WO1991018880A1 - Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene - Google Patents

Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene Download PDF

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WO1991018880A1
WO1991018880A1 PCT/US1991/003399 US9103399W WO9118880A1 WO 1991018880 A1 WO1991018880 A1 WO 1991018880A1 US 9103399 W US9103399 W US 9103399W WO 9118880 A1 WO9118880 A1 WO 9118880A1
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compound
aliphatic
aryl
alkyl
substituted
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PCT/US1991/003399
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English (en)
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Robert A. Daines
William Dennis Kingsbury
Israil Pendrak
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Smithkline Beecham Corporation
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Priority to KR1019920703090A priority Critical patent/KR930700445A/ko
Priority to JP91509448A priority patent/JPH05507475A/ja
Publication of WO1991018880A1 publication Critical patent/WO1991018880A1/fr
Priority to NO92924700A priority patent/NO924700L/no
Priority to FI925544A priority patent/FI925544A0/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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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

  • This invention relates to certain substituted pyridyl-(2- hydroxyethyl)benzoic acid derivatives and their ketone analogs which are useful for treating diseases associated with leukotrienes. These compounds are particularly useful in treating diseases attributable to the 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.
  • SRS-A Slow Reacting Substance of Anaphylaxis
  • 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).
  • PMNs polymorphonuclear leukocytes
  • LTB4 Leukotriene B4
  • 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 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.
  • R is Ci to C20 -aliphatic, unsubstituted or substituted phenyl Ci to Cio-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 _a l h tic-O-, or R is unsubstituted or substituted phenyl C to Cj 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 ali ⁇ hatic)CHO, -(Ci 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 LTB4, or related pharmacologically active mediators at the end organ, are within the scope of this invention.
  • This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient in 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.
  • 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 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: Ci to Cio alkyl, phenyl-Ci - C6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxy methyl, propionyloxymethyl, glycyloxy methyl, phenylglycyloxymethyl, or thienylglycyloxy methyl.
  • 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)r 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.
  • 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 R 4 is OH.
  • 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 Cio-aliphatic-O-;
  • Rj is -(Ci to C5 aliphatic)R3 or -(Ci 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 C6 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.
  • 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.
  • Second 2,6-lutidine- ⁇ 2 ,3-diol is oxidized to the 3-hydroxy-6- methyl-2-pyridine carboxaldehyde.
  • This aldehyde is then treated with a 1-halosubstituted group which adds to the 3-hydroxy group to form an ether.
  • This reaction is effected by base, for example a carbonate such as K2CO2. Hydrazine hydrate is then used to form an aminohydrazone. This reaction is carried out at an elevated temperature. The reaction mixture is then cooled and treated with a base before recovering the aminohydrazone.
  • This hydrazone is then converted to a triazolo[l,5- ⁇ ]pyridine(2a) by means of O2 or another oxidizing agent such as KFe(CN)6- If nickel peroxide is used, 'he 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.
  • 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. Analogs of the compounds in Scheme 2 where Ri is an alkanoic acid can be made by simply hydrogenating the unsaturated bonds in that chain. Such process is illustrated in Scheme 3.
  • Reducing the double bond is effected by catalytic mean using a heavy metal catalyst and hydrogen gas. Mild conditions will suffice.
  • 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.
  • 2-4 can be oxidized to the corresponding ketone, that is where T is - CH 2 C(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.
  • 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 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.
  • the diluent When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
  • the pharmaceutical composition For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • the pharmaceutical composition For topical administration 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.
  • 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.
  • 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] -LTB 4 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
  • Total and non-specific binding of [ 3 H] -LTB4 were determined in the absence or presence of 2 ⁇ M of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding.
  • the radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [ 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.
  • 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+ ]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 Ki for calcium mobilization was determined using the formula:
  • 6-(4-Methoxyphenyl)octan-l-ol (5.9g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C . To this was added pyridine (2.5mL, 30mmol) and 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 ⁇ 4).
  • 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).
  • 6-(4- Methoxyphenyl)hexan-l-ol (5.36g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and cooled to 0°C. To this was added pyridine (2.5mL, 30mmol) and 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 ⁇ 4) .
  • 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 (MgS04).
  • This compound was prepared from 2-(E-3-hydroxypropenyl)-3- decyloxy-6-[2-(3-iodophenyl)-2-hydroxy]ethylpyridine according to the procedure described in Example 1(e).
  • 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- hydroxy]ethylpyridine, dilithium salt [Example l(i)].
  • 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 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 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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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne certains composés de phényle-(2-hydroxy)éthylpyridine substitués ainsi que leurs analogues de cétone et d'alkyle utiles comme antagonistes de leucotriène.
PCT/US1991/003399 1990-06-07 1991-05-15 Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene WO1991018880A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1019920703090A KR930700445A (ko) 1990-06-07 1991-05-15 로이코트리엔-관련 질병치료용 벤조산 유도체
JP91509448A JPH05507475A (ja) 1990-06-07 1991-05-15 ロイコトリエン関連疾患治療用安息香酸誘導体
NO92924700A NO924700L (no) 1990-06-07 1992-12-04 Benzosyrederivater for behandling av leukotrienrelaterte sykdommer
FI925544A FI925544A0 (fi) 1990-06-07 1992-12-07 Bensoesyraderivat foer behandling av leukotrienassocierade sjukdomar

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US53438890A 1990-06-07 1990-06-07
US534,388 1990-06-07

Publications (1)

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WO1991018880A1 true WO1991018880A1 (fr) 1991-12-12

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PCT/US1991/003399 WO1991018880A1 (fr) 1990-06-07 1991-05-15 Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene

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Country Link
EP (1) EP0532550A1 (fr)
JP (1) JPH05507475A (fr)
KR (1) KR930700445A (fr)
CN (1) CN1058016A (fr)
AU (1) AU7901791A (fr)
CA (1) CA2083958A1 (fr)
FI (1) FI925544A0 (fr)
HU (1) HUT64748A (fr)
IE (2) IE911913A1 (fr)
IL (1) IL98388A0 (fr)
MA (1) MA22196A1 (fr)
MX (1) MX26142A (fr)
PL (1) PL290586A1 (fr)
PT (1) PT97912A (fr)
WO (1) WO1991018880A1 (fr)
ZA (1) ZA914323B (fr)

Cited By (7)

* 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
EP0649412A1 (fr) * 1992-06-30 1995-04-26 Smithkline Beecham Corporation Composes pharmaceutiques a base de pyridine
EP0675718A4 (fr) * 1992-12-23 1995-08-22 Smithkline Beecham Corp Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes.
WO1995028386A1 (fr) * 1994-04-13 1995-10-26 F. Hoffmann-La Roche Ag Antagonistes des leucotrienes b4 a substitution pyridine
EP0733044A1 (fr) * 1993-12-08 1996-09-25 Smithkline Beecham Corporation Composes
US8093253B2 (en) 2008-03-06 2012-01-10 Hoffmann-La Roche Inc. Leukotriene B4 inhibitors
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
WO2002076226A1 (fr) * 2001-03-27 2002-10-03 Meiji Seika Kaisha, Ltd. Procede de production d'encas souffles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0135316A1 (fr) * 1983-07-27 1985-03-27 Takeda Chemical Industries, Ltd. Dérivés d'acides carboxyliques vinyliques et leur préparation
EP0194093A2 (fr) * 1985-03-01 1986-09-10 Beecham Group Plc Acides et esters acryliques hétérocycliques substitués, leur préparation et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0135316A1 (fr) * 1983-07-27 1985-03-27 Takeda Chemical Industries, Ltd. Dérivés d'acides carboxyliques vinyliques et leur préparation
EP0194093A2 (fr) * 1985-03-01 1986-09-10 Beecham Group Plc Acides et esters acryliques hétérocycliques substitués, leur préparation et compositions pharmaceutiques les contenant

Cited By (11)

* 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
EP0649412A1 (fr) * 1992-06-30 1995-04-26 Smithkline Beecham Corporation Composes pharmaceutiques a base de pyridine
EP0649412A4 (fr) * 1992-06-30 1995-07-05 Smithkline Beecham Corp Composes pharmaceutiques a base de pyridine.
EP0675718A4 (fr) * 1992-12-23 1995-08-22 Smithkline Beecham Corp Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes.
EP0675718A1 (fr) * 1992-12-23 1995-10-11 Smithkline Beecham Corporation Composes de pyridyle a substitution utiles comme antagonistes des leucotrienes
EP0733044A1 (fr) * 1993-12-08 1996-09-25 Smithkline Beecham Corporation Composes
EP0733044A4 (fr) * 1993-12-08 1997-03-05 Smithkline Beecham Corp Composes
WO1995028386A1 (fr) * 1994-04-13 1995-10-26 F. Hoffmann-La Roche Ag Antagonistes des leucotrienes b4 a substitution pyridine
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
US8093253B2 (en) 2008-03-06 2012-01-10 Hoffmann-La Roche Inc. Leukotriene B4 inhibitors

Also Published As

Publication number Publication date
FI925544A (fi) 1992-12-07
IE911913A1 (en) 1991-12-18
PT97912A (pt) 1992-03-31
CN1058016A (zh) 1992-01-22
HU9203866D0 (en) 1993-03-29
ZA914323B (en) 1992-06-24
MX26142A (es) 1994-02-28
EP0532550A1 (fr) 1993-03-24
PL290586A1 (en) 1992-04-06
FI925544A0 (fi) 1992-12-07
AU7901791A (en) 1991-12-31
IL98388A0 (en) 1992-07-15
IE911912A1 (en) 1991-12-18
JPH05507475A (ja) 1993-10-28
MA22196A1 (fr) 1992-04-01
CA2083958A1 (fr) 1991-12-08
KR930700445A (ko) 1993-03-15
HUT64748A (en) 1994-02-28

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