CA2138631A1 - 6,8 dioxabicyclo¬3.2.1|octanes as inhibitors of leukotriene biosynthesis - Google Patents

Abstract

Compounds having the formula I:

(see fig.I) are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, antiallergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.

Description

TITLE OF THE INVENTION
6,8-DIOXABICYCLO[3.2.1]0CTANES AS INHIBITORS OF
LEUKOTRIENE BIOSYNl~ESIS

The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. The major leukotrienes are Leukotriene B4 (abbreviated as LTB4), LTC4, LTD4, and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various diseases states are also discussed in the book by Rokach.
European patent application 375,404 (27 June 1990) describes certain naphthalene cont~ining heterocyclic ethers of structure A which are inhibitors of the enzyme 5-lipoxygenase. EP 375,452 (27 June 1990) describes naphthalene containing hydrocarbon ethers of structure B which are reported to possess the same activity. EP 462,830 (27 December 1991) describes bicyclic heterocycle-cont~ining hydrocarbon ethers of structure C which are reported to possess the same activity. All these series of prior art compounds differ significantly from the present invention in that they lack the aryl substituent of the present compounds.
A series of natural products known as the justicidins are referred to in the Merck Index, l 1th edition, 1989, no. 5154. The justicidins differ considerably from the present compounds in that they lack the large pyranylphenyl group.

21~85:31 Ar1-A1 O-Ar2 c lR2 A EP 375,404 R3 ICI-Pharma Ar1-A1_o-Ar2-c-l 2 B EP 375,452 Ar1-A1-o-Ar2-c-R2 ICI-Pharma CH30~ Justicidins, 1l 1 ~ Merck Index CH30/~ 0 No. 5154 201~1~
o~o SUMMARY OF THE INVENTION
The present invention relates to heteroarylnaphthalenes having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to methods and ph~rm~ceutical formulations for using these compounds in m~mmAl~ (especially humans).
Because of their activity as leukotriene biosynthesis 3 ~ inhibitors, the compounds of the present invention are useful as anti-asthmatic, anti-allergic, anti-infl~mm~tory, and cytoprotective agents.
They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.

21386~1 - 3 - l9l 58 DETAILED DESCRIP~ION OF THE INVENTION
The compounds of the present invention may be represented by the following formula I:

~f R10~A 2 wherein:

Rl and RS is each independently H, OH, lower alkyl, or lower alkoxy;
R2 is H, or lower alkyl;
R3 is H, OH, lower alkyl, lower alkoxy, lower alkylthio, F or CF3;
R4 is lower alkyl, F, CF3 or together with R3 forms a double-bonded oxgen (=0), or together with R3 forms a saturated carbon ring of 3 to 8 members;
R6 is H or lower alkyl, or two R6 groups attached to the same carbon may form a saturated ring of 3 to 8 members;
R7 is H, OH, lower aLkyl, lower aLkoxy, lower alkylthio, lower alkylcarbonyloxy~ or O-RlS;
R8 is H, halogen, lower alkyl, hydroxy, lower alkoxy, CF3, CN, or CORl3;
R9 is H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, (R8)2-phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO2, CF3, N3, N(Rl2)2, NRl2CoRl3 NR12CON(R12)2, SR14, S(o)R14, S(0)2R14, - 213~631 S(0)2N(R12)2, CoR13, CON(R12)2, Co2Rl3~
C(R1 3)20C(CR1 3)2-Co2Rl 3, C(R1 3)2CN, or halogen;
R10 and R11 iS each independently H, lower alkyl, lower aL~oxy, hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkylthio lower alkyl, (R8)2-phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO2, CF3, N3, NR13R16, NR16coR13, NRl6coNRl3Rl6~ SR14, S(o)R14, S(0)2R14, S(0)2NR13R16, CoR13, CoNR13R16, Co2Rl3~ C(R13)20C(CR13)2-Co2R13, C(R13)2CN, halogen, C(R13)2NR16CoR13~ or C(R1 3)2NRl 6-CON(R1 3)2;
R12 is H or lower alkyl, or two R12 groups attached to the same nitrogen may form a saturated ring of 5 or 6 members, optionally cont2ining a second heteroatom chosen from O, S or NR2;
R13 is H or lower alkyl;
R14 is lower alkyl, CF3, or phenyl-(R8)2;
20 R15 is carboxy lower aL~ylcarbonyl, pyridylcarbonyl, hydroxy lower alkylcarbonyl, polyoxa lower alkylcarbonyl, a functionalized or unfunctionalized derivative of a standard amino acid, or a benzoyl group substituted by CH2N(R12)2;
25 R16 is H, lower alkyl, or ORl 3;
xl and X4 is each independently O or S;
x2 is ~' S, C(R6)2, or a bond;
X3 is C(R6)20, OC(R6)2 or S;
Ar1 is arylene-(R8)2, wherein arylene is a 5-membered aromatic ring containing one O and 0-2 N, one S and 0-2 N, or 1-3 N; a 6-membered aromatic ring cont~ining 0-3 N; 2- or 4-pyranone; or 2- or 4-pyridinone;
Ar2 is aryl-(R9)2 wherein aryl is a 5-membered aromatic ring cont~ining one O and 0-3 N, one S and 0-3 N, or 1-4 N; a 6-membered aromatic ring cont~ining 0-3 N; 2- or 4-21~631 pyranone; 2- or 4-pyridinone; or a bicyclic 8-, 9-, or 10-membered aromatic ring wherein 0-2 carbon atoms are replaced by either O or S or a combination thereof and 0-3 carbon atoms are replaced by N;
Ar2 iS attached to either ring of the naphthalene ring system;
mis Oor 1; and n is 1 or 2;
or a pha~naceutically acceptable salt thereof.

A preferred embodiment of the present invention is represented by Formula Ia:

R3~r1_X~_ CN
R4 Ar la wherein:
R3 is H or CH3;
R4 is CH3;
R7 is OH or OCH3;
Ar1 is 6,2-Pye, 3-Phe or 3-(5-F-Phe);
Ar2 is 3-Fu, 3-Th or Ph;
X3 is CH20, OCH2 or S.

DEFINITIONS

The following abbreviations have the indicated meanings:

Ac = acetyl Bn = benzyl i-Pr = isopropyl - 21386'3 1 n-Pr = normal propyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butyl Et = ethyl Fu = 2- or 3-furyl Me = methyl Ph = phenyl Py = 2-, 3-, or 4-pyridyl Th = 2- or 3-thienyl Tz = 2-, 4-, or 5-thiazolyl Tf = trifluoromethanesulfonyl AIBN = azoisobutyronitrile Bu4NF = tetra-n-butylammonium fluoride CH2N2 = diazomethane CSA = camphorsulfonic acid DCC = 1,3-dicyclohexylcarbodiimide DDQ = 2,3-dichloro-5,6-dicyano- 1 ,4-benzo-2 o quinone DHP = 3,4-dihydro-2H-pyran DIBAL-H = diisobutylaluminum hydride DIPHOS = 1,2-Bis(diphenylphosphino)ethane DMAP = 4-dimethylaminopyridine DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide Et3N = triethylamine LDA = lithium diisopropylamide Ms = methanesulfonyl = mesyl Phe = benzenediyl Pye = pyridindiyl Pym = pyrimidinyl PCC = pyridinium chlorochromate RLA = radioimmuno assay - 21~86~1 r.t. = room temperature Super-Hydride = lithium triethylborohydride t-BOC = tertiary butyloxy carbonyl Tet = lH (or 2H)-tetrazol-5-yl TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran TMSCl = chlorotrimethylsilane Ts = p-toluenesulfonyl = tosyl Tze = thiazoldiyl Alkyl is intended to include linear, branched, and cyclic structures and combinations thereof.
The term "alkyl" includes "lower alkyl" and extends to cover carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclopentylmethyl, cyclododecyl, ~ m~ntyl, and the like.
The term "lower alkyl" means those alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentylmethyl, cyclohexyl, and the like.
The term "lower alkoxy" means those aLkoxy groups of 2s from 1 to 7 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
"Lower alkylcarbonyl" means alkylcarbonyl groups of 30 from 1 to 8 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkylcarbonyl groups are formyl, acetyl, 2-methylbutanoyl, cyclohexylacetyl, etc. By way of illustration, the 2-methylbutanoyl group signifies -C(O)CH(CH3)CH2CH3.
"Lower alkylcarbonyloxy" means alkylcarbonyloxy groups of from 1 to 8 carbon atoms of a straight, branched or cyclic 21~86~ 1 configuration. Examples of lower alkylcarbonyloxy groups are formyloxy, acetyloxy, 2-methylbutanoyloxy, cyclohexylacetyloxy, and the like. By way of illustration, the 2-methylbutanoyloxy group signifies -OC(O)CH(CH3)CH2CH3 .
"Carboxy lower alkylcarbonyl" means the group -C(O)(CH2)pCO2H, wherein p is 0 to 6.
"Hydroxy lower alkylcarbonyl" means the group -C(O)(CH2)p-OH, wherein p is 1-6.
"Hydroxy lower alkyl" means a lower alkyl group carrying a hydroxy group; e.g., -CH2CH(OH)CH2CH3.
"Lower alkoxy lower alkyl" means a lower alkyl group carrying a lower alkoxy group; e.g., -CH2CH2OCH3.
"Lower alkylthio" means alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, ethylthio, isopropylthio, cyclobutylthio, and the like.
"Lower alkylthio lower alkyl" means a lower alkyl group carrying a lower alkylthio group; e.g., -CH2CH2S-c-Pr.
"Lower alkylthio lower alkylcarbonyl" means a lower alkylcarbonyl group carrying a lower alkylthio group; e.g., -COCH2SCH2CH3.
"(R8)2-phenylthio lower alkyl" means a lower alkyl group carrying phenylthio group which in turn carries two R8 substituents;
e.g., -CH2CH2S-Ph4-CN.
The term "standard amino acid" means the following amino acids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. (See F.H.C. Crick, Symposium of the Society of Experimental Biology, 1958 (12), p. 140). Examples of R15 derived from standard amino acids are C(O)(CH2)q-N(R12)2, -C(O)CH(NH-t-BOC)(CH2)qCO2H~ and ~C(O)CH(N(R12)2)(CH2)qCO2R13~ wherein q is 1 or 2.

21~85~ 1 Examples of saturated rings which may be formed by two R12 groups attached to the same nitrogen are pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine, and N-lower alkyl piperazine.
s Examples of "arylene" (Ar1) are furan, thiophene, oxazole, thiazole, 1,3,4-oxadiazole, 1,3,4-thi~ 7ole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyrrole, imidazole, 1,3,4-triazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, and 1 ,3,5-triazine.
Examples of "aryl" (Ar2) are furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,5-oxadiazole, 1,2,5-thiadiazole, pyrrole, pyrazole, imidazole, 1,3,4-triazole, tetrazole, benzene, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, thieno[2,3-b]furan, thieno[3,2-b]pyrrole, indole, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzo[2,1,3]thiadiazole, furano[3,2-b]pyridine, naphthalene, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, phth~l~7ine, 1,8-naphthyridine, and the like.
Halogen includes F, Cl, Br, and I.
It is intended that the definitions of any substituent (e.g., R6, R12, etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, C(R6)2 represents CH2, CHCH3, C(CH3)2, etc.

Optical Isomers - Diastereomers - Geometric Isomers Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and ph~ ceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

- 213863~

Salts The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~ ceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from ph~rm~Geutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenecli~mine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylene~ mine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometh~mine and the like.
When the compound of the present invention is basic, salts may be prepared from ph~rm~Geutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

2138 63 t It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

5 Utilities The ability of the compounds of Formula I to inhibit biosynthesis of the leukotrienes makes them useful for preventing or reversing the symptoms induced by the leukotrienes in a human subject.
This inhibition of the m~mm~ n biosynthesis of leukotrienes indicates that the compounds and ph~rm~Geutical compositions thereof are useful to treat, prevent, or ameliorate in m~mm~l~ and especially in hllm~n~:
1) pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) infl~mm~tion such as arthritis or infl~mm~tory bowel disease, 4) pain, 5) skin disorders such as psoriasis, atopic eczema, and the like, 6) cardiovascular disorders such as angina, formation of atherosclerotic plaques, myocardial ischemia, hypertension, platelet aggregation and the like, 7) renal insufficiency arising from ischaemia induced by imlllullological or chemical (cyclosporin) etiology and 8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10) hepatitis resulting from chemical, immunological or infectious stimuli, 11) trauma or shock states such as burn injuries, endotoxemia and the like, 12) allograft rejection, 13) prevention of side effects associated with therapeutic ~lmini~tration of cytokines such as Interleukin II and tumor necrosis factor, 14) chronic lung diseases such as cystic fibrosis, bronchitis and other small- and large-airway diseases, 15) cholecystitis, and 16) multiple sclerosis.
Thus, the compounds of the present invention may also be used to treat or prevent m~mm~ n (especially, hllm~n) disease states such as erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm;
premature labor; spontaneous abortion; dysmenorrhea; ischemia;
noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal ll~m~3~e caused by hepatoxic 2138fi31 agents such as CC14 and D-galactosamine; ischemic renal failure;
disease-induced hepatic damage; bile salt induced pancreatic or gastric ~m~ge; trauma- or stress-induced cell ~1~m~ge; and glycerol-induced 5 renal failure. The compounds also act as inhibitors of tumor metastasis and exhibit cytoprotective action.
The cytoprotective activity of a compound may be observed in both ~nim~l~ and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-infl~mm~tory drugs on the gastrointestinal tract, ~nim~l studies show that cytoprotective compounds will prevent gastric lesions induced by oral a-lmini~tration of strong acids, strong bases, ethanol, hypertonic saline solutions, and 15 the like.
Two assays can be used to measure cytoprotective ability.
These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,684.

20 Dose Ranges The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of atlmini~tration. It will also vary according 25 to the age, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-infl~mm~tory use and generally, uses other than cytoprotection, lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a m~mm~l, preferably 0.01 mg to about 10 mg per kg, and most 30 preferably 0.1 to 1 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
For use where a composition for intravenous lmini~tration is employed, a suitable dosage range for anti-asthmatic, anti-infl~mm~tory or anti-allergic use is from about 0.001 mg to about - 213~31 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
In the case where an oral composition is employed, a suitable dosage range for anti-asthmatic, anti-infl~mm~tory or anti-allergic use is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day.
For the treatment of diseases of the eye, ophth~lmic preparations for ocular a~lmini~tration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
The exact amount of a compound of the Formula I to be used as a cytoprotective agent will depend on, inter alia, whether it is being ~lmini~tered to heal ~l~m~ged cells or to avoid future ~l~m~ge, on the nature of the cl~m~ged cells (e.g., gastrointestinal ulcerations vs.
nephrotic necrosis), and on the nature of the causative agent. An example of the use of a compound of the Formula I in avoiding future ~l~m~ge would be co-~-lmini~tration of a compound of the Formula I
with a non-steroidal anti-infl~mmatory drug that might otherwise cause such tl~m~ge (for example, indomethacin). For such use, the compound of Formula I is a-lmini~tered from 30 minutes prior up to 30 minutes after ~mini~tration of the NSAID. Preferably it is a~lmini~tered prior to or simultaneously with the NSAID, (for example, in a combination dosage form).

Ph~rm~ceutical Compositions Any suitable route of a-lmini~tration may be employed for providing a m~mm~l, especially a hllm~n with an effective dosage of a 213~31 compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~ ceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophth~lmic), pulmonary (nasal or buccal inh~l~tion), or nasal ~lministration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For ~lrninistration by inh~l~tion, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inh~l~tion is a metered dose inh~l~tion (MDI) aerosol, which may be formulated as a suspension or solution of compound I in suitable propellants, such as fluorocarbons or hydrocarbons.
3 0 Suitable topical formulations of Compound I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for ~lrnini~tration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of ~(lmini~tration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be ~ ini~tered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; and 4,008,719, the disclosures of which are hereby incorporated herein by reference.
Ph~rm~ceutical compositions of the present invention suitable for oral ~tlmini~tration may be presented as discrete units such as capsules, cachets or tablets each cont~ining a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intim~tely admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired - 21~863~

presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.5 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 2.5 to about 500 mg of the active ingredient.
The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:

Injectable Suspension (I.M.) m~/mL
Compound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 BenzaL~onium chloride 1.0 Water for injection to a total volume of 1 mL

Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Povidone 14.0 Pregel~tini7ed Starch 43.5 Magnesium Stearate 2.5 Capsule mg/capsule Compound of Formula I 25 Lactose Powder 573.5 Magnesium Stearate 1.5 Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg Trichlorofluoromethane, NF 4.025 gm Dichlorodifluoromethane, NF 12.15 gm Combinations with other drugs In addition to the compounds of Formula I, the ph~rm~ceutical compositions of the present invention can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-infl~mm~tory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient.
Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I
and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
NSAlDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;
(4) the oxicams; and (5) the biphenylcarboxylic acid derivatives, or a ph~ ceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flulbil~rofen, ibuprofen, indoprofen, 21386~1 .

ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen. Structurally related propionic acid derivatives having similar analgesic and anti-infl~mm~tory properties are also intended to be included in this group.
Thus, "propionic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-infl~mm~tory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO-Na+ or -CH2CH2COO~Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
The acetic acid derivatives which may be used comprise:
indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac. Structually related acetic acid derivatives having similar analgesic and anti-infl~mm~tory properties are also intended to be encompassed by this group.
Thus, "acetic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a ph~rm~ceutically acceptable salt group, e.g. -CH2COO~Na+), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise:
flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid. Structurally related fenamic acid derivatives having similar analgesic and anti-infl~mm~tory properties are also intended to be encompassed by this group.
Thus, "fenamic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-infl~mm~tory drugs which contain the basic structure:

- 21386~ 1 ~NH~
COOH

which can bear a variety of substituents and in which the free -COOH
group can be in the form of a ph~rm~ceutically acceptable salt group, e.g., -COO-Na+.
The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal. Structurally related biphenyl-carboxylic acid derivatives having similar analgesic and anti-infl~mm~tory properties are also intended to be encompassed by this group.
Thus, "biphenylcarboxylic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-infl~mm~tory drugs which contain the basic structure:

~3 ~COOH

which can bear a variety of substituents and in which the free -COOH
group can be in the form of a ph~rm~ceutically acceptable salt group, e.g., -COO~Na+.
2 5 The oxicams which can be used in the present invention comprise: isoxicam, piroxicam, sudoxicam andtenoxican. Structurally related oxicams having similar analgesic and anti-infl~mm~tory properties are also intended to be encompassed by this group.
Thus, "oxicams" as defined herein are non-narcotic analgesics/non-steroidal anti-infl~mm~tory drugs which have the general formula:

- 21~86~1 OH O

~C H3 (~)2 wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used: amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine, beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fis~l~mine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofen~m~te, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofen~m~te sodium, meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide HCl, tifl~mi7ole, timegadine, tolpadol, tryptamid, and ufen~m~te.
The following NSAIDs, designated by company code number (see, e.g., Pharmaprojects), may also be used:
480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102, PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1- indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770.

- 213~6~1 Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and ph~rm~ceutically acceptable salts thereof.
In addition to indomethacin, other preferred NSAIDs are 5 acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin.
Pharmaceutical compositions comprising the Formula I
compounds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP
115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP
140,709 (May 8, 1985), which are hereby incorporated herein by reference.
The compounds of the Formula I may also be used in combination with leukotriene antagonists such as those disclosed in EP
106,565 (April 25, 1984) and EP 104,885 (April 4, 1984) which are hereby incorporated herein by reference and others known in the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No.
2,058,785 (April 15, 1981), which are hereby incorporated herein by reference.
Pharmaceutical compositions comprising the Formula I
compounds may also contain as the second active ingredient, prostaglandin antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane antagonists such as those disclosed in U.S. Pat. 4,237,160. They may also contain histidine decarboxylase inhibitors such as a-fluoromethylhistidine, described in U.S. Pat.
4,325,961. The compounds of the Formula I may also be advantageously combined with an Hl- or H2-receptor antagonist, such as for instance acetamazole, aminothi~ 7.01es disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, fr~m~mine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508. The ph~rm~ceutical compositions may also contain a K+/H+

~ 21~631 ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of Formula I may also be usefully combined with most cell stabilizing agents, such as 1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane and related compounds described in British Patent Specifications 1,144,905 and 1,144,906. Another useful ph~ ceutical composition comprises the Formula I compounds in combination with serotonin antagonists such as methysergide, the serotonin antagonists described in Nature, Vol. 316, pages 126-131, 1985, and the like. Each of the references referred to in this paragraph is hereby incorporated herein by reference.
Other advantageous pharmaceutical compositions comprise the Formula I compounds in combination with anti-cholinergics such as ipratropium bromide, bronchodilators such as the beta agonist salbutamol, metaproterenol, terbutaline, fenoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipine, etc. and the corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like.

Methods of Synthesis Compounds of the present invention can be prepared according to the following methods. Temperatures are in degrees 25 Celsius. The substituents are the same as in Formula I except where de~ned otherwise.

2138~31 Scheme I
One method for the synthesis of naphthol intermediates (Method A) is outlined in Scheme I. A 4-aryl-4-oxobutanoic acid III, on heating with acetic anhydride and NaOAc, is transformed into the corresponding enol lactone, which condenses in situ with an aldehyde II
to afford lactone IV. Upon refluxing in a mixture of glacial AcOH and concentrated HCl, transformation to naphthoic acid V occurs. Heating with pyridine hydrochloride then affords the free naphthol VI.
Scheme II
In the preparation of naphthol intermediates via Method B, an aldehyde of type II is initially condensed with a succinic acid diester VII, in the presence of an alkoxide such as LiOMe, with the corresponding alcohol (MeOH) as solvent, to afford a 3-carbalkoxy-4-phenyl butenoic acid vm. This material, on treatment with TFAA in the presence of NaOAc in a solvent such as CH2C12, cyclizes to the naphthoic ester IX. The trifluoroacetyl group is cleaved by treatment with an inorganic base such as K2CO3 in a polar solvent such as MeOH, to afford phenol X which is transformed, using trifluoromethane 20 sulfonic anhydride, in the presence of an amine such as Et3N, in a neutral solvent such as CH2C12, to the corresponding triflate XI.
Alternatively, treatment of VIII with Tf20, with or without a suitable solvent such as CH2C12, affords triflate XI directly. Cross coupling of this material with an aryl lithium species (resulting from reaction of an aryl halide (Br or I) with an alkyl lithium such as n-BuLi in a mixture of THF-hexane), in the presence of trimethyl borate and catalyzed by a Pd(0) species such as (Ph3P)4Pd, in a n~i~lule of THF and water as solvent, affords the 1-aryl-3- naphthoic ester XII. Where Rl = methyl, this material, on heating with pyridine hydrochloride, affords naphthol 3 ~ acid VI which is esterified, such as by treatment with CH2N2, to the corresponding methyl ester XV (R2 = Me). Where R1 = benzyl, the benzyl group is removed by heating in a mixture of TFA and thioanisole, to afford naphthol ester XV. Alternatively, alkoxy naphthoic ester XII can be transformed to the corresponding nitrile XIII

21~8631 by initial reaction with dimethyl aluminum amide, in a high-boiling solvent such as toluene, producing an intermediate amide which is converted to the nitrile using a dehydrating agent such as TFAA.
Subsequent transformation to the phenol XIV is effected using, whether R1 is methyl or benzyl, the appropriate method as described above for the preparation of naphthol ester XV.

Scheme m An alternative method for the preparation of naphthols of type VI, XIV, and XV is outlined in Scheme III. The intermediate 3-carbalkoxy-4-phenyl butenoic acid vm from Scheme II is reduced, by hydrogenation over a noble metal catalyst such as palladium, in a solvent such as acetic acid, to the corresponding butanoic acid XVI.
This material is cyclized, using a dehydrating agent such as TFAA in the presence of NaOAc, to the tetralone ester XVII. Condensation of this material with an aryl magnesium halide or an aryl lithium species, in an ethereal solvent such as diethyl ether, affords an intermediate tertiary alcohol and/or the corresponding lactone; the crude product, on refluxing in an inert solvent such as benzene in the presence of a strong acid such as CSA, affords the dihydro naphthoate XVlII which is dehydrogenated, using an oxidant such as DDQ in an inert solvent such as benzene, to the naphthoate xn. Transformation to the naphthols VI, XIV, and XV is effected as described in Scheme II.

Scheme IV
This scheme outlines the preparation of several other types of naphthol interrnediates. The 3-carboxy-6-naphthol VI from Scheme 1 is decarboxylated by heating with metallic copper in a high-boiling solvent such as quinoline, to afford naphthol XIX. Alternatively, coupling of VI with an alkyl lithium species, in an ethereal solvent such as diethyl ether, affords ketone derivatives XX, which can be reduced by hydrogenation over a noble metal catalyst such as palladium, to the corresponding alkyl analogs XXI. Esterification of naphthol acids VI, in an alcoholic solvent in the presence of an acid, such as gaseous HCl, 21~8~

leads to esters XXII. These esters can be converted to the corresponding amides XXIII, by reaction with an alulni~ amide species in a solvent such as toluene. Esters XXII can be transformed, by the procedure described in Scheme II for the conversion of XII to XIII, to nitriles XIV. Conversion to aldehydes XXIV is achieved through the use of an aluminum hydride reagent, such as DIBAL-H, in an inert solvent such as toluene. Reduction of acid VI or ester XXII, using an al~ hydride reagent such as DIBAL-H, in an ethereal solvent such as THF, produces alcohol XXV. This material is converted to the corresponding halide XXVI through the action of triphenyl phosphine in a halogenated solvent such as CC14 or CBrCl3. Coupling of this halide with a thioalkoxide, resulting from reaction of a thiol with a metal hydride such as NaH in a polar solvent such as DMF, generates sulfides XXVII.
Scheme V
The preparation of compounds of Formula I (wherein X3 =
-C(R6)20-) is described in Scheme V. A first method requires coupling of a naphthol XXIX (prepared according to Schemes I-IV) with a benzylic halide or activated alcohol xxvm (wherein X = Cl, Br, I, OMs, OTs) in a polar organic solvent such as DMF in the presence of an inorganic base such as Cs2CO3.
In an alternate procedure, naphthol XXIX is condensed with a benzylic alcohol xxvm (wherein X = OH) in the presence of a phosphine such as Ph3P and a azodicarboxylate diester, in a solvent such as THF, to afford Formula I compounds (wherein X3 = -C(R6)20-).

Scheme VI
The syntheses of several types of Formula I compounds are outlined in Scheme VI. An ester of type L~ (a sub-group of I (wherein X3 = -C(R6)20-))can be reduced, by treatment with an alllmimlm hydride reagent such as DIBAL-H, in a solvent such as a THF-toluene mixture, to the corresponding benzylic alcohol ID, which, on treatment with a metal hydride such as NaH in a solvent such as THF, with subsequent addition of an alkyl halide, (R2X), is converted to the alkoxy methyl derivative IG.
A similar alkylation of ID using a halo acid or ester (XC(R13)2Co2R13)~ in a polar solvent such as DMF in the presence of an inorganic base such as Cs2CO3, affords carbalkoxy methoxy methyl derivates of formula IH.
Esters LA can be hydrolyzed to the corresponding acids IB
by reaction with an inorganic alkali metal hydroxide, such as LiOH, in a polar solvent, such as a mixture of THF, MeOH and H2O, followed by acidification with an aqueous solution of a proton acid such as aq. HCl.
An acid of type IB is transformed, via condensation with an alkyl lithium species, R2Li, in an ethereal solvent such as Et2O, to the corresponding ketone IC which on reduction with a hydride reagent such as NaBH4, in a protic solvent such as ethanol, is converted to the secondary alcohol IF. In turn, this species can be alkylated, by treatment with a metal hydride such as NaH in a solvent such as THF, with subsequent addition of an alkyl halide, (R2X), to the alkoxy derivative L~. Compounds of formula IE are obtained by condensation of the ester IA with an alkyl Grignard or alkyl lithium species, R2Li, in an ethereal solvent such as Et2O.

Scheme VII
The synthesis of compounds of Formula I (wherein X3 =
-OCH2-) iS described in Scheme VII. The phenol XXIX may be converted to the triflate XXX by treatment with trifluoromethane-sulfonic anhydride in the presence of an organic base such as pyridine in a solvent such as CH2Cl2. Subsequent treatment of XXX in a solvent such as DMSO/methanol with an organic base such as triethylamine, a phosphine such as 1,1'-bis(diphenylphosphino)ferrocene and a palladium(II) salt such as palladium(II)acetate under an atmosphere of carbon monoxide will lead to the ester XXXI. The hydrolysis of the ester XXXI may be achieved using an inorganic base such as lithium hydroxide in water and the resulting acid XXXII may be reduced to the alcohol xxxm by treatment with a chloroformate such as isopropyl 2 1 3 ~

chloroformate in the presence of an organic base such as triethylamine in an organic solvent such as THF, followed by addition of a reducing agent such as sodium borohydride in water. The alcohol XXXIII may be then converted to the halide XXXIV by treatment with 5 triphenylphosphine, imidazole and CBr4 in an organic solvent such as CH2Cl2. Coupling of halide XXXIV with the appropriate phenol XXXV in an organic solvent such as DMF using an inorganic base such as K2CO3 provides compounds of formula I (wherein X3 = -OCH2-) of the present invention.

Scheme VIII
The preparation of compounds of Formula I (wherein R7 =
OR15) is outlined in Scheme VIII. The tertiary alcohol I (wherein R7 =
OH) can be converted to the acylated derivative I (wherein R7 = OR15) by treatment with the appropriate carboxylic acid in the presence of a dehydrating agent such as DCC and of an organic base such as DMAP in an organic solvent such as CH2Cl2. In the cases wherein the R15 group contains an ester functionality, this ester can be selectively hydrolyzed 20 under basic conditions. In the cases wherein the R15 group contains an amine functionality bearing a protecting group such as t- Boc, this group can be selectively removed under acidic conditions. In the cases where the R15 group contains an alcohol functionality bearing a protecting group such as tert-butyldiphenylsilyl, this group can be selectively removed by treatment with Bu4NF.

Scheme IX
The intermediate naphthol XXXIX may be prepared from 2-bromo-5-benzyloxy benzaldehyde dimethylacetal XXXVI as outlined 30 in Scheme IX. The bromo derivative XXXVI is converted to the alcohol XXXVII by treatment with a base such as n-butyl lithium in an organic solvent such as hexane followed by the addition of an aryl carboxaldehyde such as 3-furaldehyde in an organic solvent such as THF. The Diels-Alder reaction is achieved by heating the alcohol XXXVII in the presence of a Michael acceptor of type CH2=CH-E

'- 213862 1 (wherein E = CN, Co2Rl3~ CON(R12)2, N02, S(0)2R14, S(0)2N(R12)2, or CoRl3) in an organic solvent such as toluene, providing the nitrile compound xxxvm. The debenzylation process 5 to provide the naphthol intermediate XXXIX is described in Scheme II.

Scheme X
The naphthalene intermediate XLII may be prepared by using a naphthol such as XV or XXII where the phenol is converted to the trifluoromethanesulfonate using trifluoromethanesulfonic anhydride in the presence of an amine such as Et3N in a neutral solvent such as CH2C12. Reduction of the ester XL using an aluminum hydride such as DiBAL-H, in an ethereal solvent such as THF, produces the alcohol XLI. Subsequent treatment of XLI in a solvent such as DMSO/methanol 15 with an organic base such as triethylamine, a phosphine such as 1,1'-bis(diphenylphosphino)ferrocene and a palladium(II) salt such as palladium(II) acetate under an atmosphere of carbon moxoxide will lead to the naphthalene intermediate XLII.

20 Scheme XI
The preparation of the naphthol intermediate XLVI may be prepared starting from the corresponding naphthol XXII. The naphthol XXII is converted to the ester XLIV through the corresponding triflate XLm using the same procedure as described in Scheme X. The 25 ketoester XLIV is transformed to the corresponding acetate XLV via a Baeyer-Villager type reaction using an oxidant such as m-chloroperbenzoic acid in a refluxing organic solvent such as CHC13.
The corresponding acetate XLV is then transformed to the naphthol intermediate XLVI by a base treatment such as K2C03 in a protic 30 solvent such as methanol.

Scheme XII
The naphthalene intermediate XLVII may be prepared as outlined in Scheme XII. The naphthol XXXIX (from Scheme IX) is transformed using the same strategy as outlined in Scheme X. Using the - 2l3~63 l same starting material, the naphthol XXXIX is converted to the methyl ketone XLVm by first hydrolysis of the ester using an inorganic base such as NaOH in a solvent such as MeOH/H20. Then the corresponding acid is treated with methyl lithium in an ethereal solvent such as diethyl ether affording the ketone derivative XLVIII. This ketone is then subsequently converted to the naphthol XLIX using the same chemistry as described in Scheme XI.

Scheme XIII
The preparation of naphthol intermediates LIII and LIV
may be prepared using the same approach as described in Scheme IX.
The bromo derivative XXXVI is converted to the alcohol L by treatment with a base such as n-butyl lithium in an organic solvent such as hexane followed by the addition of formaldehyde. The Diels-Alder reaction is acheived by heating the alcohol L in the presence of a Michael acceptor of type Ar2CH=CH-E (wherein E = CN, Co2R
CON(R12)2, NO2, S(0)2R14, S(0)2N(R12)2, or CoR13) such as transmethylcinn~m~te in an organic solvent such as toluene providing the corresponding ester LI and Ln. The debenzylation process to provide the naphthol intermediates LIII and LIV is described in Scheme II.

Scheme XIV
The naphthalene intermediate LV may be prepared by using naphthol such as LIII and using the same protocol described in Scheme X. The naphthol intermediate LVII may be obtained from LIII
using the same protocol as described in Scheme XII.

Scheme XV
The naphthalene intermediate LVm may be obtained by using naphthol such as LIV and using the same protocol as described in Scheme X. The naphthol intermediate LX may be prepared from LIV
using the protocol described in Scheme XII.

21~6~ 1 Scheme XVI
The preparation of compounds of Formula I (wherein X3 =
-OCH2-) is described in Scheme XVI. The naphthalene LXI is condensed with a phenol XXXV in the presence of a phosphine such as 5 Ph3P and an azodicarboxylate diester, in a solvent such as THF to afford Formula I compounds (wherein X3 = -OCH2-).

2l38~3l -SCHEME I

PREPARATION OF NAPHTHOL INTERIIEDIATES (METHOD A) s o R~O~, CHO O AC2O, NsOAc R~O~
R10 V Ar2 ~ CO2H ~E~J ~<

(Rl~Me,CH2Ph) HCI, AcOH

15R10~ CO2H Pyr.HCI Rl~~ CO2H

V I Ar2 V Ar2 32213~63 19158 SCHEME n PREPARATION OF NAPHTHOL INTER~tEDlATES (l~iETHOD B) R~~~ CHO~ CO R Li, MeOH R10.33~ Co R2 I I Vll Vlll (R1~Me,CH2Ph)(R2-Lower Alkyl) TFAA, NaOAc e R'~~ CO2R2 K2CO3, MeOH R'~~ CO2R2 l 5 X OH IX OCOCF3 ~Tf20 Ar X, BuLi, R10~, (ph3p)4PdR~o?~ CO2R2 (R1-~e) HO~, CO2H

Xl OTf Xll ~r2 \ (R,.CH2ph) Vl Ar2 1) i~t-2AINH2 \~,A~Thi~ Ole 2) TFAA ~
25 HO ~ CN TFATi~ R10~ CN R~CO2R2 XIV Ar2 Xlll Ar2 XV Ar2 2138~ 1 SCHEME m PREPARATION OF NAPHTHOL INTERMEDIATES (METHOD C) MeO~ CO R2 H2 ,R10~ CO~R2 Vlll XVI
(FROM SCHEME 11) (R1=Me) TFAA, NaOAc (R2=Lower Alkyl) 1 ) Ar2M ~ X
or A~2L ~ ' 15UeO ~p, CO2R2 2) CSA Rl~~ CO2R2 XVIII Ar2 XVII O

DC)Q

(SEE SCHEME 11) Xll ~ Vl.XIV. XV
(SCHEME 11) 213863~
.

SCHEME IV

PREPARATION OF FURTHER NAPHTHOL INTERMEDIATES

HO?~
R1o ~ ~NAPH BELOW

NAPH-H ~ NAPH-CO2H ~ NAPH-COR2 ~ NAPH-CH2R2 XIX Vl XX XXI
(FROM SCHEME 1)(R2-Lower Alkyl) NAPH-C02R2 NAPH-CoN(R13)2 NAPH-CH20H
XXII XXIII XXV
(R2-Lower Alkyl) NAPH-CN ~NAPH-CHO NAPH-CH2X ~NAPH-CH2SRl4 XIV XXIV XXVI XXVII

2138~31 SCHEME V
PREPARATION OF FINAL PRODUCTS

3~ R1o~\~

XXVIII
(X=CI, Br, 1, OMs, OTs) Base; or (X=OH) R2O2CN=NC02R2, Ph3P

RC~A.

(Wherein X3=-C(R6)2o-) 213~5~1 SCHEME Vl PREPARATION OF FINAL PRODUCTS

Rl ~ Ar1C(R6)2 R4~ Q~= TNAPH BELO\~

15TNAPH-cO2R2 TNAPH-CO2H , TNAPH-COR2 (R2=lower alkyl) 20TNAPH-''H20H TNAPH-c(OH)(R2)2TNAPH-CH(OH)R2 ID \ IE IF

TNAPH-CH2oC(Rl3)2Co2R13 ~ IH
TNAPH-CH20R2 TNAPH-cH(OR2)R2 IG IJ

SCHEME VII
PREPARATION OF FINAL PRODUCTS

R10~ = NAPH BELOW

R11 is as defined in structures Vl, XIV, XV, and XIX-XXVII

HO-NAPH ~ TfO-NAPH , MeO2C-NAPH
XXIX XXX XXXI

BrCH2-NAPH ~ HOCH2-NAPH ~ HO2C-NAPH
XXXIV XXXIII XXXII

2 o \ R3 ~RA7r~OH
\R4~\ 4XR2 R'~

(Wherein X3 =-OCH2-) 21~ 8~3 1 SCHEME VIII
PREPARATION OF FINAL PRODUCTS

R~ R11 (Wherein R7= OH) R15-oH, DCC, DMAP

R4 ~ ;

(Wherein R7= oR15) - 21~863~

SCHEME IX

PREPARATION OF NAPHTHOL INTERMEDIATES (UETHOD D) i3nO~cH(OM~)2 1) n-i3uLii~nO CH(OMeh R~~ ~J~Br 2) Ar2 CHO R10~OH

10XXXVI XXXvII Ar2 ~E

R'~~p~ TFA, Thioani~olo EnO~'E

XXXIX A~2 XXXVIII Al2 2l3~63l SCHEME X

FURTHER PREPARATION OF NAPHTH~LENE IHTERUIEDIATES
s HO~_co2R, ~tO~~CO~R~ TtO~ CH20H
Rl~ ~J~ ~Rl~ ~J~ ~ Rl~

XL X Ll (FROM SCHEME 11) XXII
(FROM SCHEME IY) 5 R1~~CO~ 0p ~ç~CH20H

~,2 XLII

- 21~31 SCHEME XI

FURTHERPREPARATION OFNAPHTHOLINTERMEDIATES
s HO COR2 T10~COR2 ~02C ~,~COR2 R~~~p-- ~ Rl~ ,~ R'~ ,~

XXII XLIII ' XLIV
(FROM SCHEME IV) HO~ ~CO2Me bl-O2C ~OH ~02C ~OCOR2 15 R10--~W Rl~ ~J~ ~ R'~~
A~2 A,2 Ar2 XLVI XLV

- 21~63:1 SCHEME XII

FURTHER PREP~RATION OF N~PHTHALENE INTERMEDIATES

A~2 HO~ ~ Rl~Y~ HOCH2 ~

~CO2M- ~CH20H CO2~h Ar2 (SEE SCHEME X) Ar2 (FROM SCHEME IX) (~..... ... h~r~in E ~ CO2M~) 15 Ho~ ~o2c HO~
Rl~ ~l T 1 ~ Rl~ ll ¦ ¦ -- Rl~
~COM. ~OH --cO
~,2 (SEE SCHEME Xl) Ar2 XLVIII XLIX

21385~ 1 SCHEME xm PREPARATION OF NAPHTHOL INTERMEDIATES (METHOD E) Rlo~CH(OMe)2 1) n;BuLi Rl~~(oMeh X,~O~VI L

~,/ A~2 R10~A~2 R10~ Er2 Ll Lll TFA, Thio~n-~ol~

HO~ E HO~ Ar2 2 5 R~~--~A,2 Rl~ ~ E

Llll LIV

'- 213~531 SCHEME XIV

FURTHER PREPARATION OF NAPHTHALENE INTERI~'IEDIATES

HO~CO2Me ~O,C~X~C40H HOCH, 3~G~C02Me (SEE SCHEME X) ~ LV
(FROM SCHEME Xlll) (~.hcrL:n E ~ CO2Me) Rl~~COM- ~Ibo2c ~X~OH A" ~O~C02Mc (SEE SCHEME Xl) LVI LVII

21386? 1 SCHEME XV

FURTHER PREP~ RATION OF NAPHTHALENE INTERblEDlArES

Rl~~ ~ Rlo~,2 HOCH2 ~0~
CO2~h CH20H ~,2 CO2bh (SEE SCHEME X) (FROM SCHEME Xlll) (wh~roin E . CO2Me) 5 HO ~ 0~ r2 HO~o~

COM~ OH ~,2 CO2Me (SEE SCHEME Xl) LIX LX

SCHEME XVI
PREPARATION OF FINAL PRODUCTS

~/

LXI
XXXV
R2O2CN=NC02R2, Ph3P

~~ ~X~/ 10~ A~

(Wherein X3=-oCH2-) 2138~ ~

Representative Compounds Table I illustrates compounds of Formula Ia which are representative of the present invention.

TABLE I

Ar1 X

1~ rl~5l* B3 ~4 }~7 Arl Ar2 ~3 S,S Me Me OH 6,2-Pye 3-Fu CH20 2 R,R Me Me OH 6,2-Pye 3-Fu CH20 3 SR,SR Me Me OH 6,2-Pye 3-Fu CH20 2 o 4 S,S Me Me OMe 6,2-Pye 3-Fu CH20 S,S Me Me OH 6,2-Pye 3-Th CH20 6 S,S Me Me OH 6,2-Pye Ph CH20 7 S,R H Me OH 6,2-Pye 3-Fu CH20 8 S,R H Me OH 6,2-Pye 3-Th CH20 9 S,R H Me OH 6,2-Pye Ph CH20 S,S Me Me OH 3-Phe 3-Fu CH20 11 S,S Me Me OH 3-Phe 3-Fu OCH2 12 S,S Me Me OH 3-(5- 3-Fu OCH2 FPhe) 13 S,S Me Me OH 6,2-Pye 3-Fu OCH2 14 S,S Me Me OH 3-Phe 3-Fu S
S,S Me Me OH 6,2-Pye 3-Fu S
* Absolute stereochemistry is tentative 21386~

Assays for Determining Biological Activity Compounds of Formula I can be tested using the following assays to determine their m~mm~ n leukotriene biosynthesis inhibiting activity.

Human 5-Lipoxygenase Inhibitor Screen Objective of the Assay: The objective of the assay is to select agents which specifically inhibit the activity of human 5-lipoxygenase using a 100,000x g supern~t~nt fraction prepared from insect cells infected with recombinant baculovirus cont~ining the coding sequence for human 5-lipoxygenase. Enzyme activity is measured spectrophotometrically from the optimal rate of conjugated diene formation (A234) measured after the incubation of the enzyme with arachidonic acid in the presence of ATP, calcium ions and phosphatidylcholine .
Description of Procedure: The activity of 5-lipoxygenase is measured using a spectrophotometric assay and recombinant human 5-lipoxygenase as a source of enzyme. The 100,000x g fraction from 20 S19 cells infected with the recombinant baculovirus rvHSLO(8-1) containing the coding region sequence for human 5-lipoxygenase is prepared as described by Denis et al. (J. Biol. Chem., 266, 5072-5079 (1991)).The enzymatic activity is measured, using a spectrophotometric assay from the optimal rate of conjugated diene formation (A234) using 25 the procedure described by Riendeau et al. (Biochem. Pharmacol., 38, 2323-2321, 1989) with minor modifications. The incubation mixture contains 50 mM sodium phosphate pH 7.4, 0.2 mM ATP, 0.2 mM
CaC12, 20 ~M arachidonic acid (5 ,uL from a 100-fold concentrated solution in ethanol), 12 ,ug/mL phosphatidylcholine, an aliquot of the 30 100,000X g fraction (2-10 ~L) and inhibitor (0.5 ,uL final volume).
Inhibitors are added as 500-fold concentrated solutions in DMSO.
Reactions are initiated by the addition of an aliquot of the enzyme preparation and the rate of conjugated diene formation is followed for 2 minutes at room temperature. The reactions are performed in semi-micro cuvettes (0.7 mL capacity, 10 mm path length and 4 mm internal - 21386~

width). The absorbance changes are recorded with a Hewlett-Packard diode array spectrophotometer (HP 8452A) connected to the ChemStation using UV/VIS Kinetics Software (Hewlett-Packard).
Enzymatic activity is calculated from the optimal rate of the reaction by a linear fit of the variation of A234 during the first twenty seconds using the least square method for the equation A234=Vot + Ao where VO is the rate, t is the time and Ao is the absorbance at zero time. The results are expressed as percentages of inhibition of the reaction rate relative to controls cont~ining the DMSO vehicle.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay Rats under ether anesthesia are injected (i.p.) with 8 mL of a suspension of sodium caseinate (6 grams in ca. 50 mL water). After 15-24 hr. the rats are sacrificed (CO2) and the cells from the peritoneal cavity are recovered by lavage with 20 mL of buffer (Eagles MEM
containing 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells are pelleted (350x g, 5 min.), resuspended in buffer with vigorous sh~king, filtered through lens paper, recentrifuged and finally suspended in buffer at a concentration of 10 cells/mL. A 500 ,uL
aliquot of PMN suspension and test compound are preincubated for 2 mimltes at 37~C, followed by the addition of 10 ,uM A-23187. The suspension is stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an aliquot to a second 500 ~L portion of the PMN at 37~C. The LTB4 produced in the first incubation causes aggregation of the second PMN, which is measured as a change in light tr~n~mi~sion. The size of the assay aliquot is chosen to give a submaximal tr~n~mi~sion change (usually -70%) for the untreated control. The percentage inhibition of LTB4 formation is calculated from the ratio of transmission change in the sample to the tr~n~mi~sion change in the compound-free control.

Human Polymorphonuclear (PMN) Leukocyte LTB_ Assay A. Preparation of Human PMN. Human blood is obtained by antecubital venepuncture from consenting volunteers who 21385~31 have not taken medication within the previous 7 days. The blood is immediately added to 10% (v/v) trisodium citrate (0.13 M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNs are isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-Hypaque (specific gravity 1.077), as described by Boyum, A., Scand. J. Clin. Lab. Invest., 21 (Supp 97), 77, (1968). Cont~min~ting erythrocytes are removed by lysis following exposure to ammonium chloride (0.16 M) in Tris buffer (pH 7.65), and the PMNs resuspended at 5x 105 cells/mL in HEPES (15 mM)-buffered Hanks balanced salt solution cont~ining Ca2+ (1.4 mM) and Mg2+ (0.7 mM), pH 7.4. Viability is assessed by Trypan blue exclusion.

B. Generation and Radioimmunoassay of LTB4. PMNs (0 5 mL; 2.5 x 105 cells) are placed in plastic tubes and incubated (37~C, 2 min) with test compounds at the desired concentration or vehicle (DMSO, final concentration 0.2%) as control. The synthesis of LTB4 is initiated by the addition of calcium ionophore A23187 (final concentration 10 ,uM) or vehicle in control samples and allowed to proceed for 5 minutes at 37~C. The reactions are then termin~ted by the addition of cold methanol (0.25 mL) and samples of the entire PMN
reaction mixtme are removed for radioimmunoassay of LTB4.
Samples (50 ~lL) of authentic LTB4 of known concentration in radioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM; Thimerosal 0.025 mM;
gelatin 0.1%, pH 7.3) or PMN reaction mixture diluted 1:1 with RIA
buffer are added to reaction tubes. Thereafter [3H]-LTB4 (10 nCi in 100 ~lL RIA buffer) and LTB4-antiserum (100 ~L of a 1:3000 dilution in RIA buffer) are added and the tubes vortexed. Reactants are allowed to equilibrate by incubation overnight at 4~C. To separate antibody-bound from free LTB4, aliquots (50 ~L) of activated charcoal (3%
activated charcoal in RIA buffer containing 0.25% Dextran T-70) are added, the tubes vortexed, and allowed to stand at room temperature for 10 minutes prior to centrifugation (1500x g; 10 min; 4~C). The supernatants containing antibody-bound LTB4 are decanted into vials 21~863 1 and Aquasol 2 (4 mL) is added. Radioactivity is quantified by liquid scintillation spectrometry. The specificity of the antiserum and the sensitivity of the procedure have been described by Rokach et aL
Prostaglandins Leukotrienes and Medicine, 13, 21 (1984). The amount 5 of LTB4 produced in test and control samples is calculated. Inhibitory dose-response curves are constructed using a four-parameter algorithm and from these the ICso values determined.

Asthmatic Rat Assay Rats are obtained from an inbred line of asthmatic rats.
Both female (190-250 g) and male (260-400 g) rats are used.
Egg albumin (EA), grade V, crystallized and lyophilized, is obtained from Sigma Chemical Co., St. Louis. Aluminum hydroxide is 15 obtained from the Regis Chemical Company, Chicago. Methysergide bimaleate is supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory recordings are carried out in a clear plastic box with internal dimensions lOx6x4 inches. The top of the box is removable; in use, it is held firmly in 20 place by four clamps and an airtight seal is m~int~ined by a soft rubber gasket. Through the center of each end of the chamber a DeVilbiss nebulizer (No. 40) is inserted via an airtight seal and each end of the box also has an outlet. A Fleisch No. 0000 pneumotachograph is inserted into one end of the box and coupled to a Grass volumetric 25 pressure transducer (PT5-A) which is then connected to a Beckman Type R Dynograph through a~rop~iate couplers. While aerosolizing the antigen, the outlets are open and the pneumotachograph is isolated from the chamber. The outlets are closed and the pneumotachograph and the chamber are connected during the recording of the respiratory 30 patterns. For challenge, 2 mL of a 3% solution of antigen in saline is placed into each nebulizer and the aerosol is generated with air from a small Potter diaphragm pump operating at 10 psi and a flow of 8 liters/minute.
Rats are sensitized by injecting (subcutaneously) 1 mL of a suspension CO~t~ it-g 1 mg EA and 200 mg aluminum hydroxide in - 213~631 saline. They are used between days 12 and 24 postsensitization. In order to elimin~te the serotonin component of the response, rats are pretreated intravenously 5 minutes prior to aerosol challenge with 3.0 mg/lcg of methysergide. Rats are then exposed to an aerosol of 3% EA
in saline for exactly 1 minute, then their respiratory profiles are recorded for a further 30 minlltes. The duration of continuous dyspnea is measured from the respiratory recordings.
Compounds are generally ~tlmini~tered either orally 1-4 hours prior to challenge or intravenously 2 minutes prior to challenge.
They are either dissolved in saline or 1% methocel or suspended in l ~o methocel. The volume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Prior to oral treatment rats are starved overnight. Their activity is determined in terms of their ability to decrease the duration of symptoms of dyspnea in comparison with a group of vehicle-treated controls. Usually, a compound is evaluated at a series of doses and an EDso is determined. This is defined as the dose (mglkg) which would inhibit the duration of symptoms by 50%.

Pulmonary Mechanics in Trained Conscious Squirrel Monkeys The test procedure involves placing trained squirrel monkeys in chairs in aerosol exposure chambers. For control purposes, pulmonary mechanics measurements of respiratory parameters are recorded for a period of about 30 minutes to establish each monkey's normal control values for that day. For oral a-lmini~tration, compounds are dissolved or suspended in a 1% methocel solution (methylcellulose, 65HG, 400 cps) and given in a volume of 1 mL~g body weight. For aerosol ~(lmini.stration of compounds, a DeVilbiss ultrasonic nebulizer is utilized. Pretreatment periods vary from 5 minutes to 4 hours before the monkeys are challenged with aerosol doses of Ascaris antigen.
Following challenge, each minute of data is calculated by computer as a percent change from control values for each respiratory parameter including airway resistance (RL) and dynamic compliance (Cdyn). The results for each test compound are subsequently obtained for a minimum period of 60 nlillut~s post challenge which are then 21386vl compared to previously obtained historical baseline control values for that monkey. In addition, the overall values for 60 minutes post-challenge for each monkey (historical baseline values and test values) are averaged separately and are used to calculate the overall percent inhibition of Ascaris antigen response by the test compound. For statistical analysis, paired t-test is used. (See McFarlane, C.S. et ah, Prostaglandins, 28:173-182, 1984, and McFarlane, C.S. et al., Agents Actions 22:63-68, 1987.) Prevention of Induced Bronchoconstriction in Allergic Sheep A. Rationale. Certain allergic sheep with known sensitivity to a specific antigen (Ascaris suum) respond to inhalation challenge with acute and late bronchial responses. The time course of both the acute and the late bronchial responses approximates the time course observed in asthmatics and the pharmacological modification of both responses is similar to that found in man. The effects of antigen in these sheep are largely observed in the large airways and are conveniently monitored as changes in lung resistance or specific lung resistance.
B. Methods. Animal Preparation: Adult sheep with a mean weight of 35 kg (range, 18 to 50 kg) are used. All ~nim~ used meet two criteria: a) they have a natural cutaneous reaction to 1: 1,000 or 1:10,000 dilutions of Ascaris suum extract (Greer Diagnostics, 25 Lenois, NC) and b) they have previously responded to inh~l~tion challenge with Ascaris suum with both an acute bronchoconstriction and a late bronchial obstruction (Abraham, W.M. et al., Am. Rev. Resp.
Dis., 128, 839-44 (1983)).

Measurement of Airway Mechanics: The unsedated sheep are restrained in a cart in the prone position with their heads immobilized. After topical anesthesia of the nasal passages with 2%
lidocaine solution, a balloon catheter is advanced through one nostril into the lower esophagus. The ~nim~l~ are then intubated with a cuffed endotracheal tube through the other nostril using a flexible fiberoptic 213~53 1 bronchoscope as a guide. Pleural pressure is estimated with the esophageal balloon catheter (filled with one ml of air), which is positioned such that inspiration produces a negative pressure deflection with clearly discernible cardiogenic oscillations. Lateral pressure in the trachea is measured with a sidehole catheter (inner dimension, 2.5 mm) advanced through and positioned distal to the tip of the nasotracheal tube. Transpulmonary pressure, the difference between tracheal pressure and pleural pressure, is measured with a differential pressure o transducer (DP45; Validyne Corp., Northridge, CA). Testing of the pressure transcuder catheter system reveals no phase shift between pressure and flow to a frequency of 9 Hz. For the measurement of pulmonary resistance (RL), the maximal end of the nasotrachel tube is connected to a pneumotachograph (Fleisch, Dyna Sciences, Blue Bell, PA). The signals of flow and transpulmonary pressure are recorded on an oscilloscope (Model DR-12; Electronics for Medicine, White Plains, NY) which is linked to a PDP-l 1 Digital computer (Digital Equipment Corp., Maynard, MA) for on-line calculation of RL from transpulmonary pressure, respiratory volume obtained by integration 20 and flow. Analysis of 10-lS breaths is used for the determination of RL. Thoracic gas volume (Vtg) is measured in a body plethysmograph, to obtain specific pulmonary resistance (SRL = RL-Vtg).

Aerosol Delivery Systems: Aerosols of Ascaris suum 25 extract (1:20) are generated using a disposable medicalnebulizer (Raindrop~), Puritan Bennett), which produces an aerosol with a mass median aerodynamic diameter of 6.2 ',lM (geometric standard deviation, 2.1) as determined by an electric size analyzer (Model 3030; Thermal Systems, St. Paul, MN). The output from the nebulizer is directed into 30 a plastic t-piece, one end of which is attached to the nasotracheal tube, the other end of which is conected to the inspiratory part of a Harvard respirator. The aerosol is delivered at a tidal volume of S00 mL of a rate of 20 per minute. Thus, each sheep receives an equivalent dose of antigen in both placebo and dr~g trials.

Experimental Protocol: Prior to antigen challenge baseline measurements of SRL are obtained, infusion of the test compound is started 1 hr prior to challenge, the measurement of SRL repeated and then the sheep undergoes inh~l~tion challenge with Ascaris suum 5 antigen. Measurements of SRL are obtained immediately after antigen challenge and at 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, and 8 hrs after antigen ch~ nge. Placebo and drug tests are separated by at least 14 days. In a further study, sheep are given a bolus dose of the test compound followed by an infusion of the test compound for 0.5-1 hr prior to ascaris challenge and for 8 hrs after ascaris as described above.

Statistical Analysis: A Kruskal-Wallis one way ANOVA
test is used to compare the acute immediate responses to antigen and the 15 peak late response in the controls and the drug treated ~nim~

PREPARATION OF BENZYL HALIDES

Halide 1: 3-r4-(4-Methoxy)tetrahydropyranyllbenzylbromide ~J~Br 0~

25 Step 1: 3-r4-(4-hydroxy)tetrahydropyranylltoluene To a solution of 3-bromotoluene (24.3 mL; Aldrich) in THF (250 mL) stirred at -78~C was added a solution of n-BuLi in hexane (1.75 M; 114 mL; Aldrich). After 45 min., the resulting white suspension was treated with a solution of tetrahydropyran-4-one (18.5 30 mL; Aldrich) in THF (125 mL). After 45 min. at -78~C, the mixture was stirred for 1.5 hr. at r.t. Saturated aqueous NH4Cl was then added and the organic phase separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica 21386~ 1 - ~6 - 19158 gel; hexane/EtOAc (1:1)) fol~ ~y crys~l1i7~tion in hexane/EtOAc afforded the title compound ~ a wli~te ~}~d.

Step 2: 3-r4-(4-Methoxy~y~ ~ylltoluene To a 0~C solutian ~ ol from Step 1 (38 g) in DMF
(300 mL) were added NaH ~ i;n mme~ oil; 16 g) and methyl iodide (31 mL). The mixture was ~d ~ nitrogen at r.t. for 15 hr.
before H20 (1 L) was added. ~e a~us phase was extracted with O EtOAc and the combined or~ hq~ were washed with brine, dried (MgS04) and evapo~:d. Fl2~ c~romatography of the residue (silica gel; hexane/EtOAc ~ yiel~d t~e title ether as a colorless liquid.

Step 3: 3-r4-(4-Metho~ dropyranyllbenzylbromide A mixture of -~ ~lu~ne (16 g) from Step 2, N-bromosuccinimide (14.6 g) allsd azoisobutyronitrile (AIBN) (127 mg) in CC14 (250 mL) was refluxed for 1.5 hr. Filtration and evaporation of the filtrate gave the desired benzyl bromide.

Halide 2: 3-r4-(4-Hydroxy)tetrahydropyranyllbenzylbromide ,~l~, Br Following the procedure described for Halide 1, Step 3, but substituting 3-[4-(4-hydroxy)tetrahydropyranyl]toluene (from Halide 1, Step 1) for 3-[4-(4-methoxy)tetrahydropyranyl]toluene, the title product 30 was obtained as a yellow solid.

Halide 3: 3-[4-(4,B-Hydroxy-2,6-dimethyl)tetrahydropyranyl]-benzylbromide '~ 2138~31 0~
Me~ OH

~ Br Step 1: 3-Bromo-O-tetrahydropyranylbenzyl alcohol o To a solution of 3-bromobenzyl alcohol (11.5 g; Aldrich) dissolved in CH2C12 (100 mL) at 0~C and p-toluenesulfonic acid monohydrate (116 mg) was added DHP (6.2 mL). The resulting solution was stirred at r.t. for 3 hr. then was quenched with NH40Ac.
The aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried (MgS04) and evaporated. Flash chromatography of the residue (silica gel: hexane/EtOAc (9:1) afforded the title compound as an oil.

Step 2: 2 6-Dimethyltetrahydropyran-4-one A solution of 2,6-dimethyl-~-pyrone (17 g, Aldrich) in 300 mL of EtOH 95% was hydrogenated for 3 days under 70 psi. After filtration over celite, the solvent was evaporated and replaced by CH2Cl2. The solution was then treated with celite (30 g) and PCC (48.5 g). The suspension was stirred for 3 hr. and the reaction was diluted with Et20 (300 mL) and then filtered over a pad of celite. The filtrate was evaporated to dryness and the residual solution was then chromatographed using hexane/Et20 (1:1) to give the title compound.

Step 3: 3-[4-(4,~-Hydroxy-2,6-dimethyl)tetrahydropyranyl]-0-tetrahydropyranylbenzyl alcohol Following the procedure described in Halide 1, Step 1, but subsliluling 3-bromo-0-tetrahydropyranylbenzyl alcohol (from Step 1) for 3-bromotoluene and sub~lilulillg 2,6-dimethyltetrahydropyran-4-one (from Step 2) for tetrahydropyran-4-one, the title compound was obtained as a mixture of a and ~ isomers (30:70). Both isomers were 21~3 1 isolated from a flash column (hexane/EtOAc) (6:4). The ,~-hydroxy isomer is more polar than the a-hydroxy isomer.

Step 4: 3-[4-(4,B-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl alcohol The ~-hydroxy-THP derivative (1.0 g) from Step 3, was dissolved in EtOH (10 mL) and treated with p-toluenesulfonic acid (30 mg). The reaction was stirred at r.t. for 90 min. The EtOH was evaporated and the resulting syrup was flash chromatographed to give the title compound.

Step 5: 3-[4-(4~-Hydroxy-2,6-dimethyl)tetrahydropyranyl]-benzylbromide To a solution of the alcohol (183 mg) from Step 4 in CH2Cl2 (9 ml) was added CBr4 (269 mg). The reaction was then cooled at -30~C and DIPHOS (298 mg) was added in portions. After 10 min., the reaction was quenched with a solution (10 mL) of 10% EtOAc in hexane and without evaporation, the solvent was poured onto a silica gel column and eluted with EtOAc/hexane (3:7) affording the title compound.

Halide 4: 3-[4-(4a-Hydroxy-2,6-dimethyl)tetrahydropyranyl]benzyl bromide 2 5 Me~ Br OH
3 0 Following the procedure described in Halide 3, Step 4-5, but sub~iluling a-hydroxy-THP derivative (from Halide 3, Step 3) for ,~-hydroxy-THP derivative, the title product was obtained.

Halide 5: 4-Bromomethyl-2-[4-(4-hydroxy)tetrahydropyranyl]-thiazole 2138~ ~

~N~ Br 5 Step 1: 4-Methyl-2-~4-(4-hydroxy)tetrahydropyranyllthiazole To a solution of 4-methyl thiazole (990 mg) in THF (10 mL) at -78~C there was added n-BuLi (1.1 M) in hexanes (10 mL). The resulting suspension was stirred at -78~C for 45 min. then there was added slowly a solution of tetrahydro-4H-pyran-4-one (1.20 g) in THF
l0 (2 mL). The mixture was then stirred at 0~C for 1 hr., then quenched with saturated aqueous NH4Cl (8 mL), and diluted with EtOAc. The organic phase was washed (3x) with brine, dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane to afford the product as a light yellow 1 5 solid.

Step 2: 4-Bromomethyl-2-[4-(4-hydroxy)tetrahydropyranyl]-thiazole Following the procedure described in Halide 1, Step 3, but 20 substituting 4-methyl-2-[4-(4-hydroxy)tetrahydropyranyl]thiazole from Step 1, for 3-[4-(4-methoxy)tetrahydropyran]toluene, the title product was obtained as a white solid.

Halide 6: 3-[4-(2,2-Dimethyl-4-ethyl-1,3-dioxolanyl)]benzyl bromide o~~ Br Me~o Et Me Step 1: 3-Methylpropiophenone To a 0~C solution of EtMgBr in Et2O (3.0 M, 570 mL, Aldrich) was slowly added m-tolunitrile (102 mL, Aldrich). After - ' 213~63~

stirring at r.t. for 19 hr., benzene (300 mL) was added and the resulting mixture was cooled to 0~C. HCI (6N, 600 mL) was then slowly added.
The organic phase was separated, washed with 5% NaHCO3 and brine, dried (MgSO4) and evaporated to afford the desired ketone as a yellow liquid.

Step 2: 3-r2-(1-Isopropoxydimethylsilylbutan-2-ol)ltoluene A solution of the ketone from Step 1 (2.5 g) in THF (15 mL) was added dropwise to a 0~C solution of isopropoxydimethyl-silylmethylmagnesium chloride (5.6 mmoL, J. Org. Chem., 1983, 48, 2120) in THF (10 mL). The mixture was stirred at r.t. under argon for 2 hr. before it was washed with saturated NH4Cl solution and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (95:5)) yielded the title alcohol as a colorless oil.

Step 3: 3-r2-(Butane-1,2-diol)ltoluene A mixture of the alcohol from Step 2 (3.67 g), THF (20 mL), MeOH (20 mL), NaHCO3 (1.25 g) and H2~2 (30%) (12.8 mL) was refluxed for 3 hr. After evaporation, the residue was taken up in EtOAc and the organic phase was washed with brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel;
hexane/EtOAc (3:2)) yielded the desired diol as a colorless oil.

Step 4: 3-r4-(2 2-Dimethyl-4-ethyl-1.3-dioxolanyl)ltoluene Concentrated sulphuric acid (1 drop) was added to a solution of the diol from Step 3 (1.0 g) in acetone (50 mL). The reaction mixture was stirred for 2 hr. at r.t. before it was neutralized by the addition of lN NaOH and evaporated. Flash chromato-graphy of the residue (silica gel; hexane/EtOAc (75:5)) afforded the title toluene as a colorless oil.

Step 5: 3-[4-(2,2-Dimethyl-4-ethyl-1,3-dioxolanyl)]benzyl bromide ' 21386~1 Following the procedure described in Halide 1, Step 3, but substituting the toluene from Step 4, for 3-[4-(4-methoxy)tetrahydro-pyranyl]toluene, the title benzyl bromide was obtained as an oil.

PREPARATION OF ALCOHOLS

Alcohol 1: 3-r4-(4-Hydroxy)tetrahydropyranyllbenzyl alcohol o ~_,OH

0~

Step 1: 3-Bromo-O-tert-butyldiphenylsilylbenzyl-alcohol To a solution of 3-bromobenzyl alcohol (25 g, 134 mmoL) in anhydrous DMF (300 mL) was added triethylamine (17.6 g, 174 mmoL) followed by t- butyldiphenylsilyl chloride (40.4 g, 147 mmoL).
The mixture was stirred for 24 hr, poured into a saturated aqueous NH4Cl solution (1 L), and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and evaporated.
Flash chromatography on silica gel (2.5% EtOAc in hexane) afforded the title compound as a colorless oil.

Step 2: 3-r4-(4-Hydroxy)tetrahydropyranyllbenzyl-alcohol Following the procedure described in Halide 1, Step 1, but substituting 3-bromo-O-tert-butyldiphenylsilylbenzyl alcohol (from Step 1) for 3-bromotoluene, the tert-butyldiphenylsilylether derivative of the title compound was obtained. The crude product was treated with 5 equivalents of Bu4NF in dry THF at r.t. for 1.5 hr. After evaporation of the solvent, the crude product was flash chromatographed on silica gel (toluene:EtOAc/1 :4) to afford the pure title compound as a colorless oil.

- 21386~1 Alcohols 2 and 3: 3-[4-(4a-Hydroxy-2-methyl)tetrahydropyranyl]-benzyl alcohol (2) and 3-[4-(4,~-hydroxy-2-methyl)-tetrahydropyranyllbenzyl alcohol (3) OMe ~ ,OH \~

[~ OH

Following the procedure in Halide 1, Step 1, but substituting 3-bromo-O-tert-butyldiphenylsilylbenzyl alcohol (from 15 Alcohol 1, Step 1) for 3-bromotoluene and sub~ u~ g 2-methyl-tetrahydropyran-4-one (JACS, 1982, 104, 4666) for tetrahydropyran-4-one. The tert-butyldiphenylsilylether derivatives of the title compounds were obtained as a mixture of a and ~-isomers. This mixture was then treated with S equivalents of Bu4NF in dry THF at r.t. for 1.5 hr.
20 After evaporation of the solvent both isomers were separated by using flash chromatography (toluene:EtOAc/1:4) affording first the a-hydroxy isomer (Alcohol 2) followed by the ,~-isomer (Alcohol 3) in a ratio 1:2.8.

2s Alcohol 4: [lS,SR] 3-[3-(3a-Hydroxy-6,8-dioxabicyclo-[3.2.1]-octanyl)lbenzyl alcohol O-Step 1: 2.4-Di-O-p-toluenesulfonyl-1.6-anhydro-,B-D-glucose To a solution of 1,6-anhydro-~-D-glucose (50 g, 308 mmoL) in dry pyridine (100 mL) at 0~C was added dropwise to a solution of p-toluenesulfonyl chloride (123 g, 647 mmoL) dissolved in - 21~8~

CHCl3 (350 mL) and pyridine (200 mL). The reaction mixture was stirred at r.t. for at least 2 days. Water was added and the reaction mixture was stirred for 1 hr, then the organic layer was decanted and 5 the aqueous phase was reextracted with CHCl3. The combined organic layers were washed with H2SO4 (10%) until the pH remained acidic, then finally washed with a saturated NH40Ac solution. The resulting organic layer was dried over MgSO4 and the solvent evaporated. The syrup obtained was flash chromatographed on silica gel eluting with hexane:EtOAc (1:1) to give the title compound an oil.

Step 2: ~lS.3S~SRl 6~8-Dioxabicyclor3.2.1loctan-3-ol The ditosylate derivative from Step 1 (107 g, 0.228 mmoL) was dissolved in THF (1.6 L) at -40~C and Super-Hydride(E~ in THF
15 (800 mL, 1 M, 0.8 mmoL) was slowly added. The resulting reaction mixture was stirred at r.t. overnight. The reaction was cannulated into cold H2O (226 mL) using external cooling, then NaOH 3N (640 mL, 1.92 mmol) and H2~2 (30%) (490 mL, 4.3 mmol) were successively added. The reaction was stirred at r.t. for 1 hr, then the supernatant 20 (THF layer) was separated from the aqueous layer and concentrated.
The resulting residue was combined with the aqueous layer and extracted with CH2C12 using a continuous extractor. The organic layer was dried (MgSO4) and evaporated to dryness. The oily residue was dissolved in hot Et2O, filtered and evaporated to dryness affording the 25 title compound con~min~ted with the 2-octanol isomer. The crude product was used as such for the next step.

Step 3: r1S.5Rl 6~8-dioxabicyclor3.2.1loctan-3-one The crude alcohol from Step 2 (16.6 g, 89 mmoL) in 3 0 CH2C12 (200 mL) was added slowly to a suspension of PCC (38.4 g, 178 mmoL) and celite (22 g) in CH2Cl2 (400 mL) and stirred for 1 hr.
The reaction mixture was diluted with Et2O (600 mL) and filtered over celite. The filtrate was evaporated and the residue distilled with a Kugelrohr apparatus (100~C, 1.8 mm/Hg) affording the title product as an oil.

2138fi31 Step 4: [lS,SR] 3-[3-(3a-Hydroxy-6,8-dioxabicyclo-[3,2,1]-octanyllbenzyl alcohol Following the procedure described in Halide 1, Step 1, but sub~lilulillg 3-bromo-O-tert-butyldiphenyl-silylbenzyl alcohol (from Alcohol 1, Step 1) for 3-bromotoluene, the tert-butyldiphenyl-silylether derivative of the title compound was obtained. The crude product was treated with 1 equivalent of Bu4NF in dry THF at r.t. for 1.5 hr. After evaporation of the solvent, the crude product was flash chromato-graphed on silica gel (hexane:EtOAc, 4:1) to afford the pure title product as a colorless oil.

Alcohol 5: 5-r4-(4-Hydroxy)tetrahydropyranyllpyridin-3-ylmethanol l 5 ~ OH
O

Step 1: 5-Bromo-0-tert-butyldiphenylsilylpyridin-3-ylmethanol To a solution of 5-bromopyridin-3-ylmethanol (Chem.
Pharm. Bull. 1990, 38, 2446) (29 g, 154 mmoL) and tert-butyl-chlorodiphenylsilane (47.5 g, 173 mmoL) in CH2Cl2 (500 mL) at r.t., there was added imidazole (15.8 g, 232 mmoL). The mixture was stirred for 1 hr. and filtered. The filtrate was evaporated and the residue chromatographed on silica gel eluting with a 1 :7 mixture of EtOAc and hexane, to afford the product as a colorless oil.

Step 2: 5-[4-(4-Hydroxy)tetrahydropyranyl]-0-tert-butyldi-3 o phenylsilylpyridin-3-ylmethanol To a solution of the silylether from Step 1 (50 g, 117 mmoL) in THF (500 mL), cooled to -70~C, there was slowly added n-BuLi 1.12 M in hexanes (115 mL, 129 mmoL) affording a dark brown solution. To this, there was added a solution of tetrahydro-4H-2138~1 pyran-4-one (14.1 g, 141 mmoL) in THF (925 mL). The resulting mixture was stirred for 1 hr. at -70~C, then quenched slowly with saturated aqueous NH4Cl (50 mL) and allowed to warm up to r.t. After diluting with EtOAc (500 mL) the mixture was washed (4x) with brine, 5 dried over Na2SO4 and evaporated. Chromatography on silica gel, eluting with EtOAc, afforded the product as an oil which solidified.

Step 3: 5-r4-(4-Hydroxy)tetrahydropyranyllpyridin-3-ylmethanol To a solution of the silylether from Step 2 (20.35 g, 45.5 mmoL) in THF (350 mL), there was added Bu4NF lM in THF (52 mL) and the mixture was stirred at r.t. for 1 hr. The solvent was evaporated and the residue chromatographed as a short column of silica gel, eluting with a 1 :4 mixture of EtOH and EtOAc to afford the title product which was obtained, after trituration with Et2O and filtration, as a light yellow solid; m.p. 145-147~C.

Alcohol 6: 6-14-(4-Hydroxy)tetrahydropyranyllpyridin-2-ylmethanol ~ OH
O

Step 1: 2-Bromo-6-r4-(4-hydroxy)tetrahydropyranyllpyridine A solution of 2,6-dibromopyridine (15 g) in Et2O (375 mL) was cooled to -78~C. To the resulting suspension was slowly added n-BuLi 2M in hexanes (47.5 mL, 0.9 eq.) and the resulting mixture was stirred for a further 15 min. at -78~C. There was slowly added a solution of tetrahydro-4H-pyran-4-one (11.6 g) in Et2O (25 mL). The 30 resulting white suspension was stirred at -78~C for an additional 15 min.
There was added saturated aqueous NH4Cl (100 mL) and the mixture was allowed to warm up to r.t. After dilution with EtOAc, the organic phase was washed (4x) with brine, dried and evaporated. The residue was triturated with Et2O and filtered to afford the title product as a white solid; m.p. 131-133~C.

2138~31 Step 2: 6-r4-(4-hydroxy)tetrahydropyranyllpyridin-2-ylmethanol To a solution of the bromo derivative from Step 1 (7.7 g) in THF (50 mL) and Et2O (150 mL), cooled to 0~C, there was slowly added n-BuLi 2M in hexanes (30 mL) affording a red-brown suspension. An inlet tube above the surface of the mixture was connected to a flask in which paraformaldehyde (25 g) was gently heated at 175~C to generate formaldehyde. When all the paraformaldehyde had been decomposed, to the reaction mixture was added saturated aqueous NH4Cl (100 mL) and EtOAc (500 mL). The organic phase was washed (4x) with brine, dried and evaporated to a residue which was chromatographed on silica gel, eluting with EtOAc to afford the title product as a thick yellow oil.

Alcohol 7: 6-r4-(4-Methoxy)tetrahydropyranyllpyridin-2-ylmethanol ~ OH

o~

Step 1: 2-Bromo-6-r4-(4-methoxy)tetrahydropyranyllpyridine To a suspension of KH (35% dispersion in oil, 1.25 g) in THF (75 mL), cooled to 0~C, there was added 2-bromo-6-[4-(4-25 hydroxy)tetrahydropyranyl]pyridine from Alcohol 6, Step 1. Whengassing had subsided, the mixture was warmed to r.t. and a thick suspension resulted. To this was added methyl iodide (1.71 g) and the resulting suspension was stirred at r.t. for 30 min. The THF was evaporated away, and the residue was partitioned between H2O and 30 EtOAc. The residue from evaporation of the organic phase was triturated with hexane and filtered to afford the product as a white solid; m.p. 69-71~C.

213863 l Step 2: 6-r4-(4-Methoxy)tetrahydropyranyllpyridin-2-ylmethanol Following the procedure described in Alcohol 6, Step 2, but substituting the bromo derivative from Step 1 for 2-bromo-6-[4-(4-hydroxy)tetrahydropyranyl]pyridine, the title product was obtained as a white solid; m.p. 84-86~C.

Alcohol 8: 4-r4-(4-Hydroxy)tetrahydropyranyllpyridin-2-ylmethanol o ~ ,OH

O

Following the procedure described in Alcohol 5, Steps 1-3, 5 but substituting 4-bromopyridin-2-ylmethanol (Chem. Pharm. Bull.
1990, 38, 2446) for 5-bromo-pyridin-3-yl methanol as starting material, the title product was obtained as a white solid.

Alcohol 9: [lS,5R]-5-[3-(3a-Hydroxy-6,8-dioxabicyclo[3.2.1]-2 o octanyl)lpyridin-3-yl-methanol O- OH

Following the procedure described in Alcohol 5, Steps 2-3, but sub~ g [lS,5R] 6,8-dioxabicyclo[3.2.1]octan4-one from Alcohol 4, Step 3, for tetrahydro-4H-pyran-4-one, the title product was 3 0 obtained as a white solid.

Alcohol 10: [lS,5R]-6-[3-(3a-Hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)lpyridin-2-ylmethanol - 21~8~31 =~
O- OH

Step 1: 6-Bromo-0-tert-butyldiphenylsilypyridin-2-ylmethanol Following the procedure described in Alcohol 5, Step 1, but substituting 6-bromopyridin-2-ylmethanol (Chem. Pharm. Bull., o 1990, 38, 2446) for 5-bromopyridin-3-ylmethanol, the title product was obtained as a colorless oil.

Step 2: [1 S,SR]-6-[3-(3a-Hydroxy-6,8-dioxabicyclo[3.2. 1]-octanyl)lpyridin-2-ylmethanol Following the procedure described in Alcohol 5, Steps 2-3, but substituting 6-bromo-0-tert-butyldiphenylsilylpyridin-2-ylmethanol from Step 1 for 5-bromo-0-tert-butyldiphenylsilylpyridin-3-ylmethanol, and substituting [lS,SR] 6,8-dioxabicyclo-[3.2.1]octan-4-one from Alcohol 4, Step 3, for tetrahydro-4H-pyran-4-one, the title product was 20 obtained as a white solid.

Alcohol 1 1: 2-[4-(4-Hydroxy)tetrahydropyranyl)pyridin-4-ylmethanol N~
~,OH
0~

Following the procedure described in Alcohol 5, Steps 1-3, but substituting 2-bromopyridin-4-ylmethanol (Chem. Pharm. Bull.
1990, 38, 2446) for 5-bromo-pyridin-3-ylmethanol as starting material, the title product was obtained as a white solid.

Alcohol 12: [ 1 S, 5R] 5-Fluoro-3-[3 -(3a-hydroxy-6,8-dioxa-bicyclor3.2. 1 loctanyl)lphenol F

~OH
O- OH

Step 1: 2,4-Di-O-p-toluenesulfonyl-1.6-anh~-~D-~lucose To a solution of 1,6-anhydro-,B-D-g}~ t50 g, 308 mmoL) in dry pyridine (100 mL) at 0~C was ad~d ~r~pwise a solution of p-toluenesulfonyl chloride (123 g, 647 mmoL) diss~l~ed in CHC13 (350 mL) and pyridine (200 mL). The reacti~n mi~hlre was stirred at r.t. for at least 2 days. Water was added and ~e ~eaction ~ lur~ was stirred for approx. 1 hr. then the organic layer ~as de~ant~d and the aqueous phase was re-extracted with CHCl3. ~ c~n~bined organic layers were washed with H2S04 (10%) until the pH ~emained acidic, 20 then finally washed with a saturated NH40Ac soluti~n. The resulting organic layer was dried over MgSO4 and the solvent evaporated. The syrup obtained was flash chromatographed on silica gel eluting with hexane:EtOAc (1:1) to give the title compound as an oil.

2s Step 2: ~lS,3S,5Rl 6,8-Dioxabicyclo~3.2.1loctan-3-ol The ditosylate derivative from Step 1 (107 g, 0.228 mmoL) was dissolved in THF (1.6 L) at -40~C and Super-Hydride in THF (800 mL, lM, 0.8 mmoL) was slowly added. The resulting reaction mixtllre was stirred at r.t. overnight. The reaction was c~nmll~ted into cold 30 H2O (226 mL) using external cooling, then NaOH 3N (640 mL, 1.92 mmoL) and H2~2 (30%) (490 mL, 4.3 mmoL) were successively added. The reaction was stirred at r.t. for 1 hr. Then the supernatant (THF layer) was separated from the aqueous layer and concentrated.
The resulting residue was combined with the aqueous layer and extracted with CH2C12 using a continuous extractor. The organic layer 2138~31 was dried (MgSO4) and evaporated to dryness. The oily residue was dissolved in hot Et2O, filtered and evaporated to dryness affording the title compound cont~min~ted with the 2-octanol isomer. The crude 5 product was used as such for the next step.

Step 3: rlS.SRl 6~8-Dioxabicyclor3.2.1loctan-3-one The crude alcohol from Step 2 (16.6 g, 89 mmoL) in CH2Cl2 (200 mL) was added slowly to a suspension of PCC (38.4 g, 178 mmoL) and celite (22 g) in CH2Cl2 (400 mL) and stirred for 1 hr.
The reaction mixture was diluted with Et20 (600 mL) and filtered over celite. The filtrate was evaporated and the residue distilled with a Kugelrohr apparatus (10~C, 1.8 mm/Hg) affording the title product as an oll.

Step 4: [ 1 S,SR] O-Benzyl-3-[3-(3a-hydroxy-6,8-dioxa-bicyclo-r3.2. 1 loctanyl)l-5-fluorophenol To a solution of O-benzyl-3-bromo-5-fluoro-phenol (1.03 g, EP 385,662) in THF (15 mL) stirred at -78~C was added a solution of n-BuLi in hexane (2.5 M, 1.62 mL). After 1 hr. a solution of [lS,SR]
6,8-dioxabicyclo[3.2.1]octan-3-one (471 mg) from Step 3 in THF (2 mL) was added dropwise to the resulting mixture. After 45 min. at -78~C, the reaction mixture was stirred at 0~C for 1 hr. Saturated aqueous NH4Cl was then added and the organic phase separated. The aqueous phase was extracted was EtOAc (3x) and the combined organic phases were washed with brine, dried (MgSO4), and evaporated to afford the title product as an oil.

Step 5: [lS,SR] 5-Fluoro-3-[3-(3a-hydroxy-6,8-dioxabicyclo-3 o 13.2.1 loctanyl)lphenol A mixture of O-benzylphenol derivative (1.1 g) from Step 4, Pd/C (10%) (100 mg) in EtOH (20 mL) was stirred over H2 (1 Atm.) for 1 hr. Then, CH2Cl2 (20 mL) was added and the resulting mixture was filtered over celite. The filtrate was evaporated and the 21~63 1 crude product was flash chromatographed on silica gel eluting with EtOAc/hexane (3:2) to afford the title product as a white solid.

PREPARATION OF NAPHTHOLS

Naphthol 1: 1-Phenyl-3-carboxy-6-naphthol 1 o HO~,CO2H
Ph Method A (Scheme I):

15 Step 1: 4-Hydroxy-2-(3-methoxybenzylidene)-4-phenylbut-3-enoic acid lactone A mixture of 4-phenyl-4-oxobutanoic acid (52 g), m-anisaldehyde (47.6 g), sodium acetate (24 g) and acetic anydride (177.5 g) was stirred and heated at 70~C for 8 hr. After cooling down to r.t., the resulting yellow slurry was diluted with H2O (1 L) and after stirring for 15 min. the supernatant was decanted. The solids were washed in the same manner with H2O (3x), then filtered and washed well with H2O. The yellow-orange solid, still clamped, was used as such in the next step.

Step 2: 1-Phenyl-3-carboxy-6-methoxynaphthalene The crude, lactone from Step 1 was suspended in glacial AcOH (750 mL) and 37% HCl (750 mL), and the mixture was refluxed for 2.5 hr. After cooling down to r.t., H2O (1.5 L) was added, the mixture was stirred for 15 min. and the supernatant was decanted. The solid was again stirred with H2O (2 L) and filtered, washed copiously with H2O and dried under vacuum. This solid was stirred in a 1:1 mixture of Et2O and hexane (500 mL) for 2 hr. and filtered to afford the desired naphthoic acid as a beige solid.

213863~
-Step 3: 1-Phenyl-3-carboxy-6-naphthol The acid from Step 2 (55 g) and pyridine-HCl (400 g) were heated together at 175~C for 10 hr. After cooling to r.t., H2O (2 L) was added, and after stirring for 15 min., the mixture was filtered. The solid was dissolved in H2O (1.5 L) and 10 N aqueous NaOH (35 mL), the solution was filtered and the filtrate acidified with lN aqueous HCl.
The resulting precipitate was filtered, washed copiously with H2O and dried to afford the desired naphthol as a tan solid.

Naphthol 2: 1-(3-Furyl)-3-carboxy-6-naphthol HO~,CO2~

Step 1: Ethyl 4-(3-furyl)-4-oxobutanoate Under N2, 3-furoic acid (25 g, 0.223 mmoL) was dissolved 20 in CH2Cl2 (200 mL) and DMF (few drops) then oxalyl chloride (23.9 mL, 0.267 mmoL) was added at 0~C. The resulting solution was stirred at 0~C for 15 min. and at r.t. for 30 min. The solvent was evaporated and replaced by dry benzene (200 mL) for the addition. In a separate flask, the ethyl 3-iodopropionate (73.25 g, 0.334 mmoL) was dissolved in dry benzene (400 mL) then dimethylacetamide (45 mL) and Zn-Cu (32 g, 0.512 mmoL) were added. The mixture was stirred at r.t. for 1 hr. and at 60~C for 3 hr. The (Ph3P)4Pd~ (10.25 g, 8.87 mmoL) was added and the reaction was stirred at the same temperature for 5 min.
The oil bath was removed and the solution of acyl chloride in benzene 30 was added all at once. The resulting mixture was stirred for 30 min., diluted with EtOAc, washed successively with HCI lN (2x), saturated NaHCO3 and brine, dried over MgSO4, filtered and evaporated. The crude residue was purified by chromatography on silica gel eluting with hexane:EtOAc (9:1) to afford the title product as a while solid.

213~63 ~

Step 2: 4-(3-Furyl)-4-oxobutanoic acid The keto ester from Step 1 (38.9 g, 0.193 mmoL) was dissolved in a mixture of MeOH:H2O:THF (3: 1 :2) (150 mL) and NaOH
lN (213 mL, 0.213 mmoL) was added. The reaction was stirred at r.t.
overnight. The mixture was concentrated, acidified with HCl lN
extracted (2x) with EtOAc, washed with brine, dried over MgSO4, filtered and evaporated to afford the title product as a beige solid.

Step 3: 1-(3-Furyl)-3-carboxy-6-naphthol Following the procedure described in Naphthol 1, Steps 1-3, but substituting 4-(3-furyl)-4-oxobutanoic acid from Step 2 for 4-phenyl-4-oxobutanoic acid, the title product was obtained as a beige solid.

Naphthol 3: 1-(2-Thienyl)-3-cyano-6-hydroxynaphthalene HO~,CN

~S

Method B (Scheme II):

25 Step 1: 3-Carbethoxy-4-(3-benzyloxyphenyl)-3(Z)-butenoic acid To a solution of LiOMe in MeOH (2.7M, 450 mL) was added dropwise a mixture of 3-benzyloxybenzaldehyde (100 g, 0.47 mmoL) and diethylsuccinate (123 g, 0.71 mL). The reaction mixture was refluxed for 16 hr., cooled to r.t. and the solvent evaporated.
30 The residue was acidifed to pH 2 with HCl 50% and extracted with EtOAc (800 mL). The organic phase was washed with H2O (3x) then extracted with a saturated NaHCO3 solution. The basic extracts were acidified to pH 2 with HCl 6N and extracted with EtOAc (3x250 mL).
The organic phase was washed with brine, dried over MgSO4 and evaporated to afford the title compound as an oil.

21~86~1 Step 2: 1 -Trifluoroacetyl-3-carbomethoxy-6-benzyloxy-naphthalene To a solution of the corresponding acid from Step 1 (71 g, 0.22 mmoL) in TFAA (270 mL) and CH2Cl2 (70 mL) was added portionwise at -10~C NaOAc (36 g, 0.44 mmoL). The cooling bath was then removed and the reaction mixture was stirred at r.t. for 2 hr. The solvent was then evaporated and the residue was dissolved in EtOAc, washed a few times with saturated solution of NaHCO3, brine and the solvent evaporated to afford the title compound as an oil.

Step 3: 1-Hydroxy-3-carbomethoxy-6-benzyloxynaphthalene The trifluoroacetoxy derivative from Step 2 was dissolved in MeOH (300 mL) and K2CO3 (30 g, 0.22 mmoL) was added portionwise. The resulting reaction mixture was stirred for 16 hr. then transferred to a solution of HCl lN, extracted with EtOAc. The combined organic phases were washed successively with H2O, brine, dried over MgSO4 and evaporated. Purification by flash chromatography (hexanes:EtOAc; 4:1) gave the title compound as an oil.

Step 4: 1-Trifluoromethanesulfonyl-3-carbomethoxy-6-benzyl-oxynaphthalene To a solution of the alcohol from Step 3 (410 mg, 1.3 mmoL) in CH2C12 (20 mL) was added Et3N (0.2 mL, 1.6 mmoL) and at 0~C trifluoromethanesulfonic anhydride (0.25 mL, 1.55 mmoL). The reaction mixture was stirred for 3 hr., diluted with CH2Cl2, washed successively with HCl lN, brine, dried over MgSO4 and evaporated.
Purification by flash chromatography (hexanes:EtOAc; 85:15) gave the title compound as an oil.

Step 5: 1-(2-Thienyl)-3-carbomethoxy- 6-benzyloxynaphthalene To a solution of 2-bromothiophene (579 mg, 3.6 mmoL) in dry THF (10 mL) was added at -78~C n-BuLi in hexane (1.8 mL, 3.6 mmoL, 1.96 M). The resulting solution was stirred for 1 hr., then (MeO)3B (0.4 mL, 3.6 mmoL) was added dropwise and after 30 min., a mixture of the corresponding triflate from Step 4 in THF (6 mL) and H2O (2 mL) cont~inin~ (Ph3P)4Pd (340 mg, 0.3 mmoL) was added.
The cooling bath was removed and the resulting mixture was heated to 60~C for 1 hr. The solvent was evaporated and H2O was added followed by extraction with EtOAc. The combined organic phases were washed successively with H2O, brine, dried over MgSO4 and evaporated. Purification by flash chromatography (toluene:EtOAc;
99.5:0.5) gave the title compound as a solid.

Step 6: 1-(2-Thienyl)-3-cyano-6-benzyloxynaphthalene To a suspension of the ester from Step 5 (420 mg, 1.1 mmoL) in toluene (10 mL) was added a solution of dimethylaluminium amide (lM, 3.4 mL, 3.4 mmoL). The mixture was refluxed for 16 hr., then transferred to a solution of HCl lN and extracted with EtOAc.
The combined organic phases were washed with brine, dried over MgSO4, and evaporated. The crude product was then dissolved in THF
(8 mL) and TFAA (0.5 mL, 3.4 mmoL) was added at 0~C. The cooling bath was removed and the reaction mixture was stirred at r.t. for 2 hr.
Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed successively with H2O, brine, dried over MgSO4, and evaporated to afford the title compound as an oil.
Step 7: 1-(2-Thienyl)-3-cyano-6-hydroxynaphthalene To a solution of the crude benzyloxy naphthalene derivative from Step 6, in thioanisole (2 mL) and TFA (6 mL) was heated at 65~C
for 1 hr. Then the solvent was evaporated and the resulting mixture was applied onto a flash chromatography column and eluted with hexanes: EtOAc(95:5) to give the title compound as a solid.

~38fi3 1 Naphthol 4: 1-(3-Thienyl)-3-cyano-6-hydroxynaphthalene HO~[~CN

Following the procedure described in Naphthol 3, Steps 5-7, but sub~ ulillg 3-bromothiophene for 2-bromothiophene and Et2O
for THF, the title product was obtained as a white solid.

Naphthol 5: 1 -(2-Thiazolyl)-3-carbomethoxy-6-naphthol Ho~co2Me S~N
\~
Method C (Scheme I~):

Step 1: 3-Carbethoxy-4-(3-methoxyphenyl)-3(Z)-butenoic acid To a solution of LiOEt in EtOH (1.92M, 450 mL) at reflux 25 was added dropwise a mixture of m-anisaldehyde (90 g) and diethyl succinate (150 g). The reaction was acidified to pH 2 with HCI 50% and extracted with EtOAc (800 mL). The organic phase was washed with H20 (3x) then extracted with saturated NaHCO3 solution. The basic extracts were acidified to pH 2 with HCl 6N and extracted with EtOAc 30 (3x, 250 mL). The organic phase was washed with brine, dried over MgSO4 and evaporated to afford the title compound as an oil.

Step 2: 3-Carbethoxy-4-(3-methoxyphenyl)butanoic acid A solution of mono acid from Step 1 (115 g) in AcOH (320 mL) cont~ining Pd/C 10% (4 g) was hydrogenated (Parr, 20 psi) for 5 21381~31 hr. The reaction mixture was filtered and the solvent evaporated to afford the title compound as an oil.
~ Step 3: 3-Carbethoxy-6-methoxy-1-tetralone To a mixture of mono acid from Step 2 (30 g) and NaOAc (20 g) at 0~C was added TFAA (100 mL) dropwise (over 3 hr. period).
The reaction mixture was stirred 3 hr. at r.t. then poured into crushed ice, neutralized with NaOH 6N, extracted with EtOAc, washed with H2O, brine, dried over MgSO4 and evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc (80:20 ? 75:25) to afford the title compound as an oil.

Step 4: 1-(2-Thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro- 1 -naphthol To a solution of thiazole (428 mL, 6.04 mmoL) in Et2O
(20 mL) was added at -78~C dropwise a solution of n-BuLi in hexanes (1.96 M, 3.08 mL) and the solution was stirred for 30 min. A solution of keto ester from Step 3 (1 g, 4.02 mmoL) in Et2O (2 mL) was then added dropwise and the reaction was stirred at -78~C for 1 hr. and warmed to r.t. A saturated NaHCO3 solution was added and the mixture was extracted with Et2O (2x), washed with H2O, dried over MgSO4, filtered and evaporated. The crude compound was purified by flash chromatography on silica gel (hexanes:EtOAc; 7:3) to afford as a yellow oil a mixture of the title alcohol and the lactone resulting from a loss of EtOH.

Step 5: 1-(2-Thiazolyl)-3-carbethoxy-6-methoxy-3,4-dihydro-naphthalene To the mixture of alcohol ester and lactone from Step 4 (490 mg, 1.47 mmoL) in benzene (20 mL) was added CSA (273 mg, 1.47 mmoL) and the resulting mixtllre was refluxed with a Dean Stark for 16 hr. The solution was diluted with EtOAc, washed successively with saturated NaHCO3 and H2O, dried over MgSO4 and evaporated to afford the title product as a brown oil.

-- 21~8S~l Step 6: 1-(2-Thiazolyl)-3-carbethoxy-6-methoxynaphthalene To a solution of the dihydronaphthalene derivative from Step 5 (407 mg, 1.47 mmoL) in benzene (20 mL) was added DDQ (334 mg, 1.47 mmoL). After 5 min., t~e solvent was evaporated and the crude material was purified on silica gel column eluting with EtOAc:hexane (3:7) to afford the title product as a dark oil.

Step 7: 1-(2-Thiazolyl)-3-carboxy-6-naphthol Following the procedure described in Naphthol 1, Step 3, but substituting 1-(2-thiazolyl)-3-carbethoxy-6-methoxynaphthalene from Step 6, for 1-phenyl-3-carboxy-6-methoxynaphthalene, the title product was obtained and used as such for the next step.

Step 8: 1-(2-Thiazolyl)-3-carbomethoxy-6-naphthol To a solution of the acid from Step 7 (108 mg, 0.4 mmoL) in EtOAc (20 mL) was added an excess of CH2N2 in Et2O. After 5 min., the solution was evaporated to afford the title compound as an 20 orange o11-Naphthol 6: 1 -(5-Thiazolyl)-3-carbomethoxy-6-naphthol HO~CO2Me N~/
Step 1: 1-(5-Thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro- 1 -naphthol To a solution of 2-trimethylsilylthiazole (2.2 g, 13.9 mmoL) (J. Org. Chem., 1988, 53, 1748) in Et2O (12 mL) was added at -78~C, dropwise a solution of n-BuLi in hexanes (2.45M, 5.68 mL) and the solution was stirred for 30 min. A solution of keto ester from Naphthol 5, Step 3, (2.0 g, 8.05 mmoL) in Et2O (5 mL) was then added - 21~86~ 1 dropwise and the reaction was stirred at -78~C for 1 hr. and warmed to r.t. A saturated NaHCO3 solution was added and the mixture was extracted with Et2O (2x), washed with H2O, dried over MgSO4, filtered and evaporated. The crude compound was purified by flash chromatography on silica gel eluting with hexanes: EtOAc (7:3) to afford directly the title alcohol as an oil.

Step 2: 1-(5-Thiazolyl)-3-carbomethoxy-6-naphthol Following the procedure described in Naphthol 5, Steps 5-8, but sub~ u~ g 1-(5-thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro-1-naphthol from Step 1, for 1-(2-thiazolyl)-3-carbethoxy-6-methoxy-1,2,3,4-tetrahydro-1-naphthol, the title product was obtained as an orange solid.

Naphthol 7: 1-Phenyl-6-naphthol HO~

Ph A mixture of 1-phenyl-3-carboxy-6-naphthol (Naphthol 1, 250 mg) and copper powder (125 mg) in quinoline (6 mL) was heated at 225~C for 3.5 hr. The cooled mixture was diluted with EtOAc, 25 washed twice with lN aqueous HCl, then with H2O, aqueous NaHCO3 and again H2O, dried and evaporated. The residue was chromato-graphed on silica gel, eluting with a 1:3 mixture of EtOAc and hexane, to afford the final naphthol as an oil which solidified to a light brown solid.
Naphthol 8: 1-Phenyl-3-acetyl-6-naphthol HO~COMe Ph 213~

To a solution of l-phenyl-3-carboxy-6-naphthol (Naphthol 1) (12 g) in Et2O (150 mL) at 0~C was added MeLi in Et2O (1.4M, 160 mL) dropwise (over 45 min. period). The reaction mixture was stirred at r.t. for 24 hr., quenched with TMSCl until pH ~1, then H2O was added (100 mL). After 2 hr. with vigorous stirring, the organic phase was separated, washed with H2O, saturated K2CO3 solution (3x), brine, dried over MgSO4 and evaporated. The solid was treated with Et2O
and filtered to afford the title compound as beige solid.

Naphthol 9: 1-Phenyl-3-pentanoyl-6-naphthol HO~[~,CO-nBu Following the procedure described in Naphthol 8, but substituting n-BuLi for MeLi, the title compound was obtained as a cream solid.

Naphthol 10: 1-Phenyl-3-ethyl-6-naphthol HO~, Et Ph To a solution of l-phenyl-3-acetyl-6-naphthol (Naphthol 8) (300 mg) in EtOAc was added Pd(OH)2/C (20%, 50 mg) and stirred under H2 (balloon) for 24 hr. The mixture was filtered on celite and 3 ~ the filtrate evaporated. The residue was flash chromatographed, eluting with hexanes:EtOAc:CH2Cl2 (9:1:5) to afford the title compound.

2l3863l Naphthol 11: 1-Phenyl-3-carbomethoxy-6-naphthol HO~,CO2Me Ph To a suspension of 1-phenyl-3-carboxy-6-naphthol (Naphthol 1) (5 g) in MeOH (60 mL) there was added dropwise thionyl chloride (1.52 mL). The mixture was stirred at r.t. overnight affording a red solution. The MeOH was evaporated and the residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexanes, to afford the ester as a tan solid.

15 Naphthol 12: 1-(3-Furyl)-3-carbomethoxy-6-naphthol HO~CO2Me ¢?

To a solution of 1-(3-furyl)-3-carboxy-6-naphthol (Naphthol 2) (50 g) in MeOH (300 mL) was bubbled HCl (g) for 10 25 min. The reaction mixture was stirred at r.t. for 1 hr., then 70~C for 3 hr. The solvent was evaporated and the residue dissolved in Et(~Ac, washed with H2O, saturated NH4Cl solution, brine, dried over MgSO4 and the solvent evaporated to afford the title compound as a pale yellow solid.

Naphthol 13: 1-Phenyl-3-cyano-6-naphthol HO~,CN

Ph 21~8~1 To a suspension of 1-phenyl-3-carbomethoxy-6-naphthol (Naphthol 11) (890 mg, 3.19 mmoL) in toluene (50 mL) was added dimethylaluminum amide (lM, 9.59 mmoL), 9.59 mL). The mixture was heated at reflux for 16 hr. At 0~C, HCl lN (excess) was carefully added and the mixture was stirred at 0~C for 15 min., then extracted (2x) with CH2C12. A precipitate (O was filtered from the extracts.
The organic phase was washed with brine, dried over MgSO4, filtered and evaporated to give a white solid (O. Precipitate 1 was stirred in EtOAc for 30 min., filtered and the filtrate was evaporated. The residue was dissolved in dioxane (5 mL) and pyridine (969 ~L, 12 mmoL) was added and the solution was cooled at 0~C. Then TFAA
(867 ,uL, 6 mmoL) was added, the ice bath was removed and the mixture was stirred at r.t. for 1 hr. Water was added to the reaction and the solution was extracted (2x) with EtOAc, washed with brine, dried and evaporated to give a solid (O. The crude compound (~ + ~) was purified by flash chromatography using EtOAc:hexane (7:3) as eluent. The title compound was then obtained as a yellow solid.

Naphthol 14: 1-(3-Furyl)-3-cyano-6-naphthol HO~,CN

¢~

Following the procedure described in Naphthol 13, but sub~ uti.lg 1-(3-furyl)-3-carbomethoxy-6-naphthol (Naphthol 12) for 1-phenyl-3-carbomethoxy-6-naphthol, the title product was obtained as a solid; m.p. 194-195~C.

- 21~863:~

Naphthol 15: 1-(3-Furyl)-3-formyl-6-naphthol HO~CHO

To a solution of 1-(3-furyl)-3-cyano-6-naphthol (Naphthol 14) (1.5 g) in THF (30 mL) at -78~C was added DIBAL-H in toluene (1.SM, 9.3 mL) dropwise. The reaction mixture was warmed to r.t., stirred for 1 hr., cooled to 0~C, quenched with HCl 10% dropwise and diluted with EtOAc. The organic phase was separated, washed with H2O, brine, dried over MgSO4 and the solvent evaporated to afford the 15 title compound as a foam.

Naphthol 16: 1-Phenyl-3-methylthioacetyl-6-naphthol HO~l,COCH2SMe Ph Step 1: 1-Phenyl-3-carbomethoxy-6-benzyloxynaphthalene Following the procedure described in Naphthol 3, Step 5, but substituting bromobenzene for 2-bromothiophene, the title compound was obtained.

Step 2: 1-Phenyl-3-carboxy-6-benzyloxynaphthalene Following the procedure described in Naphthol 2, Step 2, but sub~ u~ g l-phenyl-3-carbomethoxy-6-benzyloxynaphthalene from Step 1, for ethyl 4-(3-furyl)-4-oxobutanoate, the title compound was obtained.

- 2138~

Step 3: 1-Phenyl-3-chloroacetyl-6-benzyloxynaphthalene To a solution of acid from Step 2, (1.5 g) in CH2Cl2 (50 ,uL) was added oxalyl chloride (700 mL). The reaction mixture was stirred at r.t. for 6 hr. and the solvent evaporated. The residue was dissolved in Et2O (20 mL), an excess of CH2N2 in Et2O was added.
After 1 hr. at r.t., HCl (gas) was bubbled for 10 min. through the reaction mixture. The mixture was then diluted with Et2O, washed with H2O (2x), pH 7 buffer solution, brine, dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc:CH2Cl2 (95:5:30) to afford the title compound as a pale yellow solid.

Step 4: 1-Phenyl-3-methylthioacetyl-6-benzyloxynaphthalene A mixture of chloroacetyl derivative from Step 3 (150 mg), Cs2C03 (75 mg), thioacetic acid (30 ,uL) in EtOH (10 mL) was stirred at r.t. for 1 hr. The reaction mixture was diluted with Et2O, washed with pH 7 buffer solution, brine and the solvent evaporated.
The residue was dissolved in MeOH, NaOMe (lM, 3 drops) and MeI (50 ~L) was added. The mixture was stirred at r.t. for 3 hr. and diluted 20 with a saturated NH4Cl solution and Et2O. The organic phase was separated, washed with H2O, brine, dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc (85:15) to afford the title compound as a foam.

Step 5: 1-Phenyl-3-methylthioacetyl-6-naphthol A solution of methylthioacetyl derivative from Step 4 (140 mg) in AcOH (1 mL) and conc. HCl (1 mL) was stirred at r.t. 18 hr.
The reaction mixture was diluted with Et2O, washed with H2O (2x), saturated NaHCO3 solution, brine, dried over MgSO4 and the solvent evaporated. The residue was flash chromatographed, eluting with hexane:EtOAc:CH2Cl2 (85:15:50) to afford the title compound as a foam.

2138~2 1 Naphthol 17: 1-Phenyl-3-phenylthiomethyl-6-naphthol HO~,CH2SPh Ph Step 1: 1-Phenyl-3-hydroxymethyl-6-naphthol To a solution of 1-phenyl-3-carbomethoxy-6-naphthol (Naphthol 11) (2.5 g, 9 mmoL) in dry THF (50 mL) at 0~C
was added (4.8 mL, 2.7 mmoL, 3 eq.) of DIBAL-H. The resulting solution was stirred for 2 hr. Then methanol (excess) was added and the solvent evaporated. The mixture was diluted with EtOAc, washed successively with HCI, lN, H2O, brine, to give the title compound.

Step 2: 1-Phenyl-3-chloromethyl-6-naphthol To a solution of the alcohol from Step 1 (1.46 g, 5.8 mmoL) in CH2C12 (50 mL) was added CC14 (5.7 mL, 58 mmoL, 10 eq.) followed by Ph3P (3 g, 11.7 mmoL, 2 eq.). The resulting mixture was refluxed for 2 hr. The solvent was evaporated and a purification by flash chromatography on silica gel (hexanes: EtOAc; 8:2) gave the title compound.

Step 3: 1-Phenyl-3-phenylthiomethyl-6-naphthol To a solution of the halide from Step 2 (600 mg, 0.22 mmoL) in dry DMF (5 mL) was added at r.t. NaH (90 mg, 2.2 mmoL), followed by thiophenol (114 mL, 1.1 mmoL). The reaction mixture was stirred at r.t. for 18 hr., then transferred to H2O and extracted with EtOAc. The combined organic phases were washed with brine, and dried over MgSO4. After evaporation of the solvent and purification by flash chromatography on silica gel (hexanes:EtOAc; 7:3) the title compound was obtained.

213~631 Naphthol 18: 1 -Phenyl-3-dimethylcarboxamido-6-naphthol HO~,CONMe2 Ph A mixture of 1-phenyl-3-carbomethoxy-6-naphthol (Naphthol 11) (125 mg) in toluene (10 mL) and dimethylaluminum dimethylamine (Me2AlNMe2) in toluene 0.2M (5 mL) was heated to 85~C for 5 hr. The mixture was cooled to r.t., diluted with EtOAc, washed with saturated NH4Cl solution, brine, dried over MgSO4 and the solvent evaporated. The solid residue was treated with Et2O and filtered to afford the title compound as a white solid.
Naphthol 19: 1 -(3-Furyl)-2-cyano-6-naphthol ~CN

¢~

Step 1: 2-(a-Hydroxybenzyl)-5-benzyloxybenz-aldehyde 2 5 dimethylacetal To a solution of 2-bromo-5-benzyloxy benzaldehyde dimethylacetal (Tet. Lett., 22, 5027 (1981)) (130 g) in THF (2.0 L), cooled to -78~C, was added dropwise a solution of n-BuLi (210 ml, 1.91 M) in hexane. After 15 min., a solution of 3-furaldehyde (26.7 mL) in 30 THF (50 ml) was added dropwise. The cooling bath was removed, then the reaction mixture was warmed slowly (40 min.) to -10~C and quenched with a saturated NH4Cl solution. The reaction mixture was diluted with Et2O (2.0 L). The organic phase decanted, washed with H2O (3x), brine, dried over MgSO4, and the solvents evaporated. The 2138~3 l residue was chromatographed on silica gel (hexane/EtOAc 95:5 to 85:15) to give the title product as a foam.

Step 2: 1-(3-Furyl)-2-cyano-6-benzyloxynaphthalene To a solution of alcohol from Step 1 (200 mg) in chlorobenzene (20 mL), was added acrylonitrile (800 ,uL) and trifluoroacetic acid (100 ,uL). The reaction mixture was heated to reflux for 6 hr, then cooled to r.t. The solvent was evaporated and the resulting residue was flash chromatographed on silica gel (hexane:
EtOAc, 85:15) to afford the title product as a yellow solid.

Step 3: 1-(3-Fury1)-2-cyano-6-naphthol Following the procedure described in Naphthol 3, Step 7, but substituting 1-(3-furyl)- 2-cyano-6-benzyloxynaphthalene for 1-(2-thienyl)-3-cyano-6-benzyloxynaphthalene, the title product was obtained.

Naphthol 20: 1-(3-Furyl)-3-acetyl-6-naphthol O
HO~

¢~

Following the procedure described in Naphthol 8, but sub~lilulillg 1-(3-furyl)-3-cyano-6-naphthol (Naphthol 14) for 1-phenyl-3-carboxy-6-naphthol (Naphthol 1), the title product was obtained as a 3 ~ solid.

- 213~

Naphthol 21: 1-(5-Pyrimidinyl)-3-carbomethoxy-6-naphthol HO~,CO2Me N~N

Step 1: 1-(5-Pyrimidinyl)-3-carbomethoxy-6-methoxynaphthalene Following the procedure described in Naphthol 3, Step 5, but substituting 5-bromopyrimidine for 2-bromothiophene and 1-trifluoromethanesulfonyl-3-carbomethoxy-6- methoxynaphthalene for 1 -trifluoromethanesulfonyl-3 -carbomethoxy-6-benzyloxynaphthalene, 15 the title compound was obtained.

Step 2: 1-(5-Pyrimidinyl)-3-carbomethoxy-6-naphthol Following the procedure described in Naphthol 1, Step 3, but substituting 1-(5-pyrimidinyl)-3-carbomethoxy-6-methoxy-20 naphthalene for 1-phenyl-3-carboxy-6-methoxy naphthalene, the title product was obtained as a yellow solid.

Naphthol 22: 1-Cyano-3-carbomethoxy-6-naphthol HO~,CO2Me CN
Step 1: 1-Cyano-3-carbethoxy-6-methoxy-1 ,2,3,4-tetrahydro-0-3 o trimethylsilyl- 1 -naphthol To a solution of 3-carbethoxy-6-methoxy-1-tetralone from Naphthol 5, Step 3 (2 g, 7.0 mmoL) in CH2Cl2 (50 mL) at 0~C was added TMSiCN (1.4 mL, 10.6 mmoL) followed by BF3-0Et2 (260 ,uL, 1.4 mmoL), and the reaction mixture was stirred at 0~C for 15 min. and at r.t. for 1 hr. The resulting reaction mixture is then added to a 21386~l saturated aqueous NaHC03 solution, extracted with CH2Cl2, washed with brine, dried over MgS04, and evaporated. The residue was flash chromatographed eluting with hexane: EtOAc 5 (9:1 ? 7:3) to afford the title compound.

Step 2: 1-Cyano-3-carbethoxy-6-methoxy-3.4-dihydronaphthalene Following the procedure described in Naphthol 5, Step 5, but sub~ ling the ester from Step 1 for the mixture of alcohol ester o and lactone from Step 4 in Naphthol 5, the title compound was obtained and used as such for the next step.

Step 3: 1-Cyano-3-carbethoxy-6-methoxynaphthalene Following the procedure described in Naphthol 5, Step 6, 15 but substituting the ester from Step 2 for 1-(2-thiazolyl)-3-carbethoxy-6-methoxy-3, 4-dihydronaphthalene, the title product was obtained as a white solid.

Step 4: 1-Cyano-3-carboxy-6-naphthol Following the procedure described in Naphthol 1, Step 3, but substilulillg 1-cyano-3-carbethoxy-6-methoxynaphthalene from Step 3 for 1-phenyl-3-carboxy-6-methoxynaphthalene, the title compound was obtained as an orange solid.

Step 5: 1-Cyano-3-carbomethoxy-6-naphthol Following the procedure described in Naphthol 5, Step 8, but substituting 1-cyano-3-carboxy-6-naphthol from Step 4 for 1-(2-thiazolyl)-3-carboxy-6-naphthol, the title product was obtained as an orange solid.

21~63 i PREPARATION OF NAPHTHALENE INTERMEDLATE
Naphthalene 1: 1-Phenyl-3-hydroxymethyl-6-carbomethoxynaphthalene HO~CO2Me Ph Step 1: 1-Phenyl-3-carbomethoxy-6-trifluoromethanesulfonyl-oxynaphthalene Following the procedure described in Naphthol 3, Step 4,but substituting Naphthol 11 for 1-hydroxy-3-carbomethoxy-6-benzyloxynaphthalene, the title product was obtained.

Step 2: 1-Phenyl-3-hydroxymethyl-6-trifluoromethane-sulfonyloxynaphthalene Following the procedure described in Naphthol 17, Step 1, but sub~ilulil~g 1-phenyl-3- carbomethoxy-6-trifluoromethanesulfonyl-20 oxynaphthalene from Step 1 for 1-phenyl-3-carbomethoxy-6-naphthol, the title product was obtained.

Step 3: 1-Phenyl-3-hydroxymethyl-6-carbomethoxynaphthalene To a solution of the alcohol from Step 2 (162 mg) in MeOH
25 (2 mL) and DMSO (4 mL) was added triethylamine (130 ~L), Pd(OAc)2 (10 mg) and 1,1 -bis(diphenylphosphino)ferrocene (45 mg).
Then carbon monoxide was bubbled through the resulting mixture for 10 min. Then an atmosphere of CO was m~int~ined while the solution was heated to 70~C for one hour. The reaction mixture was then 30 allowed to cool to r.t. diluted with EtOAc washed successively with HCl lN, saturated aqueous NaHCO3, brine, dried and evaporated. Flash chromatography on silica gel (Hexane: EtOAc: 6:4) afforded the title compound.

21~g~3~

The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting. All temperatures are in degrees Celsius.

[1 S ,5S] 1 -(3-Furyl)-3-cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo r3 .2.1 l octanyl)lpyridin-2-ylmethoxy ~ naphthalene Step 1: 5-Methyl-4-hexen-2-ol To a solution of 5-methyl-4-hexen-2-one (20.0 g, 178 mmol), prepared from 5-methyl-3-hexen-2-one according to literature procedure (Yang N.C., Jorgenson M.J., Tet. Lett. (1964) 19, 1203, Breuilles P., Uguen D., Bull. Soc. Chim. Fr. (1988) _, 705), in MeOH
(700 ml) at 0~C was added NaBH4 (6.76g, 179mmol). The mixture was stirred at 0~C for 1 hr. A solution of saturated aqueous NH4Cl was added and the mixture was extracted with EtOAc. The organic layer was dried over Na2S04 and concentrated. The resulting colorless oil was used as such in the next step.
H NMR (400 MHz, CD3COCD3) ~ 1.06 (3H, d, J=6 Hz), 1.59 (3H, s), 1.67 (3H, s), 2.15 (2H, m), 3.36 (lH, d, J=5Hz), 3.71 (lH, m), 5.69 (lH, m).

Step 2: 2-Benzoyloxy-5-methyl-4-hexene To a solution of 5-methyl-4-hexen-2-ol (17.0 g, 149 mmol, from Step 1) and Et3N (52.0 mL, 373 mmol) in THF (750 mL) at r.t.
was added benzoyl chloride dropwise (34.6 mL, 298 mmol). After stirring for 18 hrs, the mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and with distilled H2O. The organic layer was dried over Na2SO4 and concentrated. The resulting oil was purified by flash chromatography eluting with a mixture of EtOAc in hexane (1 :9) to give a colorless oil.

- Z138~3 1 H NMR (400 MHz, CD3COCD3) ~ 1.33 (3H, d, J=6 Hz), 1.65 (3H, s), 1.68 (3H, s), 2.40 (2H, m), 5.10 (lH, sextet J=6Hz), 5.22 (lH, m), 7.45-7.68 (3H, m), 7.95-8.05 (2H, m).

Step 3: 5-Benzoyloxy-23(S)-dihydroxy-2-methylhexane To a mixture of t-butyl alcohol (350 mL) and water (350 mL) was added AD-mix-a (100.0 g, from Aldrich, described by Sharpless K.B. et. ah, J. Org. Chem. (1992), 10, 2768 and Crispino G.A., and Sharpless K.B., Synlett (January 1993), 47), stirring at r.t.
produced two clear phases. Methane sulfonamide (6.79g, 71 mmol) was added and the mixture was cooled to 4~C. Then 2-benzoyloxy-5-methyl-4-hexene (15.3 g, 70.0 mmol) from Step 2 was added at once and the heterogeneous slurry was stirred vigorously at 4~C for 18 hrs.
15 While the mixture was stirred at 4~C, solid sodium dithionite (74g, 425 mmol) was added and the mixture was allowed to warm to r.t. and stirred for 1 hr. The mixture was extracted with EtOAc, the organic layer was washed with 2N KOH, dried over Na2SO4 and concentrated in vacuo. This crude product was purified by flash chromatrography 20 eluting with a mixture of EtOAc in hexane (1:1) to give a colorless oil.
[a]D = -11.6~(CHC13, C=1) (Absolute stereochemistry is tentative).
H NMR of the diastereomeric mixture (400 MHz, CD3COCD3) o 1.16 (3H, s), 1.19 (3H, m), 1.39 (3H, 2d), 1.80 (2H, m), 3.34 and 3.42 (lH, 2s), 3.44-3.56 (lH, m), 3.65 and 3.78 (lH, 2d, J=5 Hz), 5.30-5.46 25 (lH, m), 7.45-7.68 (3H, m), 8.04 (2H, dd).

Step 4: 5,5-Dimethyl-2-methoxy-4(S)-[2-(benzoyloxy)prop-1-yl]-1.3-dioxolane To a solution of 5-benzoyloxy-2,3(S)-dihydroxy-2-30 methylhexane (1.10 g, 4.36 mmol, from Step 3) in trimethyl-orthoformate (2.4 mL, 21.9 mmol) was added (+) 10-camphorsulfonic acid (100 mg, 0.43 mmol). The mixture was stirred at r.t. for 1 hr.
Then Et3N (0.2 mL, 1.4 mmol) was added, solvents and excess Et3N
were removed by evaporation in vacuo to afford the crude title compound as an oil.

2 1 ~
-lH NMR of the diastereomeric mixture (400 MHz, CD3COCD3) ~
1.14-1.35 (6H, 6s), 1.45 (3H, 2d, J=7Hz), 1.72-1.97 (2H, m), 3.15-3.28 (3H, 4s), 3.86-4.13 (lH, m), 5.25-5.40 (lH, m), 5.60-5.66(1H,4s), 7.52 (2H, broad t), 7.63 (lH, td), 8.04 (lH, dd).

Step 5: 5,5-Dimethyl-2-methoxy-4(S)-(2-hydroxyprop-1-yl)-1,3-dioxolane To a solution of 5,5-dimethyl-2-methoxy-4(S)-[2-(benzoyloxy)prop-1-yl]-1,3-dioxolane (1.22 g, 4.15 mmol from Step 4) in THF (60 mL) was added MeOH (24 mL) followed by aqueous sodium hydroxide lN (12.4 mL, 12.4 mmol). The mixture was stirred at r.t.
overnight. The reaction was diluted with EtOAc, washed with H2O, and washed with aqueous sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated to give the crude product as an oil.

Step 6: 5,5-Dimethyl-2-methoxy-4(S)-(2-oxoprop- 1 -yl)- 1,3-dioxolane To a solution of oxalylchloride (505 ,uL, 5.8 mmol) in 15 mL of CH2C12 at -63~C, DMSO (822 ,uL, 11.6 mmol) was slowly added. Upon completion of addition, the mixture was stirred for 2 min.
and then 5,5-dimethyl-2-methoxy-4(S)-(2-hydroxyprop-1-yl)-1,3-dioxolane (1.0 g, 5.3 mmol from Step 5) was added dropwise over 5 min. After 15 min., Et3N (3.7 mL, 26.3 mmol) was slowly added and the mixture was stirred for 5 min. at -63~C and then at -30~C for 25 min. The reaction was stopped by addition of saturated aqueous NH4Cl and CH2Cl2. The organic layer was decanted, washed with H2O, dried over Na2S04 and concentrated in vacuo. The resulting crude product was dissolved in EtOAc and filtered through a plug of silica gel to give the title compound as an oil.
H NMR of the diastereomeric mixture (400 MHz, CD3COCD3) ~
1.09-1.34 (6H, 4s), 2.17 (3H, S), 2.72 (2H, m), 3.23 and 3.25 (3H, 2s), 4.16-4.30 (lH, 2dd), 5.61 and 5.63 (lH, 2s).

213~631 Step 7: 5,5-Dimethyl-2-methoxy-4(S)-[2-(t-butyldimethylsilyloxy) prop-2-en- 1 -yll - 1.3 -dioxolane To a solution of 5,5-dimethyl-2-methoxy-4(S)-(2-oxoprop-1-yl)-1,3-dioxolane (1.0 g, 5.32 mmol from Step 6) in 1,2-dichloro-ethane (50 mL) at 0~C was added N,N-diisopropylethyl~mine (4.6 mL, 26.6 mmol) followed by the dropwise addition of t-butyldimethylsilyl trifluoromethanesulfonate (1.6 mL, 6.9 mmol). The reaction was allowed to proceed at 0~C for 1 hr, then it was stopped by addition of saturated aqueous sodium bicarbonate and extracted with EtOAc/Hexane (1:1). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography eluted with Et3N/EtOAc/Hexane (1:10:100) to give the title compound as a colorless oil.
1H NMR of the diastereomeric mixture (400 MHz, CD3COCD3) ~ 0.20 (6H, s), 0.94 (9H, s), 1.12 (3H, s) 1.32 (3H, s 2.15-2.42 (2H, m), 3.23 and 3.26 (3H, 2s), 3.98 and 4.08 (lH, 2dd), 4.15 (lH, s), 4.19 (lH, s), 5.61 (lH, 2s).

Step 8: rlS.SSl 7.7-Dimethyl-6.8-dioxabicyclor3.2.1loctan-3-one To a solution of the silylenol ether from Step 7 (2.95 g, 9.77 mmol) in CH2Cl2 (130 mL), at -78~C was added, a solution of Tin(IV) chloride lM in CH2C12 (1.95 mL, 1.95 mmol) and the reaction was allowed to proceed for 5 min. The reaction was stopped by addition of Et3N, diluted with EtOAc and washed once with H2O. The organic layer was dried over Na2SO4 and concentrated in yacuo. The crude product was purified by flash chromatography eluted with 20%
EtOAc in hexane to give a colorless oil. [a]D = -52~(CHCl3, C=1) lH NMR (400 MHz, CD3COCD3) ~ 1.22 and 1.24 (6H, 2s), 2.35 (lH, d, t), 2.55 (2H, m), 2.66 (lH, dd), 4.39 (lH, d), 5.70 (lH, s).

Step 9: [lS,SS] 6-[3-(7,7-Dimethyl-3a-hydroxy-6,8-dioxabicyclo-13.2.1 loctanyl)lpyridin-2-ylmethanol Following the procedure described in Alcohol 5, Steps 2-3, but substituting 6-bromo-O-tert-butyldiphenylsilylpyridin-2-ylmethanol 21386'31 from Alcohol 10, Step 1 for 5-bromo-O-tert-butyldiphenylsilylpyridin-3-ylmethanol, and sub~ u~ g [lS,SS] 7,7-dimethyl-6,8-dioxabicyclo-[3.2.1]octan-4-one from Step 4, for tetrahydro-4H-pyran-4-one, the title product was obtained.

Step 10: [lS,5S] 1-(3-Furyl)-3-cyano-6-{6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethoxy ~ naphthalene To a mixture of [lS,SS] 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethanol from Step 9 (100 mg), 1-(3-furyl)-3-cyano-6-naphthol (Naphthol 14, 98 mg) and triphenylphosphine(128 mg) in THF (4 mL), was added, after 5 min. di-tert-butyl azodicarboxylate (128 mg) and the resulting mixture was 15 stirred at r.t. for 1 hr. After evaporation of the THF, the residue was flash chromatographed on silica gel, eluting with a mixture of hexane/EtOAc (8:2) to afford the pure title product. [a]D =
-9.6~(CH3CN,C=0.25). Massspectrum: MH+=495.12757 1H NMR (400 MHz, CDCl3): ~ 1.33 (3H, s, Me); 1.62 (3H, s, Me); 2.00 20 (lH, d, H4e); 2.10 (lH, d, H4a); 2.47 (lH, d, H2e); 2.65 (lH, dd, H2a);
4.10 (lH, d, H1); 4.90 (lH, s, OH); 5.35 (2H, s, benzylic proton); 5.72 (lH, s, Hs); 6.65 (lH, s, AR); 7.30 (lH, d, Ar); 7.35-7.47 (3H, Ar);
7.5-7.7 (3H, Ar); 7.72 (lH, dd, Ar); 8.08 (2H, Ar).

[1 R,SR] 1 -(3-Furyl)-3-cyano-6- (6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclor3.2.1 loctanyl)lpyridin-2-ylmethoxy ~naphthalene Following the procedure described in Example 1, but 30 sub~ u~ g AD-mix-,B for AD-mix-a in Step 3, the title compound is obtained.

2138fi~1 1 -(3-Furyl)-3-cyano-6- { 6- [3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo r3.2. 1 loctanyl)lpyridin-2-ylmethoxy ~naphthalene Step 1: 2-(4-Methoxybenzyloxy)-2-methyl-3-butene To a solution of 2-methyl-3-butene-2-ol (8.6 g) in dry DMF (100 mL) were added, 4-methoxy benzyl chloride (18.8 g) followed by NaH (2.64 g, 95%). The reaction was stirred overnight at r.t. The excess of NaH was destroyed by adding H2O at 0~C and the reaction was extracted with Et2O. The combined ether fraction was dried over MgSO4, filtrated and evaporated. A flash column chromatography on silica gel using hexane/ethyl acetate (9:1) gave the pure title compound.
Step 2: 2-(4-Methoxybenzyloxy)-2-methylpropionaldehyde A solution of 2-(4-methoxybenzyloxy)-2-methyl-3-butene (12.3 g) in CH2Cl2 (300 mL), MeOH (100 mL) and NaHCO3 (2.6 g) 20 was cooled to -78~C. Ozone was passed through until blue colour persisted. Nitrogen was then bubbled through and Me2S was added.
After warming to r.t. and stirring overnight, the reaction was filtered and concentrated. Water (34 mL) and AcOH (12 mL) were added followed by Zn dust (8.0 g). After stirring vigourously for 60 min., the mixture was filtered and the residue washed with Et2O. The filtrate 25 was extracted with Et2O and the organic layer was washed with brine and saturated aqueous NaHCO3 then dried over MgSO4, filtrated and concentrated in vacuo. The residue obtained was purified by flash chromatrography on silica gel to give the pure desired product.
30 lH NMR (400 MHz, CDCl3) ~ 1.35 (6H, s, 2xMe), 3.78 (3H, s, OMe), 4.40 (2H, s, CH2), 6.88 (2H, broad doublet, aromatic), 7.25 (2H, broad doublet, aromatic), 9.6 (lH, s, CHO).

- 21~8~

Step 3: 2-(2-Hydroxyprop-2-yl)-2.3-dihydro-4H-pyran-4-one A solution of 2-(4-methoxybenzyloxy)-2-methyl-propionaldehyde (1.25 g) in dry THF (30 mL), under N2 was cooled to 5 -10~C and magnesium bromide freshly prepared from 1,2-dibro-moethane and magnesium in dry Et2O, was added dropwise. After the addition completed, the cooling bath was removed and the reaction stirred at r.t. for 15 min. prior to be cooled back to -10~C. Then, a solution of l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (1.72 g) in dry THF (5 mL) was added. The mixture was warmed up to r.t. and stirred for 3 days. Water and AcOH were added and the reaction was stirred for 15 min. and extracted with Et2O. The organic layers were washed with brine, then dried over MgSO4, filtrated and concentrated in vacuo. The resulting sirup was taken in CH2C12 and CF3CO2H. The solution was stirred for 15 min. at r.t. then coevaporated with toluene 15 and H2O. The residual sirup was purified by flash chromatography on silica gel with EtOAc as solvent. The material obtained is used right away in the next step.
lH NMR (400 MHz, CDC13) ~ 1.20 (3H, s, Me), 1.3 (3H, s, Me), 1.95 20 (lH, broad s, OH), 2.45 (lH, dd,), 2.65 (lH, dd), 4.2 (lH, dd), 5.4 (lH,d), 7.4 (lH, d).

Step 4: 7-7-Dimethyl-6 8-dioxabicyclol 3.2.1 loctan-3-one The residue obtained from the previous step was taken in 2s CH2C12 and a catalytic amount of camphor sulphonic acid was added.
The reaction was refluxed overnight, then evaporated to dryness.
Purification by flash chromatography on silica gel using hexane EtOAc (8:2) as solvent gave the title compound.
lH NMR (400 MHz, acetone d6): ~ 1.20 (3H, s, Me), 1.23 (3H, s, Me), 30 2.35 (lH, d, H4e)~ 2.50 (lH, d, H2e), 2.58 (lH, dd, H2a), 2.65 (lH, dd, H4a),4.38(1H,d,Hl),5.70(1H,s,Hs) - 21386~1 Step 5: 6-[3-(7~7-Dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2. 1 ] -octanyl)lpyridin-2-ylmethanol Following the procedure described in Alcohol 5, Steps 2-3, but substituting 6-bromo-O-tert-butyldiphenylsilylpyridin-2-ylmethanol from Alcohol 10, Step 1 for 5-bromo-O-tert-butyldiphenylsilylpyridin-3-ylmethanol, and subsli~u~ g 7,7-dimethyl-6,8-dioxabicyclo[3.2.1]-octan-4-one from Step 4, for tetrahydro-4H-pyran-4-one, the title product is obtained.

Step 6: 1 -(3-Furyl)-3-cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethoxy}-naphthalene Following the procedure described in Example 1, but substituting 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo-[3.2.1]octanyl)] pyridin-2-ylmethanol from Step 5, for [lS,5S] 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2. 1 ]octanyl)]pyridin-2-ylmethanol, the title compound is obtained.

~1 S ,5S] 1 -(3-Furyl)-3-cyano-6- { 6-[3 -(7,7-dimethyl-3a-methoxy-6,8-dioxabicyclor3.2.110ctanyl)1pyridin-2-ylmethoxy~naphthalene To a solution of [ 1 S,5S] 1 -(3-furyl)-3-cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3 .2.1 ]octanyl)]pyridin-2-ylmethoxylnaphthalene in dry THF at 0~C is added KH (35% in mineral oil) in dry THF. After 10 min., methyl iodide is added and the resulting mixture is stirred for 30 min. at 0~C. The reaction mixture is poured into saturated aqueous NH4Cl and extracted with EtOAc to afford after evaporation the title product.

213~31 -[ 1 S ,SS] 1 -(3-Thienyl)-3-cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8 -5 dioxabicyclor3.2.1loctanyl)lpyridin-2-ylmethoxy~naphthalene Following the procedure described in Example 1, Step 10, but substituting 1-(3-thienyl)-3-cyano-6-naphthol (Naphthol 4) for 1-(3-furyl)-3-cyano-6-naphthol, the title compound is obtained.

o EXAMPLE 6 [ 1 S,SS] 1 -Phenyl-3-cyano-6- ~ 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclor3.2.110ctanyl)1pyridin-2-ylmethoxy~naphthalene Following the procedure described in Example 1, Step 10, but substituting 1-phenyl-3-cyano-6-naphthol (Naphthol 13) for 1-(3-furyl)-3-cyano-6-naphthol, the title compound is obtained.

[lS,SR] 1-(3-Furyl)-3-cyano-6-{6-[3-(7-methyl-3a-hydroxy-6,8-dioxabicyclor3 .2.1 loctanyl)lpyridin-2-ylmethoxy ~naphthalene Following the procedure described in Example 1, but sub~liluling 4-hexen-2-one for 5-methyl-4-hexen-2-one in Step 1, the title product is obtained.

[lS,SR] 1-(3-Thienyl-3-cyano-6-{6-[3-(7-methyl-3a-hydroxy-6,8-dioxabicyclor3.2. 1 loctanyl)lpyridin-2-ylmethoxy ~naphthalene Following the procedure described in Example 1, but sub~liluling 4-hexen-2-one for 5-methyl-4-hexen-2-one in Step 1, and substituting 1-(3-thienyl)-3-cyano-6-naphthol (Naphthol 4) for 1-(3-furyl)-3-cyano-6-naphthol in Step 10, the title compound is obtained.

213&~1 -[ 1 S ,5R] 1 -Phenyl-3-cyano-6- { 6-[3-(7-methyl-3a-hydroxy-6,8-dioxabicyclor3.2.110ctanyl)1pyridin-2-ylmethoxy~naphthalene Following the procedure described in Example 1, but subsituting 4-hexen-2-one for 5-methyl-4-hexen-2-one in Step 1, and sub~ilulillg 1-phenyl-3-cyano-6-naphthol (Naphthol 13) for 1-(3-furyl)-3-cyano-6-naphthol in Step 10, the title compound is obtained.

[ 1 S,5S] 1 -(3-Furyl)-3-cyano-6- { 3-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo~3 .2.1 loctanyl)lbenzyloxy ~naphthalene Step 1: [lS,5S] 3-[3-(7,7-Dimethyl-3a-hydroxy-6,8-dioxa-bicyclor3.2.1loctanyl)lbenzyl alcohol Following the procedure described in Halide 1, Step 1, but subsliluli~g [lS,5S] 7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo-20 [3.2.1]octan-3-one (from Example 1, Step 8) for tetrahydropyran-4-one and subslilulillg 3-bromo-O-tert-butyldiphenylsilybenzyl alcohol (from Alcohol 1, Step 1) for 3-bromotoluene, the tert-butyldiphenylsilylether derivative of the title compound is obtained. This intermediate is treated with 1 equivalent of Bu4NF in dry THF at r.t. for a few hours to afford the title product.

Step 2: [lS,5S] 1-(3-Furyl)-3-cyano-6-~3-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3 .2.1 ]octanyl)]benzyloxy ) -naphthalene Following the procedure described in Example 1, Step 10, but substituting [lS,SS] 3-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxa-bicyclo[3.2.1]octanyl)]benzyl alcohol from Step 1 for [lS,SS] 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)] pyridin-2-ylmethanol, the title compound is obtained.

2 13 ~

[1 S,5S] 1 -(3 -Furyl)-3 -cyano-6- ~ 3 -[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclor3.2.1 loctanyl)lphenoxymethyl ~naphthalene Step 1: 1-(3-Furyl)-3-cyano-6-trifluoromethane sulfonyloxy naphthalene To a suspension of 1-(3-furyl)-3-cyano-6-naphthol (Naphthol 14) (9.4 g, 40 mmol) in CH2Cl2 (100 mL) there was added pyridine (6.7 g, 85 mmol). The mixture was cooled to 0~C, and there was added slowly trifluoromethane sulfonic anhydride (14.1 g, 50 mmol). The mixture was stirred in the cold for 10 min., then at r.t. for 1 hr. the mixture was diluted with CH2C12 (100 mL) and washed with H2O. After drying over MgSO4, the solvent was evaporated away and the residue chromatographed on silica gel, eluting with a 1 :5 mixture of EtOAc and hexane, to afford the desired triflate as an oil.

Step 2: Methyl 1-(3-furyl)-3-cyano-6-naphthoate A mixture of triflate from Step 1 (2.2 g, 6 mmol), palladium acetate (135 mg, 0.6 mmol), 1,1'-bis(diphenyl phosphino) ferrocene (665 mg), Et3N (1.33 g, 13.2 mmol), DMSO (35 mL) and MeOH (20 mL) was saturated with carbon monoxide (CO) and heated at 65~C under an atmosphere of CO for 10 hrs. After cooling the mixture was partitioned between EtOAc and H2O, and the crude material from the organic phase was chromotographed on silica gel, eluting with a 1 :3 mixture of EtOAc and hexane, to afford the desired ester as a cream-colored solid, mp. 172-174~C.

Step 3: 1-(3-Furyl)-3-cyano-6-hydroxymethylnaphthalene To a solution of the ester from Step 2 (840 mg, 3.03 mmol) in THF (25 mL) there was added LiBH4 (330 mg, 15 mmol) and the mixture was stirred at r.t. for 24 hrs. After careful quenching with saturated aqueous NH4CI, the mixture was diluted with EtOAc, and the organic phase was washed with H2O, dried and evaporated to dryness.

21386'31 Chromatography on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, afforded the desired alcohol as a white solid, mp. 131-134~C.

Step 4: [lS,5S] 3-[3-(7,7-Dimethyl-3a-hydroxy-6,8-dioxabicyclo-r3.2. 1 loctanyl)lphenol Following the procedure described in Alcohol 12, Steps 4 and 5, but sub~liluling [lS,SS] 7,7-dimethyl-6,8-dioxabicyclo[3.2.1]-octan-3-one (from Example 1, Step 8) for [lS,SR] 6,8-dioxabicyclo-0 [3.2.1]octan-3-one and substituting O-benzyl-3-bromophenol for O-benzyl-3-bromo-5-fluorophenol, the title compound is obtained.

StepS: [lS,SS] 1-(3-Furyl)-3-cyano-6-{3-[3-(7,7-dimethyl-3a-hydroxy -6,8-dioxabicyclo[3.2. 1 ]octanyl)]phenoxy-methyl ~ naphthalene Pollowing the procedure described in Example 1, Step 10, but sub~liluling [lS,SS] 3-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxa-bicyclo [3.2.1]octanyl)]phenol (from Step 4) for [lS,SS] 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3 .2.1 ]octanyl)]pyridin-2-ylmethanol and substituting 1-(3-furyl) 3-cyano-6-hydroxymethyl-naphthalene (from Step 3) for 1-(3-furyl)-3-cyano-6-naphthol, the desired title product is obtained.

[ 1 S ,SS] 1 -(3-Furyl)-3-cyano-6- { 3-[5-fluoro-3-(7 ,7-dimethyl-3a-hydroxy-6~8-dioxabicyclor3.2.1 loctanyl)lphenoxymethyl ~naphthalene Step 1: [lS,SS] 3-[5-Fluoro-3-(7,7-dimethyl-3a-hydroxy-6,8-3 0 dioxabicyclor3.2. 1 loctanyl)lphenol Following the procedure described in Alcohol 12, Steps 4 and 5, but subslilulil~g [lS,5S] 7,7-dimethyl-6,8-dioxabicyclo[3.2.1]
octan-3-one (from Example 1, Step 8) for [lS,5R] 6,8-dioxabicyclo-[3.2.1]octan-3-one, the title product was obtained.

lH NMR (400 MHz, CD3COCD3) ~ 1.25 (3H, s, Me); 1.62 (3H, s, Me);
2.0-1.9 (lH, m); 2.3-2.1 (3H, m); 4.1 (lH, d, Hl); 4.2 (lH, s, OH); 5.6 (lH, s, Hs); 6.45 (lH, dt, Ar); 6.75 (lH, dt, Ar); 6.82 (lH, s, Ar); 8.6 (lH,s,OH).

Step 2: [1 S,SS] 1 -(3-Furyl)-3-cyano-6- { 3-[5-fluoro-3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-phenoxymethyl ~ naphthalene Following the procedure described in Example 1, Step 10, but substituting [lS,5S] 3-[5-fluoro-3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]phenol (Step 1) for [lS,5S] 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethanol and substituting 1-(3-furyl)-3-cyano-6-hydroxymethyl-naphthalene (from Example 11, Step 3) for 1-(3-furyl)-3-cyano-6-naphthol, the desired title product is obtained.

[1 S ,5S] 1 -(3-Furyl)-3 -cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo~3.2.1 loctanyl)lpyrdidin-2-yloxymethyl ~naphthalene Step 1: 2-Bromo-6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo 13.2.1 loctanyl)lpyridine To a solution of 2,6-dibromopyridine in dry Et2O cooled to -70~C, is added slowly n-BuLi in hexanes (1 eq.) and the resulting mixture is stirred at -70~C until a green brown solution is obtained (~15 min.). To this resulting solution is added a solution of [lS,SS] 7,7-dimethyl-6,8-dioxabicyclo[3.2.1]octan-3-one (from Example 1, Step 8) in Et2O and the mixture is stirred at -70~C for a further 15 min. then warmed up to 0~C and quenched with saturated aqueous NH4Cl (25 mL). After dilution with EtOAc, the organic phase is washed with H2O, dried and evaporated down to afford the desired title product.

- 2138fi21 Step 2: [ 1 S,SS] 1 -(3-Furyl)-3-cyano-6- { 6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2. 1 ]octanyl)]pyridin-2-yloxymethyl ~ naphthalene To a solution of 1-(3-furyl)-3-cyano-6-hydroxy methyl-naphthalene (from Example 11, Step 3) and 2-bromo-6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclo[3.2. 1 ]octanyl)]pyridine from Step 1 in DMF is added NaH and the resulting mixture is stirred for a few days. After quenching with saturated aqueous NH4Cl, the mixture is partitioned between EtOAc and H2O. The organic layer is decanted, washed with H20, dried over MgSO4 and evaporated to dryness to afford the desired title product.

[1S,SS] 1-(3-Furyl)-3-cyano-6-{6-[3-(7,7-dimethyl-3a-hydroxy-6,8-dioxabicyclor3.2. 1 loctanyl)lpyridin-2-ylthio ~naphthalene Step 1: 1-(3-Furyl)-3-cyano-6-iodonaphthalene A mixture of triflate from Example 11, Step 1, (9.5 g, 25.9 mmol), hexamethylditin (17 g, 51.9 mmol), LiCl (4.4 g, 104 mmol) and tetrakis (triphenyl phosphine) palladium (1.2 g, 1 mmol) in dioxane (100 mL) was refluxed for 1 hr. The mixture was cooled down diluted with Et2O (50 mL) and the supernatant was decanted away from insoluble solids. To this solution there was added a solution of iodine (21.6 g, 85 mmol) in Et2O (300 mL). After 30 min. stirring at r.t., the mixture was washed with 10% aqueous sodium bisulfide, with H2O and dried over MgSO4, and evaporated down. The residue was chromatographed on silica gel, eluting with a 1:9 mixture of EtOAc and hexane, to afford, after trituration with hexane and filtration the pure iodinated compound as a white solid, mp. 132-134~C.

21~631 Step 2: 1-(3-Furyl)-3-cyano-6-(2-trimethylsilylethylthio)-naphthalene A mixture of iodide from Step 1 (1.0 g, 2.9 mmol) 2-trimethylsilylethanethiol (390 mg, 2.9 mmol), potassium tert-butoxide (650 mg, 5.8 mmol), and tetrakis (triphenyl phosphine) palladium (100 mg, 0.09 mmol) in EtOH (50 mL) was refluxed for 1.5 hr. The EtOH
was evaporated off and the residue was partitioned between Et2O and H2O. Chromatography of the residue from the organic phase, on silica gel, eluting with a 1:9 mixture of EtOAc and hexane, afforded the title product as a yellow oil.

Step 3: 1-(3-Furyl)-3-cyano-6-thionaphthol To the intermediate from Step 2 (900 mg, 2.56 mmol) dissolved in DMF (24 mL) there was added Bu4NF lM in THF (7.7 mL, 7.7 mmol). After stirring at r.t. for 30 min., there was added lN
aq. HCl (20 mL), then H2O (150 mL); the resulting precipitate was filtered to afford the desire thiol as a light orange solid, mp. 144-146~C.

Step 4: [lS,5S] 1-(3-Furyl)-3-cyano-6-{6-[3-(7,7-dimethyl-3a-hydroxy -6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylthio }naphthalene To a mixture of 2-bromo-6-[3-(7,7-dimethyl-30c-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridine (from Example 13, Step 1) and 1-(3-furyl)-3-cyano-6-thionaphthol (from Step 3) in N-methyl-2-25 pyrrolidinone, is added K2CO3 and the resulting mixture is heated under N2 atmosphere at 120~C for a few hrs. The reaction mixture is cooled to r.t., quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic extract is washed with brine, dried over MgSO4 and evaporated down to afford the desired title product.

In vitro metabolic studies of the compound of Example 1 (hereinafter referred to as Compound I) and [lS,5R] 1-(3-furyl)-3-cyano-6-{6-[3-(3a-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)] pyridin-2-ylmethoxy}naphthalene (hereinafter referred to as Compound II, see US
Patent 5~308~852) in hepatic subcellular microsomal preparations.

Compounds I and II differ at the substitution at carbon-7 (C-7) of the 6,8-dioxabicyclo[3.2.1]octanyl ring; C-7 of Compound I is substituted with two methyl groups, whereas C-7 of Compound II is unsubstituted. Previous in vitro metabolism studies had demonstrated that oxidation at the unsubstituted C-7 led to the formation of reactive intermediates which could covalently bind to proteins in the microsomal incubations. The two methyl groups were introduced at C-7 in an attempt to reduce the production of reactive intermediates.
The test compound (200 ,uM) was incubated with 1 mg of microsomal protein in the presence of an NADPH generating system (2.0 mM NADP, 20 mM glucose-6-phosphate, 2.0 mM MgC12 and 2 units glucose-6-phosphate dehydrogenase) in lOOmM phosphate buffer (pH 7.4). The total incubation volume was 500 ,uL. Control experiments were conducted in the absence of the NADPH system or using microsomes deactivated by boiling. After a 1 hour incubation at 37~C, the incubation was quenched with 500,uL of acetonitrile. The precipitated proteins were removed by centrifugation and the resulting supernatant was injected into a chromatographic system. To measure the observable metabolites and parent drug, a NovaPak C18 column was used to separate the materials and UV detection at 245nm was used to determine peak areas to quantify the peaks. A gradient mobile phase consisting of methanol and 20mM ammonium acetate (pH 5.4) was used at a flow rate of 1.0 mL/min. The "% Recovery" of the parent drug and observed metabolites was calculated according to the following formula:

% Recoverv = Total area of dru~ + metabolites in activated incubation Area of a 200,uM drug standard diluted two fold in AcCN

The results for microsomes from several species are presented in Table 1.

Table 1 Recovery in microsomal incubations Species Compound I Compound II
Rat 95% 89%
Rhesus monkey 91% 62%
o Human (sample 1) 98% 90%
Human (sample 2) 94% 80%

The low recovery observed in these experiments corresponded to the trapping of reactive metabolites by proteins to form covalently bound complexes which were precipitated during the step where acetonitrile was added to quench the incubations.
The results in Table I clearly show that the "% Recovery"
of Compound I is significantly higher than that of Compound II in all species studied, including human. Dimethyl substitution at C-7 (Compound I) clearly led to a reduction in the generation of reactive metabolites and, thereby, an overall increase in recovery.

Claims (12)

1. A compound of the formula (I) wherein:

R1 and R5 is each independently H, OH, lower alkyl, or lower alkoxy;
R2 is H, or lower alkyl;
R3 is H, OH, lower alkyl, lower alkoxy, lower alkylthio, F or CF3;
R4 is lower alkyl, F, CF3 or together with R3 forms a double-bonded oxgen (=0), or together with R3 forms a saturated carbon ring of 3 to 8 members;
R6 is H or lower alkyl, or two R6 groups attached to the same carbon may form a saturated ring of 3 to 8 members;
R7 is H, OH, lower alkyl, lower alkoxy, lower alkylthio, lower alkylcarbonyloxy, or O-R15;
R8 is H, halogen, lower alkyl, hydroxy, lower alkoxy, CF3, CN, or COR13;
R9 is H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylthio lower alkyl, (R8)2-phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO2, CF3, N3, N(R12)2, NR12COR13, NR12CON(R12)2,SR14, S(O)R14, S(O)2R14, S(O)2N(R12)2, COR13, CON(R12)2, CO2R13, C(R13)2OC(CR13)2-CO2R13, C(R13)2CN, or halogen;
R10 and R11 is each independently H, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy, lower alkyl, lower alkylthio lower alkyl, (R8)2-phenylthio lower alkyl, lower alkylthio lower alkylcarbonyl, CN, NO2, CF3, N3, NR13R16, NR16COR13, NR16CONR13R16, SR14, S(O)R14, S(O)2R14, S(O)2NR13R16, COR13, CONR13R16, CO2R13, C(R13)2OC(CR13)2-CO2R13, C(R13)2CN, halogen,C(R13)2NR16COR13, or C(R13)2NR16-CON(R13)2;
R12 is H or lower alkyl, or two R12 groups attached to the same nitrogen may form a saturated ring of 5 or 6 members, optionally containing a second heteroatom chosen from O, S or NR2;
R13 is H or lower alkyl;
R14 is lower alkyl, CF3, or phenyl-(R8)2;
R15 is carboxy lower alkylcarbonyl, pyridylcarbonyl, hydroxy lower alkylcarbonyl, polyoxa lower alkylcarbonyl, a functionalized or unfunctionalized derivative of a standard amino acid, or a benzoyl group substituted by CH2N(R12)2;
R16 is H, lower alkyl, or OR13;
X1 and X4 is each independently O or S;
X2 is O,S,C(R6)2,or a bond;
X3 is C(R6)20, OC(R6)2 or S;
Ar1 is arylene-(R8)2, wherein arylene is a 5-membered aromatic ring containing one O and 0-2 N, one S and 0-2 N, or 1-3 N; a 6-membered aromatic ring containing 0-3 N; 2- or 4-pyranone; or 2- or 4-pyridinone;
Ar2 is aryl-(R9)2 wherein aryl is a 5-membered aromatic ring containing one O and 0-3 N, one S and 0-3 N, or 1-4 N; a 6-membered aromatic ring containing 0-3 N; 2- or 4-pyranone; 2- or 4-pyridinone; or a bicyclic 8-, 9-, or 10-membered aromatic ring wherein 0-2 carbon atoms are replaced by either O or S or a combination thereof and 0-3 carbon atoms are replaced by N;
Ar2 is attached to either ring of the naphthalene ring system;
m is 0 or 1; and n is 1 or 2;
or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having the formula (Ia) wherein:
R3 is H, or CH3;
R4 is CH3;
R7 is OH or OCH3;
Ar1 is 6,2-Pye, 3-Phe or 3-(5-F-Phe);
Ar2 is 3-Fu, 3-Th or Ph;
X3 is CH2O, OCH2 or S.

3. The compound of Claim 1 which is [1S,5S]
1-(3-Furyl)-3-cyano-6-{6-[3-(7,7-dimethyl-3.alpha.-hydroxy-6,8-dioxabicyclo-[3.2.1]octanyl)]pyridin-2-ylmethoxy}naphthalene.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition of Claim 4 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors;
H1- or H2-receptor antagonists; antihistaminic agents; prostaglandin antagonists; and ACE antagonists.

6. A pharmaceutical composition according to Claim 5, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

7. A pharmaceutical composition of Claim 6, wherein the weight ratio of said compound of Claim 1 to said second active ingredient ranges from about 1000:1 to 1:1000.

8. A method of preventing the synthesis, the action, or the release of SRS-A or leukotrienes in mammal which comprises administering to said mammal an effective amount of a compound of Claim 1.

9. The method of Claim 8 wherein the mammal is man.

10. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

11. A method of treating inflammatory diseases of the eye in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

12. The method of Claim 11 wherein the mammal is man.