Technical Field This invention relates to compounds having biological activity to inhibit lipoxygenase enzymes, to pharmaceutical compositions comprising these compounds, and to a medical method of treatment. More particularly, this invention concerns certain trans 1,4 diether cyclohexyl compounds which inhibit leukotriene biosynthesis, to pharmaceutical compositions comprising these compounds and to a method of inhibiting lipoxygenase activity and leukotriene biosynthesis.

Background of the Invention 5-Lipoxygenase is the first dedicated enzyme in the pathway leading to the biosynthesis of leukotrienes. This important enzyme has a rather restricted distribution, being found predominantly in leukocytes and mast cells of most mammals. Normally 5-lipoxygenase is present in the cell in an inactive form; however, when leukocytes respond to external stimuli, intracellular 5- lipoxygenase can be rapidly activated. This enzyme catalyzes the addition of molecular oxygen to fatty acids with cis,cis-l,4-pentadiene structures, converting them to l-hydroperoxy-trans,cis-2,4-pentadienes. Arachidonic acid, the 5-lipoxygenase substrate which leads to leukotriene products, is found in very low concentrations in mammalian cells and must first be hydrolyzed from membrane phospholipids through the actions of phospholipases in response to extracellular stimuli. The initial product of 5-lipoxygenase action on arachidonate is 5-HPETE which can be reduced to 5-HETE or converted to LTA4. This reactive leukotriene intermediate is enzymatically hydrated to LTB4 or conjugated to the tripeptide glutathione to produce LTC4. LTA4 can also be hydrolyzed nonenzymatically to form two isomers of LTB4. Successive proteolytic cleavage steps convert LTC4 to LTD4 and LTE4. Other products resulting from further oxygenation steps have also been described in the literature. Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. The remarkable potencies and diversity of actions of products of the 5- lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. Alterations in leukotriene metabolism have been

demonstrated in a number of disease states including asthma, allergic rhinitis, rheumatoid arthritis and gout, psoriasis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock syndrome, atherosclerosis, ischemia induced myocardial injury, and central nervous system pathology resulting firom the formation of leukotrienes following stroke or subarachnoid hemoiThage.

The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes and therefore inhibition of this enzyme provides an approach to limit the effects of all the products of this pathway. Compounds which inhibit 5-lipoxygenase are thus useful in the treatment of disease states such as those listed above in which the leukotrienes play an important role.

EPA 375452 discloses a leukotriene inhibitor of structure

OR,

I

Aι _l -A ₁ — O— Ar ₂ — C — R ₂ ^R 3

in which Ari is optionally substituted phenyl or naphthyl; Ai is Ci-Cβ alkylene, C3-C6 alkenylene, C3-C ₆ alkynylene, or C3-C6 cycloalkylene; Aτ2 is optionally substituted phenylene or a 6-membered heterocyclene moiety containing up to three nitrogen atoms; Ri is hydrogen, C ₁ -C ₆ alkyl, C3-C ₆ alkenyl, C3-C ₆ alkynyl, cyano-substituted C1-C4 alkyl or C2-C4 alkanoyl, or optionally substituted benzoyl; R ₂ and R ₃ together form a C3-C6 alkylene group which defines an optionally substituted alkylene ring having 4 to 7 ring atoms, which ring may bear one or two substituents, which may be the same or different, selected from hydroxy, C ₁ -C ₄ alkyl, C1-C ₄ alkoxy, C ₁ -C ₄ alkythio, C ₁ -C ₄ alkylsulphinyl and C1-C4 alkylsulphonyl. In vitro inhibitory potencies of the compounds described by the generic structure against 5-lipoxygenase from stimulated LTB4 formation in human whole blood are claimed to range from 0.1-40μM. Biological data is reported for a single compound: tra s- 1,2- dimethoxy- l-[3-(naphth-2-ylmethoxy)phenyl]-cyclopentane has an IC50 of 0.20μM.

EPA 385 663 discloses a leukotriene inhibitor of structure

OR

Q-A — X— Ar — C — R ₂ I R ₃

in which Q is an optionally substituted 6-membered monocyclic or 10- membered bicylic heterocyclic moiety containing one or two nitrogen atoms; X is oxy, thio, sulphinyl, sulphonyl, or imino; Ar has the same value as defined for Aτ2 above, and Ri, R2, and R3 are as defined above. In vitro potencies for the compounds of the invention are claimed to be in the range 0. l-40μM. An IC50 of 8.0μM is reported for rrαn_.-l,2-dimethoxy-l-[3-(3-(2-pyridyl)prop-2- yn- l-yloxy)phenyl]cyclopentane.

EPA 409414 discloses a leukotriene inhibitor of structure

in which Ari, Ar2, Ri, R2 _. and R3 have the values defined in EPA 375 452, and Xi is oxy, thio, sulphinyl, or sulphonyl. In vtiro potencies for the compounds of the invention are claimed to be in the range 0.01-40μM. Biological data are reported for (IRS, 2SR)-l-[5-fluoro-3-(naphth-2- ylthio)phenyl]-l,2-dimethoxycyclopentane, IC500.2μM, and (IRS, 2SR)-1- allyloxy- 1 - [5-fluoro-3-(naphth-2-ylthio)phenyl] -2-methoxycyclopentane, IC50 0.2μM.

Summary of the Invention In its principal aspect, the present invention provides certain trans 1,4- diether cyclohexyl compounds which inhibit 5-lipoxygenase enzyme activity and are useful in the treatment of allergic and inflammatory disease states. The compounds of this invention have the structure

or a pharmaceuticvally acceptable salt thereof wherein Ar is selected from the group consisting of

(a) optionally substituted carbocyclic aryl,

(b) optionally substituted 5- or 6-membered heterocyclic aryl, (c) optionally substituted 10-membered bicylcic heterocyclic aryl containing one or two nitrogen atoms,

(d) optionally substituted 9- or 10-membered heterocycUc containing one or two nitrogen atoms and optionally containing a

(e) optionally substituted benzo[b]furyl, (f) optionally substituted benzo[b]thienyl, wherein the optional substituents are selected from the group consisting of alkyl of from one to six carbon atoms,haloalkyl of from one to six carbon atoms,alkoxy of from one to six carbon atoms, or halogen;

(i)

R.

O=< < ^N TY

R wherein R2 and R3 are independently hydrogen or alkyl of from one to four carbon atoms.

The group A is selected from 1-propynyl or methylene. The group X is selected from oxy, thio, sulfonyl, or NH.

The group Y is selected from the group consisting of alkyl of from one to six carbon atoms, haloalkyl of from one to six carbon atoms, alkoxy of from one to six carbon atoms, hydrogen, or halogen.

The group Ri is alkyl of from one to four carbon atoms. The groups R2 and R3 are as defined above.

The group R ₄ is hydroxyl or -ORi where Ri is as defined above.

The group R5 is hydrogen or alkyl of from one to four carbon atoms.

In another aspect the present invention provides pharmaceutical compositions which comprise a therapeutically effective amount of the compound as defined above in combination with a pharmaceutically acceptable carrier.

In a yet another aspect, the present invention provides a method of inhibiting leukotriene biosynthesis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined above.

Detailed Description of the Invention Definitions of Terms As used throughout this specification and the appended claims, the term "alkyl" refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and -sσ-propyl, n-, sec-, iso- and tert- butyl, and the like.

The term "carbocyclic aryl" denotes a monovalent carbocyclic ring group derived by the removal of a single hydrogen atom from a monocyclic or bicyclic fused or non-fused ring system obeying the "4n + 2π electron" or Huckel aromaticity rule. Examples of carbocyclic aryl groups include phenyl, 1-, and 2-naphthyl, biphenyl and the like.

The term "5- or 6-membered heterocyclic aryl" denotes a monovalent heterocyclic ring group derived by the removal of a single hydrogen atom from a monocyclic heterocyclic ring system obeying the "4n + 2π electron" or Huckel aromaticity rule. Examples of 5, or 6-membered heterocycUc aryl groups include pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, and pyrimidinyl.

The term "10-membered bicyclic heterocycUc aryl containing one or two nitrogen atoms" refers to a group selected from quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, and quinoxalinyl .

The term "9- or 10-membered heterocycUc aryl containing one or two nitrogen and optionally containing a further heteroatom selected from nitrogen or oxygen, and one oxo or thioxo substituent" refers to a group selected from 2- oxo-l,2-dihydroquinolinyl, 2-oxo-l,2,3,4-tetrahydroquinolinyl, 3-oxo-2,3- dihydro-4H- 1 ,4-benzoxazinyl, oxindolinyl, 3-oxo- 1 ,2-dihydro-3H-indazolyl,

2-oxo-2,3-dihydrobenzothiazolyl, 2-oxo-2,3-dihydrobenzimid__zolyl, 3-thioxo- 2,3-dihydro-4H- 1 ,4-benzoxazinyl, and 2-thioxo- 1 ,2,3,4-tetrahydroquionlinyl.

The term "oxo" denotes a carbonyl oxygen atom.

The term "thioxo" denotes an oxo group as defined above in which the oxygen atom is replaced by a sulfur atom.

The term "propynyl" refers to a straight chain, three-carbon group containing a carbon-carbon triple bond.

The term "haloalkyl" denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The terms "alkoxy" and "alkoxyl" denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. Representative alkoxy groups include methoxyl, ethoxyl, propoxyl, butoxyl, and the like. The term "alkylene" denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1 -ethylene, 1,3-propylene, 2,2- dimethylpropylene, and the like.

Preferred Embodiments

Preferred compounds of the present invention are those having the generic structure given above in which A is methylene, X is oxy, and the values of Ar, Y, Rj, R2, R3, R4, and R5 are as defined above. Particular compounds falUng within the scope of the present invention include, but are not limited to:

4-methoxy-4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexan-l-o ne; trα/w-4-methoxy-4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexan -l-ol; trαn_-l,4-d_methoxy-4-[3-(napth-2-ylmethyloxy)phenyl]cycloh exane; trαn_ ^, -4-methoxy-l-methyl-4-[3-(napth-2-ylmethyloxy)phenyl]- cyclohexanol; trans- 1 ,4-dimethoxy- l-methyl-4-[3-(napth-2-ylmethyloxy)phenyl]- cyclohexane; cis- and trαns-4-methoxy-2-methyl-4-[3-(napth-2-ylmethyloxy)phenyl]- cyclohexanone; 1RS,2RS,3RS- and lRS,2SR,3RS-4-methoxy-2-methyl-4-[3-(napth-

2-ylmethyloxy)phenyl]cyclohexanol;

1RS,2RS,3RS- and lRS,2SR,3RS-l,4-dimethoxy-2-methyl-4-[3-

(napth-2-ylmethyloxy)phenyl]cyclohexane; trfln5-4-methoxy-l-methoxymethyloxy-4-[3-(napth-2-ylmethylox y)- phenyljcyclohexane; tr-_ns-l,4-dimethoxy-4-(3-(l,2-dihydro-l-methyl-2-oxoquinoli n-6-yl- methyloxy) phenyl)cyclohexane; trans- 1 ,4-dimethoxy-4-[5-fluoro-3-(napth-2-ylmethyloxy)phenyl]- cyclohexane; trans- 1 ,4-dimethoxy-4-[5-fluoro-3-(l ,2-dihydro- l-methyl-2- oxoquinolin-6-ylmethyloxy)phenyl]cyclohexane; trαn_.-l,4-dimethoxy-4-[5-fluoro-3-(l,3-dimethyl-2-oxo-2,3- dihydro- benzimidazol-5-yl-methyloxy)phenylcyclohexane; trα/w-l,4-dimethoxy-4-[3-(3-(3-pyridyl)prop-2-yn-l-yloxy)- phenyljcyclohexane; IRS, 2RS, 3RS, and IRS, 2SR, 3RS-l,4-dimethoxy-2-methyl-4-[3-

(3-(3-pyridyl)prop-2-yn- 1 -yloxy)phenyl]cyclohexane; trans- 1 ,4-dimethoxy-4-[3-(3-(2-f uryl)prop-2-yn- lyloxy) phenyljcyclohexane; trans- 1 ,4-dimethoxy-4-[3-(3-(2-benzo[b]thienyl)prop-2-yn- 1 -yloxy)- phenyl] cyclohexane; trans- 1 ,4-dimethoxy-4- [3-(3- (2-imidazolyl)prop-2-yn- 1 -yloxy)- phenyljcyclohexane; trαn-?-l,4-dimethoxy-4-[3-(quinolin-6-ylmethyloxy)phenyl]cy clohexane; trans- 1 ,4-dimethoxy-4-[3-( 1 -methyl-2-oxo- 1 ,2,3,4- tetrahydroquinoUn- 6-ylmethyloxy)phenyl]cyclohex__ne; trans- 1 ,4-dimethoxy-4-[3-(2,2,4-trimethyl-3-oxo-2,3-dihydro-4H-

1 ,4-benzoxazain-7-ylmethyloxy)phenyl]cyclohexane; and 1RS,2RS,3RS- and lRS,2SR,3RS-l,4-dimethoxy-2-methyl-4-[3-(l,3- dimethyl-2-oxo-2,3-dihydrobenzimidazol-5-yl-methyloxy)- phenylcyclohexane.

Lipoxygenase Inhibition Determination

Inhibition of leukotriene biosynthesis was evaluated in an assay, involving calcium ionophore-induced LTB4 biosynthesis expressed human whole blood. Human heparinized whole blood was preincubated with test compounds or vehicle for 15 min at 37 °C followed by calcium ionophore A23187 challenge (final concentration of 8.3 μM) and the reaction terminated after 30 min by adding two volumes of methanol containing prostaglandin B2 as an internal recovery standard. The methanol extract was analyzed for LTB4 using a commercially available radioimmunoassay. The compounds of this invention inhibit leukotriene biosynthesis as illustrated in Table 1.

Table 1

In Vitro Inhibitory Potencies of Compounds of this Invention Against 5- Lipoxygenase from Stimulated LTB ₄ Formation in Human Whole Blood

Example ICspqO^M)

1 3.6

2 0.50

3 0.08 10 0.03

12 72% at 0.05 μM

Pharmaceutical Compositions The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceuticaUy acceptable carriers. The pharmaceutical compositions may be speciaUy formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term "parenteral" administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intraste nal, subcutaneous and intraarticular injection and infusion.

Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceuticaUy acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as weU as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a Uquid suspension of crystaUine or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystaUine form. Alternatively, delayed absorption of a parenteraUy administered drug form is accompUshed by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycoUde. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the

form of sterile soUd compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

SoUd dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylceUulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain siUcates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaoUn and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and piUs, the dosage form may also comprise buffering agents.

SoUd compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as weU as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, piUs, and granules can be prepared with coatings and shells such as enteric coatings and other coatings weU known in the pharmaceutical formulating ait They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentiaUy, in a certain part of the intestinal tract, optionaUy, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert dUuents commonly used in the art such as, for example, water or other solvents, solubUizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed,

groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of Uposomes. As is known in the art, liposomes are generally derived from phosphoUpids or other lipid substances. Liposomes are formed by mono- or multi-lameUar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologicaUy acceptable and metabolizable lipid capable of forming Uposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phosphoUpids and the phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceuticaUy acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compourid(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level wiU depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to graduaUy increase the dosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.

Preparation of the Compounds of this invention

In general, the compounds of this invention are synthesized by reaction schemes I and II as illustrated below. It should be understood that Ar, A, Y, R _l , R2, R ₃ , R ₄ , and R5 as used herein have the values defined above.

Scheme I

According to the foregoing Scheme I, 3-bromophenol (I) is converted to an O-protected intermediate (II or VI) by standard methodology. MetaUation of the 3-bromo group with n-butyl Uthium and quenching of the resulting aryl anion with the mono-ethylene ketal of cyclohex__ne-l,4-dione provides intermediates HI and VH which are methylated by exposure to sodium hydride and methyl iodide. Subsequent deprotection with aqueous hydrochloric acid in acetone provides the ketones V or IV. Selective reduction of the ketones with LS-Selectride (Uthium tris-i-amylborohydride) provides the axial alcohols, ^" VTJI or IX, to the near exclusion of their equatorial isomers. Methylation ofVm under standard conditions provides the final inhibitor X. The napthyl group may be removed by hydrogenolysis (10% Pd/C, H2, ethanol) to give XL The phenol, XI, c an also be prepared from IX by methylation under standard conditions and deprotection of the MOM group by treatment with aqueous hydrochloric acid in THF. The phenol, XI, can be easily alkylated with the desired arylmethyl or heteroarylmethyl haUde by treatment with sodium hydride in dimethyl formamide (DMF).

Scheme II

1. [base]

2. R ₂ X

According to the foregoing reaction Scheme II, treatment of ketone V with the desired Grignard reagent produces axial alcohol XII which can be converted to the desired diether as described in Scheme I. EnoUzation of ketone V with a suitable base, foUowed by trapping with the desired alkyl haUde produces the cis, trans mixture XUI, which can be converted to the diether by reduction and alkylation as described in Scheme I.

The foregoing may be better understood from the foUowing Examples, which are presented for the purpose of illustration and not intended to limit the scope of the inventive concept.

Example 1 Preparation of 4-methoxy-4-r3-(napth-2-ylmethyloxy .phenyllcvclohexan- 1 - one.

Step 1. 4-hydroxy-4-r3-(naphth-2-ylmethyloxy)phenyllcyclohexan-l-one ethylene glycol ketal.

An oven dried flask was charged with a stirbar, 3-(napth-2- ylmethyloxy)-bromobenzene (0.63 g, 2 mmol), and freshly distilled THF (5 mL). The flask was fitted with a septum, a nitrogen inlet and a gas outlet and cooled to -78°C under a nitrogen flow. To this solution was added n-butyl Uthium (1.0 mL, 2.0 M solution in hexanes, 2 mmol). After stirring at -78°C for 1.5 hours, a THF solution (5 mL) of 1,4-cycloheaxanedione mono-ethylene glycol ketal (0.31 g, 2 mmol)was added. The reaction was stirred for 1.5 hours at -78°C and judged to be complete by tic at that point. The reaction was quenched by adding excess saturated aqueous ammonium chloride. The resulting biphasic mixture was extracted with ether. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a colorless oil which was crystaUized with ethyl acetate/hexanes. The product was collected by filtration and dried in vacuo to provide 0.28 g (36 %) as a colorless solid (mp 128-129°C).

Step 2. 4-methoxy-4-r3-(naphth-2-ylmethyloxy phenyllcyclohexan- 1 -one ethylene glycol ketal.

4-hydroxy-4-[3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l- one ethylene glycol ketal (2.4 g, 6.15 mmol) prepared in step 1 was dissolved in freshly dried THF (50 mL) and sodium hydride (0.16 g, 6.76 mmol) was added portionwise to the mixture. After gas evolution ceased methyl iodide (0.5 mL, 7.99 mmol) was added and the reaction was stirred for 17 hours at ambient temperature. The reaction was quenched by adding excess saturated aqueous ammonium chloride. The resulting biphasic mixture was extracted with ether. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a solid which was purified by chromatography on silica gel (15% ethyl acetate/hexanes) to provide the corresponding methyl ether as a colorless solid (2.12 g, 85%, mp 112-114°C).

Step 3. 4-methoxy-4-( ^" 3-rnapth-2-yUnethyloxy)phenyllcvclohexan-l-one. 4-methoxy-4-[3-(naphth-2-ylmethyloxy)phenyl]cyclohexan- 1 -one ethylene glycol ketal (1.7 g, 4.2 mmol) prepared in step 2 was dissolved in ethanol (150 mL) and water (30 mL) and 3N aqueous hydrochloric acid added (10 mL). The reaction was stirrred at ambient temperature until tic indicated complete reaction (~48 h) and neutralized with aqueous sodium carbonate. The resulting solution was partitioned between ethyl acetate and saturated aqueous brine. The combined organic layers were dried (MgSO-ø, filtered and concentrated in vacuo to give a solid which was purified by chromatography on silica gel (20% ethyl acetate/hexanes) to provide the corresponding ketone as a colorless soUd. RecrystaUization from ethyl acetate/ hexanes provided the pure ketone (0.85 g, 56%). mp 104-105°C. ^l U NMR (300 MHz, CDCI3) δ 7.82- 7.92 (4H, m), 7.57 (IH, dd, J=9, 1.5 Hz), 7.47-7.52 (2H, m), 7.31 (IH, t, J= 8.5 Hz), 7.13 (IH, dd, J=2,1.5 Hz), 7.01 (IH, dt, J= 8.5,1,1 Hz), 6.97 (IH, dd, J=8.5,3 Hz), 5.23 (2H, s), 3.5 (IH, br pentetn, J= 4 Hz), 3.07 (3H, s), 2.70-2.83 (2H, m), 2.28-2.43 (4H, m), 2.12 (2H, td, J= 14.5,14.5,4.5 Hz). MS m/e 361 (M+H)+, 378 (M+NH ₄ )+. Analysis calc'd for C ₂₄ H24O ₃ : C, 79.97; H, 6.71; Found: C, 80.47; H, 6.74.

Example 2

Preparation of tr_.n_;-4-methoxy-4-r3-(napth-2-ylmethyloxy)phenyncyclohexan - l-ol.

An oven dried flask, under a nitrogen flow, was charged with a stirbar, 4-methoxy-4-(3-[napth-2-ylmethyloxy)phenyl]cyclohexan-l-one (0.36 g, 1.0 mmol), prepared as in Example 1, and freshly dried THF (30 mL). The resulting solution was cooled to -78°C and a prechiUed solution (0°C) of LS- selctride (1.0 mL, 1.0 mmol) was added via syringe. The reaction was warmed to ambient temperature and stirred for 80 hours. The reaction was carefuUy quenched by adding excess dilute aqueous hydrochloric acid. The resulting biphasic mixture was extracted with ether. The combined organic layers were dried (MgSO- , filtered and concentrated in vacuo to give an oil which was purified by chromatography on silica gel (30% ethyl acetate/hexanes) to provide the corresponding alcohol as a colorless oU. Crystallization was induced by treatment with a ether/hexanes mixture to provide the correponding axial alcohol as a colorless solid (0.25 g, 69%). mp 106-108°C. *H NMR (300 MHz, CDC13) δ 7.82-7.92 (4H, m), 7.57 (IH, dd, J=9, 1.5 Hz), 7.47-7.52 (2H, m), 7.29 (IH, d, J=9Hz), 7.13 (IH, dd, J=2,1.5 Hz), 7.04 (IH, dt, J=

9,1,1 Hz), 6.93 (IH, ddd, J=9,3,l Hz), 5.24 (2H, s), 4.10 (IH, sextet, J= 4 Hz), 2.97 (3H, s), 2.14 (2H, td, J= 14.5,14.5,4.5 Hz), 1.96 (2H, tt, J= 14.5,14.5,3,3 Hz), 1.83 (2H, br d, J= 14.5 Hz), 1.63 (2H, br dd, J= 14.5,4.5), 1.20 (IH, d, J=4 Hz). MS m e 380 (M+NH4)+. Analysis calc'd for C24H26O3: C, 79.53; H, 7.23. Found: C, 79.56; H, 7.33.

Example 3

Preparation of trans- 1.4-dimethoxy-4-r3-(napth-2-ylmethyloxy)phenyri- cyclohexane. The desired compound was prepared according to the method of

Example 1, step 2, except substituting trαn_.-4-methoxy-4-[3-(napth-2- ylmethyloxy)phenyl]cyclohexan-l-ol (0.10 g, 0.28 mmol), prepared as in Example 2, for 4-hydroxy-4-[3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l- one ethylene glycol ketal, and adding 2% dry DMF to achieve an acceptable reaction rate. The title compound was purified by chromatography on sUica gel (5% ethyl acetate/hexanes) and recrystalUzation from methanol (8 mg, 8%). mp 76-77°C. !H NMR (300 MHz, CDC13) δ 7.82-7.92 (4H, m), 7.57 (IH, dd, J=9, 1.5 Hz), 7.47-7.52 (2H, m), 7.27 (IH, t, J= 8.5 Hz), 7.13 (IH, dd, J=2,1.5 Hz), 7.02 (IH, dt, J= 8.5,1,1 Hz), 6.93 (IH, ddd, J=8.5,3,l Hz), 5.23 (2H, s), 3.5 (IH, br penteto, J= 4 Hz), 3.32 (3H, s), 2.97 (3H, s), 1.97- 2.10 (2H, m), 1.75-1.90 (6H, m). MS m/e 394 (M+NH4)+. Analysis calc'd for C25H28O3: C, 79.75; H, 7.50. Found: C, 79.49; H, 7.57.

Example 4 Preparation of trα _ ^, -4-methoxy- l-methyl-4-[3-(napth-2-ylmethyloxy phenyll- cyclohexanol.

The title compound is prepared by treatment of 4-methoxy-4-(3-[napth- 2-ylmethyloxy)phenyl]cyclohexan-l-one, prepared as in Example 1, with methylmagnesium bromide.

Example 5 Preparation of trans- 1.4-dimethoxy-l -methyl-4-.3-(napth-2- ylmethyloxy^pheny 11 cyclohexane.

The title compound is prepared according to the method of Example 1, step 2, except substituting trαns-4-methoxy-l-methyl-4-[3-(napth-2- y_methyloxy)phenyl] cyclohexanol, prepared as in Example 4, for 4-hydroxy-4- [3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l-one ethylene glycol ketal.

Example 6

Preparation of cis- and tran_ 4-methoxy-2-methyI-4-r3-(napth-2-ylmethyloxy.- phenyll cyclohexanone. The title compound is prepared by alkylation of the lithium enolate of 4- methoxy-4-(3-[napth-2-ylmethyloxy)phenyl]cyclohexan-l-one, prepared as in Example 1, in THF at -78-0°C with excess methyl iodide.

Example 7 Preparation of 1RS.2RS.3RS- and lRS.2SR.3RS-4-methoxy-2-methyl-4-r3- .napth-2-ylmethyloxy.phenyllcyclohexanol.

The title compound is prepared according to the method of Example 2, except substituting cis- and tra/w-4-methoxy-2-methyl-4-[3-(napth-2- ylmethyloxy)phenyl] cyclohexanone, prepared as in Example 6, for 4-methoxy- 4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexan-l-one.

Example 8

Preparation of 1RS.2RS.3RS- and lRS.2SR.3RS-1.4-dimethoxy-2-methyl-4-

(3-(napth-2-ylmethyloxy,phenyl.cyclohexane. The title compound is prepared according to the method of Example 1 step 2, except substituting 1RS,2RS,3RS- and lRS,2SR,3RS-4-methoxy-2- methyl-4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexanol, prepared as in

Example 7, for 4-hydroxy-4-[3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l- one.

Example 9

Preparation of tran_ 4-methoxy-l-methoxymethyloxy-4-.3-(napth-2- ylmethyloxy ^' )phenyl] cyclohexane.

The title compound is prepared by treatment of trα/w-4-methoxy-4-[3- (napth-2-ylmethyloxy)phenyl]cyclohexan- 1 -ol, prepared as in Example 2, with chloromethyl methylether (MOM-C1, 1.5 eqiuv) in the presence of NN- d sopropylethylamine (2 equiv) in dichloromethane.

Example 10

Preparation of trans- 1.4-dimethoxy-4-G- .1.2-dihvdro- 1 -methyl-2-oxoquinoUn- 6-yl-methyloxy ^" )phenyl)cyclohexane.

The title compound was prepared by removal of the napthylmethyloxy group from trans- 1 ,4-dimethoxy-4-[3-(napth-2- ylmethyloxy)phenyl]cyclohexane, prepared as in Example 3 by exposure to 10% Pd/C and 4 atmospheres of hydrogen in methanol at ambient temperature for 17 hours to give the free phenol. The phenol was alkylated as described in Example 1, step 2.except substituting l,2-dihydro-l-methyl-2-oxoquinolin-6- yl-methyl bromide (prepared as described in EPA 385-679) for methyl iodide. !H NMR (300 MHz, CDC1 ₃ ) δ 7.62-7.72 (3H, m), 7.40 (IH, d, J=9 Hz), 7.26-7.32 (IH, m), 7.02-7.10 (2H, m), 6.88 (IH, ddd, J= 8.5, 2.5, 1 Hz), 6.75 (IH, d, J= 8.5 Hz), 5.13 (2H, s), 3.76 (3H, s), 3.50 (IH, br m), 3.32 (3H, s), 2.97 (3H, s), 1.97-2.10 (2H, m), 1.75-1.90 (6H, m). MS m e 425 (M+NH ₄ )+, 408 (M+H)+. Analysis calc'd for C25H29NO4: C, 73.69; H, 7.17; N, 3.44. Found: C, 73.33; H, 7.25 ; N, 3.13.

Example 11

Preparation of trans- 1.4-dimemoxy-4-.5-fluoro-3-(napth-2-ylmethyloxyy phenyllcyclohexane.

Step 1. 4-methoxy-4-r5-fluoro-3-(napth-2-ylmethyloxy.phenyll cyclohexanone.

The desired compound is prepared according to the method of Example

1 except substituting 5-fluoro-3-(napth-2-ylmethyloxy)bromobenzene, prepared as described in EPA 385-679, for 3-(napth-2-ylmethyloxy)bromobenzene.

Step 2. trαns-4-methoxy-4-.5-fluoro-3-(napth-2-ylmethyloxy .phenyll- cvclohexan-1-ol.

The desired compound is prepared according to the method of Example 2, except substituting 4-methoxy-4-[5-fluoro-3-(napth-2-ylmethyloxy)- phenyl]cyclohexanone, prepared as in step 1, for 4-methoxy-4-(3-(napth-2- ylmethyloxy)phenyl)cyclohexanone.

Step 3. trans- 1.4-dimetooxy-4-.5-fluoro-3-.napth-2-ylmethyloxy)phenyl1 cvclohexane.

The title compound is prepared according to the method of Example 1, step 2, except substituting trαns-4-methoxy-4-[5-fluoro-3-(napth-2-

ylmethyloxy)phenyl] cyclohexan-1-ol, prepared as in step 2, for 4-hydroxy-4- [3-(naphth-2-ylmethyloxy)phenyl] cyclohexan-1-one ethylene glycol ketal.

Example 12 Preparation of trans- l. dimethoxy-4-.5-fluoro-3-(1.2-dihydro-l-methyl-2- oxoquinolin-6-ylmethyloxy)phenyllcyclohexane. Step 1. 4-methoxy-4-r5-fluoro-3-(phenylmethyloxy)phenyllcyclohexan-l -one.

The desired compound was prepared according to the method of Example 1, except substituting 5-fluoro-3-(phenylmethyloxy)bromobenzene, prepared as described in EPA 385-679, for 3-(napth-2- ylmethyloxy)bromobenzene, and substituting 1,4-cyclohexanedione mono-2,2- dimethyltrimethylene ketal for 1,4-cycloheaxanedione mσnø-ethylene glycol ketal.

Step 2. trαns-4-methoxy-4-r5-fluoro-3-(phenylmethyloxy phenyllcyclohexan- l-ol.

The desired compound was prepared according to the method of Example 2, except substituting 4-methoxy-4-[5-fluoro-3- (phenylmethyloxy)phenyl]cyclohexan-l-one, prepared as in step 1, for 4- methoxy-4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexan- 1-one.

Step 3. trans- 1.4-dimethoxy-4-.5-fluoro-3-(phenylmethyloxy phenyl]- cyclohexane.

The desired compound was prepared according to the method of Example 1, step 2, except substituting trαns-4-methoxy-4-[5-fluoro-3- (phenylmethyloxy)phenyl]cyclohexan-l-ol, prepared as in step 2, for 4- hydroxy-4-[3-(naphth-2-ylmethyloxy)phenyl] cyclohexan- 1-one ethylene glycol ketal.

Step 4. trans- 1.4-dimethoxy-4-.5-fluoro-3-.1 ,2-dihydro- l-methyl-2- oxoquinolin-6-yl-methyloxy phenyllcyclohexane.

The desired compound was prepared according to the method of Example 10, except substituting trans- l,4-dimethoxy-4-[5-fluoro-3- (phenylmethyloxy)phenyl] cyclohexane, prepared as in step 3, for trans- 1,4- dimethoxy-4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexane. mp 133-134 °C. *H NMR (300 MHz, CDC1 ₃ ) δ 7.68 (IH, d, J=9 Hz), 7.60-7.64 (2H, m), 7.38 (IH, d, J=9 Hz), 6.87 (IH, t, J=l Hz), 6.77 (IH, ddd, J=8.5,2.5,l Hz),

6.73 (IH, d, J= 8.5 Hz), 6.59 (IH, dt, J= 8.5,2 Hz), 5.11 (2H, s), 3.74 (3H, s), 3.50 (IH, br m), 3.32 (3H, s), 2.98 (3H, s), 1.90-2.03 (2H, m), 1.72- 1.90 (6H, m). MS m e 443 (M+NH ₄ ) ⁺ , 426 (M+H)+. Analysis calc'd for C25H28FNO4: C, 70.57; H, 6.63; N, 3.29. Found: C, 70.44; H, 6.57; N, 3.28.

Example 13

Preparation of trans- 1.4-dimethoxy-4-r5-fluoro-3-(l .3-dimethyl-2-oxo-2.3- dihvdro benzimidazol-5-yl-methyloxy phenylcvclohexane. Step 1. 1.3-dimethyl-2-oxo-5-bromomethyl-2.3-dihydrobenzimidazole.

A solution of l,3,5-trimethyl-2-oxo-2,3-dihydrobenzimid__zole (2.8 g, 15.9 mmol), N-bromosuccinimide (3.0 g, 16.9 mmol), and AIBΝ (10 mg, 0.061 mmol) in CCI4 (60 mL) was warmed to reflux. An additional 10 mg of AIBΝ was added and the reaction mixture was stirred for 1.5 hours at reflux. The reaction mixture was cooled to ambient temperature and partitioned between CH2CI2 and H2O. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give l,3-dimethyl-2-oxo-5- bromomethyl-2,3-dihydrobenzimidazole as a white solid which was used without further purification.

Step 2. trαns-1.4-dimethoxy-4-r5-fluoro-3-(1.3-dimethyl-2-oxo-2.3-d ihydro benzimidazol-5-yl-methyloxy.phenylcyclohexane.

The desired compound was prepared according to the method of Example 10, except substituting l,3-dimethyl-2-oxo-5-bromomethyl-2,3- dihydrobenzimidazole for l,2-dihydro-l-methyl-2-oxoquinoUn-6-yl-methyl bromide, mp 88-92°C. ^l H ΝMR (300 MHz, CDCI ₃ ) δ 7.17 (IH, dd, J=8.5,2 Hz), 7.08 (IH, br d, J=l Hz), 6.97 (IH, d, J=8 Hz), 6.87 (IH, t, J=l Hz), 6.75 (IH, ddd, J=8.5,2.5,l Hz), 6.59 (IH, dt, J= 8.5,2 Hz), 5.06 (2H, s), 3.50 (IH, br m), 3.44 (3H, s), 3.42 (3H, s), 3.32 (3H, s), 2.98 (3H, s), 1.90- 2.03 (2H, m), 1.72-1.90 (6H, m). MS m e 443 (M+ΝH4) ⁺ , 426 (M+H)+. Analysis calc'd for C24H29FN2O4: C, 67.27; H, 6.82; N, 6.53. Found: C, 67.04; H, 6.69; N, 6.40.

The compounds represented in Table 2 are prepared by alkylation of the appropriate aromatic alcohol, obtained as described in Scheme 1 and Examples 10, 12, or 13 with the requisite 3-heteroaryl-prop-2-yn-l-yl haUde which is prepared as described in EP- 385-663.

Table 2

Novel Heteroarylacetylene Substitoted trans- 1,4-dimethoxycyclohexane

Derivatives

The compounds represented in Table 3 are prepared by alkylation of the appropriate phenol, obtained as described in Scheme 1 and Examples 10, 12, or 13 with the requisite arylmethyl or heteroarylmethyl haUde according to the method of Example 1.

Table 3

Novel Heteroarylmethyloxy Substitoted trans- 1,4-dimethoxycyclohexane derived 5-Upoxygenase inhibitors.