PT97912A - PREPARATION PROCESS OF BENZOIC ACID AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

72 695 SBC CASE 14503

Scope of the Invention

This invention relates to the process of preparing certain substituted pyridyl- (2-hydroxyethyl) benzoic acid derivatives and their ketone analogs, which are useful for the treatment of diseases associated with leukotrienes. These compounds are particularly useful in the treatment of diseases attributable to hydroxyleukotrienes, especially LTB4 and LTB4 agonist active substances.

The leukotrienes are generally divided into two subclasses, the peptoleukotrienes (leukotrienes C4, D4 and E4) and the hydroxyleukotrienes (leukotriene B4), which are known as leukotrienes. ) This invention relates primarily to the hydroxyleukotrienes (LTB), but is not limited to this specific group of leukotrienes,

Peptidoleukotrienes are implicated in the biological response associated with " Anaphylaxis Slow Reaction Substance " (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction in cardiovascular effects such as coronary artery vasoconstriction and in many other biological responses. The pharmacology of peptidoleukotrienes includes smooth muscle contractions, myocardial depression, increased vascular permeability < 3 > increased.

By comparison, LTB4 exert their biological effects by stimulating the functions of leukocytes and lymphocytes. They stimulate chemotaxis, chemokinesis and polymorphonuclear leukocyte aggregation (PMN). Leukotriene B4 (LT84) was first described by Borgeat and Samuelsson in 1979, and later Corey et al. Showed that it was 5 (S), 12 (R) -dihydroxy- (Z, Ε, Ε, Ζ) -6,8,10,14-icosatetraenoic acid. 72 695 SBC CASE 14503

-5-H0

00011

LTB4 is a product of the arachidonic acid cascade resulting from an enzymatic hydrolysis of LTA4. It was found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB4 has been shown to potently stimulate in vivo PMN leukocytes, causing increased chemotactic and chemokinetic migration, adhesion, aggregation, degranulation, enhanced superoxide production and cytotoxicity. The effects of LTB4 are mediated by distinct receptor sites, from the surface of the leukocyte cell, which exhibit a high degree of stereospecificity. Pharmacological studies on PMN leukocytes from human blood indicate the presence of two classes of LTB4 specific receptors, distinct from the specific receptors for the chi-myotatic peptide factors. Each of the sets of receptors appears to be linked to a distinct set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms. LTB4 has been indicated as an in vivo inflammatory mediator. It has also been associated with hyperresponsiveness of the airways in the dog and has also been found at high levels in internal lung lavages of humans with severe lung dysfunction. In addition, LTB4, as well as other leukotrienes, has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout and psoriasis. They are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic and inflammatory diseases, including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.

The compounds and pharmaceutical compositions prepared by the present invention, by antagonizing the effects of LTB4 or other pharmacologically active mediators on the target organ, for example airway smooth muscle, are valuable in the treatment of diseases in subjects, including human beings. 695 SBC CASE 14503

-6-human or animal, in which leukotrienes are a key factor.

SUMMARY OF THE INVENTION

This invention prepares compounds represented by formula (I)

or a pharmaceutically acceptable salt thereof or N-oxide, wherein T is CO or CH (OH); R 2 is C 1 to C 20 aliphatic, unsubstituted or substituted-C 1 to C 1 aliphatic phenyl, wherein substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo, or R 3 is C 1-6 aliphatic, â € ƒâ € ƒâ € ƒwherein substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo;

(Aliphatic C 1 to C 5) R 3, - (aliphatic C 1 to C 5) CH 2, - (C 1 to C 5 aliphatic CH 2 R 7, -R 3, -CH 2 OH or CHO; R2 and R3 are independently of one another -C0 R4 where R4 is -OH, a pharmaceutically acceptable ester-forming group, -OR5, or -OX, where X is a pharmaceutically acceptable cation, or R4 is -N (R6) 2 , wherein R6 is H, or an aliphatic group having 1 to 10 carbon atoms, a cycloalkyl- (CH2) n- group having 4 to 10 carbon atoms wherein n is 0-3 or both combined R6 groups form a ring having 4-6 carbon atoms or R2 is an amine, amide or sulfonamide; and R7 is hydrogen, C1 to C6 alkyl or C1 to C4 acyl.

In another aspect, this invention covers the process of preparing pharmaceutical compositions containing the present compounds and a pharmaceutically acceptable excipient.

This invention also relates to the treatment of diseases

Or particularly by LTB2, or by related pharmacologically active mediators in the target organ. This treatment may be effected by administering one or more compounds of formula I, alone or in combination with a pharmaceutically acceptable excipient, in an amount sufficient to prevent disease or to treat it as soon as it appears.

Thus, this invention provides a process for the preparation of the compounds of this invention. This aspect of the invention is illustrated in the Reaction Schemes below and in the Examples set forth in this disclosure.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used in the disclosure of this invention and establish what the applicant believes to be his invention. " Aliphatic " is intended to include both saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or polyunsaturated chains, in which double or triple bonds may be present in any combination. The phrase "lower alkyl " means an alkyl group having 1 to 6 carbon atoms, in any isomeric form, but particularly in the normal or linear form. "Lower alkoxide " means the lower alkyl group-O-. " Halo " means fluoro, chloro, bromo or iodo. " Acyl " means the radical having a terminal carbonyl carbon.

When reference is made to a substituted phenyl ring it is meant that the ring may be substituted with one or more of the named substituents provided that they are compatible with the chemical synthesis. The multiple substituents may be the same or different, such as when there are three chlorine groups or a combination of chlorine and alkyl groups and still when the latter combination may have different alkyl radicals in the chlorine / alkyl substituent pattern. The phrase " a pharmaceutically acceptable ester forming group

72 695 SBC CASE 14503 -8 "Acceptable " in R2 and R3 covers all esters which may be produced from the acid function (s) which may be present in these compounds. The resulting esters will be those which are acceptable in their applications for a pharmaceutical use. The term mono-diesters will retain the biological activity of the parent compounds and will not have undesirable or deleterious effects on their application and use in the treatment of diseases. These esters are, for example, those formed with one of the following radicals representing Rs: C10 alkyl, phenyl C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyl-xymethyl or thienylglycyloxymethyl. Aryl includes phenyl and naphthyl or heteroaromatic radicals such as furyl, thienyl, imidazolyl, triazolyl or tetrazolyl. More preferred ester-forming radicals are those for which R 5 is alkyl, particularly alkyl having 1 to 10 carbons, (ie CH 3 - (CH 2) n - where n is 0-9) or phenyl- (CH 2) n - where n is 0-4.

When R2 is an amine, this includes the radical -NH2 and mono- or dialkylated derivatives of this -NH2 radical. Preferred alkylated amines are the mono- and disubstituted amines having 1 to 6 carbons. When R2 is an amide, this includes all acylated derivatives of the radical NH2. Preferred amides are those having 1 to 6 carbons.

When an acidic group exists the amides may be formed. Particularly preferred amides are those in which -R6 is hydrogen or alkyl of 1 to 6 carbon atoms. Diethylamide is particularly preferred. The hydroxyl group of the 2-hydroxyethylene linking group may be esterified. Lower alkyl acids having 1 to 6 carbon atoms may be used to form these esters using standard reaction conditions. This hydroxyl group may also be converted to an ether, if desired. Again, these reactions are well known in the art of synthetic chemistry. 72 695 SBC CASE 14503

-9-

It is also intended that this invention covers the pharmaceutically acceptable salts of the present compounds. These salts are those which are acceptable in their application to a pharmaceutical use. The salt disclosed will mean that the salt will retain the biological activity of the parent compound and will have no undesirable or deleterious effects on its application and use in the treatment of diseases.

Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid in the case of the acid addition salts of a base portion or in an excess of an organic or inorganic base when R 4 is OH. Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid. Cationic salts are readily prepared from bases of alkali metals such as sodium, potassium, calcium, magnesium, zinc, copper or the like and ammonia. Organic bases include the mono or disubstituted amines, ethylenediamine, piperazine, amino acids, caffeine, tromethamine, other tris compounds and the like.

The oxides of the nitrogen of the pyridyl ring may be prepared by means known in the art and illustrated herein. These are considered part of the invention.

If by virtue of some combination of substituents, a chiral center is created, or another form of isomeric center is created, in a compound of this invention, it is intended that all forms of the isomer (s) are covered herein. Compounds with a chiral center can be administered as a racemic mixture or the racemates can be separated and the individual enantiomer used alone.

As leukotriene antagonists, these compounds may be used in the treatment of various diseases associated with leukotrienes, particularly LTB4 or whose origin is attributed to them or which are affected by them. Thus it is expected that these compounds can be used to treat allergic diseases of a pulsatile nature.

-10-monar and non-pulmonary. For example, these compounds will be useful in antigen-induced anaphylaxis. They are useful in the treatment of asthma and allergic rhinitis. Eye diseases such as uveitis and allergic conjunctivitis can also be treated by these compounds.

Preferred compounds of this invention are those in which R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or unsubstituted or substituted aliphatic phenyl to C10 to C10-O-, R4 is - (C5 aliphatic) R3, - (C 5 aliphatic) CH 2 R 7 and R 2 is -CONH or N (A) (B) wherein A is H or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl having 1 to 6 carbons or - Wherein R2 is -CF3, C1 to C6 alkyl, or phenyl. More preferred compounds of this invention are those in which R is alkoxy of 8 to 15 carbon atoms or phenyl substituted by C 1 to C 1 alkoxy-alkoxy; is -COR 3, -CH 2 CH 2 COR 3 or -CH = CH-COR 3; and R2 is -CONH or -NHSCONR6, particularly when R2 is in the meta and Rg and -CF3 positions.

More preferred compounds are shown in Figure II. -11- 72 695 SBC CASE 14503

Figure II

R

R2

-CH = CH-m-COOH HOCH-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CHO- Carbonyl of the methylene is substituted on the pyridyl ring, trans configuration. Synthesis

These compounds can be produced from the starting materials, intermediates and reagents and synthetic steps set forth in the following reaction flowcharts. These diagrams outline the pathway used to make these compounds and are based on the detailed chemistry set forth in the Examples set forth below. flow diagrams are intended to act as " road map " to guide us from the starting materials to the desired products. These specific starting materials, intermediates and reagents are presented only to illustrate the general case and are not intended to limit the chemistry illustrated therein. Reagents, intermediates, temperatures, solvents, reaction times and processing procedures may be varied to accommodate differences and to optimize particular conditions of production of a particular compound. These

The variants will be apparent to a chemist or will require no more than minimal experimentation to optimize the conditions and reagents for a particular step.

These reaction schemes first illustrate how to make some portions of the R group which are not commercially available, and then illustrate a means for joining the entire compound using the materials of Reaction Scheme 1 or commercially available R-forming groups. The preparation of some embodiments of R is shown in Scheme 1.

Esauema l (a)

t-Bu (Ph) 2SiCi -► (a) H3C0-Ph-I-Pd [(Ph) 3P] 2Cl2 ξξγ- (CH2) nOSi (Ph) 2-t-BuPh2 (b) h3co

(CH2) nOSi (Ph) ri-BuPh2 (c) H2, Pd-C-

(Ph) 2-t-Bu (d)

OH

TsCl (e)

Py

(CH3) n + r0Ts

In cases where (D-in-1-ol is not commercially available, it may be prepared from a corresponding 3-in-1-ol by treatment of the alcohol with a strong base. The alcohol is then protected to add the desired phenyl group to the terminal triple bond, in which case a silylether has been formed, this illustrates the general case.

A substituted halo-phenyl adduct to add the phenyl group to the triple bond. The silyl group is removed and the resulting alcohol is converted to the tosylate or another group which is sufficiently reactive to provide rapid formation of an ether, later in the synthesis of this compound. Scheme I (b) illustrates another process for making certain phenyl groups substituted phenyl by alkoxy-alkoxy.

Scheme 1 (b) (Ph) 3 P = CH (CH 2) 3 COO-CHO -►

CO2 H (a) H3 CO

TsCl

pyr-

Although the methoxyphenyl compound is illustrated herein, this series of steps and reagents may be used to make other (unsubstituted) aliphatic or (β-substituted phenyl) aliphatic β-phenyl groups represented by R. The starting material, benzaldehydes, is commercially available or can be made readily by known methods.

To make the acid, an alkylsilazide is first added to an inert solvent under an inert atmosphere. Thereafter, the phosphonium salt is added. This addition may be carried out at or near room temperature. After a brief mixing period, this mixture is usually a suspension, the benzaldehyde is slowly added at a temperature in the region of about room temperature. A slight molar excess of the phosphonium salt is employed. After a further brief shaking period at a SBC CASE 14503

At room temperature the reaction is quenched with water. The solution is acidified and acid (a) is extracted with a suitable organic solvent. If desired, additional standard separation and purification procedures may be employed. The alcohol is made by reducing the acid using a reducing agent. Lithium aluminum hydride or similar reducing agents may be employed and the conditions for effecting the reduction may be varied according to necessity. The tosylate is prepared in an inert solvent employing p-toluenesulfonyl chloride and a base such as pyridine . Suitable conditions include carrying out the reaction at or at room temperature for a period of from 1 to 5 hours. Other suitable leaving groups, which are similar in function to the tosylate, may be prepared and these groups will be useful as a means to add this R moiety to the pyridyl ring.

The compounds of formula I may then be synthesized by the sequence of steps outlined in the schemes which follow.

1. HO oxidation.

2. RI / K? C0?

RO 3. hydrazine / 100 ° C 4. N1 O2

2. m-iodobenzaldehyde 3. Pd (0Ac) 2 / dppf / CO

1. LDA

MeOH / DMSO / TEA

RC

1. Br 2 / CH 2 Cl 2 CO 2 Me 2. AgNO 3 / EtOH · HCl

, C02Me (2c) (2b) 1. (C6 H5) 3 PCHCl2 Me

TIiOU / THF

H02C

, co2h (2d)

72 695 SBC CASE 14503 -15-

2,6-lutidine-α, β-diol is first oxidized to 3-hydroxy-6-methyl-2-pyridine-carboxaldehyde. This aldehyde is then treated with a 1-halo-substituted group which is added to the 3-hydroxy group to form an ether. This reaction is effected by a base, for example a carbonate such as K 2 CO 2. Hydrazine hydrazine is then used to form an aminohydrazine. This reaction is carried out at an elevated temperature. The reaction mixture is then cooled and treated with a base prior to recovery of the amino-hydrazone. This hydrazine is then converted to a triazolo [1,5-a] pyridine (2a), by means of NiO2 or other oxidizing agent such as KFe (CN) 6. If nickel peroxide is used, the reaction may be effected at or near room temperature, although a long reaction time may be required. For the process with nickel peroxide an inert atmosphere is preferred, as are dry conditions. Other oxidizing agents may require elevated temperatures.

The 2-hydroxyethyl product is then prepared by first preparing, in situ. a reagent capable of extracting a proton from the triazole compound, and then adding the triazole compound and then a halobenzaldehyde. A useful base is lithium diisopropylamide. It is preferred to prepare it at reduced temperatures, i.e. -40 to 0 ° C or near temperatures. After the triazole-lopyridine and the benzaldehyde are added, the reaction is allowed to proceed at or about room temperature. A carbonylation reaction is then carried out to introduce a carboxyl group on the phenyl ring. This is carried out with Pd (OAc) 2 and gaseous carbon monoxide in an appropriate solvent, preferably at an elevated temperature, i.e. 50-100 ° C. Thus the carbomethoxy-substituted phenyl compound (2b) is obtained. Treatment of the resulting triazole compound with Br2 destroys the triazole ring and joins the carbon of the 2-position of the resulting pyridine ring to provide the 2- (Î ±, Î ± -dibromomethyl) pyridyl adduct. This reaction is preferably carried out at reduced temperature, i.e. about 0 ° C and is complete after about one hour. Oxidation with silver nitrate gives the aldehyde (2c). A Wittig reaction is then performed to turn the carbomethoxyethyl group

In the 2-position of the pyridyl ring. This compound can be treated with a base, to hydrolyze the esters, which are then acidified if the free acid (2d) is desired.

Alternatively, the ethylene group at the 2-position can be saturated by catalytic hydrogenation and then saponified using a base, which provides the salt, or the acid can then be acidified to give the free acid (see Scheme 3 below). The acid may be converted into a pharmaceutically acceptable or esterified salt by known means. The amides can be made from the acids by known procedures.

Analogs of the compounds of Scheme 2 in which it is an alkanoic acid can be made only by hydrogenating the unsaturated bonds of that chain. This process is illustrated in Scheme 3.

Scheme 3

The reduction of the double bond is effected by catalytic means, using a heavy metal catalyst and hydrogen gas. Moderate conditions will suffice. The esters illustrated may be hydrolyzed with a base and then further converted into other forms of formula I or transesterification may be used to convert them to other esters.

Compounds wherein R1 is -OH-terminal group, or an ester thereof, may be prepared by the series of steps shown in Scheme 4. (See Scheme 4) 72 695 SBC CASE 14503 -17-

1. Br2 2. AqNO,

Esqueroa 4

3. (C6 H5) 3 PCHC02 Me H0 4. DIBAL

(4a)

, CO2 H (4b)

1. Pd (OAc) 2 / dppf / CO

MeOH

2. LiOH 3. The starting material is that of Scheme 2, processed by that set of steps, except that the carbomethoxy function R2 is only introduced after the alcohol R1 has been prepared. Regardless of the steps of Scheme 2, the carbomethoxy group R1 may also be reduced separately to the alcohol, using a reducing agent such as diisobutylaluminum hydride (DIBAL) or a similar reducing agent. The catalytic hydrogenation may be used to saturate the ethylene group at the 2-position of the pyridyl ring. A base may be used to saponify the ester to provide the acid salt or this acid may be acidified if the free acid is desired.

Each of the products of Schemes 2-4 containing a hydroxyl group may be oxidized to the corresponding ketone, i.e., when T is -CH2 C (O) -, by means of a moderate oxidizing agent.

Formulation

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

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of suitable pharmaceutical carriers or diluents are included: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol,

Corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water; for solid systems, lactose, kaolin, and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. In addition to the pharmaceutical carrier or diluent, the present compositions may further include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, as long as the additional ingredients do not have a debilitating effect on the therapeutic action of the present compositions. The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example, parenteral, topical, oral or inhalation.

In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus, the compositions will comprise a suspension or solution of the active ingredient in water, for administration by means of a conventional nebulizer. Alternatively, the compositions will comprise a suspension or solution of the active ingredient in a conventional liquefied propellant or in a compressed gas, to be administered by a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration by a powder inhalation device. In the foregoing compositions, the amount of carrier or diluent will vary, but will preferably be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in amounts less than, equal to or greater than those of the solid active ingredient.

For parenteral administration, the pharmaceutical composition will be in the form of a sterile injectable liquid, such as an ampoule or an aqueous or non-aqueous liquid suspension.

For topical administration, the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes and drops,

72 695 SBC CASE 14503 -19- suitable for administration to the eyes, ears or nose.

For oral administration, the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, troche, lozenge, syrup, liquid or emulsion.

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

The pharmaceutical preparations thus described are produced by the conventional techniques of the pharmaceutical chemist in an appropriate manner to obtain the desired end product.

Also within the scope of this disclosure is the method of treating an LTB4 mediated disease, 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, inhibition of the symptoms of an allergic response resulting from a mediator release by administering an effective amount of a compound of formula I is included within the scope of this disclosure. Administration may be performed in dosage units at appropriate intervals or in single doses, as necessary. Usually, this method will be exercised when symptom relief is specifically required. However, this method is also usefully performed as a 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 account factors such as the degree of severity of the condition or disease to be treated and the like.

The pharmaceutical compositions and the method for their use

The invention also includes the combination of a compound of formula I with H2 blockers, a combination which contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or a similar allergic reaction. Representative and useful blockers include sodium cromolyn, class-compounds of ethanolamines (diphenylhydramine), ethylenedi amines (pyrilamine, alkylamines (chlorpheniramine), pyrazines (chlorocyclizine and phenothiazines (promethazine). like 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5 - [(6-methylpyrid-3-yl) methyl] -4-pyrimidone are particularly useful in this aspect of the invention.

Bioassays The specificity of the antagonist activity of various compounds of this invention is demonstrated by the relatively low levels of antagonism over agonists such as potassium chloride, carbachol, histamine and PGFg. 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 β1 H] -LTB4 binding sites in human cell membranes U937. The LTB4 antagonist activity of the compounds used in the method of this invention is measured by the ability of the compounds to dose-dependently antagonize the transient LTB4 calcium, measured with fura-2, the fluorescent calcium probe. The methods employed were as follows:

Conditions for U937 Cell Culture

U937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee (SK & F, Dept. of Immunology) and cultured in RPMI-1640 medium supplemented with 10% (v / v) heat inactivated fetal calf in a humidified environment of 5% CO 2, 95% air at 37 ° C. Cells were grown in T-bottles and Spinner culture. For the differentiation of U937 cells with DMSO into monocyte-type cells, cells were seeded at a concentration of 1 x 10 5 cells / ml in the above medium with 1.3% DMSO and incubation continued for 4 days. Cells were generally at a density of 0.75-1.25 x 106 cells /

72 695 SBC CASE 14503 -21- / ml and were harvested by centrifugation at 800 x g for 10 min.

Preparation of Enriched Fraction in U937 Cell Membrane

The harvested U937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25Â ° C containing 1 mM EDTA (Buffer A). Cells were resuspended in buffer A at a concentration of 5 x 10 4 cells / ml

And ruptured by nitrogen cavitation with a Parr bomb at 51.7 x 10 -3 kPa (750 psi) for 10 min at 0 ° C. The ruptured cell preparation was centrifuged at 1000 x g for 10 min. The supernatant was centrifuged at 50,000 xg for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended to about 3 mg of membrane protein / ml with 50 mM Tris-HCl, pH 7.4 at 25 ° C and aliquots were rapidly frozen and stored at -70 ° C.

[3 H] -LTB4 binding assays were performed at 25øC in 50 mM Tris-HCl buffer (pH 7.5) containing 10 mM CaCl 2, 10 mM MgCl 2 [3H] -LTB4, U937 cell membrane protein (standard conditions) in the presence (or absence) of various concentrations of LTB4 or SK & F compounds. Each experimental point represents the average of three determinations. Total and non-specific binding of [3H] -LTB4 were determined in the absence or presence of 2 μg of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding. Competition experiments with radioligand were performed under standard conditions using approximately 0.2 nM [3H] -LTB4, 20-40 μg of the U937 cell membrane protein, increasing concentrations of LTB4 (0.1 nM to 10 nM) or other competition ligands (0.1 μg to 30 μg) in a 0.2 ml reaction volume and incubated for 30 minutes at 25 sec. The unbound radioligand and the competition drugs were separated from the membrane bound ligand by a vacuum filtration technique. Membrane bound radioactivity in the filters was determined by liquid scintillation spectrometry.

Saturation binding experiments for U937 cells were performed under standard conditions, using approximately 15-72 695 SBC CASE 14503

-22-50 μg of U937 membrane protein and increasing concentrations of [3H] -LTB4 (0.02-2.0 mM) in a 0.2 ml reaction volume and incubation at 22 ° C for 30 minutes. LTB4 (2 μΜ) was included in a separate incubation tube set to determine non-specific binding. The data obtained from the saturation binding experiments were submitted to computer-assisted, non-linear least squares approach analysis and then analyzed by the Scatchard method.

Absorption and Incorporation of Fura-2 by Differentiated U957 Cells

Cells harvested at 2 x 106 cells / ml were resuspended in Krebs Ringer's Hensilet buffer containing 0.5% BSA (grade for RIA), 1.1 mM MgSO4, 1.0 mM CaCl2 and 5 mM HEPES (pH 7.4, buffer B). The fura-2 (fura-2 / AM) diacetomethoxy ester was added to a final concentration of 2 μ, and cells were incubated in the dark for 30 minutes at 37 ° C. Cells were centrifuged at 800 x g for 10 minutes and resuspended at 2x106 cells / ml in fresh buffer B and incubated at 37 ° C for 20 minutes to allow complete hydrolysis of the retentate. Cells were centrifuged at 800 x g for 10 minutes and resuspended in cold, fresh buffer B at 5x106 cells / ml. The cells were kept on ice in the dark until used for fluorescence measurements.

Fluorescence Measurements-Calcium Mobilization Fluorescence of fura-2-containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. The fluorometer is equipped with temperature control and a magnetic stirrer under the " cuvette " The wavelengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37 ° C with constant mixing.

U937 cells were diluted with fresh buffer to a concentration of Ix106 cells / ml and kept in the dark on ice. Aliquots (2 ml) of the cell suspension were placed in cuvettes " of 4 ml and washed at 37 ° C (maintained at 37 ° C, water bath for 10 min). &Quot; cuvettes " were transferred to the fluorometer and the fluorescence was measured for about one minute

Prior to the addition of stimulants or antagonists and followed for about 2 minutes post-stimulation. Agonists and antagonists were added as 2 μl aliquots.

The antagonists were first added to the cells in the fluorometer to detect potential agonist activity. Then, after about one minute 10 nM LTB4 (an almost maximal effective concentration) was added and the maximal Ca 2+ mobilization [Ca 2+] 2 was calculated using the following formula: [Ca 2+] x ~ 224 fF-Fmin) ( Fmax-Fj F is the maximum relative fluorescence measurement of the sample.Fmax was determined by lysing the cells with 10 μl of 10% Triton C-100 (final concentration 0.02%) After determination of Fmax 67 μl of 100 mM EDTA solution (pH 10) in order to completely chelate the Ca 2+ and extinguish the fura-2 signal and obtain the Fmin-level of [Ca 2+] 4 for 10 nM LTB 4 in the absence of an antagonist was The concentration XC 50 is the concentration of antagonist that blocks 50% of the mobilization of [Ca 2+] induced by 10 nM LTB 4 The EC 50 for increasing the mobilization of [Ca 2+] ] induced by LTB4 was the concentration for the induced semi-maximal increase. Kj for calcium mobilization was determined using the formula: IC 50

Ki = 1 + ^ 1+ [EC50]

With the described experiments, the concentration of LTB 4 was 10 nM and the EC 50 was 2 nM.

The results for the compounds tested by these methods are shown in Figure III. (See Figure III) 72 695 SBC CASE 14503 -24-

Figure III

Liaacao. IC 50 (kj), μΜ Mobilization of Ca U-937 PMN U-937 PMN Cell Cell%% Structure Whole Whole Membrane IC 50 μM Aonist Aonist Ex. 1 1.6 (0.55) 0.77 0.60 3.8 0 Ex. 3 2.1 (0.72) 0.74 - 3.4 0 0 Ex. 3 2.3 (0.81) 1.6-2.9 0 20 Ex. 4 8.8 (3, 1) 1.2 - 4.0 0 0

Examples The following set of examples illustrates how to make and use the compounds of this invention. They are not intended to circumscribe or otherwise limit the scope of this invention. For the definition of what is reserved to the applicant in this document, reference is made to the claims.

Example A 8- (4-Methoxyphenyl) octan-1- (4-toluenesulfonate)

7-Chloro-1-ol

Wash with 35% hexane KH in mineral oil (27 g, 240 mmol) under an argon atmosphere and treat dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until homogeneous. The flask was cooled to 0 ° C and 3-octyn-1-ol (10 g, 79 mmol, Synthesis of Lancas-ter) was slowly added. The reaction mixture was then stirred at room temperature for 18 hours. The reaction was quenched with H2 O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl (3 x 15 mL) and brine and dried (MgSO 4). Evaporation gave the title compound which was used without further purification: NMR (90MHz, CDCl3) δ 3.65 (t, J = 5Hz, 2H, OCH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (2) 4); IR diluted to 3350, 2930, 2125 cm -1. A (2) 7-Octyn-1-t-butyldiphenylsilyl ether

7-Octyn-1-ol (3.8 g, 30 mmol) was dissolved in dimethylformamide (10 mL) and treated with t-butylchlorodiphenylsilane (10.2 mL, 33 mmol) and imidazole (3.65 g, 45 mmol) at 0 ° C. The reaction mixture I? I? The title compound was stirred at 0Â ° C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, hexanes) to give a yellow oil: NMR (250MHz, CDCl3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, CH 2), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH 2) 4, 1.05 (s, 9H, (3) 8- (4-methoxyphenyl) -7-octyn-1-butyldiphenylsilyl ether To a flask, dried over a portion of (9.84 g, 27 mmol), (Ph-5 P), 4-iodoanisole (5.34 g, 22 mmol) in triethylamine (50 ml), followed by the addition of 7-octyn-1-butyldiphenylsilyl ether The resulting mixture was warmed to 50 ° C for 4 hours. After cooling to room temperature, the reaction mixture was filtered, and the reaction mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and H2 O and the organic layer was collected and washed with brine and dried (Na2 SO4) The solvent was evaporated and the residue purified by flash column chromatography (silica, acetic acid 1 H-NMR (250MHz, CDCl 3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (m, d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2) , 1.7-1.3 (m, 8H, (CH 2) 4), 1.05 (s, 9H, t-butyl). To 8- (4-methoxyphenyl) -7-octyn-1-butyldiphenylsilyl ether (2.2 g, 4.6 mmol) in ethanol (10 mL) was added 8- (4-methoxyphenyl) octan- ) and ethyl acetate (10 ml) was added 5% Pd / C (100 mg). The mixture was subjected to 517 kPa (75 psi) H2 for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated, yielding an oil: 1 H NMR (250MHz, CDCl 3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), (D, 2H, aryl), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH 2) 6), 1.0 (s, 9H, t-butyl). SBC CASE 14503 A (5) 8- (4-Methoxyphenyl) octan-1-ol

8- (4-Methoxyphenyl) octan-1-butyl diphenylsilyl ether (2.2 g, 4.6 mmol) in tetrahydrofuran (20 ml) was cooled to 0 ° C and treated with tetrabutylammonium bromide (14 ml, 14 mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue was purified by flash column chromatography " (silica, 0-20% ethyl acetate in hexanes) to give a white solid: 1 H NMR (250MHz, CDCl 3) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl , 3.85 (s, 3H, OCH3), 3.68 (t, 2H, OCH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (6) 8- (4-Methoxyphenyl) octan-1- (4-toluenesulfonate)

6- (4-Methoxyphenyl) oc tan-1-ol (5.9 g, 25 mmol) was dissolved in dry CH 2 Cl 2 (100 mL) and cooled to 0 ° C. To this mixture was added pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonyl chloride (5.4 g, 28 mmol). The reaction mixture was stirred at 0 ° C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, 0-10% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCl3) δ 7.79 (d, 2H, aryl), 7.35 (d, 2H, aryl) , 7.08 (d, 2H, aryl), 6.82 (d, 2H, aryl), 4.04 (s, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.55 , 2H, benzylic), 2.46 (s, 3H, CH3), 1.75-1.15 (m, 12H, (CH2) 6).

Example B 6- (4-Methoxyphenyl) hexan-1- (4-toluenesulfonate) B (1) 5-hexyn-1-t-butyldiphenylsilyl ether

5-Hexin-1-ol (3 g, 30 mmol, Aldrich) was dissolved in dimethylformamide (10 mL) and treated with t-butylchlorodiphenylsilane (10.2 mL, 33 mmol) and imidazole (3 , 65 g, 45 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was la-

With Na2 SO4 and brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, hexanes) to give a yellow oil: NMR (250MHz, CDCl3) Î'7H (aryl), 7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH2), 2.2 (m, 2H, CH 2), 1.9 (t, 1H, acetylenic), 1.7 (m, 4H, CH 2 -CH 2), 1.05 (s, 9H, t-butyl). To a flask-dried flask was added, under an argon atmosphere, 4-iodoanisole (5.34 g, 22 mmol) in triethylamine (50 ml) followed by addition of 5-hexyn-1-butyldiphenylsilyl ether (8.83 g, 27 mmol), (Ph 3 P) 2 PdCl 2 (350 mg, 0.44 mmol) and Cul (200 mg, 0.88 mmol ). The resulting mixture was heated at 50 ° C for 4 hours. After cooling to room temperature, the reaction mixture was filtered and the solvent was evaporated. The residue was partitioned between ethyl acetate and H2 O and the organic layer was collected and washed with brine and dried (Na2 SO4). The solvent was evaporated and the residue was purified by flash column chromatography " (silica, 1% ethyl acetate in hexanes) to give an oil: 2. NMR (250MHz, CDCl3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7 (D, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H , CH2), 1.7 (m, 4H, CH2 -CH2), 1.05 (s, 9H, t-butyl). 6- (4-Methoxyphenyl) -5-hexyn-1-butyldiphenylsilyl ether (2.0 g, 4.6 mmol) in ethanol (10 mL) was added 6- (4-methoxyphenyl) hexan-1-butyldiphenylsilyl ether ) and ethyl acetate (10 ml) was added 5% Pd / C (100 mg). The mixture was subjected to 517 kPa (75 psi) H2 for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated, yielding an oil: 1 H NMR (250MHz, CDCl 3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), (D, 2H, aryl), 3.8 (s, 3H, OCH 3), 3.6 (t, 2H, OCH 2), 2.5 (t, 2H, benzyl), 1.55 (m, 4H, CH 2 -CH 2), 1.3 (m, 4H, CH 2 -CH 2), 1.0 (s, 9H, t-butyl). B (4) 6- (4-Methoxyphenyl) hexan-1-ol

6- (4-Methoxyphenyl) hexan-1-butyl diphenylsilyl ether (2.0 g, 4.6 mmol) in tetrahydrofuran (20 mL) was cooled to 0 ° C and SBC CASE 14503 was treated with tetrabutylammonium fluoride (14 mL, 14 mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with H 2 O and brine and dried (Na 2 SO 4). The solvent was evaporated and the residue was purified by flash column chromatography " (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCl3) δ 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl) , 3.65 (t, 2H, OCH2), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH2 -CH2), 1.4 (s, 3H, OCH3) (m, 4H, CH 2 -CH 2). B (5) 6- (4-Methoxyphenyl) hexan-1- (4-toluenesulfonate)

6- (4-Methoxyphenyl) hexan-1-ol (5.36 g, 25 mmol) was dissolved in dry CH 2 Cl 2 (100 mL) under an argon atmosphere and cooled to 0 ° C. To this mixture was added pyridine (2.5 mL, 30 mmol) and 4-toluenesulfonyl chloride (5.4 g, 28 mmol). The reaction mixture was stirred at 0 ° C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, 0-10% ethyl acetate in hexanes) to give a white solid: 1 H NMR (250MHz, CDCl 3) δ 1.6-1.3 (m, 8H, (CH 2) 4) (S, 3H, CH3), 4.0 (t, 2H, OCH2), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl).

Example E E-6- (4-Methoxyphenyl) -1- (4-toluenesulfonate) -5-hexene C (1) E-4-methoxyphenyl-5-hexenoic acid

To a freshly prepared solution of lithium hexamethyl disilazide (64 mmol) in tetrahydrofuran (30 ml) under an argon atmosphere was added a suspension of (4-carboxybutyl) triphenylphosphonium bromide (17 , 6 g, 30 mmol) in tetrahydrofuran (45 ml) at room temperature. The reaction mixture was stirred for 15 minutes, during which time the red-orange color of the ylide was revealed. A solution of 4-anisaldehyde (4.5 g, 30 mmol) in tetrahydrofuran (30 ml) was added dropwise and stirring was continued for an additional 20 minutes. A 72 695 SBC CASE 14503

JJ Se-29-

The reaction was quenched with H2 O (50 mL) and diluted with ether (30 mL). The aqueous layer was acidified to pH 1.0 with 3 N HCl and the product was extracted into ethyl acetate (3 x 50 mL). The combined organic layers were dried (MgSO4) and the product purified by flash column chromatography " (silica, 1% methanol in CH 2 Cl 2) to give the E-olefin as a solid: 1 H NMR (200MHz, CDCl 3) δ 7.3 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin), 6.0 (m, 1H, olefin), 3.8 (s, 3H, OCH 3), 2.3 (m, 4H, allyl CH 2 and CH 2 CO 2 ), 1.8 (q, 2H, CH2) -C (2) E-4-Methoxyphenyl-5-hexen-1-ol

E-4-methoxyphenyl-5-hexenoic acid (1.1 g, 5.0 mmol) in dry ether (10 ml) was slowly added to a suspension of LiAlH 4 (240 mg, 6.0 mmol) in ether ml) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. After cooling to room temperature, the reaction was quenched with H2 O (10 mL) followed by 6N H2 SO4 (7 mL). Ethyl acetate (20 ml) was added and the organic layer was separated and dried (MgSO4); evaporation gave a white crystalline solid: mp 65-66 ° C; 1 H NMR (200MHz, CDCl 3) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin), 6.1 (m, 1H, olefin), 3.8 (s, 3H, OCH 3), 3.6 (t, 2H, OCH 2), 2.2 (q, 2H, allyl), 1.5 (m, 4H, CH 2 --CH 2); Anal. Calc. Calc'd for C 20 H 13 F 3 Cl 2: C, 75.65; H, 8.80, found; C, 75.45; H, 8.95; MS (CI): 207 (M + H).

C6) E-6- (4-methoxyphenyl) -1- (4-toluenesulfonate) -S-hexene

E-4-methoxyphenyl-5-hexen-1-ol (1.6 g, 7.0 mmol) was dissolved in dry CH2 Cl2 (50 mL) under an argon atmosphere and treated with 4-toluene- sulfonyl chloride (7.0 g, 36 mmol) and pyridine (3 mL). The reaction mixture was stirred at ambient temperature for 3.5 hours. Water (40 ml) was added to the mixture and the organic layer was separated and dried (MgSO4). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give an oil: 1 H NMR (200MHz, CDCl 3) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.2 (d, 1H, olefin), 6.0 (m, 1H, olefin), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.1 (q, 2H, ), 1.6 (m, 4H, CH 2 -CH 2); MS (CI): 361 (M + H).

72 695 SBC CASE 14503 -30-

Example 1 2- (E-2-Carboxyethenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxyylethylpyridine. (a) 3-Hydroxy-6-methyl-2-pyridine-carboxaldehyde

2,6-lutidine-α2,3-diol (1.0 g, 7.18 mmol, Al-drich) was suspended in dry CH 2 Cl 2 (40 mL) and treated with MnO 2 (6.1 g, 70 mmol ). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was removed in vacuo. The aldehyde was used directly in the next step without further purification: NMR (250MHz, CDCl 3): δ 10.65 (s, 1H, OH), 10.30 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH 3). 1 (b) 3-Decyloxy-6-methyl-2-pyridine-carboxaldehyde

The 3-hydroxy-6-methyl) -2-pyridine carboxaldehyde obtained above was dissolved in dry dimethylformamide (10 mL) and treated with 1-iododecane (2.1 mL, 8.62 mmol) and anhydrous K 2 CO 3 ( 3.0 g, 21.7 mmol) under an argon atmosphere. The reaction mixture was heated at 90 ° C for 1 hour with vigorous stirring. After cooling to room temperature the reaction mixture was poured into ethyl acetate (100 ml); the ethyl acetate solution was washed with H2O (3x20 mL) and brine and dried (MgSO4). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: 1 H NMR (250MHz, CDCl 3): δ 10.40 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 4.07 (t, 2H, OCH2), 2.6 (s, 3H, CH3), 1.85-0.90 (m, 19H, aliphatic). 1 (c) 5-Decyloxy-6-methyl-2-pyridine-aminohydrazone

3-Decyloxy-6-methyl-2-pyridine-carboxaldehyde (2.15 g, 7.8 mmol) was heated with hydrazine hydrate for 1 hour at 95 ° C. After cooling to room temperature, 25% NaOH was added and the mixture was extracted with ethyl acetate. The organic extract was washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated to give an amorphous solid: 1 H NMR (250MHz, CDCl 3) δ 8.75 (broad singlet, 2H, NH2), 7.55 (s, 1H, CH-N), 7.10 ( d, 1H, 5-pyridyl), 6.95 (d, 1H, 4-pyridyl), 3.95 (t, 2H, OCH2), 2.55 (s, 3H, 90 (m, 19H, aliphatic).

72 695 SBC CASE 14503 -31-

To a flask dried under an argon atmosphere was added 3-decyloxy-6-methyl-2-pyridine-amino-hydrazone (2 , 12 g, 7.2 mmol) in dry benzene (30 mL). To the resulting solution was added NiO 2 (790 mg, 8.7 mmol). The resulting mixture was stirred at room temperature for 72 hours and then filtered through Celite. The solvent was evaporated and the residue purified by flash column chromatography " (silica, ethyl acetate, 10-15% in hexanes) to give a white solid: NMR (250MHz, CDCl3): δ 8.2 (s, 1H, CH-N), 6.68 (d, 1H , 6,4 (d, 1H, 5-pyridyl), 4.1 (t, 2H, OCH2), 2.8 (s, 3H, CH3), 1.90-0.90 ( m, 19H, aliphatic); Anal. Calc. Found: C, 70.55; H, 9.40; N, 14.52, Found: C, 70.60; H, 9.14; N, 14.47. (E) -1- (3-Iodophenyl) -2- (4-decyloxy-1,2,3-triazolof1,5-alpyridin-7-iethan-1-ol To a flame-dried flask under an argon atmosphere, diisopropylamine (500 mg, 4.9 mmol) was added in dry ether (10 ml). The resulting solution was cooled to -40 ° C (CH3 CN / dry ice bath) and n-BuLi 2, The mixture was stirred at -40Â ° C for 10 minutes and then 4-decyloxy-7-methyl-1,2,3-triazolo [2,1- 1,5-a] pyridine (1.3 g, 4.4 mmol) in dry ether (40 ml) was added with an addition funnel The resulting red-brick mixture was stirred at -40 ° C for 6 hours. 3-iodobenzaldehyde (1.15 g, 4.9 mmol) in ether (30 ml) was added in one portion A dark yellow to yellow color change was observed The mixture was allowed to warm to room temperature was added over a period of 2 hours and then stirred at room temperature for 12 hours. The resulting reaction mixture was partitioned between ethyl acetate and Na2 SO4 and the organic extract was washed with H2 O and brine and dried (Na2 SO4). the solvent was evaporated and the residue purified by flash column chromatography " (silica, 10-30% ethyl acetate in hexanes) to give the alcohol as a white solid. A second component was isolated and identified as 3-substituted triazolopyridine: NMR (250MHz, CDCl3): δ 8.2 (s, 1H, CH-N), 7.80 (s, 1H, aryl) , 7.59 (d, 1H, aryl), 7.35 (d, 1H, aryl), 7.07 (t, 1H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, (t, 2H), 3.25 (d, JT tf fo · CH 2), 3.64, 1H, OH), SBC CASE 14503 -32- 1H, 5-pyridyl), 5.36 (m, 1H, CH -0), 4.11 (dd, 1H, Pi-CH), 3.45 (dd, 1H, Pi-CH '), 1.88-0.88 (m, 19H, aliphatic). 1 (f) 1- (3-Carboxymethylphenyl) -2- (4-decyloxy-1,2,3-triazolo [1,5-a] pyridin-7-yl) ethan-1-ol To a solution of 1- ( 3-iodophenyl) -2- (4-decyloxy-1,2,3-triazolo [1,5-a] pyridin-7-yl) ethan-1-ol (500 mg, 0.96 mmol) in dimethyl was added methanol (4 ml), triethylamine (0.3 ml, 2.1 mmol), Pd (OAc) 2 (6.4 mg, 0.029 mmol) and bisdiphenylphosphino-propane (11.9 g) mg, 0.029 mmol). Carbon monoxide was bubbled into the mixture for 4 minutes. The mixture was then heated at 85 ° C under positive pressure of carbon monoxide for 6 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and H2 O. The organic layer was washed with H2 O, brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, 5-20% ethyl acetate in hexanes) to give a white solid: 1 H NMR (250MHz, CDCl 3): δ 8.2 (s, 1H, CH-N), 8.1 (s, 1H , aryl), 7.95 (d, 1H, aryl), 7.63 (d, 1H, aryl), 7.4 (t, 1H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, 1H, 5-pyridyl), 5.45 (m, 1H, CH-O), 4.11 (t, 2H, OCH2), 3.9 (s, 3H, , 3.25 (dd, 1H, Pi-CH '), 3.25 (d, 1H, OH), 1.90-0.88 (m, 19H, aliphatic ); Anal. Calc. Calc'd for C 26 H 35 N 3 O 4: C, 68.85; H, 7.78; N, 9.26, found: C, 68.81; H, 7.73; N, 9.31. 1 (q) 3-Decyloxy-2- (α-Dibromomethyl ") - 6- [2- (5-carboxymethylphenyl) -2-hydroxyylethylpyridine

1- (3-Carboxymethylphenyl) -2- (4-decyloxy-1,2,3-triazolo [1,5-a] pyridin-7-yl) ethan-1-ol (130 mg, 28 mmol) in CH 2 Cl 2 (3 mL) and cooled to 0øC. To this mixture was slowly added a solution of Br2 (46 mg, 0.28 mmol) in CH2 Cl2 (3 mL); gas evolution was observed and the reaction mixture was stirred at 0 ° C for 1 hour. The CH2 Cl2 solution was washed with

NaHCO 3, H 2 O and brine and dried (Na 2 SO 4). The solvent was evaporated to give a yellow oil: 1 H NMR (250MHz, CDCl 3): δ 8.1 (s, 1H, aryl), 7.92 (d, 1H, aryl), 7.63 (d, 1H , aryl), 7.4 (t, 1H, aryl), 7.09 (d, 1H, 3-pyridyl), 7.07 (s, 1H, CHBr2), 7.0 (d,

72 695 SBC CASE 14503 -33-1H, 4-pyridyl), 6.08 (d, 1H, OH), 5.25 (m, 1H, CHO), 4.05 (t, 2H, OCH2), 3.9 (s, 3H, CO2 CH3), 3.15 (m, 2H, Pi-CH2), 1.90-0.88 (m, 19H, aliphatic). To a solution of 3-decyloxy-2- (Î ±, Î ± -dibromomethyl) -6- [2 '- (3,5-difluoromethoxy- - (3-carboxymethylphenyl) -2-hydroxy] ethylpyridine (150 mg, 0.26 mmol) in ethanol (3 mL) was added AgNO3 (90 mg, 0.56 mmol) in H2O (1 mL). The resulting mixture was heated at reflux for 1 hour. The mixture was cooled to room temperature and concentrated HCl (1 ml) was added and the precipitated silver salt was removed by filtration. The filtrate was evaporated and the residue was treated with saturated NaHCO 3. The product was extracted into ethyl acetate and washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil: 1 H NMR (250MHz, CDCl 3): δ 10.4 (s, 1H, CHO), 8.1 (s, 1H , aryl), 7.92 (d, 1H, aryl), 7.63 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.33 (d, 1H, 3-pyridyl), (D, 1H, 4H), 3.1 (t, 2H, OCH2), 3.15 (d, 1H, 4-pyridyl) 9 (s, 3H, CO2 CH3), 3.15 (m, 2H, Pi-CH2), 1.90-0.88 (m, 19H, aliphatic); MS (CI): 277 (M + H). 1 (i) 2- (E-2-Carboximetestenyl) -3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxyethylpyridine

Dissolved 3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxy-2-pyridinecarboxaldehyde (40 mg, 0.09 mmol) in dry benzene (2 mL) under an atmosphere of argon. To this was added methyl (triphenylphosphoranylidene) acetate (60 mg, 0.18 mmol) and the resulting mixture was heated at 45 ° C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue purified by flash column chromatography " (silica, 15-20% ethyl acetate in hexanes) to give a yellow oil: 1 H NMR (250MHz, CDCl 3): δ 8.1 (s, 1H, aryl), 8.1 (d, SBC CASE 14503 -34-

(D, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.15 (d, 1H, 5-pyridyl), 7.03 (d, 1H, 4-pyridyl), 6.95 (d, J = 16 Hz, 1H, olefin), 5.65 (d, 1H, OH), 5.2 (m, 1H, CH-O), 4.05 (t, 2H, OCH2), 3.9 (s, 3H, CO2 CH2), 3.8 (s, 3H, Pi-CH2), 1.90-0.88 (m, 19H, aliphatic); MS (CI): 498 (M + H). 1 (R) -2- (E-2-Carboxyphenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxyethylpyridine. dilithium salt

2- (E-2-Carboxymethylethenyl) -3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxy] ethylpyridine (22 mg, 0.04 mmol) was dissolved in tetrahydrofuran, H2 O and methanol (0.50 ml each) and treated with LiOH monohydrate (5 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2 O and purified by reverse phase MPLC (RP-18 silica, 10-40% MeOH in H2 O). The desired fractions were lyophilized to give a colorless amorphous solid: 1H NMR (250MHz, CD30D): δ 8.01 (s, 1H, aryl), 7.80 (d, 1H, aryl), 7.76 (d (D, 1H, 5-pyridyl), 7.07 (d, 1H, aryl), 7.30 (t, 1H, aryl), 7.24 (d, 1H, (D, 1H, 4-pyridyl), 5.11 (t, 1H, CH-O), 4.0 (t, 2H, OCH2), 3.1 (m, 2H, Pi-CH2), 1.83-0.89 (m, 19H, aliphatic); FAB-MS: 474.3 (M-H, monolithium salt), 468 (M-H, free acid).

Example 2 2- (2-Carboxyethyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxy-1-ethylpyridine. (a) 2- (2-Carboxymethyl) -3-declyloxy-6- (2-C-3-Carboxymethylphenyl) -2-hydroxyethylpyridine 2- (E-2-carboxymethylethenyl) -3-decyloxy- 6- [2- (3-Carboxymethylphenyl) -2-hydroxy] ethylpyridine (13 mg, 0.02 mmol) in ethanol (3 mL) was added 5% Pd / C (2 mg). The mixture was subjected to 34.48 kPa (5 psi) H2 for 1 hour. The mixture was filtered through Celite ε and the solvent was evaporated, yielding an oil: λmax (250MHz, CDCl 3): δ 8.08 (s, 1H, aryl), 7.9 (d, 1H, aryl), 7.6 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.05 (d, 1H, 5-pyridyl), 6.87 (d, 1H, 4-pyridyl, 0 (broad singlet, 1H, 72695 SBC CASE 14503

(S, 3H, CO2 CH2), 3.8 (s, 3H, CO2 CH3), 4.01 (t, 2H, OCH2) ), 3.2 (t, 2H, CH2), 3.05 (m, 2H, CH2), 2.8 (t, 2H, CH2), 1.83-0.88 (m, 19H, aliphatic). 2 (b) 2- (2-Carboxyethyl) -3-decyloxy-6- (2- (3-carboxyphenyl) -2-hydroxy-ethylpyridine. dilithium salt

2- (2-Carboxymethylethyl) -3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxy] ethylpyridine (10 mg, 0.015 mmol) was dissolved in tetrahydrofuran, H2 O and MeOH (0.5 ml each) and treated with LiOH monohydrate (2 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2 O, filtered through a nylon filter and purified by reverse phase MPLC (RP-18 silica, 10-40% methanol in H2 O). The desired fractions were lyophilized to give a colorless amorphous solid: 1 H NMR (250MHz, CD 3 OD): δ 8.0 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.32 (d, 1H, aryl), 7.25 (t, 1H, aryl), 7.1 (d, 1H, 5-pyridyl), 6.9 (d, 1H, 4-pyridyl), 5.1 , 3.1 (t, 2H, CH 2), 3.05 (m, 2H, CH 2), 2.5 (t, 2H, CH 2), 4.0 (t, 2H, OCH 2) ), 1.8-0.90 (m, 190H, aliphatic); FAB-MS: 484 (M + H).

Example 3 2- (E-3-Hydroxypropenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxyethylpyridine. lithium salt 3 (a) 3-Decyloxy-2- (α-dibromomethyl) -6- [2- (3-iodophenyl) -2-hydroxyhexylpyridine

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

This compound was prepared from 3-decyloxy-2- (α, α-dibromomethyl) -6- [2- (3-iodophenyl) -2-hydroxy] ethylpyridine according to the procedure described in Example 1 (g) . There was obtained a white solid.

72 695 SBC CASE 14503 1 H NMR (250MHz, CDCl 3): δ 10.4 (s, 1H, CHO), 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl), 7.4 (m, 2H, 3d pyridyl, aryl), 7.3 (d, 1H, 4-pyridyl), 7.1 (t, 1H, aryl), 5.1 (m, 1H, , 3.1 (m, 2H, CH2 of Pid), 1.80-0.90 (m, 19H, aliphatic), 4.95 (d, 1H, OH), 4.1 (t, 2H, OCH2) . The title compound was prepared from 3-decyloxy-6- [2- (3-iodophenyl) -2- (2-carboxymethylethenyl) Example 3 (b)] according to the procedure described in Example 1 (h): ΣΗ NMR (250MHz, CDCl 3): δ 8.4 (s, 1 (d, J = 15.9Hz, 1H, olefin), 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl) 2 (d, 1H, 5-pyridyl), 7.05 (m, 2H, 4-pyridyl, aryl), 6.95 (d, J = 15.9Hz, 1H, olefin), 5.6 (d, 1H , 4.05 (m, 2H, OCH2), 3.8 (s, 3H, CO2 CH2), 3.05 (m, 2H, CH2 -CH2) ), 1.85-0.90 (m, 19H, aliphatic). 3 (d) 2- (E-3-Hydroxypropenyl) -3-decyloxy-6- [2- (3-iodophenyl) -2-hydroxyethylpyridine

2- (E-2-carboxymethylethenyl) -3-decyloxy-6- [2- (3-iodophenyl) -2-hydroxy] ethylpyridine (340 mg, 0.60 mmol) was dissolved in dry CH 2 Cl 2 (6 mL) under an argon atmosphere and cooled to 0 ° C. DIBAL (1.5 mL, 1.5 mmol, 1M in CH2 Cl2) was added dropwise and the reaction was maintained at 0 ° C for 20 minutes. The reaction was quenched with methanol (10 ml) and the solvent was evaporated. The residue was partitioned between ethyl acetate and H2 O and the organic layer was washed with H2 O and brine and dried (Na2 SO4). The solvent was evaporated and the residue was purified by flash column chromatography " (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil. 1 H NMR (250MHz, CDCl 3): δ 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl), 7.4 (d, 1H, aryl) olefinic, 4-pyridyl, 3-pyridyl, aryl), 6.4 (broad singlet, 1H, OH), 5.05 (m, 1H, CH-O), 4.4 (d, 2H, , 95 (t, 2H, OCH2), 3.0 (m, 2H, Pi-CH2), 1.90-0.90 (m, 19H, aliphatic). (E) 2- (E-3-HydroxyPropenyl) -3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxyethylpiperidine]

This compound was prepared from 2- (E-3-hydroxypropyl) -3-decyloxy-6- [2- (3-iodophenyl) -2-hydroxy] ethylpyridine according to the procedure described in Example 1 (and ). NMR (250MHz, CDCl3): δ 8.15 (s, 1H, aryl), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, ), 7.10 (m, 4H, olefinic, 3-pyridyl, 4-pyridyl), 6.4 (broad singlet, 1H, OH), 5.2 (m, 1H, CH- d, 2H, allyl), 4.0 (t, 2H, OCH2), 4.9 (s, 3H, CO2CH3), 3.1 (m, 2H, m, 19H, aliphatic). 3 (f) 2- (E-3-Hydroxypropenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxyethylpyridine. lithium salt

This salt was prepared from 2- (E-3-hydroxypropenyl) -3-decyloxy-6- [2- (3-carboxymethylphenyl) -2-hydroxy] ethylpyridine [Example 3 (e)] according to procedure described for 2- (E-2-carboxyethenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxy] ethylpiperidine, lithium salt [Example 1 (i)], 1 H NMR (250MHz , CD3OD): δ 8.0 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.4 (d, 1H, aryl), 7.3 (t, 1H, aryl), 7 (D, 1H, 3-pyridyl), 6.9 (m, 3H, olefinic, 4-pyridyl), 5.1 (m, 1H, allyl), 4.0 (t, 2H, OCH2), 3.1 (m, 2H, Pi-CH2), 1.85-0.85 (m, 19H, aliphatic); FAB-MS: (? Ve), 460.3 (M-Li).

Example 4 2- (E-2-Carboxyethenyl) -3- [6- (4-methoxyphenyl) hexyloxy-1- [2- (5-carboxyphenyl) -2-hydroxyethylpyridine. dithiol salt

2- (E-2-carboxyethenyl) -3- [6- (4-methoxyphenyl) hexyloxy] -6- [2- (3-carboxyphenyl) -2-hydroxy] ethylpyridine, dilithium salt according to the procedure described for 2- (E-2-carboxyethenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxy] ethylpyridine, dilithium salt, quoted in Example 1, but substituting 6- (4-methoxyphenyl) hexan-1- (4-toluenesulfonate) for 1-iodo-carbonate [Example B (5) 72 695 SBC CASE 14503

&

-38-4 (a) 3-6- (4-Methoxyphenyl) hexyloxy-6-methyl-2-pyridinecarboxaldehyde: NMR (250MHz, CDCl3: δ 10.4 (s, 1H, CHO), 7.3 (s, 2H, 4-pyridyl, 5-pyridyl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 4.1 (t, 2H, OCH2) , 2.6 (s, 3H, CH3), 2.6 (t, 2H, benzylic), 1.8-1.35 (m, 8H, aliphatic), Anal Calc'd for C 20 H 25 NO 3 --H 2 O: C 72.77 H 7.72 N 4.25, found: C 72.75, H 7.65, N, 4.10, MS (CI): 328 (M + H).

Following the procedures of Examples 1 (b) and following but replacing the adducts mentioned in Example 1 with the appropriate adducts the following compounds were produced: 3- (6-Methoxyphenyl) hexyloxy-6-methyl -2-pyridine-amino-hydrazone: 1 H NMR (250MHz, CDCl 3): δ 8.2 (s, 1H, CH-N), 7.15 (d, 2H, aryl), 7.1 (d, 1H, 5-pyridyl), 7.0 (d, 1H, 4-pyridyl), 6.8 (d, 2H, aryl), 5.7 (broad singlet, 2H, NH2), 3.95 (t, 2H , 2.6 (s, 3H, CH 3), 2.6 (t, 2H, benzylic), 1.8-1.35 (m, 8H, aliphatic ). 4 (c) 4- [6- (4-Methoxyphenyl) hexyloxy] -7-methyl-1,2,3-triazolo1,5-alipyridine: 1 H NMR (250MHz, CDCl3): δ 8.2 (s, 1H, (D, 2H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, 1H, 5- pyridyl), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.8 (s, 3H, CH3), 2.63 (t, 2H, benzylic), 1.90 -1.35 (m, 8H, aliphatic). (4-methoxyphenyl) hexyloxy) -1,2,3-triazolo1,5-a] pyridin-7-yl] ethan-1-ol: 1 H NMR (250MHz, CDCl 3) ): δ 8.2 (s, 1H, CH-N), 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl), 7.37 (d, 1H, aryl), 7 (D, 2H, aryl), 6.8 (d, 2H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, 2H, aryl) 1H), 5.4 (m, 1H, CH-O), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 3.7 (dd, 1H (D, 1H, OH), 2.63 (t, 2H, benzylic), 1.90-1.35 (m, m, 8H, aliphatic); MS (CI): 572 (M + H). 4 (e) 1- (3-Carboxymethylphenyl) -2- [4- [6- (4-methoxyphenyl) hexyloxy] -1. 1 H NMR (250MHz, CDCl 3): δ 8.2 (s, 1H, CH-N), 8.11 (s, 1H, aryl), 7 (D, 2H, aryl), 6.8 (d, 1H, aryl), 7.4 (t, 1H, aryl) , aryl), 6.6 (d, 1H, 6-pyridyl), 6.3 (d, 1H, 5-

. V

. V

(m, 1H, CH-O), 4.1 (t, 2H, QCH 2), 3.9 (s, 3H, CO 2 CH 3), 5.5 3.8 (s, 3H, OCH3), 3.7 (dd, 1H, Pi-CH), 3.5 (dd, 1H, Pi-CH *), 3.2 (d, 1H, OH), 2 , Δ (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); MS (CI): 504 (M + H). 4 (f) 3- [6- (4-Methoxyphenyl) hexyloxyl-2- (ag-dibromomethyl) -6- [2- (3-carboxymethylphenyl) -2-hydroxyethylpyridine: NMR (250MHz, CDCl3) (S, 1H, aryl), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 3-pyridyl, 4-pyridyl, aryl), 6.8 (d, 2H, aryl), 5.3 (m, 1H, CHO-), 4.1 (t, 2H, OCH2) (S, 3H, CH2CH3), 3.9 (s, 1H, CHBr2), 3.8 (s, 3H, OCH3), 3.15 (m, 2H, 2H, benzylic), 1.85-1.40 (m, 8H, aliphatic). 4 (g) 3- [6- (4-Methoxyphenyl) hexyloxyl-6- [2- (3-carboxymethylphenyl) -2-hydroxyethyl-2-pyridine carboxaldehyde: 1 H NMR (250MHz, CDCl 3): δ (S, 1H, aryl), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.35 (d, 1H, 3-pyridyl), 7.25 (d, 1H, 4-pyridyl), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl) , 5.4 (m, 1H, CH-O), 5.0 (d, 1H, OH), 44.1 (t, 2H, OCH2), 3.95 (s, 3H, CO2CH3), 3.8 , 3H (OCH3), 3.2 (m, 2H, Pi-CH2), 2.5 (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); MS (CI): 492 (M + H). 4 (h) 2- (E-2-Carboximetestenyl) -3- [6- (4-methoxyphenyl) -hexyloxyl-6- [2- (5-carboxymethylphenyl) -2-hydroxyethylpyridine: 1 H NMR (250MHz, CDCl3): δ 8.07 (s, 1H, aryl), 8.05 (d, J = 16Hz, 1H, olefin), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7 (D, J = 16 Hz, 1H, olefin), 6.8 (d, J = 16 Hz, 1H, aryl), 7.1 (m, 4H, 4-pyridyl, 5-pyridyl, 2H, Aryl), 5.7 (d, 1H, OH), 5.2 (m, 1H, CH-O), 4.05 (t, 2H, QCH2), 3.9 (s, 3H, , 3.75 (s, 3H, CO2 CH2), 3.15 (m, 2H, Pi-CH2), 2.55 (t, 2H, benzylic), 1.90-1 , 40 (m, 8H, aliphatic): Anal. Calc. Calc'd for C 32 H 37 NO 7 · 9/8 H 2 O: C, 67.68; H, 6.97; N, 2.47, found: C, 67.45; H, 6.63; N, 2.34; MS (CI): 548 (M + H). 4 (i) 2- (E-2-Carboxyethenyl) -3- [4- (4-methoxyphenyl) hexyloxyl-6- [2- (3-carboxyphenyl) -2-hydroxyylethyl) pyridine. dilithium salt: 1 H NMR (250MHz, CD 3 OD): δ 8.05 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.75

(D, J = 16 Hz, 1H, olefin), 7.35 (d, 1H, aryl), 7.25 (t, 1H, aryl), 7.2 (d, J = 16 Hz, 1H, olefin), 7.0 (m, 4H, 4-pyridyl, 5-pyridyl, aryl), 6.75 (d, 2H, aryl), 5.15 (t, 1H, 0), 4.0 (t, 2H, OCH 2), 3.7 (s, 3H, OCH 3), 3.1 (m, 2H, Pi-CH 2), 2.5 (t, 2H, , 80-1.35 (m, 8H, aliphatic); FAB-MS: (+ ve), 532.2 (M + H); (~ ve), 524.4 (M-Li).

Example 5

Formulations for pharmaceutical use may be prepared by incorporating compounds of the present invention in various forms and using various excipients. Examples of such formulations are set forth below.

Formulation for Inhalation

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

Tablets

Ingredients Per Pill Per 10 000 Tablets 1. Active ingredient (Form I compound) 40 mg 400 S 2. Corn starch 20 mg 200 g 3. Alginic acid 20 mg 200 g 4. Sodium alginate 20 mg 200 g 5. Magnesium stearate 1.3 mg 13 q 101.3 mg 1013 g

Procedure for producing tablets:

Step 1. Mix the ingredients no. 1, no. 2, no. 3 and n, 4 in a suitable mixer.

Step 2. Add enough water, in portions, to the mixture from Step 1, carefully mixing after each addition. Continue these additions of water and the mixture until the mass has a consistency that allows its conversion into wet granules. 72 695 SBC CASE 14503 -41-

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

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

Step 5. The dried granules are lubricated with ingredient no. 5

Step 6. The lubricated granules are compressed in a suitable tablet press. 1. Composition of Formula I 40.0 mg 40 g Active ingredient 2. Polyethylene glycol 1000 1350.0 mg 1350 g 3. Polyethylene glycol 4000 450.0 ml 450 mg 1840.0 mg 1840 g

Procedure:

Step 1. Melt the ingredient no. 2 and n. 3 together and shake until uniform.

Step 2. Dissolve the ingredient no. 1 in the melt of Step 1 and stir until uniform.

Step 3. Pour the molten mass from Step 2 into suppository molds and cool.

Step 4. Remove the suppositories from the mold and wrap them.

Claims (20)

A process for the preparation of a compound of formula I or an N-oxide or a pharmaceutically acceptable salt, wherein T is CO or CH (OH); R 2 is C 1 to C 20 aliphatic, C 1 to C 10 unsubstituted or substituted aliphatic phenyl, wherein substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo or R is C1-4 aliphatic, or R5 is unsubstituted or substituted C1-4 aliphatic phenyl, where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl and halo; R 1 is - (aliphatic to C 5) R 3, - (aliphatic to C 5) CHO, - (aliphatic to CEpCh ORy, -R 3, -CH 2 OH or CHO, R 2 and R 3 are independently of each other, -COR 4 where R 4 is -OH , a pharmaceutically acceptable ester-forming group, -OR 5, or -OX, where X is a pharmaceutically acceptable cation, or R 4 is -N (R 6) 2, where R 6 is H, or an aliphatic group of 1 to 10 atoms (CH2) n - 4 to 10 carbon atoms where n is 0-3 or both R6 groups form a ring having 4 to 6 carbon atoms or R2 is N (A) (B) where A is H or alkyl of 1 to 6 carbon atoms and B is H, alkyl of 1 to 6 carbon atoms, acyl of 1 to 6 carbon atoms or SO2 Rg where R8 is -OF3, C1 to C6 alkyl or phenyl and R 7 is hydrogen, C 6 to C 6 alkyl or acyl to C 6 acyl, which process comprises: a) treating an aldehyde of formula 2: (2) 72 695 SBC CASE 14503 Wherein R 2 is as defined above and R 2 is an ester, with a Wittig reagent, to give a compound of formula (I) wherein R 3 is -C 3 -C-; or b) catalytically hydrogenating a compound of formula 3: (C 1 to C 3 aliphatic) R 3 or - (C 1 to C 5 aliphatic) CH 2 R 7, to form a compound of formula (I), wherein it is a saturated - (C 5 aliphatic) R 3 or - (C 1 to C 5 aliphatic) CH 2 R 7, or c) carboxylating an iodo compound of formula 4: in which R 1 and R 2 are as defined above, except that R 1 is not COOH or a salt thereof, (d) hydrolyzing an ester of a compound of formula (5) in which R 1 and R 2 have an ester group, to give a salt or free acid of formula (I); or e) oxidizing an alcohol of formula 6: to a ketone of formula (I) 72 695 SBC CASE 14503 44- R F or; and optionally thereafter forming a pharmaceutically acceptable salt. A process according to claim 1, characterized in that a compound in which T is CH (OH) is prepared. A process according to claim 2, wherein a compound in which R 1 is aliphatic C 1 to C 2 O-R 4 is - (C 1 to C) aliphatic A compound according to claim 3, wherein a compound in which R 1 is C 1 to C 1 -C 6 alkyl, R 2 is -CH = CHC OR 5, where the substituents on the double bond are in the trans configuration, and R2 is -COOH or -NHSO2R8. 5. A process according to claim 4 for preparing 2- (E-2-carboxyethenyl) -3-decyloxy-6- [2- (3-carboxy-phenyl) -2-hydroxy] -ethylpyridine or a salt thereof pharmaceutically acceptable. A compound according to claim 2, wherein a compound in which R is C8 to C15 alkyl is C1-4 aliphatic and R2 is -COOH or -NHSO2 R8 substituted in the meta position. A process according to claim 6 for preparing 2- (E-3-hydroxypropenyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxy] ethylpyridine or a salt thereof pharmaceutically acceptable. 8. A process as claimed in claim 2 for preparing a compound in which R is substituted or unsubstituted phenyl, and * (C 1 to C 5 aliphatic) R 3 and R 2 is -COOH or -NHSO 2 R 6 substituted in the meta or para position. A process according to claim 8, characterized in that a compound in which R is a lower alkoxy-substituted phenyl-Cg-alkyl group is prepared. A process according to claim 9 for preparing 2- (E-2-carboxyethenyl) -3- [6- (4-methoxyphenyl) hexyl] -6- [2- (3-carboxyphenyl) -2- -hydroxy] -ethylpyridine or a pharmaceutically acceptable salt thereof. 11. A compound according to claim 2, wherein a compound in which R1 is - (C1 -C4 alkyl) A process according to claim 11 for preparing 2- (2-carboxyethyl) -3-decyloxy-6- [2- (3-carboxyphenyl) -2-hydroxy] ethylpyridine or a pharmaceutically acceptable salt thereof. A process according to claim 2, characterized in that a compound in which R2 is in the para position is prepared. A process according to claim 1, characterized in that a compound in which T is CQ is prepared. A process according to claim 14, wherein a compound in which R is aliphatic at C20 -O-, R5 is - (aliphatic at C5) R3 or - (C1 to C5 aliphatic) CH2 R7 and R2 is - COOH or -NHSO2 R6 substituted at the meta or para position. A process according to claim 15, wherein a compound in which R is -C1 to C15 alkyl, R4 is -CH = CHC0 R4, wherein the double bond substituents are in the cis or trans configuration and R2 is -COOH. 17. A process according to claim 14, characterized in that a compound in which R is C1-6 aliphatic substituted or unsubstituted phenyl, is - (C1-4 aliphatic C5) alkoxy or - (aliphatic C1 to C5) CH2 R7 and R2 is -C0H or -NHSO2R8 substituted at the meta or para position. 18. A process according to claim 17, characterized in that a compound in which R is aliphatic is C1-4 alkoxy. is - (C 1 to C 5 aliphatic) R 3. 19. A compound according to claim 18, wherein R 1 is C 8 to C 15 alkyl, R 5 is -CH = CHCOR 5, wherein the substituents on the double bond are in the trans configuration, and R 2 is -C00H or -NHSO2R8. A process for the preparation of a pharmaceutical composition, characterized in that a compound of formula (I) defined in claim 1 is combined with a pharmaceutically acceptable carrier. Lisbon, By SMITHKLINE BEECHAM CORPORATION = 0 OFFICIAL AGENT =