. In an acute event the compound is administered at the beginning of the symptoms and discontinued when the symptoms disappear.

Pancreatitis, shock-induced trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis can occur as an acute or chronic event.

- Thus, the treatment of these conditions contemplates any of the acute and chronic forms. The septic shock and respiratory distress of an adult, otherwise, are acute conditions treated when diagnosed.

The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

The pharmaceutical formulations of the invention are prepared by the combination (for example by mixing) a therapeutically effective amount of the phenyl glyoxamide compounds of the invention together with a pharmaceutically acceptable carrier or diluent thereof. The current pharmaceutical formulations are prepared by known procedures using readily available and well-known ingredients.

In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed or bound within a carrier which may be in the form of a capsule, pouch , paper u - - another container. When the carrier serves as a diluent, it can be a solid, semi-solid or a liquid material which acts as a vehicle, or it can be in the form of tablets, pills, powders, lozenges, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointments, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to their administration.

For pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier can be a solid, liquid, or a mixture of a solid or a liquid. Formulations in solid form include powders, tablets and capsules. A solid carrier can be one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, tablet disintegrating agents and encapsulating material.

Tablets for oral administration may contain suitable excipients such as carbonate of - - calcium, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as corn, starch, or alginic acid, and / or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate , stearic acid or talc.

In powder form, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable portions and is compacted in the desired shape and size. The powders and tablets preferably contain from about 1 to 99% by weight of the active ingredient which is the new compound of the invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting waxes, and cocoa butter.

Formulations of sterile liquid form include suspensions, emulsions, syrups and elixirs.

- - The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for example aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in a solution of aqueous starch or sodium carboxymethylcellulose or in a suitable oil.

The following pharmaceutical formulations 1 to 8 are illustrative only and are not intended to limit the scope of the invention in any way. The "active ingredient" refers to a compound according to formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof.

- Formulation 1 Hard gelatine capsules are prepared by using the following ingredients: Quantity (mg / capsule) 2- (6-carboxyhex-l-yloxy) -4- 250 phenolxypheni1-5-ethylphenylglyoxamide Starch, dry 200 magnesium stearate 1_0 Total 460 mg - - Formulation 2 A tablet is prepared using the following ingredients: Amount (mg / tablet) 2- (4-carboxibut-l-yloxy) -4- (3, 5- 250 diphenyl) phenyl) -6-methylphenylglyoxamide Cellulose, microcrystalline 400 Silicon dioxide, smoked 10 Stearic acid 5 Total 665 mg The components are combined and compressed to form tablets each weighing 665 mg.

- - Formulation 3 An aerosol solution is prepared containing the following components: Weight 2- (2-carboxyethoxy) -4- (3- (3-fluorophenyl) benzyl) -6-butylphenylglyoxamide Propellant Ethanol 22 25.75 (Chlorodifluoromethane) 74.00 Total 100.00 The active compound is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to -30 ° C and transferred to a filling device. The required quantity is then fed to a stainless steel container and diluted with the rest of the propellant. The valve units are then attached to the container.

- - Formulation 4 The tablets, each containing 60 mg of active ingredient, are made as follows: 2- (diethoxyphosphonoyl) methoxy-4- 60 mg benzylphenylglyoxamide Starch 45 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone (as a 10% solution in water) 4 mg Carboxymethyl 4.5 mg sodium starch Magnesium stearate 0.5 mg Talc 1 mg Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh US sieve and mixed vigorously. The aqueous solution containing the polyvinylpyrrolidone is mixed with the resulting powder, and the mixture is then passed through a US No. 14 mesh screen. The granules thus produced are dried at 50 ° C. and they are passed through a No. 18 mesh US sieve. The sodium carboxymethyl starch, magnesium stearate and talc are previously passed through a No. 60 mesh US sieve, and the granules are then added to the granules. which, after mixing, are compressed in a tablet machine to obtain the tablets each weighing 150 mg.

Formulation 5 The capsules, of which each contains 80 mg of active ingredient, are made as follows: 2- (4-phosphonoylbut-l-yloxy) -4- (2,6-80 mg dimethoxy) phenylphenylglyoxamide Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose and magnesium stearate are combined, passed through a US sieve.

- - No. 45 mesh, and filled into hard gelatin capsules in amounts of 200 mg.

Formulation 6 The suppositories each containing 225 mg of the active ingredient, are made as follows: 2- (4-methoxypynylbutyl-l-yloxy) -4- 225 mg (4-propyl) benzyl-5-methylphenylglyoxamide Glycerides of saturated fatty acids 2,000 mg Total 2,225 mg The active ingredient is passed through a US sieve of NO mesh. 60 and is suspended in the glycerides of saturated fatty acids previously mixed using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.

- - Formulation 7 The suspensions, each containing 50 mg of the active ingredient per 5 ml dose, are made as follows: 2- (3-methoxycarbonylprop-1-yloxy) -4- 50 mg (4-phenyl) benzylphenylglyoxamide Sodium carboxymethylcellulose 50 mg Suspension 1.25 ml Benzoic acid solution 0.10 ml Taste q.v. Color q.v. Purified water for the total 5 ml The active ingredient is passed through a US sieve of NO mesh. 45 and mixed with the sodium carboxymethylcellulose is mixed and the suspension to form a smooth paste. The benzoic acid solution, the flavor and the color are diluted with a portion of the water and added with agitation. Sufficient water is then added to produce the required volume.

- - Formulation 8 An intravenous formulation can be prepared as follows: 2-carboxymethoxy-4-phenyl-5-100 mg fluoro-6-methylphenylglyoxamide Isotonic saline 1,000 ml The solution of the above ingredients is generally administered intravenously to a subject at a rate of 1 ml per minute.

Test Experiments Test example 1 The following chromogenic assay procedures were used to identify and evaluate inhibitors of recombinant human secreted phospholipase A2, the assay described here that has been adapted by a volume of - - high search using 96 well icrotitulatory plates. A general description of this test method is found in the article "Analysis of Human Synovial Fluid Phospholipase A on Short Chain Phosp atidylcholine-Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Microtiterplate Reader", by Laure J. Reynolds, Lori L Hughes, and Edward A. Dennis, Analytical Biochemistry, 204, pp. 190-197, 1992 (the description of which is incorporated herein by reference): Reagents: REACTION SHOCK ABSORBER - CaCl2.2H20 (1.47 g / L) KCl (7455 g / L) Bovine Serum Albumin (free of fatty acid) (1 g / L) (Sigma A-7030, product of Sigma Chemical Co St. Louis MO, USA) TRIS HCl (3.94 g / L) pH 7.5 (adjusted with NaOH) ENZYME SHOCK ABSORBER - NaOAc 0.05.3H2O, pH 4.5 - - NaCl 0.2 pH adjusted to 4.5 with acetic acid DTNB - 5,5 '-dithiobis-2-nitrobenzoic acid DIHEPTANOILTIO RACEMICO - PC 1, 2-bis (hepatanoiltio) -1, 2-dideoxy-sn-glycero-3-phosphorylcholine TRITON X -100 ™ prepared at 6,249 mg / ml in the reaction buffer at 10 uM equal. TRITON X-100 ™ is a non-ionic polyoxyethylene detergent supplied by Pierce Chemical Company 3747 N. Meridian Road Rockford, Illinois 61101 REACTION MIXTURE - A measured volume of diheptanoylthio PC supplied in chloroform at a concentration of 100 mg / ml is taken to dryness and redissolved in an aqueous solution of non-ionic detergent TRITÓN X-100 ™ 10 millimolar. The reaction buffer is added to the solution, then to the DTNB to give the reaction mixture.

- - The reaction mixture thus obtained contains 1 mM of diheptanolithium-PC substrate, 0.29 mm of TRITON X-100 ™ detergent and 0.12 mm of DTMB in an aqueous solution buffered to pH 7.5.

Test Procedure: 1. Add 0.2 ml to the reaction mixture to all wells; 2. Add 10 ul of the test compound (or target solvent) to the appropriate wells mixing 20 seconds; 3. Add 50 nanograms of sPLA2 (10 microliters) to the appropriate wells. 4. Plate incubated at 40 ° C for 30 minutes; 5. Well absorbance reading at 405 nanometers with an automatic plate reader All compounds were assessed in triplicate. Typically, the compounds were titrated to a final concentration of 5 μg / ml. The compounds were considered active when they showed 40% inhibition or more compared to the control reactions without inhibiting measurements at 405 nanometers. The lack of color - - developed at 405 nanometers evidenced the inhibition. The compounds initially found to be active were evaluated again to confirm their activity, and if they were sufficiently active, determining the IC50 values. Typically the IC 50 values (see table 1 below) were determined by the dissolution of the two-fold serial test compounds so that the final concentration in the reaction ranged from 45 μg / ml to 0.35 μg / ml. The most potential inhibitors require significantly greater dilution. In all cases, the percentage of inhibition measured at 405 nanometers generated by the reactions of the enzyme containing inhibitors relative to the non-inhibited control reactions was determined. Each sample was titrated in triplicate and the resulting values were averaged to graph and calculate IC50 values. The IC50 values were determined by the concentration of the logarithms against the inhibition values in the range of 10-90% inhibition.

The compounds of the present invention were evaluated in Test Example 1 and found effective.

- - Test Example 2 Method Guinea pigs were sacrificed in male Hartley strains (500 to 700 g) by cervical dislocation and their hearts and lungs were removed and were placed in aerated Krebs cushion (02 to 95%: C02 at 5%) the dorsal pleural shorts (4 x 1 x 25 mm) were dissected from intact parenchymal segments (8 x 4 x 25 mm) cut parallel to the external angles of the lower pulmonary lobes. Two adjacent pleural strips obtained from a single lobe and representing a sample of a single tissue were immobilized at each end and joined independently to a metal support rod. A rod was attached to a displacement force transducer Grass Model FT03C, product of Grass Medial Instruments Co. , Quincy, MA, USA). The changes in the isometric voltage were presented in a monitor and thermal register (product of Modular Instruments, Malvern, PA). All tissues were placed in a coated tissue bath maintained at 37 ° C. The tissue baths were continuously aerated and contained a modified Krebs solution in the following - - composition (millimolar) NaCl, 118.2; KCl, 4.6; CaCl2.2H20 2.5; MgSO4.7H20 1.2; NaHC? 3 24.8; KH2P04; 1.0; and dextrose, 10.0. The pleural strips from the opposite lobes of the lung were used for paired experiments. The preliminary data generated from the voltage / response curves show that the latent voltage of 800 mg was optimal. The tissue was left to equilibrate for 45 minutes, while the liquid fluid changed periodically.

Cumulative response concentration curves: Initially the tissues were changed three times with KCl (40 M) to assess the viability of the tissue and to obtain a consistent response. After recording the maximum response for KCl, the tissues were washed and allowed to return to the baseline before the next change. The cumulative response concentration curves were obtained from pleural strips from the increase of the agonist concentration (sPLA2 in the tissue bath by increments of logarithmic medium while the previous concentration was maintained in contact with the tissues (reference 1, supra). The agonist concentration increased after reaching the - stabilization of the concentration produced by the preceding concentration. A response concentration curve was obtained from each tissue. To minimize the variability between the tissues obtained from different animals, the contractile responses were expressed as a percentage of the maximum response obtained with the final KCl change. When the effects of several drugs on the contractile effects of sPLA2 were studied, the compounds and their respective vehicles are added to the tissues 30 minutes prior to the start of the response curves of the sPLA concentration.

Statistical analysis: The data from different experiments were emptied and presented as percentages of the maximum KCl response (suggesting + S.E). To estimate the changes induced by the drug in the concentration response curves, the curves were analyzed simultaneously using nonlinear statistical molding methods similar to those described by Wauld (1976), Equation 26, p. 163 (Ref.2). The model includes four parameters: the maximum response of the tissue, the - - which assumes the same for each curve, the ED50 for the control curve, the escarpment of the curve, and the pA2, the concentration of the antagonist that requires an increase of two folds in an agonist to reach an equivalent response. The Schild slope equal to 1 indicates that the model is consistent with the assumptions of a competitive antagonist; therefore, pA2 can be interpreted as the apparent KB, the constant dissociation of the inhibitor.

To estimate the drug-induced suppression of the maximal response, the sPLA- responses (10 ug / ml) were determined in the absence or presence of the drug, and the 100 percent suppression was calculated for each pair of tissues. Representative examples of the inhibitory activities are shown in Table 2 below.

Reference 1 - van, J.M. : Cumulative dose-response curves. II: Techique for the making of dose-response curves in isolated organs and evaluation of drug parameters. Arch, Int. Pharmacodyn. Ther., 143: 299-330, 1963.

- - Reference 2 - Waud. D.: Analysis of dose-response in Advances in General and Cellular Pharmacology eds Narahashi, Bianchi 1: 145-178, 1976.

The compounds of the present invention were evaluated in Test Example 2 and found effective.

It is noted that, in relation to this date, the best method known by the Applicant to carry out the aforementioned invention is that which is clear from the present description.

Having described the invention as above, the content of the following is claimed as property.

Claims (13)

- - CLAIMS

1. A compound of formula (I) characterized in that: X is -O- or - (CH;) m-, where m is 0 or 1; And it is -COe, -P03-, -S0 > -; R is independently -H or -alkyl (C1-C4); R "and R" are each independently -H, halo or -alkyl (C: -Ci); RJ and R are each independently -H, alkyl (C1-C4), alkoxy (C: -d), alkylthio (C1-C4), halo, phenyl or phenyl substituted with halo; n is 1-8; and p is 1 when Y is -CO .-- or -S03- and 1 or 2 when Y is -P03- or a pharmaceutically acceptable salt thereof.

2. A compound of the formula I as claimed in claim 1, characterized in that x is oxygen, Y is -C02 n is 4-5, R, R1, R2 and R3 are -H, and R4 is phenyl or phenyl substituted with halo.

3. A compound of the formula I as claimed in claim 1, characterized in that it is 2- (4-carboxybut-1-yl-oxy) -4- (3-phenylphenoxy) phenylglyoxamide.

4. A pharmaceutical formulation characterized in that it comprises a compound of formula I as claimed in claim 1, together with a pharmaceutically acceptable carrier or diluent thereof.

5. A method for inhibiting sPLA2 in a mammal in need of inhibition of sPLA2 comprising administering to said mammal a therapeutically effective amount of a compound of formula I - - characterized in that: X is -0- or - (CH.) m-, where m is 0 or 1; And it is -CO -, -P03-, -SO--; R is independently -H or -alkyl (C-Cj); R 'and R "are each independently -H, halo or -alkyl (C: -C;); R' and R 'are each independently -H, (C1-C4) alkyl, (C- -C; ), alkylthio (C: -C?), halo, phenyl or phenyl substituted with halo; n is 1-8; and p is 1 when Y is -CO- or -S0-- and 1 or 2 when Y is -PO- - or a pharmaceutically acceptable salt thereof.

6. A method according to claim 5, characterized in that the compound is 2- (4-carboxibut-l-yl-oxy) -4- (3-phenylphenoxy) phenylglyoxamide.

7. A method for selectively inhibiting sPLA2 in a mammal in need of selective sPLA2 inhibition, comprises administering to said mammal a therapeutically effective amount of a compound of formula I characterized in that: X is -O- or - (CH ira-, where m is 0 or 1; Y is -CO-, -PO, -, -SO-; R is independently -H or -alkyl (C: -C4 ); R and R are each independently -H, halo or -aiqu loiC- e R and R are each independently -H, (C 1 -C 4) alkyl, (C 1 -C) alkoxy, (C 1 -C 4) alkylthio, halo, phenyl or phenyl substituted with halo; n is 1-8; and p is 1 when Y is -C02- or -S03- and 1 or 2 when Y is -PO3- or a pharmaceutically acceptable salt thereof.

8. A method according to claim 7 characterized in that the mammal is a human.

9. A method according to claim 7 or 8, characterized in that the compound is 2- (4-carboxibut-l-yl-oxy) -4- (3-phenylphenoxy) phenylglyoxamide.

10. A method according to claim 5 for alleviating the effects of septic shock, respiratory distress syndrome in an adult, pancreatitis, stroke induced trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis, characterized in that it comprises administering to a mammal in need of relief of said pathological effect of a compound of formula I in a - - sufficient quantity to inhibit the mediated release of sPLA2 from fatty acid and thereby inhibit the cascade of arachidonic acid and its harmful products.

11. A method according to claim 10, characterized in that the mammal is a human.

12. A method according to claim 10 or 11, characterized in that the compound is 2- (4-carboxibut-1-yl-oxy) -4- (3-phenyl phenoxy) phenylglyoxamide.

13. A compound of formula II - - characterized in that: X is -0- or - (CH2) m-, where m is 0 or 1; R1 and R2 are each independently -H, halo or -alkyl (C1-C4); R3 and R4 are each independently -H, (C1-C4) alkyl, (C1-C) alkoxy, (C1-C4) alkylthio, halo, phenyl or phenyl substituted with halo.