WO1991018883A1 - Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes - Google Patents

Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes Download PDF

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WO1991018883A1
WO1991018883A1 PCT/US1991/003940 US9103940W WO9118883A1 WO 1991018883 A1 WO1991018883 A1 WO 1991018883A1 US 9103940 W US9103940 W US 9103940W WO 9118883 A1 WO9118883 A1 WO 9118883A1
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compound
pharmaceutically acceptable
aliphatic
phenyl
pyridyl
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PCT/US1991/003940
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English (en)
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Robert A. Daines
William Dennis Kingsbury
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Smithkline Beecham Corporation
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Priority to JP91510669A priority Critical patent/JPH05507698A/ja
Priority to KR1019920703092A priority patent/KR930700448A/ko
Publication of WO1991018883A1 publication Critical patent/WO1991018883A1/fr
Priority to NO92924701A priority patent/NO924701L/no
Priority to FI925546A priority patent/FI925546A0/fi

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    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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

Definitions

  • This invention relates to amide 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 LTB 4 -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 C 4 , D 4 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 in the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response is expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses.
  • the pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and increased mucous production.
  • LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).
  • Leukotriene B4 was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S), 12(R)-dil ydro enoic acid.
  • LTB4 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.
  • 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. LTB 4 has been established as an inflammatory mediator in vivo.
  • 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 factor. Some of these compounds may also inhibit the 5-lipoxygenase enzyme or may be LTD4 antagonists.
  • R is Cj to C20- liphatic, unsubstituted or substituted phenyl Ci to Ci o -aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, or halo, or R is C ⁇ to C20-a ⁇ phatic-O-, or R is unsubstituted or substituted phenyl Cj to Ci ⁇ -aliphatic-O- where substituted phenyl has one or more radicals which are lower alkoxy, lower alkyl, trihalomethyl, or halo;
  • Rl is R4, -(Ci to C5 aliphatic)R4, -(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH20R8, -CH2OH 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(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 combine to form a ring having 4 to 6 carbons, or R2 is NHSO2R9 where R9 is -CF3, C ⁇ to C ⁇ alkyl or phenyl;
  • R3 is hydrogen, lower alkoxy, halo, -CN, COR5, or OH;
  • R4 is -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(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 combine to form a ring having 4 to 6 carbons; R ⁇ s hydrogen, C ⁇ to C6 alkyl, or Ci to C6-acyl.
  • this invention covers pharmaceutical compositions containing the instant compounds and 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 below. DETAILED DESCRIPTION OF THE INVENTION The following definitions are used in describing this invention and setting out what the inventors believe to be their invention ⁇ herein. "Aliphatic" is intended to include saturated and unsaturated radicals.
  • 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 means the radical having a terminal carbonyl carbon.
  • 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.
  • 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 their application to a pharmaceutical use. By that it is meant that the mono or diesters will retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases.
  • esters are, for example, those formed with one of the following radicals representing -OR6 where Re is: Ci to Ci 0 alkyl, phenyl-Ci -C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienyl glycyloxymethyl.
  • Re is: Ci to Ci 0 alkyl, phenyl-Ci -C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglyc
  • Aryl includes phenyl and naphthyl, or heteroaromatic radicals like furyl, thienyl, imidazolyl, triazolyl or tetrazolyl.
  • Most preferred ester-forming radicals are those where R is alkyl, particularly alkyl of 1 to 10 carbons, [i.e. CH3-(CH2)n _ where n is 0-9], or phenyl-(CH2) n - where n is 0-4.
  • 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.
  • compositions are prepared in a standard manner.
  • the parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts of a base moiety, or an excess of organic or inorganic base 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, amino acids, caffiene, tromethamine, tris compounds, triethyl amine, piperazine and the like.
  • Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.
  • 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.
  • these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4.
  • these compounds can be used to treat allergic diseases including those 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 by these compounds.
  • R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or substituted or unsubstituted phenyl-Ci to Ci o ⁇ aliphatic-0-; Ri is -(Ci to C5 aliphatic)R4 or -( to C5 aliphatic)CH20R8; and R2 is COOH or an alkali metal salt thereof or NHSO2R9 where R9 is -CF3, Ci to C ⁇ alkyl or phenyl.
  • Scheme 1 illustrates a method for making compounds useful in making the R group.
  • the other schemes use the materials whose preparation is described in scheme 1, or intermediates from commercial sources, to form the R group, then illustrate a method for making the compounds of formula I.
  • R groups in formula I are available from chemical supply houses or can be made by one of the two methods outlined in Reaction Scheme I.
  • Scheme 1(a) illustrates a method for making an unsaturated phenyl-alphatic R group.
  • an alkylsilazide is added to an inert solvent under an inert atmosphere.
  • the phosphonium salt 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 standard separatory and purification procedures may be employed as desired.
  • the alcohol 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 is prepared in an inert solvent employing p- toluene sulfonyl chloride and 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 suitable leaving groups similar in function to the tosylate may be prepared and will be useful as a means for adding this R moiety to the pyridyl ring.
  • 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 ⁇ group on the aliphatic chain, including substituted phenyl-containing groups.
  • an ⁇ -yn-1-ol in those instances where an ⁇ -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 was used. The alcohol is then protected in order to add the desired phenyl group at the terminal triple bond. A silyl ether was 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 and hydrogen. Alternatively, the triple bond could be retained and the intermediate carried on through as illustrated to the tosylate. The silyl group is removed and the resulting alcohol is converted to the " tosylate, or another group which is sufficiently reactive so as to provide ready formation of an ether later in the synthesis of these compound.
  • catalytic means
  • the foregoing scheme illustrates one synthetic route for making compounds of formula I where the carboxyl carbon is on the pyridyl ring.
  • the 3-hydroxy-2-(hydroxymethyl)pyridine is commercially available or can be prepared by known, published means. This diol may be converted either to the aldehyde, then converted to the 3 -alkoxy compound, or the 3-hydroxy group may be converted to the ether first, then the 2-position hydroxymethyl is oxidized to the aldehyde. Oxidizing the alcohol is readily accomplished using a mild oxidizing agent; manganese dioxide is preferred but other oxidizing agents could be successfully utilized in this step. Ethers are readily prepared from the corresponding ⁇ -halo-R group, or a compound such as a tosylate, under basic conditions.
  • This 3 -substituted-2-carboxy aldehyde (c) is then converted to the 2-carbomethoxyethenyl form (d) by means of the appropriate phosphoranylidene ester under conditions normally used for such a reaction.
  • the resulting ester is then treated with a peroxy acid to make the N-oxide in preparation for making the pyridone (e).
  • This step is illustrated by m-chloroperoxybenzoic acid, but ' other similar oxidizing agents could be used as well.
  • Rearrangement of the N-oxide is then accomplished by means of trifluoroacetic anhydride or a similar reagent to produce the 2-pyridone (f).
  • Converting the 2-pyridone to the amide is accomplished by acylating the 2-pyridone (g) and then reacting this ester with the desired aminobenzoate (h) in the presence of certain catalysts and carbon monoxide.
  • Trifluoromethanesulfonic anhydride illustrates the acylation step.
  • the amidation reaction is effected by bubbling carbon monoxide through a solution of the triflate in the presence of Pd(OAc)2, l ,l '-bis(diphenylphosphino)ferrocene.
  • the resulting diester (i) is then saponified using a mineral base to hydrolyze the ester groups.
  • the resulting salt may be neutralized in order to recover the free acid.
  • a free acid can be converted to another ester or made into the corresponding amide by known methods.
  • the diester is catalytically reduced (3a) by means of a heavy metal catalyst and hydrogen in a classic catalytic reduction reaction. Once the reduction is complete, a base can be used to hydrolyze the diester if the diacid (3b) is desired. Either compound can be converted to other compounds of this invention by the appropriate oxidation, reduction, esterification, amidation reaction, or by other means.
  • Carbon analogs of these compounds that is those where the atom linking the R group to the 3-position is methylene, may be prepared by the sequence of steps set out in the fourth flow chart.
  • 3-Hydroxypicolinic acid is converted to the alkyl ester by means of the corresponding alkanol and a acid catalyst.
  • the hydroxyl group is converted to the trifluoromethanesulfonate (4a) using trifluoromethanesulfonic anhydride and pyridine.
  • the lipid tail is then attached (4b) using the appropriate alkyl catechol boronate, prepared from 1-tridecene and catechol borane, using palladium coupling conditions ([Pd(OAc)2_.
  • the alkyl ester is transformed into the corresponding aldehyde using an appropriate hydride, for example diisobtylaluminum hydride.
  • This aldehyde is then subjected to a Wittig olefination, using for example, methyl(triphenyl- phosphoranylidene)acetate.
  • the resulting pyridyl acrylate is then converted to the target compound via the same set of steps outlined in Scheme 2 above.
  • Reverse amides can be made by the sequence of steps given in Scheme 5.
  • the commercially available 3-hydroxypicolinic acid is converted to an alkyl ester using an acid catalyst and the corresponding alkanol. This is followed by alkylation under standard conditions with, for example 1-idododecane or a similar 1 -halo compound. This is best done using a weak base such as K2CO3 in dimethylformamide. This gives the 3 -alkoxy derivative.
  • Oxidizing the pyridine nitrogen and rearranging the resulting N-oxide provides the 2-pyridone.
  • Oxidation is readily effected with a peroxy acid such as 3-chloroperoxybenzoic acid or similar oxidizing agent.
  • the N-oxide (5a) rearrangement can be accomplished using trifluoroacetic anhydride in an appropriate solvent such as dimethylformamide.
  • Forming the trifluoromethanesulfonate is effected by means of trifluoromethanesulfonic anhydride and a base such as pyridine.
  • Nucleophilic displacement with sodium azide gives the 2-azido pyridine derivative (5b).
  • Reducing the azide to the amine is accomplished by catalytic hydrogenation.
  • Reducing the alkyl ester to the aldehyde is done with a hydride, for example diisobutylaluminum hydride.
  • a Wittig reaction is then used to make the 2-amino pyridine acrylate (5c). For example methyl(triphenylphosphoranylidene)- acetate may be used.
  • 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 compositon 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.
  • compositions 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 pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or non-aqueous 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.
  • 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 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.
  • 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 50 mg to about 5000 mg.
  • 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 class (diphenhydramine), ethylenediamines (pyrilamine), the alkylamine class (chlorpheniramine), the piperazine class (chlorcyclizine), and the phenothiazine class (promethazine).
  • H 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 invention.
  • 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 antagonist activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows: U937 Cell Culture Conditions
  • [ 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 MgCl 2 , [ 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 ⁇ M 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 ⁇ M [ 3 H] -LTB4, 20-40 ⁇ g of U937 cell membrane protein, increasing concentrations of LTB4 (0.1 nM to 10 nM) or other competing ligands (0.1 ⁇ M to 30 ⁇ M) 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.
  • the diacetomethoxy ester of fura-2 was added to a final concentration of 2 nM 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 10 6 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 6 cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements .
  • 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 ⁇ l 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 LTB4 (a near maximal effective concentration) was added and the maximal Ca 2+ mobilization [Ca + ]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 ⁇ l of 10% Triton X-100 (final Concentration 0.02%). After Fmax was determined 67 ⁇ l 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.
  • Triton X-100 final Concentration 0.02%
  • [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 lOnM LTB4 induced [Ca 2+ ]i mobilization.
  • the EC50 for LTB 4 induced increase in [Ca 2+ ]i mobilization was the concentration for half maximal increase.
  • the Kj for calcium mobilization was determined using the formula: T ⁇ , _ IC 50 l " [LTB 4 ]
  • A(2 7-Octyn-l -f-butyldi phenyl silyl ether 7-Octyn-l -ol (3.8g, 30mmol) was dissolved in dimethyl ⁇ formamide (lOmL) and treated with f-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2S ⁇ 4).
  • 6-(4-Methoxyphenyl)octan-l-ol (5.9g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C .
  • pyridine 2.5mL, 30mmol
  • 4-toluenesulfonyl chloride 5.4g, 28mmol.
  • the reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours.
  • the reaction solution was washed with H2O and brine and dried (Na2S 04).
  • the solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: !
  • 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-6-(4-Methoxyphenyl)-5-hexen-l -ol (1.6g, 7.0mmol) was dissolved in dry CH2CI2 (50mL) under an argon atmosphere and treated with 4-toluenesulfonyl chloride (7.0g, 36mmol) and pyridine (3mL). The reaction solution was stirred at room temperature for 3.5 hours. Water (40mL) was added to the reaction and the organic layer was separated and dried (MgS ⁇ 4).
  • N-(3-Carboxymethylphenyl)-6-(E-2-carboxymethylethenyl)-5- decyloxy-2-picolinamide (60mg, 0.121mmol) was dissolved in . tetrahydrofuran (1.25mL) and MeOH (0.50mL) and treated with IM LiOH (0.50mL). The reaction was stirred at room temperature for 6 hours. The reaction was made mildly acidic by the addition of 2% HCl (0.75mL), it was then diluted with ethyl acetate (50mL) and washed with H2O (3X1 OmL) and brine and dried (MgS04); the solvent was removed in vacuo.
  • the diacid was dissolved in saturated aqueous Na2C ⁇ 3 (3-5mL) and purified by Reversed Phase MPLC (RP-18 silica, 10-65% MeOH in H2O) and isolated by lyophilization and was obtained as a white amorphous solid: - ⁇ l NMR (250MHz, CD3OD) ⁇
  • N-(3-Carboxymethylphenyl)-6-(E-2-carboxymethylethenyl)-5- decyloxy-2-picolinamide (70mg, 0.141 mmol) was dissolved in ethyl acetate (lmL), treated with 5% Pd/C (lOmg), and stirred under an atmosphere of H2 (balloon pressure) for 4 hours.
  • the reaction could not be followed by TLC and the product was not soluble in ethyl acetate.
  • the precipitated product was dissolved by the addition of CH2CI2 (5mL) and the solution was filtered through a pad of Celite.
  • N-(3-Carboxymethylphenyl)-6-(2-carboxymethylethyl)-5 - decyloxy-2-picolinamide (54mg, 0.108mmol) was suspended in tetrahydrofuran (l .lmL) and methanol (0.70mL) and treated with IM LiOH (0.45mL, 0.45mmol). The reaction was stirred at room temperature for 30 hours. The reaction mixture was diluted with ethyl acetate (50mL) and poured into 2% HCl (15mL). The ethyl acetate layer was washed with H2O (3X20mL) and brine and dried (MgS ⁇ 4).
  • Example 1 The method of Example 1 (g) was used to prepare N-(3- carboxymethylphenyl)-6-(E-2-carboxymethylethenyl)-5-decyloxy-2- picolinamide:
  • (dilithium salt) N-(3-Carboxyphenyl)-6-(E-carboxyethenyl)-5-dodecyloxy-2- picolinamide, dilithium salt was prepared according to the procedure described for N-(3-carboxyphenyl)-6-(E-carboxyethenyl)-5- tetradecyloxy-2-picolinamide, dilithium salt by substituting 1 -iodododecane for 1-iodotetradecane (See Example 3).
  • N-(3 -Carboxyphenyl)-6-(E-carboxyethenyl)-5-octyloxy-2- picolinamide, dilithium salt was prepared according to the procedure described for N-(3-carboxyphenyl)-6-(E-carboxyethenyl)-5- tetradecyloxy-2-picolinamide, dilithium salt (Example 3), substituting 1 -iodooctane for 1 -iodotetradecane.
  • Example 6 N-(3 -Carboxyphenyl)-6-(E-2-carboxyethenyl)-5 -r8-(4- methoxyphenyl)octyloxyl-2-picolinamide.
  • dilithium salt N-(3-Carboxyphenyl)-6-(E-2-carboxyethenyl)-5-[8-(4- methoxyphenyl)octyloxy]-2-picolinamide
  • dilithium salt was prepared according to the procedure described for N-(3-carboxyphenyl)-6-(E- 2-carboxyethenyl)-5-tetradecyloxy-2-picolinamide, dilithium salt (Example 4), substituting 8-(4-methoxyphenyl)octan-l -(4- toluenesulfonate) for 1 -iodotetradecane (See Example 3). Following the procedures of Example 3(d) et seq,
  • Example 7 Salts may be converted to the free acid by dissolving the salt in an aqueous solution and adding sufficient acid so as to bring the pH to about neutral (pH 7.0) or thereabouts.
  • Any acid may be used though it is preferred to use a mineral acid such as HCl or the like. It is preferred to use a dilute rather than a concentrated acid, for example a 1 to 6 normal solution is most useful. Acid may be added at room temperature or thereabouts; no special conditions are required. Once the solution reaches a neutral pH or becomes acidic, the acid will precipitate out of solution an may be recovered by crystallization techniques, or any other technique which may prove useful for a given acid.
  • Example 8 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • Inhalant Formulation A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosilized from a nebulizer operating at an air flow adjustd to deliver the desired amount of drug per use.
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portionwise 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 (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 and remove the suppositories from moulds and wrap.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de la formule (I), dans laquelle T représente une liaison amide et les groupes R ont la notation ci-définie. Ces composés sont utiles en tant qu'antagonists de leucotrienes.
PCT/US1991/003940 1990-06-07 1991-06-05 Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes WO1991018883A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP91510669A JPH05507698A (ja) 1990-06-07 1991-06-05 ロイコトリエン関連疾患治療用アミド結合ピリジル―安息香酸誘導体
KR1019920703092A KR930700448A (ko) 1990-06-07 1991-06-05 로이코트리엔-관련 질병 치료용 아마이드 결합된 피리딜-벤조산 유도체
NO92924701A NO924701L (no) 1990-06-07 1992-12-04 Amid-bundete pyridyl-benzosyrederivater for behandling avleukotrien-relaterte sykdommer
FI925546A FI925546A0 (fi) 1990-06-07 1992-12-07 Amidkopplade pyridylbensoesyraderivat foer behandling av leukotrien-associerade sjukdomar

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US53438790A 1990-06-07 1990-06-07
US534,387 1990-06-07

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AU (1) AU7982591A (fr)
CA (1) CA2083956A1 (fr)
FI (1) FI925546A0 (fr)
HU (1) HUT64521A (fr)
IE (1) IE911938A1 (fr)
IL (1) IL98412A0 (fr)
MA (1) MA22197A1 (fr)
PT (1) PT97911A (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002464A1 (fr) * 1992-07-21 1994-02-03 Schering Aktiengesellschaft Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4?
ES2065234A1 (es) * 1992-10-27 1995-02-01 Smithkline Beecham Corp Compuestos para tratar enfermedades relacionadas con los leucotrienos.
US6291530B1 (en) 1996-09-26 2001-09-18 Novartis Ag Aryl-substituted acrylamides with Leukotriene B4 (LTB-4) receptor antagonist activity
EP2520654A1 (fr) 2003-08-26 2012-11-07 The Regents of the University of Colorado Inhibiteurs de l'activité de sérine protéase et leur utilisation dans des procédés et compositions pour le traitement des infections bactériennes

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102060758B (zh) * 2010-12-21 2012-12-05 杭州师范大学 一种4-苄氧基-吡啶-2-酮的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4555520A (en) * 1984-08-20 1985-11-26 E. R. Squibb & Sons, Inc. 2-Pyridylcarboxamides which inhibit arachidonic acid release

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4555520A (en) * 1984-08-20 1985-11-26 E. R. Squibb & Sons, Inc. 2-Pyridylcarboxamides which inhibit arachidonic acid release

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994002464A1 (fr) * 1992-07-21 1994-02-03 Schering Aktiengesellschaft Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4?
ES2065234A1 (es) * 1992-10-27 1995-02-01 Smithkline Beecham Corp Compuestos para tratar enfermedades relacionadas con los leucotrienos.
US6291530B1 (en) 1996-09-26 2001-09-18 Novartis Ag Aryl-substituted acrylamides with Leukotriene B4 (LTB-4) receptor antagonist activity
EP2520654A1 (fr) 2003-08-26 2012-11-07 The Regents of the University of Colorado Inhibiteurs de l'activité de sérine protéase et leur utilisation dans des procédés et compositions pour le traitement des infections bactériennes
EP3192872A1 (fr) 2003-08-26 2017-07-19 The Regents of the University of Colorado, a body corporate Inhibiteurs de l'activité de sérine protéase et leur utilisation dans les procédés et compositions pour le traitement des infections bactériennes

Also Published As

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IL98412A0 (en) 1992-07-15
EP0532621A1 (fr) 1993-03-24
IE911938A1 (en) 1991-12-18
KR930700448A (ko) 1993-03-15
AU7982591A (en) 1991-12-31
FI925546A (fi) 1992-12-07
MA22197A1 (fr) 1992-04-01
JPH05507698A (ja) 1993-11-04
CA2083956A1 (fr) 1991-12-08
PT97911A (pt) 1992-03-31
CN1057834A (zh) 1992-01-15
ZA914369B (en) 1992-06-24
HU9203868D0 (en) 1993-03-29
FI925546A0 (fi) 1992-12-07
HUT64521A (en) 1994-01-28

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