WO1991018879A1 - Derives d'acide phtalamique utilises dans le traitement de maladies associees aux leucotrienes - Google Patents

Derives d'acide phtalamique utilises dans le traitement de maladies associees aux leucotrienes Download PDF

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WO1991018879A1
WO1991018879A1 PCT/US1991/003398 US9103398W WO9118879A1 WO 1991018879 A1 WO1991018879 A1 WO 1991018879A1 US 9103398 W US9103398 W US 9103398W WO 9118879 A1 WO9118879 A1 WO 9118879A1
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compound
aliphatic
aryl
alkyl
substituted
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PCT/US1991/003398
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Robert A. Daines
William Dennis Kingsbury
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Smithkline Beecham Corporation
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Priority to JP91510826A priority Critical patent/JPH05507701A/ja
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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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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

  • Phthalamic Acids and Their Isomers For Treating Leukotriene-related Diseases Scope of the Invention relates to substituted phthalamic acids and isomers thereof which are useful for treating diseases associated with leukotrienes. These compounds are particularly useful in treating diseases attributable to leukotrienes, especially hydroxyleukotrienes such as 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 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 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.
  • LTB 4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs).
  • LTB4 Leukotriene B4
  • SUBSTITUTE SHEET 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. 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 LTB4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity.
  • LTB4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis. They are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
  • the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor.
  • T is CO or CH(OH)
  • R is Cj to C20- a liphat_ c > unsubstituted or substituted phenyl C ⁇ to Ci 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 Ci to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Ci to Ci o-a ⁇ phatic-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)R3,-(Cl to C5 aliphatic)CHO, -(Cl to C5 aliphatic)CH20R7, R3, -CH2OH or -CHO;
  • R2 and R3 are independently -COR4 where R4 is -OH, a pharmaceutically acceptable ester-forming group -OR5, or -OX where X is a pharmaceutically acceptable cation, or R4 is -N(R6)2 where R6 is H, or an aliphatic group of 1 to 10 carbon atoms or a cycloalkyl- (CH2)n- group of 4 to 10 carbons where n is 0-3 or both R6 groups form a ring having 4 to 6 carbons, or R2 is an amine, amide or sulfonamide; and
  • R7 is hydrogen, Cl to C6-alkyl, or Ci to C6-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 LTB 4, or related pharmacologically active mediators at the end organ, are within the scope of this invention.
  • This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient in an amount sufficient to prevent disease or treat it once it has occurred.
  • this invention relates to a method for making the compounds of this invention.
  • This aspect of the invention 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.
  • 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.
  • esters whi.ch 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 R5: Cl to CiO alkyl, phenyl-Ci - C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl.
  • Aryl includes phenyl and naththyl, or heteroaromatic radicals like furyl, thienyl, imidazolyl, triazolyl or tetrazolyl.
  • the most preferred ester-forming radicals are those where R5 is alkyl, particularly alkyl of 1 to 10 carbons, [ie CH3-(CH2)n- where n is 0-9], or phenyl-(CH2)n _ where n is 0-4.
  • R2 When 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 When 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. Where there is an acid group, 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.
  • the hydroxyl group of the 2-hydroxyethylene linking group may be esterified. Lower alkyl acids of 1 to 6 carbon atoms may be used to form such esters using standard reaction conditions. This hydroxyl group also may be converted to an ether if so desired. Again, such reactions are well known in the synthetic chemical arts.
  • 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 in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts of a basic moiety, 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, other tris compounds 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. 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.
  • 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 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 phenyl Ci to Ci o-aliphatic-O-; Ri is -(Ci to C5 aliphatic)R3 or -(C- to C 5 aliphatic)CH20R7 , 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 -SO2R8 where R_ is -CF3, Ci to C ⁇ alkyl or phenyl.
  • These compounds may be made by the starting materials, intermediates and reagents and the synthetic steps set out in the following reaction flow charts. These charts trace the path used to make these compounds and are based on the detailed chemistry set out in the Examples recited below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are 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 accommodate 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.
  • reaction schemes first illustrate how to make certain portions of the R group which are not commercially available, then illustrate a means to assemble the whole compound using the materials from Reaction Scheme 1 or commercially available R- forming 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. An alkali metal amide may be 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. The silyl group is removed and the resulting alcohol 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.
  • Scheme 1(b) illustrates another method for making certain alkoxy-substitutedphenylalkoxy R groups.
  • methoxyphenyl compound is illustrated here, this series of steps and reagents may be used to make other ⁇ -(unsubstituted)phenylaliphatic or ⁇ -(substituted)phenylaliphatic groups denoted by R.
  • the starting material, the benzaldehydes, are commercially available or can be readily made by known methods.
  • 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 (a) 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.
  • 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-toluenesulfonylchloride 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.
  • This hydrazone is then converted to a triazolo[l,5- ⁇ ]pyridine(2a) by means of Ni ⁇ 2 or another oxidizing agent such as KFe(CN) 6 - If nickel peroxide is used, the reaction can be effected at room temperature or thereabouts, though it may require an extended reaction time. For the nickel peroxide process, an inert atmosphere is preferred, as are dry conditions. Other oxidizing agents may require elevated temperatures.
  • the 2-hydroxyethyl product is then made by first preparing i n situ a reagent capable of extracting a proton from the triazolopyridine compound after which the triazolo compound is added followed by a halobenzaldehyde.
  • a useful base is lithium diisopropylamide. It is preferable to prepare it at reduced temperatures, i.e. -40 to 0°C or thereabouts. After the triazolopyridine and benzaldehyde are added, the reaction is allowed to run its course at room temperature or thereabouts. A carbonylation reaction is then carried out to introduce a carboxyl group into the phenyl ring.
  • a Wittig reaction is then carried out to form the carbomethoxyethylene group at position 2 on the pyridyl ring.
  • This compound can be treated with a base to hydrolyze the esters, which is then acidified if the free acid (2d) is desired.
  • the ethylene group at position 2 can be saturated by catalytic hydrogenation, then saponified using a base, which gives the salt, or thereafter acidifying the soluton to obtain the free acid (see Scheme 3 below).
  • the acid can be converted to a pharmaceutically acceptable salt or esterified by known means.
  • Amides can be made from the acids using known procedures.
  • Compounds of this invention where the linking group T is ethylene can be prepared by following the procedure illustrated in Scheme 2, but substituting a halobenzylhalide compound for the halobenzaldehyde used in Scheme 2.
  • 2-bromobenzylbromide may be used in place of the -iodobenzaldehyde illustrated in Scheme 2 to make the triazolopyridine compound.
  • esters can be hydrolyzed with base and further converted to other forms of formula I from there or transesterification can be used to convert to another ester.
  • the Ri carbomethoxy group can be reduced to the alcohol using a reducing agent such as diisobutylaluminum hydride (DIBAL) or a similar reducing agent.
  • DIBAL diisobutylaluminum hydride
  • Catalytic hydrogenation can be used to saturate the ethylene group at position 2 on the pyridyl ring.
  • a base can be used to saponify the ester to obtain the acid salt, or that salt can be acidified if the free acid is desired.
  • Each of the products containing an hydroxyl group in Schemes 2-4 can be oxidized to the corresponding ketone, that is where T is - CH2C(0)-, by means of a mild oxidizing agent.
  • 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 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.
  • 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.
  • 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.
  • 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% CO2, 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
  • the pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25°C and aliquots were rapidly frozen and stored at -70°C . Binding of TIHI-LTB to U397 Membrane Receptors
  • [ 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 nM [ 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 (fura-2/AM) was added to a final concentration of 2 ⁇ M 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 fluorescence of fura-2 containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant mixing.
  • U937 cells were diluted with fresh buffer to a concentration of 1 x 10 6 cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 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 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 ⁇ 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.
  • the [Ca 2+ ] ⁇ 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:
  • the LTB4 concentration was 10 nM and the EC50 was 2 nM.
  • 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 (Na2S ⁇ 4).
  • the aqueous layer was acidified to pH 1.0 with 3N HCl and the product was extracted into ethyl acetate (3X50mL).
  • the combined organic layers were dried (MgS ⁇ 4) and the product was purified by flash column chromatography (silica, 1% methanol in CH2CI2) to yield the E-olefin as a solid: !H NMR (200MHz, CDCI3) ⁇ 7.3 (d, 2H, aryl), 6.8 ⁇ , 2H, aryl), 6.3 (d, IH, olefin), 6.0 (m, IH, olefin), 3.8 (s, 3H, OCH3), 2.3 (m, 4H, allylic CH2 and CH2CO2), 1.8 (q, 2H, CH2).
  • E-4-Methoxyphenyl-5-hexen-l -ol E-4-Methoxyphenyl-5-hexenoic acid (l .lg, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of LiAlH4 (240mg,
  • E-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).
  • 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry dimethylformamide (lOmL) and treated with 1-iododecane (2.1mL, 8.62mmol) and anhydrous K2CO3 (3.0g, 21.7mmol) under an argon atmosphere.
  • the reaction was heated at 90°C for 1 hour with vigorous stirring.
  • the reaction mixture was poured into ethyl acetate (lOOmL); the ethyl acetate solution was washed with H2O (3X20mL) and brine and dried (MgS ⁇ 4).
  • This salt was prepared from 2-(E-3-hydroxypropenyl)-3- decyloxy-6-[2-(3-carboxymethylphenyl)-2-hydroxy]ethylpyridine [Example 3(e)] according to the procedure described for 2-(E-2- carboxyethenyl)-3-decyloxy-6-[2-(3-carboxyphenyl)-2- hydroxyjethylpyridine, dilithium salt [Example l(i)].
  • dilithium salt 2-(E-2-Carboxyethenyl)-3- [6-(4-methoxyphenyl)hexyloxy] -6- [2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine, dilithium salt was prepared according to the procedure described for 2-(E-2- carboxyethenyl)-3 -decyloxy-6-[2-(3-carboxyphenyl)-2- hydroxy]ethylpyridine, dilithium salt recited in Example 1 , but substituting 6-(4-methoxyphenyl)hexan-l -(4-toluenesulfonate) [Example B(5)] for 1-iododecane.
  • 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.
  • 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.
  • 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 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 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 suppository moulds and chill.
  • Step 4 Remove the suppositories from moulds and wrap.

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Abstract

L'invention concerne des composés de la formule (α), dans laquelle T représente une liaison amide et les groupes R ont la notation ci-définie. Ces composés sont utiles comme antagonistes de leucotriènes.
PCT/US1991/003398 1990-06-07 1991-05-15 Derives d'acide phtalamique utilises dans le traitement de maladies associees aux leucotrienes WO1991018879A1 (fr)

Priority Applications (1)

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JP91510826A JPH05507701A (ja) 1990-06-07 1991-05-15 ロイコトリエン関連疾患治療用フタルアミド酸およびその異性体

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US534,398 1990-06-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993022285A1 (fr) * 1992-05-01 1993-11-11 Smithkline Beecham Corporation Antagonistes de leucotrienes
WO1994002464A1 (fr) * 1992-07-21 1994-02-03 Schering Aktiengesellschaft Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4?
KR100753353B1 (ko) * 2002-08-07 2007-08-30 인케, 에스.아. 졸미트립탄 화합물의 제조방법
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4056619A (en) * 1975-09-08 1977-11-01 Warner-Lambert Company 1-Substituted-2-(2-pyridinyl)ethanone N-oxides

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US4056619A (en) * 1975-09-08 1977-11-01 Warner-Lambert Company 1-Substituted-2-(2-pyridinyl)ethanone N-oxides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 110, No. 25, issued 19 June 1989, (Columbus, Ohio, USA), SZCZEPANSKI et al., Preparation of 2- (imidazlin- 231630-m abstracting, European Patent Application No. (EP) 296,109, 21 Dec. 1988. *
CHEMICAL ABSTRACTS, Vol. 53, No. 25, issued 19 June 1989, (Columbus, Ohio, USA), PLIENINGER et al., Condensation of 2-methyl substituted pyridinecarbixylic acid esters with aromatic aldehydes and ketones, pages 3221(c)- 3222(d), abstracting Chem. Ber. 91, pages 1898-1905 (1958). *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993022285A1 (fr) * 1992-05-01 1993-11-11 Smithkline Beecham Corporation Antagonistes de leucotrienes
WO1994002464A1 (fr) * 1992-07-21 1994-02-03 Schering Aktiengesellschaft Nouveaux derives de pyridine a effet antagoniste contre les leucotrienes b¿4?
US5624943A (en) * 1992-07-21 1997-04-29 Schering Aktiengesellschaft Pyridine compounds which are useful as leukotriene-B4 -antagonists
KR100753353B1 (ko) * 2002-08-07 2007-08-30 인케, 에스.아. 졸미트립탄 화합물의 제조방법
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

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JPH05507701A (ja) 1993-11-04
AU7999691A (en) 1991-12-31
EP0532634A1 (fr) 1993-03-24

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