WO1993011768A1

WO1993011768A1 - Pyridyl compounds for psoriasis treatment

Info

Publication number: WO1993011768A1
Application number: PCT/US1992/010582
Authority: WO
Inventors: Robert A. Daines
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1991-12-13
Filing date: 1992-12-11
Publication date: 1993-06-24
Anticipated expiration: 1994-06-13

Abstract

This invention relates to compounds which are LTB4 antagonists.

Description

"PYRIDYL COMPOUNDS FOR PSORIASIS TREATMENT"

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 dihydroxy leukotrienes (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 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,EJE,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 andchemokinetic 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 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. 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 formula 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 1 - 8; R is C to C20-aϋph tic, unsubstituted or substituted phenyl-Cj to C Q- 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-, or R is unsubstituted or substituted phenyl-C^ to CiQ-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 R2, - Ci to C5 aliphatic)R2, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aIiphatic)CH2OR3; R2 is tetrazol-5-yl or COOH or a salt, ester or amide thereof; and

R3 is H or lower alkyl.

In a further aspect, this invention relates to compositions comprising a compound of formula 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 formula I by treating a 6-halomethylpyridyl compound with the appropriate mercaptan, or hydroxy compound. General Embodiments

The following definitions are used in describing this invention. "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-. "Acyl-lower alkyl" refers to the group (O)C-lower alkyl where the carbonyl 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 alkyl 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 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, or an excess of organic or inorganic base where R2 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 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 aό-ministering 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 uveitis, and allergic conjunctivitis can also be treated by these compounds.

The preferred compounds are those where R is Cs to C20 alkoxy, phenyl-C4 to C10 alkoxy or substituted-phenylC4 to CJQ alkoxy; Rj is R2- - Cι-C3alkyl)R2, or -(C2-C3alkenyl)R2. The more preferred compounds are those where Z is S(O)q where q is 0, 1 or 2; R is substituted phenyl-C4 to C 10 alkoxy, particularly the substituted-phenyl(CH2)4--8-O- group or CH3(CH2)7_9-O-; m is 2 - 6, most preferably 3, 4 or 5; Ri is HO2C-CH=CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof. The most preferred compounds are:

4-[l-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)ocι-yloxy]-6- pyridyl]ethyl]butyric acid, dilithium salt;

4-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]- 6-pyridyl]ethyl]butyric acid, dilithium salt; and

4-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4- methoxyphenyl)octyloxy]-6-pyridyl]ethyl]butyric acid, dilithium salt, or the corresponding free acid or another pharmacuetically acceptable salt.

Several methods for preparing these compounds are available. 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 r-butyldiphenylsilyl ether. Other silyl ethers could be used. The alcohol is dissolved in a polar solvent, for example dimethylformamide, 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)2PdCl2 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 hydrogenation. 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.

The w-thiolalkanoic acid esters and w-hydroxyalkanoic acid esters used in the preparation of these compounds are known and can be purchased from commercial vendors or made by means well known in the art.

A synthesis of these compounds is illustrated in Scheme π. Scheme II

Oxidizing Agent Me

Acid salt or free acid

The starting material is available from Aldrich. It is treated with a mild oxidizing agent such as Mnθ2 to oxidixe the 2-hydroxymethyl group to the corresponding 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. An w- thioalkanoic acid ester or w-hydroxyalkanoic acid ester group 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.

Forparenteral 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, 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 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 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 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.

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-E-Q-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 are described in the literature, particularly in published PCT application PCT/US91/03772. That procedure is incorporate herein by reference as if set out in full here. 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 4-ri-Oxythia-2-r2-(E-2-carboxyethenylV3-r8-(4-methoxyphenyl')octyloxyl-6- pyridvnethynbutyric acid, dilithium salt 1(a) 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% HCl and brine and dried (MgSO4). Evaporation gave the product as a colorless oil which was used without further purification: ^lH 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) n_max 3350, 2930, 2125 cm"¹.

1 (b) 7-Octvn- 1 -Ibutyldiphenylsilyl 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, 1 lOmmol) followed by the dropwise addition of tøutylchlorodiphenylsilane (21mL, 81mmol). 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) 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), 05 (s, 9H, tbutyl); IR (film) n_max 3321, 2940, 2125 cm"¹.

1 (c) 8-(4-MethoxyphenylV7-octvn- 1 -ibutyldiphenylsilyl ether. To a flame dried flask containing triethylamine (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 Et2θ and washed with 5% HCl, H2O, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave an orange oil: iH MR (250MHz CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H_r aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, O-CH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4)- 1-05 (s, 9H, tbutyl). lfd) 8-(4-Methoxypheny octan-l-ibutyldiphenylsilyl 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) 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, O-CH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6), 1.0 (s, 9H, tbutyl).

1(e) 8-(4-Methoxyphenyl)octan-l-ol. To a cooled (0 °C) solution of 8-(4-methoxyphenyl)octan- l-tbutyldiphenylsilyl 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 H20, 5% HCl, NaHCO3, and brine and dried (MgSOφ). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave a colorless solid: iH NMR (250MHz, CDCI3) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OCH3), 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.

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 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 applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided the product as a colorless oil (slight contamination with triphenylphosphine): 4-tNMR (250MHz, CDCI3) δ 7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OCH3), 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). l( ^y) 3-Hydroxy-6-methyl-2-pyridine carboxaldehvde. 2,6-Lutidine-a2,3- 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: ^JH NMR (250MHz, CDCI3) 10.65 (s, IH, OH), 10.30 (s, IH, aldehyde), 7.30 (m, 2H, 4,5-pyridyl), 2.55 (s, 3H, methyl).

1 (ti) 3-r8-(4-Methoxypheny octyloxy1-6-methyl-2-pyridine 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. l(ϊ 2-(E-2-CarboxymethylethenylV3-r8-(4-methoxyphenyπoctyloxy1-6- 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 (from iodide) a pale yellow oil: H NMR (250MHz, CDCI3) 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, OCH3), 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). Iff. 2-fE-2-CarboxymethylethenylV3-18-(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 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.

1 fle- 2-fE-2-CarboxymethvlethenvlV3-r8-f4-methoxvphenvDoci-vloxvl-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 argorf 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 llg (62%; two steps) as a waxy solid: 4l NMR (250MHz, CDCI3) δ 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, OCH3), 3.78 (s, 3H, methyl ester), 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). i Methyl 4-ri-thia-2-r2-fE-2-carboxymethylethenylV3-r8-f4- methoxyphenyltoctyloxyl-6-pyridyllethyributyrate. To a cooled (0 °C) solution of SOC12 (0.26mL, 3.5mmol) in dry toluene (lmL) under an argon atmosphere was added a solution of 2-(E-2-carboxymethylethenyl)-3-[8-(4- methoxyphenyl)octyloxy]-6-hydroxymethylpyridine (150mg, 0.35mmol) in toluene (2.5mL). After 5 minutes the cooling bath was removed and the reaction was stirred for 2 hours at room temperature. The toluene and excess SOC12 were evaporated. To this was added dry DMF (lmL), methyl 4-mercaptobutyrate (70mg, 0.52mmol) [prepared from 4-mercaptobutyric acid (Pfaltz and Bauer) and methanolic HCl], tetrabutylammonium iodide (13.2mg, 0.04mmol), and anhydrous CS2CO3 (509mg, 1.57mmol). The reaction was heated at 60 °C under an atmosphere of argon for 1 hour. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H20, 10% NaOH, H2O, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 15% EtOAc in hexane) yielded a colorless oil: *H NMR (250MHz, CDCI3) δ 8.06 (d, J=15.8Hz, IH, olefin), 7.31 (d, J=8.6Hz, IH, pyridyl), 7.14 (d, J=8.6Hz, IH, pyridyl), 7.10 (d, J=8.6Hz, 2H, phenyl), 7.03 (d, J=15.8Hz, IH, olefin), 6.81 (d, J=8.6Hz, 2H, phenyl), 4.01 (t, J=6.5Hz, 2H, OCH2), 3.82 (s, 3H, methyl ester), 3.78 (s, 3H, OCH3), 3.76 (s, 2H, S-CH2-pyr), 3.65 (s, 3H, methyl ester), 2.56 (t, J=7.6Hz, 2H, benzylic), 2.55 (t, J=6.8Hz, 2H, SCH2), 2.44 (t, J=6.8Hz, 2H, CH2-CO2), 1.95 (m, 2H, CH2), 1.82 (m, 2H, CH2), 1.57 (m, 2H, CH2), 1.45 (m, 2H, CH2), 1.33 (m, 6H, aliphatic); Analysis calcd for C30H41NO6S • 1/3H2O: C, 65.55; H, 7.64; N, 2.55; found: C, 65.59; H, 7.39; N, 2.41; MS (CI): 544 (M+H).

Kπ Methyl 4-π-oxythia-2-r2-(E-2-carboxymethylethenvl')-3-r8-(4- methoxyphenyl)octyloxy1-6-pyridynethynbutyrate. Methyl 4-[l-thia-2-[-2-(E-2- carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]butyrate (107mg, 0.197mmol) was dissolved in dry CH2CI2 (2mL) under an argon atmosphere and cooled to -20 °C. To this was added 80% m-chloroperoxybenzoic acid (45mg, 0.21mmol) in two portions 20 minutes apart. The reaction was stirred for 40 minutes at -10 °C following the second addition and then quenched with 5% N-1HCO3. The product was extracted into CH2CI2 and the organic extracts were dried (MgSO4). Purification by flash column chromatography (silica, 5% MeOH in CH2CI2) gave a colorless oil: *H NMR (250MHz, CDCI3) δ 8.05 (d, J=15.8Hz, IH, olefin), 7.32 (d, J=8.6Hz, IH, pyridyl), 7.21 (d, J=8.6Hz, IH, pyridyl), 7.10 (d, J=8.6Hz, 2H, phenyl), 6.98 (d, J=15.8Hz, IH, olefin), 6.82 (d, J=8.6Hz, 2H, phenyl), 4.16 (d, J=12.9Hz, IH, S(O)-CH-pyr), 4.01 (overlapping doublet and triplet; d, J=12.9Hz, IH, S(O)-CH-pyr; t, J=6.5Hz, 2H, OCH2), 3.81 (s, 3H, methyl ester), 3.78 (s, 3H, OCH3), 3.67 (s, 3H, methyl ester), 2.75 (m, 2H, S(O)-CH2), 2.51 (m, 4H, CH2-CO2, benzylic), 2.15 (m, 2H, CH2), 1.85 (m, 2H, CH2), 1.62 (m, 2H, CH2), 1.48 (m, 2H, CH2), 1.36 (m, 6H, aliphatic); Analysis calcd for C30H41NO7S ^• 1/2H2O: C, 63.36; H, 7.44; N, 2.46; found: C, 63.14; H, 7.36; N, 2.54; MS (CI): 560.3 (M+H).

1 (ή 4-π -Oxythia-2-r2-fE-2-carboxyethenylV3-r8-(4- methoxvphenvnoctvloxvl-6-pvridvllethvnbutvric acid, dilithium salt. Methyl 4-[l- oxythia-2-[-2-(E-2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- pyridyljethyljbutyrate (69.4mg, 0.124mmol) was dissolved in THF (0.75mL) and MeOH (0.37mL) and treated with l.OM LiOH (0.37mL, 0.37mmol). 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 amorphous solid: *H NMR (250MHz, d⁴-MeOH) d 7.78 (d, J=15.8Hz, IH, olefin), 7.37 (d, J=8.6Hz, IH, pyridyl), 7.28 (d, J=8.6Hz, IH, pyridyl), 7.06 (d, J=8.6Hz, 2H, phenyl), 7.05 (d, J=15.8Hz, IH, olefin), 6.79 (d, J=8.6Hz, 2H, phenyl), 4.22 (d, J=12.9Hz, IH, S(O)-CH-pyr), 4.11 (d, J=12.9Hz, IH, S(O)-CH-pyr), 4.06 (t, J=6.5Hz, 2H, OCH2), 3.74 (s, 3H, OCH3), 2.90 (m, 2H, S(O)-CH2), 2.52 (t, J=7.6Hz, 2H, benzylic), 2.32 (t, J=6.8Hz, 2H, CH2-CO2), 2.10 (m, 2H, CH2), 1.84 (m, 2H, CH2), 1.55 (m, 4H, aliphatic), 1.36 (m, 6H, aliphatic); MS (FAB): 544 (M+H), 550.3 (M+Li).

Treating the thiol described above with a two-fold excess of m- chloroperoxybenzoic acid yielded the methyl 4-[l-dioxythia-2-[2-(E-2- carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]butyrate, which was then treated with IiOH to obtain the corresponding 4-[l-dioxythia-2-[2-(E-2- carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]butyric acid, dilithium salt.

Example 2 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) HCl. The acid is recovered by filtering out the precipitate.

Example 3 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

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 (% W/W)

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) alcohol/petrolatum mixture and stirred until the mixture congeals. It can then be packed in tubes or another appropriate package form.

Example 4 Inhalation Formulation A compound of formula 1, 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.

Claims

What is claimed is:

1. A compound of formula I

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

Z is O, NH, NCH3 or S(O)_q where q is 0, 1 or 2; m is 1 - 8;

R is Ci to C20-aϋphatic, unsubstituted or substituted phenyl-Cχ to C Q- 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-, or R is unsubstituted or substituted phenyl-Cχ to Cio-alip ric-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Ri is R2, -(Ci to C5 aliphatic)R2, -(Ci to C5 aliphatic)CHO_} -(Ci to C5 aliphatic)CH2OR3;

R2 is tetrazol-5-yl or COOH or a salt, ester or amide thereof; and

R3 is H or lower alkyl.

2. A compound of claim 1 where Z is S(O)q; R is unsubstituted or substituted phenyl-C4 to Cg-alkoxy; and R is -(C2-C3-alkenyl)R2 where R2 is

COOH or a salt, ester or amide thereof and m is 2 - 6.

3. A compound according to claim 4 where m is 3 wherein the compound is:

4-[l-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- pyridyljethyl]butyric acid, dilithium salt;

4-[l-oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]- 6-pyridyljethyljbutyric acid, dilithium salt; or

4-[l-dioxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4- methoxyphenyl)octyloxy]-6-pyridyl]ethyl]butyric acid, dilithium salt, or another pharmaceutically acceptable salt thereof or the corresponding free acid.

4. A compound according to claim 1 where Z is S(O)q and m is 4 or 5.

5. A compound according to claim 1 where Z is O and m is 3, 4 or 5.

6. A compound according to claim 1 where Z is NH or NCH3 and m is 3, 4 or 5.

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

8. A method for treating psoriasis, which method comprises administering to a patient in need thereof, an effective amount of a compound of formula I according to claim 1 either alone in combination with a pharmaceutically acceptable excipient.