AU707574B2 - Tri-aryl ethane derivatives as PDE IV inhibitors - Google Patents

Description

i WO 97/22586 PCT/CA96/00839 -1- TITLE OF THE INVENTION TRI-ARYL ETHANE DERIVATIVES AS PDE IV INHIBITORS BACKGROUND OF THE INVENTION This invention relates to compounds and pharmaceutical compositions for the treatment of diseases by raising the level of cyclic (cAMP) through the inhibition of phosphodiesterase IV (PDE IV).

Many hormones and neurotransmitters modulate tissue function by elevating intra-cellular levels of 5'-cyclic adenosine monophosphate (cAMP). The cellular levels of cAMP are regulated by mechanisms which control synthesis and breakdown. The synthesis of cAMP is controlled by adenyl cyclase which may be directly activated by agents such as forskolin or indirectly activated by the binding of specific agonists to cell surface receptors which are coupled to adenyl cyclase. The breakdown of cAMP is controlled by a family of phosphodiesterase (PDE) isoenzymes, which also control the breakdown of guanosine 3',5'-cyclic monophosphate (cGMP). To date, seven members of the family have been described (PDE I-VII) the distribution of which varies from tissue to tissue. This suggests that specific inhibitors of PDE isoenzymes could achieve differential elevation of cAMP in different tissues, [for reviews of PDE distribution, structure, function and regulation, see Beavo Reifsnyder (1990) TIPS, 11: 150- 155 and Nicholson et al (1991) TIPS, 12: 19-27].

The availability of PDE isotype selective inhibitors has enabled the role of PDEs in a variety of cell types to be investigated. In particular it has been established that PDE IV controls the breakdown of cAMP in many inflammatory cells, for example, basophils (Peachell P.T. et al., (1992) J. Immunol. 148 2503-2510) and eosinophils (Dent G. et al., (1991) Br. J. Pharmacol. 103 1339-1346) and that inhibition of this isotype is associated with the inhibition of cell activation.

Furthermore, elevation of cAMP in airway smooth muscle has a spasmolytic effect. Consequently PDE IV inhibitors are currently being developed as potential anti-inflammatory drugs particularly for the WO 97/22586 PCT/CA96/00839 -2prophylaxis and treatment of asthma, by achieving both antiinflammatory and bronchodilator effects.

The application of molecular cloning to the study of PDEs has revealed that for each isotype there may be one or more isoforms.

For PDE IV, it is has been shown that there are four isoforms B, C and D) each coded for by a separate gene in both rodents (Swinnen J.V.

et al., (1989) Proc. Natl. Acad. Sci. USA 86 5325-5329) and man (Bolger G. et al., (1993) Mol. Cell Biol. 13 6558-6571).

The existence of multiple PDE IVs raises the prospect of obtaining inhibitors that are selective for individual isoforms, thus increasing the specificity of action of such inhibitors. This assumes that the different PDE IV isoforms are functionally distinct. Indirect evidence in support of this comes from the selective distribution of these isoforms in different tissues (Swinnen et al., 1989; Bolger et al., 1993; Obernolte R. et al., (1993) Gene 129 239-247, ibid) and the high degree of sequence conservation amongst isoforms of different species.

To date full length cDNAs for human PDE IVA, B and D (Bolger et al., 1993 ibid; Obernolte et al., 1993 ibid; Mclaughlin M. et al., (1993) J. Biol. Chem. 268 6470-6476) and rat PDE IVA, B and D (Davis R. et al., (1989) Proc. Natl. Acad. Sci. USA 86 3604-3608; Swinnen J.V. et al., (1991) J. Biol. Chem. 266 18370-18377), have been reported, enabling functional recombinant enzymes to be produced by expression of the cDNAs in an appropriate host cell. These cDNAs have been isolated by conventional hybridisation methods. However using this approach, only partial cDNAs for both human and rat PDE IVC have been obtained. (Bolger et al., ibid. 1993 and Swinnen et al., ibid.

1989 and International Patent Specification No. WO 91/16457.) The design of PDE IV inhibitors for the treatment of inflammatory diseases such as asthma, has met with limited success to date. Many of the PDE IV inhibitors which have been synthesised have lacked potency and/or inhibit more than one type of PDE isoenzyme in a non-selective manner. PDE IV inhibitors that are relatively potent and selective for PDE IV, are reported to be emetic as well. Indeed this side effect has been so universal that experts have expressed their belief that WO 97/22586 PCT/CA96/00839 -3the emesis experienced upon administration of a PDE IV inhibitor, may be mechanism based.

We have now found a novel series of tri-substituted phenyl derivatives, members of which compared to known structurally similar compounds are potent inhibitors of PDE IV at concentrations at which they have little or no inhibitory action on other PDE isoenzymes. These compounds inhibit the human recombinant PDE IV enzyme and also elevate cAMP in isolated leukocytes. Certain compounds prevent inflammation in the lungs induced by carrageenan, platelet-activating factor (PAF), interleukin-5 (IL-5) or antigen challenge. These compounds also suppress the hyperresponsiveness of airway smooth muscle seen in inflamed lungs. Advantageously, compounds according to the invention have good oral activity and at orally effective doses exhibit little or none of the side-effects associated with known PDE IV inhibitors, such as rolipram. The compounds of the invention are therefore of use in medicine, especially in the prophylaxis and treatment of asthma and other inflammatory conditions.

SUMMARY OF THE INVENTION The invention encompasses novel compounds of Formula I useful in the treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP.

OR

2

R

3 0~ v .HET

RI

I

The invention also encompasses certain pharmaceutical compositions and methods for treatment of diseases by inhibition of WO 97/22586 PCT/CA96/00839 -4- PDE IV, resulting in an elevation of cAMP, comprising the use of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION The invention encompasses the novel compound of Formula I useful in the treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP,

OR

2

R

3 0

^-HET

R'

I

or a pharmaceutically acceptable salt thereof wherein: R is selected from hydrogen, C1-6alkyl, halo and CF3;

R

1 is selected from -(CH2)m-CO-N(R 4 2 -R5, wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(0)2-NR 6

R

7 -(CH2)m-S(0)2-N(R 4

)-CO-R

4 -(CH2)m-S(0)2-N(R 4

)-CO-NR

6 R7, -C(OH)(C1-6haloalkyl)2,

R

2 and R 3 are independently selected from C1-7alkyl, WO 97/22586 PCT/CA96/00839 substituted C1-7 alkyl, wherein the substituent is F, Cl, Br or I, 2-phenethyl or 2-indanyl, optionally mono or disubstituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio,

CN,

CF3, C1-6alkyl, N3, -CO2H,

R

4 is selected from hydrogen, Ci-6alkyl, phenyl, benzyl or 2-phenethyl, optionally mono or disubstituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio,

CN,

CF3, C1-6alkyl, N3, -CO2H,

R

5

R

8 and R11 are each independently selected from -CF3, C1-6alkyl, WO 97/22586 PCT/CA96/00839 -6phenyl, benzyl or 2-phenethyl, optionally mono or disubstituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio,

CN,

CF3, C1-6alkyl, N3, -CO2H,

R

6

R

7

R

9 and R 1 0 are each independently selected from hydrogen, and C1-6alkyl, or

R

6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C1-6alkyl, Cl- 6alkoxy, C1-6alkylthio, benzyl, 2-phenethyl, NHCOR 8

NR

9 NHS(O)2R11, OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N--O or CH.

Within this embodiment there is a genus of compounds wherein

R

2 is cyclopentyl, and

R

3 is methyl, Within this genus there is a class of compounds wherein R is selected from WO 97/22586 WO 9722586PCT/CA96/00839 -7hydrogen, ClI-4alcyl, halo and CF3; R1 is selected from -(CH2)m-CO-N(R 4 2 -R5, wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(O)2-NR6R7, -(CH2)m-S(O)2-N(R 4 )-C0.R4, -(CH2)m-S(O)2-N(R 4 )-CO-NR6R7, -C(OH)(C 1-6haloalkyl)2,

R

2 is cyclopentyl,

R

3 is methyl,

R

4 is selected from hydrogen, C1-6alkyl, phenyl, benzyl or 2-phenethyl, optionally mono or disubstituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, Ci -6allcoxy, C 1-6alkylthio,

CN,

CF3, C1-6alkyl, N3, -CO2H,

R

5

R

8 and R 1 1 are each independently selected from -CF3, C1-6alkyl, phenyl, benzyl. or 2-phenethyl, optionally mono or disubstituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, Cl-6alkoxy, WO 97/22586 PCT/CA96/00839 -8- C1-6alkylthio,

CN,

CF3, C1-6alkyl, N3, -CO2H,

R

6

R

7

R

9 and R 10 are each independently selected from hydrogen, and C1-6alkyl, or

R

6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C1-6alkyl, C1- 6alkoxy, C1-6alkylthio, benzyl, 2-phenethyl,

NHCOR

8

NR

9

R

1 0, NHS(O)2R11, OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N->O or CH.

Within this class there is a sub-class of compounds wherein R is selected from hydrogen, C1-3alkyl, halo, and CF3; and is ortho to R1;

R

1 is selected from -(CH2)m-CO-N(R 4 2 -R5, wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(0)2-NR6R7, -(CH2)m-S(0)2-N(R 4

)-CO-R

4 -(CH2)m-S(0)2-N(R 4

)-CO-NR

6 R7, -C(OH)(C1-6haloalkyl)2,

R

2 is cyclopentyl, WO 97/22586 PCT/CA96/00839 -9-

R

3 is methyl,

R

4 is selected from hydrogen, C1-6alkyl,

R

5

R

8 and R11 are each independently selected from -CF3, C1-6alkyl,

R

6

R

7

R

9 and R10 are each independently selected from hydrogen, and Cl-6alkyl, or

R

6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C1-6alkyl, C1-6alkoxy, C1- 6alkylthio, benzyl, 2-phenethyl, NHCOR 8

NR

9 R10, NHS(0)2R11,

OH,

CN, or CF3, and the N-oxides thereof; and X is CH.

As appreciated by those of skill in the art, Halo is intended to include F, Cl, Br, and I.

For purposes of this specification alkyl is defined to include linear, branched, and cyclic structures, with C1-6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, Cl-6alkoxy is intended to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.

Likewise, C1-6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration.

WO 97/22586 WO 9722586PCT/CA96/00839 10 Examples of allcylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies

-SCH

2

CH

2

CH

3 Cl..6haloalkyl means an alkyl group in which two or more hydrogen atoms have been replaced by halogen atoms.

Exemplifying the invention are: N- I [1 3 -Cyclopentyloxy-4methoxyphenyl).2-(4pyridyl)ethyllbenzoyl I methanesulfonamide, N- I 3 -Cyclopentyloxy-4-methoxyphenyl).2- 4 -pyridyl)ethyllbenzoyl Ibenzenesulfonamide, N- I l-( 3 -Cyclopentyloxy-4-methoxyphenyl..2-.(4pyridyl)ethyllbenzoyl I trifluoromethanesulfonamide, N- l-( 3 -Cyclopentyloxy-4-methoxyphenyl>2- 4 -pyridyl)ethyljjbenzoyl I o-toluenesulfonamide, ALIN-{ I(-ylpntlx--ehxyhnl--4 pyridyl)ethyllphenylacetyl I benzenesulfonamide, N- f [1 3 -Cyclopentyloxy-4-.methoxyphenyl)2(4pyridyl)ethyl]phenylacetyl Itrifluoromethanesulfonamide, 2 3 -Cyclopentyloxy-4-methoxyphenyl).2-[4- 1, 1,333hxfuoo2hdoypoaphenyl]ethyl Ipyridine, and N-(o-Toluoyl)-4- 3 -Cyclopentyloxy-4-.

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 pharmaceutically 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.

WO 97/22586 PCT/CA96/00839 11 In a second embodiment, the invention encompasses pharmaceutical compositions for treatment of disease by inhibition of PDE IV, as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.

Within this embodiment the invention encompasses pharmaceutical compositions for treatment of disease by inhibition of PDE IV, resulting in an elevation of cAMP, as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above.

For purposes of this specification a compound is said to selectively inhibit PDE IV in preference to other PDE's if the ratio of the IC50 concentration for all other PDE inhibition to PDE IV inhibition is 100 or greater.

The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically 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 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_dibenzylethylenediamine, diethylamine, 2 -diethylaminoethanol, 2dimethylaminoethanol, ethanolamine, ethylenediamine,

N-

ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, WO 97/22586 PCT/CA96/00839 12piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

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.

Compounds according to the invention are selective and potent inhibitors of PDE IV. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.

The compounds according to the invention are thus of particular use in the prophylaxis and treatment of human diseases where an unwanted inflammatory response or muscular spasm (for example bladder or alimentary smooth muscle spasm) is present and where the elevation of cAMP levels may be expected to prevent or alleviate the inflammation and relax muscle.

Particular uses to which the compounds of the invention may be put include the prophylaxis and treatment of asthma, especially inflamed lung associated with asthma, cystic fibrosis, or in the treatment of inflammatory airway disease, chronic bronchitis, eosinophilic granuloma, psoriasis and other benign and malignant proliferative skin diseases, endotoxic shock, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis and artherosclerosis.

Compounds of the invention also suppress neurogenic inflammation through elevation of cAMP in sensory neurones. They are, therefore, analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseases associated with irritation and pain.

Compounds according to the invention may also elevate cAMP in lymphocytes and thereby suppress unwanted lymphocyte activation in WO 97/22586 PCT/CA96/00839 13immune-based diseases such as rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft versus host disease.

Compounds according to the invention have also been found to reduce gastric acid secretion and therefore can be used to treat conditions associated with hypersecretion of gastric acid.

Compounds of the invention suppress cytokine synthesis by inflammatory cells in response to immune or infectious stimulation.

They are, therefore, useful in the treatment of bacterial, fungal or viral induced sepsis and septic shock in which cytokines such as tumour necrosis factor (TNF) are key mediators. Also compounds of the invention suppress inflammation and pyrexia due to cytokines and are, therefore, useful in the treatment of inflammation and cytokinemediated chronic tissue degeneration which occurs in diseases such as rheumatoid or osteo-arthritis.

Over-production of cytokines such as TNF in bacterial, fungal or viral infections or in diseases such as cancer, leads to cachexia and muscle wasting. Compounds of the invention ameliorate these symptoms with a consequent enhancement of quality of life.

Compounds of the invention also elevate cAMP in certain areas of the brain and thereby counteract depression and memory impairment.

Compounds of the invention suppress cell proliferation in certain tumour cells and can be used, therefore, to prevent tumour growth and invasion of normal tissues.

For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula together with one or more pharmaceutically acceptable carriers, excipients or diluents.

For the treatment of any of these, compounds of formula

I

may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles. The WO 97/22586 PCT/CA96/00839 -14term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.

These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed WO 97/22586 PCT/CA96/00839 with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or npropyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already WO 97/22586 PCT/CA96/00839 16mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.

Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.

This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Compounds of formula I may also be administered in the form of a suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

WO 97/22586 PCT/CA96/00839 17- For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.

(For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about mg to about 3.5 g per patient per day.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

WO 97/22586 PCT/CA96/00839 18- Methods of Synthesis The compounds of the present invention can be prepared according to W094/14742, published on 7 July 1994, or according to WO 95/17386, published on 29 June 1995, which are hereby incorporated by reference or by the methods described below. It will be apparent to one skilled in the art that similar methodology could be used to prepare the enantiomers or the racemates of the illustrated compounds.

CHEMISTRY

Scheme 1 Carboxylic acid derivatives were prepared by the method presented in Scheme 1. The diastereoselective addition of Grignard reagents derived from suitable bromoaryl-1,3-dioxolanes to acylsultam Michael acceptor II afforded triarylpropanoylsultam intermediates.

Removal of the chiral auxiliary, subsequent decarboxylation and aldehyde deprotection were then performed in a one-pot fashion by successive treatment with a suitable lithium thiolate followed by a saponification with aqueous hydroxide and then by an aqueous acidic treatment. In this way, carboxaldehyde intermediates were obtained.

Oxidation of those by sodium chlorite gave access to carboxylic acid intermediates 1 and 2. Acylsulfonamides were prepared by treating acids 1 and 2 with sulfonamides in the presence of a suitable carbodiimide and 4 -dimethylaminopyridine.

Scheme 2 The preparation of (1,1,1,3,3,3-hexafluoro-2hydroxypropan-2-yl)arene derivatives is shown in Scheme 2.

Monolithiation of suitable dihaloarenes followed by the addition of hexafluoroacetone gave access to the corresponding bis(trifluoromethyl)carbinol intermediates which were subsequently WO 97/22586 PCT/CA96/00839 19protected as their trimethylsilylethoxymethyl ethers. The diastereoselective addition of Grignard reagents derived from the latter intermediates to acylsultam Michael acceptor II afforded triarylpropanoylsultam intermediates. Removal of the chiral auxiliary and subsequent decarboxylation were then performed in a one-pot fashion by successive treatment with a suitable lithium thiolate followed by a saponification with aqueous hydroxide and then by an aqueous acidic treatment. Deprotection of the tertiary alcohol by treatment with tetrabutylammonium fluoride finally afforded the desired (1,1,1,3,3,3hexafluoro-2-hydroxypropan-2-yl)arene derivatives.

Scheme 3 Arenesulfonamide derivatives were prepared by the method presented in Scheme 3. Condensation of a suitable arenecarboxaldehyde with diphenyl 1-chloro-1-(heteroaryl)methanephosphonate Org.

Chem., 1992, 57, 1622) afforded the corresponding diarylalkynes. Acid catalized addition of hydrogen iodide followed by palladium catalyzed stannylation gave access to vinyltin intermediates. These were submitted to palladium catalyzed coupling with N,N-bis-(p-methoxybenzyl)-4bromobenzenenesulfonamide to yield the corresponding triarylethylene derivatives. Reduction of the double bond was performed by reaction with sodium borohydride and nickel(II) chloride hexahydrate and the sulfonamide moiety was subsequently deprotected by treatment with trifluoroacetic acid to afford the benzenesulfonamide intermediates.

Reaction of these with carboxylic acids in the presence of a suitable carbodiimide and 4 -dimethylaminopyridine gave access to acylbenzenesulfonamide derivatives.

WO 97/22586 PTC9/03 PCT/CA96/00839 20 Scheme 1 3 OR 2 RO~ HET 02 /M g 1) PrSH n-BuLl 2) NaOH 3) H 3 0+

OR

2 3 N) HET R XH NaCIO52

OR

2 R' 0-j 2

H

1 m=O 2 m=l

_R

5

S

2

NH

2 /EDC /DMAP I

OR

2

R

3 0O1t

HET

R 0-9O-NH-SO 2

-R

WO 97/22586 WO 9722586PCT/CA96/00839 21 Scheme 2 B r 1) n-BuLi 2) (CF 3 2 00 Br lBr SEM-Cl R- I/M 0CFH

OSEM

F3CF3 CF3

CF

3 1) PrSH n-BuLl 2) LiOH 3) H 3 0'

OR

2 TBAF

HET

R~ f x 0H

CF

3

CF

3 3

OR

2 zHET

SEM

CF-'CF

3 WO 97/22586 WO 9722586PCT/CA96/00839 22 Scheme 3 (PhO) 2

HET

cI t-BuOK

R

2 0

R

3 0 /HET Na! p-TsOH OR 2

R

3 Br R- p S0 2

N(PMB)

2 (Me 3 Sn) 2 Pd(Ph 3

P)

4 (Ph 3

P)

4 LiCI R3

R

3

C

TFA

OR

2

R

3

O

-HET

Me 3 Sn HET NaBH 4 NiC1 2 *6H 2 0

R

4

CO

2 H/ EDC DMAP

OR

2

R

3

HET

R-

S02 H'NOy WO 97/22586 PCT/CA96/00839 -23- Compounds of Schemes 4 to 6 were prepared as racemic mixtures, as described below.

Scheme 4 Coupling of 3,4-dihydroxy benzaldehyde with chlorodifluoromethane in the presence of potassium carbonate, using DMF as solvent at afforded 3 4 -bis-(difluoromethoxy) benzaldehyde X. This was condensed with the lithium anion of the protected 4-bromohenyl bistrifluoromethyl carbinol Xa from Example 7, to afford tertiary alcohol XI which was converted to the corresponding chloride XII using thionyl chloride in the presence of Hunig's base in toluene solution. The chloride XII was condensed with the a-anion of ethyl 4-pyridyl acetate, affording the intermediate ester derivative XIII, which on hydrolysis with lithium hydroxide in a THF-methanol-water medium, followed by acidification with aqueous ammonium chloride afforded the decarboxylated intermediate XIV. Removal of the SEM protecting group was effected using TBAF in THF, leading to the final compound

XV.

Scheme The compound XV was oxidized with m-chloroperoxy benzoic acid to afford the N-oxide XVI.

Scheme 6 The 3,4-dichloropyridine analog XVIII was elaborated as follows: the chloride XII was condensed with the lithium anion of 3,4-dichloropicoline, generated using LDA, affording the intermediate

XVII;

removal of the SEM protecting group was effected using TBAF in THF solution, to yield the final product XVIII.

WO 97/22586 PCT/CA96/00839 24 HO CHO

CHCIF

2

K

2 CO3~ DMF, 85 0

C

F2HCc F2HC a CHO Br F3C 0

,-,_TMS

CF

3 n-BuLl

OCHF

2

F

2

HC

IPr 2

NEI

F

3 C CF 3

OCHF

2

F

2

H-

N

1

OH

xi 0,1,,TMS

F

3

CF

3

KHMDS

F.2HC( 1) LICH, H 2 0 MOOH-, THF 2) aq. NH 4

CI

OCHF

2

F

2

HC

I N

,TMS

F

3 C

CF

3 .2 TBAF, THF

XIV

,,TMs 0 WO 97/22586 PTC9/03 PCT/CA96/00839 25 B~ham- OC HF 2

F

2

HC

'N 'N

OH

F

CF

3 mCPBA

OCHF

2

F

2

HC

I

N

OH

F

3

CF

3 ~b~na~A

OCHF

2

CH

3

F

2 HC .j CI

LDA

TMS

F

3 C CF 3

OCHF

2

C

F

2 HC ~-N F

CF

3 F2C OCHF 2 c N TBAF Vill

OH

F

3 C

CF

3 WO 97/22586 WO 9722586PCT/CA96/00839 26 Representative compounds are shown in Tables 1 to 3 Table 1 EX. m 1 0 OH 3 2 0 Ph~ 3 0 CF 3 4 0 o-Tol 1 Ph- 6 1 CF 3 Table 2 EX. 7 WO 97/22586 WO 9722586PCT/CA96/00839 27 Table 3

CH

3 Ex. 8 Table 4. In Vitro Potency of PDE IV inhibitors.

1050 (nM) EX. GST-Met 248 PDE lVa 3 1 4 0.4 6 0.8 7 0.2 8 0.7 Assays forDetermining Biological. Activity Establishment of CHO-Ki cell lines stably expressing PDE Wa enzyme CHO-Ki cells stably expressing the prostacyclin receptor and grown under G418 selection as described previously Boie, et al,' J. Biol.

Chem.: 269, 12173-12178, 1994) were plated at a density of 1.75 x 106 cells/175cm' in a T-175 flask (Gibco, Burlington, VT) containing alpha WO 97/22586 PCT/CA96/00839 -28- MEM media; 10% heat inactivated fetal bovine serum (FBS); 1% (v/v) penicillin/streptomycin; 25 mM Hepes, pH 7.4; and 500 gg/ml G418 (complete media). The cells were placed in an incubator for 24 hr at 37 0 C and 5% CO 2 The cells were then washed with warmed sterile phosphate buffered saline (PBS) and incubated with 2gg/ml DNA, and 9 gg/ml lipofectamine reagent in Opti-MEM for 7 hr. At 37 0 C and

CO

2 The incubation solution was diluted 1:2 with Opti-MEM containing 20% FBS and incubated overnight. Following the overnight incubation, the media was replaced by complete media containing 500 [g/ml hygromycin B. Colonies were identified and grown in T-175 flasks for further characterization.

Measurement of whole-cell cAMP content CHO-K1 cells were plated at a density of 10 6 cells/175 cm 2 containing complete media with 500 glg/ml hygromycin. The flasks were maintained in an incubator at 37 0 C with 5.0% CO 2 for 72 hr. The media was changed and the cells were allowed to grow overnight. The cells were washed and dissociated from the plate with PBS containing 0.5 mM EDTA. Cellular cAMP content was measured by centrifuging the cell suspension at 150 g x 10 min. And resuspending the cells in a Hanks buffered salt solution at a density of 0.2 x 10 6 cells/ml. The cells were preincubated at room temperature for 15 min. and then incubated with 10 tM prostaglandin I2 (PGI 2 and the indicated compound for an additional 10 min. Basal cAMP levels were determined by incubating the cells in 0.1% DMSO. The incubations were terminated by the addition of HCI (0.1 N final) and the cells measured for cAMP as described below.

Determinations of whole-cell cAMP content were performed by incubating 100 tl reconstituted rabbit anti-succinyl cAMP serum with 100 tl of the whole-cell reaction or known cAMP standard and 30 pmol of 1 25 I-cAMP TME in a ScintiStripTM well (300 pl final volume) at room temperature for 18 h. Total cpm (Bo) was determined in the absence of WO 97/22586 PCT/CA96/00839 -29sample of cAMP standard. The reaction mixture was then aspirated out of the well, and the individual wells were counted in a Beckman

LS

6000SC with the window open from 10-999 for 1 min. The data were expressed as %B/Bo [(standard or sample cpm non-specific cpm) (Bo cpm non-specific cpm)] x 100. Non-specific cpm were determined by incubating only the 1 25 I-cAMP TME with assay buffer (50 nM acetate; pH 5.8) in the ScintiStrip T M well. All determinations were performed in triplicate.

Phosphodiesterase Scintillation Proximity Assay CHO-K1 cells were lysed by sonication for 10 sees at a power setting of (Braunsonic Model 2000) in an ice cold solution containing mM Tris, pH 7.5; ImM EDTA; and 200 gM P-mercaptoethanol.

The soluble and particulate fractions of the cell were obtained by centrifuging the sonicate for 90 min. at 100,000 x g at 4 0 C. PDE activity was measured in a solution containing 50 mM Tris, pH MgCl 2 1 mM EDTA; and 100 nM (or indicated) 3 H-cAMP (100 pl final volume) in the presence of varying concentrations of inhibitor. The reaction mixture containing enzyme was incubated for 10 min. at 30 0 C in 96-well View Plates (Packard), and terminated by the addition of 50 pl Phosphodiesterase Scintillation Proximity Assay (SPA) Beads (Amersham) containing 18 mM ZnSO4. The amount of 3 H-cAMP hydrolysis was determined by counting the plates in a Wallac 1450 gBeta LSC counter.

The Elevation of cAMP in Leukocytes The effect of compounds of the invention on intracellular cAMP was investigated using human neutrophils or guinea pig eosinophils.

Human neutrophils were separated from peripheral blood, incubated with dihydrocytochalasin B and the test compound for min and then stimulated with FMLP. Guinea pig eosinophils were harvested by peritoneal lavage of animals previously treated with intra-peritoneal injections of human serum. Eosinophils were WO 97/22586 PCT/CA96/00839 separated from the peritoneal exudate and incubated with isoprenaline and test compound. With both cell types, suspensions were centrifuged at the end of the incubation, the cell pellets were resuspended in buffer and boiled for 10 min prior to measurement of cAMP by specific radioimmunoassay (DuPont).

The most potent compounds according to the Examples induced a concentration -dependent elevation of cAMP in neutrophils and/or eosinophils at concentrations of 0.lnM to ltM.

Suppression of Leukocyte Function Compounds of the invention were investigated for their effects on superoxide generation, chemotaxis and adhesion of neutrophils and eosinophils. Isolated leukocytes were incubated with dihydrocytochalasin B for superoxide generation only and test compound prior to stimulation with FMLP. The most potent compounds of the Examples caused a concentration-dependent inhibition of superoxide generation, chemotaxis and adhesion at concentrations of 0.lnM to 1 M.

Lipopolysaccharide (LPS)-induced synthesis of tumour necrosis factor (TNF) by human peripheral blood monocytes (PBM) is inhibited by compounds of the Examples at concentrations of 0.01nM to Relaxation of Constricted Airway Smooth Muscle in vitro The effects of compounds of the invention on guinea-pig isolated tracheal smooth muscle were investigated. Isolated tracheal rings were suspended in organ baths and immersed in oxygenated Krebs' solution. The smooth muscle was contracted with sub-maximal concentrations of histamine or carbachol prior to the addition of increasing concentrations of test compound to the organ baths. The most potent compounds of the Examples caused a concentrationdependent reversal of both histamine and carbachol-induced WO 97/22586 PCT/CA96/00839 -31 contractions at concentrations of InM to 10OpM. The compounds were generally more potent in reversing histamine-induced tone than carbachol-induced tone.

Effects on Cardiac Muscle in vitro Compounds of the invention have been tested for their effects on isolated cardiac muscle. Right atrial and papillary muscles were dissected out from the hearts of guinea pigs and suspended in organ baths for measuring the rate (chronotropic) of spontaneously beating atria and force (inotropic) of the electrically stimulated papillary muscle. In these preparations, selective PDE IV inhibitors such as rolipram do not have any direct effects whereas selective PDE III inhibitors such as milrinone have positive chronotropic and inotropic effects. The non-specific PDE inhibitor theophylline, which is used in asthma as a bronchodilator, also causes significant cardiovascular changes such as tachycardia.

Selective PDE IV inhibitors have advantage over theophylline, therefore, through reduced cardiovascular side effects. The most potent and selective compounds of the Examples had no direct effects on the atrial and papillary muscles in vitro at concentrations up to 10M but in combination with PDE III inhibitors, these inhibitors showed an enhancement of chronotropic and inotropic activity, typical of selective type IV inhibitors.

Anti-inflammatory Activity in vivo (IL-5)-induced pleural eosinophilia in the rat (Lisle, etal, 1993, Br.J. Pharmacol. 108 2 3 0p) is inhibited by compounds of the Examples given orally at doses of 0.0001 to 10.0mg/kg. The most potent compounds cause a dose-dependent reduction in migrating eosinophils with ED 50 s of 0.003 to 0.03mg/kg p.o.

Compounds of the invention also reduce the inflammatory responses induced in rats by platelet activating factor (PAF).

WO 97/22586 PCT/CA96/00839 -32- Anti-allergic Activity in vivo Compounds of the invention have been tested for effects on an IgEmediated allergic pulmonary inflammation induced by inhalation of antigen by sensitised guinea pigs. Guinea pigs were initially sensitised to ovalbumin under mild cyclophosphamide-induced immunosuppression, by intraperitoneal injection of antigen in combinations with aluminium hydroxide and pertussis vaccine.

Booster doses of antigen were given two and four weeks later and at six weeks, animals were challenged with aerosolised ovalbumin whilst under cover of an intraperitoneally administered antihistamine agent (mepyramine). After a further 48h, bronchial alveolar lavages (BAL) were performed and the numbers of eosinophils and other leukocytes in the BAL fluids were counted.

The lungs were also removed for histological examination for inflammatory damage. Administration of compounds of the Examples (0.001-10mg/kg i.p. or up to three times during the 48h following antigen challenge, lead to a significant reduction in the eosinophilia and the accumulation of other inflammatory leukocytes. There was also less inflammatory damage in the lungs of animals treated with compounds of the Examples.

Effects on Pulmonary Dynamics Compounds of the invention (0.001-10mg/kg by oral or other route of aministration) reduce the allergic bronchoconstruction caused by antigen in sensitized guinea pigs.

Compounds of the invention have been tested for their effects on ozone-induced hyperreactivity of the airways of guinea pigs.

Following the inhalation of ozone, guinea pigs become very much more sensitive to the bronchoconstrictor effects of inhaled histamine than naive animals (Yeadon et ~al 1992, Pulmonary Pharm., 5, 39). There is a pronounced shift to the left (10-30 fold) of the dose response curve to histamine and a highly significant increase in the maximum increase in pulmonary resistance.

WO 97/22586 PCT/CA96/00839 -33- Compounds of the Examples administered lh prior to ozone by the intraperitoneal or oral (0.001-10mg/kg) route caused a dosedependent inhibition of ozone-induced hyperreactivity.

Adverse Effects Compounds of the invention are free from adverse effects following repeated overdosage to rats or dogs. For example, over administration of 125mg/kg/day of active compounds of the Examples to rats for 30 days is not associated with adverse toxicity.

The most potent compounds of the invention are 20-30 times less active than rolipram in inducing behavioural changes, sedation or emesis in rats, ferrets or dogs.

SPA based PDE activity assay protocol Compounds which inhibit the hydrolysis of cAMP to AMP by the type-IV cAMP-specific phosphodiesterases were screened in 96well plate format as follows: In a 96 well-plate at 30 OC was added the test compound (dissolved in 2 ul DMSO), 188 ml of substrate buffer containing [2,8- 3

H]

adenosine 3',5'-cyclic phosphate (cAMP, 100 nM to 50 gM), mM MgC12, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 ml of human recombinant

PDE-IV

(the amount was controlled so that 10% product was formed in min. at 30 oC). The reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham). The product AMP generated was quantified on a Microbeta 96-well plate counter. The signal in the absence of enzyme was defined as the background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with the background subtracted.

Percentage of inhibition was calculated accordingly. IC50 value was approximated with a non-linear regression fit of the standard WO 97/22586 PCT/CA96/00839 -34 4-parameter/multiple binding sites equation from a ten point titration.

values shown in Table 4 were determined with 100 nM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system.

The invention will now be illustrated by the following nonlimiting examples in which, unless stated otherwise: all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25°C; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60 0 C; the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; melting points are uncorrected and indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; yields are given for illustration only; when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal; chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).

WO 97/22586 WO 9722586PCT/CA96/00839 35 Ac Bn cAMP

DBU

DIBA]

DMA!

DMF

Et3N

GST

LDA

m-CPL

MMPI

MPPM

Ms MsO

NSAIE

o-Tol.

OXON

Pcc

PDC

PDE

Ph Phe

PMB

Pye r.t.

rac.

SAM

SEM

SPA

TBAF

The following abbreviations have the indicated meanings: acetyl benzyl cyclic adenosine-3 ',S-monophosphate 1 ,8-diazabicyclo[5 4 .O]undec-7-ene L =diisobutylaluminum hydride 4 -(dimethylanuino)pyridine N,N-dimethylformamide triethylamine glutathione transferase lithium diisopropylamide A metachloroperbenzoic acid monoperoxyphtalic acid monoperoxyphthalic acid, magnesium salt 6H20 methanesulfonyl mesyl SO2Me methanesulfonate mesylate non-steroidal anti-inflammatory drug ortho-tolyl E® 2KHSO5.KHSO 4

-K

2 S0 4 pyridinium chlorochromate pyridiniumn dichromate phosphodiesterase phenyl benzenediyl para-methoxybenzyl pyridinediyl room temperature racemic aminosulfonyl or sulfonamide or S02NH2 2 -(trimethylsilyl)ethoxymethoxy scintillation proximity assay tetra-n-butylammonium fluoride WO 97/22586 PCT/CA96/00839 36 Th

TFA

TFAA

THF

Thi

TLC

TMS-CN

Tz 2- or 3-thienyl trifluoroacetic acid trifluoroacetic acid anhydride tetrahydrofuran thiophenediyl thin layer chromatography trimethylsilyl cyanide 1 H (or 2 allyl Alkyl Group Abbreviations Me methyl Et ethyl n-Pr normal propyl i-Pr isopropyl.

n-Bu normal butyl i-Bu isobutyl s-Bu secondary butyl t-Bu tertiary butyl.

c-Pr cyclopropyl c-Bu cyclobutyl c-Pen cyclopentyl c-Hex cyclohexyl WO 97/22586 WO 9722586PCT/CA96/00839 37 EXAMPLE 1 N-I f(R)- 4 3 Cclopentvloxy..4-.methoxyphe yl)2 4 pvyridvl)ethyllbenzoyl I methanesulfonamide A solution of carboxylic acid intermediate 1 (100 mg, 0.24 mmol), methanesulfonamide (27 mg, 0.29 mmol), l-(3dimethylaminopropyl)..3.ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol) and 4 -dimethylaminopyridine (35 mg, 0.29 mmol) in C112C2 (3 mL) was stirred at room temperature for 19 h. Glacial acetic acid (0.2 mL) was then added and, after 10 min, CH2Cl2 was added. The organic phase was washed by 25% aqueous NI{4OAc, water and brine, dried (MgS 04) and concentrated. The residue was purified by column chromatography on silica (CH2Cl2JMeOH 92:8) to afford the title compound as a white solid (63 mg, 1H1 NMR (400 MHz, acetoned6): 8 1.55 (in, 2H), 1.75 (in, 6H), 2.95 (bs, 3H1), 3.40 211), 3.70 (s, 311), 4.40 111), 4.75 (in, 111), 6.80 (mn, 2H), 6.90 1H), 7.15 (d, 2H), 7.35 211), 7.95 211), 8.35 2H).

EXAMPLE 2 N-f{ r1- 3 -Cyclopentvloxv4 -methoxphyl.( p2yridyl')ethvllbenzoyl Ibenzenesulfonamide Following the procedure described in Example 1 but substituting benzenesulfonamide for methanesulfonainide, the title compound was obtained as a white solid 1 H NMR (400 MHz, acetone-d6): 8 1.55 (mn, 211), 1.70 (in, 611), 3.40 211), 3.70 311), 4.40 111), 4.75 (in, 111), 6.80 211), 6.90 111), 7.15 211), 7.25-7.45 (in, 511), 7.95 (in, 4H1), 8.35 2H1).

EXAMPLE 3 WO 97/22586 WO 9722586PCT/CA96/00839 38 N- I rl1-( 3 -CvclopeLntvloxy-4-methoxyphenyy2-(4pvridyl)ethyllbenzoyl I trifluoromethanesulfonamide Following the procedure described in Example 1 but substituting trifluoromethane-sufonamide for methanesulfonamide, the title compound was obtained as a white solid 1H NMR (400 MHz, acetone-d6): 8 1.55 (in, 2H), 1.70 (in, 6H), 3.40 2H), 3.70 (s, 3H), 4.40 1H), 4.75 (mn, 1H), 6.80 2H), 6.90 1H), 7.15 2H), 7.35 2H), 8.00 2H), 8.35 2H-).

EXAMPLE 4 N- r 1-( 3 -Cyclopentvloxy:-4-methoxyphenyl.)-2(4pvridyl)ethyllbenzoyl }o-toluenesulfonamide Following the procedure described in Example 1 but substituting o-toluenesufonamide for inethanesulfonamide, the title compound was obtained as a white solid 'H NMR (400 MHz, DMSO-d 6 5 1.50-1.70 (in, 6H), 1.80 (in, 2H), 2.55 3H), 3.40 (d, 2H), 3.65 3H), 4.40 1H), 4.70 (in, 1H), 6.80 2H), 6.90 1H), 7.20 2H), 7.30-7.45 (in, 4H), 7.55 1H), 7.75 2H), 8.00 (d, 1H), 8.35 2H).

EXAMPLE N- -Cyclopentyloxy-4-methoxphenl).2.(4gyridflethvllphenylacetyl I benzenesulfonamide Following the procedure described in Example 1 but substituting carboxylic acid intermediate 2 for intermediate 1 and benzenesulfonainide for methanesulfonamide, the title compound was obtained as a white solid 'H NMR (400 MHz, acetone-d6): 8 1.50-1.62 (in, 2H), 1.63-1.87 (mn, 6H), 3.37 2H), 3.57 2H), 3.70 3H), 4.31 J 8 Hz, 1H), 4.74 (mn, 1H), 6.78 (mn, 2H), 6.88 1H), WO 97/22586 PCT/CA96/00839 -39- 7.07 J 8 Hz, 2H), 7.13 J 6 Hz, 2H), 7.25 J 8 Hz, 2H), 7.54 2H), 7.66 1H), 7.94 J 7 Hz, 2H), 8.33 J 6 Hz, 2H).

EXAMPLE 6 N-f 3 -Cyclopentvloxv-4-methoxvphenvl)-2-(4 pyridvl)ethvllphenvlacetvl trifluoromethanesulfonamide Following the procedure described in Example 1 but substituting carboxylic acid intermediate 2 for intermediate 1 and trifluoromethanesulfonamide for methanesulfonamide, the title compound was obtained as a white solid 1 H NMR (400 MHz, acetone-d6): 8 1.51-1.63 2H), 1.64-1.90 6H), 3.39 4H), 3.70 3H), 4.30 1H), 4.76 1H), 6.79 2H), 6.92 1H), 7.15 4H), 7.25 J 8 Hz, 2H), 8.33 2H).

EXAMPLE 7 2-( 3 -Cvclopentloxv-4-methoxyphenyl)-2- 4-1.1.3..33hexafluoro-2-hvdroxypropan-2-v)phenvl1ethyl pridine Step 1: 2 -(4-Bromophenyl)-1,1,1,3,3 3 -hexafluoro-2-propanol n-Butyllithium (2.4 M solution in hexane; 92.7 mL, 0.222 mol) was added dropwise (20 min) to a solution ofp-dibromobenzene (50.0 g, 0.212 mol) in Et20 (1.2 L) at -60 OC. After completion of the addition, the reaction was left at -50 °C for 30 min and hexafluoroacetone (42.2 g, 0.254 mol) was bubbled through the heterogeneous mixture, at the same temperature. The resulting solution was allowed to warm to -30 oC over 30 min before saturated aqueous NH4C1 was added. The aqueous layer was extracted with EtOAc (2x) and the combined organic extracts were successively washed with aqueous NH40Ac buffer, water and brine, dried (MgSO4) and WO 97/22586 PCT/CA96/00839 concentrated. The residue was distilled under reduced pressure (bp °C/12 mmHg) to afford the title compound as colorless crystals (53.5 g, 78%).

Step 2: 2-(4-Bromophenyl)-2-[ 2 -(trimethylsilyl)ethoxymethoxy]- 1,1,1,3,3,3-hexafluoropropane A solution of 2 -(trimethylsilyl)ethoxymethyl chloride (25.9 g, 0.155 mol) in CH2C12 (50 mL) was added dropwise to a solution of 2-(4-bromophenyl)- 1,1,,3,3, 3 -hexafluoro-2-propanol from Step 1 (38.6 g, 0.120 mol) in the same solvent (500 mL) at 0 oC. After completion of the addition, the mixture was allowed to warm to room temperature, and stirred for 3 h before it was diluted with CHC13 (500 mL). The resulting solution was washed successively with 1 N HC1 (2x), saturated aqueous NaHCO3, water and brine, dried (Na2SO4) and concentrated. The residue was distilled under reduced pressure (bp 128 °C/0.9 mmHg) to afford the title compound as a colorless liquid (50.0 g, 92%).

Step 3: (1R, 3

R)-

3 3 -Cyclopentyloxy-4-methoxyphenyl)-3-[4- 2 2 -(trimethylsilyl)ethoxymethoxy)- 1,1,1,3, 3 3 -hexafluoropropan-2yl)phenyl]-2-(4-pyridyl)propanoyl }-10,10-dimethyl-3-thia-4azatricyclo[5.2.1.01,5]decane-3,3-dioxide A solution of 2 -(4-bromophenyl)-2-[2- (trimethylsilyl)ethoxymethoxy]-1,1,1,3, 3 3 -hexafluoropropane from Step 2 (30.4 g, 67.1 mmol) in THF (15 mL) was added to magnesium turnings (1.71 g, 70.4 mmol) in THF (40 mL). A few crystals of iodine were added and the mixture was stirred at reflux temperature for 1 h before it was added dropwise to a solution of acyl sultam laa (12.0 g, 22.4 mmol) in THF (200 mL) at 0 OC. The reaction mixture was stirred at room temperature for 16 h and quenched by the addition of saturated aqueous NH4C1. The organic layer was concentrated and diluted with EtOAc, and the aqueous phase extracted with EtOAc The WO 97/22586 PCT/CA96/00839 -41 combined organics were washed successively with 25% aqueous buffer, water and brine, dried (MgSO4) and evaporated. The residue was recrystallized in EtOH and further purified by column chromatography on silica (acetone/CHCl3 5:95) to afford a first crop of the title compound as a white solid. The EtOH filtrate was concentrated and purified successively by column chromatography (as above) and recrystallization (EtOH) to give a second crop for a total mass of 9.48 g Step 4: 2 3 -Cyclopentyloxy-4-methoxyphenyl)-2-[4-(2-(2- (trimethylsilyl)ethoxymethoxy)-1,1,1,3 3 ,3-hexafluoropropan-2yl)phenyl]ethyl pyridine n-Butyllithium (2.4 M solution in hexane; 7.76 mL, 18.6 mmol) was added dropwise to a solution of 1-propanethiol (2.06 mL, 22.8 mmol) in THF (100 mL) at 0 After 1.5 h, a solution of (1R, 3 3 -cyclopentyloxy-4-methoxyphenyl)-3-[4-(2-(2- (trimethylsilyl)ethoxymethoxy)-1,1,1,3 3 3 -hexafluoropropan-2yl)phenyl]-2-(4-pyridyl)propanoyl }-10,10-dimethyl-3-thia-4azatricyclo[5.2.1.01,5]decane-3,3-dioxide from Step 3 (9.43 g, 10.4 mmol) in THF (25 mL) was added dropwise, at 0 and the reaction mixture was stirred at room temperature for 3 h. The reaction was then quenched by the addition of 25% aqueous NH40Ac buffer. The aqueous layer was extracted with EtOAc and the combined organics were washed successively with 25% aqueous NH40Ac buffer and brine, dried (MgSO4) and concentrated. The residue was dissolved in EtOH (170 mL) and water (57 mL), lithium hydroxide monohydrate (2.20 g, 52.0 mmol) was added and the mixture heated to reflux for 2.5 h. The reaction mixture was cooled to room temperature before the addition of AcOH (3.56 mL, 62.1 mmol). After 30 min., 25% aqueous buffer was added and the aqueous layer extracted with EtOAc The combined organics were washed successively with 25% aqueous buffer and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica WO 97/22586 PCT/CA96/00839 42 (EtOAc/hexane 1: 1) to afford the title compound as a colorless gum (4.08 g, 58%).

Step 5: f 2 3 -Cyclopentyloxy-4methoxypheny)2[4- 1, 1,3,3,3 -hexafluoro-2-hydroxypropan2yl)phenyllethyl I pyridine Tetrabutylammonium fluoride (1.0 M in THF; 30.4 mL, 30.4 mmol) was added dropwise to a solution of 2-(3cyclopentyloxy-4-methoxyphenyl)%. (trimethylsilyl)ethoxymethoxy)- 1, 1, 1,3,3,3 -hexafluoropropan-2 yl)phenyl] ethyl }pyridine from Step 4 (4.08 g, 6.09 mmol) in THF mL) at room temperature, and the resulting solution was heated to the reflux temperature for 2.5 h, allowed to cool, and 25% aqueous NH4OAc buffer was added. The aqueous layer was extracted with EtOAc and the combined organics were washed successively with aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane 1: 1) to afford a white solid subsequently triturated in 1:4 Et2O/hexane to give the title compound (2.87 g, IH NMR (400 MHz, acetone-d6) 8 1.50-1.62 (in, 2H), 1.63-1.88 (in, 6H), 3.44 (in, 2H), 3.71 3H), 4.43 J =8 Hz, 1H), 4.75 (in, 1H), 6.81 (in, 2H), 6.89 1H), 7.14 J 6 Hz, 2H), 7.44 1H), 7.51 J 8 Hz, 2H), 7.67 J 8 Hz, 2H), 8.33 J 6 Hz, 2H).

EXAMPLE 8 N-(o-Toluovl)-4-f[1-( -C clopentvloxv7mehovpenl) 12yridyl)ethyllbenzenenesulfonamide Step 1: (3Ccoetlx--ehxphnl(-yiy~ctln To a suspension of 3 -cyclopentyloxy.4methoxybenzaldehyde (6.07 g, 27.6 inmol) and diphenyl I1-chloro- 1-(4pyridyl)methanephosphonate Org. Chem., 1992, 57, 1622) (9.03g, WO 97/22586 PCT/CA96/00839 -43- 52.1 mmol) in dioxane (150 mL) there was added in portions potassium tert-butoxide (7.03g, 62.8 mmol). The mixture was stirred at room temperature for 1 h and then refluxed. After 3.5 h, there was added another 7 g of potassium tert-butoxide and refluxing was continued for 18 h. After cooling, the mixture was diluted with water (1 L) and extracted 3 times with EtOAc. The extracts were washed 3 times with water, dried and evaporated and the residue was chromatographed on silica gel (EtOAc/hexane 1:2) to afford the title acetylene (4.72g, 64%) as a cream-colored solid.

Step 2: 1-( 3 -Cyclopentyloxy-4-methoxyphenyl)-1-iodo-2-(4pyridyl)ethylene To a solution of acetylene from step 1 (8.79g, 30 mmol) in dichloromethane (600 mL) at room temperature there was added a solid mixture of sodium iodide (18g, 120 mmol) and p-toluenesulfonic acid monohydrate (11.4 g, 60 mmol). The mixture was stirred at room temperature for 18 h. The mixture was diluted with aqueous 1 N NaOH (600 mL) and stirred vigorously for 15 min. The organic phase was collected and washed 3 times with water, dried and evaporated to a residue which was stirred in a 2:1 mixture of hexane and ether (100mL) for 2 h and filtered to afford the desired vinyl iodide (8.46g, 67%) as a beige solid, assayed by NMR to be a 4:1 mixture of Z and E isomers.

Step 3: l-( 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)1-l (trimethylstannyl)ethylene A mixture of vinyl iodide from step 2 (1.9 g, 4.5 mmol) and hexamethylditin (2.15g, 6.6 mmol) in toluene (25 mL) was placed under N2 atmosphere. There was added tetrakis (triphenylphosphine)palladium(0) (180 mg, 0.12 mmol) and the mixture was heated at 90 0 C for 18 h. After cooling, the mixture was diluted with EtOAc and washed 3 times with water, dried and evaporated. The crude product was chromatographed on silica gel (hexane/EtOAc 1:1) to yield WO 97/22586 PCT/CA96/00839 -44the title vinyl stannane (1.28g, 62%) as a thick syrup, assayed by NMR to be a 10:1 mixture of Z and E isomers.

Step 4: N,N-Bis-(p-methoxybenzyl)-4-[1-(3-cyclopentyloxy-4methoxyphenyl)-2-(4-pyridyl)ethenyl]benzenenesulfonamide A solution of the vinyltin intermediate from Step 3 (2.03 g, 4.4 mmol), N,N-bis-(p-methoxybenzyl)-4-bromobenzenenesulfonamide (1.30 g, 2.7 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.26 g, 0.22 mmol) and lithium chloride (0.8 g, 19 mmol) in 1,4-dioxane mL) was refluxed for 5 days. EtOAc was then added and the organic phase was washed successively with 25% aqueous NH40Ac buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by flash-chromatography (silica gel, hexane/EtOAc 65:35 to 40:60) to afford the title compound as a yellow solid (0.81 g, 43%).

Step 5: N,N-Bis-(p-methoxybenzyl)-4-[1-( 3 -cyclopentyloxy-4methoxyphenyl)-2-(4-pyridyl)ethyl]benzenenesulfonamide Sodium borohydride (80 mg, 2.1 mmol) was added portionwise to a 0°C solution of alkene from step 4 (452 mg, 0.65 mmol) and nickel(II) chloride hexahydrate (30 mg, 0.13 mmol) in MeOH (4 mL) and THF (2 mL). The reaction mixture was stirred at room temperature for 70 min before it was cooled to 0°C and a second portion of nickel(II) chloride hexahydrate (75 mg, 0.32 mmol) and sodium borohydride (60 mg, 1.6 mmol) was added. After 18 h at room temperature, more sodium borohydride (5 X 50 mg, 6.6 mmol) was added on a period of 6 h to achieve complete transformation of the starting material. The reaction mixture was then filtered over celite, the cake was washed with MeOH and the filtrate were evaporated. The residue was dissolved in EtOAc and the organic phase was washed successively with 25% aqueous NH40Ac buffer, water and brine, dried (MgS04) and concentrated. The residue was purified by flash- WO 97/22586 PCT/CA96/00839 chromatography (silica gel, hexane/EtOAc 40:60 to 25:75) to afford the title compound as a colorless gum (236 mg, 52%).

Step 6: 3 -cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]benzenenesulfonamide Trifluoroacetic acid (0.5 mL) was added to a 0°C solution of protected sulfonamide from Step 5 (98 mg, 0.14 mmol) in CH2C12 (3 mL) and the reaction mixture was stirred at room temperature for 24 h.

EtOAc was then added and the organic phase was washed successively with 25% aqueous NH40Ac buffer, water and brine, dried (MgS04) and concentrated. The residue was purified by flash-chromatography (silica gel, EtOAc) to afford the title compound as an off-white solid (46 mg, 72%).

Step 7: N-(o-Toluoyl)-4-[1-( 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]benzenenesulfonamide WO 97/22586 PCT/CA96/00839 46- EXAMPLE 9 4- 2-(3,4-Difluoromethoxv)phenvl-2- 3 -hexafluoro-2hvdroxvpropan-2-vlphenylethyl pyridine Step 3 4 -Bis(difluoromethoxy)benzaldehyde A suspension of 3 4 -dihydroxybenzaldehyde (6.9 g, mmol) and powdered potassium carbonate (13.8 g, 100 mmol) in N,Ndimethylformamide (400 mL) was cooled to Chlorodifluoromethane was bubbled into the mixture until 19 g had been dissolved (219 mmol). A dry ice condenser was installed and the temperature was raised gradually to 85ooC, and kept at that temperature for 16 hours. After cooling to room temperature, the mixture was carefully diluted with water (600 mL) and extracted 4 times with ether, the extracts were washed 3 times with brine, dried and evaporated. The residue was chromatographed on silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to afford the desired product as a colorless liquid (4.7 g, 39.5%) H NMR (400 MHz, acetone-d6) d 7.13 large J, 1H); 7.20 large J, 1H); 7.58 1H); 7.87 1H); 7.93 1H); 10.04 1H).

Step2 [3.

4 -Bis(difluoromethoxy)phenyll- 2 -(2-trimethylsilyl ethoxy)methoxvl-1..1.13,3, 3 -hexafluoropropan-2-yl phenvl I methanol To a solution of 2 4 -bromophenyl)-2-[2-(trimethylsilyl) ethoxy methoxy]-1,1,1, 3 3 ,3-hexafluoro propane from Example 7, Step 2 (2.44 g, 5.4 mmol) in THF (15 mL) at -78ooC was added nbutyllithium in hexanes (1.25 M, 4 mL, 5 mmol), and the resulting solution was kept at -78ooC for 20 minutes. This solution was added via canula, to a solution of 3 4 -bis(difluoromethoxy) benzaldehyde from step 1 (1.31 g, 5.5 mmol) in THF (10 mL). The resulting yellow solution was stirred at -78ooC for 1 hour, then quenched with sat'd aq.

ammonium chloride, allowed to warm up and partitioned between ether and water. The crude organic product was chromatographed on silica WO 97/22586 PCT/CA96/00839 -47gel, eluting with a 1:19 mixture of ethyl acetate and toluene, to afford the desired secondary alcohol (1.86 g, 55%) as a colorless syrup.

H NMR (400 MHz, acetone-d6) d 0.05 9H), 0.98 2H); 3.86 (t, 2H); 4.93 2H); 5.28 1H, OH); 5.95 1H); 6.92 large J, 1H); 6.96 large J, 1H); 7.30 1H); 7.36 1H); 7.50 1H), 7.64 (s, 4H).

Step 3 [3, 4 -Bis(difluoromethoxy)phenyll-{ 4-r2-(2-trimethylsilvl ethoxy)methoxy 1-.1.13.

3 3 3-hexafluoro propan-2-yl phenyl chloromethane To a solution of secondary alcohol from Step 2 (918 mg, mmol) and N,N-diisopropylethylamine (275 mg, 1.65 mmol) in toluene (15 mL) was added thionyl chloride (357 mg, 3 mmol). The mixture was stirred at room temperature for 1 hour, concentrated and chromatographed as such on silica gel, eluting with a 1:5 mixture of ethyl acetate and hexane, to afford the desired chloride (762 mg, 81%) as a colorless syrup.

1 H NMR (400 MHz, acetone-d6) d 0.05 9H); 0.98 2H); 3.86 (t, 2H); 4.94 2H); 6.55 1H); 7.02 large J, 2H); 7.39 1H); 7.48 1H); 7.55 1H); 7.72 4H).

Step 4 1-Carbethoxv-2-(3.

4 -bis(difluoromethoxy)phenyll-2-[4- 2 2 -trimethvlsilyl)ethoxymethoxvy) 11.3.33hexafluoropropan-2-vl)phenyl]ethyl pyridine To a solution of ethyl 4-pyridyl acetate (236 mg, 1.43 mmol) and hexamethylphosphoramide (256 mg, 1.43 mmol) in THF (8 mL) at -78ooC was added potassium bis(trimethylsilyl)amide 0.85 M in THF (1.56 mL, 1.33 mmol). The resulting red-orange solution was stirred at -78oC for 1 hour, then was added, with canula, to a cold 78ooC) solution of chloride from Step 3 (600 mg, 0.95 mmol) in THF (8 mL). The mixture was warmed to room temperature and stirred overnight. After quenching with sat'd aq. ammonium chloride the mixture was partitioned between ethyl acetate and water. The crude organic product was used as such in the next step.

WO 97/22586 PCT/CA96/00839 -48- 4- 2- 3,4-Bis(difluoromethoxyl-2- 4 2 -(2-trimethylsilvl) ethoxymethoxy)-. 1,11.

3 3 ,3-hexafluoropropan-2yl)phenvllethyl Ipyridine The crude product from Step 4 was refluxed in a mixture of methanol (10 mL), THF (10 mL) and water (5 mL) containing lithium hydroxyde hydrate (168 mg, 4 mmol) for 1.5 hours. After cooling, sat'd aq. ammonium chloride (25 mL) was added and heating was resumed for 20 minutes. The cooled mixture was partitioned between ethyl acetate and water, and the crude organic product was chromatographed on silica gel, eluting with a 2:1 mixture of ethyl acetate and hexane affording the desired compound (327 mg, 50%) as a colorless syrup.

1 H NMR (400 MHz, acetone-d6) d 0.05 9H); 0.97 2H); 3.50 (m, 2H); 3.85 2H); 4.62 1H); 4.89 2H); 6.91 large J, 2H); 7.16 2H); 7.25 1H); 7.33 1H); 7.40 1H); 7.55-7.65 4H); 8.36 2H).

Ste 6 4 -Difluoromethoxy)phenyl-2[4 1.1.1.3.3.3hexafluoro-2-hydroxypropan-2-yl)phenvl ethyl pridine The procedure for the removal of the SEM protecting group described in Example 7, Step 5 was applied using the product of Step 5 above as starting material. The title compound was purified by chromatography, eluting with a 3:2 mixture of ethyl acetate and hexane, and was obtained in 82% yield as a thick colorless syrup. Upon trituration with ether and hexane, the title compound was obtained as a white solid, mp 138-140oC.

1H NMR (400 MHz, acetone-d6) d 3.50 2H); 4.61 1H); 6.92 (t, large J, 2H); 7.18 2H); 7.24 1H); 7.32 1H); 7.39 1H); 7.51 1H, OH); 7.55 2H); 7.70 2H); 8.35 2H).

WO 97/22586 PCT/CA96/00839 -49- EXAMPLE 4-124(3 4-Difluoromethoxy)p2hen1-2- 1 1 133 xaluoo-2 hydroxvpropan--2-Ybp-henylj ethyl lp2yridine-N-oxide To a solution of 4-1{ 2 -(3,4-difluoromethoxy)phenyl2[4-(1,1,1,3,3,3hexafluoro-2-hydroxypropan-2.yl)phenyl]ethyl I pyridine (132 mg) in dichioro methane (15 mL) was added m-chloroperoxybenzoic acid 80-85% (65 mg) and the mixture was stirred at room temperature. After 2 hours, a further 40 mg of oxidizing agent was added. One hour later, calcium hydroxide (1 gram) was added, the mixture was stirred for 5 minutes, then filtered through a bed of celite.

The filtrate was evaporated to a residue which was chromatographed on silica gel, eluting with a 1:9 mixture of methanol and dichloromethane, affording the title compound (83 mg) as a white foamy solid.

IH NMR (400 MHz, acetone-d6) d 3.45-3.57 (in, 2H); 4.59 1H); 6.91 large J, 1H); 6.94 large J, 1H); 7.18 2H); 7.30 1H); 7.33 (d, 1H); 7.40 1H); 7.55 2H); 7.57 1H, OH); 7.71 2H); 7.92 (d, 1H).

EXAMPLE 1I 3 .5-Dichloro-4-1I2-(3 4 -Difluoromethoxy)p2henyl.2-. 1.1.1.3.3.3hexafluoro-2-hydroxyp 12an-2yl)henyllethv I pridIne Ste 3. 5-Dichloro-4-f 2- [3.

4 -bis(difluoromethoxyj trimethvlsilyl) ethoxymethoxy)- 1.1.1.3.3.3- 30hexafluoropropan2vpp)1henyllethyl pyridine To freshly prepared lithium diisopropylamide in THF (0.3 M, 5 mL, 1.5 minol), at -78-oC was added a solution of 3,5-dichloro-4picoline (295 mg, 1.82 mmol) in THF (5 mL). The dark yellow solution was stirred at -78ooC for 30 minutes, and was then added, via canula, to a cold solution 8ccC) of chloride from Example A, Step 3 WO 97/22586 PCT/CA96/00839 (760 mg, 1.21 mmol) in THF (10 mL). The resulting mixture was warmed to room temperature and stirred for 2 days. Afer quenching with sat'd aq. ammonium chloride, the mixture was partitioned between ethyl acetate and water. The organic residue was chromatographed on silica gel, eluting with a 1:5 mixture of ethyl acetate and hexane, to afford the desired product (32 mg) as a colorless syrup.

H NMR (400 MHz, acetone-d6) d 0.05 9H); 0.98 2H); 3.73 (m, 2H); 3.85 2H); 4.62 1H); 4.90 2H); 6.93 large J, 1H); 6.95 large J, 1H); 7.24-7.30 2H); 7.36 1H); 7.51 2H); 7.61 (d, 2H); 8.43 2H).

A 60% recovery of starting chloride was also obtained.

Ste 2 3.5-Dichloro-4- 2-(3.

4 -Difluoromethoxv)phenvl-2- 4- 3 3 .3-hexafluoro-2-hydroxypropan-2-vl)phenyl] ethyl lpyridine To a solution of product from Step 1 (32 mg, 0.054 mmol) in THF (0.8 mL) was added tetrabutylammonium fluoride 1M in THF (0.27 mL) and the mixture was refluxed for 2 hours. After cooling, the mixture was quenched with sat'd aq. ammonium chloride and partitioned between ethyl acetate and water. The crude organic product was chromatographed on silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, to afford the title compound (11 mg) as a thick colorless syrup.

1H NMR (400 MHz, acetone-d6) d 3.68 3.85 2H); 4.63 1H); 6.93 large J, 1H); 6.96 large J, 1H); 7.28 2H); 7.33 1H); 7.43 1H, OH); 7.51 2H); 7.72 2H); 8.43 2H).

WO 97/22586 PCT/CA96/00839 -51 Following the procedure described in Example 1 but substituting o-toluic acid for carboxylic acid intermediate 1 and cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl] benzenenesulfonamide from Step 6 for methanesulfonamide, the title compound was obtained as a white solid 1H NMR (400 MHz, acetone-d6): 8 1.5-1.6 2H), 1.65-1.85 6H), 2.23 3H), 3.40 2H), 3.70 3H), 4.45 1H), 4.75 1H), 6.81 2H), 6.90 (s, 1H), 7.10-7.20 4H), 7.30 1H), 7.50 3H), 7.95 2H), 8.30 2H).

PREPARATION OF INTERMEDIATES Intermediate 1: [1 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]benzoic acid O OH Step 1: 2-(4-Bromophenyl)-1,3-dioxolane A solution of 4 -bromobenzaldehyde (66.5 g, 359 mmol), ethylene glycol (22 mL, 395 mmol) and p-toluenesulfonic acid monohydrate (120 mg) in benzene (400 mL) was refluxed for 3 hours with concomitant Dean-Stark water trapping. The organic phase was then washed successively with 5% aqueous NaHCO3, water and brine, dried (MgS04) and evaporated. The residue was distilled under reduced pressure (bp: 112°C/0.4 mmHg) to afford the title compound as a colorless liquid (79.8 g, 97%).

WO 97/22586 PCT/CA96/00839 -52- Step 2: (1R, 5S)-N- (3R)-3-(3-Cyclopentyloxy-4-methoxyphenyl)-3-[4- (1,3-dioxolan- 2 -yl)phenyl]-2-(4-pyridyl)propanoyl} -10,10-dimethyl-3thia-4-azatricyclo[5.2.1.01,5]decane-3,3-dioxide A solution of 2 -(4-bromophenyl)-l,3-dioxolane from Step 1 (55.3 g, 241 mmol) in THF (40 mL) was added to magnesium turnings (6.16 g, 254 mmol) in THF (140 mL) containing 1,2dibromoethane (0.1 mL) at a sufficient rate to maintain a gentle reflux.

The mixture was stirred at room temperature for 2 hours before the solution was added dropwise to a 0°C solution of acyl sultam II (Celltech, World Patent Application 95/17386, 29 June 1995)(43.2 g, 80.5 mmol) in THF (700 mL). The reaction mixture was stirred at room temperature for 16 hours before 10% aqueous NH4C1 was added.

The mixture was extracted with EtOAc and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The residue was recrystallized twice in EtOH to afford the title compound as an off-white solid (25.6 g, 46%).

Step 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]benzaldehyde n-Butyllithium (2.4 M solution in hexane; 10.6 mL, mmol) was added dropwise to a 0°C solution of propanethiol (4.6 mL, 51 mmol) in THF (150 mL). After 15 minutes, (1R, cyclopentyloxy-4-methoxyphenyl)-3-[4-(1, 3 -dioxolan-2-yl)phenyl]-2-(4pyridyl)propanoyl -10,10-dimethyl-3-thia-4azatricyclo[5.2.1.01, 5 ]decane-3,3-dioxide from Step 2 (9.7 g, 14.1 mmol) was added as a solid and the reaction mixture was stirred at room temperature for 3 days. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (80 mL) and water mL). Sodium hydroxide (4.5 g, 113 mmol) was added and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and treated with HC1 6 N to pH 4.5 then heated to reflux WO 97/22586 PCT/CA96/00839 -53for 1 hour. The reaction mixture was cooled to room temperature and treated with NaOH 1 N to pH 14 then extracted twice with EtOAc. The organic phase was washed with brine, dried (MgS04) and evaporated.

The residue was purified by flash-chromatography (silica gel, ether) to afford the title compound as a white foam (2.3 g, 1 H NMR (400 MHz, CDC13): 8 1.55 2H), 1.75 6H), 3.30 2H), 3.80 (s, 3H), 4.20 1H), 4.60 1H), 6.60 1H), 6.65 1H), 6.75 1H), 6.90 2H), 7.35 2H), 7.75 2H), 8.40 2H), 9.95 1H).

Step 4: (R)-4-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]benzoic acid A solution of NaC102 (149 mg, 1.64 mmol) and NaH2PO4*H20 (227 mg, 1.64 mmol) in water (1 mL) was added to a solution of aldehyde from Step 3 (508 mg, 1.27 mmol) and 2-methyl-2butene (0.94 mL, 8.9 mmol) in t-BuOH (6 mL). The reaction mixture was stirred at room temperature for 19 hours before 25% aqueous was added. The mixture was then extracted twice with EtOAc.

The organic phase was washed with brine, dried (MgSO4) and evaporated to afford the title compound as a white solid (540 mg). 1H NMR (400 MHz, CDC13): 8 1.55 2H), 1.75 6H), 3.35 2H), 3.80 3H), 4.20 1H), 4.60 1H), 6.60 1H), 6.65 1H), 6.75 1H), 7.00 2H), 7.25 2H), 8.00 2H), 8.45 2H).

Intermediate 2: 1 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]phenylacetic acid WO 97/22586 PCT/CA96/00839 -54ao C02H Step 1: 4-Bromophenylacetaldehyde A solution of 4-bromostyrene (50.0 g, 0.273 mol) in CH2C12 (550 mL) was added dropwise (1 h) to a solution of lead tetraacetate (127 g, 0.273 mol) in trifluoroacetic acid (275 mL) at After completion of the addition, the reaction was left at room temperature for 30 min and slowly poured into water (2 The resulting mixture was stirred for 15 min and filtered through celite. The aqueous layer was extracted with CHC13 (2x) and the combined organic extracts were successively washed with water (3x) and saturated aqueous NaHCO3, dried (Na2S04) and concentrated. The crude yellow liquid was purified by column chromatography on silica (EtOAc/hexane 1:9) to afford the title compound as a pale yellow liquid (44.8g, 82%).

Step 2: 4 -Bromophenyl)methyl]-1,3-dioxolane A solution of 4 -bromophenylacetaldehyde from Step 1 (44.5 g, 224 mmol), ethylene glycol (13.7 mL, 246 mmol) and ptoluenesulfonic acid monohydrate (85 mg, 0.45 mmol) in toluene (300 mL) was refluxed for 3 h with concomitant Dean-Stark water trapping.

The reaction mixture was then washed successively with 5% aqueous NaHCO3 water and brine, dried (MgSO4) and concentrated. The residue was distilled under reduced pressure (bp 110-115 °C/0.5 mmHg) to afford the title compound as a colorless liquid (30.0 g, WO 97/22586 PCT/CA96/00839 Step 3: (1R, 5S)-N- 3 -Cyclopentyloxy-4-methoxyphenyl)-3-[4- (1,3-dioxolan-2-ylmethyl)phenyl]-2-(4-pyridyl)propanoyl} -10,10dimethyl-3-thia-4-azatricyclo[5.2.1.01,5]decane-3,3-dioxide A solution of 2 4 -bromophenyl)methyl]-1,3-dioxolane from Step 2 (27.2 g, 112 mmol) in THF (20 mL) was added to magnesium turnings (2.85 g, 117 mmol) in THF (70 mL) at a sufficient rate to maintain a gentle reflux (a few crystals of iodine and heat were necessary to initiate the reaction). The mixture was stirred at room temperature for 2 h before it was added dropwise to a solution of acyl sultam II (20.0 g, 37.3 mmol) in THF (350 mL) at 0 The reaction mixture was stirred at room temperature for 16 h and quenched by the addition of saturated aqueous NH4CI. The organic layer was concentrated and diluted with EtOAc, and the aqueous phase extracted with EtOAc The combined organics were washed successively with aqueous NH40Ac buffer, water and brine, dried (MgSO4) and evaporated. The residue was recrystallized in EtOH (a minimum of CHC13 was necessary to insure dissolution) to afford the title compound as a white solid (12.2 g, 46%).

Step 4: 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]phenylacetaldehyde diethyl acetal n-Butyllithium (2.4 M solution in hexane; 13.2 mL, 31.3 mmol) was added dropwise to a solution of 1-propanethiol (3.47 mL, 38.3 mmol) in THF (160 mL) at 0 oC. After 30 min, (1R, 3 3 -cyclopentyloxy-4-methoxyphenyl)-3-[4-(1,3-dioxolan-2ylmethyl)phenyl]-2-(4-pyridyl)propanoyl}-10,10-dimethyl-3-thia-4azatricyclo[5.2.1.01,5] decane-3,3-dioxide from Step 3 (12.2 g, 17.4 mmol) was added as a solid and the reaction mixture was stirred at room temperature for 2.5 h. The volatiles were then evaporated and the resulting residue was dissolved in EtOH (100 mL) and water (50 mL).

Sodium hydroxide (5.57 g, 139 mmol) was added and the mixture WO 97/22586 PCT/CA96/00839 -56heated to reflux for 2.5 h. The reaction mixture was cooled to room temperature and treated with 6 N HC1 to pH 4.5 then heated to reflux for 2 h. The reaction mixture was cooled to room temperature and treated with 1 N NaOH to pH 14, then extracted with EtOAc The combined organics were washed successively with 25% aqueous buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (acetone/ether 1:9--1:4-41:3) to afford the title compound as an off-white gum (1.17 g, 14%).

Step 5: 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]phenylacetaldehyde A solution of (R)-4-[1-(3-cyclopentyloxy-4methoxyphenyl)-2-(4-pyridyl)ethyl]-phenylacetaldehyde diethyl acetal from Step 4 (1.14 g, 2.33 mmol), pyridinium p-toluenesulfonate (0.761 g, 3.03 mmol) in acetone (30 mL) and water (1.3 mL) was heated to reflux for 20 h. It was then allowed to cool to room temperature, diluted with EtOAc, successively washed with 5% aqueous NaHCO3 (2x) and brine, dried (MgS04) and concentrated. The residue was purified by column chromatography on silica (EtOAc/hexane to afford the title compound as a white foam (0.381 g, 39%).

Step 6: 3 -Cyclopentyloxy-4-methoxyphenyl)-2-(4pyridyl)ethyl]phenylacetic acid A solution of sodium chlorite 131 mg, 1.16 mmol) and sodium phosphate monobasic monohydrate (160 mg, 1.16 mmol) in water (1.1 mL) was added to a solution of 3 -cyclopentyloxy- 4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenylacetaldehyde from Step (371 mg, 0.893 mmol) and 2 -methyl-2-butene (665 gL, 6.25 mmol) in t-BuOH (8 mL). The reaction mixture was stirred at room temperature for 1.5 h before 25% aqueous NH40Ac buffer was added (a few drops WO 97/22586 PCT/CA96/00839 -57of acetic acid were necessary to bring the pH at The mixture was then extracted with EtOAc and the combined organics were washed successively with 25% aqueous NH40Ac buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc containing 0.5% AcOH).

Residual AcOH was co-evaporated with toluene (2x) to afford the title compound as a white foam (319 mg, 1 H NMR (400 MHz acetone-d6): 8 1.50-1.61 2H), 1.63-1.88 6H), 3.40 2H), 3.54 2H), 3.70 3H), 4.34 J 8 Hz, 1H), 4.75 1H), 6.78 (m, 2H), 6.90 1H), 7.15 J= 6 Hz, 2H), 7.20 J= 8 Hz, 2H), 7.30 J 8 Hz, 2H), 8.33 J 5 Hz, 2H).

Claims (14)

1. A compound of formula I OR 2 R 3 0 N HET or a pharmaceutically acceptable salt thereof wherein: R is selected from hydrogen, C1-6alkyl, halo and CF3; R1 is selected from -(CH2)m-CO-N(R 4 wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(O)2-NR6R7, -(CH2)m-S(O)2-N(R 4 )-CO-R 4 -(CH2)m-S(O)2-N(R 4 )-CO-NR6R7, -C(OH)(CI- 6haloalkyl)2, R 2 and R 3 are independently selected from C1-7alkyl, substituted Cl-7 alkyl, wherein the substituent is F, Cl, Br or 1,

2-phenethyl or 2-indanyl, optionally mono or di- substituted, wherein the substituents on the benzene ring are independently -selected from the group consisting of WO 97/22586 PCT/CA96/00839 59 halo, CI-6alkoxy, C1-6alkylthio, CN, CF3, Cl-6alkyl, N3, -CO2H, R 4 is selected from hydrogen, C1-6alkyl, phenyl, benzyl or 2-phenethyl, optionally mono or di- substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio, CN, CF3, C1-6alkyl, N3, -CO2H, R 5 R 8 and R 1 1 are each independently selected from -CF3, C1-6alkyl, phenyl, benzyl or 2-phenethyl, optionally mono or di- substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio, CN, WO 97/22586 PCT/CA96/00839 CF3, C1-6alkyl, N3, -CO2H, R 6 R 7 R 9 and R 1 0 are each independently selected from hydrogen, and C1-6alkyl, or R 6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C -6alkyl, C1- 6alkoxy, C1-6alkylthio, benzyl, 2-phenethyl, NHCOR 8 NR 9 NHS(0)2R11, OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N->O or CH. 2. A compound according to Claim 1 wherein: R 2 is cyclopentyl, and R 3 is methyl,

3. A compound according to Claim 1 wherein: R is selected from hydrogen, C1-4alkyl, halo and CF3; R 1 is selected from -(CH2)m-CO-N(R 4 2 -R5, wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(0)2-NR 6 R 7 -(CH2)m-S(0)2-N(R 4 )-CO-R4, WO 97/22586 PCT/CA96/00839 61 -(CH2)m-S(O)2-N(R 4 )-CO-NR6R7, -C(OH)(C -6haloalkyl)2, R 2 is cyclopentyl, R 3 is methyl, R 4 is selected from hydrogen, C1-6alkyl, phenyl, benzyl or 2-phenethyl, optionally mono or di- substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C 1-6alkylthio, CN, CF3, C1-6alkyl, N3, -CO2H, R 5 R 8 and R 11 are each independently selected from -CF3, C1-6alkyl, phenyl, benzyl or 2 -phenethyl, optionally mono or di- substituted, wherein the substituents on the benzene ring are independently selected from the group consisting of halo, C1-6alkoxy, C1-6alkylthio, CN, CF3, C1-6alkyl, N3, -CO2H, R 6 R 7 R 9 and R10 are each independently selected from hydrogen, and WO 97/22586 PCT/CA96/00839 -62- C1-6alkyl, or R 6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an O or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl and imidazolyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, C1-6alkyl, Cl- 6alkoxy, C1-6alkylthio, benzyl, 2-phenethyl, NHCOR8, NR 9 NHS(O)2R11, OH, CN, or CF3, and the N-oxides thereof; and X is selected from N, N--O or CH.

4. A compound according to Claim 3 wherein: R is selected from hydrogen, C1-3alkyl, halo and CF3; and is ortho to R1; RI is selected from -(CH2)m-CO-N(R 4 2 -R5, wherein m is 0, 1 or 2, -(CH2)m-CO-N(R 4 )-S(0)2-NR 6 R 7 -(CH2)m-S(0)2-N(R 4 )-CO-R4, -(CH2)m-S(0)2-N(R 4 )-CO-NR6R7, -C(OH)(C1-6haloalkyl)2, R 2 is cyclopentyl, R 3 is methyl, R 4 is selected from hydrogen, C1-6alkyl, R 5 R 8 and R11 are each independently selected from -CF3, C1-6alkyl, R 6 R 7 R 9 and R10 are each independently selected from WO 97/22586 PCT/CA96/00839 63 hydrogen, and Ci -6alkyl, or R 6 and R 7 may be joined to form a saturated 5, 6 or 7 membered heterocycle, said heterocycle containing a heteroatom which is nitrogen and optionally containing an additional hetero atom which is an 0 or an S atom or NR 4 and optionally containing a carbonyl group; HET is selected from pyridyl, optionally mono-, or disubstituted, wherein the substituents are independently selected from halo, CI-6alkyl, CI-.6alkoxy, Cl- 6alkylthio, benzyl, 2-phenethyl, NHCOR8, NRIO, NHS(O)2RI 1, OH, CN, or CF3, and the N-oxides thereof; and X is CH.

5. A compound according to Claim 1 selected from the group consisting of N- I [1 3 -Cyclopentyloxy-4-methoxyphenyl)>2-.(4- pyridyl)ethyllbenzoyl Imethanesulfonamide, N- l-( 3 -Cyclopentyloxy-4-methoxyphenyl).2- 4 -pyridyl)ethyl]benzoyl Ibenzene sulfonamide, N- l-( 3 -Cyclopentyloxy-4-.methoxyphenyl)..2-(4- pyridyl)ethyllbenzoyl I trifluoromethanesulfonamide, N- I -Cyclopentyloxy-4-methoxyphenyl..2- 4 -pyridyl)ethyl]benzoyl o-toluenesulfonamide, N- 3 -Cyclopentyloxy-4-methoxyphenyl>2-(4- pyridyl)ethyllphenylacetyl Ibenzenesulfonamide, N-fI l-( 3 -Cyclopentyloxy-4-methoxyphenyl..2-(4- pyridyl)ethyllphenylacetyl I trifluoromethanesulfonamjde, 2 3 -Cyclopentyloxy-4-methoxyphe 1 yl)>2-[4- 1, 1,333hxfur-2hdoyrpn2 yl)phenyl] ethyl I pyridine, N- (o-Toluoyl)-4- 3 -Cyclopentyloxy-4 mehxpey)2(-yiy~tyleznnsloaie ~1111 64 4-{2-(3,4-Difluoromethoxy)phenyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2- yl)phenyl]ethyl}pyridine, 4-{2-(3,4-Difluoromethoxy)phenyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2- yl)phenyl]ethyl}pyridine-N-oxide, and 3,5-Dichloro-4-{2-(3,4-Difluoromethoxy)phenyl-2-[4-(1,1,1, 3 ,3,3-hexafluoro-2- hydroxypropan-2-yl)phenyl]ethyl}pyridine.

6. A triarylethane PDE IV inhibitor, substantially as hereinbefore described with reference to a title compound of any one of Examples 1 to 11.

7. A pharmaceutical composition comprising: a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A method of treating asthma, comprising: administration to a patient of a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or of a composition according to claim 7.

9. A method of treating disease by inhibiting PDE-IV, comprising: administration to a patient of a non-toxic therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or of a composition according to claim 7. 20

10. A compound of formula according to any one of claims 1 to 6, or a pharmaceutically o: acceptable salt thereof, or a composition according to claim 7 when used in treating asthma.

11. A compound of formula according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a composition according to claim 7 when used in treating disease by increasing the cellular level of cyclic

12. Use of a compound of formula according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of asthma.

13. Use of a compound of formula according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for raising the level of cyclic adenosine-3'-5'-monophosphate through inhibition of phosphodiesterase.

14. Use of a compound of formula according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament as a cyclic adenosine- inhibitor. Dated 10 May, 1999 Merck Frosst Canada, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [n:\libc]03826:TAB