EP0675718A1

EP0675718A1 - Substituted pyridyl compounds useful as leukotriene antagonists

Info

Publication number: EP0675718A1
Application number: EP94904523A
Authority: EP
Inventors: Robert A. Daines; Israil Pendrak
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1992-12-23
Filing date: 1993-12-21
Publication date: 1995-10-11
Also published as: WO1994014442A1; EP0675718A4; JPH08505148A

Abstract

This invention relates to compounds which are useful as leukotriene antagonists particularly LTB4 antagonists. These compounds are characterized by their having a pyridyl ring substituted at the 2 position with a lower alkyl radical which preferably has a terminal carboxyl group, a 3 position radical which can be characterized as having a fatty nature and a 6 position substituent which can be characterized as comprising a heteroaromatic group linked to the 6 position of the pyridyl ring by means of several atoms, namely, carbon or carbon and a heteroatom.

Description

Substituted pyridyl compounds useful as leukotriene antagonists.

This invention relates to compounds which are useful as leukotriene .antagonists particularly LTB4 antagonists. These compounds are characterized by their having a pyridyl ring substituted at the 2 position with a lower alkyl radical which preferably has a terminal carboxyl group, a 3 position radical which can be characterized as having a fatty nature and a 6 position substituent which can be characterized as comprising a pyridyl group linked to the 6 position of the pyridyl ring by means of several atoms, namely, carbon or carbon and a heteroatom. As such there utility lies in antagonizing the affects of leukotrienes.

Background

The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascul-ar and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the dihydroxyleukotrienes Geukotriene B4). This invention is primmly 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 permeability 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 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)-dihydroxy-(Z,E,E,Z)- 6,8,10,14-eicosatetraenoic acid.

It is a product of the arachidonic acid ca.scade 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 stereospecificiry. Pharmacological studies on humω 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

In a first aspect, this invention covers a compound of formula I

or an N-oxide, or a pharmaceutically acceptable salt, where A is CH2 then Z is S(O)_q where q is 0, 1 or 2; (CH2)_p; CHOH, C=O, or NR_X, or

O; or when A is C=O, Z is NR_X, or A is NH and Z is C=O; p is 1-3; m is 0 -5; R_x is hydrogen or lower alkyl; Het is a 5 or 6-membered heteroaromatic ring where the atom in the ring bonded to Z or the methylene group is carbon and the ring is substituted with R2 and R3;

R is Ci to C2()-aliphatic, unsubstituted or substituted phenyl-Cj to Cjo-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trih-alomethyl, and halo, or R is Cj to C20-aϋphatic-O-, or R is unsubstituted or substituted phenyl-Cj to Cjo-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;

Rl is R4, -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH2OR5;

R2 is H, halo, CF3, CN, lower alkyl, lower alkoxy or -(CH2)_nR4 where n is 0-5; or

R2 is -CH(NH2)(R4) or -(CH2)_nR9 where n is 0-5 where R9 is -N(R )2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbons, or acyl of 1-6 carbons, or cycloalkyl-(CH2)_n- 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, halo, lower alkyl, or acyl of 1-6 carbons;

R4 is tetrazol-5-yl, or COOH or an ester or amide thereof; and

R5 is H, lower alkyl, CH3(CH2)θ-6CO or phenyl(CH2)θ-3CO. In a further aspect, this invention relates to compositions comprising a compound of formula I, or an oxide or 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. These compounds can also be used for treating diseases caused by or related to leukotrienes including LTB4, and particularly psoriasis and inflammatory bowel disease.

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; or d) utilizing one of the processes illustrated in the reaction scheme(s) and Examples given below.

General Embodiments Definitions and General Descriptions

The following definitions are used in describing this invention. The definition of "Het" includes rings with 1, 2 or 3 nitrogens, eg pyridine, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-tirazine, and 1,2,3-triazine; rings with 1 or 2 oxygens; rings with nitrogen and oxygen; and rings with nitrogen, oxygen .and sulfur. "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 a&oxy" means the group lower alkyl-O-. "Acyl-lower alkyl" refers to the group (O)C-lower alkyl where the caibonyl carbon is counted as one of the carbons of the 1 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 a^l radicals in the chloro/alkyl pattern.

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 esters 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 stand^d 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, or an excess of organic or inorganic base where R4 is COOH for example. Oxides of a ring nitrogen may be prepared by means known in the ait 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. 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, allergic rhinitis .and irritable bowel disease. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated by these compounds. Preferred compounds

Preferred compounds are those where Het is pyridyl or pyrimidyl; R is Cg to C20 alkoxy, phenyl-C2 to CJQ alkoxy or substituted-phenylC2 to CJO alkoxy; Rj is -(Cj-

C3- lkyl)R4, or -(C2-C3alken l)R4. The more preferred compounds are those where R is substituted phenyl-C2 to CJQ alkoxy, particularly the unsubstituted-phenyl(CH2)2-8-O- group, or the p-fluoro- o^/>-methoxyphenyl(C^2)2-8~ ^,- group, or 013(012)5.9-0-; m is 0 - 5, most preferably 0, 1, or 2; R\ is HO2C-CH=CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof. As regards A, the CH2 group is preferred. As regards

Z, S(O)q is preferred.

The most preferred compounds are those set out in the Examples given below. S nthetic methods

Several methods can be used to prepare these compounds. 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 m.anner 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. This method and specific illustrations in the form of concrete examples is set out in published PCT application PCT7US91/03772 and co- pending PCT application PCT/US92/07466. See also the synthetic methods and illustrative chemistry in published PCT applications PCT/US91/03940, PCT/US91/03399, and co-pending U.S. patent appUcation USSN 876950 filed OlMay 1992. These latter applications illustrate means for preparing compounds where A Z are C=O/NRχ, A Z are NH/C=0 (or the alcohol) and where A/Z are CItyalleylene respectively. Each of these applications is incorporated herein to the extent each is useful for teaching how to make compounds of formula I.

The thiols, alcohols and other compounds which can be condensed with the 6- halomethylpyridyl to make formula I compounds are available commercially or can be be prepared using analogous methods from the literature.

The condensation reaction making compounds of formula I where functional groups are protected; then further manipulating these compounds eg. deprotecting, eg saponifying; forming forming alcohols, or aldehydes; preparing esters, amides or salts; oxidixing a sulfide to the sulfoxide or sulfone; and the like are all illustrated in the pending PCT applications and U.S. application referenced above. Those procedures can be used in preparing these compounds as well. In addition, specific examples for making these compounds are given in the appended Examples.

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

In these compositions, the amount of carrier or dtiuent will v∑ny 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 formulations 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 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.

No unacceptable toxicological effects are expected when these compounds are administered in accordance with the present invention. Bioassay Assays and methodology used for confirming the putative activity of these compounds are set out in the two pending PCT applications given above, that is published PCT application PCT/US91/03772 and co-pending PCT application PCT/US92/07466. Those methods are incorporated herein by reference. 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 I l-Iodo-8-(4-methoxvphenvnoctane (a) 7-Octyn-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) w.as 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% HO and brine and dried (MgSO.₄). Evaporation gave the product as a colorless oil which was used without further purification: -^H NMR (90MHz, CDCI3) δ 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) Vmax 3350, 2930, 2125 cπr¹.

1 (b) 7-Octyn- 1 -t-butyldiphenylsil yl ether To a cooled (0 °C) solution of 7- octyn-1-ol (9.3g, 73.7 mmol) in DMF (70mL) under .an argon atmosphere was added imidazole (7.5g, 1 lOmmol) followed by the dropwise addition of t-butylchlorodiphenylsilane (21mL, 81 mmol). 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 (MgSO.₄). Purification by flash column chromatography (silica, 3% EtOAc in hexane ) provided a colorless oil: ^!H NMR (250MHz, CDCI3) δ 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, t-butyl); IR (film) v_max 3321, 2940, 2125 cm-¹. li£) 8-(4-MethoxvphenvlV7-octvn-l -t-hutvldiphenvlsilvl ether To a flame dried flask containing triethylamine (140mL) under .an argon atmosphere was added 4- iodoanisole (13.3g, 56.9mmol), 7-octyn-l-t-butyldiphenylsilyl ether (24.9g, 68.3mmol),

(Ph3P)2PdCl2 catalyst (793mg, l. mmol), 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 Et2θ and washed with 5% HO, H2O, NaHCO3, and brine and dried (MgSO.₄). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave an orange 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, OMe), 3.7 (t, 2H, O-CH₂), 2.4 (t, 2H, CH2), 1-7-1.3 (m, 8H, (CH₂)4), 1.05 (s, 9H, t-butyl). li l 8-f4-Methoxyphenvnoctan-l-t-butvldiphenvlsilvl ether

8-(4-Methoxyphenyl)-7-octyn-l-t-butyldiphenylsilyl 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: Η 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, OMe), 3.6 (t, 2H, O-CH₂), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)6), 1.0 (s, 9H, t-butyl).

Me) 8-(4-Methoxvphenvnoctan-l-ol To a cooled (0 ° C) solution of 8-(4-methoxyphenyl)octan-l-t-butyldiphenylsilyl ether (63mmol) was added tetrabutylammonium fluoride (70mL, 70mmol; 1M solution in 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 H₂O, 5% HO, NaHCO₃, and brine and dried (MgSO.₄). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave a colorless solid: ^lH NMR (250MHz, CDCI3) δ 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)_δ); MS (CI): 254.2

(M+NH4); mp 47-49 _C.

1 (f) 1 -Iodo-8-(4-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 5 minutes, I2 (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 (MgSO.₄). The solvent was removed and the resulting residue was dissolved in CH2O2 and applied 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) δ 7.08 (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, CH ), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4). Example 2 2-(E-2-CarboxymethylethenvI'>-3-r8-(4-methoxyphenyDoctyloxy1-6- chloromethylpyridine 2(H 3-Hvdroxv-6-methvI-2-pvridine carboxaldehvde. 2,6-Lutidine-α²,3-diol (15g, 107.8mmol; Aldrich) was suspended in dry CH2CI2 (200mL) and treated with Mnθ2 (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: ^lH NMR (250MHz, CDCI3) δ 10.65 (s, 1H, OH), 10.30 (s, 1H, aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).

Kb) 3-r8-(4-Methoxvphenvnoctvloxvl-6-methvI-2-pvridine carboxaldehvde. To a solution of l-iodo-8-(4-methoxyphenyl)octane (16.3g, 47.1mmol) in dry 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, aq NH₄CI, and brine and dried (MgSO4). Evaporation provided crude aldehyde as a dark oil that was used without further purification.

2l£ 2-(E-2-CarboxvmethvlethenvlV3-r8-(-4-methoxvphenvnoctvloxv1-6- 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: ^lH NMR (250MHz, CDCI3) δ 8.07 (d, J=15.7Hz, 1H, vinyl), 7.10 (m, 4H, phenyl, 4,5- pyridyl), 7.07 (d, J=15.7Hz, 1H, vinyl), 6.81 (d, J=8.6Hz, 2H, phenyl), 3.97 (t, J=6.5Hz, 2H, O-CH2), 3.79 (s, 3H, OMe), 3.78 (s, 3H, methyl ester), 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).

Kά) 2-fE-2-CarboxymethylethenylV3-r8-(4-methoxyphenyl)octyloxy1-6- methylpyridine N-oxide 2-(E-2-Carboxymethylethenyl)-3-[8-(4- methoxyphenyl)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 CH2O₂. The organic extract was washed with H O and brine .and dried (MgSO4). The crude product was obtained as a yellow solid and was used without further purification.

2i£l 2-⁽E-2-CarboxvmethvlethenvlV3-r8-(^'4-methoxvphenvnoctvloxv1-6- hydroxymethylpyridine 2-(E-2-Carboxymethylethenyl)-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 w.as 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:CH2θ2, 30:20:50) gave as a waxy solid: ^lH NMR (250MHz, CDCI3) δ 8.08 (d, J=15.7Hz, 1H, vinyl), 7.23 (d, J=8.6Hz, 1H, 5-pyridyl), 7.16 (d, J=8.6Hz, 1H, 4- pyridyl), 7.09 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.7Hz, 1H, vinyl), 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, OMe), 3.78 (s, 3H, methyl ester), 3.62 (t, J=4.1Hz, 1H, 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).

2I 2-fE-2-CarboxvmethvlethenvlV3-r8-r4-methoxvnhenvnoctyloxyl-6- chloromethylpyridine. To a cooled (0° C) solution of SOO2 (0.54 mL, 7.2 mmol) in dry toluene (4 mL) under an argon atmosphere was added a solution of 2-(E-2- carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (300 mg, 0.7 mmol) in toluene (4 mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2h at room temperature. The toluene .and excess SOO2 were evaporated. The crude product was used without further purification.

Example 3 3-ri-Oxa-2-r2-fE-2-carboxvethenvn-3-r8-(4-methoxvphenvnoctvloxv1-6- pvridvnethvnpvridine. lithium salt 3(a 3-π -Oxa-2-r2-(E-2-carboxymethylethenylV3-r8-f4- methoxyphenyl)octyloxy1-6-pyridyllethvnpyridine 2-(E-2-Carboxymethylethenyl)-3-[8- (4-methoxyphenyl)octyloxy]-6-chloromethylpyridine (0.7mmol) was dissolved in dry DMF (2mL) and treated with 3-hydroxypyridine (Aldrich, lOOmg, l.OSmmol), anhydrous CS2CO3 (1.02g, 3.5mmol), and tetrabutylammonium iodide (30mg, 0.07mmol). The reaction was heated at 65° C under an atmosphere of argon for lh. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, brine and dried (Na2SO₄). Purification by flash chromatography (silica, 10-50% EtOAc in hexane) yielded a yellow oil: ^lH NMR (250MHz, CDCI3) δ 8.4 (d, 1H, pyridyl), 8.2 (d, 1H, pyridyl), 8.05 (d, J=15.8Hz, 1H, vinyl), 7.4 (d, 1H, pyridyl), 7.25 (m, 3H, pyridyl), 7.05 (m, 3H, vinyl, phenyl), 6.8 (d, 2H, phenyl), 5.2 (s, 2H, CH₂-O), 4.01 (t, 3H, OCH₂), 3.85 (s, 3H, OMe), 3.80 (s, 3H, OMe), 2.5 (t, 2H, benzylic), 0.9-1.8 (m, 12H, aliphatic); MS (CI): 505 (M+H).

Mi 3-π-Oxa-2-r2-(E-2-carboxvethenvl)-3-r8-(4-methoxvphenvnoctvloxv1-6- pyridyllethyllpyridine. lithium salt 3-[l-Oxa-2-[2-(E-2-carboxymethylethenyl)-3-[8-(4- methoxyphenyl)octyloxy]-6-pyridyl]ethyl]pyridine (20mg, 0.03mmol) was dissolved in THF (lmL) and MeOH (lmL) and treated with 1.0M LiOH (0.2mL, 0.15mmol). The reaction was stirred under an argon atmosphere for 24h. The solvent was evaporated and the product purified by Reverse Phase MPLC (RP-18 silica, 0-60% MeOH in H2O). Lyophilization yielded a colorless amorphous solid: ^lH NMR (250MHz, CD3OD) δ 8.3 (d, 1H, pyridyl), 8.15 (d, 1H, pyridyl), 7.8 (d, J=15.8Hz, 1H, vinyl), 7.55-7.30 (m, 4H, pyridyl), 7.05 (m, 3H, vinyl, phenyl), 6.8 (d, 2H, phenyl), 5.2 (s, 2H, CH₂-O), 4.01 (t, 3H, OCH₂), 3.75 (s, 3H, OMe), 2.5 (t, 2H, CH₂Ph), 0.9-1.8 (m, 12H, aliphatic); MS (FAB): 491 (M+H, free acid). Example 4

Preparation of Free Acids The acid foπn 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) HO. The acid is recovered by filtering out the precipitate. Example 5

Formulations for pharmaceutical use incorporating compounds 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. Specific examples of formulations are given below.

OINTMENTS Hydrophyllic Petrolatum

Ingredients Amount (% WAV

Cholesterol 30.0g

Stearyl Alcohol 30.0g

White Wax 78.0g

Active Ingredient 2.0g

White Petrolatum 860.0g

The stearyl alcohol, white wax and white petrolatum are melted together (steam bath for example) and cholesterol and the active ingredient are added. Stirring is commenced and continued until the solids disappear. The source of heat is removed and the mix allowed to congeal and packaged in metal or plastic tubes. Emulsion Ointment Ingredients Amount (% WAV)

Methylp.araben 0.25g

Propylparaben 0.15

Sodium Lauryl Sulfate lO.Og

Active Ingredient 5.0g

Propylene Glycol 120.0g

Stearyl Alcohol 250.0g

White Petrolatum 250.0g

Purified Water QS to lOOO.Og

The stearyl alcohol and white petrolatum are combined over heat. Other ingredients are dissolved in water, then this solution is added to the warm (ca 50 to 100^c C) alcohol/petrolatum mixture and stirred until the mixture conge s. It can then be packed in tubes or .another appropriate package form.

Claims

What is claimed is:

1. A compound of formula I

O; or when A is C=O, Z is NR_X, or A is NH and Z is C=O; p is 1-3; m is 0 -5;

R_x is hydrogen or lower alkyl; Het is a 5 or 6-membered heteroaromatic ring where the atom in the ring bonded to Z or the methylene group is carbon and the ring is substituted with R2 and R3;

R is Cj to C20^_1-*diphatic, unsubstituted or substituted phenyl-Cj to Cio-^phatic 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 C2Q-aϋpha.ύc-0-, or R is unsubstituted or substituted phenyl-Cj to Cjo-aliphatic-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, -(Ci to C5 aliρhatic)R4, -(Ci to C5 aliphatic)CHO, -(Cl to C5 aliphatic)CH2OR5; R2 is H, halo, CF3, CN, lower alkyl, lower alkoxy or -(CH2)_nR4 where n is 0-5; or

R2 is -CH(NH2)(R4) or -(CH2)_nR9 where n is 0-5 where R9 is -N(R7)2 where each R7 is independently H, or an aliphatic group of 1 to 10 carbons, or acyl of 1-6 carbons, or cycloalkyl-(CH2)_n- 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, halo, lower alkyl, or acyl of 1-6 carbons;

R4 is tetrazol-5-yl, or COOH or an ester or amide thereof; and

R5 is H, lower alkyl, CH3(CH2)θ-6CO or phenyl(CH2)θ-3CO.

2. A compound of claim 1 where R is substituted phenyl-C4 to C10 alkoxy, particularly the unsubstituted-phenyl(CH2)2-8^_C^|- group, or the /?-fluoro- or p- methoxyphenyl(CH2)2-8"0- E∞up_* ^or 13(012)7.9-0-; and m is 0 - 5 and Het is pyridyl or pyrimidyl.

3. A compound of claim 2 where A is CH2, Z is O and m is 0 or 1.

4. A compound of claim 3 which is 3-[l-oxa-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- pyridyl]ethyl]pyridine, lithium salt or another pharmaceutically acceptable salt thereof.

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

6. A method of treating a leukotriene-related disease in a mammal suffering from such a disease, which method comprises administering an effective amount of a compound of formula I according to claim 1 either neat or in combination with a pharmaceutically acceptable carrier.