WO1998025600A1 - Leukotriene antagonists for treatment or inhibition of gout - Google Patents

Abstract

This invention provides methods for the inhibition or treatment of gout which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene antagonist.

Description

Title

LEUKOTRIENE ANTAGONISTS FOR TREATMENT OR INHIBITION OF GOUT

Background of the Invention

Clinical gout is characterized by acute attacks of arthritis thought to be initiated by the local precipitation of crystals of monosodium urate (MSU) . The participation and relative importance of the chemical mediators involved in the development of these acute and severe inflammatory reactions have not yet been completely defined.

Needle-shaped MSU crystals are deposited in avascular (e.g., cartilage) or relatively avascular (e.g., tendons, ligaments) tissues about distal peripheral joints and cooler tissues like the ears. In severe, long-standing disease, MSU crystals may be deposited in larger central joints and in the parenchyma of organs such as the kidney. Tophi represent crystal aggregates large enough to be seen, first on radiographs of the joints as "punched-out " lesions and later to be seen or felt as subcutaneous nodules . At the acid pH of urine, uric acid itself is precipitated readily as small platelike crystals that may aggregate to form gravel or stones. These may cause obstructive uropathy. Sustained hyperuricamia is most commonly caused by decreased renal clearance of urate, especially in patients receiving chronic diuretic therapy and also in primary abnormality or may be due to increased nucleoprotein turnover in hematologic conditions such as lymphoma, leukemia, or hemolytic anemia and in any condition with increased rates of cellular proliferation and death, eg, psoriasis . Dietary purines also contribute to serum uric acid. Marked rises in uric acid often follow overindulgence in rich foods, especially if alcoholic beverages are also consumed. Ethyl alcohol both induces nucleotide catabolism in the liver and increases the formation of lactic acid, which like other organic acids, blocks urate secretion by the renal tubules .

The acute inflammatory reaction in gouty arthritis is a vicious circle. It is initiated by the deposition of MSU and proceeds as a result of emigration of polymorphonuclear leukocytes (PMNs) into the joint and phagocytosis of the MSU. The inflammatory reaction is simplified by the release of lysosomal enzymes and chemotactic factors into the effusion. Thus, there is a progressive accumulation of neutrophils and progressive inflammation unless the cycle is interrupted by appropriate therapy.

Research in the area of allergic reactions of the lung has provided evidence that arachidonic acid derivatives formed by the action of lipoxygenases are related to various disease states . Some of these arachidonic acid metabolites have been classified as members of a family eicosatetraenoic acids termed leukotrienes . Three of these substances are currently thought to be major components of what has been previously called slow reacting substance of anaphylaxis

(SRS-A) and have been designated leukotrienes C₄, D₄, and E₄ (LTC₄, LTD₄, and LTE₄, respectively) .

Another arachidonic acid metabolite, leukotriene B4 (LTB4), is a proinflammatory lipid which has been implicated in the pathogenesis of psoriasis, arthritis, chronic lung diseases, acute respiratory distress syndrome, shock, asthma, inflammatory bowel diseases, and other inflammatory states characterized by the infiltration and activation of polymorphonuclear leukocytes and other proinflammatory cells. Thus when activated, the polymorphonuclear leukocytes liberate tissue-degrading enzymes and reactive chemicals causing the inflammation. Antagonism of LTB4 should therefore provide a novel therapeutic approach to treatment of these and other conditions. Because of the debilitating effects of gout, there continues to exist a need for effective treatments. Summar of the Invention

This invention provides a method for the inhibition or treatment of gout in mammals comprising administering to a mammal in need thereof an effective amount of a compound Formula I

wherein:

Rl is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C4 alkoxy, (C1-C4 alkyl) thio, halo, or R2- substituted phenyl;

each R2 and R3 are each independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl) -S (O)q-, trifluoromethyl, or di- (C1-C3 alkyl) amino;

X is -0-, -S-, -C(=0), or -CH2-;

Y is -0- or -CH2-;

or when taken together, -X-Y- is -CH=CH- or

Z is a straight or branched chain Cχ-Cιo alkylidenyl; A is a bond, -0-, -S-, -CH=CH-, or -CR_aRb-, where R_a and Rb are each independently hydrogen, C1-C5 alkyl, or R7-substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring;

where ,

each Rβ is independently -COOH, 5-tetrazolyl , -CON(R^Q)2. or -CONHSO2R1O;

each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-Rg, -T-G-Rβ, (C1-C4 alkyl) -T- (C1-C4 alkylidenyl ) -0- , or hydroxy ;

R8 is hydrogen or halo;

each R9 is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;

RlO is C1-C4 alkyl or phenyl;

Rll is R2, -W-R6, or -T-G-R6;

each is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;

each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;

each T is a bond, -CH2-, -0-, -NH-, -NHCO-,

-C(=0)-, or -S(0)_q-;

K is -C(=0)- or -CH(OH)-;

each q is independently 0, 1, or 2 ;

p is 0 or 1; and

t is 0 or 1;

provided when X is -0- or -S-, Y is not -0-;

provided when A is -0- or -S-, R4 is not Rς ;

provided when A is -0- or -S- and Z is a bond, Y is not -0-; and

provided is not a bond when p is 0; Detailed Description

The following definitions refer to the various terms used throughout this disclosure. The term "Cι~C6 alkyl" refers to the straight and branched aliphatic radicals of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, 2 , 2-dimethylpropyl , hexyl , and the like. Included within this definition are the terms "C1-C3 alkyl", "C1-C4 alkyl" and "C₁-C5 alkyl".

The term "C₂-C₅ alkenyl" refers to straight and branched aliphatic radicals of 2 to 5 carbon atoms containing one double bond, such as -CH=CH₂, -CH₂CH=CH₂, -CH₂CH₂CH=CH2, -CH₂C (CH₃ ) =CH₂ , -CH2CH=C (CH₃ ) ₂ , and the like. The term "C₂-C₅ alkynyl" refers to straight and branched aliphatic residues of 2 to 5 carbon atoms containing one triple bond, such as -C≡CH, -CH₂-C≡-CH, -CH₂CH₂C≡CH, -CH₂CH(CH₃)CsCH, -CH₂C≡CCH₃ , and the like. The term "C1-C4 alkoxy" refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, and tert-butoxy. The term "halo" refers to fluoro, chloro, bromo, and iodo .

The term "C₁-C₁₀ alkylidenyl" refers to a divalent radical derived from a C1-C₁0 alkane such as -CH2-. -CH(CH₃)-, -C(CH₃)₂-. -CH(C₂H₅)-, -CH₂CH₂-, -CH₂CH (CH₃ ) - ,

-CH(CH₃)CH₂-, -CH(CH₃)CH(CH₃)-, -CH₂C (CH₃ ) ₂- , -CH₂CH (C₂H₅ ) - , -CH2CH2CH2- , -CH (CH₃ ) CH2CH2- , -CH₂CH (CH₃ ) CH₂- _. -CH₂CH(C₂H₅)CH₂-, -CH2CH₂CH(C₂H5)-, -C (CH₃ ) ₂CH₂CH₂- , -CH(CH₃)CH₂CH(CH₃) -, -CH2CH2CH2CH2- , -CH₂C (CH3 ) 2CH₂CH₂- , -CH₂C(CH₃)₂CH₂-, -CH2CH₂CH(C2H5)CH₂-,-CH2CH2CH2CH₂CH2-,

-CH(CH₃)CH₂CH₂CH2CH2-, -CH2CH2CH2CH2CH2CH2- , -(CH₂)ιo-. and the like. Included within this definition are the terms "C₁-C₄ alkylidene" and "C₂-C₄ alkylidene" .

The term "C4-C8 cycloalkyl" refers to a cycloalkyl ring of four to eight carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexyl, 4 , 4-dimethylcyclohexyl , cycloheptyl, cyclooctyl, and the like. The term "straight or branched chain divalent hydrocarbyl residue of one to eight carbon atoms" refers to a divalent radical derived from a straight or branched alkane, alkene, or alkyne of one to eight carbon atoms. Depending upon the branching and number of carbon atoms, as will be appreciated by organic chemists, such a moiety can contain one, two or three double or triple bonds, or combinations of both. As such, this term can be considered an alkylidene group as defined above containing from 1 to 8 carbon atoms optionally containing one to three double or triple bonds, or combinations of the two, limited as noted in the preceding sentence.

This invention includes the pharmaceutically acceptable base addition salts of the compounds of Formula I. Such salts include those derived from inorganic bases, such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates , and the like, as well as salts derived from basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methyl amine, diethyl amine, ethylene diamine, cyclohexylamine, ethanolamine, and the like. The potassium and sodium salt forms are particularly preferred.

This invention includes both mono-salt forms, ie, a 1:1 ratio of a compound of Formula I with a base as previously described, as well as di-salt forms in those instances where a compound of Formula I has two acidic groups. In addition, this invention includes any solvate forms of the compounds of Formula I or salts thereof, such as ethanol solvates, hydrates, and the like.

It is recognized that in compounds having branched alkyl, alkylidenyl, or hydrocarbyl functionality, and in those compounds bearing double or triple bonds, various stereoisomeric products may exist. This invention is not limited to any particular stereoisomer but includes all possible individual isomers and mixtures thereof. The term "5-tetrazolyl" refers to both tautomers, ie, (lH)-5- tetrazolyl and (2H) -5-tetrazolyl .

Preferred Embodiments

A most preferred group of compounds employed in the methods of the present invention are those compounds of Formula la:

-A-R₄

la

and pharmaceutically acceptable base addition salts thereof. Especially preferred are those compounds wherein R2 is halo, particularly fluoro. Preferred Ri substituents are propyl and especially ethyl.

Preferred Z substituents include C₂-C₄ alkylidene, particularly -CH2CH2- and -CH₂CH₂CH₂CH₂- . Preferred A groups include -0-, -CH -, -CH (R₇-substituted phenyl)-, and -

C(CH₃)₂.

Preferred R₄ groups include -COOH, 5-tetrazolyl , or a mono-, di-, or tri-cyclic group as drawn above wherein there is at least one acidic group attached to a ring, such as -W- COOH, -T-G-COOH, or the corresponding tetrazole derivatives.

The preferred moiety is that of a bond or straight chain

C₁-C₄ alkylidene; preferred G moieties are straight chain

C₁-C₄ alkylidene. It is preferred that R₅ or R₇ be C1-C₄ alkyl, especially n-propyl . Particularly preferred groups are those wherein A is -

CH(R₇-substituted phenyl)- and R₄ is -COOH or 5-tetrazolyl . Also preferred are those compounds wherein A is -0- and R₄ is

Preferred aspects of this substructure are those therein R₇ is C₁-C₄ alkyl, especially n-propyl, and Rς is - W-COOH. Particularly preferred are those compounds wherein T is -0- or -S- and W is a bond. Preferred compounds of the instant invention include :

2- [2 -propyl -3- [3- [2-ethyl-4- (4-fluorophenyl ) -5- hydroxyphenoxy] propoxy] phenoxy]benzoic acid;

3- (2- (3- (2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) -6- (4-carboxy- phenoxy) phenyl) propionic acid;

1- (4- (carboxy-methoxy) phenyl) -1- (lH-tetrazol-5- yl) -6- (2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane; 3-[4-[7-carboxy-9-oxo-3-[3-[2-ethyl-4-(4- fluorophenyl) -5-hydroxyphenoxy] -propoxy] -9H- xanthene] ] propanoic acid; and

5-[3-[2-(l-carboxy) -ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy] -propoxy] phenyl] -4- pentynoic acid; or a pharmaceutically acceptable salt or solvate thereof.

The leukotriene B4 (LTB4) antagonists employed in the methods of the present invention may be synthesized essentially as described in US Patent No. 5,462,954 issued October 31, 1995, the entire contents of which are herein incorporated by reference.

The following examples further illustrate the preparation of the compounds employed in this invention. The examples are illustrative only and are not intended to limit the scope of the invention. Melting points were determined on a Thomas-Hoover apparatus and are uncorrected.

NMR spectra were determined on a GE QE-300 spectrometer.

All chemical shifts are reported in parts per million (_) relative to tetramethylsilane . Chemical shifts of aromatic protons of quinoline species in DMSO-dg are concentration dependent. The following abbreviations are used to denote signal patterns: s = singlet, d = doublet, t = triplet, q = quartet, b = broad, m = multiplet. Infrared spectra were determined on a Nicolet DX10 FT-IR spectrometer. Mass spectral data were determined on a CEC-21-110 spectrometer using electron impact (El) conditions, a MAT-731 spectrometer using free desorption (FD) conditions, or a VG ZAB-3F spectrometer using fast atom bombardment (FAB) conditions. Silica gel chromatography was performed using ethyl acetate/hexane gradients unless otherwise indicated. Reverse-phase chromatography was performed on MCI CHP20P gel using an acetonitrile/water or ethanol/water gradient unless otherwise indicated. Tetrahydrofuran (THF) was distilled from sodium/benzophenone ketyl immediately prior to use. All reactions were conducted under argon atmosphere with stirring unless otherwise noted. Where structures were confirmed by infra-red, proton nuclear magnetic resonance, or mass spectral analysis, the compound is so designated by "IR", "NMR", or "MS", respectively.

Exampl e 1

3- [2- [3- [ (5-Ethyl-2-hydroxy [1, 1 ' -biphenyl] -4- yl) oxy] propoxy] -1-dibenzofuran] propanoic acid disodium salt

COONa

A. Preparation of 3 , 3-diethoxy-2 , 3-dihydro-lH- benzofuro- [3 , 2-f] [1] benzopyran.

A solution of 2-hydroxydibenzofuran (5.00 g, 27.2 mmol), triethylorthoacrylate (10.1 g, 54.3 mmol) and pivalic acid (1.39 g, 13.6 mmol) in toluene (100 mL) was refluxed for 18 hours . The mixture was cooled to room temperature and washed once with water and once with a saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide an orange oil. This material was diluted with hexane and maintained at -20°C for

18 hours. The resulting crystals were collected via vacuum filtration to provide 5.67 g (67%) of the desired title intermediate, mp 64°C; NMR (CDC1₃) 7.96 (d, J = 7.8 Hz, 1H) , 7.57 (d, J = 8.0 Hz, 1H) , 7.46 (t, J = 8 Hz, 1H) , 7.35 (m, 2H) , 7.06 (d, J = 8.8 Hz, 1H) , 3.82 (q, J = 7.2 Hz, 2H) , 3.73 (q, J = 6.8 Hz, 2H) , 3.35 (t, J = 6.9 Hz, 2H) , 2.29 (t, J = 7.0 Hz, 2H) , 1.23 (t, J = 7.1 Hz, 6H) ; MS-FD m/e 312 (p); IR (CHC1₃, cm^"1) 2982, 1494, 1476, 1451, 1434, 1251,

1090, 1054, 975.

Analysis for C]_ 9H2 θθ4 ^:

Calc : C , 73 . 06 ; H , 6 . 45 ;

Found : C , 72 . 81 ; H , 6 . 72 .

B. Preparation of 3- [ 1- ( 2-hydroxydibenzofuran) ] - propanoic acid ethyl ester.

A mixture of 3 , 3-diethoxy-2 , 3-dihydro-lH-benzofuro- [3 , 2-f] [l]benzopyran (3.50 g, 11.2 mmol) and 10% aqueous hydrochloric acid (5 mL) in ethyl acetate (30 mL) was stirred at room temperature for 1 hour. The resulting mixture was washed once with water, dried over sodium sulfate, filtered and concentrated in vacuo to provide a tan solid. Recrystallization from hexane/ethyl acetate provided

3.11 g (98%) of the desired title intermediate as an off- white crystalline material: mp 128-131°C; NMR (CDCI3) 7.88

(d, J = 7.7 Hz, 1H) , 7.59 (d, J = 8.4 Hz, 1H) , 7.47 (t, J = 7.2 Hz, 1H) , 7.37 (d, J = 8.9 Hz, 1H), 7.36 (t, J = 6.6 Hz, 1H) , 7.13 (d, J = 8.8 Hz, 1H) , 7.13 (q, J = 8.8 Hz, 2H) ,

3.43 (t, J = 5.8 Hz, 2H) , 3.01 (t, J = 7.7 Hz, 2H) , 1.23 (t, J = 7.2 Hz, 3H) ; MS-FD m/e 284 (100, p), 256 (65), 238 (17); IR (KBr, cm^-1) 2985 (b) , 1701, 1430, 1226, 1183, 1080. Analysis for Ci E^β^A '- Calc: C, 71.82; H, 5.67;

Found: C, 71.90; H, 5.43.

C. Preparation of 3- [2- [3- [ [5-ethyl-2- (phenylmethoxy) -[1,1' -biphenyl] -4-yl] oxy]propoxy] -1- dibenzofuran] ropanoic acid ethyl ester. 3- [1- (2-Hydroxydibenzofuran) ] propanoic acid ethyl ester

(625 mg, 2.20 mmol) was dissolved in dimethylformamide (10 mL) and carefully treated at room temperature with 95% sodium hydride (58 mg, 2.4 mmol) . When gas evolution had ceased, 2-benzyloxy-l-phenyl-5-ethyl-4- (3-chloro-l- propyloxy) benzene (836 mg, 2.20 mmol) was added and the resulting mixture was stirred for 18 hours. The mixture was diluted with ether and washed once with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a dark oil. Silica gel chromatography (ethyl acetate/hexane) provided 200 mg (14%) of the desired titled intermediate as a colorless oil : NMR (CDC1₃) 8.11 (d, J = 7.7 Hz, 1H) , 7.57 (m, 3H) , 7.48 (t, J =

7.3 Hz, 1H) , 7.20-7.44 (m, 10 H) , 7.17 (s, 1H) , 7.08 (d, J = 8.9 Hz, 1H) , 6.67 (s, 1H) , 5.05 (s, 2H) , 4.29 (t, J = 6.2

Hz, 2H) , 4.26 (t, J = 6.1 Hz, 2H) , 4.15 (q, J - 7.2 Hz, 2H) , 3.54 (t, J = 8.5 Hz, 2H) , 2.67 (m, 4H) , 2.37 (t, J = 6.0 Hz, 2H) , 1.21 (m, 6H) .

D. Preparation of 3- [2- [3- [ (5-ethyl-2-hydroxy [1 , 1 ' - biphenyl ] -4-yl ) oxy] propoxy] -1-dibenzofuran] propanoic acid disodium salt.

To a nitrogen-purged solution of 3- [2- [3- [ [5-ethyl-2- (phenylmethoxy) [1 , 1 ' -biphenyl ] -4-yl] oxy] ropoxy] -1- dibenzofuran] ropanoic acid ethyl ester (200 mg, 0.318 mmol) in a 1:1 mixture of methanol/tetrahydrofuran (40 mL) was added 10% palladium on carbon (25 mg) . The resulting suspension was hydrogenated at 1 atm pressure for 24 hours at room temperature. The mixture was filtered through a short pad of Florisil® and the filtrate concentrated in vacuo . The residue was dissolved in a 1:1 mixture of methanol/tetrahydrofuran (20 mL) and treated with 5N sodium hydroxide solution (2 L) at room temperature for 24 hours. The resulting mixture was extracted once with diethyl ether. The aqueous layer was acidified with 5N hydrochloric acid solution and extracted twice with methylene chloride. The combined methylene chloride fractions were concentrated in vacuo . The residue was dissolved in a minimum of IN sodium hydroxide solution and purified on HP-20 resin to provide 53 mg (30%) of the desired title product as a fluffy white solid: NMR (DMSO-d₆) 8.12 (d, J = 6.9 Hz, 1H) , 7.64 (d, J =

8.2 Hz, 1H) , 7.37-7.57 (m, 5H) , 7.30 (m, 2H) , 7.14 (m, 2H) , 6.96 (s, 1H) , 6.93 (s, 1H) , 4.30 (t, J = 7.3 Hz, 2H) , 4.14 (t, J = 5.4 Hz, 2H) , 2.48 (m, 4H) , 2.23 ( , 4H) , 1.10 (t, J

= 7.6 Hz, 3H) ; MS-FAB m/e 555 (88, p + 1), 533 (62); IR (CHC1₃, cm^"1) 3384 (b) , 2969, 1566, 1428, 1257, 1181 Analysis for C32H28θ6^a2:

Calc: C, 69.31; H, 5.09; Found: C, 69.51; H, 5.39.

Example 2

7-Carboxy-9-oxo-3- [3- (2-ethyl-5-hydroxy-4- phenylphenoxy) propoxy] -9H-xanthene-4-propanoic acid disodium salt monohydrate

COONa

A mixture of 2-benzyloxy-l-phenyl-5-ethyl-4- (3-chloro- 1-propyloxy) benzene (749 mg, 1.97 mmol), ethyl 7- carboethoxy-3-hydroxy-9-oxo- H-xanthene-4-propanoate (729 mg, 1.97 mmol), potassium carbonate (1.36 g, 9.85 mmol) and potassium iodide (33 mg, 0.20 mmol) was refluxed for 24 hours. Dimethylsulfoxide (2 mL) was added and heating continued for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed once with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to reveal a tan solid. This material was dissolved in ethyl acetate (30 mL) and the resulting solution purged with nitrogen. To this solution was added 10% palladium on carbon (120 mg) and the resulting suspension hydrogenated at 1 atmosphere of pressure. The solution was filtered and concentrated in vacuo to provide a colorless oil. This material was dissolved in a solution of 1:1 methanol/tetrahydrofuran (30 mL) and treated with 5N sodium hydroxide solution (2 mL) at room temperature for 18 hours. The resulting solution was extracted once with diethyl ether and the aqueous layer acidified with 5N hydrochloric acid solution. The resulting precipitate was collected via suction filtration. This material was converted to the di-sodium salt and purified as described above for the preparation of Example 1(D) to provide 390 mg (56%) of the desired title product as a fluffy white solid: NMR (DMSO-dg) 12.65 (s, 1H, -OH), 8.65

(s, 1H) , 8.28 (dd, J = 8.5, 2.0 Hz, 1H) , 8.01 (d, J = 8.9 Hz, 1H) , 7.50 (m, 3H) , 7.29 (t, J = 7.8 Hz, 2H) , 7.17 ( , 2H) , 6.93 (s, 1H) , 6.89 (s, 1H) , 4.26 (m, 4H) , 3.12 (m, 2H) , 2.47 (m, 2H) , 2.23 (m, 2H) , 1.10 (t, J = 7.4 Hz, 3H) ; MS-FAB m/e 627 (24, p) , 605 (40), 583 (24), 331 (24), 309 (100); IR (KBr, cm^"1) 3419 (b) , 2962, 1612, 1558, 1443, 1390, 1277, 1084. Analysis for 034^809^2 -^0 :

Calc: C, 63.34; H, 4.69; Found: C, 63.36; H, 4.50.

Example 3

2-[2-Propyl-3-[3- [2-ethyl-4- (4-fluorophenyl ) -5- hydroxyphenoxy] propoxy] henoxy] benzoic acid sodium salt

A. Preparation of 2- [2-propyl-3- [3- [2-ethyl-4- (4- fluorophenyl) -5- (phenylmethoxy) phenoxy] propoxy] phenoxy] - benzoic acid methyl ester.

A mixture of 2 -benzyloxy-1- (4-fluorophenyl ) -5-ethyl-4- (3-chloro-l-propyloxy)benzene (20.0 g, 50.2 mmol) and sodium iodide (75.3 g, 502 mmol) in 2-butanone (200 mL) was refluxed for 6 hours. The mixture was diluted with ether and washed once with water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide a colorless oil. This material was dissolved in dimethylformamide (100 mL) and treated with 2 - (3-hydroxy-2- propylphenoxy) benzoic acid methyl ester (14.4 g, 50.2 mmol) and potassium carbonate (20.8 g, 151 mmol) at room temperature for 24 hours. This mixture was diluted with water and twice extracted with ether. The aqueous layer was separated and back-extracted once with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. Silica gel chromatography provided 25.4 g (78%) of the desired title intermediate as a pale golden oil: NMR

(CDCI3) 7.91 (d, J = 7.8 Hz, 1H) , 7.54 (d, J = 8.6 Hz, 1H) ,

7.52 (d, J = 8.5 Hz, 1H) , 7.25-7.43 ( , 6H) , 7.03-7.38 (m, 5H) , 6.84 (d, J = 8.3 Hz, 1H) , 6.71 (d, J = 8.1 Hz, 1H) , 6.63 (s, 1H) , 6.47 (d, J = 8.1 Hz, 1H) , 5.03 (s, 2H) , 4.24 (t, J = 5.7 Hz, 2H) , 4.21 (t, J = 5.8 Hz, 2H) , 3.86 (s, 3H) , 2.69 (t, J = 7.8 Hz, 2H) , 2.64 (t, J = 7.7 Hz, 2H) , 2.34 (quintet, J = 6.0 Hz, 2H) , 1.60 (hextet, J = 5.0 Hz, 2H) , 1.22 (t, J = 7.5 Hz, 3H) , 0.94 (t, J = 7.5 Hz, 3H) ; MS-FD m/e 648 (p) ; IR (CHCI3, cm^"1) 2960, 1740, 1604, 1497, 1461, 1112.

Analysis for C4 H4i_OgF:

Calc: C, 75.91; H, 6.37; Found: C, 76.15; H, 6.45.

B. Preparation of 2- [2-propyl-3- [3- [2-ethyl-4- (4- fluorophenyl) -5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid methyl ester.

2- [2-Propyl-3- [3- [2-ethyl-4- (4-fluorophenyl ) -5- (phenylmethoxy) phenoxy] propoxy] phenoxy] benzoic acid methyl ester (33.0 g, 50.9 mmol) was de-benzylated as described above for the preparation of Example 2 to provide 27.3 g

(96%) of the title intermediate as an amber oil: NMR (CDCI3) 7.90 (dd, J = 7.8, 1.7 Hz, 1H) , 7.42 (m, 3H) , 7.05- 7.23 (m, 4H) , 6.99 (s, 1H) , 6.84 (d, J = 8.1 Hz, 1H) , 6.70

(d, J = 8.1 Hz, 1H) , 6.55 (s, 1H) , 6.46 (d, J = 8.1 Hz, 1H) , 5.05 (s, 1H, -OH), 4.23 ( , 4H) , 3.86 (s, 3H) , 2.68 (t, J = 7.4 Hz, 2H) , 2.62 (q, J = 7.5 Hz, 2H) , 2.36 (quintet, J = 6.0 Hz, 2H) , 1.60 (hextet, J = 7.7 Hz, 2H) , 1.20 (t, J = 7.6 Hz, 3H) , 0.94 (t, J = 7.4 Hz, 3H) ; MS-FD m/e 558 (p) ; IR (CHC1₃, cm^-1) 2965, 1727, 1603, 1496, 1458, 1306, 1112. Analysis for C34H35θ F:

Calc: C, 73.10; H, 6.31; Found: C, 73.17; H, 6.42.

C. Preparation of 2- [2-propyl-3- [3- [2-ethyl-4- (4- fluorophenyl) -5-hydroxyphenoxy] ropoxy] phenoxy] benzoic acid sodium salt.

2-[2-Propyl-3-[3- [2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] propoxy] phenoxy] benzoic acid methyl ester

(21.5 g, 38.5 mmol) was hydrolyzed as described above for the preparation of Example 2. The acid was converted to the sodium salt and purified as described above for the preparation of Example 1(D) to provide 16.7 g (77%) of the desired title product as a white amorphous solid: NMR

(DMSO-dg) 10.50 (bs, 1H, -OH), 7.51 ( , 3H) , 7.20 (t, J =

7.4 Hz, 1H) , 7.13 ( , 2H) , 7.00 (m, 2H) , 6.95 (s, 1H) , 6.67 (dd, J = 8.2, 3.3 Hz, 2H) , 6.62 (s, 1H) , 6.26 (d, J = 8.2 Hz, 1H) , 4.14 (t, J - 5.8 Hz, 2H) , 4.02 (t, J = 5.7 Hz, 2H) , 2.60 (t, J = 6.8 Hz, 2H) , 2.47 (q, J = 7.3 Hz, 2H) , 2.16 (t, J = 5.9 Hz, 2H) , 1.45 (hextet, J = 7.5 Hz, 2H) , 1.07 (t, J =

7.5 Hz, 3H) , 0.81 (t, J = 7.4 Hz, 3H) ; MS-FAB m/e 568 (38, p

+ 1), 567 (100, p) , 544 (86), 527 (77), 295 (65), 253 (45);

IR (KBr, cm^"1) 3407 (b) , 2962, 1603, 1502, 1446, 1395, 1239, 1112.

Analysis for C33H32θgFNa:

Calc: C, 69.95; H, 5.69; F, 3.35; Found: C, 69.97; H, 5.99; F, 3.52.

Acute gouty arthritis appears without warning. It may be precipitated by minor trauma, overindulgence in food or alcohol, surgery, fatigue, emotional stress, or medical stress such as infection or vascular occlusion. Acute ono- or polyarticular pain, often nocturnal, is usually the first symptom. This becomes progressively more severe and is often excruciating. Examination shows signs resembling an acute infection, with swelling, warmth, redness, and exquisite tenderness. The overlying skin is tense, warm, shiny, and red or purplish. The metatarsophalangeal joint of the great toe is most often involved, but the instep, ankle, knee, wrist, and elbow are common sites. Initially, only a single joint may be affected; in later attacks, several joints can be affected simultaneously or sequentially. Fever, tachycardia, chills, malaise, and leukocytosis may occur. The first few attacks usually last only a few days, but later untreated attacks may persist for weeks. Local symptoms and signs eventually regress, and joint function returns. Asymptomatic intervals vary but tend to become shorter as the disease progresses. Without prophylaxis, several attacks may occur each year, and chronic joint symptoms may develop with permanent erosive joint deformity. Limitation of motion often involves multiple joints of the hands and feet; rarely, the shoulder, sacroiliac, sternoclavicular joints, or the cervical spine is involved. Urate deposits are common in the walls of bursae and tendon sheaths . Enlarging tophi on the hands and feet may erupt and discharge chalky masses of urate crystals.

The clinical features of acute gouty arthritis are so distinctive that a tentative diagnosis usually can be made by history and physical examination. Elevated serum urate (> 7 mg/dL) supports the diagnosis but is not specific. Demonstration in tissue or synovial fluid of needle-shaped urate crystals that are free in the fluid or engulfed by phagocytes is pathognomonic . Objectives of treatment include (1) termination of the acute attack with anti-inflammatory drugs, (2) prevention of recurrent acute attacks (if frequent) by daily prophylactic use of colchicine, and (3) prevention of further deposition of monosodium urate crystals and resolution of existing tophi (achieved by lowering the urate concentration in body fluids) . A preventive maintenance program aims at averting both the disability resulting from erosion of bone and joint cartilage and the renal damage. Specific treatment depends on the stage and severity of the disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in acute attacks of established gout. Daily doses are usually taken with food for 2 or 3 days. The NSAIDs include indomethacin, ibuprofen, naproxen, tolmetin sodium, piroxicam, and sulindac. NSAIDs may cause life-threatening hyperkalemia in patients whose renal blood flow is prostaglandin E2 -dependent (an example of hyporeninemic hypoaldosteronism) .

Colchicine may also be prescribed. However, severe bone marrow suppression and death may occur in patients receiving oral colchicine prophylactically who are also given IV doses of this drug. Severe electrolyte imbalance can accompany many colchicine-induced diarrheal episodes with disastrous consequences, especially in elderly patients .

Patients at particular risk include the elderly and those with dehydration, especially if there is a history of renal disease. Gouty attacks also may be treated by aspiration of affected joints, followed by instillation of corticosteroid esters.

The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective to inhibit or treat gout.

The methods of the present invention describe the use of leukotriene antagonists for the prevention or treatment of gout which is characterized by the excessive release of leukotriene B4. The term "excessive release" of a leukotriene refers to an amount of the leukotriene sufficient to cause gout. The amount of leukotriene which is considered to be excessive will depend on a variety of factors, including the amount of leukotriene required to cause the disease, and the species of the mammal involved. As will be appreciated by those skilled in the art, the success of treating a mammal suffering from or susceptible to gout by an excessive release of leukotriene with a compound of Formula I will be measured by the regression or prevention of the symptoms of the condition.

Assays Assay 1

T³H1 -LTB Radiolicrand Binding Assay in Guinea Pig Lunσ

Membranes

[³H]-LTB₄ (196-200 Ci/ mole) was purchased from New England Nuclear (Boston, MA) . All other materials were purchased from Sigma (St. Louis, MO). Incubations (555 L) were performed in polypropylene minitubes for 45 minutes at 30°C and contained 25 mg of guinea pig lung membrane protein (Silbaugh, et. al_.. , European Journal of Pharmacology, 223 (1992) 57-64) in a buffer containing 25 mM MOPS, 10 mM

MgCl₂, 10 mM CaCl₂, pH 6.5, approximately 140 pM [³H]-LTB₄, and displacing ligand or vehicle (0.1% DMSO in 1 mM sodium carbonate, final concentration) as appropriate. The binding reaction was terminated by the addition of 1 mL ice cold wash buffer (25 mM Tris-HCl, pH 7.5) followed immediately by vacuum filtration over Whatman GF/C glass fiber filters using a Brandel (Gaithersburg, MD) 48 place harvester. The filters were washed three times with 1 L of wash buffer. Retained radioactivity was determined by liquid scintillation counting at 50% counting efficiency using Ready Protein Plus cocktail (Beckman, Fullerton, CA) . Nondisplaceable binding was determined in the presence of 1 mM LTB₄ and was usually less than 10% of total binding. Data were analyzed using linear regression analysis of log-logit plots of the values between 10% and 90% of control binding to calculate IC₅₀S and slope factors (pseudo-Hill coefficients) . IC50 values thus obtained were corrected for radioligand concentration (Cheng and Prusoff, Biochem. Pharmacol . , 22 , 3099 (1973)) to calculate Ki values. pKi is the mean -log Ki for n experiments.

Compounds of the instant invention tested in the above assay were found to have a pKi of between 7 and 11.

The ability compounds of formula I to effectively treat experimental gout can be evaluated on the acute inflammation induced in stifle (knee) joints of dogs by intrasynovial injection of microcrystalline suspensions of sodium urate (McCarty, et al . , J . Ex . Med .. 124, 99-114, 1996).

Assay 2

Suspensions of urate crystals are prepared by dissolving 0.4 gm of sodium hydroxide pellets in 400 ml distilled water in a glass container. To this 1.68 gm uric acid is added. The opaque preparation is allowed to sit overnight at room temperature. The crystals are harvested the next day by filtration and subsequently washed 3 times in cold saline. The material is then resuspended in saline (15 g/ml) and sterilized in an autoclave. Most crystals should be 10 to 15 microns long.

Dogs weighing 15 to 25 kg are lightly anesthetized by administering a bolus of sodium pentobarbital (25 to 35 mg/kg) and given additional small doses as needed for maintenance during the 4-hour observation period after injecting urate crystals into the joint. Body temperature is maintained ±2°C by keeping the animal covered with a temperature-controlled electric blanket. Animals are positioned on their side or back so that one of the hind legs can be fixed with a 90° angle between the femur and tibia. The skin over the knee joint is shaved and cleaned. A No. 17 Intracath® needle is inserted through the patellar tendon into the joint. The fluid is removed with a syringe and the joint washed out by inserting 5-10 ml of sterile saline. A sterile polyethylene catheter is then inserted through the needle. Following this, the needle is removed, the catheter pulled tight as its proximal end and the other end connected to a sterile 3 -way stopcock. The other 2 ends of the stopcock are connected to a syringe for the insertion of the urate crystals or removal of joint fluid and to a pressure transducer for measuring intra-articular pressure (IAP) . The tip of the catheter is carefully positioned so that free exchange of fluid takes place. The transducer is positioned at the level of the knee joint. Prior to use, the instrument is sterilized with a 1:1000 solution of dimethylbenzyl-ammonium chloride, flushed thoroughly and filled with sterile saline. The signal from the transducer is continuously recorded. A satisfactorily positioned catheter will reveal minute rhythmical changes in IAP due to variations during the cardiac and respiratory cycle. If these changes become attenuated or disappear, it indicates blockage of the catheter opening.

Prior to injection of the urate crystal suspension, the joint is aspirated dry and then 15 mg of crystals are introduced. IAP recordings are taken continuously for 4 hours. Initially, IAP will fall for 30 minutes coincident with resorption of the injected fluid. Afterwards, there is a steady rise until a peak increase of 30-40 mmHg is achieved. Animals injected with only saline will not have any increase in pressure. At 4 hours, fluid is aspirated from the joint and total and differential cell counts done. In urate-injected joints, there is usually a 10-fold increase in the number of neutrophils.

Treatment of each dog is done in the following manner. Control values are first obtained on one of the knee joints after injection of urate crystals. Three days later the dog is given either vehicle a compound of formula I orally and 2 hours later the opposite knee is injected with crystals and the ensuing responses measured. Dose-response effects are obtained by dividing the animals into 4 groups of 5 dogs each. Animals are initially treated orally with either vehicle, 10, 25, or 50 mg/kg of a compound of formula I and then injected in the knee with urate crystals. The effectiveness of a treatment is accessed by comparing the increase in IAP and neutrophil count in urate-injected knee joints of the drug treated group to that of the corresponding vehicle control.

The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit or treat gout.

The term "inhibit" includes its generally accepted meaning which includes prohibiting, preventing, restraining and slowing, stopping or reversing progression, severity or a resultant symptom. As such, the present method includes both medical therapeutic and/or prophylactic administration as appropriate.

While it is possible to administer a compound employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one active ingredient (the compound of the present invention) . The compounds or formulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, e.g., by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, for example, containing from 0.01 to 90% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions. Such formulations are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See , e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed . 1980) .

In making the formulations employed in the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, tragacanth, gelatin, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the ar . The compounds of this invention may be delivered transdermally using known transdermal delivery systems and excipients . Most preferably, a compound of this invention is admixed with permeation enhancers including, but not limited to, propylene glycol, polyethylene glycol monolaurate, and azacycloalkan-2-ones , and incorporated into a patch or similar delivery system. Additional excipients including gelling agents, emulsifiers, and buffers may be added to the transdermal formulation as desired. For topical administration, a compound of this invention ideally can be admixed with any variety of excipients in order to form a viscous liquid or cream-like preparation.

For oral administration, a compound of this invention ideally can be admixed with carriers and diluents and molded into tablets or enclosed in gelatin capsules .

In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine. For such purpose there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.

Preferred pharmaceutical forms of the present invention include capsules and tablets .

The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a mammal in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof that is effective to inhibit or treat gout.

Advantageously for this purpose, formulations may be provided in unit dosage form, preferably each dosage unit containing from about 5 to about 500 mg (from about 5 to 50 mg in the case of parenteral or inhalation administration, and from about 25 to 500 mg in the case of oral or rectal administration) of a compound of Formula I. Dosages from about 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.

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 surrounding the case, including, for example, the route of administration the age, weight and response of the individual patient, the condition being treated and the severity of the patient's symptoms. In general, the compounds of the invention are most desirably administered at a concentration that will generally afford effective results without causing any serious 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.

While all of the compounds illustrated above exemplify LTB₄ inhibition activity in vitro, we have also discovered that compounds bearing a single acidic group {Re ) are considerably more orally bioactive when administered to mammals compared with those compounds bearing two such acidic groups. Thus, a preferred embodiment when administering compounds of Formula I orally to mammals comprises administering compounds bearing a single acidic R functionality.

The following formulation examples may employ as active compounds any 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. Formulation 1

Hard gelatin capsules are prepared using the following ingredients :

Quantity (mσ/capsule)

3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) -6- (4-carboxy- phenoxy) henyl) propanoic acid 250

Starch 200

Magnesium stearate 10

The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.

Formulation 2

A tablet is prepared using the ingredients below:

Quantity (mg/tablet)

1- ( 4- (Carboxymethoxy) phenyl ) -1- ( 1H- tetrazol-5-yl)-6-(2-ethyl-4-(4- fluorophenyl) -5-hydroxyphenoxy) hexane 250

Cellulose, microcrystalline 400

Silicon dioxide, fumed 10

Magnesium stearate 5

The components are blended and compressed to form tablets each weighing 665 mg. Formulation 3

An aerosol solution is prepared containing the following components:

Weight %

3- [4- [7-Carboxy-9-oxo-3- [3- [2-ethyl-4-

(4-fluorophenyl ) -5-hydroxyphenoxy] propoxy] - 9H-xanthene] ] propanoic acid 0.25

Ethanol 30.00

Propellant 11 10.25

( richlorofluoromethane )

Propellant 12 29.75 (Dichlorodifluoromethane)

Propellant 114 29.75 (Dichlorotetrafluoroethane)

The active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -30°C. and transferred to a filling device. The required amount is then fed to a container and further filled with the pre-mixed propellants 12 and 114 by means of the cold-filled method or pressure-filled method. The valve units are then fitted to the container.

For ulation 4

Tablets each containing 60 mg of active ingredient are made up as follows:

2- [2-Propyl-3- [3- [2-ethyl-5-hydroxy-4- (4- fluorophenyl ) phenoxy] propoxy] phenoxy] - benzoic acid sodium salt 60 mg Starch 45 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 4 mg

(as 10% solution in water)

Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg

Talc 1 mg

Total 150 mg

The active ingredient, starch and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve. The granules so produced are dried at 50-60° and passed through a No . 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No . 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg .

Formulation 5

Capsules each containing 80 mg of medicament are made as follows:

5- [3- [2- (1-Carboxy) ethyl] -4- [3- [2-ethyl-4- (4- fluorophenyl) -5-hydroxyphenoxy] propoxy] - phenyl] -4-pentynoic acid 80 mg

Starch 59 mg Microcrystalline cellulose 59 mg

Magnesium stearate 2 mg

Total 200 mg

The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No . 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities .

Formulation 6

Suppositories each containing 225 mg of active ingredient are made as follows:

3- (2- (3- (2-Ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy) propoxy) -6- (4-carboxy- phenoxy) phenyl) propanoic acid 225 mg

Unsaturated or saturated fatty acid glycerides to 2,000 mg

The active ingredient is passed through a No . 60 mesh U.S. sieve and suspended in the fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool . Formulation 7

Suspensions each containing 50 mg of medicament per 5 mL dose are made as follows:

2- [2-Propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) - 5-hydroxyphenoxy] propoxy] phenoxy] benzoic acid 50 mg

Sodium carboxymethyl cellulose 50 mg Sugar 1 g

Methyl paraben 0.05 mg

Propyl paraben 0.03 mg

Flavor q.v.

Color q.v. Purified water to 5 mL

The medicament is passed through a No . 45 mesh U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension. The parabens, flavor and color are dissolved and diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.

Formulation 8 An intravenous formulation may be prepared as follows :

2- [2-propyl-3-[3-[2-ethyl-4-(4- 100 mg fluorophenyl) -5- hydroxyphenoxy] ropoxy] phenoxy] benzoi c acid

Isotonic saline 1,000 ml

The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute.

Claims

We claim :

1. A method for inhibiting or treating gout in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of the formula I

wherein:

Rl is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl , C1-C4 alkoxy, (C1-C4 alkyl) thio, halo, or R2- substituted phenyl;

each R2 and R3 are each independently hydrogen, halo, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, (C1-C4 alkyl) -S (O)q-, trifluoromethyl , or di-(Cι~C3 alkyl) amino;

X is -0-, -S-, -C(=0), or -CH2-;

Y is -O- or -CH2-;

or when taken together, -X-Y- is -CH=CH- or

^•C:

Z is a straight or branched chain C1-C10 alkylidenyl; A is a bond, -0-, -S-, -CH=CH-, or CR_aRb~, where R_a and Rb are each independently hydrogen, C1-C5 alkyl, or R7 -substituted phenyl, or when taken together with the carbon atom to which they are attached form a C4-C8 cycloalkyl ring;

where ,

each R6 is independently -COOH, 5-tetrazolyl , -CON⁽Rg⁾2- or -CONHSO2R10

each R7 is hydrogen, C1-C4 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, benzyl, methoxy, -W-Rg , -T-G-Rg, (C1-C4 alkyl) -T- (C1-C4 alkylidenyl) -0- , or hydroxy;

R8 is hydrogen or halo;

each R9 is independently hydrogen, phenyl, or C1-C4 alkyl, or when taken together with the nitrogen atom form a morpholino, piperidino, piperazino, or pyrrolidino group;

RlO is C1-C4 alkyl or phenyl;

Rll is R2, -W-Rg, or -T-G-Rg;

each W is a bond or straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;

each G is a straight or branched chain divalent hydrocarbyl radical of one to eight carbon atoms;

each T is a bond, -CH2-, -0-, -NH-, -NHCO-,

-C(=0)-, or -S(0)_q-_;

K is -C(=0)- or -CH(OH)-;

each q is independently 0, 1, or 2;

p is 0 or 1; and

t is 0 or 1;

provided when X is -O- or -S-, Y is not -0-;

provided when A is -0- or -S-, R4 is not Rg ;

provided when A is -O- or -S- and Z is a bond, Y is not -0-; and

provided W is not a bond when p is 0;

aceutically acceptable salt or solvate thereof.

2. The method as claimed in Claim 1 employing a compound of the formula

or a pharmaceutically acceptable salt or solvate thereof.

3. The method as claimed in Claim 2 employing 2- [2-propyl-3- [3- [2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] ropoxy] phenoxy] benzoic acid or a pharmaceutically acceptable salt or solvate thereof.

4. The method as claimed in Claim 2 employing 3- (2- (3- (2 -ethyl-4- (4-fluorophenyl) -5-hydroxyphenoxy) propoxy) - 6- (4-carboxy-phenoxy) phenyl )propionic acid or a pharmaceutically acceptable salt or solvate thereof.

5. The method as claimed in Claim 2 employing 1- (4- (carboxy-methoxy) phenyl) -1- (lH-tetrazol-5-yl) -6- ( 2 -ethyl- 4- (4-fluorophenyl) -5-hydroxyphenoxy) hexane or a pharmaceutically acceptable salt or solvate thereof.

6. The method as claimed in Claim 2 employing 3- [4- [7-carboxy-9-oxo-3- [3- [2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] -propoxy] -9H-xanthene] ] propanoic acid or a pharmaceutically acceptable salt or solvate thereof.

7. The method as claimed in Claim 2 employing 5- [3- [2- (1-carboxy) -ethyl] -4- [3- [2-ethyl-4- (4-fluorophenyl) -5- hydroxyphenoxy] -propoxy] phenyl ] -4-pentynoic acid or a pharmaceutically acceptable salt or solvate thereof.

8. The method as claimed in any one of Claims 1 ich the mammal is a human.