WO1992016104A1

WO1992016104A1 - Leukotriene antagonists

Info

Publication number: WO1992016104A1
Application number: PCT/US1992/002114
Authority: WO
Inventors: Robert A. Daines; William D. Kingsbury; Israil Pendrak
Original assignee: SmithKline Beecham Corp
Current assignee: SmithKline Beecham Corp
Priority date: 1991-03-13
Filing date: 1992-03-13
Publication date: 1992-10-01
Anticipated expiration: 1993-09-13
Also published as: AU1583392A; JPH06507886A; EP0575494A1; EP0575494A4

Abstract

This invention relates to certain novel disubstituted quinolines of formula (I) where R1 and R2 are defined herein which are useful leukotriene antagonists useful for treating allergies and the like.

Description

Sropp. of the Tnypnt-inn

This invention relates to disubstituted quinolines which are useful as leukotriene antagonists. More particularly, these quinolines are 2,7-disubstituted compounds which have utility in treating diseases related to leukotriene B wherein the treatment is affected by virtue of the antagonist activity of these 2,7-disubstituted quinolines. 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 hydroxyleukotrienes (leukotriene B4) . This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes. The peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting

Substance of Anaphylaxis" (SRS-A) . This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production.

By comparison, LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs) . It is critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.

Leukotriene B4 (LTB4) was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co- workers to be 5(S) , 12<R)-dihydroxy-(Z,E,E,Z)-β,8,10,14- eicosatetraenoic acid (Figure I) .

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

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. In addition, as with the other leukotrienes, LTB4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor.

Summary of the Invention

This invention relates to disubstituted quinolines of formula I

(I) Rl is CH3(CH2)nHOHC- or

where n is 3-20, m is 1-6 and R3 is lower alkyl, lower alkoxy or halo; and

R2 is HOCH2 (CH2) _rCH0HCH2-, XOC (CH2) rCHOHCH2- , XOC(CH2)q-2CH=CH-, XOC (CH2) qCH2-, COX where X is OH or an ester-forming group or an amide-forming group,

In another aspect, this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient.

Treating diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ are within the scope of this invention. This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient. In yet another aspect, this invention relates to a method for making a compound of formula I which method is illustrated in the Schemes given below and in the Examples set forth in this specification. Additionally, this case relates to a method for making a compound of formula I which method comprises: a) forming a salt, or b) hydrolyzing an ester to the salt or free acid, or c) forming an ester, or d) forming an amide, or e) alkylating the quinoline, or f) inserting an R2 group at position 2 by means of a triflate intermediate, or g) reducing a double bond in the R2 group. DETAILED DESCRIPTION OF THE INVENTION The following definitions are used in describing and defining this invention and setting out what the inventors believe to be their invention herein. The phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-. "Halo" means fluoro, chloro, bromo or iodo.

An ester-forming group is any group where an oxygen is covalently bonded to a carbonyl carbon and a second carbon atom wherein the resulting group is denominated an ester. Similarly, an amide-forming group is one where a nitrogen is bonded to a carbonyl carbon and otherwise has one or two hydrogens or one or two bonds to a carbon atom, resulting in a group which is identified as an amide. All esters or amides made thereby will retain some useful activity in treating a disease or for some other industrial application. When the phrase "a pharmaceutically acceptable ester-forming group" or "pharmaceutically acceptable amide forming group" is used, it is intended to refer to all esters or amides which can be used in the medicinal arts, either the human or animal medicinal arts. The preferred esters are those having of the formula CH3 (CH2)u~0- where u is 0-6. The most preferred amides are those where the nitrogen is substituted with just hydrogen or one or two lower alkyl groups. The diethylamide is particularly preferred.

If there is an acidic or basic function which is sufficiently acidic or basic so as to be able to form a salt, this invention is intended to cover such a salt having industrial application. If the phrase "a pharmaceutically acceptable salt" is used, that is intended to cover salts which have use and application in the human and animal medicinal arts.

Salts are prepared in a standard manner, in a suitable solvent. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of a basic functionality, or an excess of organic or inorganic base where X is OH.

N-oxides may also be prepared by means of selected oxidizing agents. These oxides are useful as intermediates in prepar ng t e compoun s o ormu a I an may ave use n and of themselves. Hence, for example, one can administer the N-oxides of formula I to a subject who is susceptible to or is suffering from a disease related to or caused by LTB4 or similar leukotrienes.

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. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.

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

Preferred compounds are those where Rl is

is 1-6; and R2 is -COX, HOCH2 (CH2)_rCHOHCH2- XOC(CH2)_qCH2- XOCH2(CH2)_rCHOHCH2-, XOC(CH2)q-2CH=CHCH2-, where q is 2-5 an

where t is 0, 1 or 2. More preferred are those compounds where Rl is CH3 (CH2)nHOHC- where n is 7, 8 or 9, or is

-(OH)CH(CH2)nCH3 where n is 7, 8 or 9, or is

OH where m is 2, 3 or 4 and R3 is lower alkoxy; and R2 is -CH2 (OH) (CH2)_rCH2θH, XOCH2 (CH2)_rCH0HCH2-, XOC(CH2)qCH2- or XOC(CH2)q-2CH=CHCH2- where r is 3 ana q is

5, or R2 is one of

where R4 is COOH or a salt thereof and is substituted at the 3 or 4 position, most preferably the 3 position. Preferred compounds include pharmaceutically acceptable salts thereof as well, provided such salts can be prepared from a given compound. The most preferred compounds are:

2-(2-hydroxypentane-5-carboxylate)-7- (1-hydroxynonyl)- quinoline;

2-(6-carboxy-l-pentenyl)-7-(1-hydroxynonyl)quinoline; 2-(6-carboxy-l-ρentyl)-7-(1-hydroxynonyl)quinoline; 2- (2, 6-dihydroxy-n-hexyl)-7-(1-hydroxynonyl)quinoline; 3-[l-hydroxy-2-[7-(1-hydroxynonyl)-2-quinolinyl]ethyl]- benzoic acid;

3-[l-hydroxy-2-[7-[l-hydroxy-5-(4-methoxyphenyl)- pentyl]-2-quinolinyl]ethyl] benzoic acid;

4-[l-hydroxy-2-[7-[l-hydroxy-5- (4-methoxyphenyl)- pentyl]-2-quinolinyl]ethyl] benzoic acid; 3-[2-[7-(1-hydroxynonyl)-2-quinolinyl]ethyl]benzoic acid;

3-[l-thia-2- (7-(1-hydroxynonyl)-2-quinolinyl)- ethyl]benzoic acid;

4-[ [ [7-(1-hydroxynonyl)-2-quinolinyl]methyl]- sulfinyl]benzoic acid; and

7-(1-hydroxynonyl)quinoline-2-carboxylic acid.

Synthes-is

These compounds may be made by the starting materials, intermediates and reagents set out in the reaction flow charts given below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are given only to illustrate the general case and are not intended to limit the chemistry illustrated thereby. Reagents, intermediates, temperatures, solvents, reaction times, work-up procedures, all may be varied to accommodate differences in the processes needed to optimize the particular conditions for making a given . will not require more than minimal experimentation to optimize conditions and reagents for a particular step.

Scheme I illustrates a method for making useful intermediates and for converting them into several of the compounds of this invention.

Scheme I

The 7-methylquinoline is known. It is oxidized to the aldehyde 2 by means of an oxidizing agent, for example by using selenium dioxide at elevated temperature. Compounds of 3 are prepared from the aldehyde by means of a Grignard reagent employing the appropriate 1-haloalkane needed to form 3. The alcohol group is then protected (4) by some means such as that of a silyloxy group. In this instance the preferred silyloxy group is t-butyldimethylsilyloxy. Preferred starting material, the reagent used to form the silyloxy adduct, is t-butyldimethylsilyltri- fluoromethansulfonate. Compounds of 4 are then methylated, (5) , by adding the protected alcohol to a cooled solution of methyllithium and tetramethylenediamine in an appropriate solvent (e.g. tetrahydrofuran) under an inert atmosphere, then allowing the solution to warm to ambient temperature. Air is then introduced into the reaction vessel after which oxygen is bubbled through the solution. These compounds (5) are then transformed to 6 by means of a reagent which forms a carbanion from the 2-methyl group (e.g. titanium chloride triisopropoxide) and base after which a w-formylalkanoic acid ester is added. Preferably these steps are carried out at reduced temperature (e.g -78°C) under an inert atmosphere. The silyloxy protecting group is then cleaved (HF-pyridine) to give the ester which is hydrolyzed with base to give the corresponding salt (7) , or the acid if the solution is acidified before recovering the product.

Compound 8 is derived from 6 by causing it to undergo loss of water, accomplished by means of treatment with ammonium chloride at about room temperature followed by removal of the silyloxy protecting group on the 7-position substituent as well as the ester on the 2-position substituent. Catalytic hydrogenation gives the fully saturated side chain of quinoline 9. Compound 8 can also be prepared by treating 6 with tetrabutylammonium fluoride through an initial lactone formation followed by elimination and opening the lactone to give the corresponding acid (8) . hydroxyl group of an a,w-alkanediol, then oxidizing the other hydroxyl group to the aldehyde. For example 1,5- pentane-diol is treated with a siloxane such as t- butyldiphenylsilyl chloride under conditions which form 5-t- butyldiphenlylsilyloxy-1-pentanol. An oxidizing agent is then used to prepare the corresponding aldehyde. For example a chromate such as pyridinium chlorochromate may be used, the reaction being carried out under an inert atmosphere such as argon for a time sufficient to effect the reaction. This aldehyde is then added to a solution of 5 to which has been added a base such as n-butyl lithium. In this reaction, reagents are usually added at reduced temperature, e.g. -78°C, under an inert atmosphere, then the solution is allowed to warm to about room temperature after which the product is isolated. This process gives 10.

A second method for making certain of these compounds is illustrated by the sequence of steps set out in Scheme

II . Scheme II

_L,+

To form the triflate 11, one first prepares the necessary triflurormethylsulfonyl-substituted benzaldehyde from the corresponding hydroxybenzaldehyde and N- phenyltrifluoromethane sulfonimide. This triflate is then added to an already prepared solution of 5 to which has been added n-butyl lithium. Reduced temperature (e.g. -78°C) and an inert atmosphere are used to mix the reactants and to affect the reaction, though the temperature may be increased after the triflate is added. A triflate can be converted to an ester by bubbling carbon monoxide through a solution of the triflate in the presence of Pd(0Ac)2 and 1,1- bis (diphenylphosphino)propane. Fluoride anion is then used to remove the protecting group (tetrabutylammonium fluoride) and the salt is obtained by saponifying the ester with a base such as lithium hydroxide. The other chemistries illustrated in Scheme II use the same type of reagents and processes described in Scheme I for introducing the 7- position substituent, except that the specific reagents are changed to match the substituent being introduced. Introducing the 2-, 3-, and 4- (1-hydroxyethyl)benzoic acid group tracks the same chemistries as are described for making 12, 14 and 16.

Yet another process for making certain of these compounds, starting with an intermediate prepared in Scheme I is illustrated in Scheme III.

Scheme III

Compounds 19 and 20 are made by first introducing the 7-position group as described Schemes I and II, then protecting the hydroxyl group. At this point, the N-oxide 17 is prepared; an oxidizing agent such as m-chloroperbenzoic acid can be employed. This N-oxide is treated with an amine and trifluoroacetic anhydride as a means for introducing an -OH group at the 2 position. A triflate is then formed (18) using conditions similar to those described in Scheme II. From this triflate, 19 can be made by adding methyl-3-ethynylcarboxylate to a solution of the triflate, then introducing bis (triphenylphosphine)- palladium (II) chloride and copper iodide. This reaction can be carried out at room temperature under an inert atmosphere. Catalytic hydrogenation is used to reduce the ethynyl group after which 20 is prepared as before by first removing the silyloxy protecting group and then hydrolyzing the ester with an alkali metal base . The acid can be prepared instead of the salt by acidifying the solution following the saponification reaction.

An additional set of chemistries for making yet another of the sub-set of compounds disclosed herein is illustrated in Scheme IV.

Scheme IV

n = 0,1 ,2

_Li+

The first two compounds illustrated here are made by the methods described in the preceding Schemes. A reducing agent is used to reduce the ester 21 to the aldehyde 22. For example, di-isobutyl aluminum hydride can be employed using standard conditions for this reagent. To form 23, the aldehyde 22 is treated with a reducing agent such as sodium borohydride using standard conditions. Converting the alcohol to the bromide (24) is effected using carbon tetrabromide and (Ph)3P. This reaction is carried out at about 0°C. The mercapto group is introduced by treating 24 with a mercaptobenzoate in an inert solvent. The reaction can be carried out at a slightly reduced temperature, such at between about -10° to +10°C. As before, the protecting group on the 7-position substituent is then removed and the ester on the benzene ring may be hydrolized with base to recover the salt or, the solution is acidified, the free acid. A mild oxidizing reagent such as m-chloroperbenzoic acid can be use to oxidize the thio ether to the corresponding sulfinyl or sulfonyl forms. The acid salt 27 can be made by treating 21 with a base to hydrolyze the ester. The salt is obtained unless the solution is acidified, which gives the free acid. Formulations

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

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

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

For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension. For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, paste, and drops suitable for administration to the skin, eye, ear, or nose. will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.

Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. When employed in this manner, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 100 mg to about 5000 mg.

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

Included within the scope of this disclosure is the method of treating a disease mediated by LTB4 which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the symptoms of an allergic response resulting from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth. Pharmaceutical compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction. Representative Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines (diphenhydramine) , ethylenediamines (pyrilamine) , the alkylamines (chlorpheniramine) , the piperazines (chlorcyclizine) , and the phenothiazines (promethazine) . Hi blockers such as 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] -5- [ ( 6- methylpyrid-3-yl) ethyl ] -4-pyrimidone are particularly useful in this aspect of the invention .

Bioassays

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

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

U937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee [SmithKline & French (SK&F), Dept. of Immunology] and grown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2, 95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with di ethylsulfoxide to monocyte-like cells, the cells were seeded at a concentration of 1 x 105 cells/ml in the above medium with 1.3% dimethylsulfoxide and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 106 cells/ml and were harvested by centrifugation at 800 x g for 10 min.

Preparation of U937 Cell Membrane Enriched Fraction

Harvested U937 cells were washed with 50mM Tris-HCl, pH 7.4 @ 25°C containing lmM ethylenediaminetetraacetic acid (buffer A) . Cells were resuspended in buffer A at a concentration of 5 x 10^ cells/ml and disrupted by nitrogen cavitation with a Parr bomb at 750 psi for 10 min. at 0°C. The broken cell preparation was centrifuged at 1,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°C. Binding of T-^HI-L B^ to U397 Membrane Receptors

[³H]-LTB4 binding assays were performed at 25°C, in 50mM Tris-HCl (pH 7.5) buffer containing lOmM CaCl2, 10mM MgCl2, [³H]-LTB4, U937 cell membrane protein (standard conditions) in the presence (or absence) of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [³H]-LTB4 were determined in the absence or presence of 2μM of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding. The radioligand competition experiments were performed, under standard conditions, using approximately 0.2nM [³H]-LTB4, 20-40μg of U937 cell membrane protein, increasing concentrations of LTB4 (O.lnM to lOnM) or other competing ligands (O.lμM to 30μM) in a reaction volume of 0.2ml and incubated for 30 minutes at 25°C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrance bound radioactivity on the filters was determined by liquid scintillation spectrometry.

Saturation binding experiments for U937 cells were performed, under standard conditions, using approximately 15-50μg of U937 membrane protein and increasing concentrations of [³H]-LTB4 (0.02-2.0 mM) in a reaction volume of 0.2ml and incubation at 22°C, for 30 minutes. LTB4 (2|iM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard. Uptake of Fura-2 by Differentiated U937 Cells

Harvested cells were resuspended at 2 x 10 cells/ml in Krebs Ringer Hensilet buffer containing 0.1% BSA (RIA grade), l.lmM MgS04, l.OmM CaCl2 and 5mM HEPES (pH 7.4, buffer B) . The diacetomethoxy ester of fura-2 (fura-2/AM) was added to a final concentration of 2μM and cells incubated in the dark for 30 minutes at 37°C. The cells were centrifuged at 800 x g for 10 minutes and resuspended at 2 x 106 cells/ml in fresh buffer B and incubated at 37°C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 10^ cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements. Fluorescent Measurement-. Calcium Mobilization

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

U937 cells were diluted with fresh buffer to a concentration of 1 x 106 cells/ml and maintained in the dark on ice. Aliquots (2ml) of the cell suspension were put into 4ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min) . Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2μl aliquots.

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

[Ca²+]i = 224{E __JIl__I.} {Fmax-F } F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with lOμl of 10% Triton X-100 (final Concentration 0.02%) . After F_max was determined 67μl of lOOmM EDTA solution (pH 10) was added to totally chelate the Ca²⁺ and quench the fura-2 signal and obtain the Fmin . The [Ca²⁺]i level for lOnM LTB4 in the absence of an antagonist was 100% and basal [Ca²⁺]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the lOnM LTB4 induced [Ca²⁺]i mobilization. The EC50 for LTB4 induced increase in [Ca²⁺]i mobilization was the concentration for half maximal increase. The Ki for calcium mobilization was determined using the formula:

IC50

Ki =

[LTB4]

1+ [EC50]

With the experiments described, the LTB4 concentration was lOnM and the EC50 was 2nM. Several of the compounds of this invention were tested in one or more of the aforementioned assays. The range of values for the compounds in the Examples is given in Figure III.

Figure III

Binding , IC 1-. (Kj) , IM Ca-Mobilization j±tø

U-937 PMN U-937 PMN Membrane

Whole Cell Whole cell IQ5&, IM % Agonist IZ5Q_., m

RangβO.12-25 0.02-36 0.045-31

Examples The following are a set of examples which 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 by this document. Example 1 Preparation of 7- ( -hγdroxypentane-5-r.arboxy1ate.-7- (1- hydroxynonyl.quinoline. lithium salt 1A. 7-Formy1φ.inol ne. 7-Methylquinoline (26.Og, O.lδmol) was heated to 160°C and selenium dioxide (13.Og, 0.117mol) was added. The reaction mixture was maintained at 150 - 155°C for 12 hr and then cooled to room temperature, diluted with CH2CI2, and filtered. Hexanes were added to the filtrate and the resulting precipitate was filtered and washed with hexanes. The combined organic filtrates were concentrated in vacuo and the residue was purified by flash column chromatography (silica, 15 - 30% ethyl acetate/hexanes) to afford the aldehyde. ---H NMR (90 ME_Z, CDCI3) : δ 7.5 (dd, IH, 5-quinolinyl), 7.9 (d, IH, 6- quinolinyl, 8.05 (dd, IH, 3-quinolinyl), 8.2 (br d, IH, 4- quinolinyl) , 8.55 (s, IH, 8-quinolinyl) , 9.05 (dd, IH, 2- quinolinyl) , 10.2 (s, IH, CHO) .

____ 7-fl-Hγdroxγnonyl .qninol ins. 1-Bromooctane (5.9g,

30.5mmol) was added to magnesium turnings (0.9g, 37.0mmol) in tetrahydrofuran (40ml) while maintaining a gentle reflux during the addition. When the magnesium was dissolved, the solution was cooled to -15cC, and 7-formylquinoline (4.0g, 25.5mmol) dissolved in tetrahydrofuran (20ml) was added while maintaining the temperature at -15°C. When addition was complete, the reaction mixture was warmed to room temperature, H2O was added, and the reaction mixture was partitioned between H2O and ethyl acetate. The organic extract was washed with H2O, NaCl (sat) , and dried (Na2Sθ4) . Purification by flash column chromatography (silica, 5% ethyl acetate in hexane) afforded 4.2g of the hydroxyquinoline. Recrystallization from hexanes gave the desired product as an off-white crystalline solid: ^H NMR (90MHz, CDCI3) : δ 0.9 (t, 3H, aliphatic), 1.25 (br, 12H, aliphatic), 1.65 - 2.0 (m, 2H, aliphatic), 2.9 (br s, IH, OH), 4.9 (br t, IH, CHOH), 7.35 (dd, IH, 5-quinolinyl), 7.6 (dd, IH, 6-quinolinyl) , 7.8 (d, IH, 3-quinolinyl), 8.0 (br s, IH, 8-quinolinyl), 8.15 (dd, IH, 4-quinolinyl) , 8.85 (dd, IH, 2-quinolinyl). Anal., calc. for C18H25NO: C 79.66, H 9.29, N 5.16; found: C 79.34, H 9.34, N 5.03. - - - . . - -

Hydroxy-nonyl)quinoline (4.0g, 14.8mmol) was mixed with CH2CI2 (60ml), cooled to -10°C, 2,6-lutidine (4.3ml, 3.95g,

37.0mmol) added, followed by the dropwise addition of t- butyldimethylsilyltrifluoro-methanesulfonate (4.29g,

16.2mmol) . The resulting solution was allowed to warm to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with NaHC03 (aq) , H2O, NaCl (sat) and dried (Na2S04) . Purification by flash column chromatography (silica, hexane) afforded the protected hydroxyquinoline. IH, 7-ιl-t-B.ιtyldirnethγlsilγloxynonγl. -2-methylquinoline.

Tetramethylethylenediamine (4.5ml, 29.8mmol) and tetrahydrofuran (100ml) were cooled to 0°C under an argon atmosphere and methyl lithium (1.4M, 21.4ml, 30.0mmol) was added. After stirring several minutes at 0°C, 7-(l-t- butyldimethylsilyloxy-nonyl)quinoline (3.85g, 2.60mmol) dissolved in tetrahydrofuran (75ml) was added dropwise and the reaction mixture warmed to room temperature and then exposed to air. Oxygen was bubbled into the solution for 1 hr, and the mixture partitioned between H2O and ethyl acetate. The organic layer was separated and washed with H2O, NaCl (sat) and dried (Na2S04) . Purification by flash column chromatography (silica, 2% ethyl acetate/hexane) afforded the titled product.

U Titanium chloride triisopropo ide. Titanium tetra- isopropoxide (23.66g, O.Oδmol) was cooled to 0°C under an argon atmosphere and titanium tetrachloride (5.28g, 0.03mol) was added over a 5 min period and then warmed to room temperature. Purification was achieved by distillation (10.5 torr) collecting the product fraction between 95 - 100°C. The desired product crystallized on standing.

IΣ-, 7-(l-t.-Butyldimethylsilyloxynonyl)-2-(2-hydroxyl-5- carbomethoxypentyl)quinoline. To a flame-dried flask containing n-butyl lithium (2.5M 0.13ml, 0.33mmol) dissolved in tetrahydrofuran (2ml) and cooled to -78°C was added of 7-

(1-t-butyl-dimethyl-silyloxynonyl)-2-methylquinoline (lOOmg, 0.25mmol) dissolved tetrahydrofuran (2ml). After stirring for 20 min at -78°C, titanium chloride triiisopropoxide (79mg, 0.30mmol) dissolved in tetrahydrofuran (2ml) was added and the mixture stirred for 2.5h at -78°C. To this reaction mixture, methyl 4-formylbutanoate (40mg, 0.31mmol) dissolved in tetrahydrofuran (2ml) was added and the mixture stirred for lh at -78°C. The reaction mixture was warmed to room temperature, stirred for 12h, cooled to -78°C and quenched with H2O. The reaction mixture was partitioned between H2O and ethyl acetate, the organic layer separated, washed with NaCl (sat) and dried (MgSθ4) . Purification by flash column chromatography (silica, 1 - 10% ethyl acetate/hexane) afforded the product: ¹H NMR (90MHz, CDCI3) : δ 0.25 (s, 6H, CH3SD, 1.15 (s, 9H, t-BuSi) , 0.85 - 2.2 ( , 21H, aliphatic), 2.56 (m, 2H, CH2CO2CH3) , 3.05 (dd, IH, CH quinolinyl), 3.28 (d, IH, ) , 3.8 (s, 3H, CH3CO2) , 4.35 (m, IH,), 4.95 (br t, IH) , 5.9 (br s, IH) , 7.35 (d, IH, 5- quinolinyl), 7.66 (dd, IH, 6-quinolinyl) , 7.9 (d, IH, 3- quinolinyl) , 7.96 (br s, IH, 8-quinolinyl), 8.2 (d, IH, 4- quinolinyl) ; MS (m/e, rel. int.): 73 (100), 530 (98). L___- 2-(2-Hydroxy-5-c.arbomethoxypentyl. -7- (l-hvdroxγnonγl)- quinoline. 7-(1-t-Butyldimethylsilyloxynonyl)-2-(2- hydroxyl-5-carbomethoxypentyl)quinoline (lOO g, 0.19mmol) was mixed with CH3CN (11ml) and a solution of HF-pyridine (1.1ml) was added. The resulting mixture was stirred at room temperature under an argon atmosphere for 20 min, the solvent was concentrated, and the residue was purified by flash column chromatography (silica, 5% CH3OH/CH2CI2) to afford the product as a yellow oil. ¹H NMR (250MHz, CDCI3) : δ 0.82 (t, 3H, CH3 aliphatic), 1.1 - 1.95 (m, 18H, aliphatic), 2.48 (t, 2H, CH2CO2CH3) , 2.97 (dd, IH, CH- quinolinyl) , 3.08 (br dd, IH, CH-quinolinyl) , 3.65 (s, 3H, CH3O2C) , 4.19 (m, IH, CHOH), 4.85 (t, IH, CHOH), 7.20 (d,

IH, 5-quinolinyl), 7.53 (dd, IH, 6-quinolinyl), 7.75 (d, IH, 3-quinolinyl), 7.90 (br s, IH, 8-quinolinyl), 8.05 (d, IH, 4-quinolinyl) . Anal., calc. for C25H37NO •1/8 H2θ: C 71.87, H 8.99, N 3.35; found: C 71.59, H 8.59, N 3.21. IH. 2-(2-Hydroxypentane-5-carboxγlate)-7-1l-hvdroxvnonyl)- quinoline. lithium salt.

2-(2-Hydroxy-5-carbomethoxypentyl)-7-(1- hydroxynonyl)quinoline (60mg, 0.14mmol) was dissolved in 1:1 tetrahydrofuran/H2θ (2ml) and lithium hydroxide monohydrate (31mg, 0.74mmol) was added. The resulting. reaction mixture , MPLC (RP-18 silica, 0-70% CH3OH/H2O) and the product fractions combined and lyophilized to afford the captioned product: ¹H NMR (250MHz, CD3OD) : δ 0.85 (t, 3H, CH3 aliphatic), 1.15 - 1.95 (m, 18H, aliphatic), 2.16 (t, 2H, CH2CO2 Li), 3.02 (dd, IH, CH quinolinyl), 3.11 (dd, IH, CH quinolinyl), 4.10 (m, IH, CHOH), 4.80 (t, IH, CHOH), 7.44 (d, IH, 5-quinolinyl), 7.55 (dd, IH, 6-quinolinyl), 7.85 (d, IH, 3-quinolinyl), 7.90 (s, IH, 8-quinolinyl), 8.22 (d, IH, 9-quinolinyl) ; MS (m/e, rel. int.): 402 (100).

Example 2

Preparation of 2- (6-carboxy-l-pentenγl. -7- .1- hydroxynony.l.quinoline and 2- (fi- arboxy-l-pentyl. -1- ( 1 - hydroxynonyl. quinoline

2__- 7- π- -Bntyldiιrιethylsilyloxynonγ1 ) -7- (fi-f.arhnxy-1- pentenyl . -quinoline. To a flame-dried flask containing n- butyl lithium (2.5M, 0.56 ml, 1.4mmol) in tetrahydrofuran (2ml) cooled to -78°C under an argon atmosphere, was added 7- (1-t-butyldimethylsilyloxynonyl)-2-methyl quinoline (0.5g, 1.25mmol) dissolved in tetrahydrofuran (10ml). After stirring for 20 min at -78°C, titanium chloride triisopropoxide (0.36g, 1.38mmol) dissolved in tetrahydrofuran (4ml) was added and the mixture stirred for 2.5h maintaining the temperature at -78°C. Methyl 4- formylbutanoate (0.18g, 1.36mmol) dissolved in tetrahydrofuran (3ml) was added and the mixture stirred for an additional lh. The solution was warmed to room temperature, stirred for 12h, treated with ammonium chloride, and then partitioned between H2O and ethyl acetate. The organic layer was separated and washed with NaCl (sat) and dried (MgSθ4) . Purification by flash column chromatography (silica, 2% CH3OH/CH2CI2) afforded the captioned product: MS (m/e, rel. int.): 257 (26), 364 (20) 366 (98), 367 (24), 384 (23), 440 (55), 482 (42), 496 (23), 498 (100) . 2B. 2- .6-Carboxγ- -pentenyl. -7- (1-hvdroxvnonvl. quinolins.

7- (1-t-Butyldimethylsilyloxynonyl)-2- (6-carboxy-l- pentenyl)quinoline (lOOmg, 0.20mmol) was dissolved in tetrahydrofuran (1ml) and cooled to 0°C. To this solution was added tetrabutylammonium fluoride (1M in tetrahydrofuran, 1.0ml, l.Ommol) and the resulting solution stirred for 5 min at 0°C and warmed to room temperature.

After stirring at room temperature for 8h, the mixture was partitioned between H2θ and ethyl acetate, the organic layer separated and washed with NaCl (sat) and dried (Na2Sθ4) . Purification by flash column chromatography (silica, 5% CH3OH/CH2CI2) afforded the desired product as a white crystalline solid: MS (m/e, rel. int.): 366 (71), 382 (20), 384 (100) .

Anal.. calc. for C24H33N03-1/2 H2O: C 73.44, H 8.73, N 3.57; found: C 73.54, H 8.99, N 3.70. 2_-__ 2-(6-Carboxy-l-pentyl. -7-f1-hydroxynonyl.quinoline.

2-(6-Carboxyl-l-pentenyl)-7-(1-hydroxynonyl)quinoline (18mg, 0.03mmol) dissolved in ethanol (3ml) was added Pd/C (5%, 20mg) and the mixture hydrogenated on a Parr hydrogenator (60 psi, H2) for 2h. The solvent was concentrated and the residue was dried to afford the product:. NMR (250MHz, CD3OD) : δ 0.87 (br t, 3H, CH3 aliphatic), 1.02 (t, 2H, aliphatic), 1.15 - 1.55 (m, 14H, aliphatic), 1.55 - 1.95 (m, 4H, aliphatic), 2.25 (t, 2H, CH2CO2H) , 2.95 (t, 2H, CH2 quinolinyl), 4.8 (t, IH, CHOH), 7.4 (d, IH, 5-quinolinyl), 7.56 (dd, IH, 6-quinolinyl), 7.85 (d, IH, 3-quinolinyl), 7.91 (br s, IH, 8-quinolinyl), 8.2 (d, IH, 4-quinolinyl) ; MS (m/e, rel. int.): 143 (41), 298 (28), 342 (50), 386 (100) .

Example 3

Preparation of 2- ( 2 .6-dihydroxy-n-hexγl . -7- ti -hydroxy- n-nonyl)quinoline

3A. 5-t-B.ιtylriiphenyls.i 1yloxy-1-pentanol. To a solution of

1,5-pentane-diol (2.0g, 19.2mmol) dissolved in dimethylformamide (DMF, 5ml) and cooled to 0°C was added t- butyldiphenylsilyl chloride (5.28g, 19.2mmol) and imidazole (1.96g, 28.8mmol). The resulting solution was warmed to room temperature and was stirred until the reaction was completed (tic) . The mixture was partitioned between ethyl acetate and H2O and the organic extract was separated and washed with H2O, NaCl (sat) and dried (Na2Sθ ) . Purification by flash column chromatography (silica, 5% e y ace a e exane gave e mono-s y a e ma er a . NMR (250MHz, CDCI3) : δ 1.05 (s, 9H, t-BuSi) , 1.3 - 1.67 (m,

5H, aliphatic), 3.61 (br t, 2H, CH2OH) , 3.69 (t, 2H, CH20Si) , 7.4 (m, 6H, aromatic), 7.68 (m, 4H, aromatic) . -3_B_, 5-t-Butvldiρhenvlsilvloxvpentanal.

5-t-Butyldiphenylsilyloxy-l-pentanol (l.Og, 2.92mmol) was dissolved in CH2CI2 (10ml) under an argon atmosphere and treated with pyridinium chlorochromate (1.26g, 5.84mmol) . The resulting mixture was stirred at room temperature for 24h, and then filtered through Celite. The filtrate was triturated with hexanes and filtered again. The solvent was concentrated and the residue purified by flash column chromatography (silica, 2% ethyl acetate/hexane) to give the desired aldehyde. _2£L, 2- (6-t-Butvldiphenvlsilvloxv-2-hvdroxy-n-hexyl. -7- d-t- butvldimethvlsilyloxy-n-nonvl) σuinoline. To a flame-dried flask containing ..-butyl lithium (2.5M, 0.22ml, 0.55mmol) and tetrahydrofuran (2ml) and cooled to -78°C under an argon atmosphere was added 7- (1-t-butyldimethylsilyloxynonyl) -2- methylquinoline (200mg, 0.50mmol) dissolved in tetrahydrofuran (3ml) . The resulting red solution was stirred for 20 min at -78°C, and 5-t- butyldiphenylsilyloxypentanal (187mg, 0.55mmol) dissolved in tetrahydrofuran (3ml) was added at once. After stirring for 20 min at -78°C, the solution was warmed to room temperature, ammonium chloride was added, and the mixture was partitioned between ethyl acetate and H2O, the organic layer separated and washed with NaCl (sat) and dried (Na2S04) . Purification by flash column chromatography (silica, 1 - 5% ethyl acetate/hexane) afforded the desired material.

211_* 2-(2,6-Pihydrpχy-n-hexyl)-7-(i-hydrpχy-n- nonyl)quinoline.

2- (6-t-Butyldiphenylsilyloxy-2-hydroxy-n-hexyl) -7- (1-t- butyldimethylsilyloxy-n-nonyl) quinoline (200mg, 0.27mmol) was dissolved in tetrahydrofuran (2ml) , cooled to 0°C, and treated with tetrabutylammonium fluoride (1M in THF, 1.1ml, l.lmmol) . The reaction mixture was warmed to room temperature, stirred for 48h, partitioned between H2O and ethyl acetate, separated and the organic layer washed with H2O, NaCl (sat) and dried ( a2S0 ) . Purification by flash column chromatography (silica, 2% CH3OH / CH2CI2) gave the product as a white crystalline solid: ¹H NMR (90MHz, CDCI3) : δ - 0.7 - 2.1 (m, 23H, aliphatic), 2.65 (dd, IH, CH quinolinyl), 2.9 (d, IH, CH quinolinyl), 3.65 (m, 2H, CH20H) , 4.15 (m, IH, CHOH), 4.85 (br t, IH,), 7.2 (d, IH, 5- quinolinyl) , 7.5 (br d, IH, 6-quinolinyl), 7.75 (d, IH, 3- quinolinyl), 7.9 (br s, IH, 8-quinolinyl), 8.05 (d, IH, 4- quinolinyl) . Anal.. calc. for C24H37N03"3/4 H2O: C 71.87, H 9.68, N 3.49; found: C 71.80, H 10.02, N 3.74.

Example 4 Preparation of 3-ri-hγdroxγ-2-T7- .1-hγdroxvnonγl. -2- qπinolinynethyl1benzoic acid, lithium salt: 4A. 3-(Trifluoromethylsulfonyl.benzaldehyde. 3-Hydroxy- benzaldehyde (0.5g, 4.0mmol, Aldrich) was dissolved in dry DMF (2ml) and treated with sodium hydride (60% oil dispersion, 0.19g, 4.4eq). To this was added dropwise a solution containing N-phenyltrifluoro-methane sulfonimide (1.75g, 4.9mmol, Aldrich) in dry tetrahydrofuran (10ml). The reaction mixture was stirred at room temperature for

12h. Ethyl acetate (50ml) was added to the reaction mixture and the resulting mixture washed with H2O, NaCl (sat.) and dried (Na2Sθ4) . The compound was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) to give the product: ¹H NMR (250MHz, CDCI3) δ 10.05 (s, IH, CHO) ,

8.0 (d, IH, aromatic), 7.80 (d, IH, aromatic), 7.65 (t, IH, aromatic), 7.55 (dd, IH, aromatic).

-£_-__ 3-n-Hydroxy-2- π-(1-t-butyldimethylsilyloxynonyl)-2- quinolinyl1ethyl1benzene tri luoromethylsulfonate. 7-(l-t- Butyl-dimethylsilyloxynonyl)-2-methylquinoline (250mg, 0.6mmol) was dissolved in tetrahydrofuran (2ml). This solution was added dropwise to a solution of n-BuLi (0.22ml, 0.66eq, 2.5M in tetrahydrofuran) in tetrahydrofuran (2ml) under argon at -78°C. The resulting purple reaction mixture was stirred for an additional lh followed by the addition of 3-(trifluoromethylsulfonyl)-benzaldehyde. The light yellow reaction mixture was stirred at -78°C for lh, allowed to warm to 0°C and stirred for an additional lh. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, NaCl (sat) and dried (Na2Sθ ) . The product was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) to give the product: ¹H NMR (250MHz, CDCI3) δ 8.1

(d, IH aromatic), 8.0 (s, IH, aromatic), 7.8 (d, IH, aromatic), 7.7-7.1 (m, 6H, aromatic; quinolinyl), 5.4 (m, IH, methynyl), 4.9 (t, IH, CHOSi) , 3.3 (d, 2H, CH2 quinolinyl), 1.8-1.3 (m, 17H, aliphatic), 0.9 (m, 9H, t- butyl), 0.1 (s, 3H, CH3Si) , -0.1 (s, 3H, CH3Si) .

ΛΩ-. 3- ri-Hydroxγ-2- T7- tl-hydroxynonyl. -2-qninolinyl. - ethyllbenzoic acid. A solution containing the triflate prepared above (180mg, 0.2mmol), DMSO (1ml), MeOH (1ml), Et3N (8.4μl, 2.2eq), Pd(OAc)2 (2.2mg, 0.04mmol) and

1, 1-bis (diphenylphosphino)propane (4.2mg, 0.06mmol) was saturated with CO and stirred at 70°C for 32h. The reaction mixture was diluted with ethyl acetate and washed with water, NaCl (sat) and dried ( a2Sθ4) . The product was purified by flash column chromatography (silica, ethyl acetate in hexane: 100ml of 2%, 200ml of 3%, 100ml of 4% and 300ml of 5%) to give methyl 3-[l-hydroxy-2-[7-(1-t- butyldimethylsilyloxynonyl)-2-quinonyl]-ethyl]benzoate.

The ester was dissolved in tetrahydrofuran (1ml) under an argon atmosphere, cooled to 0°C, and treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, 210μl, 2.2 eq) . Following the addition, the cooling bath was removed and the reaction was stirred at room temperature for 3h. The reaction solution was diluted with ethyl acetate and washed with water, NaCl (sat) and dried (Na2S04) . Flash column chromatography (silica, CH2CI2) gave the desired product. The methyl ester was dissolved in tetrahydrofuran (lml)-methanol (2 drops)-water (1ml) and LiOH (lO g) was added. The reaction was stirred at room temperature for 24h and the product purified by MPLC chromatography (RP-18 reversed phased silica, 70:30 MeOH:H2θ) to give a lyophilized solid: ¹H NMR (250MHz, CD3OD) : δ 8.15 (d, IH, aromatic), 8.07 (s, IH, aromatic), 7.98 (s, IH, quinolinyl), 7.8 (m, 2H, quinolinyl), 7.6 (d, IH, aromatic), 7.4 (d, IH, aromatic), 7.3 (m, 2H, quinolinyl), 5.3 (m, IH, CHOH), 4.8 (m, IH, CHOH), 3.4 (d, 2H, CH2 quinolinyl), 1.8-1.3 (m, 14H, aliphatic), 0.99 (m, 3H, aliphatic); MS (FAB): 436 (M+H) . Example 5 Preparation of 3- i^~1-Hγdroxy-2- \ 1- M -hγdroxy-5- (4- methoxyphenyl .pentyll-2-quinolinγn ethyl1benzoic acid. lithium salt. _52 7- α-Hydroxy-5- (4-methoxγphenγl. pentyl. quinoline.

7-Formyl-quinoline (0.3g, 2mmol) was dissolved in dry tetrahydrofuran (5ml) under an argon atmosphere and cooled to -15°C. To this solution was added 4-(p- methoxyphenyl)butyl-l-magnesium bromide (prepared from 0.56g of 4- (p-methoxy-phenyl)butyl-l-bromide and 70mg (Mg) dissolved in tetrahydrofuran (20ml) dropwise maintaining the temperature at -15°C. After stirring for 20 min the cooling bath was removed and the reaction allowed to come to room temperature, quenched with water, extracted with ethyl acetate and the organic layer washed with water, NaCl (sat) and dried (Na2S04) . The product was purified by flash column chromatography (silica, 5% ethyl acetate in hexane) gave the product: ¹H NMR (250MHz, CDCI3) : δ 8.9 (dd, IH, 2- quinolinyl) , 8.13 (dd, IH, 4-quinolinyl) , 8.08 (s, IH, 3- quinolinyl), 7.8 (d, IH, 5-quinolinyl), 7.6 (dd, IH, 6- quinolinyl) , 7.4 (dd, IH, 3-quinolinyl), 7.1 (d, 2H, aromatic), 6.8 (dd, 2H, aromatic), 4.9 (t, IH, CHOH), 3.8 (s, 3H, OCH3) , 2.5 (t, 2H, CH2C6H5), 1.8-1.4 (m, 6H, aliphatic). Anal., calc for C21H23NO2: C 78.47, H 7.21, N 4.36; found: C 78.56, H 7.25, N 4.42.

5B. 7-ι-1-t-Butγldimethγlsilyloxy-5-(4- methoxyphenyl)pentyl. -quinol ne. 7-(l-Hydroxy-5-(4- methoxyphenyl)pentyl)quinoline was dissolved in CH2CI2 (30ml) under an argon atmosphere and cooled to -10°C and 2, 6-lutidine (1.7ml, 14.8mmol, 2.5eq) was added. To this solution t-butyldimethylsilyltriflate (1.63ml, 7.1 mmol, 1.2eq) was added dropwise. After addition was completed, the cooling bath was removed and the solution stirred at room temperature until the reaction was complete. The reaction mixture was washed with NaHC03, water, NaCl (sat) and dried (Na2Sθ4) . The product was purified by flash column chromatography (silica, hexane) to afford the triflate. 5C. 7-(1-t-Bπtγlsilyloxy-5-(4-methoxyphenvl)pentyl . -7- methyl uinoline. Tetramethylethylenediamine (2.2ml, l4.4mmol) in tetrahydrofuran (40ml) under an argon atmosphere was cooled to 0°C and treated with methyl lithium

(1.4M in hexane, 13.1ml, 14.4mmol). After stirring for several minutes at 0°C, a solution containing 7-(l-t- butyldimethylsilyloxy-5-(4-methoxyphenyl)pentyl)quinoline (2.1g, 4.8mmol) and tetrahydrofuran (40ml) was added dropwise and the resulting reaction mixture was warmed to room temperature and exposed to air. Oxygen was bubbled into the solution for lh, and the mixture was then partitioned between H2O and ethyl acetate. The organic extract was washed with water, NaCl (sat) and dried ( a2S0 ) . The product was purified by flash chromatography

(silica, 2% ethyl acetate in hexane) to afford the methyl quinoline: ¹H NMR (250MHz, CDCI3) : δ 8.08 (d, IH, 8- quinolinyl), 8.0 (d, IH, 4-quinolinyl) , 7.8 (d, IH, 5- quinolinyl), 7.6 (dd, IH, 6-quinolinyl), 7.2 (d, IH, 3- quinolinyl) , 7.1 (d, 2H, aromatic), 6.8 (d, 2H, aromatic), 4.9 ( t, IH, CHOH), 3.8 (s, 3H, OCH3) , 2.6 (s, 3H, 2-CH3 quinolinyl), 2.5 (t, 2H, benzylic) , 1.8-1.4 (m, 6H, aliphatic), 0.9 (s, 9H, t-butylSi) , 0.3 (s, 3H, CH3Si) , -0.1 (s, 3H, CH3Si) .

J2____ 3-ri-Hγdroxγ-2-r7-ri-f.-butγlsilγloxv-5-.4- ethoxyphenyl. -pentyl1-2- -inolinyl 1ethy11benzene trifluoromethylsulfonate. 7- (l-t-Butylsilyloxy-5- (4- methoxyphenyl)pentyl)-2-methylquinoline (0.77g, 1.7mmol) was dissolved in tetrahydrofuran (15ml) and added to a solution containing n-BuLi (2.5M, 0.75ml, 1.leq) and tetrahydrofuran (7ml) that had been cooled to -78°C under an argon atmosphere. The reaction mixture was stirred for 20 min and then 3- (trifluoromethyl-sulfonyl)benzaldehyde (0.48g,

1.9mmol) dissolved in tetrahydrofuran (10ml) was added at once. The reaction was stirred at -78°C for 5 min, at 0°C for 20 min, warmed to room temperature and stirred for lh. The reaction was diluted with ethyl acetate (75ml) , washed with water, NaCl (sat) and dried (Na2Sθ ) ; flash column chromatography (silica, 0-8% ethyl acetate in hexane) gave the product: ---H NMR (250MHz, CDCI3) : δ 8.15 (d, IH, 4- quinolinyl) , 7.95 (s, IH, 8-quinolinyl), 7.8 (d, IH, 5- quinolinyl), 7.6-7.4 (m, 4H, aromatic), 7.2 (d, 2H, 3,6- quinolinyl), 7.1 (d, 2H, aromatic), 6.8 (d, 2H, aromatic). 5.4 (m, IH, CHOH), 4.9 (m, IH, CHOH), 3.8 (s, 3H, CH3O) , 3.3 (m, 2H, CH2 quinolinyl), 2.5 (t, 2H, benzylic) , 1.8-1.4 (m, 6H, aliphatic), 0.9 (s, 9H, t-BuSi) , 0.3 (s, 3H, CH3SD , -0.1 (s, 3H, CH3SD . 5E. 3- ri-Hyriroxγ-2- F7-Tl-hydroxy-5- (4- methoxyphenyl . pentyll-2-quinolinyl1 ethyl)be.n7.0ic ac d. lithium sal . 3-[l-Hydroxy-2-[7-[l-t-butylsilyloxy-5-(4- methoxyphenyl)pentyl]-2-quinolinyl]ethyl]-benzene trifluoromethylsulfonate (0.54g, 0.76mmol) was converted to the methyl ester by palladium catalyzed carbonylation as described in the preparation of methyl 3-[l-hydroxy-2-[7-(1- t-butyldimethyl-silyloxynonyl)-2-quinolinyl]ethyl]benzoate. Purification by flash column chromatography (silica, 5% and 10% ethyl acetate in hexane) afforded the desired product. The t-butyldimethylsilyl blocking group was removed as previously described to provide the diol after flash column chromatography (silica, 20% and 40% ethyl acetate in hexane) .

The methyl ester (250mg, 0.5mmol) was hydrolized (LiOH, tetrahydrofuran, MeOH, water) as previously described and purified by MPLC (RP-18 silica, 0-40% CH3OH, H2O) to afford a lyophilized solid: ---H NMR (250MHz, CD3OD) : δ 8.15 (d,

IH, 4-quinolinyl) , 8.0 (s, IH, 8-quinolinyl), 7.9 (s, IH, aromatic), 7.8 (d, 2H, 3,5-quinolinyl) , 7.6 (d, IH, aromatic), 7.4 (d, IH, aromatic), 7.3 (m, 2H, aromatic, 6- quinolinyl), 7.0 (d, 2H, aromatic), 6.7 (d, 2H, aromatic), 5.3 (t, IH, CHOH), 4.8 (t, IH, CHOH), 3.7 (s, 3H, CH3O) , 3.35 (m, 2H, CH2 quinolinyl), 2.5 (t, 2H, CH2C6H5) , 1.8-1.3 ( , 6H, aliphatic) . Anal. : calc. for C30H31NO5 • 2 1/2 H2O: C 67.91, H 6.83, N 2.64; found: C 67.95, H 6.64, N 2.36. xamp e

Preparation of 4-fl-hγdroxy-2-H-fl-hvdroxv-5- .4- methoxyphenvl..pentyl 1-2-quinolinγllethvllbenzoic acid. l thium salt. £ 4- .Trifluoromethyl ulfonyl.benzaldehyde. 4-Hydroxy- benzaldehyde (2g, 16mmol), tetrahydrofuran (40ml), NaH (60% dispersion in oil, 0.73g, l.leq), and N- phenyltrifluoromethane-sulfonimide (7g, 19.6mmol) dissolved in tetrahydrofuran (20ml) were reacted as described previously in the preparation of 3-

(trifluoromethylsulfonyl) enzaldehyde. .a..., 4-n-Hydroxy-2- \1-ri-t-butylsllylQ__y-5- (4- methoxyphenyl . -pentyl1-2-quinolinyl 1ethyl1 benzene trifluoromethylsulfonate... 7- (l-t-Butylsilyloxy-5- (4-methoxyphenyl)pentyl)-2- methylquinoline (0.33g, 0.73mmol) was dissolved in tetrahydrofuran (7ml) , treated with n-BuLi (3M in tetrahydrofuran, 0.32ml, l.leq) and 4- (trifluoromethylsulfonyl)benzaldehyde (0.21g, 0.82mmol) using the procedure described in the preparation above for 3-[l-hydroxy-2-[7-[l-t-butylsilyloxy-5-(4- methoxyphenyl)pentyl]-2-quinolinyl]ethyl]benzene trifluoromethylsulfonate to afford, after flash chromatography the desired product: -^LH NMR (250 MHz, CDCI3) : δ 8.1 (d, IH, 4-quinolinyl), 7.9 (s, IH, 8-quinolinyl), 7.75

(d, IH, 3-quinolinyl), 7.6 (m, 3H, 5-quinolinyl, aromatic), 7.25 (d, 2H, aromatic), 7.2 (d, IH, 6-quinolinyl), 7.1 (d, 2H, aromatic), 6.8 (d, 2H, aromatic), 5.4 (t, IH, CHOSi) , 4.8 (t, IH, CHOH), 3.8 (s, 3H, CH3O) , 3.3 (m, 2H, CH2 quinolinyl), 2.5 (t, 2H, CH2C6H5) , 1.8-1.3 (m, 6H, aliphatic), 0.9 (s, 9H, t-Bu) , 0.1 (s, 3H, CH3SD , -0.1 (s,

3H, CH3SD .

£_.__ 4-n-Hydrσxy-2- \1-n-hydroxy-5- (4- methoxyphenyl .pentyll-2-quinolinγl 1ethyllbenzoi r. acid. 1 ithium salt. 4-[l-Hydroxy-2-[7-[l-t-butylsilyloxy-5- (4- methoxyphenyl)pentyl]-2-quinolinyl]ethyl]-benzene trifluoromethylsulfonate (0.18g, 0.26mmol), dimethyl- sulfoxide (0.8ml), CH3OH (0.55ml), triethylamine (0.07ml), Pd(OAc)2 (1.75 mg) and 1,1-bis (diphenylphosphino)propane (3.2mg) were reacted as described above in the preparation of methyl 3-[l-hydroxy-2-[7-(1-t-butyl¬ dimethylsilyloxynonyl)-2-quinolinyl]-ethyl]benzoate to afford, after flash column chromatography, the desired product. This was treated with tetrabutylammonium fluoride to remove the silyl group and then hydrolyzed with LiOH as previously described to afford, after MPLC (RP-18 silica, 0- 40% CH3OH, H2O) and lyophilization of the product fractions, a white solid: NMR (250MHz, CD3OD) : δ8.2 (d, IH, 4- quinolinyl) , 7.9 (m, 4H, 3, 8-quinolinyl, aromatic), 7.6 (d, IH, 5-quinolinyl), 7.45 (d, 2H, aromatic), 7.42 (d, IH, 6- quinolinyl) , 7.1 (d, 2H, aromatic), 6.75 (d, 2H, aromatic), 5.2 (t, IH, CHOH), 4.8 (t, IH, CHOH), 3.7 (s, 3H, CH3O) , 3.3 (m, 2H, CH2 quinolinyl), 2.5 (t, 2H, CH2C6H5) , 1.8-1.3 (m, 6H, aliphatic); MS (FAB) 492 (M+H)⁺.

Example 7

Preparation of 3- \2-l^~7- (1-hydroxynonyl. -2-quinolinyl!ethvll benzoic acid, lithium salt 2A_÷ 7-(1-t-Butγl imethylsi1yloxynonyl . -2-hγdroxγquinol ine. 7- (1-t-Butyldimethylsilyloxynonyl)quinoline (1.35g,

3.5mmol) was dissolved in CH2CI2 (15ml), cooled to 0°C, and treated with _π-chloroperbenzoic acid (MCPBA, 80%, 0.8g, 3.5mmol) . The reaction was stirred for 12h and the reaction was gradually warmed to room temperature. The reaction was diluted with CH2CI2 (50ml) and washed with NaHC03, H2O, NaCl (sat) and dried (Na2Sθ4) . Purification by flash column chromatography (silica, CH2CI2 then 1% CH3OH in CH2CI2) afforded the N-oxide.

7-(l-t-Butyldimethylsilyloxynonyl)quinoline-N-oxide (1.2g, 3.0mmol) was dissolved in tetrahydrofuran (10ml), cooled to 0°C under an argon atmosphere, treated with Et3N

(1.25ml, 9mmol) and trifluoroacetic anhydride (4.24ml, 30mmol) . After stirring for 30 min the reaction mixture was poured into a mixture containing 5% NaHCθ3, ice and ethyl acetate and the organic phase separated and dried (Na2Sθ4) . Purification by flash column chromatography (silica, hexane then 10% ethyl acetate in hexane) afforded the product: -^LH NMR (250MHz, CDCI3) : δ 7.75 (d, IH, 4-quinolinyl), 7.45 (d,

IH, aromatic), 7.36 (s, IH, aromatic), 7.20 (d, IH, aromatic), 6.69 (d, IH, 3-quinolinyl), 4.72 (m, IH, CHOSi), . . , , , . , , , .

(s, 3H, CH3Si), -0.17 (s, IH, CH3Si) .

7B. 7- .1-r-Butyldimethyl ilyloxynonyl)-2-trifluoro- methanesulfonyl xyquinol ine. 7- (1-t-Butyldimethylsilyloxynonyl) -2-hydroxyquinoline

(0.84g, 2.1mmol) was treated with dry pyridine (15ml) and cooled to -20°C under an argon atmosphere and trifluoro ethanesulfonic anhydride (1ml, 6mmol) was added. The reaction was stirred for 30min at -20°C, for 30min at 5°C and for 12h at room temperature. The reaction was diluted with ethyl acetate and washed with H2O, NaCl (sat) and dried (Na2S0 ) . Purification by flash column chromatography

(silica, hexane then 10% ethyl acetate in hexane) afforded the product: ¹H NMR (250MHz, CDCI3) : δ 8.31 (d, IH, 4- quinolinyl), 7.86 (m, 2H, aromatic), 7.19 (d, IH, aromatic), 7.20 (d, IH, 3-quinolinyl), 4.82 (m, IH, CHOSi), 1.8-1.2 ( , 17H, aliphatic), 0.89 (s, 9H, t-BuSi) , 0.08 (s, 3H, CH3SD , -0.12 (s, 3H, CH3SD . -_-___. Methyl-3-T2- \ 1- (1-t-butyldimethylsilyloxγnonyl. -2- quinolinyl1-ethynyl1benzoate.

7-(1-t-Butyldimethylsilyloxynonyl)-2- trifluoromethanesulfonyloxyquinoline (0.27g, 0.5mmol), methyl 3-ethynylbenzoate (0.088g, 0.55mmol), and Et3N (2ml) were combined and degassed with a stream of argon for 10 min. Then bis (triphenylphosphine) palladium(II) chloride (Aldrich, 0.007g, O.Olmmol) and copper iodide (O.OOlg, 0.005mmol) were added and the reaction mixture stirred under an argon atmosphere for 6h. The reaction mixture was diluted with CH2CI2 (50ml) and washed with H2O, NaCl (sat) and dried ( a2S0 ) . Purification by flash column chromatography (silica, hexane, 1-4% ethyl acetate in hexane) afforded the product: ¹H NMR (250MHz, CDCI3) : δ

8.36-7.42 (m, 9H, aromatic), 4.85 (t, IH, CHOSi), 3.93 (s, 3H, CH3O2C) , 1.9-1.6 (bs, 2H, CH2CHSi) , 1.3-1.2 (bs, 15H, aliphatic), 0.9 (s, 9H, t-BuSi) , 0.07 (s, 3H, CH3Si) , -0.11 (s, 3H, CH3SD .

IH. Methyl-3- \2-R- (1- -butyldimethγlsilyloxγnonyl)-2- quinolinyl1-ethyl1benzoate. Methyl 3-[2-[7- (1-t- butyldimethylsilyloxynonyl)-2-quinolinyl]ethynyl]benzoate (0.153g, 0.28mmol) was dissolved in CH3OH (20ml) and 5% Pd/C (0.014g) added and the mixture hydrogenated at 50 psi for 3h. Filtration of catalyst and evaporation of solvent afforded the product: ¹H NMR (250MHz, CDCI3) : δ 8.1-6.9 ( ,

9H, aromatic), 4.85 (t, IH, CHOSi), 3.9 (s, 3H, CH3O2C) , 3.27 (m, 4H, ethylene), 1.8-1.6 (bs, 2H, CH2CHSi) , 1.4-1.2 (bs, 15H, aliphatic), 0.9 (s, 9H, t-BuSi) , 0.1 (s, 3H, CH3SD, -0.1 (s, 3H, CH3SD .

Example 8

Preparation of 3- 2- 11-(1-hydroxynonyl)-2- quinolinyl1ethyl]benzoic acid, lithium salt.

Methyl 3-[2-[7-(1-t-butyldimethylsilyloxynonyl)-2- quinolinyl]ethyl]benzoate (0.2g, 0.36mmol) was dissolved in tetrahydrofuran (4ml) , treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, 1ml, l.Ommol) and the reaction mixture stirred for 5.5h. The reaction mixture was concentrated and the residue diluted with ethyl acetate (75ml) and washed with H2O, NaCl (sat) and dried (Na2Sθ4) . Purification by flash column chromatography (silica, hexane then 5% and 25% ethyl acetate in hexane) afforded the product: ¹H NMR (250MHz, CDCI3) : δ 8.05-7.19 (m, 9H, aromatic), 4.88 (m, IH, CHOH), 3.9 (s, 3H, CH3O2C) , 3.34- 3.17 (m, 4H, ethylene), 2.19-0.83 (18H, aliphatic); Anal.. calc for C28H35NO3 • 0.5 H2O: C 75.98, H 8.20, N 3.16; found: C 76.14, H 8.06, N 2.95. The ester (O.lg, 0.23mmol) was dissolved in tetrahydrofuran (1ml) and CH3OH (2ml) and treated with LiOH (monohydrate, 0.097g, 2.3mmol) and H2O (1ml) . The reaction mixture was stirred for 4h and purified by chromatography (HP-20, H2O, 50% CH3OH, 100% CH3OH) . The u.v. absorbing fractions were combined and lyophilized to afford the product: ^λE NMR of the free acid (250MHz, CDCI3) : δ 8.22-

7.26 ( , 9H, aromatic), 4.89 (t, CHOH), 3.37 ( , 2H, CH2Ar) , 3.23 (m, 2H, CH2Ar), 1.86 (m, 2H, CH2 CHOH), 1.6-1.2 (bs, 12H, aliphatic), 0.85 (t, 3H, CH3 aliphatic); Anal.. calc for C27H32LiN03 • 1.75 H2O: C 72.14, H 7.77, N 3.12; found: C 72.05, N 7.63, N 3.16. Preparation of 3- r1-thi -2- .7- .1-hydroxynonyl. - 2-quinol inyl. thvl1benzoic arid, potassium salt

___2__ Methyl 7- .1-t-butyldimethγlsi 1yloxynonyl. -quinoline- - carboxylate. 7- (1-t-Butyldimethylsilyloxynonyl)-2- trifluoro-methanesulfonyloxyquinoline (lg, 1.9mmol) was dissolved in DMSO (6ml), CH3OH (4ml) and Et3N (0.67ml, 4.8mmol) and Pd(0Ac)2 (0.014g, 0.06mmol) and 1,1- bis (diphenylphosphino)propane (0.025g, 0.06mmol) added. Carbon monoxide was bubbled through the reaction mixture for 5 min and the reaction heated to 65°C and maintained at this temperature for 3h, cooled to room temperature, and diluted with diethyl ether. The resulting solution was washed with H2O, NaHC03 and NaCl (sat) and dried (MgS04) . Purification by flash column chromatography (silica, 5%, 10%, 15%, 20%, and 30% ethyl acetate in petroleum ether) afforded the product: ¹H NMR (250MHz, CDCI3) : δ 8.3-7.7 (m, 5H, aromatic), 4.87 (t, IH, CHOSi), 4.09 (s, 3H, CH3O2C) , 1.8- 1.65 (b , 2H, CH2 aliphatic), 1.23 (bs, 15H, aliphatic), 0.9 (s, 9H, t-BuSi), 0.074 (s, 3H, CH3SD , -0.12 (s, 3H, CH3SD .

-2____ 7- H - -Butyldimethvlsi 1yl oxynonyl . quinoline-2- carboxal ehyde.

Methyl 7- (1-t-butyldimethylsilyloxynonyl)quinoline-2- carboxylate (0.7g, 1.6mmol) was dissolved in CH2CI2 (8ml) and cooled to -78°C. To this solution was added diisobutylaluminumhydride (1M in CH2CI2, 2.7ml, 2.7mmol) over a 20 min period and the resulting solution stirred for lh, quenched with ethyl acetate and a potassium sodium tartrate solution. The organic phase was separated and washed with tartrate solution, NaCl (sat) and dried (MgSθ4) . Purification by flash column chromatography (silica, 2-30% ethyl acetate in petroleum ether) afforded the aldehyde: !H NMR (250MHz, CDCI3) δ 10.23 (s, IH, CHO) ; MS (DCI, CH4) : 414

(M+H)+. 2£_^ 7- π- -Butγldimethylsi 1yloxynonyl.. -2- hydroxymethylquinoline.

7- (1-t-Butyldimethylsilyloxynonyl)quinoline-2- carboxaldehyde (0.25g, 0.61mmol) was dissolved in CH3OH (6ml), cooled to 0°C, and NaBH4 (0.024g, 0.65mmol) was added. After stirring for 15 min, the reaction was quenched with aqueous NH₄CI (sat) , diluted with ethyl acetate, washed with H2O, NaCl (sat) and dried (MgS04) . Evaporation of the solvent afforded the alcohol: ¹H NMR (250MHz, CDCI3) : δ 8.1-7.23 (m, 5H, aromatic), 4.9 (s, 2H, CH2 quinolinyl), 4.85 (t, IH, CHOSi), 1.81-1.63 (m, 2H, CH2 aliphatic), 1.23 (bs, 15H, aliphatic), 0.9 (s, 9H, t-BuSi) , 0.066 (s, 3H, CH3Si), -0.125 (s, 3H, CH3Si) . 9D. 7-π-f-Butvldimethγlsilyloxynonyl.-2- bromo e by1 qninnlin . 7-(1-t-Butyldimethylsilyloxynonyl)-2- hydroxymethylquinoline (0.255g, 0.62mmol) was dissolved in CH2CI2 (2.5ml), cooled to 0°C, CBr4 (0.51g, 1.5mmol) added followed by (Ph) 3P (0.41g, 1.6mmol) and the reaction mixture stirred for 2h. After warming to room temperature, the reaction mixture was concentrated and the product purified by flash column chromatography (silica, 3-7% ethyl acetate in petroleum ether) to afford the bromide: ^H NMR (250MHz, CDCI3) : δ 8.15-6.8 (m, 5H, aromatic), 4.82 (t, IH, CHOSi),

4.71 (s, 2H, CH2 quinolinyl), 1.7-1.68 (m, 2H, CH2 aliphatic), 1.23 (bs, 15H, aliphatic), 0.89 (s, 9H, t-BuSi) , 0.055 (s, 3H, CH3Si) , -0.135 (s, 3H, CH3Si) .

_2£ 3-π-Thia-2-(7-(1-hydroxynonyl)-2- quinolinyl)ethyllbenzoic acidr potassium salt.

7-(1-t-Butyldimethylsilyloxynonyl)-2-bromomethyl- quinoline (O.lg, 0.22mmol) was dissolved in dimethylformamide (1.5ml), cooled to 0°C, and methyl

3-mercaptobenzoate (0.077g, 0.46mmol) and K2CO3 (0.068g, 0.492mmol) were sequentially added. After stirring for 0.5h, the reaction mixture was diluted with CH2CI2, washed with H2O, NaCl (sat) and dried (MgSθ4) . Purification by flash column chromatography (silica, 2-30% ethyl acetate in petroleum ether) afforded the product: IR NMR (250MHz, CDCI3) : δ 8.08-7.25 (m, 9H, aromatic), 4.81 (t, IH, CHOSi), 4.47 (s, 2H, CH2SAr) , 3.87 (s, 3H, CH3O2C) , 1.65-1.17 (bm, 17H, aliphatic), 0.88 (s, 9H, t-BuSi) , 0.049 (3H, CH3Si) , -0.14 (s, 3H,CH3Si) .

The silyl ester (O.llg, 0.2mmol) was dissolved in tetrahydrofuran (0.4ml), treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.5ml), and the reaction mixture stirred for 4h. It was then diluted with CH2CI2, , . by flash column chromatography (silica, 20-40% ethyl acetate in hexane) afforded the alcohol: ¹H NMR (250MHz, CDCI3) : δ

8.09-7.25 (m, 9H, aromatic), 4.86 (bt, IH, CHOH), 4.46 (s, 2H, CH2SAr), 3.87 (s, 3H, CH3O2C) , 1.84-1.67 (m, 3H, aliphatic and OH) , 1.24 (bs, 12H, aliphatic), 0.86 (t, 3H, CH3 aliphatic); Anal., calc for C27H33NO3S: C 71.81, H 7.37, N 3.10; found: C 71.95, H 7.51, N 3.22.

The ester (0.065g, 0.144mmol) was dissolved in CH3OH (0.5ml) and tetrahydrofuran (0.5ml), degassed with a stream of argon, and treated with a 1M aqueous solution of LiOH (0.43ml, 0.43mmol) . Upon completion of reaction, the solvents were evaporated and the product converted to the potassium salt (acidification, CH2CI2 extraction, concentration and treatment of the residue with KHCO3) and purified by MPLC (RP-18 silica, 0-10% CH3OHH2O) to afford the product: ¹H NMR (250MHz, CD3OD) δ 8.35-7.20 (m, 9H, aromatic), 4.95-4.80 (m, IH, CHOH + CD3OH) , 4.46 (s, 2H, CH2SAr) , 1.90-1.70 (m, 2H, aliphatic), 1.27 (bs, 12H, aliphatic), 0.86 (t, 3H, CH3 aliphatic); MS (FAB) : 476.1 (M+H)+.

-2H_ 3- r r r7- .1-Hydroxynonyl) -2-quinolinyl1methyl1 sulfinyl1 - benzoic acid, lithium salt.

Methyl 3- [ [ [7- (1-t-butyldimethylsilyloxynonyl) -2- quinolinyl]methyl]sulfinyl]benzoate (0.063g, O.llmmol) was dissolved in CH2CI2 (1ml), cooled to 0°C, and MCPBA (0.022g,

0.127mmol) added in 5 portions. After stirring for 0.5h, the reaction mixture was diluted with CH2CI2 (3ml) and washed with H2O, NaHC03, NaCl (sat) and dried (MgSθ4) . Purification by flash column chromatography (silica, 10-30% ethyl acetate in hexane) afforded the product: ---H NMR (250MHz, CDCI3) : δ 8.25-7.80 (m, 9H, aromatic), 4.81 (t, IH, CHOSi), 4.40 (s, 2H, CH2SOAr) , 3.87 (s, 3H, CH3O2C) , 1.88-1.60 (bm, 2H, CH2 aliphatic), 1.25 (bs, 12H, aliphatic), 0.90 (s, 9H, t-BuSi) , 0.88 (t, 3H, CH3 aliphatic), 0.049 (3H, CH3SD , -0.14 (s, 3H,CH3Si); MS (DCI, CH4) 582 (M+H)⁺.

The silyloxy ester was dissolved in CH3CN (0.5ml), HF- pyridine (0.2ml) was added, and the reaction mixture stirred for 20 min. It was poured into dilute NaHC03, extracted with CH2CI2, washed with H2O, NaCl (sat) and dried (MgS04) . Purification by flash column chromatography (silica, 60-100% ethyl acetate in petroleum ether) afforded the product: MS (DCI, NH3) 468 (M+H)⁺. Anal.. calc for C2₇H33NO4S • 0.66 H2O: C 67.61, H 7.21, N 2.98; found: C 67.46, N 7.13, N 2.78.

The ester (0.036g, 0.077mmol) was dissolved in CH3OH (0.25ml) and tetrahydrofuran (0.7ml), degassed with argon, and treated with a 1M aqueous LiOH solution (0.23ml, 0.23 mmol) . The reaction was stirred for lh, the solvents concentrated and the residue purified by MPLC as previously described to give the product: ---H NMR (250MHz, CD3OD) : δ

8.25-7.25 (m, 9H, aromatic), 5.0-4.8 (m, IH, CHOH + CD3OH) , 4.55 (s, 2H, CH2SOAr) , 1.88-1.75 (bm, 2H, CH2 aliphatic), 1.3 (bs, 12H, aliphatic), 0.88 (t, 3H, CH3 aliphatic); MS (FAB) 460.2 (M+H)⁺.

Example 10 Preparation of 4-. " '7-(1-hydroxynonyl)-2- quinolinyl! ethylIsulfinyllbenzoic acid, lithium salt This compound was prepared using procedures identical to those used in the preparation of 3-[ [ [7-(1-hydroxynonyl)- 2-quinolinyl]methyl]sulfinyl]benzoic acid, lithium salt. ^H NMR (250MHz, CD3OD) : δ 8.25-7.20 (m, 9H, aromatic), 5.1-4.8 (m, IH, CHOH + CD3OH) , 4.50 (s, 2H, CH2SOAr) , 1.88-1.75 (bm, 2H, CH2 aliphatic), 1.28 (bs, 12H, aliphatic), 0.88 (bt, 3H, CH3 aliphatic); MS (FAB) 460.3 (M+H)⁺.

Example 11 Preparation of 7-t1-hydroxynonyl)quinoline-2-carboxylic acid, lithium salt Methyl 7-(1-t-butyldimethylsilyloxynonyl)quinoline-2- carboxylate (0.17g, 0.38mmol) was dissolved in tetrahydrofuran (3.5ml) and treated with tetrabutylammonium fluoride (1M in tetrahydrofuran, 0.85ml, 0.85mmol). The reaction was stirred for 3h, diluted with ether, washed with H2O, NaCl (sat) and dried (MgSθ4) . Concentration gave a white solid that was purified by flash column chromatography (silica, 30-80% ethyl acetate in hexane) to afford the product. . , . tetrahydrofuran (1ml), CH3OH (1ml) and H2O (0.5ml) and LiOH monohydrate (0.12g, 2.85mmol) was added. After stirring for lh, purification by MPLC (RP-18 silica, H2θ-70% CH3OHH2O) afforded the product: ¹H NMR (250MHz, CD3OD) : δ 8.39-7.60 (m, 5H, aromatic), 4.8-4.7 (m, IH, CHOH + CD3OH) , 1.90-1.70 (bm, 2H, CH2 aliphatic), 1.3 (bs, 12H, aliphatic), 0.88 (t, 3H, CH3 aliphatic); MS (FAB) 322 (M+H)⁺.

Example 12

As a specific embodiment of a composition of this invention, a compound of Example 1-11 is dissolved in isotonic saline at a concentration of 1 to 10 mg/ml and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.

Example 13

Parenteral Dosage Unit Composition A preparation which contains 20 mg of a compound of any of the foregoing Examples 1-11 as a sterile dry powder is prepared as follows: 20 mg of the compound is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions into a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. Subsequent dilution may be made by addition of a metered volume of this dosage unit to another volume of D5W for injection, or a metered dose may be added to another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion or other injection-infusion system.

Example 14 Oral Dosage Unit Composition

A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Examples 1-11 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule. Example 15 Oral Dosaσe Unit Composit on A tablet for oral administration is prepared by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of any of the foregoing Examples 1-11 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mg starch, 5 mg talc and 3 mg stearic acid, and compressed into a tablet.

Claims

What is claimed is:

1. A disubstituted quinoline of formula I

or a salt thereof wherein

Rl is CH3(CH2)nHOHC- or

where n is 3-20, m is 1-6 and R3 is lower alkyl, lower alkoxy or halo; and

R2 is H0CH2 (CH2) _rCHOHCH2-, XOC(CH2) _rCHOHCH2-, XOC(CH2)q-2CH=CH-, XOC(CH2)_qCH2~, COX where X is OH or an ester-forming group or an amide-forming group, or

where r is 1-5, q is 1-10, t is 0, 1 or 2 and R4 is -COX.

2. A compound of claim 1 where R2 is

HOCH2 (CH2)_rCH0HCH2-, XOC(CH2)rCHOHCH2~, XOC(CH2)qCH2", XOC(CH2)q-2CH=CH-, COX where X is OH, an ester-forming group or an amide-forming group, or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 where R2 is HOCH2(CH2)_rCHOHCH2- where r is 2-4.

4. A compound of claim 3 where Ri is CH3 (CH2)nHOHC-

where n is 6-10 or OH where m is 1-6.

5. A compound of claim 4 where Ri is CH3(CH2)nHOHC- where n is 7 and R2 is H0CH2 (CH2)_rCHOHCH2~ where r is 3, the compound 2- (2, 6-dihydroxy-n-hexyl)-7- (1- hydroxynonyl)quinoline.

6. A compound of claim 2 where R2 is X0C(CH2)_rCH0HCH2- where r is 2-4.

7. A compound of claim 6 where Ri is CH3 (CH2)nH0HC- and r in R2 is 4, and X is OH or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7 which is 2- (2- hydroxypentane-5-carboxylate)-7-(1-hydroxynonyl)quinoline, lithium salt or another pharmaceutically acceptable salt.

9. A compound of claim 2 where R2 is XOC(CH2)qCH2~ where q is 2-5.

10. A compound of claim 9 where Ri is CH3 (CH2)nHOHC- and q is 5, X is OH or a pharmaceutically acceptable salt thereof.

11. A compound of claim 10 which is 2-(6-carboxy-l- pentyl)-7- (1-hydroxynonyl)quinoline, its lithium salt or another pharmaceutically acceptable salt.

12. A compound of claim 2 where R2 is XOC(CH2)q-2CH=CHCH2- where q is 2-5.

13. A compound of claim 12 where, in R2, q is 3 and Ri is CH3 (CH2)nHOHC-.

14. A compound of claim 13 which is 2- (6-carboxy-l- pentenyl)-7-(1-hydroxynonyl)quinoline, its lithium salt or another pharmaceutically acceptable salt.

15. A compound of claim 2 where Ri is CH3(CH2)nHOHC-

where n is 6 where m is 1-6 and R2

is the group

where R4 is defined above.

16. A compound of claim 15 where Ri is

where m is 2, 3 or 4 and the R4 group in R2 is COX.

17. A compound of claim 16 which is 3-[l-hydroxy-2-[7- [l-hydroxy-5-(4-methoxyphenyl)pentyl]-2- quinolinyl]ethyl]benzoic acid, 4-[l-hydroxy-2-[7-[1-hydroxy- 5-(4-methoxyphenyl)pentyl]-2-quinolinyl]ethyl]benzoic acid, a lithium salt thereof, or another pharmaceutically acceptable salt.

18. A compound of claim 15 where Ri is CH3(CH2)nHOHC- and the R4 group in R2 is COX.

19. A compound of claim 18 which is 3-[l-hydroxy-2-[7- (1-hydroxynonyl)-2-quinolinyl]ethyl]benzoic acid, its lithium salt, or another pharmaceutically acceptable salt.

20. A compound of claim 2 where Ri is CH3 (CH2)nHOHC-

where n is 6 -10 or

where is 1-6 and

is the R2 group.

21. A compound of claim 20 where Ri is CH3 (CH2)nHOHC- and the R4 group in R2 is COX.

22. A compound of claim 21 which is 3-[2-[7-(l- hydroxynonyl)-2-quinolinyl]ethyl]benzoic acid, its lithium salt, or another pharmaceutically acceptable salt.

23. A compound of claim 2 where Ri is CH3 (CH2)nHOHC-

where n is 6 -10 or

where m is 1-6 and ^y is the R2 group.

24. A compound of claim 23 where R4 in the R2 group is COX.

25. A compound of claim 21 which is 3-[l-thia-2-(7- (1- hydroxynonyl) -2-quinolinyl)ethyl]benzoic acid, 4-[[[7-(l- hydroxynonyl)-2-quinolinyl]methyl]sulfinyl]benzoic acid or a lithium salt thereof, or another pharmaceutically acceptable salt.

26. A compound of claim 2 where R2 is COX.

27. A compound of claim 26 which is 7-(l- hydroxynonyl)-quinoline-2-carboxylic acid, its lithium salt or another pharmaceutically acceptable salt.

28. A pharmaceutical composition comprising a compound of formula I as described in claim 1 and a pharmaceutically acceptable excipient.

29. A method for treating a disease related to or caused by leukotrienes or related pharmacologically active mediators at the end organ, which method comprises administering one or more of the compounds of formula I of claim 1 alone or in combination with a pharmaceutically acceptable excipient.

30. The method of claim 29 where the disease being treated is an allergy.

31. The method of claim 30 where the disease is antigen-induced anaphylaxis, asthma or allergic rhinitis.

32. The method of claim 30 where the disease is an inflammatory disease.