Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

• This invention relates to amine, ether or thioether linked pyridyl-benzoic acid derivatives which are useful for treating diseases associated with leukotrienes. These compounds are particularly useful in treating diseases attributable to hydroxyleukotrienes, especially LTB4 and LTB4-agonist active substances.
• 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.
• 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.
• LTB4 Leukotriene B4
• Fig. I It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4 (Figure I). It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB 4 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 LTB 4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity.
• LTB 4 has been established as an inflammatory mediator in vivo.
• LTB 4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis.
• 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.
• Some of these compounds may also inhibit the 5-lipoxygenase enzyme or may be LTD 4 antagonists.
• T is S(0) n where n is 0, 1 or 2, O, NH or NCH3;
• R is C ⁇ to C20 -aliphatic, unsubstituted or substituted phenyl Cj to Cj o-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is C ⁇ to C20 -a liph tic-O-, or R is unsubstituted or substituted phenyl C ⁇ to Cj o-aliphatic-O- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo;
• Rl is -(Ci to C5 aliphatic)R4, -(Ci to C 5 aliphatic)CHO, -(Ci to C 5 aliphatic)CH20Rs, -R4, -CH OH, or CHO;
• R2 is hydrogen, -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group -OR6, or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R ⁇ )2 where R7 is H, or an aliphatic group of 1 to 10 carbon atoms, a 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, or R2 is -CH(NH2)(R4) or an amine, amide or sulfonamide;
• R3 is hydrogen, lower alkoxy, halo, -CN, COR5, NHCONH2, or OH;
• R4 is -COR5 where R5 is -OH, a pharmaceutically acceptable ester-forming group -OR ⁇ , or -OX where X is a pharmaceutically acceptable cation, or R5 is -N(R7)2 where R7 is H, or an aliphatic group of 1 to 10 carbon atoms, a 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; an d
• R8 is hydrogen, Ci to C alkyl, or Ci to C ⁇ -acyl.
• this invention covers pharmaceutical compositions containing the instant compounds and a pharmaceutically acceptable excipient.
• Treatment of 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.
• this invention relates to a method for making a compound of formula I which method is illustrated in the Reaction Schemes given below and in the Examples set forth in this specification.
• 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-.
• Halo means fluoro, chloro, bromo or iodo.
• Acyl means the radical having a terminal carbonyl carbon.
• a substituted phenyl ring When reference is made to a substituted phenyl ring, it is meant that the ring can be substituted with one or more of the named substituents as may be compatible with chemical synthesis. 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 substituent pattern.
• a pharmaceutically acceptable ester-forming group in R2 and R3 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 its application to a pharmaceutical use.
• esters are, for example, those formed with one of the following radicals: Ci to C alkyl, phenyl Ci -C6alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
• ester-forming radicals are those where R3 is alkyl, particularly alkyl of 1 to 10 carbons, (ie CH3-(CH2)n _ where n is
• R2 is referred to as being an amine, that includes the radical -NH2 and mono- or dialkylate derivatives of this -NH2 radical.
• Preferred alkylated amines are the mono- or disubstituted amines having 1 to 6 carbons.
• R2 is referred to as being an amide, that includes all acylate derivatives of the NH2 radical.
• the preferred amides are those having 1 to 6 carbons.
• amides may be formed.
• the most preferred amides are those where -R6 is hydrogen or alkyl of 1 to 6 carbon atoms. Particularly preferred is the diethylamide.
• salts of the instant compounds are 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.
• compositions 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 acid addition salts, or an excess of organic or inorganic base in the case where R4 is OH.
• Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid.
• Cationic salts are readily prepared from alkali metal bases such as sodium, potassium, calcium, magnesium, zinc, copper or the like and ammonia.
• Organic bases include the mono or disubstituted amines, ethylene diamine, piperazine, amino acids, caffeine, tromethamine, tris compounds and the like.
• N-oxides may also be prepared by means of selected oxidizing agents. These oxides are useful as intermediates in preparing the compounds of formula I and have useful pharmaceutical activity in and of themselves. Hence 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.
• these compounds can be used in treating a variety of disease assoicated with or attributing their origin or affect to leukotrienes, particularly LTB4.
• these compounds can be used to treat allergic diseases such of a pulmonary and non-pulmonary nature.
• these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated with these compounds.
• R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or substituted or unsubstituted pheny-Ci to Cj o-aliphatic-O-;
• Rj is -(C to C5 aliphatic)R4 or -(Ci to C 5 aliphatic)CH20Rs, and
• R2 is -COOH or -N(A)(B) where A is H, or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons or -SO2R9 where R9 is -CF3, Ci to C alkyl or phenyl.
• R2 is -COOH or a sulfonamide, particularly -NHSO2CF3.
• Another set of preferred compounds are the analines, those where R2 is N(R7)2, particularly where R7 is hydrogen.
• each of the compounds the methylene carbon of the T groups is substituted on the pyridyl ring.
• Synthesis may be made by the starting materials, intermediates and reagents set out in the following reaction flow charts. 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 only given 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 accomodate differences and optimize the particular conditions for making a particular compound. Such variations will be apparent to a chemist or will not require more than minimal experimentation to optimize conditions and reagents for a particular step.
• These compounds are made by forming the R group first, then preparing the intermediate form of the Ri group and finally coupling the phenyl containing the R2 group with the pyridyl ring. Thereafter the Ri and R2 groups may be further modified as desired.
• Scheme 1 illustrates means for making intermediates useful for preparing the R group which are not commercially available.
• Scheme 2 itself illustrates how to form the R group and thereafter how to further synthesize these compounds once the R group is formed.
• Scheme Ha illustrates how to form the R group and thereafter how to further synthesize these compounds once the R group is formed.
• an alkylsilazide is added to an inert solvent under an inert atmosphere.
• the phosphonium salt is added. This addition can be done at room temperature or thereabouts. After a brief period of mixing, this mixture is usually a suspension, the benzaldehyde is added slowly at about room temperature. A slight molar excess of the phosphonium salt is employed. After an additional brief period of stirring at about room temperature, the reaction is quenched with water. The solution is acidified and the acid extracted with a suitable organic solvent. Further separatory and purification procedures may be employed as desired.
• the alcohol (b) is made by reducing the acid using a reducing agent.
• a reducing agent Lithium aluminum hydride or similar reducing agents may be employed, and conditions may be varied as needed to effect the reduction.
• the tosylate (c) is prepared in an inert solvent employing a base such as pyridine. Suitable conditions include carrying out the reaction at room temperature or thereabouts for a period of 1 to 5 hours. Other leaving groups similar in function to the tosylate may be prepared and will be useful as a means for forming the R moiety.
• Reaction Scheme 1(b) outlines one method for making an alkoxyphenylalkyl R group. This method could be used to make other R groups where phenyl is the w group on the alphatic chain, including substituted phenyl-containing groups.
• an w-yn-1-ol in those instances where an w-yn-1-ol is not commercially available, it can be prepared from a corresponding 3-yn-l-ol by treating the alcohol with a strong base. Here an alkali metal amide is used. The alcohol is then protected in order to add the desired phenyl group at the terminal triple bond. A silyl ether is formed in this instance; it illustrates the general case. A halo-substituted -phenyl adduct is used to add the phenyl group at the triple bond. At this point, the triple bond can be reduced, most conveniently by catalytic means, eg. palladium-on-carbon under hydrogen. Alternatively, the triple bond could be retained and the intermediate carried on through to the tosylate as illustrated. The silyl group is removed and the resulting alcohol is converted to the tosylate or another group which is sufficiently reactive so as to form an ether in the synthesis of these compound.
• catalytic means eg. palla
• the starting material is available from Aldrich. It is treated with a mild oxidizing agent such as Mn ⁇ 2 to oxidize the 2-hydroxyethyl group to the corresponding aldehyde.
• the R group is then formed.
• an ether is prepared under basic conditions using an a-halo intermediate.
• a tosylate made as per Scheme 1, can also be used in this step.
• Introducing the acid function at position 2 (2a) is accomplished by means of a triphenylphosphoranylidene reagent. The acetate form is illustrated here but other similar reagents could be used.
• the N-oxide is then formed by means of a peroxy acid. Trifluoroacetic anhydride is used to oxidize the 6- position methyl group.
• This hydroxymethyl group is then converted to the corresponding halide (2b), (in the hydrohalide form) in this case the chloride, by means of thionyl chloride.
• An alkyl hydroxybenzoate is then reacted with the 6-chloromethyl compound in the presence of tetrabutylammonium iodide and a weak base.
• the resulting diester (2c) can be hydrolyzed to the salt or, further, acidified to give the free acid (2d).
• An oxidant can be used to regenerate the N-oxide (2e) which can then be treated with base to hydrolyze the esters (2f).
• Esters can be converted to salts, the free acids and other derivatives.
• Catalytic hydrogenation can be used to reduce the double bond in the Ri group described here.
• the starting hydrochloride is described in Scheme 2. Instead of treating the hydrochloride with an alcohol, in this instance the mercapto analog of the hydroxybenzoate described above is used.
• the resulting thioether (3a) can be hydrolyzed to give the salt or treated further to give the free acid from which other derivatives of the carboxyl function can be prepared, including alcohols and aldehydes.
• the double bond in the Ri group can be reduced by catalytic means using a heavy metal catalyst and hydrogen.
• the sulfone (3b, 3c) and sulfoxide (3d, 3e) can be prepared by treating the thioether with an oxidizing agent.
• an oxidizing agent A peroxy acid or other oxidizing agent can be used.
• 2-hydroxypicolinic acid is converted to the alkyl ester using the corresponding alcohol and an acid to catalyze the reaction.
• the hydroxyl group is then converted to the trifluoromethysulfonate (4a) by means of trifluoromethanesulfonic anhydride and a base, e.g. pyridine.
• the lipid tail is attached using the appropriate alkyl catechol boronate under palladium coupling conditions.
• 1-iododecene and catechol borane are reacted to form the alkyl catechol boronate.
• the alkylation reaction is effected using Pd(OAc)2 giving the compound 4b.
• the ester is reduced to the corresponding aldehyde with a hydride such as diisobutylaluminum hydride (DIBAL).
• DIBAL diisobutylaluminum hydride
• a Wittig olefination is then carried out using, for example, methyl(triphenylphosphoranylidene)- acetate.
• the resulting pyridyl ethyl acrylate (4C) is then oxidized to the N-oxide with an oxidizing agent such as 3-chloroperoxybenzoic acid. This oxide is then rearranged to the 2-pyridone with trif uoroacetic anhydride.
• a trifluoromethylsulfonate is then formed using trifluoromethanesulfonic anhydride and pyridine.
• Carbomethylation is then effected by means of Pd(OAc)2, a simple alcohol, and carbon monoxide (4d).
• Pd(OAc)2 a simple alcohol
• carbon monoxide (4d) Selectively reducing the pyridyl- ester (using a hydride such as NaBH 4 in a low molecular weight alcohol) yields the 2-(hydroxymethyl)-pyridine.
• This compound is treted with thionyl chloride to form the 6-chloromethyl compound of formula 4e.
• This intermediate, the aliphatic equivalent of 2b, is transformed to the ethers (4e) for thioether (4c) of formula I in the same manner as is illustrated in Schemes 2 and 3.
• the starting chloro compound can be prepared as per the same starting material in Schemes 2 and 3.
• the 6-chloromethyl compound is reacted with a t-BOC-protected amine or another protected amine or an unprotected amine, where R2 is preferably a ester group such as a carbomethoxy group.
• R2 is preferably a ester group such as a carbomethoxy group.
• Sodium hydride in dimethylformamide will affect the amine formation.
• the ester groups may then be hydrolyzed with a base to obtain the salt and the t-BOC protecting group removed by acidification (if utilized). This procedure is particularly useful for making compounds where the atom of the R group bonded to pyridyl is carbon or oxygen.
• 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.
• 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.
• 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.
• the compositions will be in a form suitable for administration by inhalation.
• the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
• 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.
• 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.
• the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
• the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose.
• the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
• 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.
• the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration.
• 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.
• 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.
• a therapeutically effective amount of a compound of formula I preferably in the form of a pharmaceutical composition.
• 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.
• 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.
• 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)methyl] -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 [ 3 H]-LTB4 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 (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% CO 2 , 95% air at 37°°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with DMSO to monocyte- like cells, the cells were seeded at a concentration of 1 x 10 5 cells/ml in the above medium with 1.3% DMSO and the incubation continued for 4 days.
• the cells were generally at a density of 0.75-1.25 x 10 6 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 50 mM Tris-HCl, pH
• [ 3 H] -LTB4 binding assays were performed at 25°°C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCl 2 , 10 mM MgCh, [ 3 H] - 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 [ 3 H]-LTB4 were determined in the absence or presence of 2 mM of unlabeled LTB 4, 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 0.2 nM [3H] -LTB , 20-40 mg of U937 cell membrane protein, increasing concentrations of LTB4(0.1 nM to 10 nM) or other competing ligands (0.1 mM to 30 mM) in a reaction volume of 0.2 ml 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.
• 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 2 ml aliquots.
• Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one minute 10 nM LTB 4 (a near maximal effective concentration) was added and the maximal Ca 2+ mobilization [Ca 2+ ]i was calculated using the following formula:
• F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with 10 ml of 10% Triton X- 100 (final Concentration 0.02%). After Fmax was determined 67 ml of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca 2 + and quench the fura-2 signal and obtain the Fmin.
• the [Ca 2+ ]i level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca 2+ ]i was 0%.
• the IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced [Ca 2+ ]i mobilization.
• the EC50 for LTB4 induced increase in [Ca 2+ ]i mobilization was the concentration for half maximal increase.
• the Kj for calcium mobilization was determined using the formula: IC50
• the LTB 4 concentration was 10 nM and the EC 50 was 2 nM.
• Several of the compounds of this invention were tested in one or more of the aforementioned assays. Results for those tests are given in Figure III; average results are given where more than one test was done.
• 6-(4-Methoxyphenyl)octan-l -ol was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C .
• 6-(4-Methoxyphenyl)hexan- l -f-butyldiphenylsilyl ether (2.0g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2S04).
• 6-(4-Methoxyphenyl)hexan-l-ol (5.36g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C .
• E-4-Methoxyphenyl-5-hexen-l -ol E-4-Methoxyphenyl-5-hexenoic acid (l . l g, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of LiAlH4 (240mg, ⁇ .Ommol) in ether (lOmL) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. Upon cooling to room temperature the reaction was quenched with H2O (lOmL) followed by 6N H2SO4 (7mL). Ethyl acetate (20mL) was added and the organic layer was separated and dried (MgS04); evaporation gave a white crystalline solid: mp.
• 3-Dodecyloxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry toluene (12mL) under an argon atmosphere and treated with methyl (triphenylphosphoranylidene)- acetate (5.0g, 15mmol). The reaction was heated for 1 hour at 50°C .
• Methyl 3-[ l -thia-2-[2-(E-2-carboxymethylethenyl)-3- dodecyloxy-6-pyridyl]ethyl]benzoate (320mg, 0.606mmol) was dissolved in dry CH2CI2 (2.5mL) and cooled to 0°C. 85% m- Chloroperoxybenzoic acid (130mg, 0.64mmol) was added and the solution was stirred for 10 minutes at 0°C. The reaction was diluted with ethyl acetate (60mL) and washed with saturated aqueous NaHC03 (2X20mL) and brine and dried (MgS ⁇ 4).
• Methyl 3-[l -oxythia-2-[2-(E-2-carboxymethylethenyl)-3- dodecyloxy-6-pyridyl]ethyl]benzoate 120mg, 0.221 mmol was dissolved in tetrahydrofuran (1.3mL) and methanol (0.66mL) under an argon atmosphere and treated with 1M LiOH (0.66mL, 0.66mmol).
• Methyl 3-[ l -thia-2-[2-(E-2-carboxymethylethenyl)-3- dodecyloxy-6-pyridyl]ethyl]benzoate (107mg, 0.197mmol) was dissolved in dry CH2CI2 (2mL), cooled to 0°C, and treated with 85% - chloroperoxybenzoic acid (44mg, 0.217mmol). The reaction was stirred at 0°C for 1.5 hours. The reaction was diluted with ethyl acetate (30mL) and washed with saturated aqueous NaHC ⁇ 3 (15mL) and brine and dried (MgS ⁇ 4).
• Methyl 3-[l -oxa-2-[2-(E-2-carboxymethylethenyl)-3- dodecyloxy-6-pyridyl]ethyl]benzoate (80mg, 0.156mmol) was dissolved in tetrahydrofuran (1.34mL) and methanol (0.50mL) and treated with 1M LiOH (0.50mL, 0.50mmol). The reaction was stirred at room temperature for 20 hours.
• the reaction was poured into aqueous NaHC ⁇ 3 and the product extracted into CH 2 C1 2 .
• the organic extract was washed with H 2 0 and brine and dried (MgS ⁇ 4).
• the crude product was obtained as a yellow solid and was used without further purification.
• the captioned compound was prepared according to the method set out in Scheme 5 above by reacting the appropriate t- O C- protected aminobenzoic acid with 2-(E-2-carboxymethylethenyl)-3- dodecyloxy-6-(chloromethyl)-pyridine hydrochloride or a similar intermediate, the captioned compound was prepared.
• Example 14 Preparation of Free Acids Any of the salts described in the foregoing Examples may be converted to the free acid by dissolving the salt in water, then adding sufficient acid, for example HCl, to bring down the pH to 7.0 or less will provide the free acid. It, the free acid, will either precipitatate out of solution, or may be extracted, or recovered by other separatory means know in the art.
• sufficient acid for example HCl
• Example 15 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.
• Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
• Step 2 Add sufficient water portion wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
• Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
• Step 4 The wet granules are then dried in an oven at 410°F (60°C) until dry.
• Step 5 The dry granules are lubricated with ingredient No. 5.
• Step 6 The lubricated granules are compressed on a suitable tablet press.
• Step 1 Melt ingredient No. 2 and No. 3 together and stir until uniform.
• Step 2 Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
• Step 3 Pour the molten mass from Step 2 into supository moulds and chill.
• Step 4 Remove the suppositories from moulds and wrap.
• Inhalation Formulation A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow. Adjusted to deliver the desired amount of drug per use.

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