EP0639975A1

EP0639975A1 - Heterocyclic-substituted pyridine compounds and uses

Info

Publication number: EP0639975A1
Application number: EP93900943A
Authority: EP
Inventors: Robert A. Daines
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1991-12-06
Filing date: 1992-12-04
Publication date: 1995-03-01
Also published as: WO1993010780A1; EP0639975A4; MX9207079A; AU3244493A; ZA929462B; JPH07501550A

Abstract

This invention relates to compounds which have anti-psoriatic activity.

Description

"Heterocyclic-substituted Pyridine Compounds and Uses"

Scope of the Invention This invention relates to the use of certain heterocycle-substituted pyridine compounds useful for treating diseases arising from or related to leukotrienes, particularly leukotriene B4. As such there utility lies in antagonizing the affects of leukotrienes.

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 C4, D4 and E4) and the dihydroxyleukotrienes (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 in the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response is 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 peπneabϋity and increased mucous production.

By comparison, LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).

Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fϊbrosis, 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)-dihydroxy-(Z,E,E,Z)-6,8,10,14- eicosatetraenoic acid.

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. LTB4 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 that exhibit a high degree of stereospecifiάty. 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. LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction.

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 this invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor. Summary of the Invention

This invention relates to compounds of foπnula I

or anN-oxide, or a pharmaceutically acceptable salt, where

Z is O, NH, NCH3 or S(O)q where q is 0, 1 or 2; mis 0-5;

R is C_j to C2o-aliphatic, unsubstituted or substituted phenyl-Cχ to Cio-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 C to C20-aliphatic-O-, orR is unsubstituted or substituted phenyl-Cj to Cjo-aϋphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rj is R4, -(Cj to C5 a_iphatic)R4, -(Ci to C5 aliphatic) CHO, -(Ci to C5 aHp_at_c)CH20R8, -CH2OH or -CHO; Het is a 5- or 6-membered heteroaromatic ring;

R2is H, or-( ____2)nR4 where nis 0-5; or 2 is -OT(NH2) (R4) or - C-B^RQ where n is 0-5 where R9 is - R7>2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbons, or acyl of 1-6 carbons, or cycloalkyKCH^- group of 4 to 10 carbons where n is 0-3, or both R7 groups foπn a ring having 4 to 6 carbons;

R3 is H, lower alkyl, or acyl of 1-6 carbons or is absent; R4 is tetrazol-5-yl, or COOH or a salt, ester or amide thereof. In a further aspect, this invention relates to compositions comprising a compound of foπnula I, or a salt thereof, in admixture with a carrier. Included in these compositions are those suitable for pharmaceutical use and comprising a pharmaceutically acceptable excipient or carrier and a compound of formula I which may be in the form of a pharmaceutically acceptable salt.

Processes for making these compounds are also included in the scope of this invention, which processes comprise: a) forming a salt, or b) forming an ester, c) oxidizing a thio ether to the sulfoxide or sulfone; d) forming a compound of foπnula I by treating a 6-halomethylpyridyl compound with the appropriate mercaptoheterocycle, or hydroxyheterocycle.

General Embodiments The following definitions are used in describing this invention. "Aliphatic" is intended to include saturated and unsaturated radicals. This includes noimal 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-. "Acyl-lower alkyl" refers to the group (O)C-lower alkyl where the carbonyl carbon is counted as one of the carbons of the _ to 6 carbons noted under the definition of lower alkyl. "Halo" refers to and means fluoro , chloro, bromo or iodo. The phenyl ring may be substituted with one or more of these radicals.

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 pattern.

The term "heteroaromatic" or grammatical variations thereof includes five and six membered monocyclic aromatic rings which have one or more non-carbon atoms such as nitrogen, oxygen, sulfur, or silicon. A list of such heteroaromatic radicals can be found in chemistry reference books such as the Handbook of Chemistry and Physics,R. C. West, Ed., 65th Edition, CRC Press Inc., Boca Raton, Florida, USA, or a later edition. More specifically, the group includes: furyl, thienyl, pyrrolyl, thiazolyl, thiadiazolyl, tetrazolyl, isothiazolyl, isoxazolyl, fiirazanyl, benzothienyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, and the like.

The phrase "a pharmaceutically acceptable ester-forming group" covers all esters which 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.

Amides may be formed from acid groups. The most preferred amides are those where the nitrogen is substituted by hydrogen or alkyl of 1 to 6 carbons. The diethylamide is particularly preferred.

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, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base where R4 is tetrazol-5-yl for example, or an excess of organic or inorganic base where R4 is COOH for example.

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 f oπns 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. Inflammatory diseases such as psoriasis and inflammatory bowel disease may be treated by applying or administering the compounds described herein. It is also expected that these compounds can be used to treat allergic diseases including those 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 uveϊtis, and allergic conjunctivitis can also be treated by these compounds.

The preferred compounds are those where Zis S(O)q, or O; m is 0-3; R is Cg to C20 alkoxy, phenyl-C4 to Cχo alkoxy or substituted-phenylC^ to CJQ alkoxy; R^ is R4, -(Cj- C3_lkyl)R4, or -(C2-C3 alkenyl)]_4; and the heteroaromatic group is a five-membered ring with 2 or more nitrogens, a sulfur and two nitrogens, or a sulfur and a nitrogen. The more preferred compounds are those where Z is S(O)q where q is 0 or 2; R is substituted phenyl-C4 to Cχo alkoxy, particularly the substituted-phenyl(CH2)4_g-O- group or CH^CR^-j- -O-; m is 0 or 1; Rl is HO2C-CH= CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof. Preferred heteroaromatic groups are tetrazol-5-yl, imidazol -2-yl, t_i_zol-2-yl, triazol -2-yl, and l,3,4-tbiadiazol-5-yl. The most preferred compounds are: l-memyl-2-[l-tMa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyljethyljimidazole; l-[2-acetylammc_;thyl]-5-[l-thia-2-i2-(E-2-cai_>oxyethenyl)-3-(8-(4- methoxyphenyl)octyloxy)-6-pyridyl]ethyl]tetrazole; l-memyl-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]tetrazole;

2-__c___no-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]-l,3,4-thiadiazole ; 2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6-pyridyl]ethyl]-

1,3-thiazole;

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]imidazole;

3-ammo-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]- 1 ,2,4-triazole; l-memyl-2-[l-oxythia-2-[2-(E-2-caιboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]imidazole; l-methyl-2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4- methoxyphenyl)butyloxy)-6-pyridyl]ethyl]imidazole, hthium salt;

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole, lithium salt;

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]thiazole, lithium salt;

2-[l-thia-2-[2-(E-2-caι_>oxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]thiazole, lithium salt; 2-[l-thia-2-[2-(2-carboxyethanyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]thiazole, lithium salt; l-methyl-2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]propyl]imidazole, lithium salt; and

2-[2-tbia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]propyl]thiazole, lithium salt.

The methods for preparing these compounds are several. One generic process comprises preparing a 6-halomethylpyridyl adduct and then condensing that fragment with the appropriate mercaptan or alcohol to make compounds where Z is a sulfur or oxygen atom. Normally this will be a protected product; any acid group will be derivatized in some manner to render it unreactive. Derivatizing groups may be removed to provide a parent functionality, such as an acid or a salt of an acid. Further modifications of these reactive groups can then be carried out, such as forming a salt, an amide, an ester or the like.

Schematic methods for making these compounds are illustrated in the following reaction schemes. An illustrative method for making the carbon-containing fragment of the R group is given in Scheme I. Scheme I

The starting alcohol, represented here as the 3-octyn-l-ol, is commercially available (Lancaster Synthesis). To migrate the triple bond to the w-carbon, KH and 1,3-diaminopropane are combined and stirred to a homogeneous mix. This can be done at ambient temperature or thereabouts. This mix is then cooled, preferably to about 0°C or thereabouts, whereupon the alcohol is added. Stirring is then commenced at about room temperature for 15 to 20 hours or so. Water is added to quench the reaction and the product is recovered.

Protecting the alcohol is accomplished by forming a silyl ether illustrated here as the t- butyldiphenyls-lyl ether. Other silyl ethers could be used. The alcohol is dissolved in a polar solvent, for example dimemylfoπnamide, and imidazole is added followed by the desired silane. All this is carried out under an inert atmosphere such as argon. Ambient temperature is acceptable for effecting the reaction.

Adding the phenyl group is done in a dry environment using an amine for a solvent and an inert atmosphere. To a flask containing a solvent such as triethylamine under argon is added the silylether followed by a halophenyl compound, eg. iodoanisole, a palladium catalyst (Ph3P)2PdC-2 and Cul, both of the latter in catalytic amounts. Heat is used to effect the reaction, usually a temperature of up to about 50°C will be sufficient. Two or more hours, up to six but often about four at the elevated temperature will usually cause the reaction to go to completion.

The triple bond is then saturated, preferably by catalytic hy rogenation. For example, the silyl ether can be dissolved in a saturated solvent such as an alcohol, a heavy metal catalyst added (Pd-C) and the mixture put under H2 for a time sufficient to reduce the triple bond. Stirring for 2 to 6 hours will usually effect the reaction.

Recovering the alcohol is done by treating the silyl ether with a fluoride source such as tetrabutylammonium fluoride. Reactants are combined at a mildly reduced temperature, eg. 0°C, then the reaction is allowed to run its course at ambient temperature or there about. Several hours may be needed for the reaction to go to completion. Product was recovered by extraction means.

Converting the alcohol to the iodo compound is accomplished using a phosphine, imidazole and I2. In actual practice, this transformation is accomplished by adding to a solution of alcohol under argon, a molar excess of triphenylphosphine, for example, and a three- fold excess of imidazole followed by iodine. Materials are combined at room temperature, but then the reaction pot may be heated to between 50 - 70°C for a brief period, 10 minutes to an hour to complete the reaction. Standard procedures are then used to recover and purify the product.

This procedure, with appropriate variations, can be used to make the full spectrum of R groups which have a terminal phenyl group, including the substituted phenylaliphatic radicals. A majority of thioaromatic and hydroxyaromatic compounds which can be used to add the "Het" group are commercially available or can be made by reference to the literature. An alternative procdure for the preparation of the 2-mercaptomethylimidazoles and 2- mercaptomethylthiazoles is shown in Scheme II. The 2-position of the heterocyclic ring can be formylated to the hydroxymethyl compound followed by conversion of the chloromethyl derivative. This is accomplished according to procedures in the art, for example P. C. Jocelyn, J. Chem. Soc. 305 (1957), and A. Dondoni, et al., Synthesis. 998 (1987). This chloro compound is then reacted with thiourea to produce the thiouronium salt which is then hydrolyzed to the desired mercaptan.

Scheme II

A general method for making compounds of foπnula I is outlined in Scheme HI.

Scheme Iff

Salt (or free acid if neutralized)

The starting material is available from Aldrich. It is treated with a mild oxidizing agent such as MnO2 to oxidixe the 2-hydroxymethyl group to the coπesponding aldehyde. The R group is then formed. An ether is prepared under basic conditions using an a-halo intermediate. Introducing the acid function at position 2 is accomplished by means of a triphenylphosphoranylidene reagent. The acetate form is illustrated here but other similar reagents could be used. The N-oxide is then formed by means of an oxidant, in this case a peroxy acid. Trifluoroacetic anhydride is used to oxidize the 6-position methyl group. This hydroxymethyl group is then converted to the corresponding halide, (in the hydrohalide form) in this case the chloride, by means of thionyl chloride. A thio-substituted or hydroxy-substituted aromatic group (illustrated by SAr in the reaction scheme) is then reacted with the 6- chloromethyl compound in the presence of a base, preferably CS2CO3 in this instance. The resulting compound can be saponified using a base to obtain the corresponding salt or, if acidified, the corresponding free acid of the thioether or ether. Further, an oxidant can be used to generate the sulfoxide or the sulfone analogs of the thioethers, depending on whether one or two equivalents of oxidizing agent are used. Preferably this oxidation step will be done before the ester is saponified.

Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and some amount of a compound of the formula (I). The compound may be present in an amount to effect a physiological response, or it may be present in a lesser amount such that the user will need to take two or more units of the composition to effect the treatment intended. These compositions may be made up as a solid, liquid or in a gaseous form. Or one of these three forms may be transformed to another at the time of being administered such as when a solid is delivered by aerosol means, or when a liquid is delivered as a spray or aerosol.

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.

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.

For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, aerosols, and drops suitable for administration to the skin, eye, ear, or nose.

For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous liquid suspension. For oral administration the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

When the phaimaceutical 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, com 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 phaimaceutical 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 pharmaceutical preparations thus described are made following the conventional techniques of the phaimaceutical chemist as appropriate to the desired end product. In these 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

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. Topical foπnulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the composition is selected from the range of from 50 mgto 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.

No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention. BiQassays 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 andPGF2-

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 [^H]-LTB4 binding sites on human U937 cell membranes. The LTB4 antagonist 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 (SmithKline Beecham Corp., 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 macrophage-like cells, the cells were seeded at a concentration of 1 x 10^ 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^ 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 10⁷ 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 cen' aged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°C. Binding of [3-H 1-L TB4 to U937 Membrane Receptors

[³H]-LTB4 binding assays were performed at 25° C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaC_2, 10 mM MgCl2, [³H]-LTB4, U937 cell membrane protein (standard conditions) in the presence or absence of varying concentrations of LTB4, or test compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [³H]-LTB4 were determined in the absence or presence of 2 mM of unlabeled L TB4, 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 [3H]-LTB4, 20-40 mg of U937 cell membrane protein, increasing concentrations of LTB4 (0.1 mM to 10 mM) or other competing ligands (0.1 nM to 30 mM) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25° C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrane bound radioactivity on the filters was determined by liquid scintillation spectrometry.

Saturation binding experiments for U937 cells were performed, under standard conditions, using approximately 15-50 mg of U937 membrane protein and increasing concentrations of [ ]-L TB4 (0.02-2.0 nM) in a reaction volume of 0.2 ml and incubation at 22°C, for 30 minutes. LTB4 (2 mM) 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. Loading bv Differentiated U937 Cells with Fura-2

Harvested cells were resuspended at 2 x 10^ cellsΛnl in Krebs Ringer Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgSO4, 1.0 mM CaCl2 and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of fura-2 (ftιra-2/AM) was added to a final concentration of 2 mM 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** 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^ cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements. Fluorescent Measurements-Calcium Mot, l zafioπ

The fluorescence of ____t-2-containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. A fluorometer was 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 perfoπned at 37°C with constant mixing.

U937 cells were diluted with fresh buffer to a concentration of 1 x 10^ 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 ml 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^⁺ mobilization [Ca^+k was calculated using the following formula:

F was the maximum relative fluorescence measurement of the sample. Fmax was deteimined by lysing the cells with 10 ml of 10% Triton X-100 (final Concentration 0.02%). After Fmax was deteimined 67 ml of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca²⁺ and quench the fura-2 signal and obtain the Fmin. The [Ca-^+j_j level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca^+j_j was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the lOnM LTB4 induced [Ca²⁺]_j mobilization. The EC50 for LTB4 induced increase in [Ca²⁺] j mobilization was the concentration for half maximal increase. The Ki for calcium mobilization was deteimined using the formula: K, = JC50

!+^■ fLTB4l [EC5O]

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

The following examples are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors. EXAMPLE 1 l-Methyl-2-ri-thia-2-r2-(Ε-2-carboxyethenylV3-f8-f4-methoxypheny octyloxy)-6- pyridyllethyllimidazole. lithium salt 1A. 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 and brine and dried (MgSO4). Evaporation gave the product as a colorless oil that was used without further purification: ^!H NMR (90MHz, CDCI3) d 3.65 (t, J=5Hz, 2H, O-CH2), 2.23 (m, 2H, CH2),

2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2.4); IR (neat) n_max 3350, 2930, 2125 cm^"1. 1 B . 7-Octvn- 1 -foutyldiphenylsil yl ether. To a cooled (0° C) solution of 7-octyn-l-ol (9.3g, 73.7mmol) in DMF (70mL) under an argon atmosphere was added imidazole (7.5g, 11 Ommol) followed by the dropwise addition of t-butylchlorodiphenylsilane. The reaction was then stirred at room temperature for 2 hours. The reaction solution was diluted with Et2θ and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 3% EtOAc in hexane ) provided a colorless oil: *H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O-CH2), 2.23 (m, 2H, CH2), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH2)4), 1-05 (s, 9H, ^lbutyl); IR (film) n_max 3321, 2940, 2125 cm^"1. 1 C. 8-(4- Methoxyphenyl^'.-7-octyn- 1 -foutyldiphenylsilyl ether. To a flame dried flask

COntaining tπethylamine (140mL) under an argon atmosphere was added 4-iodoanisole (13.3g, 56.9mmol), 7-octyn-l-^tbutyldiphenylsilyl ether (24.9g, 68.3mmol), (Ph3P)2PdCl2 catalyst (793mg, 1.13mmol), and Cul (431mg, 2.27mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered, the solids were washed with Et2θ and the solvent was evaporated. The residue was diluted with E.2O and washed with 5% HC1, H2O, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave an orange oil: H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.7 (t, 2H, O-CH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), L05 (s, 9H, ^lbutyl). D. 8-r4-Methoxyphenyl.octan-l-tbutvldiphenvlsilvl ether. 8-(4-Methoxyphenyl)-7-octyn- l-tbutyldiphenylsilyl ether (30g, 63.7mmol) was dissolved in EtOH (125mL) and EtOAc

(125mL) and treated with 5% Pd-C catalyst (3g). The reaction was vigorously stirred under an H2 atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The resulting pale yellow oil was pure by nmr analysis and was used directly for the next step: *H NMR (250MHz, CDCI3) d 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.6 (t, 2H, O- CH2)» 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6), 1.0 (s, 9H, tbutyl). IE. 8-r4-Methoxypheny octan-l-ol. To a cooled (0° solution of 8-(4-methoxyphenyl)octan-l-^tbutyldiphenylsilyl ether (63mmol) was added tetrabutylammonium fluoride [70mL, 70mmol; 1M solution in tetrahydrofurn (THF)]. The cooling bath was removed and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated and the residue was dissolved in Et2θ. This was washed with H20, 5% HCl, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave a colorless solid: *H NMR (250MHz, CDCI3) d 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, O-CH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6). MS (CI): 254.2 (M+NH4); MP 47-49 °C.

IF. l-ϊodo-8-f4-methoxyphenyl.octane. To a stirred solution of 8-(4-methoxyphenyl)octan- l-ol (12.3g, 52mmol) in dry toluene (200mL) under an argon atmosphere was added triphenylphosphine (17.8g, 67.6mmol) and imidazole (10.6g, 156mmol). After the imidazole had dissolved 12 (17. lg, 67.6mmol) was added. The reaction was then heated at 65 °C for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2θ and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2CI2 and appli ed to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided the product as a colorless oil (slight contamination with triphenylphosphine): *H NMR (250MHz, CDCI3) d7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4Hz, 2H, I-CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).

1G. 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde. 2,6-Lutidine-a2,3-diol (15g, 107.8mmol; Aldrich) was suspended in dry CH2CI2 (200mL) and treated with Mhθ2 (47g, 539mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The crude aldehyde was obtained as a tan solid and was used directly for the next step: 4l NMR (250MHz, CDCI3) d 10.65 (s, 1H, OH), 10.30 (s, 1H, aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl). IH. 3-(^"8-r4-Methoxyphenyl.octyloxy1-6-methyl-2-pyridine carboxaldehyde. To a solution of l-iodo-8-(4-methoxyphenyl)octane (16.3g, 47.1mmol) in dry dimethylformamide (DMF) (45mL) under an argon atmosphere was added 3-hydroxy-6-methyl-2-pyridine carboxaldehyde (7.7g, 56.2mmol) and anhydrous K2CO3 (32g, 235mmol). The reaction was vigorously stirred at 90° C for 1.5 hours. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, aqueous NH4CI, and brine and dried (MgSO4). Evaporation provided crude aldehyde as a dark oil that was used without further purification. II. 2-(E-2-Ca__x xymemylethenyl)-3-r8-(4-methoxyphenv -octyloxy1-6-methylpyridine. 3-[8-(4-Methoxyphenyl)octyloxy]-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (lOOmL) under an argon atmosphere and treated with methyl

(triphenylphosphoranylidene)acetate (16g, 48mmol). The reaction was heated for 1 hour at 50° C. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 20% EtOAc in hexane) gave a pale yellow oil: ^!H NMR (250MHz, CDCI3) d 8.07 (d, J=15.7Hz, IH, olefin), 7.10 (m, 4H, phenyl, 4,5-pyridyl), 7.07 (d, J=15.7Hz, IH, olefin), 6.81 (d, J=8.6Hz, 2H, phenyl), 3.97 (t, J=6.5Hz, 2H, O-CH2), 3.79 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 2.54 (t, J=7.6Hz, 2H, benzylic), 2.48 (s, 3H, methyl), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.37 (m, 8H, aliphatic); MS (CI): 412.3 (M+H). 1 J. 2-fE-2-Caι_ _)xymethylethenyl')-3-r8-(4-methoxyphenyl')-octyloxyl-6-methylpyridine N- oxide.

2-(E-2-Carboxymethylethenyl)-3-[8-(4-methoxy-phenyl)octyloxy]-6-methylpyridine (17. lg, 41.5mmol) was dissolved in dry CH2CI2 (105mL) and cooled to 0 °C; 50% mCPBA (15.8g, 45.8mmol) was added in three portions over 10 minutes. The cooling bath was removed and the reaction was stirred for 15 hours at room temperature. The reaction was poured into aqueous NaHCO3 and the product extracted into CH2CI2. The organic extract was washed with

H2O and brine and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.

IK. 2-(Ε-2-Carboxymethylethenyl')-3-r8-('4-methoxyphenylVoctyloxyl-6- hvdroxymethylpyridine. 2-(E-2-Caιt)θxymemylethenyl)-3-[8-(4-methoxyphenyl)-octyloxy]-6-methylpyridine N- oxide obtained above was suspended in dry DMF (130mL) and cooled to 0° C under an argon atmosphere. To this was slowly added trifluoroacetic anhydride (56mL, 400mmol). The reaction was maintained at 0° C for 20 minutes followed by 18 hours at room temperature. The reaction solution was slowly added to a solution of saturated aqueous Na2CO3 and stirred for 1 hour. The product was then extracted into EtOAc; the combined organic extracts were washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, EtOAc:hexane:CH2Cl2, 30:20:50) gave a waxy solid: ^lB NMR (250MHz, CDCI3) d 8.08 (d, J=15.7Hz, IH, olefin), 7.23 (d, J=8.6Hz, IH, 5-pyridyl), 7.16 (d, J=8.6Hz, IH, 4-pyridyl), 7.09 (d, J =8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.69 (d, J =4.1Hz, 2H, CH2-OH), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.62 (t, J=4.1Hz, IH, OH), 2.55 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.58 (m, 2H, CH2), 1.44 (m, 8H, aliphatic); MS (CI): 428.2 (M+H). IL. l-Methyl-2-ri-t a-2-r2-_5-2-caitx)xymemyletheny -3-(8-(4-methoxyphenyl.octyloxy^'.- 6-pyridvnethvnimidazole. To a cooled (0° C) solution of SOCI2 (0.33mL, 4.7mmol) in dry toluene (5mL) under an argon atmosphere was added a solution of 2-(E-2- c<__x)xyme ylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hyά_Oxymemylpyridine(2C)0mg_^ 0.47mmol) in toluene (2mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 4 hours at room temperature. The toluene and excess SOCI2 were evaporated. To this was added dry DMF (lmL), 2-mercapto-l-methy]imidazole (70mg, O.όllmmol), and anhydrous CS2CO3 (766mg, 2.35mmol). The reaction was stirred at room temperature under an atmosphere of argon for 1 hour. The reaction was diluted with EtOAc and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 2% MeOH in CH2CI2) yielded an oil: *H NMR (250MHz, CDCI3) d 8.02 (d, J=15.7Hz, IH, olefin), 7.10 (m, 6H, pyridyl, phenyl, imidazole), 7.01 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.28 (s, 2H, S-CH2), 3.97 (t, J =6.5Hz, 2H, O-CH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OMe), 3.44 (s, 3H, N-Me), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1-58 (m, 2H, CH2), 1.44 (m, 8H, aliphatic); Analysis calcd for C29H37N3O4S: C, 66.51; H, 7.12; N, 8.02; found: C, 66.18; H, 6.92; N, 7.73; MS (ES): 524 (M+H).

1M. l-Methyl-2-ri-thia-2-r2-fE-2-carboxyethenylV3-f8-f4-methoxyphenyl.octyloxyV6- pyridynethyllimidazole. hthium salt. l-Methyl-2-[l-thia-2-[2-(TE-2-ca_boxymethylethenyl)-3- (8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]imidazole (145mg, 0.277mmol) was dissolved in THF (l.lmL) and MeOH (0.55mL) and treated with 1.0M LiOH (0.55mL, 0.55mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2θ-MeOH gradient). Lyophilization yielded a colorless amoiphous solid: NMR (250MHz, d -MeOH) d 7.72 (d, J=15.7Hz, IH, olefin), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.06 (m, 3H, pyridyl, phenyl), 6.98 (s, 2H, imidazole), 6.93 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.10 (s, 2H, S- CH2), 3.99 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 3.41 (s, 3H, N-Me), 2.53 (t, J=7.6Hz, 2H, benzylic), 1.82 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); Analysis calcd for C28H34N3θ4SLi3/2H2θ: C, 63.02; H, 6.80; N, 7.87; found: C, 63.12; H, 6.82; N, 7.89; MS (ES+): 510.0 (M+H; free acid); (ES-): 508.0 (M-H; free acid).

In a similar manner, the following compounds were prepared using the appropriate mercaptan: l-[2-acetylaminoethyl]-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4- methoxyphenyl)octyloxy)-6-pyridyl]ethyl]tetrazole, lithium salt

Colorless amorphous solid: ^XH NMR (250MHz, d -MeOH) d 7.74 (d, J=15.7Hz, IH, olefin), 7.34 (d, J=8.6Hz, IH, pyridyl), 7.30 (d, J=8.6Hz, IH, pyridyl), 7.05 (d, J=8.6Hz, 2H, phenyl), 7.02 (d, J=15.7Hz, IH, olefin), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.59 (s, 2H, S-CH2), 4.39 (t, J=5.6Hz, 2H, CH2), 4.03 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 3.57 (t, J=5.6Hz, 2H, CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.83 (s, 3H, acetate), 1.81 (m, 2H, CH2), 1.50 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); Analysis calcd for C29H37N6θsSLi ^• H2O: C, 57.41; H, 6.48; N, 13.85; found: C, 57.33; H, 6.23; N, 13.67; MS (ES): 583.2 (M+H; free acid). l-Methyl-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]tetrazole, lithium salt: Colorless amorphous solid: ^JH NMR (250MHz, d⁴-MeOH) d 7.75 (d, J=15.7Hz, IH, olefin), 7.31 (s, 2H, pyridyl), 7.05 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin),

6.78 (d, J=8.6Hz, 2H, phenyl), 4.56 (s, 2H, S-CH2), 4.03 (t, J=6.5Hz, 2H, O-CH2), 3.91 (s, 3H, N-Me), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.52 (m, 4H, aliphatic), 1.35 (m, 6H, aliphatic); Analysis calcd for C26H32N5θ4SLi ^• 3/2H2O: C, 57.34; H, 6.48; N, 12.86; found: C, 57.26; H, 6.28; N, 12.66; MS (ES): 512.2 (M+H; free acid). 2-Amino-5-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]-l,3,4-thiadiazole, lithium salt:

Colorless amorphous solid: NMR (250MHz, d⁴-MeOH) d 7.70 (d, J=15.7Hz, IH, olefin), 7.29 (d, J=8.6Hz, IH, pyridyl), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.07 (d, J=8.6Hz, 2H, phenyl), 6.92 (d, J=15.7Hz, IH, olefin), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.30 (s, 2H, S-CH2),

3.98 (t, J=6.5Hz, 2H, O-CH2), 3.75 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.81 (m, 2H, CH2), 1.56 (m, 2H, CH2), 1.42 (m, 2H, CH2), 1.32 (m, 6H, aliphatic); Analysis calcd for C26H3lN4θ4S2Li ^• 3/2H2O: C, 55.60; H, 6.10; N, 9.98; found: C, 55.81; H, 5.72; N, 9.70; MS (ES+): 529.0 (M+H; free acid); (ES-): 527.0 (M-H; free acid). 2-[l-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]imidazole, lithium salt:

Colorless amorphous solid: H NMR (250MHz, d⁴-MeOH) d 7.76 (d, J=15.7Hz, IH, olefin), 7.26 (d, J=8.6Hz, IH, pyridyl), 7.05 (rή, 5H, pyridyl, imidazole, phenyl), 6.97 (d, J=15.7Hz, IH, olefin), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.19 (s, 2H, S-CH2), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.82 (m, 2H, CH2), 1.57 (m,

4H, aliphatic), 1.36 (m, 6H, aliphatic); Analysis calcd for C27H32N3θ4SLi ^• 7/4H2O: C, 60.83; H, 6.71; N, 7.88; found: C, 60.84; H, 6.71; N, 7.69; MS (ES+): 496.0 (M+H; free acid); (ES-): 494.0 (M-H; free acid).

3-Amino-5-tl-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl] - 1 ,2,4-triazole, Mthium salt

Colorless amorphous solid: ^XH NMR (250MHz, d⁴-MeOH) d 7.76 (d, J=15.7Hz, IH, olefin), 7.28 (s, 2H, pyridyl), 7.06 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, IH, olefin),

6.79 (d, J=8.6Hz, 2H, phenyl), 4.88 (s, 2H, S-CH2), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzylic), 1.83 (m, 2H, CH2), 1.55 (m, 4H, ahphatic), 1.35 (m, 6H, ahphatic); Analysis calcd for C26H32N5O4SU • 2H2O: C, 56.41; H, 6.56; N, 12.65; found: C, 56.77; H, 6.41; N, 12.26; MS (ES+): 512.2 (M+H; free acid); (ES-): 510.2 (M-H; free acid). 2-[l-Thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyιidyI]ethyl]thiazole, hthium salt: colorless amorphous solid: *H NMR (250MHz, d >- DMSO) d7.73 (d, J=3.3Hz, IH, thiazole), 7.64 (d, J=3.3Hz, IH, thiazole), 7.49 (d, J=15.7Hz, IH, olefin), 7.38 (d, J=8.6Hz, IH, pyridyl), 7.33 (d, J=8.6Hz, IH, pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 6.84 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.51 (s, 2H, S- CH2), -01 (t, J=6.5Hz, 2H, O-CH2), 3.70 (s, 3H, OMe), 2.51 (t, J=7.6Hz, 2H, benzyUc), 1.75 (m, 2H, CH2), 1.51 (m, 2H, CH2), 1.39 (m, 2H, CH2), 1.29 (m, 6H, ahphatic); Analysis calcd forC27H3lN2θ4S2Li ^• l³/4H2θ: C, 58.95; H, 6.32; N, 5.09; found: C, 58.76; H, 5.95; N, 4.77; MS (ES+): 513.2 (M+H; free acid); (ES-): 511.2 (M-H; free acid). l-Methyl-2-[l-thia-2-[2-(E-2-caιboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole, hthium salt: Colorless amorphous solid: *H NMR (250MHz, d⁴-

MeOH) d 7.72 (d, J=15.7Hz, IH, olefin), 7.20 (d, J=8.6Hz, IH, pyridyl), 7.06 (m, 3H, pyridyl, phenyl), 6.98 (s, 2H, imidazole), 6.93 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.10 (s, 2H, S-CH2), 3.99 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 3.41 (s, 3H, N-Me), 233 (t, J=7.6Hz, 2H, benzyhc), 1.82 (m, 4H, ahphatic); MS (ES+): 454.0 (M+H; free acid); (ES-): 452.0 (M-H; free acid).

2-[l-Thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole, hthium salt:. Colorless amorphous solid: 4ϊ NMR (250MHz, d⁴- MeOH) d 7.76 (d, J=15.7Hz, IH, olefin), 7.26 (d, J=8.6Hz, IH, pyridyl), 7.05 (m, 5H, pyridyl, imidazole, phenyl), 6.97 (d, J=15.7Hz, IH, olefin), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.19 (s, 2H, S-CH2), 4.01 (t, J=6.5Hz, 2H, O-CH2), 3.74 (s, 3H, OMe), 2.52 (t, J=7.6Hz, 2H, benzyhc),

1.81 (m, 4H, ahphatic); Analysis calcd for C23H24N3θ4SLi ^• l³/4H2θ: C, 57.92; H, 5.81; N, 8.81; found: C, 57.76; H, 5.55; N, 8.65; MS (ES+): 440.2 (M+H; free acid); (ES-): 438.0 (M-H; free acid).

2-[l-Thia-2-[2-^-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]thiazole, hthium salt: colorless amoiphous solid: lHNMR (250MHz, d*>-

DMSO) d 7.73 (d, J=3.3Hz, IH, thiazole), 7.64 (d, J=3.3Hz, IH, thiazole), 7.49 (d, J=15.7Hz, IH, olefin), 7.38 (d, J=8.6Hz, IH, pyridyl), 7.33 (d, J=8.6Hz, IH, pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 6.84 (d, J=15.7Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.51 (s, 2H, S- CH2). -01 (t, J=6.5Hz, 2H, O-CH2), 3.70 (s, 3H, OMe), 2.51 (t, J=7.6Hz, 2H, benzyhc), 1.73 (m, 4H, ahphatic); Analysis calcd for C23H23N2O4S2U ^• ?l³/4H2θ: C, 55.92; H, 5.41; N, 5.67; found: C, 55.99; H, 5.35; N, 5.56; MS (ES+): 457.0 (M+H; free acid); (ES-): 455.0 (M- H; free acid).

Using the procedure described above the following compounds were also made: l-meihyl-2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole, hthium salt;

2-[l-thia-2-[2-(E-2-c_rboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole, hthium salt; 2-[l -thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]thiazole, hthium salt;

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]t_iazole, hthium salt;

2-[l-thia-2-t2-(2-ca_boxyethanyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]thiazole, hthium salt; l-methyl-2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]propyl]imidazole, hthium salt; and

2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]propyl]thiazole, hthium salt.

Example 2 l-Memyl-2-ri-oxytMa-2-r2-(E-2-ca_boxyethenylV3-(8-(^'4-methoxyphenyl')octyloxy^")-6- pyridyllethyllimidazole. lithium salt 2A. l-Methyl-2-ri-oxythia-2-r2-(E-2-carboxymethylethenylV3-f8-C4- methoxyphenyl.octyloxyVό-pyridyllethynimidazole

To a cooled (0° C) solution of l-methyl-2-[l-thia-2-[2-(E-2-carboxymethylethenyl)-3- (8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]imidazole (204mg, 0.39mmol) in CH2CI2 (7mL) under an argon atmosphere was added 80% mCPBA (86mg, 0.40mmol). The reaction was maintained at 0° C for 40 minutes. The reaction was quenched with aqueous NaHCO3 solution and the product extracted into EtOAc. The organic extract was washed with H2O and brine and dried (MgSO4). The product was purified by flash column chromatography (silica, 3% MeOH in CH2CI2 ) to give a colorless oil: ^lH NMR (250MHz, CDCI3) d 7.99 (d, J=15.7Hz, IH, olefin), 7.22 (d, J=8.6Hz, IH, pyridyl), 7.19 (d, J=8.6Hz, IH, pyridyl), 7.15 (d, J=8.6Hz, IH, imidazole), 7.12 (d, J=8.6Hz, IH, imidazole), 7.09 (d, J=8.6Hz, 2H, phenyl), 6.92 (d, J=15.7Hz, IH, olefin), 6.80 (d, J=8.6Hz, 2H, phenyl), 4.74 (d, J=12.6Hz, IH, S(O)-CH),

4.66 (d, J=12.6Hz, IH, S(O)-CH'), 3.98 (t, J=6.5Hz, 2H, O-CH2), 3.80 (s, 3H, methyl ester), 3.77 (s, 3H, OMe), 3.73 (s, 3H, N-Me), 2.54 (t, J=7.6Hz, 2H, benzyhc), 1.82 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.44 (m, 2H, CH2), 1.34 (m, 6H, ahphatic); Analysis calcd for C29H37N3O5S ^• 1/2H2O: C, 63.48; H, 6.98; N, 7.66; found: C, 63.63; H, 6.89; N, 7.36; MS (ES): 540 (M+H).

2B l-Methyl-2-ri-oxytMa-2-r2--E-2-ca_boxyethenvD-3-.8-r4-methoxyphenyl.octyloxy')-6- pyridynethynimidazole. lithium salt l-Methyl-2-[l-oxythia-2-[2-(E-2-carboxymethylethenyl)- 3-(8-(4-methoxyphenyl)octyloxy)-6-pyridyl]ethyl]imidazole (125mg, 0.23mmol) was dissolved in THF (1.86mL) and MeOH (0.46mL) and treated with l.OM LiOH (0.46mL, 0.46mmol). The reaction was stirred under an argon atmosphere for 20 hours. The solvent was evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H2θ-MeOH gradient). LyopMhzation yielded a colorless amorphous sohd: *H NMR (250MHz, d⁴-MeOH) d 7.69 (d, J=15.7Hz, IH, olefin), 7.25 and 7.13 (multiplets, 4H total, pyridyl, imidazole), 7.05 (d,

J=8.6Hz, 2H, phenyl), 6.92 (d, J=15.7Hz, IH, olefin), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.73 (d, J=12.6Hz, IH, S(O)-CH), 4.67 (d, J=12.6Hz, IH, S(O)-CH'), 4.00 (t, J=6.5Hz, 2H, OCH2), 3.74 (s, 6H, OMe, N-Me), 2.52 (t, J=7.6Hz, 2H, benzyhc), 1.81 (m, 2H, CH2), 1.52 (m, 4H, ahphatic), 1.35 (m, 6H, ahphatic); Analysis calcd for C28H34N3θ5SLi - 2H2O: C, 59.25; H, 6.75; N, 7.40; found: C, 59.61; H, 6.57; N, 7.01; MS (ES+): 526.0 (M+H; free acid); (ES-): 524.0 (M-H; free acid).

Example 3 Preparation of Free Acids The acid form of any of the foregoing salts may be prepared by dissolving the salt in water, then acidifying that solution with a mineral acid such as dilute (6N) HC1. The acid is recovered by filtering out the precipitate.

Example 4 Formulations for pharmaceutical use incorporating compo unds of the present invention can be prepared in various forms and with numerous excipients. Means for making various formulations can be found in standard texts such as Remington's Pharmaceutical Sciences, and similar publications and compendia.

Claims

What is claimed is:

1. A compound of f ormula I

or an N-oxide, or a pharmaceutically acceptable salt, where

Z is O, NH, NCH3 or S(O)_q where q is 0, 1 or 2; m is 0-5;

R is C_j to C2o-alip__atic, unsubstituted or substituted phenyl-C_j to Cio-anphat . where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C\ to C20-alip_ιatic-O-, or R is unsubstituted or substituted phenyl-Ci to Cio-ahphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rj is R , -(Cj to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci to C5 ahphatic)CH2OR8, -CH2OH or -CHO;

Het is a 5 or 6-membered heteroaromatic ring;

R2 is H, or -(CH2)_n 4 where n is 0-5; or

R2 is -CH(NH2)(R4) or -(CH2._nR9 where n is 0-5 where R9 is -N(T_ )2 where each R7 is independently H, or an ahphatic group of 1 to 10 carbons, or acyl of 1-6 carbons, or cycloalkyl-(CH2)_π- group of 4 to 10 carbons where n is 0-3, or both R7 groups form a ring having 4 to 6 carbons;

R3 is H, lower alkyl, or acyl of 1-6 carbons or is absent; R4 is tetrazol-5-yl or COOH, or a salt, ester or amide thereof.

2. A compound of claim 1 where the heteroaromatic ring is tetrazol-5-yl, imidazol-2-yl, thiazol-2-yl, l,3,4-thaidiazol-5-yl or triazol-2-yl.

3. A compound of claim 2 where Z is S(O)q; R is unsubstituted or substituted phenyl-C_j to Ciø-aliphatic-O-; j i_s _(C_j to C5 ahphatic)R4 where R4 is COOH or a salt, ester or amide thereof; m is 0 or 1 and R3 is absent.

4. A compound of claim 3 which is l-[2-acetylaminoethyl]-5-[l-thia-2-[2-(E-2-car_>oxyethenyl)-3-(8-(4- methoxyphenyl)octyloxy)-6-pyridyl]ethyl]tetrazole, or l-methyl-5-[l-thia-2-[2-(E-2-carboxye_henyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]tetrazole, or

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)-octyloxy)-6- pyridyl]ethyl]imidazole; l-memyl-2-[l-tMa-2-[2-(E-2-ca_boxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]imidazole; l-methyl-2-[l-t a-2-[2-(E-2-C-_rboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole; 2-[l-thia-2-[2-(E-2-caιboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]imidazole;

2-[l-_ιia-2-[2-(E-2-c__boxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]thiazole;

2-[l-thia-2-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]thiazole;

2-[l-thia-2-[2-(2-carboxyethanyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]ethyl]tbiazole; l-methyl-2-[2-tMa-3-t2-(E-2-C-_ι _)xyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]propyI]imidazole; and 2-[2-thia-3-[2-(E-2-carboxyethenyl)-3-(4-(4-methoxyphenyl)butyloxy)-6- pyridyl]propyl]thiazoIe, or l-memyl-2-[l-oxvtMa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]imidazole, or l-methyl-2-[l-dioxytMa-2-[2-(E-2-carboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)- 6-pyridyl]ethyl]imidazole, or

3-aii--no-5-[l-tMa-2-[2-(E-2-C--rboxyethenyl)-3-(8-(4-methoxyphenyl)octyloxy)-6- pyridyl]ethyl]-l,2,4-triazole, or

2-amino-5-[l-thia-2-[2-(E-2-ca_boxyethenyl)-3-(8-(4-methoxyhenyl)octyloxy)-6- pyridyl]ethyl]-l,3,4-thiadiazole, or a pharmaceutically acceptable salt, ester or amide thereof.

5. A composition comprising a carrier or excipient and a compound of formula 1 according to claim 1.

6. A method for treating treating diseases arising from or related to leukotrienes, which method comprises administering to a patient in need thereof, an effective amo unt of a compound of formula I according to claim 1 either alone in combination with a pharmaceutically acceptable excipient

7. The method of claim 6 wherein the disease is psoriasis.