WO1995028386A1 - Antagonistes des leucotrienes b4 a substitution pyridine - Google Patents

Antagonistes des leucotrienes b4 a substitution pyridine Download PDF

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Publication number
WO1995028386A1
WO1995028386A1 PCT/EP1995/001262 EP9501262W WO9528386A1 WO 1995028386 A1 WO1995028386 A1 WO 1995028386A1 EP 9501262 W EP9501262 W EP 9501262W WO 9528386 A1 WO9528386 A1 WO 9528386A1
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Prior art keywords
oxy
compound
hexyl
formula
pyridinyl
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Application number
PCT/EP1995/001262
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English (en)
Inventor
Noal Cohen
Ferdinand Kwo-Chen Lee
Keith Alan Yagaloff
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F. Hoffmann-La Roche Ag
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Priority to BR9507459A priority Critical patent/BR9507459A/pt
Priority to JP7526671A priority patent/JP2866202B2/ja
Priority to AU22569/95A priority patent/AU690258B2/en
Priority to EP95915853A priority patent/EP0755381A1/fr
Priority to NZ284069A priority patent/NZ284069A/en
Publication of WO1995028386A1 publication Critical patent/WO1995028386A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Substituted pyridine leukotriene tu antagonists The invention relates to compounds of the formula
  • Y is CN, S(O) u R 8 , NR 5 SO 2 R 8 , OR 9 , R 10 or -C 6 H 4 R 10 ;
  • Z is -(O) y -(CR 5 R 6 ) s -R 10 , -(O) y -(CR 5 R 6 ) v -OR 9 or R 10 ;
  • R 1 , R 3 are, independently, aryl, substituted aryl, heteroaryl, lower alkyl or aralkyl;
  • R 2 is hydrogen, lower alkyl, halogen or lower alkoxy
  • R 4 is hydrogen or lower alkyl
  • R 5 , R 6 are, independently, each occurrence, hydrogen or lower alkyl
  • R 7 is hydroxy, lower alkoxy or NR 5 R 6 ;
  • R 8 is lower alkyl, aryl, substituted aryl or aralkyl
  • R 9 is hydrogen, lower alkyl, aryl, substituted aryl, aralkyl, lower alkanoyl or aroyl;
  • R 10 is COR 7 , CONHSO 2 R 8 or 1H-tetrazol-5-yl;
  • n is an integer from 3 to 8;
  • n and s are, independently, an integer from 1 to 12; t is an integer from 0 to 1;
  • u is an integer from 0 to 2;
  • v is an integer from 2 to 12;
  • Pop/So 29.3.95 y is an integer from 0 to 1;
  • z is an integer from 0 to 1;
  • the compounds of formula I are potent leukotriene B4 antagonists and are therefore useful in the treatment of inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammatory bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis such as rheumatoid arthritis, dermatitis such as contact dermatitis, NSAID-induced gastropathy, gout, ischemia/ reperfusion injury, and trauma-induced inflammation, such as, spinal cord injury.
  • inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary disease, inflammatory bowel disease, asthma, acute respiratory distress syndrome, cystic fibrosis, allergy, arthritis such as rheumatoid arthritis, dermatitis such as contact dermatitis, NSAID-induced gastropathy, gout, ischemia/ reperfusion injury, and trauma-induced inflammation, such as, spinal cord injury.
  • the invention relates to pharmaceutical compositions and methods of use comprising the compound of formula I.
  • aryl preferably denotes naphthalenyl, phenyl, anthracenyl, phenanthrenyl or the like.
  • substituted aryl preferably denotes an aryl group which may be mono-, di- or trisubstituted by, for example, halogen, trifluoromethyl, lower alkyl, phenyl, lower alkoxy, cyano or nitro or combinations thereof.
  • heteroaryl denotes a 5- or 6- membered aromatic heterocyclic radical containing one or more hetero atoms, selected from nitrogen, oxygen and sulfur, which radical may optionally be substituted by one or two lower alkyl, lower alkoxy groups, chlorines or fluorines. It is understood that heterocyclic refers to a carbocyclic moiety in which one or more of the carbons are replaced, independently, by oxygen, nitrogen or sulfur.
  • Exemplary of 5- or 6- membered aromatic heterocyclic radicals are pyridinyl, imidazolinyl, thienyl, 2-chlorothienyl, furyl, pyrimidinyl, oxazolinyl or the like.
  • aralkyl denotes an alkyl group substituted by an aryl group, for example, benzyl, phenethyl, or the like, which may be substituted by halogen, trifluoromethyl, lower alkyl, lower alkoxy, cyano, nitro or the like.
  • halogen denotes all the halogens, i.e., bromine, chlorine, fluorine, and iodine.
  • lower alkoxy denotes an alkyl ether group in which the alkyl group is as described above, for example, methoxy, ethoxy, propoxy, pentoxy and the like.
  • lower alkanoyl denotes a primary or secondary alkanoyl group containing up to 7 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl and the like.
  • aroyl preferably denotes the benzoyl group or a substituted benzoyl group, for example a nitrobenzoyl group such as p-nitrobenzoyl or a halobenzoyl group such as o-, m- or p-iodobenzoyl.
  • the group -C 6 H 4 R 1 0 may be ortho, meta or para
  • exemplary of the group -(CR 5 R 6 )- n ,s,v are 1 ,1-dimethylpropylenyl, 2,2-dimethylpropylenyl, 2,6-dimethylheptylenyl, 1 -methyl-1 -ethylpentylenyl, 1 -ethyl-3-methylhexylenyl or the like.
  • a leaving group denotes halogen
  • an acid sensitive hydroxyl protecting group denotes any protecting group for hydroxyl which can be cleaved by acid treatment, such as tetrahydropyranyl, trityl, 1 -ethoxyethyl and the like.
  • a preferred group of compounds of formula I is one in which R 1 and R 3 are aryl and R 2 and R 4 are hydrogen.
  • a further preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, Y is S(O) u R 8 , OR 9 or R 10 and Z is -(O) y (CR 5 R 6 ) s -R 10 or -(O) y - (CR 5 R 6 ) v -OR 9 .
  • a more preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, Y is R 10 , Z is -(O)y-(CR 5 R 6 ) v -OR 9 or -(O)y-(CR 5 R 6 ) s -R 10 , or R 7 is hydroxy,
  • R 9 is hydrogen, and R 10 is -COR 7 .
  • a most preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, X is O, z is zero, t is 1, n is 3-5, Y is R 10 , Z is -(O) y -(CR 5 R 6 ) v -OR 9 or -(O) y - (CR 5 R 6 ) s -R 10 , y is zero, s or v is 2-6, R 7 is hydroxy, R 9 is hydrogen, and R 10 is -COR 7 .
  • Another more preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, Y is
  • Z is -(O)y-(CR 5 R 6 ) s -R 1 0, R 7 is hydroxy, R 8 is lower alkyl, R 9 is hydrogen and R 10 is -COR 7 .
  • Another most preferred group of compounds of formula I is one in which R 1 and R 3 are aryl, R 2 and R 4 are hydrogen, X is
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, m, n, z and t are as previously defined and Y' and Z' are as previously defined with the proviso that in any COR 7 R 7 is lower alkoxy,
  • Y and/or Z contain(s) a -COR 7 group and R 7 is lower alkyl to mono- or di-acid derivatives, or c) reacting a compound of the general formula I, wherein the group(s) Y and/or Z contain(s) the group -COOH, with an amin of the formula
  • R 5 is as defined above and R 13 is hydrogen, lower alkyl or a group -SO 2 R 8 and R 8 is as previously described, to the corresponding mono- or disubstituted amides or sulfonamides,
  • L is a leaving group
  • M is an alkali metal cation
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, m, n, z, and t are as previously defined.
  • Y' is Y as previously defined with the proviso that any COR 7 are COR 7 ' wherein R 7' is lower alkoxy.
  • Y" is Y as previously defined with the provisos that any COR 7 are COR 7" wherein R 7' is hydroxy, and any R 9 are R 9" wherein R 9" is hydrogen.
  • Z' is Z as previously defined with the proviso that any COR 7 are COR 7' wherein R 7' is lower alkoxy.
  • Z" is Z as previously defined with the provisos that any COR 7 are COR 7 " wherein R 7" is hydroxy, and any R 9 are R 9" wherein R 9" is hydrogen.
  • the pyridone of formula 1-1 is alkylated with a compound of formula 1-2 giving the product of formula la.
  • This alkylation is carried out in the presence of a base, and in an inert solvent.
  • bases utilized in this alkylation reaction are alkali metal carbonates such as sodium or potassium carbonate, or transition metal carbonates such as silver carbonate.
  • Preferred inert solvents for carrying out this alkylation are toluene and N,N-dimethylformamide. It is preferred that this alkylation be carried out within a temperature range of from 80 to 120°C.
  • the compound of formula la can be recovered by conventional chromatography. Saponification of the compound of formula la, which can contain one or two ester functions, is carried out under standard conditions for the saponification of esters, giving the
  • this saponification can be carried out using an alkali metal
  • R 5 , R 6 , and L are as previously defined, R 7' is lower alkoxy, R 1 1 is an acid sensitive hydroxyl protecting group, and q and r are, independently, an integer from 1-10.
  • an alkali metal carbonate such as sodium or potassium carbonate as the base, within a
  • the compound of formula 2-4 is converted to the compound of formula 2-5 using conditions generally employed for the removal of acid sensitive hydroxyl protecting groups.
  • the compound of formula 2-4 can be treated with an acid in a lower alkanol solvent. It is preferred that this deprotection reaction be carried out using oxalic acid in aqueous methanol, within a temperature range of from about 25 oC to about 65 °C.
  • the product of formula 2-5 is recovered by chromatography and is converted to the corresponding
  • the compound of formula 2-5 can be converted to the corresponding sulfonate of formula 2-6 by conventional methods such as treatment with an arylsulfonyl chloride and an organic amine.
  • These sulfonic esters can, in turn, be converted into the corresponding iodides of formula 2-6 by treatment with an alkali metal iodide in a polar, aprotic solvent. It is preferred that this conversion be carried out using sodium iodide, in acetonitrile, within a temperature range of 20-80 °C.
  • the compounds of formula 2-6 are recovered by conventional extractive work-up. Reaction Scheme 3
  • a phenol of formula 2-1 is alkylated with a compound of formula 3-1, which represents known compounds or compounds which can be prepared by known methods, in the presence of a base, to give a product of formula 3-2 which is recovered by standard chromatographic methods.
  • This alkylation reaction is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3.
  • Catalytic hydrogenation of the compound of formula 3-2 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4.
  • R 5' is lower alkyl, M' is lithium or
  • acylsulfonamide of formula Ic by reaction with the amine or sulfonamide R5R !3NH, which represents known compounds. This reaction can be carried out using any of the standard methods of forming amides or acylsulfonamides from acids.
  • Ic is recovered by chromatography or recrystallization.
  • This reaction can be carried out using any of the common azide reagents including sodium azide, lithium azide, magnesium azide, aluminum azide, and tri(lower alkyl)stannyl azides. It is preferred that this reaction be carried out using tri(n-butyl)stannyl azide in dioxane solution, within a temperature range of from about 80°C to about 100°C. Saponification of the ester le is carried out as described in Reaction Scheme 1 for the conversion of the compound of formula la to the compound of formula lb, giving the tetrazole acid of formula If which is recovered by
  • This alkylation reaction is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3.
  • Deprotection of the compound of formula 6-2 to give the alcohol product of formula 6-3 is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-4 to the compound of formula 2-5.
  • the compound of formula 6-3 is transformed into the compound of formula 6-4 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
  • L, R , R , q, and v are as previously defined, and Ar is aryl.
  • a phenol of formula 2-1 is condensed with a compound of formula 7-1 , which represents known compounds or compounds which can be prepared by known methods, in the presence of a phosphine and an azodicarboxylic diester, to give a product of formula 7-2 which is recovered by standard chromatographic methods.
  • phosphines which can be employed in this condensation are triaryl phosphines such as triphenylphosphine.
  • the preferred azodicarboxylic diesters which can be employed in this condensation are lower alkyl azodicarboxylic diesters such as diethyl azodicarboxylate. It is preferred that this condensation be carried out in an inert, ether solvent such as diethyl ether or tetrahydrofuran within a temperature range of 25-75 °C .
  • the compound of formula 8-2 is recovered by conventional chromatographic methods and is converted to the corresponding 2-hydroxycinnamate of formula 8-3 by alcoholysis of the lactone ring using an alkali metal lower alkoxide in a lower alkanol solvent.
  • transformation is carried out using lithium, sodium, or potassium lower alkoxide. It is preferred that this transformation be carried out in methanol or ethanol with sodium methoxide or sodium ethoxide, at a temperature in the range of 60-120 °C.
  • the compound of formula 8-3 is recovered by standard chromatographic methods. Alkylation of the compound of formula 8-3 with a compound of formula 8-4, which represents known compounds such as 1 ,5-dibromopentane, 1 -bromo-3-chloropropane and the like, is carried out as described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3, and affords the compound of formula 8-5 which is recovered by chromatography.
  • the invention also relates to a salt of the compound of formula I when it contains an acidic functionality which lends itself to salt formation with a base.
  • Salts of compounds of formula I which have a carboxy group are prepared by the reaction with a base having a non-toxic, pharmacologically acceptable cation. In general, any base which will form a salt with a carboxylic acid and whose pharmacological properties will not cause an adverse physiological effect is within the scope of this invention.
  • Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates or the like, for example, calcium hydroxide, sodium hydroxide, sodium
  • a salt thus produced is the functional equivalent of the corresponding compound of formula I wherein R 7 is hydroxy and one skilled in the art will appreciate that the variety of salts embraced by the invention is limited only by the criterion that a base employed in forming the corresponding salts be both non-toxic and physiologically acceptable.
  • guinea pigs Male guinea pigs (Hartley strain) weighing 300 to 500 g are anesthetized with urethane (2g/kg) intraperitoneally and a polyethylene cannula is inserted into the jugular vein for drug administration. Tracheal pressure is recorded from a cannula inserted into the trachea and connected to a Gould P23ID pressure transducer. After surgical preparation of the animals, a period of time is allowed for pulmonary functions to stabilize.
  • test compound is administered orally 2 hours prior to leukotriene B 4 administration according to the following protocol: Animals are paralyzed with succinylcholine (1.2 mg/kg i.v.) and mechanically respirated (Harvard rodent respirator) at 40 breaths/minute and 2.5 cc tidal volume.
  • Propranolol (0.1 mg/kg) is then administered intravenously five minutes prior to leukotriene B4 administration. Animals are then challenged with an intermediate constrictory dose of leukotriene B4 (200 ⁇ g/kg) delivered intravenously.
  • Human neutrophils are prepared from citrated or heparinized blood.
  • the blood was diluted 1:1 with Hank's balanced salt solution (HBSS) minus calcium and magnesium and underlay ed with 10 ml lymphocyte separation medium
  • HBSS Hank's balanced salt solution
  • Binding assays are performed in microtiter wells. Isolated human neutrophils in Gey's salt solution are incubated on ice for 45 minutes with 0.5nM 3H-LTB4 in the presence or absence of test compounds. Assays are terminated by adding 12 ml ice cold 50 mM Tris (pH 7.4) followed by rapid filtration under vacuum through GF/C filters. Radioactivity is determined by scintillation counting. Non- specific binding is defined as the binding not displaced by 100 fold excess of unlabelled LTB4. Specific binding is defined as the difference between total binding and non-specific binding. Non linear analysis of the binding data is performed using LIGAND (Munson and Rodbard, 1980). Ki (Inhibition Constant) values were determined using the Cheng-Prusoff relationship (Cheng and Prusoff, 1973).
  • the dose of a compound of formula I or a salt thereof to be administered and the frequency of administration will be dependent on the potency and duration of activity of the particular compound of formula I or salt to be administered and on the route of administration, as well as the severity and nature of the condition and age of the mammal to be treated and the like.
  • Oral doses of a compound of formula I or a salt thereof contemplated for use in practicing the invention can be in the range of from 2 mg to about 2 g per day, preferably about 2 mg to about 1 gm per day, either as a single dose or in divided doses.
  • a compound of formula I, or a salt or a composition containing a therapeutically effective amount of a compound of formula I, an enantiomer or a racemate or a salt thereof can be administered by methods well known in the art.
  • a compound of formula I, or a salt thereof can be administered either singly or with other pharmaceutical agents, for example, antihistamines, mediator release inhibitors, methyl xanthines, beta agonists or antiasthmatic steroids such as prednisone and prednisolone, orally, parenterally, rectally, or by inhalation, for example in the form of an aerosol, micropulverized powder or nebulized solution.
  • antihistamines for example, mediator release inhibitors, methyl xanthines, beta agonists or antiasthmatic steroids such as prednisone and prednisolone
  • parenterally, rectally or by inhalation, for example in the form of an aerosol, micropulverized powder or nebul
  • ingredients that is, pharmaceutically acceptable carriers, or in the form of aqueous solutions, suspensions, elixirs or aqueous alcoholic solutions, for example, in admixture with sugar or other sweetening agents, flavoring agents, colorants, thickeners and other conventional pharmaceutical excipients.
  • parenteral administration they can be administered as solutions or suspension, for example, as an aqueous or peanut oil solution or suspension using excipients and carriers conventional for this mode of administration.
  • a suitable pharmaceutically acceptable solvent for example, ethyl alcohol or combinations of miscible solvents
  • aerosol compositions are packaged for use in pressurized container fitted with an aerosol valve suitable for release of the pressurized composition.
  • the aerosol valve is a metered valve, that is one which on activation releases a predetermined effective dose of the aerosol
  • compounds of formula I of the invention may possess an asymmetric carbon atom, they are ordinarily obtained as racemic mixtures. It is to be understood the enantiomers and diastereomers also form part of this invention.
  • the resolution of such racemates into the optically active isomers can be carried out by known procedures. Some racemic mixtures can be precipitated as eutectics and can thereafter be separated. Chemical resolution is, however, preferred.
  • diastereomers are formed from the racemic mixture of a compound of formula I, with an optically active resolving agent. The formed diastereomers are separated by selective crystallization or chromatography and converted to the
  • the "usual work-up" procedure involves three extractions with the specified solvent. The organic extracts were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under water aspirator pressure. The residue was dried to constant weight at 45°C/high vacuum. All reactions except hydrogenations were carried out under an inert atmosphere of nitrogen or argon.
  • this material was redissolved in 250 mL of methanol and 7.5 g (117.86 mmol) of potassium hydroxide was added. The solution was stirred and refluxed for 21 hr before being concentrated in vacuo. The residual paste was taken up in 250 mL of water and the resulting milky solution was filtered with suction. The filtrate was acidified with 3N_ aqueous hydrochloric acid and worked-up with ether in the usual manner. There was obtained 13.18 g of a pale-yellow solid which was recrystallized from acetonitrile giving 12.48 g (91.6%) of the pure title diacid, as a colorless solid, mp 77-79 °C .
  • Example 9 the title compound (0.37 g; 82.9%) was obtained as a white solid, mp 104.5-106.5°C (recrystallized from hexane-ethyl acetate).
  • Example 25 the title compound (0.37 g; 82.9%) was obtained as a white solid, mp 104.5-106.5°C (recrystallized from hexane-ethyl acetate).
  • N,N-dimethylformamide was stirred and heated at 85-90 °C. for 16 hr.
  • the reaction mixture was cooled and filtered with suction.
  • the solids were washed with ethyl acetate and then the filtrate and washes were combined and concentrated in vacuo.
  • the oily residue was flash-chromatographed on silica gel, eluting with hexane-ether mixtures. There was obtained 0.56 g (37%) of the title diester as a pale-yellow oil.
  • Example 34 saponification procedure of Example 34, the title compound was obtained as a white solid, mp 134.5-137.5 °C. (recrystallized from hexane-ethyl acetate).
  • Example 51 Using the procedure of Example 51 with the modification that only one methanol-p-toluenesulfonic acid treatment was employed, rac-2-[3-[2-(methoxycarbonyl)phenyl]propoxy]-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester (2.11 g) from the preceding Example, was converted into the title compound, a colorless oil, in 95% yield (1.69 g).
  • Example was saponified. There was obtained 1.09 g (56%) of the title diacid as a colorless solid, mp 126-128 °C, recrystallized from acetonitrile.
  • Step 4 Pass the granulation from Step 3 through a suitable milling equipment.

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Abstract

Composés de la formule (I) dans laquelle X représente O ou C=O; Y représente CN, S(O)uR?8, NR5SO¿2R?8, OR9, R10¿ ou -C¿6H4R?10; Z représente -(O)¿y?-(CR?5R6)¿s-R10, (O)y-(CR5R6)v-OR?9 ou R10; R1, R3¿ représentent indépendamment aryle, aryle substitué, hétéroaryle, alcoyle ou aralcoyle inférieur; R2 représente hydrogène, alcoyle inférieur, halogène ou alcoxy inférieur; R4 représente hydrogène ou alcoyle inférieur; R5, R6 représentent indépendamment, dans chaque cas, hydrogène ou alcoyle inférieur; R¿7? représente hydroxy, alcoxy inférieur ou NR?5R6; R8¿ représente alcoyle inférieur, aryle, aryle substitué ou aralcoyle; R9 représente hydrogène, alcoyle inférieur, aryle, aryle substitué, aralcoyle, alcanoyle inférieur ou aroyle; R10 représente COR7, CONHSO¿2R?8 ou 1H-tétrazol-5-yle; m est un nombre entier valant de 3 à 8; n et s sont, indépendamment, un nombre entier de 1 à 12; t est un nombre entier de 0 à 1; u est un nombre entier de 0 à 2; v est un nombre entier de 2 à 12; y est un nombre entier de 0 à 1; et z est un nombre entier de 0 à 1; à la condition que soit Y représente R10 ou -CH¿6H4R?10, soit Z représente -(O)¿y?-(CR?5R6)¿s-R?10 ou R10¿ et à la condition supplémentaire que lorsque n vaut 1, Y représente R10 ou -C¿6H4R?10. L'invention concerne également un isomère optique desdits composés, lorsque R5 et R6 ne représentent pas tous deux hydrogène ou le même alcoyle inférieur, et lorsque R7 représente hydroxy, ainsi qu'un sel de ces composés avec une base, acceptable sur le plan pharmacologique. Les composés de la formule (I) sont de puissants antagonistes des leucotriènes B¿4? et sont par conséquent utiles dans le traitement de maladies inflammatoires telles que le psoriasis, les rhinites, la bronchopneumopathie chronique obstructive, les affections intestinales inflammatoires, l'asthme, le syndrome de détresse respiratoire aiguë, les fibroses kystiques, les allergies, l'arthrite telle que la polyarthrite rhumatoïde, les dermatites telles que l'eczéma de contact, les gastropathies induites par les anti-inflammatoires non stéroïdiens, la goutte, les lésions induites par l'ischémie/reperfusion, les inflammations induites par les traumatismes comme la lésion de la moelle épinière.
PCT/EP1995/001262 1994-04-13 1995-04-06 Antagonistes des leucotrienes b4 a substitution pyridine WO1995028386A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR9507459A BR9507459A (pt) 1994-04-13 1995-04-06 Antagonistas á base de piridino-leucotrieno b4 substituído
JP7526671A JP2866202B2 (ja) 1994-04-13 1995-04-06 置換ピリジンロイコトリエンｂ▲下４▼拮抗物質
AU22569/95A AU690258B2 (en) 1994-04-13 1995-04-06 Substituted pyridine leukotriene B4 antagonists
EP95915853A EP0755381A1 (fr) 1994-04-13 1995-04-06 Antagonistes des leucotrienes b 4 a substitution pyridine
NZ284069A NZ284069A (en) 1994-04-13 1995-04-06 Benzene alkanoic acid substituted pyridine derivatives; medicaments

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US22824694A 1994-04-13 1994-04-13
US39509295A 1995-03-06 1995-03-06
US08/228,246 1995-03-06
US395,092 1995-03-06

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WO1995028386A1 true WO1995028386A1 (fr) 1995-10-26

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EP (1) EP0755381A1 (fr)
JP (1) JP2866202B2 (fr)
CN (1) CN1145619A (fr)
AU (1) AU690258B2 (fr)
BR (1) BR9507459A (fr)
CA (1) CA2186252A1 (fr)
NZ (1) NZ284069A (fr)
WO (1) WO1995028386A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8093253B2 (en) * 2008-03-06 2012-01-10 Hoffmann-La Roche Inc. Leukotriene B4 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018880A1 (fr) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene
WO1992001675A2 (fr) * 1990-07-24 1992-02-06 Rhone-Poulenc Rorer S.A. Composes bis-aryle bicycliques substitues ayant une activite antagoniste selective sur le leukotriene b4, leur preparation et utilisation dans des compositions pharmaceutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018880A1 (fr) * 1990-06-07 1991-12-12 Smithkline Beecham Corporation Derives d'acide benzoique utilises dans le traitement de maladies associees au leucotriene
WO1992001675A2 (fr) * 1990-07-24 1992-02-06 Rhone-Poulenc Rorer S.A. Composes bis-aryle bicycliques substitues ayant une activite antagoniste selective sur le leukotriene b4, leur preparation et utilisation dans des compositions pharmaceutiques

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CA2186252A1 (fr) 1995-10-26
CN1145619A (zh) 1997-03-19
AU690258B2 (en) 1998-04-23
AU2256995A (en) 1995-11-10
JP2866202B2 (ja) 1999-03-08
JPH09505605A (ja) 1997-06-03
BR9507459A (pt) 1997-11-11
EP0755381A1 (fr) 1997-01-29
NZ284069A (en) 1997-10-24

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