WO1994014797A1

WO1994014797A1 - Quinoline compounds and the treatment of leucotriene related diseases therewith

Info

Publication number: WO1994014797A1
Application number: PCT/US1993/012434
Authority: WO
Inventors: Robert A. Daines; Israil Pendrak
Original assignee: Smithkline Beecham Corporation
Priority date: 1992-12-23
Filing date: 1993-12-21
Publication date: 1994-07-07

Abstract

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

Description

QUINOLINE COMPOUNDS AND THE TREATMENT OF LEUCOTRIENE

RELATED DISEASES THEREWITH

Scope of the Invention

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

The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the dihydroxyleukotrienes (leukotriene B4). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.

The peptidoleukotrienes are implicated in the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include smooth muscle contractions, yocardial depression, increased vascular permeability and increased mucous production.

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

Leukotrienes are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease. Leukotriene B4 (LTB4) was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)- 6,8,10,14-eicosatetraenoic acid.

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

LTB4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of this invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a factor. Summary of the Invention

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

or an N-oxide, or a pharmaceutically acceptable salt, where the (CH2)m group is bonded to the quinolinyl group at any carbon atom and where

R2 and R3 are present on any carbon atom of the quinolinyl group;

A is CH2 then Z is S(O)_q where q is 0, 1 or 2; (CH₂)_p; CHOH, C=O, or NR_X, or O; or when A is C=O, Z is NR_X, or A is NH and Z is C=O; p is 1-3; m is 0 -5;

R_x is hydrogen or lower alkyl;

R is C\ to C2()-aliphatic, unsubstituted or substituted phenyl-Cj to CiO'^atip^natic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C\ to C20-aϋph tic-O-, or R is unsubstituted or substituted phenyl-Cj to Cjo-aϋphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Ri is R4, -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH2OR5;

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

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

R3 is H, halo, lower alkyl, or acyl of 1-6 carbons;

R4 is tetrazol-5-yl, or COOH or an ester or amide thereof; and R5 is H, lower alkyl, CH3(CH₂)θ-6CO or phenyl(CH₂)θ-3CO.

In a further aspect, this invention relates to compositions comprising a compound of formula I, or an oxide or salt thereof, in admixture with a carrier. Included in these compositions are those suitable for pharmaceutical use and comprising a pharmaceutically acceptable excipient or carrier and a compound of formula I which may be in the form of a pharmaceutically acceptable salt.

These compounds can also be used for treating diseases caused by or related to leukotrienes including LTB4, and particularly psoriasis and inflammatory bowel disease.

Processes for making these compounds are also included in the scope of this invention, which processes comprise: a) forming a salt, or b) forming an ester; c) oxidizing a thio ether to the sulfoxide or sulfone; or d) utilizing one of the processes illustrated in the schemes and Examples given below. General Embodiments

Definitions and General Descriptions

The following definitions are used in describing this invention. "Aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase "lower alkyl" means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. "Lower alkoxy" means the group lower alkyl-O-. "Acyl-lower alkyl" refers to the group (O)C-lower alkyl where the carbonyl carbon is counted as one of the carbons of the 1 to 6 carbons noted under the definition of lower alkyl. "Halo" refers to and means fluoro, chloro, bromo or iodo. The phenyl ring may be substituted with one or more of these radicals. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl pattern.

The phrase "a pharmaceutically acceptable ester-forming group" covers all esters which can be made from the acid function(s) which may be present in these compounds. The resultant esters will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the esters will retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases.

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

Pharmaceutically acceptable salts of the instant compounds are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.

Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound, dissolved in a suitable solvent, is treated with an excess of an organic or inorganic acid, in the case of acid addition salts of a base, or an excess of organic or inorganic base where R4 is COOH for example.

Oxides of the pyridyl ring nitrogen, and of the quinolyl nitrogen, may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.

If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. Compounds with a chiral center may be administered as a racemic mixture or the racemates may be separated and the individual enantiomer used alone. As leukotriene antagonists, these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4. Inflammatory diseases such as psoriasis and inflammatory bowel disease may be treated by applying or administering the compounds described herein. It is also expected that these compounds can be used to treat allergic diseases including those of a pulmonary and non-pulmonary nature. For example these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma, allergic rhinitis and irritable bowel disease. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated by these compounds. Preferred compounds

Preferred compounds are those where R is Cβ to C20 alkoxy, phenyl-C2 to CJQ alkoxy or substituted-phenylC2 to C\Q alkoxy; R\ is -(C]-C3alkyl)R4, or -(C2- C3alkenyl)R4. The more preferred compounds are those where R is substituted phenyl- C2 to C10 alkoxy, particularly the unsubstituted-phenyl(CH2)2-8"0- group, or the p- fluoro- orp-methoxyphenyl(CH2)2-8"C'- group, or CH3(CH2)5_9-O-; m is 0 - 5, most preferably 0, 1, or 2; Ri is HO2C-CH=CH-, or HO2C-CH2CH2- or a salt, ester or amide derivative thereof. As regards A, the CH2 group is preferred. As regards Z, S(O)q is preferred.

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

Several methods can be used to prepare these compounds. One generic process comprises preparing a 6-halomethylpyridyl adduct and then condensing that fragment with the appropriate mercaptan or alcohol to make compounds where Z is a sulfur or oxygen atom. Normally this will be a protected product; any acid group will be derivatized in some manner to render it unreactive. Derivatizing groups may be removed to provide a parent functionality, such as an acid or a salt of an acid. Further modifications of these reactive groups can then be carried out, such as forming a salt, an amide, an ester or the like. This method and specific illustrations in the form of concrete examples is set out in published PCT application PCT/US91/03772 and co- pending PCT application PCT/US92/07466. See also the synthetic methods and illustrative chemistry in published PCT applications PCT/US91/03940, PCT/US91/03399, and co-pending U.S. patent application USSN 876950 filed OlMay 1992. These latter applications illustrate means for preparing compounds where A/Z are C=O/NRx, A/Z are NH/C=O (or the alcohol) and where A/Z are CH₂/alkylene respectively. Each of these applications is incorporated herein to the extent each is useful for teaching how to make compounds of formula I. If the desired thioquinoline is not commercially available, it can be made by the process illustrated in the following reaction scheme, and as specifically illustrated in the Examples given below.

Scheme I

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

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

Included within the scope of this disclosure is the method of treating a disease mediated by LTB4 which comprises administering to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition. For example, inhibiting the symptoms of an allergic response resulting from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure. The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth.

The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.

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

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

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

When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water, for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.

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

In these compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.

Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor. Topical formulations will contain between about 0.01 to 5.0% by weight of the active ingredient and will be applied as required as a preventative or curative agent to the affected area. When employed as an oral, or other ingested or injected regimen, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.

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

Assays and methodology used for confirming the putative activity of these compounds are set out in the two pending PCT applications given above, that is published PCT application PCT/US91/03772 and co-pending PCT application PCT/US92/07466. Those methods are incorporated herein by reference. Specific Embodiments

The following examples are given to illustrate how to make and use the compounds of this invention. These Examples are just that, examples, and are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors. Example I l-Iodo-8-(4-methoxyphenyl)octane 1(a) 7-Octvn-l-ol 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C and 3-octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether. The organic layer was washed with 10% HC1 and brine and dried (MgSO.4). Evaporation gave 9.73g (97%) of the product as a colorless oil which was used without further purification: 1H NMR (90MHz, CDCI3) δ 3.65 (t, J=5Hz, 2H, O-CH2), 2.23 ( , 2H, CH2), 2.0 (m, IH, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) v_max 3350, 2930, 2125 cm^{" 1}.

Kb) 7-Octyn-l-t-butyldiphenyIsilyl ether To a cooled (0° C) solution of 7- octyn-1-ol (9.3g, 73.7mmol) in DMF (70mL) under an argon atmosphere was added imidazole (7.5g, HOmmol) followed by the dropwise addition of t-butylchlorodiphenylsilane (21mL, 81mmol). The reaction was then stirred at room temperature for 2 hours. The reaction solution was diluted with Et2θ and washed with H2O and brine and dried (MgSO4). Purification by flash column chromatography (silica, 3% EtOAc in hexane ) provided 24.9g (93%) as a colorless oil: ^lH NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, O-CH ), 2.23 (m, 2H, CH₂), 1.97 (t, IH, acetylenic), 1.6-1.3 (m, 8H, (CH₂)4), 1.05 (s, 9H, t-butyl); IR (film) Vmax 3321, 2940, 2125 cm^"1. Kcl 8-(4-MethoxyphenylV7-octyn-l-t-butyldiphenylsilyl ether To a flame dried flask containing triethylamine (140mL) under an argon atmosphere was added 4- iodoanisole (13.3g, 56.9mmol), 7-octyn-l-t-butyldiphenylsilyl ether (24.9g, 68.3mmol), (Ph3P)2PdCl2 catalyst (793mg, 1.13mmol), and Cul (431mg, 2.27mmol). The resulting mixture was heated at 50° C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered, the solids were washed with Et2θ and the solvent was evaporated. The residue was diluted with Et2θ and washed with 5% HC1, H2O, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 2% EtOAc in hexane) gave 30g (93%) as an orange oil: ^lH NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.7 (t, 2H, O-CH2), 2.4 (t, 2H, CH₂), 1.7-1.3 (m, 8H, (CH₂)4), 1.05 (s, 9H, t-butyl).

1(d) 8-(4-Methoxyphenyl)octan-l-t-butyldiphenylsilyl ether 8-(4-Methoxyphenyl)-7-octyn-l-t-butyldiphenylsilyl ether (30g, 63.7mmol) was dissolved in EtOH (125mL) and EtOAc (125mL) and treated with 5% Pd-C catalyst (3g). The reaction was vigorously stirred under an H2 atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a pad of Celite and the solvent was evaporated. The resulting pale yellow oil was pure by nmr analysis and was used directly for the next step: *H NMR (250MHz, CDCI3) δ 7.7 (d,-4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OMe), 3.6 (t, 2H, O-CH₂), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)6), 1.0 (s, 9H, t-butyl).

1(e) 8-(4-Methoxyphenyl)octan-l-ol To a cooled (0° C) solution of 8-(4-methoxyphenyl)octan-l-t-butyldiphenylsilyl ether (63mmol) was added tetrabutylammonium fluoride (70mL, 70mmol; 1M solution in THF). The cooling bath was removed and the reaction was stirred at room temperature for 4.5 hours. The solvent was evaporated and the residue was dissolved in Et2θ. This was washed with H20, 5% HC1, NaHCO3, and brine and dried (MgSO4). Purification by flash column chromatography (silica, 30% EtOAc in hexane) gave 12.6g (85%; two steps) as a colorless solid: ^lU NMR (250MHz, CDCI3) 6 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OMe), 3.68 (t, 2H, O-CH₂), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH₂)6); MS (CI): 254.2 (M+NH4); mp 47-49 _C.

1(f) l-Iodo-8-(4-methoxyphenyPoctane To a stirred solution of 8-(4- methoxyphenyl)octan-l-ol (12.3g, 52mmol) in dry toluene (200mL) under an argon atmosphere was added triphenylphosphine (17.8g, 67.6mmol) and imidazole (10.6g, 156mmol). After 5 minutes, I2 (17. lg, 67.6mmol) was added. The reaction was then heated at 65° C for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2θ and washed with H2O and brine and dried (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2CI2 and applied to a flash chromatography column (silica). Elution with 2% EtOAc in hexane provided 16.3g (90%) of the product as a colorless oil (slight contamination with triphenylphosphine): *H NMR (250MHz, CDCI3) δ 7.08 (d, J=8.6Hz, 2H, aryl), 6.82 (d, J=8.6Hz, 2H, aryl), 3.78 (s, 3H, OMe), 3.17 (t, J=7.4Hz, 2H, I-CH2), 2.54 (t, J=7.6Hz, 2H, benzylic), 1.85 (m, 2H, CH ), 1.60 (m, 2H, CH₂), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).

Example 2 7-ri-Thia-2-r2-(E-2-carboxyethenyl)-3-r8-(4-methoxyphenyl)octyloxyl-6- pyridyllethyllquinoline. lithium salt 2(a O-7-quinolinyl dimethylthiocarbamate To a cooled (0° C) solution of 7- hydroxyquinoline (2g, 13.7mmol, Kodak) in DMF (lOmL) under an argon atmosphere was added NaH (0.55g, 13.7mmol, 60% dispersion) and the mixture was allowed to warm up to room temperature. The mixture was cooled to 10° C and dimethylthiocarbomoylchlori.de (2.2 lg, 17.9mmol) was added in one portion. An increase in temperature was noted. The water bath was removed and the mixture heated at 80° C under an argon atmosphere for lh. Upon cooling to room temperature the reaction was diluted with EtOAc and washed with H2O, brine and dried (Na2SO₄). Purification by flash chromatography (silica, 5-30% EtOAc in hexane) yielded an off white solid (2.5g, 77%): ^lH NMR (90MHz, CDCI3) δ 9.0 (m, LH, 2-quinolinyl), 8.1 (d, IH, 4-quinolinyl), 7.8 (m, 2H, 6,8-quinolinyl), 7.2 (m, 2H, 3,5-quinolinyl), 3.5 (s, 3H, NCH3), 3.45 (s, 3H, NCH3).

2(b) S-7-quinolinyl dimethylthiocarbamate The O-7-quinolinyl dimethylthiocarbamate was heated at 220° C for 2h. The mixture was cooled to room temperature. Purification by flash chromatography (silica, 0-5% MeOH in CH2CI2) yielded a yellow solid (1.35g, 54%): lH NMR (90MHz, CDCI3) δ 9.0 (m, IH, 2- quinolinyl), 8.2 (s, IH, 8-quinolinyl), 8.1 (d, IH, 4-quinolinyl), 7.8 (m, 2H, 6,5- quinolinyl), 7.2 (m, IH, 3-quinolinyl), 3.0 (s, 6H, NCH3).

2(c) 7-Thioquinoline To the solution of S-7-quinolinyl dimethylthiocarbamate (1.17g, 5mmol) in MeOH (50mL) was added NaOH (0.3g, 7.5mmol) in H2O (30mL). The mixture was refluxed under an argon atmosphere for 16h. Upon cooling to room temperature the reaction mixture was evaporated and the resulting residue was acidified with 3N HC1 to pH 7.0. The mixture was extracted with CH2CI2 and washed with H2O and brine and dried (Na2SO4). Purification by flash chromatography (silica, 5-10% MeOH in CH2CI2) yielded a red solid (0.5g, 61%): ^]H NMR (90MHz, CDCI3) δ 8.6 (m, IH, 2-quinolinyl), 7.8 (d, IH, 4-quinolinyl), 7.2 (m, 8,5-quinolinyl), 7.0 (m, 2H, 3,6-quinolinyl), 3.7 (s, IH, SH).

2(d 7-π -Thia-2-r2-(E-2-carboxymethylethenyl)-3-r8-(4- methoxyphenyl)octyloxyl-6-pyridyllethyllquinoline 2-(E-2-Carboxymethylethenyl)-3- [8-(4-methoxyphenyl)octyloxy]-6-chloromethylpyridine hydrochloride (1.17mmol), prepared as previously described in published PCT application PCT/US91/03772 was dissolved in dry DMF (lOmL) and sequentially treated with 7-thioquinoline prepared above (1.28mmol), anhydrous CS2CO3 (5.8mmol), and tetrabutylammonium iodide (43mg, O.lmmol) under an argon atmosphere. The reaction was stirred at room temperature for lh. The reaction was diluted with EtOAc and washed with H2O and brine and dried (Na2SO4). Purification by flash chromatography (silica, 0-2% MeOH in CH2CI2) gave a yellow oil (58mg, 65%): H NMR (250MHz, CDCI3) δ 8.9 (m, IH, quinolinyl), 8.1 (m, 3H, quinolinyl, vinyl), 7.6 (d, IH, pyridyl), 7.55 (m, IH, quinolinyl), 7.35 (m, 2H, pyridyl.quinolinyl), 7.1 (m, 4H, quinolinyl, vinyl, phenyl), 6.8 (d, 2H, phenyl), 4.4 (s, 2H, CH₂-S), 4.05 (t, 2H, OCH₂), 3.8 (s, 3H, OMe), 3.75 (s, 3H, OMe), 2.5 (t, 2H, CH₂Ph), 0.9-1.8 (m, 12H, aliphatic); MS (SI): 571 (M+H).

2(e) 7-ri-Thia-2-r2-(E-2-carboxyethenyl)-3-r8-(4-methoxyphenvnoctyloxyl- 6-pyridyllethyllquinoline. lithium salt 7-[l-Thia-2-[2-(E-2-carboxymethylethenyl)-3- [8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]quinoline (58mg, O.lmmol) was dissolved in tetrahydrofuran (2mL) and MeOH (2mL) and treated with 1.0M LiOH

(O.lmL, 0.25mmol). The reaction was stirred under an argon atmosphere for 24h. The solvent was evaporated and the product purified by Reverse Phase MPLC (RP- 18 silica, 0-60% MeOH in H2O). Lyophilization yielded a colorless amorphous solid: ^lU NMR (250MHz, CD3OD) δ 8.8 (m, IH, quinolinyl), 8.3 (dd, IH, quinolinyl), 7.85 (m, 2H, quinolinyl), 7.75 (d, IH, J=15.8Hz, vinyl), 7.55 (m, IH, quinolinyl), 7.7 (dd, IH, quinolinyl), 7.4 (m, 4H, quinolinyl, vinyl, phenyl), 7.0 (dd, 2H, pyridyl), 6.8 (d, 2H, phenyl) 4.4 (s, 2H, CH₂-S), 4.05 (t, 2H, OCH₂), 3.8 (s, 3H, OMe), 2.5 (t, 2H, CH₂Ph), 0.9-1.8 (m, 12H, aliphatic); MS (SI): 557 (M+H, free acid).

Example 3 7-ri-Oxythia-2-r2-(E-2-carboxyethenyl)-3-r8-(4-methoxyphenyl)octyloxy1-6- pyridyllethynquinoline. lithium salt 3(a) 7-ri-Oxythia-2-r2-(E-2-carboxymethylethenylV3-r8-(4- methoxyphenyl)octyloxyl-6-pyridyllethyllquinoline 7-[l-Thia-2-[2-(E-2- carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]quinoline (150mg, 0.26mmol) was dissolved in dry CH2CI2 (7mL) and cooled to -20° C. 85% m- chloroperbenzoic acid (51mg, 0.29mmol) was added in two ponions and the mixture was stirred at -20° C for 15 min. The reaction was diluted with EtOAc and washed with saturated NaHCO3 and brine and dried (Na2SO₄). Purification by flash chromatography (silica, 0-2% MeOH in CH2CI2) gave an amorphous solid (89mg, 58%): ^!H NMR (250MHz, CDCI3) δ 9.0 (m, IH, quinolinyl), 8.2 (m, 2H, quinolinyl), 7.95 (d, IH, quinolinyl), 7.8 (d, J=15.8Hz, IH, vinyl), 7.7 (dd, IH, quinolinyl), 7.5 (dd, IH, quinolinyl), 7.2 (m, 4H, pyridyl, phenyl), 6.8 (d, 2H, phenyl), 6.4 (d, J=15.8Hz, IH, vinyl), 4.3 (dd, 2H, CH₂-SO), 4.0 (t, 2H, OCH₂), 3.8 (S, 3H, OMe), 3.75 (s, 3H, OMe), 2.6 (t, 2H, CH₂Ph), 1.8-1.3 (m, 12H, aliphatic); Anal, calculated for C₃₄H38N₂O₅S: C,

69.60; H, 6.53; N, 4.77, found: C, 69.52; H, 6.44; N, 4.58.

3(b) 7-π-Oxythia-2-r2-(E-2-carboxyethenylV3-r8-(4- methoxyphenyl)octyloxyl-6-pyridynethyllquinoline. lithium salt 7-[l-Oxythia-2-[2-(E- 2-carboxymethylethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6-pyridyl]ethyl]quinoline

(78mg, 0.13mmol) was dissolved in tetrahydrofuran (3mL) and MeOH (2mL) and treated with 1.0M LiOH (0.66mL, 0.66mmol). The reaction was stirred under an argon atmosphere for 24h. The solvent was evaporated and the product purified by Reverse

Phase MPLC (RP-18 silica, 0-80% MeOH in H2O). Lyophilization yielded a colorless amorphous solid : *H NMR (250MHz, CD3OD) δ 8.9 (d, IH, quinolinyl), 8.4 (d, IH, quinolinyl), 8.1 (m, 2H, quinolinyl, vinyl), 7.75 (d, IH, quinolinyl), 7.6 (m, 2H, quinolinyl), 7.25 (d, IH, pyridyl), 7.1 (d, IH, pyridyl), 7.05 (d, 2H, phenyl), 6.8 (d, 2H, phenyl), 6.7 (d, IH, vinyl), 4.4 (s, 2H, CH₂-SO), 4.0 (t, 2H, CH₂O), 3.75 (s, 3H, OMe),

2.5 (t, 2H, CH₂Ph), 1.8-1.3 (m, 12H, aliphatic); MS (FAB): 573.2 (M+H, free acid); Anal, calculated for C33H35N₂O₅SLi ^• 1.5 H₂O: C, 65.44; H, 6.32; N, 4.63; found: C,

65.30; H, 6.14; N, 4.31.

Example 4

Preparation of Free Acids

The acid form of any of the foregoing salts may be prepared by dissolving the salt in water, then acidifying that solution with a mineral acid such as dilute (6N) HCl.

The acid is recovered by filtering out the precipitate.

Example 5

Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Means for making various formulations can be found in standard texts such as Remington's

Pharmaceutical Sciences, and similar publications and compendia. Specific examples of formulations are given below.

OINTMENTS Hydrophyllic Petrolatum Ingredients Amount (% WAV)

Cholesterol 30.0g

Stearyl Alcohol 30.0g

White Wax 78.0g

Active Ingredient 2.0g

White Petrolatum 860.0g The stearyl alcohol, white wax and white petrolatum are melted together (steam bath for example) and cholesterol and the active ingredient are added. Stirring is commenced and continued until the solids disappear. The source of heat is removed and the mix allowed to congeal and packaged in metal or plastic tubes.

Emulsion Ointment

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

Claims

What is claimed is:

1. A compound of formula I

R2 and R3 are present on any carbon atom of the quinolinyl group; A is CH2 then Z is S(O)_q where q is 0, 1 or 2; (CH₂)_p; CHOH, C=O, or NR_X, or O; or when A is C=O, Z is NR_X, or A is NH and Z is C=O; p is 1-3; m is 0 -5;

R_x is hydrogen or lower alkyl;

R is C to C20-^a^P^natic, unsubstituted or substituted phenyl-Cj to Cio-a phatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C] to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl-Cj to CiQ-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Rj is R4, -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH2OR5;

R2 is H, halo, CF3, CN, lower alkyl, lower alkoxy or -(CH2)_n 4 where n is 0-5; or

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

R3 is H, halo, lower alkyl, or acyl of 1-6 carbons; R4 is tetrazol-5-yl, or COOH or an ester or amide thereof; and R5 is H, lower alkyl, CH₃(CH₂)θ-6CO or phenyl(CH₂)θ-3CO.

2. A compound of claim 1 where R is substituted phenyl-C4 to C\Q alkoxy, particularly the unsubstituted-phenyl(CH2)2-8"C*- group, or the p-fluoro- or p- methoxyphenyl(CH2)2-8"0- g^rouP> ^or CH3(CH2)7_9-O-; and m is 0 - 5.

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

4. A compound of claim 3 which is 7-[l-thia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- pyridyl]ethyl]quinoline, or 7-[l-Oxythia-2-[2-(E-2-carboxyethenyl)-3-[8-(4-methoxyphenyl)octyloxy]-6- pyridyl] ethyl] quinoline, or a pharmaceutically accpectble salt thereof.

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

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