Scope of the Invention This invention relates to disubstituted napthalenes which are useful as leukotriene antagonists. More particularly, these napthalenes are 2,7-disubstituted compounds which have utility in treating diseases related to leukotriene B ₄ wherein the treatment is affected by virtue of the antagonist activity of these 2,7-disubstituted naphthalenes.

Background of the Invention

The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C ₄ , D4 and E4) and the hydroxyleukotrienes (leukotriene B ₄ ). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.

The peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production.

By comparison, LTB ₄ exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs). It is critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.

Leukotriene B4 (LTB ₄ ) was first described by B orgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)-6,8,10,14-eicosatetraenoic acid (Figure I).

It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB ₄ has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB ₄ are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity.

Pharmacological studies on human blood PMN leukocytes indicate the presence of two classes of LTB ₄ -specific receptors that are separate from receptors specific for the peptide chemotactic factors. Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms.

LTB ₄ has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB ₄ has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis.

By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor. Summary of the Invention

This invention relates to disubstituted napthalenes of formula I

or a salt thereof wherein

R _l is -CH(OH)(CH ₂ ) _n CH ₃ where n is 3-20; and R2 is COX, or

n is 0, 1 or 2, and R3 is -COX and X is OH or a salt, ester or amide thereof.

In another aspect, this invention covers pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.

Treating diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ are within the scope of this invention. This treatment can be effected by administering an effective amount of one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient.

In yet another aspect, this invention relates to methods for making a compound of formula I. These methods are illustrated in the Schemes given below and in the Examples set forth in this specification. Included in these methods are those comprising a.) forming a salt from an acid, or b) hydrolyzing an ester to a salt, or c) converting a salt to the free acid, or d) converting one salt to another salt, or e) forming an ester, or f) forming an amide, or g) inserting an R2 group at position 2 by means of a triflate intermediate.

DETAILED DESCRIPTION OF THE INVENTION The following definitions are used in describing and defining this invention.

The phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo.

An ester-forming group is any group where an oxygen is covalently bonded to a carbonyl carbon and a second carbon atom wherein the resulting molecule is called an ester. Similarly, an amide-forming group is one where a nitrogen is bonded to a carbonyl carbon and otherwise is substituted by two hydrogens, a hydrogen and a carbon or two carbons where the resulting molecule is called an amide. All esters or amides within the scope of this invention will retain some useful activity in treating a disease relating to or caused by leukotrienes particularly LTB ₄ , or for some other industrial application. When the phrase "a pharmaceutically acceptable ester-forming group" or "pharmaceutically acceptable amide forming group" is used, it is intended to refer to all esters or amides which can be used in the medicinal arts, including both the human and animal medicinal arts. The preferred esters are those having the formula CH3(CH ₂ ) _u -0- where u is 0-6, a lower alkoxy group. The most preferred amides are those where the nitrogen is substituted with just hydrogen or one or two lower alkyl groups. The preparation of esters and amides diethylamide is particularly preferred. If there is an acidic or basic function which is sufficiently acidic or basic so as to be able to form salts, this invention is intended to cover all salts which have industrial application. If the phrase "a pharmaceutically acceptable salt" is used, that is intended to cover salts which have use and application in the human and animal medicinal arts. Examples of pharmaceutically acceptable salts can be found in the review article by Merge, S.M., et al., /. Pharm Sc , Vol. 66, No. 1, January 1977/1.

Salts are prepared in a standard manner, in a suitable solvent. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of a basic functionality, or an excess of organic or inorganic base where X is OH.

If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.

As leukotriene antagonists, these compounds can be used in treating a variety of disease associated with or attributing their origin or affect to leukotrienes, particularly hydroxyleukotrienes

(LTB ₄ ). It is expected that these compounds can be used to treat pulmonary and non-pulmonary allergic diseases. For example, these compounds can be useful in treating antigen-induced anaphylaxis. They will be useful also in treating asthma and allergic rhinitis, psoriasis, and inflammatory bowel disease. Ocular diseases such as uveitis, and allergic conjunctivitis will also be treated with these compounds.

The preferred compounds of this invention are those where Ri is -CH(OH)(CH2) _n CH3 and n is 5-15. More preferred compounds are those where the n in Ri is 8 and R ₂ is -COX, or group A where n is 0, 1 or 2 and R3 is in the 3 or 4 position, or R2 is B where R3 is in the 3 or 4 position or C where R3 is in the 3 or 4 position. The most preferred compounds are:

3-[ l -thia-2-(7-( l -hydroxynonyl)-2-naphthyl)ethyl]benzoic acid, or its lithium salt;

3-[ l -oxythia-2-(7-( l -hydroxy nonyl)-2-naphthyl)ethyl]benzoi c acid, or its lithium salt;

3-[ l -dioxythia-2-(7-(l -hydroxynonyl)-2-naphthyl)ethyl]benz oic acid, or its lithium salt; 7-(l -hydroxynonyl)-2-naphthalene carboxylic acid, or its lithium salt; and

3-[ l -oxa-2-(7-(l -hydroxynonyl)-2-naphthyl)ethyl]benzoic acid, or its sodium salt.

Syntheses These compounds may be made from the starting materials and using the intermediates and reagents set out in the reaction flow charts below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are given to illustrate the general case and are not intended to limit the chemistries which can be used in making these compounds. All reagents, intermediates, temperatures, solvents, reaction times, and work-up procedures may be varied to accommodate differences in the processes used in making these compounds and may be varied to optimize the particular conditions or reagents for making any given compound. Variations for making specific compounds based on these general conditions will be apparent to a chemist or will not require more than minimal experimentation to optimize conditions and reagents for a particular step.

Scheme I illustrates a method for making useful intermediates and for converting them into several of the compounds of this invention.

Scheme I

8

9 1 0

1 1 1 2

1 3

The 2,7-dihydroxynapthalene starting material is a known compound available from a number of commercial chemical houses. First protected is one of the hydroxyl groups, preferably by means of a silyloxy group as illustrated by 2. Herein, a f-butyldimethyl- silyloxy protecting group is preferred. The triflate 3 is prepared by treating 2 with trifluoromethanesulfonic anhydride under an inert atmosphere in a dry solvent such as methylene dichloride. Slightly reduced temperature, e.g. -10° to 10°C, is preferred; the reaction is run for between about 10 minutes and 2 hours. An ester function is introduced at the 7 position by mixing 3 with dppp and the palladium catalyst Pd(OAc)2, then bubbling carbon monoxide through the solution to produce the ester (4). The ester is then reduced to the alcohol (5) by means of a reducing agent such as 1-BU2AI-H. This reaction is carried out at reduced temperature (e.g. -78°C) under an inert atmosphere, the reaction being completed in a relatively short time of about 5 to 25 minutes. The aldehyde 6 is made by treating 5 with a mild oxidizing agent such as manganese dioxide. A Grignard reagent is employed to add the alkyl chain to the carbonyl carbon of 6 resulting in the 1 -hydroxy alky 1 compound 7. This 1 -hydroxy group is then protected, preferably employing the same protecting group used to protect the 2-position hydroxy group. Conditions which are the same as or similar to those used to prepare 2 may be used to prepare 8. Then the 2-position is

selectively deprotected. This may be accomplished using a nucleophile such as an alkali metal alkoxide, e.g., potassium methoxide. An inert atmosphere, methanol, and anhydrous potassium carbonate comprise the preferred reactants and conditions for this reaction. An hour or so of stirring at about room temperature is sufficient to effect the reaction, giving 9. Preparing 10, converting it to the ester 11 and reducing the ester to the alcohol 12 is accomplished using the same or similar reagents and conditions described for making 3, 4 and 5. The alcohol 12 is converted to the bromo 13 using carbon tetrabromide and triphenylphosphine under an inert atmosphere and an inert solvent. Then a mercaptobenzene adduct is reacted with 13 in the presence of a weak base to form 14. An anhydrous alkali metal carbonate is preferred for this reaction, for example potassium carbonate. Dimethylformamide or a similar solvent may be used. The reaction can be carried out at room temperature or thereabouts. Next the 1 -hydroxy group on the 7-position substitution is deprotected by means of a fluoride source such as tetrabutylammonium fluoride giving (15). A base such as an alkali metal base is used to hydrolyze the ester on the benzene ring. This is for the case where LiOH is used. The free acid can be obtained by acidifying a solution of the salt obtained from the saponification process, or by some other process.

One can prepare the oxides of 16 by treating the thioether with a mild oxidizing agent such as m-chloroperbenzoic acid. Scheme II illustrates the process schematically.

Scheme II

2 equiv oxidizing base agent

As illustrated in this scheme, the sulfoxide 17 is obtained if one equivalent of the oxidizing agent is used. Two equivalents provide the sulfone 19. Then base, preferably an alkali metal base, can be used to hydrolyze the ester to the salts 18 and 20. Here Z represents the cation of whatever base was used to effect the hydrolysis. Ethers can be made by treating 13 (see Scheme I) or an analog thereof with an hydroxybenzoate as outlined in Scheme III.

Scheme III

Starting material 13 is prepared as described in Scheme I. Ether 21 is made by combining the appropriate hydroxybenzoate with 13 in the presence of a weak base. In this case, alkali metal carbonate is preferred, particularly anhydrous potassium carbonate. As with the thioether-forming reaction noted in Scheme II, this reaction is carried out at a temperature between about 30° - 90° C under an inert atmosphere in a dry solvent such as DMF. Then, such as tetrabutylammonium fluoride is used to deprotect the hydroxyl group on Ri. The ester 22 is then saponified, preferably using an alkali metal base which gives an alkali metal salt, though

23 can have any cation.

Compounds where R ₂ is an acid can be prepared by the route outlined in Scheme IV.

Sche e IV

Z2> 2A

1 ) acid

2) base

Starting material 12, or an analog thereof, is prepared by the method set out in Scheme I. The hydroxyl group is treated with an oxidizing agent, for example a chromium-based oxidizing agent exemplified by pyridinium dichromate. A preferred method is to treat 12 with an excess of pyridinium dichromate in DMF under an inert atmosphere for an extended period, e.g.. 18 hours at room temperature. This gives 24. The protecting group may be removed by acid such as acetic acid. An elevated temperature, between about 30° - 90° C with stirring for 2-6 hours will hydrolyze the silyl ether. Basifying the solution provides 25 where X ⁺ represents a cation.

Formulations

Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes.

The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems,

water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrif uoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.

In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.

For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension. For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose.

For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, • liquid, or emulsion.

Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. When employed in this manner, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of

active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 100 mg to about 5000 mg. The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.

Included within the scope of this disclosure is the method of treating a disease mediated by leukotrienes, particularly by LTB4. which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the symptoms of an allergic response resulting from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth.

Pharmaceutical compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction. Representative Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines (diphenhydramine), ethylenediamines (pyrilamine), the alkylamines (chlorpheniramine), the piperazines (chlorcyclizine), and the phenothiazines (promethazine). Hi blockers such as 2-[4- (5-bromo-3 -methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3- yl)methyl]-4-pyrimidone are particularly useful in this aspect of the invention. Bioassays

The specificity of the antagonist activity of a number of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2.

The receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [ ³ H]-LTB ₄ binding sites on human U937 cell membranes. The LTB ₄ antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB ₄ elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows: U937 Cell Culture Conditions U937 cells were obtained from Dr. John Bomalaski (Medical

College of PA) and Dr. John Lee (SK&F, Dept. of Immunology) and grown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2, 95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with DMSO to monocyte-like cells, the cells were seeded at a concentration of 1 x 10 ⁵ cells/ml in the above medium with 1.3% DMSO and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 10 ⁶ cells/ml and were harvested by centrifugation at 800 x g for 10 min.

Preparation of U937 Cell Membrane Enriched Fraction

Harvested U937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25°C containing 1 mM EDTA (buffer A). Cells were resuspended in buffer A at a concentration of 5 x 10 ⁷ cells/ml and disrupted by nitrogen cavitation with a Parr bomb at 750 psi for 10 min. at 0°C. The broken cell preparation was centrifuged at 1,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris- HCl, pH 7.4 at 25° C and aliquots were rapidly frozen and stored at -70°C. Binding of .-3-HI-LTBΛ to U397 Membrane Receptors

[ ³ H]-LTB ₄ binding assays were performed at 25° C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCh, 10 mM MgCl ₂ , [ ³ H]- LTB4 _. U937 cell membrane protein (standard conditions) in the presence (or absence of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [ ³ H] - LTB4 were determined in the absence or presence of 2 μM of unlabeled LTB ₄ , respectively. Specific binding was calculated as the

difference between total and non-specific binding. The radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [ ³ H]-LTB ₄ , 20-40 μg of U937 cell membrane protein, increasing concentrations of LTB ₄ (0.1 nM to 10 nM) or other competing ligands (0.1 μM to 30 μM) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25° C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrane bound radioactivity on the filters was determined by liquid scintillation spectrometry.

Saturation binding experiments for U937 cells were performed, under standard conditions, using approximately 15-50 μg of U937 membrane protein and increasing concentrations of [ ³ H] - LTB ₄ (0.02-2.0 mM) in a reaction volume of 0.2 ml and incubation at 22°C, for 30 minutes. LTB ₄ (2 μM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard. Uptake of Fura-2 bv Differentiated U937 Cells

Harvested cells were resuspended at 2 x 10 ⁶ cells/ml in Krebs Ringer Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgS0 ₄ , 1.0 mM CaCl ₂ and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of fura-2 (fura-2/AM) was added to a final concentration of 2 μM and cells incubated in the dark for 30 minutes at 37° C. The cells were centrifuged at 800 x g for 10 minutes and resuspended at 2 x 10 ⁶ cells/ml in fresh buffer B and incubated at 37° C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 10 ⁶ cells/ml.

Cells were maintained on ice in the dark until used for fluorescent measurements.

Fluorescent Measurements Calcium Mobilization

The fluorescence of fura-2 containing U937 cells was measured with a fluorometer designed by the Johnson Foundation

Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37° C with constant mixing.

U937 cells were diluted with fresh buffer to a concentration of 1 x 10 ⁶ cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 μl aliquots.

Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one minute 10 nM LTB4 (a near maximal effective concentration) was added and the maximal Ca ²⁺ mobilization [Ca ²⁺ ]i was calculated using the following formula:

[Ca2+]i = 224fF-Fminl Fmax-F }

F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with 10 μl of 10% Triton X-100 (final Concentration 0.02%). After Fmax was determined 67 μl of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca ²⁺ and quench the fura-2 signal and obtain the Fmin. The [Ca ²⁺ ]i level for 10 nM LTB ₄ in the absence of an antagonist was 100% and basal [Ca ²⁺ ]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced [Ca ² +]i mobilization. The EC50 for LTB4 induced increase in [Ca ²⁺ ]i mobilization was the concentration for half maximal increase. The Ki for calcium mobilization was determined using the formula:

With the experiments described, the LTB ₄ concentration was 10 nM and the EC5 ₀ was 2 nM. Several of the compounds of this invention were tested in one or more of the aforementioned assays. Results for those tests are given in Figure III; average results are given where more than one test was done.

Examples The following are a set of examples which are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors by this document.

Example 1 3-π -Thia-2-( ^, 7-d -hvdroxynonyl . -2-naphthyl ^' )ethvnbenzoic acid. lithium salt 1A. 2-t-Butyldimethylsilyloxy-7-hydroxy naphthalene.

To a cooled (0°C) solution of 2,7-naphthalenediol (lO.Og, 62.5mmol, Aldrich) and imidazole (4.3g, 63.0mmol) in dry dimethylformamide (60mL) under an argon atmosphere was added t-butyldimethylsilyl chloride (8.4g, 56.2mmol) in two equal portions. The reaction was maintained at 0°C for 2 hours. The reaction mixture was poured into Et2θ and washed several times with H2O followed by brine and dried (MgS0 ₄ ). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give a colorless solid: *H NMR (250MHz, CDCI3) δ 7.65 and 7.60 (doublets, J=8.4Hz, 2H total, 4,5- naphthyl), 7.02 and 6.98 (doublets, J=1.6Hz, 2H total, 1,8 -naphthyl), 6.90 (m, 2H, 3,6-naphthyl), 5.05 (dd, 1H, OH), 1.0 (s, 9H, r-butyl), 0.20 (s, 6H, Me ₂ ).

IB. 2-t-Butyldimethylsilyloxynaphthalene-7-trifluoromethyl- sulfonate.

To a cooled (0°C) solution of 2-t-butyldimethylsilyloxy-7- hydroxynaphthalene (8.27g, 30.1mmol) in dry CH ₂ CI ₂ (60mL) under an argon atmosphere was added dry pyridine (3.7mL, 45.7mmol) and trifluoromethanesulfonic anhydride (lOg, 35.4mmol). The reaction was stirred at 0°C for 1 hour. The reaction solution was diluted with E. ₂ O and washed with H2O, 5% HCl, aqueous NaHC03,

and brine and dried (MgSθ ₄ ). The product was purified by flash column chromatography (silica, 2% ethyl acetate in hexane) to give a pale yellow oil: lH NMR (250MHz, CDCI3) δ 7.85 and 7.75 (doublets, J=8.4Hz, 2H total, 4,5 -naphthyl), 7.58 (d, J=1.6Hz, IH, 1-naphthyl), 7.20 (m, 3H, 3,6,8-naphthyl), 1.02 (s, 9H, t-butyl), 0.28 (s, 6H, Me ₂ ).

IC. 2-t-Butyldimethylsilyloxy-7-carboxymethylnaphthalene.

To a flask containing 2-t- butyldimethylsilyloxynaphthalene-7-trifluoromethylsulfonate (813mg, 2.0mmol) was added dry dimethylsulfoxide (6mL), anhydrous CH3OH (4mL), triethylamine (0.56mL, 4.4mmol), Pd(OAc)2 catalyst (13.4mg, 0.06mmol), and l,3-bis(diphenylphosphino)propane (25mg, 0.06mmol). Carbon monoxide was passed through the solution for 4 minutes. The entire mixture was then heated at 75°C under a carbon monoxide atmosphere (balloon pressure) for 1 hour. Upon cooling to room temperature the reaction mixture was filtered through Celite and the CH3OH was evaporated. The remaining solution was diluted with Et2θ and washed with H2O, 5% HCl, aqueous NaHC03, and brine and dried (MgSθ4). The product was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) to give a colorless oil: IH NMR (250MHz, CDCI3) δ 8.49 (s, IH, 8-naphthyl), 7.90 (d, J=8.4Hz, IH, 6-naphthyl), 7.85 and 7.75 (doublets, J=8.4Hz, 2H total, 4,5-naphthyl), 7.30 (d, J=1.6Hz, IH, 1 -naphthyl), 7.15 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 3.95 (s, 3H, methyl ester), 1.05 (s, 9H, t-butyl), 0.28 (s, 6H, Me ₂ ); MS (CI): 317 (M+H).

IE. 2-t-Butyldimethylsilyloxy-7-hydroxymethylnaphthalene.

To a cooled (-78°C) solution of 2-t-butyldimethylsilyloxy-7- carboxymethylnaphthalene (460mg, 1.45mmol) in CH2CI2 (5mL) under an argon atmosphere was added diisobutylaluminum hydride (4.5mL, 4.5mmol; 1.0M solution in CH ₂ CI2). The reaction was stirred for 15 minutes at -78° C. The reaction was treated with ethyl acetate (5mL) followed by warming to room temperature. The reaction solution was diluted with E_2θ and washed with 2% HCl, H2O, aqueous potassium sodium tartrate, and brine and dried (MgSθ ₄ ). Purification by flash column chromatography (silica, 10% ethyl acetate in hexane) gave the captioned product: H NMR (250MHz, CDCI3) δ 7.76 (d, J=8.4Hz, IH, 5-naphthyl), 7.71 (d, J=8.4Hz, IH, 4-naphthyl), 7.67 (d, J=1.6Hz, IH, 8-naphthyl), 7.33 (dd, J=8.4,

1.6Hz, IH, 6-naphthyl), 7.18 (d, J=1.6Hz, IH, 1-naphthyl), 7.07 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 4.83 (d, J=5.9Hz, 2H, CH ₂ 0), 1.75 (t, J=5.9Hz, IH, OH), 1.02 (s, 9H, t-butyl), 0.24 (s, 6H, Me ₂ ).

IF. 2-t-ButyldimethylsiIyloxy-7-naphthalene carboxaldehyde. 2-t-Butyldimethylsilyloxy-7-hydroxymethylnaphthalene (399mg, 1.38mmol) was dissolved in CH2CI2 (3mL) under an argon atmosphere and treated with Mnθ2 (1.2g, 13.8mmol). The reaction mixture was stirred at room temperature for 18 hours, filtered through Celite, and concentrated. Purification by flash column chromatography (silica, 3% ethyl acetate in hexane) gave the product as an oil: H NMR (250MHz, CDCI3) δ 10.15 (s, IH, aldehyde), 8.20 (s, IH, 8-naphthyl), 7.80 (m, 3H, 4,5,6-naphthyl), 7.32 (d, J=1.6Hz, IH, 1-naphthyl), 7.22 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 1.02 (s, 9H, t-butyl), 0.30 (s, 6H, Me ₂ ).

1G. 2-t-Butyldimethylsilyloxy-7-π -hydroxynonvDnaphthalene.

A solution of n-octylmagnesium bromide was prepared from 1-bromooctane (2.7mL, 15.6mmol) and Mg (450mg, 18.5mmol) in dry tetrahydrofuran (40mL) under an argon atmosphere. The cooled (0°C) solution containing the Grignard reagent was transferred via canula to a cooled (-25° C) solution of 2-t- butyldimethylsilyloxy-7-naphthalene carboxaldehyde (2.63g, 9.2mmol) in dry tetrahydrofuran (lOmL). The reaction was stirred at -25° C for 10 minutes followed by the addition of H2O and aqueous NH ₄ CI. The reaction mixture was diluted with Et2θ and washed with H2O and brine and dried (MgSθ4). The product was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) to yield the captioned product: H NMR (250MHz, CDCI3) δ 7.80 (d, J=8.4Hz, IH, 5-naphthyl), 7.75 (d, J=8.4Hz, IH, 4-naphthyl),

7.65 (d, J=1.6Hz, IH, 8-naphthyl), 7.33 (d, J=8.4, 1.6Hz, IH, 6-naphthyl), 7.18 (d, J=1.6Hz, IH, 1-naphthyl), 7.07 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 4.82 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.95 (broad singlet, IH, OH), 1.88 (m, 2H, CH ₂ ), 1.30 (m, 12H, aliphatic), 1.02 (s, 9H, t-butyl), 0.90 (t, J=6.8Hz, 3H, CH3), 0.24 (s, 6H, Me ₂ ); MS (CI): 401 (M+H).

1H. 2-t-Butyldimethylsilyloxy-7-fl-t-butyldimethylsilyloxynonvD- naphthalene.

To a- cooled (0°C) solution of 2-t-butyldimethylsilyloxy-7- (l-hydroxynonyl)naphthalene (3.0g, 7.49mmol) in dry CH2CI ₂ (20mL) under an argon atmosphere was sequentially added

2,6-lutidine (2.6mL, 22.3mmol) and t-butyldimethylsilyl triflate (2.6mL, 11.3mmol). The temperature was maintained at 0°C for 30 minutes. The reaction was diluted with E_2θ and washed with H ₂ O , 5% HCl, aqueous NaHCθ3, and brine and dried (MgSθ ₄ ). The solvent was evaporated and the product was used directly in the next step without further purification: ^l H NMR (250MHz, CDCI3) δ 7.72 (d, J=8.4Hz, IH, 5-naphthyl), 7.68 (d, J=8.4Hz, IH, 4-naphthyl), 7.55 (d, J=1.6Hz, IH, 8-naphthyl), 7.31 (dd, J=8.4, 1.6Hz, IH, 6-naphthyl), 7.15 (d, J=1.6Hz, IH, 1-naphthyl), 7.02 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 4.72 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.70 (m, 2H, CH ₂ ), 1.28 (m, 12H, aliphatic), 1.02 (s, 9H, t-butyl), 0.91 (s, 9H, t-butyl), 0.89 (t, J=6.8Hz, 3H, CH3), 0.28 (s, 6H, Me ₂ ), 0.040 and -0.13 (singlets, 6H total, Me ₂ ).

II. 2-Hydroxy-7-(T -t-butyldimethylsilyloxynonyl)naphthalene. Crude 2-t-butyldimethylsilyloxy-7-(l -t-butyldimethyl- silyloxynonyl)naphthalene obtained from the previous step was dissolved in CH3OH (20mL) and tetrahydrofuran (lOmL) and treated with an excess of anhydrous K2CO3 under an argon atmosphere. The reaction was vigorously stirred for 1 hour. The reaction solution was treated with aqueous NH ₄ CI and diluted with Et ₂ θ. The organic phase was separated and washed with H2O and brine and dried (MgSθ ₄ ). Purification by flash column chromatography (silica, 7% ethyl acetate in hexane) provided the desired product: !H NMR (250MHz, CDCI3) δ 7.71 (m, 2H, 4,5-naphthyl), 7.54 (d, J=1.6Hz, IH, 8-naphthyl), 7.30 (dd, J=8.4, 1.6Hz, IH, 6-naphthyl), 7.12 (d, J=1.6Hz, IH, 1-naphthyl), 7.06 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 5.07 (s, IH, OH), 4.76 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.71 (m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.89 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH3), 0.040 and -0.13 (singlets, 6H total, Me ₂ ).

1 J. 7-C1 -t-ButyldimethylsilyloxynonylV2-naphthalenetrif luoro- methylsulfonate.

2-Hydroxy-7-(l -t-butyldimethylsilyloxynonyl)naphthalene (3.0g, 7.49mmol) was dissolved in dry CH2CI ₂ (20mL) under an

argon atmosphere, cooled to 0°C, and treated sequentially with dry pyridine (2.5mL, 31.0mmol) and trifluoromethanesulfonic anhydride (2.5mL, 15.5mmol); stirring was continued for 30 minutes. The reaction was diluted with E_2θ and washed with H2O , 5% HCl, aqueous NaHC03, and brine and dried (MgSθ ₄ ). The product was purified by flash column chromatography (silica, 1% E.2O in hexane) to give 3.58g (90%) as a pale yellow oil: *H NMR (250MHz, CDCI3) δ 7.89 (d, J=8.4Hz, IH, 4-naphthyl), 7.84 (d, J=8.4Hz, IH, 5-naphthyl), 7.71 (m, 2H, 1,8-naphthyl), 7.56 (dd, J=8.4, 1.6Hz, IH, 6-naphthyl), 7.32 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 4.80 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.70 (m, 2H, CH ₂ ), 1.27 (m, 12H, aliphatic), 0.90 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH3), 0.058 and -0.13 (singlets, 6H total, Me2).

IK. 7-f l -t-ButyldimethylsilyloxynonyP-2-carboxymethyl- naphthalene.

To a flask containing 7-(l-t-butyldimethylsilyloxynonyl)-2- naphthalene trifluoromethylsulfonate (533mg, l .Ommol) was added dry DMSO (3mL), anhydrous CH3OH (2mL), triethylamine (0.28mL, 2.2mmol), Pd(OAc)2 catalyst (6.7mg, 0.03mmol), and l,3-bis(diphenylphosphino)-propane (12.5mg, 0.03mmol). Carbon monoxide was passed through the solution for 4 minutes. The entire mixture was then heated at 75° C under a carbon monoxide atmosphere (balloon pressure) for 1 hour. Upon cooling to room temperature the reaction mixture was filtered through Celite and the CH3OH was evaporated. The remaining solution was diluted with Et2θ and washed with H2O, 5% HCl, aqueous NaHC03, and brine and dried (MgS0 ₄ ). The product was purified by flash column chromatography (silica, 3% Et2θ in hexane) to give the desired product: *H NMR (250MHz, CDCI3) δ 8.58 (d, J=1.6Hz, IH,

1-naphthyl), 8.02 (dd, J=8.4, 1.6Hz, IH, 3-naphthyl), 7.83 (m, 3H, 4,5,8-naphthyl), 7.57 (dd, J=8.4, 1.6Hz, IH, 6-naphthyl), 4.80 (dd, J=6.8, 5.4Hz, IH, -CH-O), 3.98 (s, 3H, methyl ester), 1.70 (m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.90 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH ₃ ), 0.051 and -0.14 (singlets, 6H total, Me ₂ ); MS (CI): 443 (M+H).

IL. 7-d -t-Butyldimethylsilyloxynonyl ^' )-2-hvdroxy methyl - naphthalene.

To a cooled (-78°C) solution of 7-(l-t-butyldimethyl- silyloxynonyl)-2-carboxymethylnaphthalene (434mg, 0.98mmol) in

dry CH2CI2 (2mL) under an argon atmosphere was added diisobutylaluminum hydride (3.0mL, 3.0mmol; 1.0M solution in CH ₂ CI ₂ ). After 20 minutes ethyl acetate (2mL) was added and the reaction was warmed to room temperature. The reaction solution was diluted with Et ₂ θ and vigorously shaken with aqueous potassium sodium tartrate. The organic layer was then washed with brine and dried (MgS04). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to yield the capitoned product: IH NMR (250MHz, CDCI3) δ 7.78 (m, 3H, 1,4,5-naphthyl), 7.69 (s, IH, 8-naphthyl), 7.46 (m, 2H,

3,6-naphthyl), 4.85 (d, J=6Hz, 2H, CH2-O), 4.78 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.74 (t, J=6Hz, IH, OH), 1.70 (m, 2H, CH ₂ ), 1.23 (m, 12H, aliphatic), 0.90 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH3), 0.041 and -0.14 (singlets, 6H total, Me ₂ ); MS (CI): 413 (M-H).

1M. 7-α -t-

Butyldimethylsilyloxynonyl)-2-bromomethylnaphthaIene.

7-(l -t-Butyldimethylsilyloxynonyl)-2-hydroxymethyl- naphthalene (234mg, 0.564mmol) was dissolved in dry CH2CI2 (ImL) and cooled to 0°C under an atmosphere of argon. To this was sequentially added CBr ₄ (280mg, 0.845mmol) and triphenylphosphine (210mg, 0.80mmol). After 1 hour the solvent was evaporated and the resulting residue applied directly to a flash chromatography column for purification (silica, 2% Et ₂ θ in hexane); the product was obtained as a colorless oil: ^X H NMR (250MHz, CDCI3) δ 7.79 (m, 3H, 1,4,5- naphthyl), 7.67 (s, IH, 8-naphthyl), 7.47 (m, 2H, 3,6-naphthyl), 4.78 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.67 (s, 2H, CH ₂ -Br), 1.70 (m, 2H, CH2), 1.23 (m, 12H, aliphatic), 0.88 (s, 9H, t- butyl), 0.87 (t, J=6.8Hz, 3H, CH3), 0.044 and -0.14 (singlets, 6H total, Me2).

IN. Methyl 3-ri-thia-2-('7-( ^' l -t-butyldimethylsilyloxynonylV2- naphthyPethyllbenzoate.

7-(l-t-Butyldimethylsilyloxynonyl)-2-bromomethyl- naphthalene (140mg, 0.293mmol) and methyl 3-mercaptobenzoate (55mg, 0.327mmol) were dissolved in dry dimethylformamide (1.5mL) and treated with anhydrous K2CO3 (85mg, 0.615mmol). The reaction mixture was vigorously stirred under an argon atmosphere for 30 minutes. The reaction was diluted with Et2θ and washed with H2O and brine and dried (MgSθ4). Purification by flash

column chromatography (silica, 2% ethyl acetate in hexane) gave the desired product: IH NMR (250MHz, CDC1 ₃ ) δ 8.04 (dd, J=1.6Hz, IH,

2-phenyl), 7.84 (ddd, J=7.8, 1.6Hz, IH, 6-phenyl), 7.75 (m, 2H, 4,5-naphthyl), 7.65 and 7.60 (singlets, 2H total, 1,8-naphthyl), 7.42 (m, 3H, 4-phenyl, 3,6-naphthyl), 7.28 (dd, J=7.8Hz, IH, 5-phenyl), 4.76 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.30 (s, 2H, CH ₂ -S), 3.88 (s, 3H, methyl ester), 1.70 (m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.89 (s, 9H, t-butyl), 0.88 (t, J=6.8Hz, 3H, CH3), 0.037 and -0.15 (singlets, 6H total, Me2).

10. Methyl 3-π -thia-2-.7-π -hvdroxynonvn-2-naphthyl .- ethyllbenzoate.

Tetrabutylammonium fluoride (ImL, l .Ommol; 1.0M solution in tetrahydrofuran) was added to a stirred solution of methyl 3-[ l -thia-2-(7-( l -t-butyldimethylsilyloxynonyl)-2-naphthyl)ethyl]- benzoate (156mg, 0.276mmol) in tetrahydrofuran (0.5mL) under an argon atmosphere. After 1.5 hours the reaction was diluted with Et ₂ θ and washed with aqueous NH ₄ CI and brine and dried (MgS0 ₄ ). The product was purified by flash column chromatography (silica, 10% ethyl acetate in CH ₂ CI ₂ ) to give a colorless solid: H NMR

(250MHz, CDCI ₃ ) δ 8.0 (dd, J=1.6Hz, IH, 2-phenyl), 7.80 (m, 3H, 6-phenyl, 4,5-naphthyl), 7.77 (m, 2H, 1,8-naphthyl), 7.46 (m, 3H, 4-phenyl, 3,6-naphthyl), 7.28 (dd, J=7.8Hz, IH, 5-phenyl), 4.80 (ddd, J=8.0, 6.8, 5.4Hz, IH, -CH-O), 4.30 (s, 2H, CH ₂ -S), 3.87 (s, 3H, methyl ester), 1.96 (d, J=8.0Hz, IH, OH), 1.84(m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.86 (t, J=6.8Hz, 3H, CH3); MS (CI): 468 (M+NH ₄ ).

IP. 3-π -Thia-2-π-d -hvdroxynonvn-2-naphthvnethvnbenzoic acid, lithium salt. Methyl 3-[l-thia-2-(7-(l-hydroxynonyl)-2-naphthyl)- ethyljbenzoate (38mg, 0.085mmol) was dissolved in tetrahydrofuran (0.40mL) and CH3OH (0.20mL) and treated with 1.0M LiOH (0.20mL, 0.20mmol). The reaction was stirred under an atmosphere of argon for 4 hours. The tetrahydrofuran and CH3O H were evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-CH3OH gradient). Lyophilization gave the product as a colorless amorphous solid: ^l H NMR (250MHz, d4-CH ₃ OH) δ 8.03 (dd, J=1.6Hz, IH, 2-phenyl), 7.75 (m, 3H, 6-phenyl, 4,5-naphthyl), 7.71 (m, 2H, 1,8-naphthyl), 7.44 (m, 2H, 3,6-naphthyl), 7.33 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 7.19 (dd,

J=7.8Hz, IH, 5-phenyl), 4.72 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.33 (s, 2H, CH ₂ -S), 1.78 (m, 2H, CH ₂ ), 1.25 (m, 12H, aliphatic), 0.87 (t, J=6.8Hz, 3H, CH ₃ ); MS (FAB): 435.2 (M-H, free acid).

Example 2

3-ri -Oxythia-2-(7-d-hydroxynonyl')-2-naphthyl ^" .ethyπbenzoic acid. lithium salt

2A. Methyl 3-ri -oxythia-2-f7-fl -hydroxynonyl -2-naphthyl)ethyl1-benzoate. Methyl 3-[l-thia-2-(7-(l-hydroxynonyl)-2-naphthyl)- ethyljbenzoate (30mg, 0.067mmol) was dissolved in dry CH2CI2 (ImL) under an argon atmosphere and cooled to 0°C. To this was added 80% -chloroperoxy-benzoic acid (16mg, 0.074mmol); stirring was continued for 30 minutes. The reaction was poured into aqueous NaHCθ3 ^{anα< tne} product extracted into CH2CI2. The organic layer was washed with brine and dried (MgSθ ₄ ). The product was purified by flash column chromatography (silica, 40% ethyl acetate in hexane) to give a colorless solid: !H NMR (250MHz, CDCI3) δ 8.1-2 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 7.96 (dd, J=1.6Hz, IH, 2-phenyl), 7.77 (d, J=8.4Hz, IH, 4-naphthyl), 7.70 (d, J=8.4Hz, IH, 5-naphthyl), 7.62 (s, IH, 8-naphthyl), 7.50 (m, 3H, 5,6-phenyl, 6-naphthyl), 7.36 (s, IH, 1 -naphthyl), 7.06 (d, J=8.4Hz, IH, 3-naphthyl), 4.80 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.19 (q, J=13Hz, 2H, CH2-S), 3.80 (s, 3H, methyl ester), 2.20 (broad singlet, IH, OH), 1.84 (m, 2H, CH ₂ ), 1.25 (m, 12H, aliphatic), 0.86 (t, J=6.8Hz, 3H, CH ₃ ).

2B. 3-ri -Oxythia-2- 7-α-hydroxynonylV2-naphthvDethvnbenzoic acid, lithium salt. Methyl 3-[l-oxythia-2-(7-(l-hydroxynonyI)-2- naphthyl)ethyl]-benzoate (22mg, 0.047mmol) was dissolved in tetrahydrofuran (0.30mL) and CH3OH (0.15mL) and treated with 1.0M LiOH (0.15mL, 0.15mmol). The reaction was stirred under an atmosphere of argon for 4 hours. The tetrahydrofuran and CH3O H were evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2O-CH3OH gradient). Lyophilization gave the desired product as a colorless amorphous solid: ^l H NMR (250MHz, d4-CH ₃ OH) δ 8.20 (dd, J=1.6Hz, IH, 2-phenyl), 8.10 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 7.80 (d, J=8.4Hz, IH, 4-naphthyl), 7.72 (d, J=8.4Hz, IH, 5-naphthyl), 7.67 (s, IH, 8-naphthyl), 7.57 (s, IH, 1-naphthyl),

7.42 (m, 3H, 5,6-phenyl, 6-naphthyl), 7.15 (d, J=8.4Hz, IH, 3-naphthyl), 4.73 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.35 (q, J=13Hz, 2H, CH ₂ -S), 1.78 (m, 2H, CH ₂ ), 1.26 (m, 12H, aliphatic), 0.87 (t, J=6.8Hz, 3H, CH ₃ ); MS (FAB): 451.2 (M-H, free acid).

Example 3 3-π -Dioxythia-2-(7-π -hydroxynonyD-2-naphthyDethyllbenzoic acid, lithium salt

3A. Methyl 3-ri -dioxythia-2-f7-π -hvdroxynonyl . -2-naphthyl .- ethyllbenzoate.

Methyl 3-[l -thia-2-(7-(l -hydroxynonyl)-2-naphthyl)- ethyljbenzoate (29mg, 0.065mmol) was dissolved in dry CH2CI2 (ImL) under an argon atmosphere and cooled to 0°C. To this was added 80% m-chloroperoxy-benzoic acid (30mg, 0.14mmol); stirring was continued for 2 hours. The reaction was poured into aqueous NaHCθ ₃ and the product extracted into CH ₂ CI2. The organic layer was washed with brine and dried (MgSθ ₄ ). The product was purified by flash column chromatography (silica, 20% ethyl acetate in hexane) to give as a colorless solid: *H NMR (250MHz, CDCI3) δ 8.30 (s, IH, 2-phenyl), 8.23 (d, J=7.8Hz, IH, 4-phenyl), 7.80 (d, J=8.4Hz, IH, 4-naphthyl), 7.73 (d, J=8.4Hz, IH, 5-naphthyl), 7.63 (s, IH, 8-naphthyl), 7.50 (m, 4H, 5,6-phenyl, 1,6-naphthyl), 7.19 (d, J=8.4Hz, IH, 3-naphthyl), 4.82 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.49 (s, 2H, CH ₂ -S), 3.85 (s, 3H, methyl ester), 1.98 (broad singlet, IH, OH),

1.84 (m, 2H, CH ₂ ), 1.25 (m, 12H, aliphatic), 0.86 (t, J=6.8Hz, 3H, CH3).

3B.

3-f l -Dioxythia-2-(7-π -hvdroxynonvπ-2-naphthvPethvπbenzoic acid, lithium salt.

Methyl 3-[l -dioxythia-2-(7-(l -hydroxynonyl)-2-naphthyl)- ethyljbenzoate (27mg, 0.056mmol) was dissolved in tetrahydrofuran (0.40mL) and CH3OH (0.20mL) and treated with 1.0M LiOH (0.20mL, 0.20mmol). The reaction was stirred under an atmosphere of argon for 4 hours. The tetrahydrofuran and CH3O H were evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H ₂ O-CH3OH gradient). Lyophilization gave a colorless amorphous solid: Η NMR (250MHz, d ⁴ -CH ₃ OH) δ 8.47 (dd, J=1.6Hz, IH, 2-phenyl), 8.20 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 7.80 (d, J=8.4Hz, IH, 4-naphthyl), 7.72 (d, J=8.4Hz, IH, 5-naphthyl), 7.64

(s, IH, 8-naphthyl), 7.60 (s, IH, 1-naphthyl), 7.50 (m, 2H, 6-phenyl, 6-naphthyl), 7.40 (dd, J=7.8Hz, IH, 5-phenyl), 7.25 (d, J=8.4Hz, IH, 3-naphthyl), 4.76 (dd, J=6.8, 5.4Hz, IH, -CH-O), 4.65 (s, 2H, CH ₂ -S), 1.78 (m, 2H, CH ₂ ), 1.26 (m, 12H, aliphatic), 0.87 (t, J=6.8Hz, 3H, CH ₃ ); MS (FAB+): 475.2 (M+H), (FAB-): 473.2 (M-H).

Example 4 3-ri -Oxa-2-r7-d -hydroxynonyl -2-naphthyl)ethyllbenzoic acid. sodium salt

4A. Methyl 3-ri-oxa-2-(7-( l-t-butyldimethylsilyloxynonyπ-2- naphthyPethyll benzoate.

7-(l-t-Butyldimethylsilyloxynonyl)-2-bromomethyl- naphthalene (150mg, 0.314mmol) and methyl 3 -hydroxybenzoate (72mg, 0.471mmol) were dissolved in dry dimethylformamide

(1.2mL) and treated with anhydrous K ₂ CO ₃ (87mg, 0.63mmol). The reaction was heated at 60° C for 1 hour under an atmosphere of argon. Upon cooling to room temperature the reaction mixture was diluted with E-2O and washed with H ₂ O and brine and dried (MgS0 ₄ ). The product was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) to give a pale yellow oil: ⁱ H NMR (250MHz, CDCI3) δ 7.86 (dd, J=1.6Hz, IH, 2-phenyl), 7.78 and 7.65 (multiplets, 5H total, 6-phenyl, 1,4,5,8-naphthyl), 7.52 (m, 2H, 3,6-naphthyl), 7.36 (dd, J=7.8Hz, IH, 5-phenyl), 7.20 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 5.26 (s, 2H, CH ₂ -0), 4.79 (dd, J=6.8, 5.4Hz, IH, -CH-O), 3.92 (s, 3H, methyl ester), 1.70 (m, 2H, CH2), 1.24 (m, 12H, aliphatic), 0.90 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH3), 0.046 and -0.14 (singlets, 6H total, Me2).

4B. Methyl 3-ri-oxa-2-r7-α -hydroxynonvn-2-naphthynethyl1- benzoate.

Tetrabutylammonium fluoride (ImL, l.Ommol; 1.0M solution in tetrahydrofuran) was added to a stirred solution of methyl 3-[l-oxa-2-(7-(l -t-butyldimethylsilyloxynonyl)-2-naphthyl)ethyl]- benzoate (155mg, 0.282mmol) in tetrahydrofuran (0.5mL) under an argon atmosphere. After 1.5 hours the reaction was diluted with Et2θ and washed with aqueous NH ₄ CI and brine and dried (MgSθ4). The product was purified by flash column chromatography (silica, 15% ethyl acetate in CH2CI2) to give a colorless solid: ^l R NMR (250MHz, CDCI3) δ 7.85 (dd, J=1.6Hz, IH, 2-phenyl), 7.80 and 7.65

(multiplets, 5H total, 6-phenyl, 1,4,5,8-naphthyl), 7.52 (m, 2H, 3,6-naphthyl), 7.35 (dd, J=7.8Hz, IH, 5-phenyl), 7.19 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 5.25 (s, 2H, CH ₂ -0), 4.80 (dd, J=6.8, 5.4Hz, IH, -CH-O), 3.91 (s, 3H, methyl ester), 1.91 (s, IH, OH), 1.82 (m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.86 (t, J=6.8Hz, 3H, CH ₃ ); Analysis calculated for C28H3 ₄ O ₄ : C, 77.39; H, 7.89; found: C, 77.09; H, 8.26; MS (CI): 452(M+NH ₄ ).

4C. 3-1 ^" l -Oxa-2-.7-d -hydroxy nonyl , -2-naphthyl ethyllbenzoic acid. sodium salt.

Methyl 3-[ l -oxa-2-(7-( l -hydroxynonyl)-2-naphthyl)- ethyl] benzoate (65mg, 0.15mmol) was dissolved in tetrahydrofuran (0.90mL) and CH ₃ OH (0.45mL) and treated with 1.0M LiOH (0.45mL, 0.45mmol). The reaction was stirred under an atmosphere of argon for 6 hours. The reaction solution was diluted with E_2θ and washed with 5% HCl (aqueous phase pH~l). The organic phase was washed with H ₂ O and brine and dried (MgS0 ₄ ). After removing the solvent the crude acid was dissolved in aqueous Na2C03 (1.5mL, 3 equiv. Na ₂ Cθ ₃ ). The product was then purified by Reversed Phased MPLC (RP-18 silica, H ₂ O-CH ₃ OH gradient). Lyophilization gave a colorless amorphous solid: iH NMR (250MHz, d -CH30H) δ 7.91 (s, IH, 8-naphthyl), 7.84 and 7.83 (doublets, J=8.4Hz, 2H total, 4,5-naphthyl), 7.77 (s, IH, 1-naphthyl), 7.67 (dd, J=1.6Hz, IH, 2-ρhenyl), 7.53 (m, 3H, 6-phenyl, 3,6-naphthyl), 7.26 (dd, J=7.8Hz, IH, 5-phenyl), 7.08 (ddd, J=7.8, 1.6Hz, IH, 4-phenyl), 5.26 (s, 2H,

CH2-O), 4.75 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.81 (m, 2H, CH ₂ ), 1.26 (m, 12H, aliphatic), 0.87 (t, J=6.8Hz, 3H, CH3); MS (FAB+): 443.3 (M+H), (FAB-): 419.4 (M-Na).

Example 5

7-f l -HydroxynonyP-2-naphthalene carboxylic acid, lithium salt

5A. 7-d -t-Butyldimethylsilyloxynonvπ-2-naphthalene carboxylic acid. 7-(l -t-Butyldimethylsilyloxynonyl)-2-hydroxymethyl- naphthalene (200mg, 0.482mmol) was dissolved in anhydrous dimethylformamide (2.0mL) and treated with pyridinium dichromate (550mg, 1.46mmol) under an atmosphere of argon. After 18 hours the reaction mixture was diluted with ethyl acetate and washed with H2O and brine and dried (MgS04). The product

was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to give a tan solid: ^l K NMR (250MHz, CDCI3) δ 8.69 (s, IH, 1 -naphthyl), 8.09 (d, J=8.4Hz, IH, 3-naphthyl), 7.90 (d, J=8.4Hz, IH, 4-naphthyl), 7.86 (d, J=8.4Hz, IH, 5-naphthyl), 7.84 (s, IH, 8-naphthyl), 7.61 (d, J=8.4Hz, IH, 6-naphthyl), 4.82 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.72 (m, 2H, CH ₂ ), 1.24 (m, 12H, aliphatic), 0.91 (s, 9H, t-butyl), 0.86 (t, J=6.8Hz, 3H, CH3), 0.062 and -0.13 (singlets, 6H total, Me2).

5B. 7-d -Hydroxynonyl ^' )-2-naphthalene carboxylic acid, lithium salt.

To a flask containing 7-(l-t-butyldimethylsilyloxynonyl)-2- naphthalene carboxylic acid (146mg, 0.34mmol) was added tetrahydrofuran (0.68mL), H2O (0.68mL), and acetic acid (2.0mL). The starting material precipitated out of solution; tetrahydrofuran was then added until the solution just became homogeneous. The reaction solution was heated at 65° C for 4 hours. Upon cooling to room temperature the reaction was diluted with ethyl acetate and washed several times with H2O followed by brine and dried _, (MgS0 ₄ ). After concentrating the crude acid was dissolved in IM LiOH (ImL) and purified by Reversed Phased MPLC (RP-18 silica, H2O-CH3OH gradient). Lyophilization provided a colorless amorphous solid: *H NMR (250MHz, d4-CH ₃ OH) δ 8.45 (s, IH, 1-naphthyl), 8.02 (d, J=8.4Hz, IH, 3-naphthyl), 7.85 (m, 3H, 4,5,8-naphthyl), 7.53 (d, J=8.4Hz, IH, 6-naphthyl), 4.76 (dd, J=6.8, 5.4Hz, IH, -CH-O), 1.82 (m, 2H, CH ₂ ), 1.26 (m, 12H, aliphatic), 0.87 (t, J=6.8Hz, 3H, CH3); MS (FAB): 327.1 (M+Li).