Background of the Invention The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C ₄ , D ₄ and E4) and the hydroxyleukotrienes (leukotriene B4). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.

The peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production. By comparison, LTB ₄ exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).

They are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.

Leukotriene B4 (LTB4) was first described by Borgeat and

Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydro oic acid.

SUBSTITUTE SHEET

It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB ₄ has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity. Pharmacological studies on human blood PMN leukocytes indicate the presence of two classes of LTB4- specific receptors that are separate from receptors specific for the peptide chemotactic factors. Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms. LTB 4 has been established as an inflammatory mediator in vivo

It has also been associated with airway hyperresponsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis. They are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor. SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula (I)

or a pharmaceutically acceptable salt or N-oxide thereof where T is CO or CH(OH)

R is Cj to C20- ^a liphat_ ^c _> unsubstituted or substituted phenyl C\ to Ci o-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Ci to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Ci to Ci o-aϋphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rl is -(Ci to C5 aliphatic)R3,-(Cl to C5 aliphatic)CHO, -(Cl to C5 aliphatic)CH20R7, R3, -CH2OH or -CHO; R2 and R3 are independently -COR4 where R4 is -OH, a pharmaceutically acceptable ester-forming group -OR5, or -OX where X is a pharmaceutically acceptable cation, or R4 is -N(R6)2 where R6 is H, or an aliphatic group of 1 to 10 carbon atoms or a cycloalkyl- (CH2)n- group of 4 to 10 carbons where n is 0-3 or both R6 groups form a ring having 4 to 6 carbons, or R2 is an amine, amide or sulfonamide; and

R7 is hydrogen, Cl to C6-alkyl, or Ci to C6-acyl. In another aspect, this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient.

Treatment of diseases related to or caused by leukotrienes, particularly LTB 4, or related pharmacologically active mediators at the end organ, are within the scope of this invention. This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient in an amount sufficient to prevent disease or treat it once it has occurred.

In yet another aspect, this invention relates to a method for making the compounds of this invention. This aspect of the invention is illustrated in the reaction schemes given below and in the examples set forth in this specification.

DETAILED DESCRIPTION-OF THE INVENTION The following definitions are used in describing this invention and setting out what the inventors believe to be their invention herein.

"Aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase "lower alkyl" means

an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo. "Acyl" means the radical having a terminal carbonyl carbon. When reference is made to a substituted phenyl ring, it is meant that the ring can be substituted with one or more of the named substituents as may be compatible with chemical synthesis. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl substituent pattern.

The phrase "a pharmaceutically acceptable ester-forming group" in R2 and R3 covers all esters whi.ch can be made from the acid function(s) which may be present in these compounds. The resultant esters will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the mono- or diesters will retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases. Such esters are, for example, those formed with one of the following radicals representing R5: Cl to CiO alkyl, phenyl-Ci - C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. Aryl includes phenyl and naththyl, or heteroaromatic radicals like furyl, thienyl, imidazolyl, triazolyl or tetrazolyl. The most preferred ester-forming radicals are those where R5 is alkyl, particularly alkyl of 1 to 10 carbons, [ie CH3-(CH2)n- where n is 0-9], or phenyl-(CH2)n ^_ where n is 0-4.

When R2 is referred to as being an amine, that includes the radical -NH2 and mono- or dialkylate derivatives of this -NH2 radical. Preferred alkylated amines are the mono- or disubstituted amines having 1 to 6 carbons. When R2 is referred to as being an amide, that includes all acylate derivatives of the NH2 radical. The preferred amides are those having 1 to 6 carbons. Where there is an acid group, amides may be formed. The most preferred amides are those where -R6 is hydrogen or alkyl of 1 to 6 carbon atoms. Particularly preferred is the diethylamide.

The hydroxyl group of the 2-hydroxyethylene linking group may be esterified. Lower alkyl acids of 1 to 6 carbon atoms may be

used to form such esters using standard reaction conditions. This hydroxyl group also may be converted to an ether if so desired. Again, such reactions are well known in the synthetic chemical arts. Pharmaceutically acceptable salts of the instant compounds are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts of a basic moiety, or an excess of organic or inorganic base in the case where R4 is OH. Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid. Cationic salts are readily prepared from alkali metal bases such as sodium, potassium, calcium, magnesium, zinc, copper or the like and ammonia. Organic bases include the mono or disubstituted amines, ethylene diamine, piperazine, amino acids, caffeine, tromethamine, other tris compounds and the like.

Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention. If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. Compounds with a chiral center may be administered as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.

As leukotriene antagonists, these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4. Thus it is expected that these compounds can be used to treat allergic diseases of a pulmonary and non-pulmonary nature. For example these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated with these compounds.

The preferred compounds of this invention are those where R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or substituted or unsubstituted phenyl Ci to Ci o-aliphatic-O-; Ri is -(Ci to C5 aliphatic)R3 or -(C- to C ₅ aliphatic)CH20R7 _, and R2 is -COOH or N(A)(B) where A is H, or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons or -SO2R8 where R_ is -CF3, Ci to Cβ alkyl or phenyl. The more preferred compounds of this invention are those where R is alkoxy of 8 to 15 carbon atoms or alkoxy-substituted phenyl-Ci to Cg-alkoxy; Ri is COR4, -CH2CH2COR3 or -CH=CH-COR3; and R2 is -COOH or -NHS02R8. particularly where R2 is at the meta position and R8 is -CF3.

The most preferred compounds are set out in Figure II.

* The methylene carbon is substituted on the pyridyl ring. ** Trans configuration.

Synthesis

These compounds may be made by the starting materials, intermediates and reagents and the synthetic steps set out in the following reaction flow charts. These charts trace the path used to make these compounds and are based on the detailed chemistry set out in the Examples recited below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are only given to illustrate the general case and are not intended to limit the chemistry illustrated thereby. Reagents, intermediates, temperatures, solvents, reaction times, work-up procedures all may be varied to accommodate differences and

optimize the particular conditions for making a particular compound. Such variations will be apparent to a chemist or will not require more than minimal experimentation to optimize conditions and reagents for a particular step.

These reaction schemes first illustrate how to make certain portions of the R group which are not commercially available, then illustrate a means to assemble the whole compound using the materials from Reaction Scheme 1 or commercially available R- forming groups.

The preparation of certain embodiments of R are given in Scheme 1.

(a)

H ₃ CO-Ph-I

-≡—(CH ₂ ) _n OSi(Ph) ₂ -t-BuPh ₂ ► (b ) Pd [(Ph) ₃ P] ₂ Cl ₂

(d)

In those instances where an ω-yn-1 -ol is not commercially available, it can be prepared from a corresponding 3-yn-l-ol by treating the alcohol with a strong base. An alkali metal amide may be used. The alcohol is then protected in order to add the desired phenyl group at the terminal triple bond. A silyl ether was formed in this instance; it illustrates the general case. A halo-substituted-phenyl adduct is used to add the phenyl group at the triple bond. The silyl group is removed and the resulting alcohol converted to the tosylate,

or another group which is sufficiently reactive so as to provide ready formation of an ether later in the synthesis of these compound.

Scheme 1(b) illustrates another method for making certain alkoxy-substitutedphenylalkoxy R groups.

Scheme Kb)

(a)

TsCl iAlH ₄

(b)

(c)

While the methoxyphenyl compound is illustrated here, this series of steps and reagents may be used to make other ω-(unsubstituted)phenylaliphatic or ω-(substituted)phenylaliphatic groups denoted by R. The starting material, the benzaldehydes, are commercially available or can be readily made by known methods.

To make the acid, first an alkylsilazide is added to an inert solvent under an inert atmosphere. Then the phosphonium salt is added. This addition can be done at room temperature or thereabouts. After a brief period of mixing, this mixture is usually a suspension, the benzaldehyde is added slowly at about room temperature. A slight molar excess of the phosphonium salt is employed. After an additional brief period of stirring at about room temperature, the reaction is quenched with water. The solution is acidified and the acid (a) extracted with a suitable organic solvent. Further standard separatory and purification procedures may be employed as desired.

The alcohol is made by reducing the acid using a reducing agent. Lithium aluminum hydride or similar reducing agents may be employed and conditions may be varied as needed to effect the reduction.

The tosylate is prepared in an inert solvent employing p-toluenesulfonylchloride and a base such as pyridine. Suitable conditions include carrying out the reaction at room temperature or thereabouts for a period of 1 to 5 hours. Other suitable leaving groups similar in function to the tosylate may be prepared and will be useful as a means for adding this R moiety to the pyridyl ring.

Compounds of formula I can then be synthesized by the sequence of steps outlined in the following schemes.

Scheme 2

(2b) (2c)

(2d) First 2,6-lutidine-α ² ,3-diol is oxidized to the 3-hydroxy-6- methyl-2-pyridine carboxaldehyde. This aldehyde is then treated with a 1-halosubstituted group which adds to the 3-hydroxy group to form an ether. This reaction is effected by base, for example a carbonate such as K ₂ CO ₂ . Hydrazine hydrate is then used to form an aminohydrazone. This reaction is carried out at an elevated temperature. The reaction mixture is then cooled and treated with a base before recovering the aminohydrazone. This hydrazone is then converted to a triazolo[l,5-α]pyridine(2a) by means of Niθ2 or another oxidizing agent such as KFe(CN) ₆ - If nickel peroxide is used, the reaction can be effected at room temperature or thereabouts, though it may require an extended reaction time. For the nickel peroxide

process, an inert atmosphere is preferred, as are dry conditions. Other oxidizing agents may require elevated temperatures.

The 2-hydroxyethyl product is then made by first preparing i n situ a reagent capable of extracting a proton from the triazolopyridine compound after which the triazolo compound is added followed by a halobenzaldehyde. A useful base is lithium diisopropylamide. It is preferable to prepare it at reduced temperatures, i.e. -40 to 0°C or thereabouts. After the triazolopyridine and benzaldehyde are added, the reaction is allowed to run its course at room temperature or thereabouts. A carbonylation reaction is then carried out to introduce a carboxyl group into the phenyl ring. This is effected by Pd(OAc)2 and gaseous carbon monoxide in an appropriate solvent, preferably at an elevated temperature, i.e. 50-100°C. This gives the carbomethoxy- substituted phenyl compound (2b). Treating the resulting triazolo compound with Br2 destroys the triazole ring and brominates the resulting 2-position carbon on the pyridine ring to afford the 2-(α,α-dibromomethyl)pyridyl adduct. This reaction is best carried out at reduced temperature, i.e. about 0°C and is complete in about an hour or so. Silver nitrate oxidation gives aldehyde (2c). A Wittig reaction is then carried out to form the carbomethoxyethylene group at position 2 on the pyridyl ring. This compound can be treated with a base to hydrolyze the esters, which is then acidified if the free acid (2d) is desired.

Alternatively, the ethylene group at position 2 can be saturated by catalytic hydrogenation, then saponified using a base, which gives the salt, or thereafter acidifying the soluton to obtain the free acid (see Scheme 3 below). The acid can be converted to a pharmaceutically acceptable salt or esterified by known means. Amides can be made from the acids using known procedures. Compounds of this invention where the linking group T is ethylene can be prepared by following the procedure illustrated in Scheme 2, but substituting a halobenzylhalide compound for the halobenzaldehyde used in Scheme 2. For example, 2-bromobenzylbromide may be used in place of the -iodobenzaldehyde illustrated in Scheme 2 to make the triazolopyridine compound. This l -(halophenyl)-2-(4-substituted- l,2,3-triazolo[l ,5,a]pyridine-7-yl)ethane intermediate is then treated in the same manner as the 2-hydroxyethane compound in Scheme 2 to afford compounds of formula I where T is -CH2CH2-.

Analogs of the compounds in Scheme 2 where Ri is an alkanoic acid can be made by simply hydrogenating the unsaturated bonds in that chain. Such process is illustrated in Scheme 3.

Reducing the double bond is effected by catalytic mean using a heavy metal catalyst and hydrogen gas. Mild conditions will suffice. The illustrated esters can be hydrolyzed with base and further converted to other forms of formula I from there or transesterification can be used to convert to another ester.

Compounds where Ri contains a terminal -OH group, or an ester thereof, can be prepared by the series of steps given in Scheme 4. Scheme 4

(4a)

(4b)

Starting material is derived from Scheme 2, then carried through that set of steps, except that the R2 carbomethoxy function is not introduced until after the Ri alcohol has been prepared. Also, separately and apart from the steps in Scheme 2, the Ri carbomethoxy group can be reduced to the alcohol using a reducing agent such as diisobutylaluminum hydride (DIBAL) or a similar reducing agent. Catalytic hydrogenation can be used to saturate the ethylene group at position 2 on the pyridyl ring. A base can be used to saponify the ester to obtain the acid salt, or that salt can be acidified if the free acid is desired.

Each of the products containing an hydroxyl group in Schemes 2-4 can be oxidized to the corresponding ketone, that is where T is - CH2C(0)-, by means of a mild oxidizing agent.

Formulations

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

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non- aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions. The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.

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

preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.

For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.

For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose. For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. When employed in this manner, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.

The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.

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

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

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

The receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [ ³ H]-LTB4 binding sites on human U937 cell membranes. The LTB4 antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows. U937 Cell Culture Conditions

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

Harvested U937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25°C containing 1 mM EDTA (buffer A). Cells were resuspended in buffer A at a concentration of 5 x 10 ⁷ cells/ml and disrupted by

nitrogen cavitation with a Parr bomb at 750 psi for 10 min at 0°C . The broken cell preparation was centrifuged at 1 ,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°C . Binding of TIHI-LTB to U397 Membrane Receptors

[ ³ H] -LTB4 binding assays were performed at 25°C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCl ₂ , 10 mM MgCl ₂ , [ ³ H] - LTB4, U937 cell membrane protein (standard conditions) in the presence (or absence of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [ ³ H] -LTB4 were determined in the absence or presence of 2 μM of unlabeled LTB 4, respectively. Specific binding was calculated as the difference between total and non-specific binding. The radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [ H] -LTB4, 20-40 μg of U937 cell membrane protein, increasing concentrations of LTB4 (0.1 nM to 10 nM) or other competing ligands (0.1 μM to 30 μM) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25°C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrance bound radioactivity on the filters was determined by liquid scintillation spectrometry. Saturation binding experiments for U937 cells were performed, under standard conditions, using approximately 15-50 μg of U937 membrane protein and increasing concentrations of [ ³ H] -LTB4 (0.02- 2.0 mM) in a reaction volume of 0.2 ml and incubation at 22°C, for 30 minutes. LTB4 (2 μM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard. Uptake of Fura-2 bv Differentiated U937 Cells Harvested cells were resuspended at 2 x 10 ⁶ cells/ml in Krebs

Ringer Hensilet buffer containing 0.1 % BSA (RIA grade), 1.1 mM MgS0 , 1.0 mM CaCl ₂ and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of fura-2 (fura-2/AM) was added to a final concentration of 2 μM and cells incubated in the dark for 30 minutes

at 37°C. The cells were centrifuged at 800 x g for 10 minutes and resuspended at 2 x 10 ⁶ cells/ml in fresh buffer B and incubated at 37°C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 10 ⁶ cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements . Fluorescent Measurements-Calcium Mobilization

The fluorescence of fura-2 containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant mixing. U937 cells were diluted with fresh buffer to a concentration of 1 x 10 ⁶ cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 μl aliquots.

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

F-Fmin]

[Ca ² +]i = 224'

F αx-F

F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with 10 μl of 10% Triton X- 100 (final concentration 0.02%). After Fmax was determined 67 μl of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca ^{2 +} and quench the fura-2 signal and obtain the Fmin. The [Ca ²⁺ ]ι level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca ²⁺ ]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced [Ca ²⁺ ]i

mobilization. The EC50 for LTB4 induced increase in [Ca ²⁺ ]i mobilization was the concentration for half maximal increase. The Kj for calcium mobilization was determined using the formula:

With the experiments described, the LTB4 concentration was 10 nM and the EC50 was 2 nM.

Results for compounds tested by these methods are given in Figure III.

Figure III

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

Example A

8-(4-Methoxyphenyl octan- l -(4-toluenesulfonate

Am 7-Octvn-l -ol.

35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1 ,3- diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0°C and 3-octyn-l -ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether.

The organic layer was washed with 10% HC1 (3X15mL) and brine and dried (MgS04). Evaporation gave the title product which was used

without further purification: iH NMR (90MHz, CDCI3) δ 3.65 (t, J=5Hz, 2H, OCH2), 2.23 (m, 2H, CH ₂ ), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) υmax 3350, 2930, 2125 cm- 1.

A(2 7-Octyn-l -r-butyldiphenylsilyl ether.

7-Octyn-l -ol (3.8g, 30mmol) was dissolved in dimethyl- formamide (lOmL) and treated with r-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2S 04). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: ΪH NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, OCH ₂ ), 2.23 (m, 2H, CH ₂ ), 1.97 (t, IH, acetylenic), 1.6-1.3 (m, 8H, (CH ₂ )4), 1.05 (s, 9H, r-butyl); IR~(film)υmax 3321 , 2940, 2125 cm" ¹ .

A(3 ^" ) 8-(4-MethoxyphenylV7-octyn-l -r-butyldiphenylsilyI ether To a flame-dried flask under an argon atmosphere was added

4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 7-octyn-l -t-butyldiphenylsilyl ether.(9.84g, 27mmoI), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, 0.88mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2S 04). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: !H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH ₂ )4), 1.05 (s, 9H, f-butyl) .

A(4 8-C4-Methoxyphenyl octan-l -t-butyldiphenylsilyl ether.

To 8-(4-methoxyphenyl)-7-octyn-l -t-butyldiphenylsilyl ether (2.2g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent

evaporated to give an oil: ^l B. NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH ₂ ), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH ₂ )6)> 1 -0 (s, 9H, f-butyl).

A(5 8-(4-Methoxyphenyl octan-l -ol.

8-(4-Methoxyphenyl)octan- l -t-butyldiphenylsilyl ether (2.2g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1 M in tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2S θ4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: H NMR (250MHz, CDCI3) δ 7.15 (d,

2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OCH3), 3.68 (t, 2H, OCH ₂ ), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2>6).

A(6 8-(4-Methoxyphenyl octan-l -(4-toluenesuIfonate . 6-(4-Methoxyphenyl)octan-l -ol (5.9g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C .

To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2S θ4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: H NMR (250MHz, CDCI3) δ 7.79 (d, 2H, aryl), 7.35 (d, 2H, aryl), 7.09 (d, 2H, aryl), 6.82 (d, 2H, aryl), 4.04 (s, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.55 (t, 2H, benzylic), 2.46 (s, 3H, CH3), 1.75-1.15 (m, 12H, (CH ₂ )6).

Example B 6-(4-Methoxyphenyl ^' )hexan- l -(4-toluenesulfon ate

B(l) 5-Hexyn - l -t-butyldiphenylsilyl ether

5-Hexyn-l -ol (3g, 30mmol, Aldrich) was dissolved in dimethylformamide (l OmL) and treated with f-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at

room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2S θ4). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: !H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH2), 2.2 (m, 2H, CH ₂ ), 1.9 (t, IH, acetylenic), 1.7 (m, 4H, CH ₂ -CH ₂ ), 1.05 (s, 9H, f-butyl).

B(2 6-(4-Methoxyphenyl -5-hexyn-l -f-butyldiphenylsilyl ether. To a flame-dried flask under an argon atmosphere was added

4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 5-hexyn-l -f-butyldiphenylsilyl ether (8.83g, 27mmol), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, O.88mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2S04). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: !H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH ₂ ), 2.4 (t, 2H, CH ₂ ), 1.7 (m, 4H, CH ₂ -CH ₂ ), 1.05 (s, 9H, f-butyl).

B(3 ό-^-MethoxyphenyPhexan-l -t-butyldiphenylsilyl ether.

To 6-(4-methoxyphenyl)-5-hexyn-l -f-butyldiphenylsilyl ether (2.0g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: ! H NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH ₂ ), 2.5 (t, 2H, benzylic), 1.55 (m, 4H, CH ₂ -CH ₂ ), 1.3 (m, 4H, CH ₂ -CH ₂ ), 1.0 (s, 9H, f-butyl).

B(4 6-(4-Methoxyphenyl hexan-l -ol.

6-(4-Methoxyphenyl)hexan-l -f-butyldiphenylsilyl ether (2.0g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction

was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2Sθ4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: *H NMR (250MHz, CDCI3) δ 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.65 (t, 2H, OCH ₂ ), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH2-CH2), 1.4 (m, 4H, CH ₂ -CH ₂ ).

B(5 6-(4-MethoxyphenyOhexan-l -(4-toluenesulfonate). 6-(4- Methoxyphenyl)hexan-l -ol (5.36g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C. To this was added pyridine (2.5mL, 30mmol) and 4- toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2S 04) .

The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: ^J H NMR (250MHz, CDCI3) δ 1.6-1.3 (m, 8H, (CH ₂ )4), 2.4 (s, 3H, CH3), 2.5 (t, 2H, benzylic), 3.8 (s, 3H, OCH3), 4.0 (t, 2H, OCH ₂ ), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl).

Example C E-6-(4-methoxyphenyl)- l -(4-toluenesulfonate -5 -hexene

Cd E-4-Methoxyphenyl-5-hexenoic acid.

To a freshly prepared solution of lithium hexamethyldisilazide (64mmol) in tetrahydrofuran (30mL), under an argon atmosphere, was added a suspension of (4- carboxybutyl)triphenylphosphonium bromide (17.6g, 30mmol) in tetrahydrofuran (45mL) at room temperature. The reaction was stirred for 15 minutes during which time the orange-red color of the ylide developed. A solution of 4-anisaldehyde (4.5g, 30mmol) in tetrahydrofuran (30mL) was added dropwise and stirring was continued for an additional 20 minutes. The reaction was quenched with H2O (50mL) and diluted with ether (30mL). The aqueous layer was acidified to pH 1.0 with 3N HCl and the product was extracted into ethyl acetate (3X50mL). The combined organic layers were dried (MgSθ4) and the product was purified by flash column chromatography (silica, 1% methanol in CH2CI2) to yield the E-olefin as a solid: !H NMR (200MHz, CDCI3) δ 7.3 (d, 2H, aryl), 6.8

α, 2H, aryl), 6.3 (d, IH, olefin), 6.0 (m, IH, olefin), 3.8 (s, 3H, OCH3), 2.3 (m, 4H, allylic CH2 and CH2CO2), 1.8 (q, 2H, CH2).

C(2) E-4-Methoxyphenyl-5-hexen-l -ol. E-4-Methoxyphenyl-5-hexenoic acid (l .lg, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of LiAlH4 (240mg,

6.0mmol) in ether (lOmL) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. Upon cooling to room temperature the reaction was quenched with H2O (lOmL) followed by 6N H2SO4 (7mL). Ethyl acetate (20mL) was added and the organic layer was separated and dried (MgSθ4); evaporation gave a white crystalline solid: mp. 65-66°C; *H NMR (200MHz, CDCI3) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, IH, olefin), 6.1 (m, IH, olefin), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH ₂ ), 2.2 (q, 2H, allylic), 1.5 (m, 4H, CH ₂ - CH ₂ ); Anal. Calcd. for C13H-Ϊ ₈ θ2: C, 75.65; H, 8.80, found: C, 75.45; H, 8.95; MS (CI): 207 (M+H).

C(3) E-6-(4-methoxyphenyD-l -(4-toluenesulfonate)-5-hexene.

E-4-Methoxyphenyl-5-hexen-l -ol (1.6g, 7.0mmol) was dissolved in dry CH2CI2 (50mL) under an argon atmosphere and treated with 4-toluenesulfonyl chloride (7.0g, 36mmol) and pyridine (3mL). The reaction solution was stirred at room temperature for 3.5 hours. Water (40mL) was added to the reaction and the organic layer was separated and dried (MgSθ4). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give an oil: H NMR (200MHz, CDCI3) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl),

7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.2 (d, IH, olefin), 6.0 (m, IH, olefin), 4.1 (t, 2H, OCH ₂ ), 3.8 (s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.1 (q, 2H, allylic ), 1.6 (m, 4H, CH ₂ - CH ₂ ); MS (CI): 361 (M+H).

Example 1

2-(E-2-Carboxyetheny1)-3-decyloxy-6-r2-(3-carboxyphenyl)- 2- hydroxylethylpyridine. dilithium salt

1 (a 3-Hydτoxy-6-methyl-2-pyridine carboxaldehyde.

2,6-Lutidine-α2,3-diol (l .Og, 7.18mmol, Aldrich) was suspended in dry CH2CI2 (40mL) and treated with Mnθ2 (6.1g, 70mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was

removed in vacuo. The aldehyde was used directly in the next step without further purification: *H NMR (250MHz, CDCI3): δ 10.65 (s, IH,

OH), 10.30 (s, IH, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH ₃ ).

Kb) 3-Decyloxy-6-methyl-2-pyridine carboxaldehyde.

3-Hydroxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry dimethylformamide (lOmL) and treated with 1-iododecane (2.1mL, 8.62mmol) and anhydrous K2CO3 (3.0g, 21.7mmol) under an argon atmosphere. The reaction was heated at 90°C for 1 hour with vigorous stirring. Upon cooling to room temperature the reaction mixture was poured into ethyl acetate (lOOmL); the ethyl acetate solution was washed with H2O (3X20mL) and brine and dried (MgSθ4). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: iH NMR (250MHz, CDCI3): δ 10.40 (s, IH, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 4.07 (t, 2H, OCH ₂ ), 2.6 (s, 3H, CH3), 1.85-0.90 (m, 19H, aliphatic).

1 (c) 3-Decyloxy-6-methyl-2-pyridine aminohydrazone

3-decyloxy-6-methyl-2-pyridine . carboxaldehyde (2.15g, 7.8mmol) was heated with hydrazine hydrate for 1 hour at 95°C .

Upon cooling to room temperature 25% NaOH was added and the mixture was extracted with ethyl acetate. The organic extract was washed with H2O and brine and dried (Na2S 04). The solvent was evaporated to give an amorphous solid: iH NMR (250MHz, CDCI3) δ 8.75 (broad singlet, 2H, NH ₂ ), 7.55 (s, IH, CH-N), 7.10 (d, IH, 5- pyridyl), 6.95 (d, IH, 4-pyridyl), 3.95 (t, 2H, OCH ₂ ), 2.55 (s, 3H, CH3),

1.80-0.90 (m, 19H, aliphatic).

1 (d) 4-Decyloxy-7-methyl-l .2,3-triazolo. 1 ,5-alpyridine.

To a flame-dried flask under an argon atmosphere was added 3- decyloxy-6-methyl-2-pyridine aminohydrazone (2.12g, 7.2mmol) in dry benzene (30mL). To the resulting solution was added Niθ2 (790mg, 8.7mmol). The resulting mixture was stirred at room temperature for 72 hours and then filtered through Celite. The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-15% ethyl acetate in hexanes) to give a white solid: iH NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 6.68 (d, IH,

o-pyridyl), 6.4 (d, IH, 5-pyridyl), 4.1 (t, 2H, OCH ₂ ), 2.8 (s, 3H, CH3 ), 1.90-0.90 (m, 19H, aliphatic); Anal. Calcd. for C17H27N3 : C, 70.55; H, 9.40; N, 14.52, found: C, 70.60; H, 9.14; N, 14.47.

1 (e) l -(3-Iodophenyl)-2-(4-decyloxy-1.2.3-triazoloF 1 .5-a .pyridin-7- yl)ethan-l -ol .

To a flame dried flask under an argon atmosphere was added diisopropylamine (500mg, 4.9mmol) in dry ether (lOmL). The resulting solution was cooled to -40°C (CH3CN/dry ice bath) and 2.5M «-BuLi (1.97mL, 4.9 mmol) was added. The mixture was stirred at - 40°C for 10 minutes followed by the dropwise addition of 4-decyloxy- 7-methyl-l,2,3-triazolo[l ,5- a]pyridine (1.3g, 4.4mmol) in dry ether (40mL) via addition funnel. The resulting red-brick colored mixture was stirred at - 40°C for 6 hours. 3-Iodobenzaldehyde (1.15g, 4.9mmol) in ether (30mL) was added in one portion. A color change from deep-red to yellow was observed. The mixture was allowed to warm to room temperature over a 2 hour period and then stirred at room temperature for 12 hours. The resulting reaction mixture was partitioned between ethyl acetate and H2O and the organic extract was washed with H2O, brine, and dried (Na2S 04). The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give the alcohol as a white solid. A second component was isolated and identified as the 3-substituted triazolopyridine: NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 7.80 (s, IH, aryl), 7.59 (d, IH, aryl), 7.35 (d, IH, aryl), 7.07 (t, IH, aryl), 6.65 (d, IH, 6-pyridyl), 6.4 (d, IH, 5-pyridyl), 5.36 (m, IH, CH-O), 4.11 (t, 2H, OCH2), 3.64 (dd, IH, Py-CH), 3.45 (dd, IH, Py-CH),

3.25 (d, IH, OH), 1.88-0.88 (m, 19H, aliphatic).

1 (f) 1 -(3-Carboxymethylphenyl)-2-(4-decyloxy-l .2.3-triazolo- π .5-alpyridine-7-yl)ethan- l -ol.

To a solution of l-(3-iodophenyl)-2-(4-decyloxy-l,2,3- triazolo[l ,5-a]pyridine-7-yl)ethan-l -ol (500mg, 0.96mmol) in dimethylsulfoxide (lOmL) was added methanol (4mL), triethylamine (0.3mL, 2.1mmol), Pd(OAc)2 (6.4mg, 0.029mmol), and bis diphenylphosphinopropane (1 1.9mg, 0.029mmol). Carbon monoxide was bubbled into the mixture for 4 minutes. The mixture was then heated at 85°C under positive carbon monoxide pressure for 6 hours. The mixture was cooled to room temperature and partitioned between

ethyl acetate and H2O. The organic layer was washed with H2O, brine, and dried (Na2S 04). The solvent was evaporated and the residue purified by flash column chromatography (silica, 5-20% ethyl acetate in hexanes) to give a white solid: *H NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 8.1 (s, IH, aryl), 7.95 (d, IH, aryl), 7.63 (d, IH, aryl), 7.4 (t, IH, aryl), 6.65 (d, IH, 6-pyridyl), 6.4 (d, IH, 5-pyridyl), 5.45 (m, IH, CH-O), 4.11 (t, 2H, OCH ₂ ), 3.9 (s, 3H, C0 ₂ CH ), 3.70 (dd, IH, Py-CH),

3.45 (dd, IH, Py-CH), 3.25 (d, IH, OH), 1.90-0.88 (m, 19H, aliphatic); Anal. Calcd. for C26H35N3O4: C, 68.85; H, 7.78; N, 9.26, found: C, 68.81 ; H, 7.73; N, 9.31.

Kg) 3-Decyloxy-2-(α. α-dibromomethyl )-6- T2-(3-carbox y methyl - phenyl )-2-hydroxy lethylpyridine. l -(3 -Carboxymethylphenyl)-2-(4-decyloxy- l ,2,3-triazolo- [l,5-a]pyridine-7-yl)ethan-l -ol (130mg, 0.28mmol) was dissolved in CH2CI2 (3mL) and cooled to 0°C. To this was slowly added a solution of Br2 (46mg, 0.28mmol) in CH2CI2 (3mL); gas evolution was observed and the reaction mixture was stirred at 0°C for 1 hour. The CH2CI2 solution was washed with NaHCθ3, H2O, and brine and dried (Na2Sθ4). The solvent was evaporated to give a yellow oil: H NMR (250MHz, CDCI3): δ 8.1 (s, IH, aryl), 7.92 (d, IH, aryl), 7.63 (d, IH, aryl), 7.4 (t, IH, aryl), 7.09 (d, IH, 3-pyridyl), 7.07 (s, IH, CHBr ₂ ), 7.0

(d, IH, 4-pyridyl), 6.08 (d, IH, OH), 5.25 (m, IH, CH- O), 4.05 (t, 2H, OCH ₂ ), 3.9 (s, 3H, C0 ₂ CH ₃ ), 3.15 (m, 2H, Py-CH ₂ ), 1.90-0.88 (m, 19H, aliphatic).

Kh) 3-Decyloxy-6-r2-(3-carboxymethylphenyl)-2-hydroxylethyl-2- pyridine carboxaldehyde.

To a solution of 3-decyloxy-2-(α,α-dibromomethyl)-6-[2-(3 - carboxymethylphenyl)-2-hydroxy]ethylpyridine ( 150mg, 0.26mmol) in ethanol (3mL) was added AgNθ3 (90mg, 0.56mmol) in H ₂ 0 (lmL).

The resulting mixture was heated at reflux for 1 hour. The mixture was cooled to room temperature and concentrated HCl (lmL) was added and the precipitated silver salt was removed by filtration. The filtrate was evaporated and the residue treated with saturated NaHCθ3. The product was extracted into ethyl acetate and was washed with H 0 and brine and dried (Na ₂ S 04). The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil:

iH NMR (250MHz, CDC1 ₃ ): δ 10.4 (s, IH, CHO), 8.1 (s, IH, aryl), 7.92 (d, IH, aryl), 7.63 (d, IH, aryl), 7.4 (t, IH, aryl), 7.33 (d, IH, 3- pyridyl), 7.25 (d, IH, 4-pyridyl), 5.25 (m, IH, CH-O), 5.0 (d, IH, OH), 4.1 (t, 2H, OCH ₂ ), 3.9 (s, 3H, C0 ₂ CH ₃ ), 3.15 (m, 2H, Py-CH ₂ ), 1.90- 0.88 (m, 19H, aliphatic); MS (CI): 277 (M+H).

l (i) 2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-r2-(3-carboxy- methylphenyl)-2-hydroxy lethylpyridine.

3-Decyloxy-6-[2-(3 -carboxymethylphenyl)-2-hydroxy]ethyl-2- pyridine carboxaldehyde (40mg, 0.09mmol) was dissolved in dry benzene (2mL) under an argon atmosphere. To this was added methyl (triphenylphosphoranylidene)acetate (60mg, 0.18mmol) and the resulting mixture was heated at 45° C for 1 hour. Upon cooling to room temperature the reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2S 04). The solvent was evaporated and the residue purified by flash column chromatography (silica, 15-20% ethyl acetate in hexanes) to give a yellow oil: iH NMR (250MHz, CDCI3): δ 8.1 (s, IH, aryl), 8.1 (d, J=16Hz, IH, olefin), 7.9 (d, IH, aryl), 7.65 (d, IH, aryl), 7.4 (t, IH, aryl), 7.15 (d, IH, 5-pyridyl), 7.03 (d, IH, 4-pyridyl), 6.95 (d, J=16Hz, IH, olefin), 5.65 (d, IH, OH), 5.2 (m, IH, CH-O), 4.05 (t, 2H, OCH ₂ ), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, C0 ₂ CH ₃ ), 3.10 (m, 2H, Py-CH ₂ ), 1.90-0.88 (m, 19H, aliphatic); MS (CI): 498 (M+H).

Kj) 2-(E-2-Carboxyethenyl)-3-decyloxy-6- 2-(3-carboxyphenyl)-2- hydroxylethylpyridine. dilithium salt.

2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-[2-(3- carboxymethylphenyl)-2-hydroxy]ethyIpyridine (22mg, 0.04mmol) was dissolved in tetrahydrofuran, H ₂ 0, and methanol (0.50mL each) and treated with LiOH monohydrate (5mg, 0.2mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2O and purified by Reversed Phased MPLC (RP-18 silica, 10-40% MeOH in H2O). The desired fractions were lyophilized to give a colorless amorphous solid: iH NMR (250MHz, CD3OD): δ 8.01 (s, IH, aryl), 7.80 (d,lH, aryl),

7.76 (d, J=16Hz, IH, olefin), 7.36 (d, IH, aryl), 7.30 (t, IH, aryl), 7.24 (d, IH, 5- pyridyl), 7.07 (d,J=16Hz, IH, olefin), 7.01 (d, IH, 4-pyridyl), 5.11 (t, IH, CH-O), 4.0 (t, 2H, OCH ₂ ), 3.1 (m, 2H, Py-CH ₂ ), 1.83- 0.89

(m, 19H, aliphatic); FAB-MS: 474.3 (M-H, monolithium salt), 468 (M- H, free acid).

Example 2 2-(2-Carboxyethyl)-3 -decy1oxy-6-. 2-(3 -carboxyphenyl)-2- hydroxylethylpyridine. dilithium salt

2(a) 2-(2-Carbox vmethylethyl)-3-decyloxy-6-r2-(3-carboxy methyl - phenyl )-2-hydroxy lethylpyridine. To 2-(E-2-carboxymethylethenyl)-3-decyloxy-6-[2-(3- carboxymethylphenyl)-2-hydroxy]ethylpyridine (13mg, 0.02mmol) in ethanol (3mL) was added 5% Pd/C (2mg). The mixture was subjected to 5 psi of H2 for 1 hour. The mixture was filtered through Celite and the solvent was evaporated to give an oil: iH NMR (250MHz, CDCI3): δ 8.08 (s, IH, aryl), 7.9 (d, IH, aryl),

7.6 (d, IH, aryl), 7.4 (t, IH, aryl), 7.05 (d, IH, 5-pyridyl), 6.87 (d, iH, 4-pyridyl), 6.0 (broad singlet, IH, OH), 5.15 (m, IH, CH-O), 4.01 (t, 2H, OCH ₂ ), 3.9 (s, 3H, C0 ₂ CH ₃ ), 3.8 (s, 3H, CO2CH3), 3.2 (t, 2H, CH ₂ ), 3.05 (m, 2H, CH ₂ ), 2.8 (t, 2H, CH ₂ ), 1.83-0.88 (m, 19H, aliphatic).

2(b) 2-(2-Carboxyethyl)-3-decyloxy-6-.2-(3-carboxyphenyl)-2- hvdroxylethylpyridine. dilithium salt.

2-(2-Carboxymethylethyl)-3 -decyloxy-6- [2-(3 - carboxymethylphenyl)-2-hydroxy]ethyIpyridine (lOmg, 0.015mmol) was dissolved in tetrahydrofuran, H2O, and MeOH (0.5mL each) and treated with LiOH monohydrate (2mg, O.lOmmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2O, filtered through a nylon filter and purified by Reversed Phased MPLC (RP-18 silica, 10- 40% methanol in H2O). The desired fractions were lyophilized to give a colorless amorphous solid: *H NMR (250MHz, CD3OD): δ 8.0 (s, IH, aryl), 7.8 (d, IH, aryl), 7.32 (d, IH, aryl), 7.25 (t, IH, aryl), 7.1 (d, IH, 5-pyridyl), 6.9 (d, IH, 4-pyridyl), 5.1 (t, IH, CH-O), 4.0 (t, 2H, OCH ₂ ), 3.1 (t, 2H, CH ₂ ), 3.05 (m, 2H, CH2), 2.5 (t, 2H, CH ₂ ), 1.8-0.90 ( , 19H, aliphatic); FAB-MS: 484 (M+H).

Example 3

2-(E-3-Hydτoxypropenyl)-3 -decyloxy-6-. 2-(3 -carboxyphenyl )-2- hydroxy .ethylpyridine, lithium salt.

3(a) 3-Decyloxy-2-(α.α-dibromomethyl)-6-r2-(3 -iodophenyl )-2- hydroxylethylpyridine.

This compound was prepared from l -(3-iodophenyl)-2-(4- decyloxy-l,2,3-triazolo[l ,5-a]pyridin-7-yl)ethan-l -ol [Example 1 (d)] according to the procedure described for 3-decyloxy-2-(α,α- dibromomethyl)-6-[2-(3-carboxymethylphenyl)-2- hydroxy]ethylpyridine [Example 1(f)].

3(b) 3-Decyloxy-6-r2-(3-iodophenyl)-2-hydroxy ,ethyl-2-pyridine carboxaldehyde. This compound was prepared from 3-decyloxy-2-(α,α- dibromomethyl)-6-[2-(3-iodophenyl)-2-hydroxy]ethylpyridine according to the procedure described in Example 1 (g). It was obtained as a white solid. iH NMR (250MHz, CDCI3): δ 10.4 (s, IH, CHO), 7.8 (s, IH, aryl), 7.6 (d, IH, aryl), 7.4 (m, 2H, 3d pyridyl, aryl), 7.3 (d, IH, 4-pyridyl), 7.1 (t, IH, aryl), 5.1 (m, IH, CH-O), 4.95 (d, IH, OH), 4.1 (t, 2H, OCH ₂ ), 3.1 (m, 2H, Pyd CH2), -1.80-0.90 (m, 19H, aliphatic).

3(c) 2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-r2-(3-iodophenyl - 2-hydroxy lethylpyridine.

The captioned compound was prepared from 3-decyloxy-6-[2- (3-iodophenyl)-2-hydroxy]ethyl-2-pyridine carboxaldehyde [Example 3(b)] according to the procedure described for in Examplel(h): iH NMR (250MHz, CDCI3): δ 8.1 (d, J=15.9Hz, IH, olefin), 7.8 (s, IH, aryl), 7.6 (d, IH, aryl), 7.4 (d, IH, aryl), 7.2 (d, IH, 5- pyridyl),

7.05 (m, 2H, 4-pyridyl, aryl), 6.95 (d, J=15.9Hz, IH, olefin), 5.6 (d, IH, OH), 5.1 (m, IH, CH-O), 4.05 (t, 2H, OCH ₂ ), 3.8 (s, 3H, CO2CH3), 3.05 (m, 2H, Py-CH2), 1.85-0.90 (m, 19H, aliphatic).

3(d) 2-(E-3-Hydroxypropenyl)-3-decyloxy-6-.2-(3-iodophenyl)-2- hydroxy lethylpyridine.

2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-[2-(3- iodophenyl)-2-hydroxy]ethylpyridine (340mg, 0.60mmol) was dissolved in dry CH2CI2 (6mL) under an argon atmosphere and cooled

to 0°C. DIBAL (1.5mL, 1.5mmol, 1M in CH2θ ₂ ) was added dropwise and the reaction was maintained at 0°C for 20 minutes. The reaction was quenched with methanol (lOmL) and the solvent was evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was washed with H2O and brine and dried (Na2S 04) . The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil. iH NMR (250MHz, CDCI3): δ 7.8 (s, IH, aryl), 7.6 (d, IH, aryl), 7.4 (d, IH, aryl), 7.10 (m, 5H, olefinic, 4-pyridyl, 3-pyridyl, aryl), 6.4

(broad singlet, IH, OH), 5.05 (m, IH, CH-O), 4.4 (d, 2H, allylic), 3.95 (t, 2H, OCH ₂ ), 3.0 (m, 2H, Py-CH ₂ ), 1.90-0.90 (m, 19H, aliphatic).

3(e) 2-(E-3-Hydroxypropenyl)-3-decyloxy-6-[2-(3-carboxymethyl- phenyl)-2-hydroxy lethylpyridine.

This compound was prepared from 2-(E-3-hydroxypropenyl)-3- decyloxy-6-[2-(3-iodophenyl)-2-hydroxy]ethylpyridine according to the procedure described in Example 1 (e). iH NMR (250MHz, CDCI3): δ 8.15 (s, IH, aryl), 7.9 (d, IH, aryl), 7.65 (d, IH, aryl), 7.4 (t, IH, aryl), 7.10 (m, 4H, olefinic, 3-pyridyl, 4- pyridyl), 6.4 (broad singlet, IH, OH), 5.2 (m, IH, CH-O), 4.4 (d, 2H, allylic), 4.0 (t, 2H, OCH ₂ ), 4.9 (s, 3H, CO2CH3), 3.1 (m, 2H, Py-CH ₂ ),

1.90-0.90 (m, 19H, aliphatic).

3(f) 2-(E-3-Hydroxypropenyl)-3-decyloxy-6-r2-(3-carboxyphenyl)- 2-hydroxy]ethylpyridine. lithium salt.

This salt was prepared from 2-(E-3-hydroxypropenyl)-3- decyloxy-6-[2-(3-carboxymethylphenyl)-2-hydroxy]ethylpyridin e [Example 3(e)] according to the procedure described for 2-(E-2- carboxyethenyl)-3-decyloxy-6-[2-(3-carboxyphenyl)-2- hydroxyjethylpyridine, dilithium salt [Example l(i)].

H NMR (250MHz, CD3OD): δ 8.0 (s, IH, aryl), 7.8 (d, IH, aryl), 7.4

(d, IH, aryl), 7.3 (t, IH, aryl), 7.2 (d, IH, 3-pyridyl), 6.9 (m, 3H, olefinic, 4-pyridyl), 5.1 (m, IH, CH-O), 4.3 (d, 2H, allylic), 4.0 (t, 2H, OCH ₂ ), 3.1 (m, 2H, Py-CH ₂ ), 1.85-0.85 (m, 19H, aliphatic); FAB-MS:

(-ve), 460.3 (M-Li).

Example 4 2-(E-2-Carboxyethenyl)-3-[6-(4-methoxyphenyl)hexyloxyl -6-F2-(3 - carboxyphenyl)-2-hydroxy1ethylpyridine. dilithium salt 2-(E-2-Carboxyethenyl)-3- [6-(4-methoxyphenyl)hexyloxy] -6- [2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine, dilithium salt was prepared according to the procedure described for 2-(E-2- carboxyethenyl)-3 -decyloxy-6-[2-(3-carboxyphenyl)-2- hydroxy]ethylpyridine, dilithium salt recited in Example 1 , but substituting 6-(4-methoxyphenyl)hexan-l -(4-toluenesulfonate) [Example B(5)] for 1-iododecane.

4(a) 3-r6-(4-Methoxyphenyl)hexyloxy1 -6-methyl-2-pyridine carboxaldehyde: iH NMR (250MHz, CDCI3): δ 10.4 (s, IH, CHO), 7.3 (s,

2H, 4-pyridyl, 5-pyridyl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 4.1 (t, 2H, OCH ₂ ), 3.8 (s, 3H, OCH3), 2.6 (s, 3H, CH3), 2.6 (t, 2H, benzylic), 1.8-

1.35 (m, 8H, aliphatic); Anal. Calcd. for C20H25NO3 • 1/8 H ₂ 0: C, 72.87; H, 7.72; N, 4.25, found: C, 72.75; H, 7.65; N, 4.10; MS (CI): 328 (M+H).

Following the procedures in Examples 1(b) et seq, but substituting the appropriate adducts here for those recited in Example 1, the following compounds were made:

4(b) 3-[6-(4-Methoxyphenyl)hexyloxy1 -6-methyl-2-pyridine aminohydrazone: iH NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 7.15 (d, 2H, aryl), 7.1 (d, IH, 5-pyridyl), 7.0 (d, IH, 4-pyridyl), 6.8 (d, 2H, aryl), 5.7 (broad singlet, 2H, NH ₂ ), 3.95 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.6 (s, 3H, CH3), 2.6 (t, 2H, benzylic), 1.8-1.35 (m, 8H, aliphatic).

4(c) 4-r6-(4-Methoxyphenyl)hexyloxy1-7-methyl-1.2,3-triazolo-r i .5- alpyridine: iH NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.65 (d, IH, 6-pyridyl), 6.4 (d, IH, 5-pyridyl),

4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.8 (s, 3H, CH3), 2.63 (t, 2H, benzylic), 1.90-1.35 (m, 8H, aliphatic).

4(d) 1 -(3-Iodophenyl)-2-r4-r6-(4-methoxyphenyl)hexyloxy1-l .2.3- triazolon .5-alpyridin-7-yllethan-l -ol: ! H NMR (250MHz, CDCI3): δ

8.2 (s, IH, CH-N), 7.8 (s, IH, aryl), 7.6 (d, IH, aryl), 7.37 (d, IH, aryl), 7.06 (t, IH, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.65 (d, IH, 6- pyridyl), 6.4 (d, IH, 5-pyridyl), 5.4 (m, IH, CH-O), 4.1 (t, 2H, OCH ₂ ), 3.8

(s, iH, OCH3), 3.7 (dd, IH, Py-CH), 3.5 (dd, IH, Py-CH), 3.2 (d, IH, OH), 2.63 (t, 2H, benzylic), 1.90-1.35 (m, 8H, aliphatic); MS (CI): 572 (M+H).

4(e) 1 -(3-Carboxymethylphenyl)-2-[4-r6-(4-rnethoxyphenyl )- hexyloxy1- 1.2.3-triazoloπ .5-a1pyridin-7-yllethan-l -ol : ! H NMR (250MHz, CDCI3): δ 8.2 (s, IH, CH-N), 8.11 (s, IH, aryl ), 7.95 (d, IH, aryl), 7.6 (d, IH, aryl), 7.4 (t, IH, aryl), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.6 (d, IH, 6-pyridyl), 6.3 (d, IH, 5- pyridyl), 5.5 (m, IH, CH-O), 4.1 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, OCH3), 3.7 (dd, IH, Py- CH), 3.5 (dd, IH, Py- CH), 3.2 (d, IH, OH), 2.55 (t, 2H, benzylic), 1.90-

1.40 (m, 8H, aliphatic); MS (CI): 504 (M+H).

4(f) 3-r6-(4-Methoxyphenyl)hexyloxy1 -2-(α.α-dibromomethyl)-6-[2-

(3-carboxymethylphenyl)-2-hvdroxy1ethylpyridine: H NMR (250MHz, CDCI3): δ 8.15 (s, IH, aryl), 7.9 (d, IH, aryl), 7.65 (d, IH, aryl), 7.4 (t, IH, aryl), 7.1 (m, 4H, 3-pyridyl, 4-pyridyl, aryl), 6.8 (d, 2H, aryl), 5.3 (m, IH, CH-O), 4.1 (t, 2H, OCH2), 3.95 (s, 3H, CO2CH3), 3.9 (s, IH, CHBr ₂ ), 3.8 (s, 3H, OCH3), 3.15 (m, 2H, Py-CH ₂ ), 2.55 (t, 2H, benzylic), 1.85-1.40 (m, 8H, aliphatic).

4(g) 3-[6-(4-Methoxyphenyl)hexyloxy1-6-[2-(3-carboxymethyl- phenyl)-2-hydroxylethyl-2-pyridine carboxaldehyde: 1 H NMR (250MHz, CDCI3): δ 10.4 (s, IH, CHO), 8.1 (s, IH, aryl), 7.9 (d, IH, aryl),

7.65 (d, IH, aryl), 7.4 (t, IH, aryl), 7.35 (d, IH, 3-pyridyl), 7.25 (d, IH, 4-pyridyl), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 5.4 (m, IH, CH-O), 5.0 (d,

IH, OH), 44.1 (t, 2H, OCH2), 3.95 (s, 3H.. CO2CH3), 3.8 (s, 3H, OCH3), 3.2 (m, 2H, Py-CH2), 2.5 (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); MS (CI): 492 (M+H).

4(h) 2-(E-2-Carboxymethylethenyl)-3-r6-(4-methoxyphenyl)- hexyloxy . -6-r2-(3-carboxymethylphenyl)-2-hydroxy1ethylpyridine: iH NMR (250MHz, CDCI3): δ 8.07 (s, IH, aryl), 8.05 (d, J=16Hz, IH, olefin), 7.9 (d, IH, aryl), 7.65 (d, IH, aryl), 7.4 (t, IH, aryl), 7.1 (m, 4H, 4-pyridyl, 5-pyridyl, aryl), 6.95 (d, J=16Hz, IH, olefin), 6.8 (d, 2H, aryl), 5.7 (d, IH, OH), 5.2 (m, IH, CH-O), 4.05 (t, 2H, OCH ₂ ), 3.9 (s, 3H, C0 ₂ CH ), 3.8 (s, 3H, OCH3), 3.75 (s, 3H, CO2CH3), 3.15 (m, 2H, Py-CH ₂ ), 2.55 (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); Anal. Calcd. for: C32H37NO7 • 9/8 H ₂ 0: C, 67.68; H, 6.97; N, 2.47, found: C, 67.45; H,

6.63; N, 2.34; MS (CI): 548 (M+H).

4(i) 2-(E-2-Carboxyethenyl)-3-r6-(4-methoxyphenyl)hexyloxyl-6-[2-

(3-carboxyphenyl)-2-hvdroxy1ethylpyridine. dilithium salt: iH NMR (250MHz, CD3OD): δ 8.05 (s, IH, aryl), 7.8 (d, IH, aryl), 7.75

(d, J_=16Hz, IH, olefin), 7.35 (d, IH, aryl), 7.25 (t, IH, aryl), 7.2 (d, J=16Hz, IH, olefin), 7.0 (m, 4H, 4-pyridyl, 5- pyridyl, aryl), 6.75 (d, 2H, aryl), 5.15 (t, IH, CH-O), 4.0 (t, 2H, OCH2), 3.7 (s, 3H, OCH3), 3.1 (m, 2H, Py-CH2), 2.5 (t, 2H, benzylic), 1.80-1.35 (m, 8H, aliphatic); FAB -MS: (+ve), 532.2 (M+H); (-ve), 524.4 (M-Li).

Example 5

Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.

Inhalant Formulation

A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug .per use.

1013 g

Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.

Step 2 Add sufficient water portion wise to the blend from Step with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.

Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.

Step 4 The wet granules are then dried in an oven at 410°F (60°C) until dry.

Step 5 The dry granules are lubricated with ingredient No. 5.

Step 6 The lubricated granules are compressed on a suitable tablet press.

Suppositories:

In gredients Per Supp. Per 1000 Supp.

1. Formula I compound 40.0 mg 40 g Active ingredient

2. Polyethylene Glycol 1350.0 mg 1 ,350 g 1000

3. polyethylene glycol 450.0 mg 450 g 4000 1840.0 mg 1 ,840 g

Procedure: Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.

Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.

Step 3. Pour the molten mass from Step 2 into suppository moulds and chill.

Step 4. Remove the suppositories from moulds and wrap.