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EP0755381A1 - Substituted pyridine leukotriene b 4 antagonists - Google Patents

Substituted pyridine leukotriene b 4 antagonists

Info

Publication number
EP0755381A1
EP0755381A1 EP95915853A EP95915853A EP0755381A1 EP 0755381 A1 EP0755381 A1 EP 0755381A1 EP 95915853 A EP95915853 A EP 95915853A EP 95915853 A EP95915853 A EP 95915853A EP 0755381 A1 EP0755381 A1 EP 0755381A1
Authority
EP
European Patent Office
Prior art keywords
oxy
compound
hexyl
formula
pyridinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95915853A
Other languages
German (de)
French (fr)
Inventor
Noal Cohen
Ferdinand Kwo-Chen Lee
Keith Alan Yagaloff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Publication of EP0755381A1 publication Critical patent/EP0755381A1/en
Withdrawn legal-status Critical Current

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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

  • the invention relates to compounds of the formula
  • Y is CN, S(O) u R 8 , NR5SO2R 8 , OR9, RIO 0 r -C6H4R 10 ;
  • Z is -(O) y -(CR5R6) s -RlO ⁇ -(O) Y -(CR5R6) V -OR9 or RlO;
  • R l , R3 are, independently, aryl, substituted aryl, heteroaryl, lower alkyl or aralkyl;
  • R2 is hydrogen, lower alkyl, halogen or lower alkoxy
  • R4 is hydrogen or lower alkyl
  • R-5, R6 are, independently, each occurrence, hydrogen or lower alkyl
  • R7 is hydroxy, lower alkoxy or NR-5R6;
  • R 8 is lower alkyl, aryl, substituted aryl or aralkyl
  • R9 is hydrogen, lower alkyl, aryl, substituted aryl, aralkyl, lower alkanoyl or aroyl;
  • RlO is COR7, CONHSO2R 8 or lH-tetrazol-5-yl;
  • m 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;
  • 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.
  • lower alkyl denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and 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 -C6H4R I O may be ortho, meta or para substituted.
  • Exemplary of the group -(CR-5R6)- n s v are 1 ,1-dimethyl- propylenyl, 2,2-dimethylpropylenyl, 2,6-dimethylheptylenyl, 1 - methyl-1 -ethylpentylenyl, l -ethyl-3-methylhexylenyl or the like.
  • a leaving group denotes halogen, preferably, bromine and iodine; lower alkylsulfonyloxy, such as, (methylsulfonyl)oxy, (trifluoromethylsulfonyl)oxy or the like; arylsulfonyloxy, such as, para-toluenesulfonyloxy or the like.
  • 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 Rl and R3 are aryl and R- and R4 are hydrogen.
  • a further preferred group of compounds of formula I is one in which R and R3 are aryl, R2 and R4 are hydrogen, Y is S(0) u R 8 , OR9 or RlO and Z is -(O) y (CR5R6) s _RlO 0 r -(O) y -
  • a more preferred group of compounds of formula I is one in which Rl and R3 are aryl, R-2 and R4 are hydrogen, Y is R , Z is -(O)y-(CR5R6) v -OR9 or -(O)y-(CR5R6) s -Rl O > 0 r R7 is hydroxy,
  • R 9 is hydrogen, and Rl° is -COR 7 .
  • a most preferred group of compounds of formula I is one in which Rl and R- are aryl, R- and R ⁇ are hydrogen, X is O, z is zero, t is 1, n is 3-5, Y is R J 0, Z is -(O) y -(CR5R6) v -OR9 or -(0) y - (CR 5 R 6 ) S -R1 °, y is zero, s or v is 2-6, R 7 is hydroxy, R 9 is hydrogen, and RlO is -COR 7 .
  • Another more preferred group of compounds of formula I is one in which Rl and R ⁇ are aryl, R2 and R ⁇ are hydrogen, Y is
  • Another most preferred group of compounds of formula I is one in which Rl and R3 are aryl, R2 and R4 are hydrogen, X is
  • z is zero, t is 1, n is 3-5, Y is S(0) u R 8 or OR9, Z is -(O) y - (CR-5R6) S -R10 ⁇ y i s zero> s i s 2-6, R 7 is hydroxy, R 8 is lower alkyl, R9 is hydrogen and Rl is -COR 7 .
  • L is a leaving group
  • 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, or
  • Y and/or Z contain(s) a -COR 7 group and R 7 is lower alkyl to mono- or di-acid derivatives, or
  • R 5 is as defined above and R 13 is hydrogen, lower alkyl or a group -SO2R 8 and R 8 is as previously described, to the corresponding mono- or disubstituted amides or sulfonamides, or
  • L is a leaving group
  • M is an alkali metal cation
  • Rl R 2 , R 3 , R 4 , R-5, R6, 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 R9 are R9 " wherein R9" 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 are R9" wherein R9" 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-dimethyl- formamide. 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 chromato- graphy.
  • Saponification of the compound of formula la is carried out under standard conditions for the saponification of esters, giving the corresponding mono- or diacid of formula lb.
  • this saponification can be carried out using an alkali metal hydroxide, such as sodium, potassium, or lithium hydroxide, in a lower alkanol solvent such as methanol or ethanol, within a temperature range of from 60 to 80 °C.
  • the acid of formula lb is recovered by recrystallization.
  • R-5, R , and L are as previously defined, R 7 ' is lower alkoxy, Rl 1 is an acid sensitive hydroxyl protecting group, and q and r are, independently, an integer from 1-10.
  • a phenol of formula 2-1 which represents known compounds prepared as described in U.S. Patent No. 5,273,999, is alkylated with a compound of formula 2-2, 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 2-3 which is recovered by standard chromatographic methods.
  • This alkylation reaction is preferably carried out using an alkali metal carbonate such as sodium or potassium carbonate as the base, within a temperature range of from about 25 C. to about 110 C, in a polar, aprotic solvent such as acetonitrile, N,N-dimethyl- formamide, 2-butanone, or dimethyl sulfoxide.
  • Catalytic hydro- genation of the compound of formula 2-3 gives the product of formula 2-4 which is recovered by chromatography. It is preferred that this hydrogenation be carried out using palladium on carbon as the catalyst, and ethyl acetate as the solvent.
  • 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 C to about 65 °C.
  • the product of formula 2-5 is recovered by chromatography and is converted to the corresponding derivative 2-6 using standard methods known in the art for transforming hydroxy groups into leaving groups. These methods include treatment with halogenating reagents such as
  • 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.
  • the deprotection of the compound of formula 3-3 to give the alcohol product of formula 3-4 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 3-4 is transformed into the compound of formula 3-5 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
  • R-5' is lower alkyl
  • M' is lithium or halomagnesium
  • L, R 7 , RU , n, and q are as previously defined.
  • Reaction Scheme 4 a phenol of formula 2-1 is catalytically hydrogenated to give the corresponding reduced compound of formula 4-1 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4.
  • the deprotection of the compound of formula 4-1 to give the alcohol product of formula 4-2 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 reagent 4-3 be a Grignard or organolithium reagent and that this reaction be carried out in an inert solvent such as ether or tetrahydrofuran, within a temperature range of from 0°C to about 65 °C.
  • the product of formula 4-4 is recovered by chromatography. Alkylation of the compound of formula 4-4 with a compound of formula 4-5, which represents known compounds, 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 gives the compound of formula
  • R6_ X> ⁇ » _ Z ', Z", m, n, z, and t are as previously defined and Y"' is Y as previously defined with the proviso that any COR 7 is COR 7 " wherein R 7 "' is NR 5 R 6 , Z'" is Z as previously defined with the proviso that any COR 7 is COR 7 '" wherein R 7 '" is NR 5 R 6 , R l3 is hydrogen, lower alkyl, or SO2 ⁇ wherein R8 is as previously defined, M" is sodium, lithium, aluminum, magnesium, or tri(lower alkyl)stannyl, and k is an integer from 1 to 3 depending on the valence of M".
  • an acid of formula lb (Reaction Scheme 1) is converted to the corresponding amide 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. These include treatment of the acid with l,r-carbonyldiimida- zole and the amine or exposure of the acid to a base, a carbodiimide and the amine or sulfonamide.
  • Ic is recovered by chromatography or recrystallization.
  • 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.
  • 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.
  • this condensation be carried out in an inert, ether solvent such as diethyl ether or tetrahydrofuran within a temperature range of 25-75 °C .
  • Catalytic hydrogenation of the compound of formula 7-2 to give the corresponding saturated compound 7-3 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.
  • Deprotection of the compound of formula 7-3 to give the alcohol product of formula 7-4 is carried out as described in Reaction
  • 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. This 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 chromato ⁇ graphic methods.
  • 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 carbonate, potassium carbonate or the like, ammonia, primary, secondary and tertiary amines, such as, monoalkylamines, dialkylamines, trialkylamines, for example, methylamine, diethylamine, triethylamine or the like, nitrogen containing heterocyclic amines, for example, piperidine or the like.
  • the alkali metal and alkaline earth metal hydroxides, carbonates or the like for example, calcium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate or the like, ammonia, primary, secondary and tertiary amines, such as, monoalkylamines, dialkylamines, trialkylamines, for example, methylamine, diethylamine, triethylamine or the like, nitrogen containing heterocyclic amines,
  • 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.
  • the test compound is administered orally 2 hours prior to leukotriene B4 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 (Organon Teknika), followed by centrifugation at 500 x g for 30 minutes, at room temperature. Supernatants are removed down to the red blood cell pellet.
  • HBSS minus calcium and magnesium is added to give 25 ml. To this is added 25 ml 6% dextran in
  • Samples are mixed and allowed to stand 20 minutes at room temperature. Supernatants are removed and centrifuged at 500 x g for 5 minutes at 4°C. Pellets are resuspended with 20 ml 0.2% saline for 20 seconds followed by the addition of 20 ml 1.6% saline. Samples are centrifuged at
  • 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 H-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.
  • oral administration they can be administered in the form of tablets, capsules, for example, in admixture with talc, starch, milk sugar or other inert 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.
  • aerosols For administration as aerosols, they can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant.
  • 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 composition.
  • 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 corresponding optical isomer.
  • the invention covers the racemates of the compounds of formula I as well as their optically active isomers (enantiomers).
  • 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.
  • 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 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.
  • Compound A is 2-(3-Carboxypropoxy)-6-[6-[[4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid.
  • Step 4 Pass the granulation from Step 3 through a suitable milling equipment.

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  • Pyridine Compounds (AREA)

Abstract

Compounds of formula (I), wherein X is O or C=O; Y is CN, S(O)uR?8, NR5SO¿2R?8, OR9, R10¿ or -C¿6H4R?10; Z is -(O)¿y?-(CR?5R6)¿s-R10, -(O)¿y?-(CR?5R6)¿v-OR?9 or R10; R1, R3¿ are, independently, aryl, substituted aryl, heteroaryl, lower alkyl or aralkyl; R2 is hydrogen, lower alkyl, halogen or lower alkoxy; R4 is hydrogen or lower alkyl; R5, R6 are, independently, each occurrence, hydrogen or lower alkyl; R7 is hydroxy, lower alkoxy or NR5R6; R8 is lower alkyl, aryl, substituted aryl or aralkyl; R9 is hydrogen, lower alkyl, aryl, substituted aryl, aralkyl, lower alkanoyl or aroyl; R?10 is COR7¿, CONHSO¿2R?8 or 1H-tetrazol-5-yl; m 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; y is an integer from 0 to 1; and z is an integer from 0 to 1; with the proviso that either Y is R10 or -C¿6H4R?10 or Z is -(O)¿y?-(CR?5R6)¿s-R?10 or R10¿ and the further proviso that when n=1, Y is R10 or -C¿6H4R?10, an optical isomer when R?5 and R6¿ are not both hydrogen or the same lower alkyl and, when R7 is hydroxy, a pharmaceutically acceptable salt thereof with a base. The compounds of formula (I) are potent leukotriene B¿4? 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.

Description

Substituted pyridine leukotriene tu antagonists
The invention relates to compounds of the formula
wherein X is O or C=O;
Y is CN, S(O)uR8, NR5SO2R8, OR9, RIO 0r -C6H4R10;
Z is -(O)y-(CR5R6)s-RlO} -(O)Y-(CR5R6)V-OR9 or RlO; R l , R3 are, independently, aryl, substituted aryl, heteroaryl, lower alkyl or aralkyl;
R2 is hydrogen, lower alkyl, halogen or lower alkoxy;
R4 is hydrogen or lower alkyl;
R-5, R6 are, independently, each occurrence, hydrogen or lower alkyl;
R7 is hydroxy, lower alkoxy or NR-5R6;
R 8 is lower alkyl, aryl, substituted aryl or aralkyl;
R9 is hydrogen, lower alkyl, aryl, substituted aryl, aralkyl, lower alkanoyl or aroyl; RlO is COR7, CONHSO2R8 or lH-tetrazol-5-yl; m 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; and z is an integer from 0 to 1; with the proviso that either Y is R1 0 or -C6H4R IO or Z is -(O)y- (CR5R6)s-R1 0 or R O and the further proviso that when n=l, Y
an optical isomer when R-5 and R^ are not both hydrogen or the same lower alkyl and, when R? is hydroxy, a pharmaceutically acceptable salt thereof with a base.
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.
In another aspect, the invention relates to pharmaceutical compositions and methods of use comprising the compound of formula I.
As used herein, the term "aryl" preferably denotes naphthalenyl, phenyl, anthracenyl, phenanthrenyl or the like. The term "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.
The term "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.
The term "lower alkyl", denotes a straight or branched chain saturated hydrocarbon containing 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, neopentyl, pentyl, heptyl, and the like.
The term "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.
The term "halogen" denotes all the halogens, i.e., bromine, chlorine, fluorine, and iodine.
The term "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.
The term "lower alkanoyl" denotes a primary or secondary alkanoyl group containing up to 7 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl and the like.
The term "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 -C6H4R I O may be ortho, meta or para substituted.
Exemplary of the group -(CR-5R6)-n s v are 1 ,1-dimethyl- propylenyl, 2,2-dimethylpropylenyl, 2,6-dimethylheptylenyl, 1 - methyl-1 -ethylpentylenyl, l -ethyl-3-methylhexylenyl or the like.
As used herein, a leaving group denotes halogen, preferably, bromine and iodine; lower alkylsulfonyloxy, such as, (methylsulfonyl)oxy, (trifluoromethylsulfonyl)oxy or the like; arylsulfonyloxy, such as, para-toluenesulfonyloxy or the like.
As used herein, 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 Rl and R3 are aryl and R- and R4 are hydrogen.
A further preferred group of compounds of formula I is one in which R and R3 are aryl, R2 and R4 are hydrogen, Y is S(0)uR8, OR9 or RlO and Z is -(O)y(CR5R6)s_RlO 0r -(O)y-
(CR5R6)V-OR9.
A more preferred group of compounds of formula I is one in which Rl and R3 are aryl, R-2 and R4 are hydrogen, Y is R , Z is -(O)y-(CR5R6)v-OR9 or -(O)y-(CR5R6)s-Rl O> 0r R7 is hydroxy,
R9 is hydrogen, and Rl° is -COR7.
A most preferred group of compounds of formula I is one in which Rl and R- are aryl, R- and R^ are hydrogen, X is O, z is zero, t is 1, n is 3-5, Y is RJ0, Z is -(O)y-(CR5R6)v-OR9 or -(0)y- (CR5R6)S-R1 °, y is zero, s or v is 2-6, R7 is hydroxy, R9 is hydrogen, and RlO is -COR7.
Another more preferred group of compounds of formula I is one in which Rl and R^ are aryl, R2 and R^ are hydrogen, Y is
S(0)uR8 or OR9, Z is -(O)y-(CR5R6)S-Rl0τ R7 is hydroxy, R8 is lower alkyl, R9 is hydrogen and RlO is -COR7.
Another most preferred group of compounds of formula I is one in which Rl and R3 are aryl, R2 and R4 are hydrogen, X is
O, z is zero, t is 1, n is 3-5, Y is S(0)uR8 or OR9, Z is -(O)y- (CR-5R6)S-R10} y is zero> s is 2-6, R7 is hydroxy, R8 is lower alkyl, R9 is hydrogen and Rl is -COR7.
Most preferred examples of this invention are:
2-(3-Carboxypropoxy)-6-[6-[(4,6-diphenyl-2-pyridinyl)- oxy]hexyl]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[(4- hydroxy-4-methylpentyl)oxy]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[4-(methyl- sulfonyl)butoxy]benzenepropanoic acid
4-[3-[6-[(4,6-Diρhenyl-2-ρyridinyl)oxy]hexyl]-2-(3- hydroxy-3-methylbutyl)phenoxy]butanoic acid 3-(2-Carboxyethyl)-4-[6-[(4,6-diphenyl-2-pyridinyl)- oxy]hexyl]-benzenepentanoic acid
5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2-pyridinyl)- oxy]hexyl]benzenepropanoic acid.
Other preferred examples include:
2-[3-(2-Carboxyphenyl)propoxy]-6-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[3-(3-Carboxyphenyl)propoxy]-6-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid 2-(3-Carboxypropoxy)-6-[5-[(4,6-diphenyl-2-pyridinyl)- oxy]pentyloxy]benzenepropanoic acid
2-(3-Carboxypropoxy)-6-[6-[(4-phenyl-6-(4-fluoro- phenyl)-2-pyridinyl)oxy]hexyl]benzenepropanoic acid 2-(3-Carboxypropoxy)-6-[6-[(4-phenyl-6-(2-thienyl)-2- pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[(2-Carboxyphenyl)methoxy]-6-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid.
Compounds of general formula I as well as their pharma- ceutically acceptable salts can be manufactured in accordance with the invention by
a) reacting a compound of the general formula
with a compound of the general formula
wherein L is a leaving group, R1, R2, R3, R4, R5, R6, X, m, n, z and t are as previously defined and Y' and Z' are as previously defined with the proviso that in any COR7 R7 is lower alkoxy, or
b) saponifying a compound of the general formula I, wherein
Y and/or Z contain(s) a -COR7 group and R7 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
HNR5R13
wherein R5 is as defined above and R13 is hydrogen, lower alkyl or a group -SO2R8 and R8 is as previously described, to the corresponding mono- or disubstituted amides or sulfonamides, or
d ) reacting a compound of the general formula I, wherein Y is -CN with an metal azide to a compound of the formula I, wherein Y is lH-tetrazol-5-yl, and
e) if desired, converting a compound of the general formula I into a pharmaceutically acceptable salt.
Further, the compounds of formula I can be prepared as hereinafter described in Reaction Schemes 1-5 in more detail. Reaction Scheme 1
la
MOH
lb
wherein L is a leaving group, M is an alkali metal cation, Rl» R2, R3, R4, R-5, R6, X, m, n, z, and t are as previously defined. Y' is Y as previously defined with the proviso that any COR7 are COR7' wherein R7' is lower alkoxy. Y" is Y as previously defined with the provisos that any COR7 are COR7" wherein R7' is hydroxy, and any R9 are R9" wherein R9" is hydrogen. Z' is Z as previously defined with the proviso that any COR7 are COR7' wherein R7' is lower alkoxy. Z" is Z as previously defined with the provisos that any COR7 are COR7'' wherein R7" is hydroxy, and any R are R9" wherein R9" is hydrogen.
In Reaction Scheme I, 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. Among the preferred 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-dimethyl- formamide. 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 chromato- graphy. 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 corresponding mono- or diacid of formula lb. For example, this saponification can be carried out using an alkali metal hydroxide, such as sodium, potassium, or lithium hydroxide, in a lower alkanol solvent such as methanol or ethanol, within a temperature range of from 60 to 80 °C. The acid of formula lb is recovered by recrystallization.
Exemplary of known intermediates of formula 1-1 are the following which are prepared as described in Journal of Medicinal Chemistry, Vol. 35, pp. 4315-4324, 1992:
4,6-Diphenyl-2-pyridone, 4-(3-Methoxyphenyl)-6-phenyl-2-pyridone,
4-(2-Fluorophenyl)-6-phenyl-2-pyridone, 6-(4-Fluorophenyl)-4-phenyl-2-pyridone, and 6-(4-Methylphenyl)-4-phenyl-2-pyridone. Other examples of known intermediates of formula 1-1 are:
4,6-Diphenyl-5-methyl-2-pyridone, prepared as described in Tetrahedron Letters, Volume 29, pp. 4855-4858, 1988,
6-tert.-Butyl-4-phenyl-2-pyridone and 4-Phenyl-6-(2-thienyl)-2-pyridone both prepared as described in International Patent Application WO 92/01675, 4,6-Diphenyl-5-methoxy-2-pyridone prepared as described in J. Chem. Soc, pp. 2588-2594, 1959, and
5-Bromo-4,6-diphenyl-2-pyridone prepared as described in An. Quim., Vol. 75, pp. 124-127, 1979.
Exemplary of known intermediates of formula 1-2 are the following which are prepared as described in U.S. Patent No.
5,273,999:
2-[[5-[(Methylsulfonyl)oxy]pentyl]oxy]-5-(4-ethoxy-4- oxobutoxy)benzenepropanoic acid ethyl ester 2-[6-[(Methylsulfonyl)oxy]hexyl]-5-(4-methoxy-4- oxobutoxy)-benzenepropanoic acid methyl ester
6-(5-Ethoxy-5-oxopentyloxy)-2-[[5-[(methylsulfonyl)oxy]- pentyl]oxy]benzenepropanoic acid methyl ester
4-[(5-Bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-δ- oxobenzenepentanoic acid ethyl ester
4-[(5-Bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-γ- oxobenzene-butanoic acid ethyl ester
(E)-4-[3-(3-Methoxy-3-oxo-l -propenyl)-4-[6-[(methyl- sulfonyl)oxy]hexyl]phenoxy]butanoic acid methyl ester 2-(5-Methoxy-5-oxopentyloxy)-6-[6-[(methylsulfonyl)- oxy]hexyl]benzenepropanoic acid methyl ester
2-[[5-[(Methylsulfonyl)oxy]pentyl]oxy]-4-(4-methoxy-4- oxobutoxy)benzenepropanoic acid methyl ester
2-(2-Methoxy-2-oxoethoxy)-6-[6-[(methylsulfonyl)- oxy]hexyl]-benzenepropanoic acid methyl ester 2-[(6-Methoxy-6-oxohexyl)oxy]-6-[6-[(methylsulfonyl)- oxy]hexyl]benzenepropanoic acid methyl ester
4-[[5-[(Methylsulfonyl)oxy]pentyl]oxy]-l ,3-benzene- dipropanoic acid dimethyl ester 2-(3-Methoxy-3-oxopropyl)-3-[6-[(methylsulfonyl)- oxy]hexyl]benzenehexanoic acid methyl ester
2-[(4,4-Dimethyl-5-methoxy-5-oxopentyl)oxy]-6-[6- [(methyl-sulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester 2-[[5-(Acetyloxy)ρentyl]oxy]-6-[6-[(methylsulfonyl)oxy]- hexyl]benzenepropanoic acid methyl ester
2-[(8-Methoxy-8-oxooctyl)oxy]-6-[6-[(methylsulfonyl)- oxy]hexyl]benzenepropanoic acid methyl ester
2-[(9-Methoxy-9-oxononyl)oxy]-6-[6-[(methylsulfonyl)- oxy]hexyl]benzenepropanoic acid methyl ester
2-(4-Methoxy-4-oxobutoxy)-6-[6-[(methylsulfonyl)oxy]- hexyl]benzenepropanoic acid methyl ester
4-(6-Bromohexyl)-3-(3-ethoxy-3-oxopropyl)-δ- oxobenzenepentanoic acid ethyl ester 4-(5-Bromopentyloxy)-3-(3-ethoxy-3-oxopropyl)benzene- pentanoic acid ethyl ester
4-(6-Bromohexyl)-3-(3-ethoxy-3-oxopropyl)benzene- pentanoic acid ethyl ester
2-[(7-Methoxy-7-oxoheρtyl)oxy]-6-[6-[(methylsulfonyl)- oxy]hexyl]benzenepropanoic acid methyl ester.
H2, Catalyst
2-4 2-5
2-6
wherein, R-5, R , and L are as previously defined, R7' is lower alkoxy, Rl 1 is an acid sensitive hydroxyl protecting group, and q and r are, independently, an integer from 1-10.
In Reaction Scheme 2, a phenol of formula 2-1, which represents known compounds prepared as described in U.S. Patent No. 5,273,999, is alkylated with a compound of formula 2-2, 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 2-3 which is recovered by standard chromatographic methods. This alkylation reaction is preferably carried out using an alkali metal carbonate such as sodium or potassium carbonate as the base, within a temperature range of from about 25 C. to about 110 C, in a polar, aprotic solvent such as acetonitrile, N,N-dimethyl- formamide, 2-butanone, or dimethyl sulfoxide. Catalytic hydro- genation of the compound of formula 2-3 gives the product of formula 2-4 which is recovered by chromatography. It is preferred that this hydrogenation be carried out using palladium on carbon as the catalyst, and ethyl acetate as the solvent. 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. For example, 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 C to about 65 °C. The product of formula 2-5 is recovered by chromatography and is converted to the corresponding derivative 2-6 using standard methods known in the art for transforming hydroxy groups into leaving groups. These methods include treatment with halogenating reagents such as
N-bromosuccinimide/triphenylphosphine or iodine/triphenyl- phosphine in dichloromethane. Alternatively, 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
3- 3-5
wherein L, R7', R11, Y', n, and q are as previously defined.
In 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. The deprotection of the compound of formula 3-3 to give the alcohol product of formula 3-4 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 3-4 is transformed into the compound of formula 3-5 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
Reaction Scheme 4
Acid
wherein R-5' is lower alkyl, M' is lithium or halomagnesium, and L, R7 , RU , n, and q are as previously defined.
In Reaction Scheme 4, a phenol of formula 2-1 is catalytically hydrogenated to give the corresponding reduced compound of formula 4-1 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-3 to the compound of formula 2-4. The deprotection of the compound of formula 4-1 to give the alcohol product of formula 4-2 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. Reaction of the compound of formula 4-2 with an excess of the organometallic reagent of formula 4-3, which represents known compounds, gives the triol of formula 4-4. It is preferred that the reagent 4-3 be a Grignard or organolithium reagent and that this reaction be carried out in an inert solvent such as ether or tetrahydrofuran, within a temperature range of from 0°C to about 65 °C. The product of formula 4-4 is recovered by chromatography. Alkylation of the compound of formula 4-4 with a compound of formula 4-5, which represents known compounds, 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 gives the compound of formula
4-6, which is recovered by chromatography. The compound of formula 4-6 is transformed into the compound of formula 4-7 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
Reaction Scheme 5
lb
Id
Ie
If
wherein M, Rl, R2, R3, R4, R5. R6_ X> γ»_ Z', Z", m, n, z, and t are as previously defined and Y"' is Y as previously defined with the proviso that any COR7 is COR7 " wherein R7"' is NR5R6, Z'" is Z as previously defined with the proviso that any COR7 is COR7'" wherein R7'" is NR5R6, R l3 is hydrogen, lower alkyl, or SO2 ^ wherein R8 is as previously defined, M" is sodium, lithium, aluminum, magnesium, or tri(lower alkyl)stannyl, and k is an integer from 1 to 3 depending on the valence of M".
In Reaction Scheme 5, an acid of formula lb (Reaction Scheme 1) is converted to the corresponding amide 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. These include treatment of the acid with l,r-carbonyldiimida- zole and the amine or exposure of the acid to a base, a carbodiimide and the amine or sulfonamide. It is understood that if more than one carboxyl moiety is present in the starting acid, all such groups will be converted to the corresponding amide or acylsulfonamide linkage. It is preferred that the reaction be performed by treating the acid of formula lb with l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, 4-dimethylaminopyridine, and the amine or sulfonamide R-5R 13NH, in dichloromethane solution, at ambient temperature. The amide or acylsulfonamide of formula
Ic is recovered by chromatography or recrystallization.
Treatment of the nitrile of formula Id, which can be prepared as described in Reaction Schemes 1 and 3, with a metal azide M"(N3)k, which represents known compounds, gives the tetrazole of formula Ie, which 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 chromatography or recrystallization.
Reaction Scheme 6
6-3
6-4 wherein L, R , R , n, and q are as previously defined. In Reaction Scheme 6, a phenol of formula 4-1 is alkylated with a compound of formula 6-1, 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 6-2 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. 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.
Reaction Scheme 7
H2, catalyst
7-5 wherein L, R , R , q, and v are as previously defined, and Ar is aryl.
In Reaction Scheme 7, 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. Among the preferred phosphines which can be employed in this condensation are triaryl phosphines such as triphenylphosphine. Among 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 . Catalytic hydrogenation of the compound of formula 7-2 to give the corresponding saturated compound 7-3 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. Deprotection of the compound of formula 7-3 to give the alcohol product of formula 7-4 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 7-4 is transformed into the compound of formula 7-5 as described in Reaction Scheme 2 for the conversion of the compound of formula 2-5 to the compound of formula 2-6.
Reaction Scheme 8
C CHjλ.COR7
wherein R1, R2, R3, R4, Rτ, L, M, n and v are as previously defined. In Reaction Scheme 8, alkylation of a coumarin of formula 8-1, which represents compounds known in the art, with an ester of formula 4-5, which also represents compounds known in the art, in the presence of a base, gives the product of formula 8-2. This alkylation is carried out under standard conditions for effecting the alkylation of a phenol such as those described in Reaction Scheme 2 for the conversion of the compound of formula 2-1 to the compound of formula 2-3. 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. This 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 chromato¬ graphic 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, l -bromo-3-chloro- propane 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. Alkylation of the pyridone of formula 1-1 with the compound of formula 8-
5 is carried out as described in Reaction Scheme 1 for the conversion of the compound of formula 1-1 to the compound of formula la, and gives the compound of formula 8-6, which is recovered by chromatography. Catalytic hydrogenation of the compound of formula 8-6 using the procedure described in
Reaction Scheme 3 for the conversion of the compound of formula 3-2 to the compound of formula 3-3, gives the corresponding saturated compound of formula 8-7, a sub-species of la. 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 carbonate, potassium carbonate or the like, ammonia, primary, secondary and tertiary amines, such as, monoalkylamines, dialkylamines, trialkylamines, for example, methylamine, diethylamine, triethylamine or the like, nitrogen containing heterocyclic amines, for example, piperidine or the like. A salt thus produced is the functional equivalent of the corresponding compound of formula I wherein R7 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.
The useful activity of the compounds of formula I as leukotriene B4 antagonists can be demonstrated as hereinafter set forth.
Guinea Pig Bronchoconstriction In Vivo.
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. The test compound is administered orally 2 hours prior to leukotriene B4 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 μg/kg) delivered intravenously.
The change (cm H2O) between pre and peak ventilatory pressure readings is averaged for six control and six drug treated animals. The percent inhibition is calculated from the formula:
((Control - Drug Treated)/Control)xl00
When compounds of formula I were tested, the percent inhibition of a 0.1 mg/kg oral dose was as follows.
% inhibition, 0.1 mg/kg test compound dose
2-(3-Carboxypropoxy)-6-[6-[(4,6-diphenyl- 8 6
2-pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- 27
[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- 55
[4-(methylsulfonyl)butoxy]benzenepropanoic acid
4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-2- 4 1 (3-hydroxy-3-methylbutyl)phenoxy]butanoic acid
5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2- 40 pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[3-(2-Carboxyphenyl)propoxy]-6-[6-[(4,6- 5 6 diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[3-(3-Carboxyphenyl)propoxy]-6-[6-[(4,6- 50 diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid
2-(3-Carboxypropoxy)-6-[[5-[(4,6-diρhenyl-2- 62 pyridinyl)oxy]pentyl]oxy]benzenepropanoic acid
2-(3-Carboxypropoxy)-6-[6-[[6-(4-fluorophenyl)- 6 8
4-phenyl-2-pyridinyl]oxy]hexyl]benzenepropanoic acid 2-(3 -Carboxypropoxy)-6- [6-[ [4-phenyl-6- 6 5
(2-thienyl)-2-pyridinyl]oxy]hexyl]benzene- propanoic acid
2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6- 42 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic acid
2-[(2-Carboxyphenyl)methoxy]-6-[6-[(4,6- 55 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic Acid
2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6- 42 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic Acid
Isolation of Intact Neutrophils
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 (Organon Teknika), followed by centrifugation at 500 x g for 30 minutes, at room temperature. Supernatants are removed down to the red blood cell pellet. HBSS minus calcium and magnesium is added to give 25 ml. To this is added 25 ml 6% dextran in
0.85% NaCl. Samples are mixed and allowed to stand 20 minutes at room temperature. Supernatants are removed and centrifuged at 500 x g for 5 minutes at 4°C. Pellets are resuspended with 20 ml 0.2% saline for 20 seconds followed by the addition of 20 ml 1.6% saline. Samples are centrifuged at
500 x g for 5 minutes at 4°C. The lysis is repeated and the cells (90-95% neutrophils) are resuspended at 2xl06 cell/ml in GEY's salt solution. LTB4 Receptor Binding Assay
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 H-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).
When representative compounds of formula I of the invention were tested, the results, as set forth below, expressed as inhibition of 3H-LTB4 binding, were obtained.
HUMAN NEUTROPHIL
TEST COMPOUND CELLS CK-i nM)
2-(3 -Carboxypropoxy)-6-[6- [(4,6-diphenyl-2- 1 pyridinyl)oxy]hexyl]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- 40
[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid
2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- 45
[4-(methylsulfonyl)butoxy]benzenepropanoic acid
4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl] -2- 2 5 (3-hydroxy-3-methylbutyl)phenoxy]butanoic acid 5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2- 1 pyridinyl)oxy]hexyl]benzenepropanoic acid
2- [3-(2-Carboxyphenyl)propoxy] -6-[6-[(4,6- 1 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic acid
2-(3-Carboxypropoxy)-6-[[5-[(4,6-diphenyl-2- 0.4 pyridinyl)oxy]pentyl] oxy]benzenepropanoic acid
2-(3-Carboxypropoxy)-6-[6-[ [6-(4-fluorophenyl)- 0.2 4-phenyl-2-pyridinyl]oxy]hexyl]benzenepropanoic acid
2-(3-Carboxypropoxy)-6-[6-[[4-phenyl-6- 0.6
(2-thienyl)-2-pyridinyl]oxy]hexyl]benzene- propanoic acid
2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6- 0.3 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic acid
2-[(2-Carboxyphenyl)methoxy]-6-[6-[(4,6- 0.2 diphenyl-2-pyridinyl)oxy] hexyl]benzene- propanoic acid
2-[(3 -Carboxyphenyl)methoxy]-6-[6-[(4,6- 0.3 diphenyl-2-pyridinyl)oxy]hexyl]benzene- propanoic acid
In the practice of the invention, 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. Thus, 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. For oral administration they can be administered in the form of tablets, capsules, for example, in admixture with talc, starch, milk sugar or other inert 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. For 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. For administration as aerosols, they can be dissolved in a suitable pharmaceutically acceptable solvent, for example, ethyl alcohol or combinations of miscible solvents, and mixed with a pharmaceutically acceptable propellant. Such aerosol compositions are packaged for use in pressurized container fitted with an aerosol valve suitable for release of the pressurized composition. Preferably, the aerosol valve is a metered valve, that is one which on activation releases a predetermined effective dose of the aerosol composition.
Since 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. By this method, 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 corresponding optical isomer. Thus the invention covers the racemates of the compounds of formula I as well as their optically active isomers (enantiomers).
The examples which follow further illustrate the invention.
In the following examples, 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. Example 1
Preparation of 2-(6-Iodohexyl)-6-(4-methoxy-4-oxobutoxy)- benzenepropanoic acid methyl ester.
A mixture of 10.81 g (ca. 23.37 mmol) of crude 2-(4- methoxy-4-oxobutoxy)-6-[6-[(methylsulfonyl)oxy]hexyl]- benzenepropanoic acid methyl ester, 7.01 g (46.7 mmol) of anhydrous sodium iodide, and 44 mL of dry acetonitrile was stirred at room temperature for 17 hr and then refluxed for 3.5 hr. After being cooled, the mixture was diluted with 200 mL of ether and filtered with suction. The solids were washed thoroughly with ether. The filtrate and washes were combined and washed with 12% aqueous sodium bisulfite, and work-up was completed in the usual manner. There was obtained 11.14 g (97.3%) of 2-(6-iodohexyl)-6-(4-methoxy-4-oxobutoxy)- benzenepropanoic acid methyl ester as a yellow oil.
Example 2
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-(4- methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester.
A mixture of 12.86 g (26.24 mmol) of 2-(6-iodohexyl)-6- (4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester,
6.18 g (25 mmol) of 4,6-diphenyl-2-pyridone, 3.45 g (12.51 mmol) of silver carbonate, and 250 mL of toluene was stirred and refluxed for 18 hr. After being cooled, the mixture was filtered with suction through a pad of Celite. The solid cake was washed well with toluene. The filtrate and washes were combined and concentrated in vacuo giving a yellow oil. This material was treated with 1 g (4.05 mmol) of the pyridone, 3.45 g (12.51 mmol) of fresh silver carbonate, and 250 mL of toluene. The mixture was stirred under reflux for an additional 2 hr and at room temperature for 16 hr. Work-up as before gave 17.96 g of an oily product. This material was chromatographed on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 14.29 g (89.4%) of pure title dimethyl ester, as a viscous, amber oil.
Example 3
Preparation of 2-(3-Carboxypropoxy)-6-[6-[(4,6-diρhenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid.
A mixture of 2-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]- 6-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester (preceding example) (14.29 g; 23.46 mmol), 4.48 g (70.4 mmol) of potassium hydroxide, and 250 mL of methanol was stirred and refluxed, for 4.5 hr. The resulting pale-yellow solution was concentrated in vacuo to remove most of the solvent and the residue was dissolved in water and acidified with IN. aqueous hydrochloric acid. The mixture was worked-up with dichloromethane in the usual manner giving a viscous, yellow gum. Thin layer chromatographic and NMR spectral analysis of this product revealed that saponification was incomplete. Therefore, 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 .
Anal. Calcd for C36H39NO6: C, 74.33; H, 6.76; N, 2.41. Found: C, 74.14; H, 6.64; N, 2.40. Example 4
Preparation of rac-(E)-3-[2-[(4-Hydroxy-4-methyl-2-pentynyl)- oxy] -6-[6- [(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenyl] - 2-propenoic acid methyl ester.
A mixture of 1.08 g (6.11 mmol) of 5-bromo-2-methyl-3- pentyn-2-ol, 2.19 g (6.11 mmol) of rac-(E)-3-[2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]-l -hexynyl]phenyl]-2- propenoic acid methyl ester, 3.38 g (24.45 mmol) of anhydrous, granular potassium carbonate in 50 mL of 2-butanone was stirred and heated at reflux for 5.33 hr. Another portion of 5- bromo-2-methyl-3-pentyn-2-ol (0.17 g; 0.94 mmol) and 10 mL of 2-butanone were added and the reaction was allowed to proceed for another 17.33 hr. After being cooled to room temperature, the mixture was filtered through some anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (3:1) to afford 2.52 g (90.6%) of the title compound as a yellow oil.
Anal. Calcd for C27H34C-6 : C, 71.34; H, 7.54. Found: C, 71.31; H, 7.36.
Example 5
Preparation of rac-2-[(4-Hydroxy-4-methylpentyl)oxy] -6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester.
To a solution of 2.4 g (5.28 mmol) of rac-(E)-3-[2-[(4- hydroxy-4-methyl-2-pentynyl)oxy] -6- [6- [(tetrahydro-2H- pyran-2-yl)oxy]- l -hexynyl]phenyl] -2-propenoic acid methyl ester in 100 mL of ethyl acetate was added 1.0 g of 10% Pd/C and the mixture was hydrogenated at atmospheric pressure and room temperature overnight. The mixture was filtered through a pad of celite, and the solids were washed thoroughly with ethyl acetate. After removal of the solvent, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (3:1), to afford 2.01 g (81.8%) of the title compound as a colorless oil.
Anal. Calcd for C27H44O6 : C, 69.79; H, 9.55. Found: C, 69.98; H, 9.40.
Example 6
Preparation of 2-(6-Hydroxyhexyl)-6-[(4-hydroxy-4- methylpentyl)oxy]benzenepropanoic acid methyl ester.
To a solution of 2.0 g (4.3 mmol) of rac-2-[(4-hydroxy-4- methylpentyl)oxy] -6-[6-[(tetrahydro-2H-pyran-2- yl)oxy]hexyl]-benzenepropanoic acid methyl ester in 75 mL of methanol were added 10 mL of water and 2.0 g (15.86 mmol) of oxalic acid dihydrate and the resulting solution was stirred at room temperature for 17 hr. Most of the methanol was removed under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate solution was then washed twice with water. After completion of the usual workup, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (2:1 then 1 : 1) to give 1.40 g (85.2%) of the title compound as a pale yellow oil.
Anal. Calcd for C22H36O5 : C, 69.44; H, 9.54. Found: C, 69.22; H, 9.51.
Example 7
Preparation of 2-(6-Bromohexyl)-6-[(4-hydroxy-4-methyl- pentyl)oxy]benzenepropanoic acid methyl ester.
To a mixture of 1.36 g (3.56 mmol) of 2-(6-hydroxy- hexyl)-6-[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester, 1.77 g (5.34 mmol) of carbon tetrabromide and 1.40 g (5.34 mmol) of triphenylphosphine was added 75 mL of ether and the resulting mixture was stirred at room temperature for 24 hr. Additional portions of carbon tetrabromide (1.77 g; 5.34 mmol) and triphenylphosphine (1.40 g; 5.34 mmol) were added and the reaction was allowed to proceed for another 17.25 hr. The mixture was filtered through anhydrous magnesium sulfate, and the solids were washed thoroughly with ether. After the usual workup, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (3:1), to give 1.04 g (65.5 %) of the title compound as a colorless oil. Anal. Calcd for C22H35BrO4: C, 59.59; H, 7.96; Br, 18.02.
Found: C, 59.66; H, 8.14; Br, 17.77.
Example 8
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-
[(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester.
A mixture of 0.29 g (1.17 mmol) of 4,6-diphenyl-2- pyridone, 0.52 g (1.17 mmol) of 2-(6-bromohexyl)-6-[(4- hydroxy-4-methylpentyl)oxy]benzenepropanoic acid methyl ester, 0.33 g (1.19 mmol) of silver carbonate and 40 mL of toluene was stirred and refluxed, with protection from light by aluminum foil, for 46.2 hr. The mixture was cooled to room temperature, filtered through some anhydrous magnesium sulfate, and the solids were washed with ethyl acetate. After concentrating the combined filtrate and washes, the crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (3:1), to afford 0.60 g (84.7%) of the title compound as a light tan oil.
Anal. Calcd for C39H47NO5 : C, 76.82; H, 7.77; N, 2.30. Found: C, 76.63; H, 7.71; N, 2.30.
Example 9
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6- [(4-hydroxy-4-methylpentyl)oxy]benzenepropanoic acid.
To a mixture of 0.60 g (0.99 mmol) of 2-[6-[(4,6-diphenyl- 2-pyridinyl)oxy]hexyl] -6-[(4-hydroxy-4-methylpentyl)oxy] - benzene-propanoic acid methyl ester in 13 mL of THF and 13 mL of water was added 85.0 mg (2.03 mmol) of lithium hydroxide monohydrate and the resulting mixture was stirred at room temperature for 42.5 hr. The solution was acidified with the addition of 25 mL of 3N_ sulfuric acid solution, and the resulting mixture was worked-up with ethyl acetate in the usual manner. The crude product was recrystallized from hexane-ethyl acetate to give 0.51 g (86.1%) of the title compound as a white solid, mp 83-84.5 °C . Anal. Calcd for C38-H45NO5 : C, 76.61; H, 7.61; N, 2.35.
Found: C, 76.60; H, 7.76; N, 2.24.
Example 10
Preparation of rac-(E)-3-[2-[4-(Methylsulfonyl)butoxy]-6-[6-
[(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenyl] -2- propenoic acid methyl ester.
Starting with 1.16 g (3.23 mmol) of rac-(E)-3 -[2-hydroxy- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenyl] -2- propenoic acid methyl ester and 0.71 g (3.30 mmol) of 4- (methylsulfonyl)butyl bromide, the title compound (1.39 g; 87.4%) was obtained as a white solid, mp 42-43 °C, following the procedure of Example 4. Anal. Calcd for C26H36O7S: C, 63.39; H, 7.37; S, 6.51.
Found: C, 63.25; H, 7.20; S, 6.50.
Example 11
Preparation of rac-2-[4-(Methylsulfonyl)butoxy]-6-[6-
[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic Acid Methyl Ester.
Starting with 1.33 g (2.71 mmol) of rac-(E)-3 -[2-[4- (methylsulfonyl)butoxy] -6-[6- [(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenyl]-2-propenoic acid methyl ester, hydrogenation following the procedure of Example 5 gave the title compound (1.23 g; 90.8%) as a colorless oil.
Anal. Calcd for C26-H42O7S: C, 62.62; H, 8.49; S, 6.43. Found: C, 62.27; H, 8.75; S, 6.41.
Example 12
Preparation of 2-(6-Hydroxyhexyl)-6-[4-(methylsulfonyl)- butoxy]benzenepropanoic acid methyl ester.
Starting with 1.18 g (2.37 mmol) of rac-2-[4-(methyl- sulfonyl)butoxy]-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl] - benzenepropanoic acid methyl ester, hydrolysis following the procedure of Example 6 gave the title compound (0.79 g; 80.6%) as a colorless oil.
Anal. Calcd for C21 H34O 6S: C, 60.83; H, 8.27; S, 7.73. Found: C, 61.02; H, 8.16; S, 7.45. Example 13
Preparation of 2-(6-Bromohexyl)-6-[4-(methylsulfonyl)butoxy] - benzenepropanoic acid methyl ester.
Starting with 0.72 g (1.73 mmol) of 2-(6-hydroxyhexyl)- 6-[4-(methylsulfonyl)butoxy]benzenepropanoic acid methyl ester, the title compound (0.71 g; 86.1%) was obtained as a colorless oil, following the procedure of Example 7. Anal. Calcd for C2 l H33B rθ5 S: C, 52.83; H, 6.97; Br,
16.74; S, 6.72. Found: C, 53.03; H, 6.90; Br, 16.49; S, 6.56.
Example 14
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[4-
(methylsulfonyl)butoxy]benzenepropanoic acid methyl ester.
Starting with 0.34 g (1.39 mmol) of 4,6-diphenyl-2- pyridone and 0.66 g (1.39 mmol) of 2-(6-bromohexyl)-6-[4- (methylsulfonyl)butoxy]benzenepropanoic acid methyl ester, the title compound (0.86 g; 96.2%) was obtained as a colorless oil, following the procedure of Example 8.
Example 15
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[4- (methylsulfonyl)butoxy]benzenepropanoic acid.
Starting with 0.77 g (1.20 mmol) of 2-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl] -6-[4-(methylsulfonyl)butoxy]benzene- propanoic acid methyl ester, hydrolysis following the procedure of Example 9 gave the title compound (0.49 g; 64.5%) as a white solid, mp 72.5-74.5 °C (recrystallized from hexane-ethyl acetate). Anal. Calcd for C37H43NO6S: C, 70.56; H, 6.88; N, 2.22; S, 5.09. Found: C, 70.26; H, 6.84; N, 2.05; S, 5.10.
Example 16
Preparation of rac-2-Hydroxy-6-[6-[(tetrahydro-2H-pyran-2- yl)oxy]hexyl]benzenepropanoic acid methyl ester.
Starting with 3.29 g (9.19 mmol) of rac-(E)-3-[2-hydroxy- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]- l -hexynyl]phenyl]-2- propenoic acid methyl ester, hydrogenation following the procedure of Example 5 gave the title compound (3.07 g; 91.6%) as a colorless oil.
Anal. Calcd for C21H32O5: C, 69.20; H, 8.85. Found: C, 69.26; H, 8.87.
Example 17
Preparation of 2-Hydroxy-6-(6-hydroxyhexyl)benzene- propanoic acid methyl ester.
Starting with 3.02 g (8.29 mmol) of rac-2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester, hydrolysis following the procedure of Example 6 gave the title compound (2.13 g; 91.7%) as a colorless oil.
Anal. Calcd for C16H24O4: C, 68.55; H, 8.63. Found: C,
68.19; H, 8.18.
Example 18
Preparation of 3-Hydroxy-2-(3-hydroxy-3-methylbutyl)- benzenehexanol.
To a stirred solution of 2.0 g (7.13 mmol) of 2-hydroxy-6- (6-hydroxyhexyl)benzenepropanoic acid methyl ester in 40 mL of THF was added 20 mL of methylmagnesium chloride solution in THF (3M_; 60 mmol), at room temperature, and the resulting solution was then refluxed for 4.33 hr. After being cooled to room temperature, the reaction mixture was treated with 75 mL of IN. aqueous sulfuric acid and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (1 :1), to afford 1.81 g (90.6%) of the title compound as a white solid, mp 72-73.5 °C . Anal. Calcd for C17H28O3: C, 72.82; H, 10.07. Found: C,
72.79; H, 10.30.
Example 19
Preparation of 4-[3-(6-Hydroxyhexyl)-2-(3-hydroxy-3- methylbutyl)phenoxy]butanoic acid ethyl ester.
A mixture of 0.68 g (2.41 mmol) of 3-hydroxy-2-(3- hydroxy-3-methylbutyl)benzenehexanol, 0.47 g (2.42 mmol) of ethyl 4-bromobutyrate and 1.33 g (9.66 mmol) of anhydrous, granular potassium carbonate in 25 mL of 2-butanone was stirred and refluxed for 21.5 hr. A second portion of ethyl 4- bromobutyrate (0.24 g; 1.25 mmol) in 5 mL of 2-butanone was added and the reaction mixture was stirred and refluxed for an additional 22 hr. After being cooled to room temperature, the mixture was filtered through some anhydrous magnesium sulfate, and the solids were washed thoroughly with ethyl acetate. The filtrate and the washings were combined and concentrated. A second run was carried out starting with 0.91 g (3.24 mmol) of 3-hydroxy-2-(3-hydroxy-3-methylbutyl)- benzenehexanol. The crude products from both runs were combined and purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (1 : 1), to afford 2.09 g (93.7%) of the title compound as a colorless oil. Anal. Calcd for C23H38O5 : C, 70.02; H, 9.71. Found: C, 69.99; H, 9.57.
Example 20
Preparation of 4-[3-(6-Bromohexyl)-2-(3-hydroxy-3- methylbutyl)phenoxy]butanoic acid ethyl ester.
Starting with 2.04 g (5.16 mmol) of 4-[3-(6-hydroxy- hexyl)-2-(3-hydroxy-3-methylbutyl)phenoxy]butanoic acid ethyl ester, the title compound (2.11 g; 89.4%) was obtained as a colorless oil, following the procedure of Example 7.
Anal. Calcd for C23H37BrO4: C, 60.39; H, 8.15; Br, 17.47. Found: C, 60.36; H, 8.06; Br, 17.66.
Example 21
Preparation of 4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-2- (3-hydroxy-3-methylbutyl)phenoxy]butanoic acid ethyl ester.
Starting with a mixture of 0.59 g (2.39 mmol) of 4,6- diphenyl-2-pyridone and 1.09 g (2.39 mmol) of 4-[3-(6- bromohexyl)-2-(3-hydroxy-3-methylbutyl)phenoxy]butanoic acid ethyl ester, the title compound (1.43 g; 95.8%) was obtained as a colorless oil, following the procedure of Example 8.
Anal. Calcd for C40H49NO5: C, 77.01; H, 7.92; N, 2.25. Found: C, 76.54; H, 7.77; N, 2.15.
Example 22
Preparation of 4-[3-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-2- (3-hydroxy-3-methylbutyl)phenoxy]butanoic acid.
Starting with 1.36 g (2.18 mmol) of 4-[3-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]-2-(3 -hydroxy -3 -methylbutyl)- phenoxyjbutanoic acid ethyl ester and following the procedure of Example 9, the title compound (1.08 g; 83.6%) was obtained as a white solid, mp 97.5-98.5 °C (recrystallized from hexane- ethyl acetate). Anal. Calcd for C38H45NO5 : C, 76.61 ; H, 7.61 ; N, 2.35.
Found: C, 76.30; H, 7.88; N, 2.26.
Example 23
Preparation of 4-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-3-(3- ethoxy-3-oxopropyl)benzenpentanoic acid ethyl ester.
Starting with a mixture of 0.24 g (0.97 mmol) of 4,6- diphenyl-2-pyridone and 0.46 g (0.97 mmol) of 4-(6- bromohexyl)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester, the title compound (0.56 g; 90.3%) was obtained as a colorless oil, following the procedure of Example 8.
Anal. Calcd for C41H49NO5: C, 77.45; H, 7.77; N, 2.20. Found: C, 77.22; H, 7.52; N, 2.11.
Example 24
Preparation of 3-(2-Carboxyethyl)-4-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepentanoic Acid.
Starting with 0.49 g (0.77 mmol) of 4-[6-[(4,6-diρhenyl-2- pyridinyl)oxy]hexyl]-3-(3-ethoxy-3-oxopropyl)benzene- pentanoic acid ethyl ester and following the procedure of 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
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-5-(4- methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester.
A mixture of 0.68 g (2.75 mmol) of 4,6-diphenyl-2- pyridone, 1.145 g (2.50 mmol) of 2-[6-[(methylsulfonyl)oxy]- hexyl]-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, 0.76 g (5.5 mmol) of anhydrous potassium carbonate, 0.037 g (0.25 mmol) of sodium iodide, and 6.2 mL of
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 26
Preparation of 5-(3-Carboxypropoxy)-2-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid.
A mixture of 0.56 g (0.92 mmol) of 2-[6-[(4,6-diphenyl- 2-pyridinyl)oxy]hexyl] -5-(4-methoxy-4-oxobutoxy)benzene- propanoic acid methyl ester from the preceding example, 0.26 g (4.64 mmol) of potassium hydroxide, and 15 mL of methanol was stirred and refluxed for 20 hr. The resulting solution was cooled and concentrated in vacuo. The residue was dissolved in water and the aqueous, alkaline solution was extracted once with ether (the extract was discarded) before being acidified with 3N_ HCl. The mixture was worked-up with dichloromethane in the usual manner giving a solid product. Recrystallization from acetonitrile gave the title diacid (0.4 g; 75%) as a colorless solid, mp 133-134 «c . Anal. Calcd for C36H39NO 6 : C, 74.33; H, 6.76; N, 2.41. Found: C, 73.92; H, 6.60; N, 2.34.
EXAMPLE 27
Preparation of 2-[6-[[6-(4-Fluorophenyl)-4-phenyl-2-pyridinyl]- oxy]hexyl]-6-(4-methoxy-4-oxobutoxy) benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 2, 4-phenyl-6-(4-fluoro- phenyl)-2-pyridone was alkylated with 2-(6-iodohexyl)-6-(4- methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester giving the title diester in quantitative yield, as a pale-yellow oil.
EXAMPLE 28
Preparation of 2-(3-Carboxypropoxy)-6-[[6-(4-fluoro-phenyl)-4- phenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[6-[[6-(4- fluorophenyl)-4-phenyl-2-pyridinyl]oxy]hexyl] -6-(4-methoxy-4- oxobutoxy)benzene-propanoic acid methyl ester from the preceding Example was saponified giving the title diacid monohydrate, in 29% yield, as a colorless solid, mp 78.5-81.0 °C, recrystallized from acetonitrile.
Anal. Calcd for C36H38FNO6-H20: C, 70.00; H, 6.53; N, 2.27. Found: C, 70.25; H, 6.27; N, 2.24.
EXAMPLE 29
Preparation of 2-(4-Methoxy-4-oxobutoxy)-6-[6-[[4-phenyl-6- (2-thienyl)-2-pyridinyl]oxy]hexyl]benzene-propanoic Acid Methyl Ester.
Using the procedure of Example 2, 4-phenyl-6-(2-thienyl)- 2-pyridone was alkylated with 2-(6-iodohexyl)-6-(4-methoxy-4- oxobutoxy)benzenepropanoic acid methyl ester giving the title diester in 94% yield, as a pale-yellow oil.
EXAMPLE 30
Preparation of 2-(3-Carboxypropoxy)-6-[6-[[4-phenyl-6-(2- thienyl)-2-pyridinyl]oxy]hexyl]benzenepropanoic Acid.
Using the procedure of Example 3, 2-(4-methoxy-4-oxo- butoxy)-6-[6- [[4-phenyl-6-(2-thienyl)-2-pyridinyl]oxy]hexyl] benzenepropanoic acid methyl ester from the preceding Example was saponified giving the title diacid, in 33% yield, as a colorless solid, mp 119.0-120.5 °C, recrystallized from acetonitrile.
Anal. Calcd for C34H37NO6S: C, 69.48; H, 6.35; N, 2.38. Found: C, 69.43; H, 6.47; N, 2.29.
EXAMPLE 31
Preparation of 2-(6-Hydroxyhexyl)-6-[[4-(methoxy-carbonyl)- phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 1.15 g (3.16 mmol) of rac-2-hydroxy-6-[6-
[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester from Example 16, 1.59 g (6.94 mmol) of 4- bromomethylbenzoic acid methyl ester and 2.62 g (18.93 mmol) of anhydrous, granular potassium carbonate in 30 mL of 2- butanone was heated at reflux in an oil bath for 20.5 hr. The mixture was cooled to room temperature and filtered through anhydrous magnesium sulfate. The filter cake was washed with ethyl acetate and then the filtrate and washes were combined and concentrate in vacuo. The residue was dissolved in 50 mL of methanol, concentrated sulfuric acid (1 mL) was added, and the resulting solution was stirred at room temperature for 21 hr. Most of the methanol was removed in vacuo and the residue was taken up in 250 mL of ethyl acetate. The solution was washed with saturated sodium bicarbonate solution and work-up was completed in the usual manner. Flash chromatography of the residue on 200 g of silica gel (eluting with 2:1 hexane-ethyl acetate) afforded 1.01 g (74.9%) of the title compound as a white solid, mp 60 °C.
Anal. Calcd for C25H32O6: C, 70.07; H, 7.53. Found: C, 69.97; H, 7.59.
EXAMPLE 32
Preparation of 2-(6-Bromohexyl)-6-[[4-(methoxy-carbonyl)- phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
To a mixture of 0.50 g (1.17 mmol) of 2-(6-hydroxyhexyl)- 6-[[4-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid methyl ester, 1.17 g (3.51 mmol) of carbon tetrabromide and 0.92 g (3.51 mmol) of triphenylphosphine was added 25 mL of ether and the resulting mixture was stirred at room temperature for 24.5 hr. The mixture was filtered through celite, and the filter cake was washed thoroughly with ether. The filtrate and washes were combined and concentrated in vacuo. Flash chromato- graphy of the residue on 70 g of silica gel (eluting with 8: 1 hexane-ethyl acetate) afforded 0.32 g (55.7%) of the title compound as a colorless oil.
Anal. Calcd for C25H3ιBrO5: C, 61.10; H, 6.36; Br, 16.26. Found: C, 61.03; H, 6.52; Br, 16.36. EXAMPLE 33
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[[4- (methoxycarbonyl)phenyl] methoxy] benzenepropanoic Acid Methyl Ester.
A mixture of 1.35 g of crude 2-(6-bromohexyl)-6-[[4- (methoxycarbonyl)phenyl] methoxy ]benzenepropanoic acid methyl ester, 0.68 g (2.75 mmol) of 4,6-diphenyl-2-pyridone, and 0.76 g (2.75 mmol) of silver carbonate, in 50 mL of toluene was stirred and refluxed, protected from light, for 45.8 hr. The mixture was cooled to room temperature and filtered through anhydrous magnesium sulfate. The filter cake was washed thoroughly with ethyl acetate and then the filtrate and washes were combined and concentrated in vacuo. Flash chromato¬ graphy of the residue on 300 g of silica gel (eluting with 7:1 hexane-ethyl acetate) afforded 1.06 g (71.3% for two steps) of the title compound as a pale yellow oil.
Anal. Calcd for C42H43NO6: C, 76.69; H, 6.59; N, 2.13. Found: C, 76.46; H, 6.56; N, 2.09.
EXAMPLE 34
Preparation of 2-[(4-Carboxyphenyl)methoxy]-6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
To a mixture of 863.2 mg (1.31 mmol) of 2-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]-6- [[4-(methoxycarbonyl)- phenyl] methoxy] benzenepropanoic acid methyl ester in 8 mL of tetrahydrofuran and 8 mL of water was added 187.8 mg (4.48 mmol) of lithium hydroxide monohydrate and the reaction mixture was stirred at room temperature for 113 hr. After the addition of 15 mL of 3N_ aqueous sulfuric acid, the mixture was extracted twice with ethyl acetate. The organic solutions were combined and washed with 50 mL of 3N_ aqueous sulfuric acid and work-up was completed in the usual manner. The crude product was recrystallized from hexane-ethyl acetate to give 688 mg (83.3%) of the title compound as an off-white solid, mp 100- 103 °C. Anal. Calcd for C4oH39NO6: C, 76.29; H, 6.24; N, 2.22. Found:
C, 75.98; H, 6.24; N, 2.16.
EXAMPLE 35
Preparation of 2-(6-Hydroxyhexyl)-6-[[2(methoxycarbonyl) phenyl]methoxy] benzenepropanoic Acid Methyl Ester.
Starting with 810 mg (2.22 mmol) of 2-hydroxy-6-[6- [(tetrahydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester and 1.12 g (4.89 mmol) of 2-bromomethylbenzoic acid methyl ester, the title compound (635 mg; 66.8%) was obtained as a tan solid, mp 43-44 °C, following the procedure of Example 31.
Anal. Calcd for C25H32O6: C, 70.07; H, 7.53. Found: C, 70.00; H, 7.62.
EXAMPLE 36
Preparation of 2-(6-Bromohexyl)-6-[[2-(methoxycarbonyl)- phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
Starting with 470 mg (1.10 mmol) of 2-(6-hydroxyhexyl)- 6-[[2-(methoxycarbonyl)phenyl]methoxy]benzenpropanoic acid methyl ester, the title compound (518 mg; 96.1%) was obtained as a colorless oil, following the procedure of Example 32.
Anal. Calcd for C25H3ιBrO5: C, 61.10; H, 6.36; Br, 16.26. Found: C, 61.09; H, 6.43; Br, 16.21. EXAMPLE 37
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[[2- (methoxycarbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 1.04 g of crude 2-(6-bromohexyl)-6-[[2- (methoxycarbonyl)phenyl] methoxy] benzenepropanoic acid methyl ester, 0.53 g (2.12 mmol) of 4,6-diphenyl-2-pyridone, and 0.59 g (2.12 mmol) of silver carbonate in 50 mL of toluene was stirred and refluxed, protected from light, for 67 hr. Work- up as described in Example 33 gave a residue which was purified by flash chromatography on 300 g of silica gel (eluting with 6:1 hexane-ethyl acetate). This afforded 0.78 g (80.4% for 2 steps) of the title compound as a yellow oil.
Anal. Calcd for C42H43NO6: C, 76.69; H, 6.59; N, 2.13. Found: C, 76.53; H, 6.60; N, 2.17.
EXAMPLE 38
Preparation of 2-[(2-Carboxyphenyl)methoxy]-6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl] benzenepropanoic Acid.
Starting with 732 mg (1.11 mmol) of 2-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]-6-[[2-(methoxycarbonyl)phenyl]methoxy]- benzenepropanoic acid methyl ester and following the 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). Anal. Calcd for C4θH39NO6: C, 76.29; H, 6.24; N, 2.22. Found:
C, 75.91; H, 6.09; N, 2.14. EXAMPLE 39
Preparation of 2-(6-Hydroxyhexyl)-6-[[3(methoxy-carbonyl)- phenyl]methoxy]benzenpropanoic Acid Methyl Ester.
Starting with 1.35 g (3.69 mmol) of 2-hydroxy-6-[6-[(tetra- hydro-2H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester and 1.86 g (8.13 mmol) of 3-bromomethylbenzoic acid methyl ester, the title compound (1.11 g; 70.1%) was obtained as a colorless oil, following the procedure of Example 31.
Anal. Calcd for C25H32O6: C, 70.07; H, 7.53. Found: C, 69.91; H, 7.61.
EXAMPLE 40
Preparation of 2-(6-Bromohexyl)-6-[[3-(methoxycarbonyl)- phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
Starting with 1.11 g (2.59 mmol) of 2-(6-hydroxyhexyl)-6- [[3-(methoxycarbonyl)phenyl]methoxy]benzenpropanoic acid methyl ester, the title compound (0.96 g; 75.7%) was obtained as a colorless oil, following the procedure of Example 32.
Anal. Calcd for C25H3iBrO5: C, 61.10; H, 6.36; Br, 16.26. Found: C, 61.08; H, 6.29; Br, 16.34.
EXAMPLE 41
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[[3- (methoxycarbonyl)phenyl]methoxy]benzenepropanoic Acid Methyl Ester.
A mixture of 919 mg (1.87 mmol) of 2-(6-bromohexyl)-6- [[3-(methoxycarbonyl)phenyl]methoxy]benzenepropanoic acid methyl ester, 462 mg (1.87 mmol) of 4,6-diphenyl-2-pyridone and 515 mg (1.87 mmol) of silver carbonate in 50 mL of toluene was stirred and refluxed for 44.7 hr. A second portion of 4,6- diphenyl-2-pyridone (100.2 mg; 0.41 mmol) was added and the reaction was continued for another 7 hr, and then cooled to room temperature while stirring for 3 d. Work-up as described in Example 33 gave a residue which was purified by flash chromatography on 300 g of silica gel (eluting with 6:1 hexane- ethyl acetate). This afforded 1.09 g (88.9%) of the title compound as a pale yellow oil.
Anal. Calcd for C42H43NO6: C, 76.69; H, 6.59; N, 2.13. Found: C, 76.58; H, 6.47; N, 2.05.
EXAMPLE 42
Preparation of 2-[(3-Carboxyphenyl)methoxy]-6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Starting with 1.01 g (1.54 mmol) of 2-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl]-6-[[3-(methoxycarbonyl)phenyl]methoxy]- benzenepropanoic acid methyl ester and following the procedure of Example 34, the title compound was obtained as an off-white solid, mp 157.5-159.5 °C. (recrystallized from hexane-ethyl acetate).
EXAMPLE 43
Preparation of 4-[(2-Oxo-2H-l -benzopyran-5-yl)oxy]- butanoic Acid Ethyl Ester.
A mixture of 8.78 g (54.15 mmol) of 5-hydroxycoumarin, 10.56 g of ethyl 4-bromobutyrate, 18.93 g (137 mmol) of anhydrous, granular potassium carbonate, and 50 mL of dry dimethyl sulfoxide was stirred at room temperature for 3 d. The resulting slurry was filtered with suction over a Celite pad and then the filter cake was washed with ethyl acetate. The filtrate and washes were combined and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed 3 times with water. Work-up was completed in the usual manner giving an oil which was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 9.90 g (66.2%) of the title ester as a pale-yellow oil.
EXAMPLE 44
Preparation of (E)-4- [3-Hydroxy-2-(3-methoxy-3-oxo- l - propenyl)phenoxy]butanoic Acid Methyl Ester.
A solution of 9.90 g (35.87 mmol) of 4-[(2-oxo-2H-l- benzopyran-5-yl)oxy]butanoic acid ethyl ester from the preceding Example, 20 mL of 25% methanolic sodium methoxide, and 60 mL of methanol was stirred and refluxed for 32 hr and then kept at room temperature for 24 hr. The resulting yellow solution was concentrated in vacuo giving a solid residue which was treated with ethyl acetate and excess IN. aqueous hydrochloric acid. The mixture was worked-up with ethyl acetate and ether in the usual manner (the organic extracts were additionally washed with saturated, aqueous sodium bicarbonate solution) giving 9.42 g of a white solid. This material was dissolved in 50 mL of methanol and 0.934 g of p-toluenesulfonic acid monohydrate was added. The solution was stirred and refluxed for 24 hr and then cooled and concentrated in vacuo. The residue was worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated, aqueous sodium bicarbonate solution) giving 11.07 g of a beige solid. This material was purified by flash chromato¬ graphy on 1500 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 2.60 g (24.6%) of the pure title diester as a colorless solid. EXAMPLE 45
Preparation of (E)-4- [3 - [(5-Bromopentyl)oxy)]-2-(3-methoxy-3 - oxo-1 -propenyl)phenoxy]butanoic Acid Methyl Ester.
A mixture of 2.60 g (8.84 mmol) of (E)-4-[3-hydroxy-2-(3- methoxy-3-oxo-l -propenyl)phenoxy]butanoic acid methyl ester from the preceding Example, 9.73 mL (16.27 g; 70.75 mmol) of 1,5-dibromopentane, 3.86 g (27.99 mmol) of anhydrous, granular potassium carbonate, and 150 mL of acetonitrile was stirred at room temperature, for 48 hr. The resulting slurry was diluted with ether and filtered with suction over a pad of Celite. The filter cake was washed with ether and then the filtrate and washes were combined and concentrated in vacuo. The oily residue was flash chromatographed on 750 g of silica gel, eluting with hexane-ethyl acetate mixtures. There was obtained 3.20 g (81.6%) of the title bromide as a pale-yellow oil.
EXAMPLE 46
Preparation of (E_)-4-[3-[[5-[(4,6-Diphenyl-2-pyridinyl)oxy] pentyl]oxy)] -2-(3-methoxy-3-oxo- l -propenyl)phenoxy] - butanoic Acid Methyl Ester.
Alkylation of 4,6-diphenyl-2-pyridone (1.23 g; 5 mmol) with (E)-4- [3- [(5-bromopentyl)oxy)] -2-(3-methoxy-3-oxo- l - propenyl)- phenoxy]butanoic acid methyl ester (2.22 g; 5 mmol) from the preceding Example, was carried out using the procedure of Example 2. There was obtained 2.19 g (72.0%) of the title compound as an oil. EXAMPLE 47
Preparation of 2-[[5-[(4,6-Diphenyl-2-pyridinyl)oxy]- pentyl]- oxy] -6-(4-methoxy-4-oxobutoxy)benzenepropanoic Acid Methyl Ester.
A mixture of 2.19 g (3.59 mmol) of (E)-4-[3-[[5-[(4,6- diphenyl-2-pyridinyl)oxy]pentyl] oxy)] -2-(3-methoxy-3 -oxo- 1 - propenyl)- phenoxy]butanoic acid methyl ester from the preceding Example, 0.219 g of 10% palladium on carbon, 25 mL of methanol, and 25 mL of ethyl acetate was stirred in an atmosphere of hydrogen, at room temperature, until gas uptake ceased. The mixture was filtered with suction over a pad of Celite and then the filter cake was washed with ethyl acetate. The filtrate and washes were combined and concentrated i n vacuo. There was obtained 1.86 g (84.6%) of the title diester as a pale-yellow oil.
EXAMPLE 48
Preparation of 2-(3-Carboxypropoxy)-6-[[5-[(4,6-diphenyl-2- pyridinyl)oxy]pentyl]oxy]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[[5-[(4,6-diphenyl-2- pyridinyl)oxy]pentyl]oxy] -6-(4-methoxy-4-oxobutoxy)benzene- propanoic acid methyl ester from the preceding Example was saponified giving the title diacid, in 46.9% yield, as a colorless solid, mp 130-131 °C, recrystallized from acetonitrile.
Anal. Calcd for C35H37NO7: C, 72.02; H, 6.39; N, 2.40. Found: C, 71.86; H, 6.35; N, 2.39. EXAMPLE 49
Preparation of rac-(E_)-3 - [3- [2-(3 -Methoxy-3-oxo- l -propenyl)-3- [6-[(tetrahydro-2H-pyran-2-yl)oxy]- l -hexynyl]phenoxy]propyl]- benzoic Acid Ethyl Ester.
A mixture of 1.45 g (4.04 mmol) of rac-(E_)-3- [2-hydroxy-6- [6- [(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenyl] -2- propenoic acid methyl ester, 0.841 g (4.04 mmol) of 3-(3- hydroxypropyl)- benzoic acid ethyl ester, 3.15 g (12.0 mmol) of triphenylphosphine, 1.91 mL (12 mmol) of diethyl azodicar- boxylate, and 100 mL of dry tetrahydrofuran was stirred at room temperature for 3 d. Additional triphenylphosphine (3.15 g) and diethyl azodicarboxylate (1.91 mL) were added and stirring was continued for 24 hr. The reaction mixture was concentrated in vacuo and then the oily residue was flash chromatographed on 500 g of silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.70 g (76.6%) of the title compound as a slightly pink oil.
EXAMPLE 50
Preparation of rac-2-[3-[3-(Ethoxycarbonyl)phenyl]- propoxy]-6- [6-[(tetrahydro-2H-pyran-2-yl)oxy]- hexyl]benzenepropanoic Acid Methyl Ester.
A mixture of 1.70 g (3.10 mmol) of rac-(E)-3-[3-[2-(3- methoxy-3 -oxo- l -propenyl)-3- [6- [(tetrahydro-2H-pyran-2- yl)oxy]-l -hexynyl]phenoxy]propyl]benzoic acid ethyl ester from the preceding Example, 0.5 g of 10% palladium on carbon, and
170 mL of methanol was stirred in an atmosphere of hydrogen, at room temperature, until gas uptake ceased. The catalyst was removed by suction filtration over Celite and then the filtrate was concentrated in vacuo. There was obtained 1.53 g (89%) of the title compound as an oil. EXAMPLE 51
Preparation of 2-[3-[3-(Methoxycarbonyl)phenyl]propoxy]-6-(6- hydroxyhexyl)benzenepropanoic Acid Methyl Ester.
A solution of 1.53 g (2.76 mmol) of rac-2-[3-[3-(ethoxy- carbonyl)phenyl]propoxy] -6-[6-[(tetrahydro-2H-pyran-2-yl)- oxy]hexyl]benzenepropanoic acid methyl ester from the preceding Example, 0.1 g of p-toluenesulfonic acid monohydrate, and 50 mL of methanol was stirred and refluxed for 20 hr before being cooled and concentrated in vacuo. The residue was worked-up with ether in the usual manner giving an oily residue, lK NMR analysis of which revealed complete removal of the tetrahydropyranyl protecting group but the presence of a mixture of methyl and ethyl esters. This material was retreated with methanol-p-toluenesulfonic acid monohydrate (24 hr reflux; 48 hr room temperature) affording 1.30 g (100%) of a yellow oil which was now mainly the desired, title dimethyl ester.
EXAMPLE 52
Preparation of 2-[3-[3-(Methoxycarbonyl)phenyl]propoxy]-6-[6- [(methylsulfonyl)oxy]hexyl]benzenepropanoic Acid Methyl Ester.
To a stirred solution of 1.30 g (ca. 2.76 mmol) of 2-[3-[3- (methoxycarbonyl)phenyl]propoxy] -6-(6-hydroxyhexyl)benzene- propanoic acid methyl ester from the preceding Example, 2.9 mL of triethylamine, and 20 mL of ethyl acetate was added 0.9 mL (11.63 mmol) of methanesulfonyl chloride, with ice-bath cooling.
The resulting slurry was stirred at 0-5 °C. for 3.5 hr and then refrigerated for 24 hr. The reaction mixture was treated with IN. hydrochloric acid and ice, and then worked-up with ether in the usual manner. This afforded 1.59 g (100%) of the title mesylate as a pale-yellow oil. EXAMPLE 53
Preparation of 2-(6-Iodohexyl)-6-[3-[3-(methoxycarbonyl) phenyl]propoxy]benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 1, 2-[3-[3-(methoxy- carbonyl)phenyl]propoxy]-6-[6-[(methylsulfonyl)oxy]hexyl]- benzenepropanoic acid methyl ester from the preceding Example was converted into the title iodide, an oil, in quantitative yield.
EXAMPLE 54
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[3- [3-(methoxycarbonyl)phenyl]propoxy]benzene-propanoic Acid
Methyl Ester.
Using the procedure of Example 2, 0.828 g (3.35 mmol) of 4,6-diphenyl-2-pyridone was alkylated with 2-(6-iodohexyl)-6- [3-[3-(methoxycarbonyl)phenyl]propoxy]benzenepropanoic acid methyl ester from the preceding Example. There was obtained 0.96 g (50.8%) of the title diester as a pale-yellow oil.
EXAMPLE 55
Preparation of 2-[3-(3-Carboxyphenyl)propoxy]-6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[6-[(4,6-diphenyl-2- pyridinyl)oxy] hexyl]-6-[3-[3-(methoxycarbonyl)phenyl] propoxy] benzenepropanoic acid methyl ester (0.96 g) from the preceding Example was saponified. There was obtained 0.58 g (63%) of the title diacid as a colorless solid, mp 102-105 °C, recrystallized from acetonitrile. Anal. Calcd for C42H43NO6: C, 76.69; H, 6.59; N, 2.13. Found: C, 76.39; H, 6.63; N, 2.12.
EXAMPLE 56
Preparation of rac-(E_)-2- [3 -[2-(3 -Methoxy-3-oxo- l -propenyl)-3 - [6-[(tetrahydro-2H-pyran-2-yl)oxy] - l -hexynyl]phenoxy]propyl] - benzoic Acid Methyl Ester.
Using the procedure of Example 49, 1.45 g (4.04 mmol) of rac-(E -3 -[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy] - l - hexynyl]phenyl]-2-propenoic acid methyl ester and 0.784 g (4.04 mmol) of 2-(3-hydroxypropyl)benzoic acid methyl ester were converted into the title diester, a colorless oil, in quantitative yield.
EXAMPLE 57
Preparation of rac-2-[3-[2-(Methoxycarbonyl)phenyl]- propoxy]- 6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]hexyl]- benzenepropanoic
Acid Methyl Ester.
Using the procedure of Example 50, rac-(E.)-2-[3-[2-(3- methoxy-3-oxo- l -propenyl)-3- [6- [(tetrahydro-2H-pyran-2- yl)oxy]-l-hexynyl]phenoxy]propyl]benzoic acid methyl ester from the preceding Example (2.2 g) was catalytically hydrogenated giving the title compound, a colorless oil, in 97% yield (2.11 g).
EXAMPLE 58
Preparation of 2-[3-[2-(Methoxycarbonyl)phenyl]propoxy]-6-(6- hydroxyhexyl)benzenepropanoic Acid Methyl Ester.
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 59
Preparation of 2-[3-[2-(Methoxycarbonyl)phenyl]propoxy]-6-[6-
[(methylsulfonyl)oxy]hexyl]benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 52, 2-[3-[2-(methoxy- carbonyl)phenyl]propoxy]-6-(6-hydroxyhexyl) benzenepropanoic acid methyl ester from the preceding Example (1.69 g) was converted into the title mesylate, a yellow oil, in quantitative yield.
EXAMPLE 60
Preparation of 2-(6-Iodohexyl)-6-[3-[2-(methoxycarbonyl)- phenyl]propoxy] benzenepropanoic Acid Methyl Ester.
Using the procedure of Example 1, 2-[3-[2-(methoxy- carbonyl) phenyl]propoxy]-6-[6-[(methylsulfonyl)oxy]hexyl]- benzenepropanoic acid methyl ester, from the preceding Example, was converted into the title iodide, a pale-yellow oil, in quantitative yield. EXAMPLE 61
Preparation of 2-[6-[(4,6-Diphenyl-2-pyridinyl)oxy]hexyl]-6-[3- [2-(methoxycarbonyl)phenyl]propoxy]benzene-propanoic Acid Methyl Ester.
Using the procedure of Example 2, 0.998 g (4.04 mmol) of 4,6-diphenyl-2-pyridone was alkylated with 2-(6-iodohexyl)-6- [3-[2-(methoxycarbonyl)phenyl]propoxy]benzenepropanoic acid methyl ester from the preceding Example. There was obtained
2.02 g (80%) of the title diester as a pale-yellow oil.
EXAMPLE 62
Preparation of 2-[3-(2-Carboxyphenyl)propoxy] -6-[6-[(4,6- diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic Acid.
Using the procedure of Example 3, 2-[6-[(4,6-diphenyl-2- pyridinyl)oxy]hexyl] -6- [3-[2-(methoxycarbonyl)phenyl]propoxy] - benzenepropanoic acid methyl ester (2.02 g) from the preceding
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.
Anal. Calcd for C42H43NO6: C, 76.69; H, 6.59; N, 2.13. Found: C, 76.30; H, 6.75; N, 2.07.
EXAMPLE 63
TABLET FORMULATION (Wet Granulation)
In gredients m tablet
1. Compound A.*
2. Lactose Anhydrous
3. Povidone K30 4. Magnesium Stearate
TOTAL 120.0 120.0 200.0 500.0
* Compound A is 2-(3-Carboxypropoxy)-6-[6-[[4,6-diphenyl-2- pyridinyl)oxy]hexyl]benzenepropanoic acid.
Manufacturing Procedure:
1 ) Mix Items 1 and 2 in a suitable mixer for 15 minutes.
2) Granulate the powder mix from Step 1 with 15% PVP K30 solution.
3 ) Dry the granulation from Step 2 at 50°C.
4 ) Pass the granulation from Step 3 through a suitable milling equipment.
5 ) Add the Item 4 to the milled granulation from Step 4 and mix for 3 minutes.
6 ) Compress the granulation from Step 5 on a suitable press. EXAMPLE 64
CAPSULE FORMULAΗON
TOTAL 200.0 200.0 300.0
Manufacturing Procedure:
1 ) Mix Items 1, 2 and 3 in a suitable mixer for 30 minutes.
2 ) Add Items 4 and 5 and mix for 3 minutes.
3 ) Fill into suitable capsule.

Claims

Claims
1. A compound of the formula
wherein X is O or C=O;
Y is CN, S(O)uR8, NR5SO2R8, OR9, R10 or -C6H4R10;
Z is -(O)y-(CR5R6)s-R10, -(O)y-(CR5R6)v-OR9 or R10; R 1 , R3 are, independently, aryl, substituted aryl,
heteroaryl, lower alkyl or aralkyl;
R2 is hydrogen, lower alkyl, halogen or lower alkoxy;
R4 is hydrogen or lower alkyl;
R5 , R6 are, independently, each occurrence, hydrogen or lower alkyl;
R7 is hydroxy, lower alkoxy or NR5R6 ;
R8 is lower alkyl, aryl, substituted aryl or aralkyl;
R9 is hydrogen, lower alkyl, aryl, substituted aryl, aralkyl, lower alkanoyl or aroyl;
R10 is COR7, CONHSO2R8 or 1H-tetrazol-5-yl;
m 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;
y is an integer from 0 to 1; and
z is an integer from 0 to 1;
with the proviso that either Y is R10 or -C6H4R 10 or Z is -(O)y-(CR5R6)s-R1 0 or R1 0 and the further proviso that when n=l, Y is R10 or -C6H4R10, an optical isomer when R5 and R6 are not both hydrogen or the same lower alkyl and, when R7 is hydroxy, a pharmaceutically acceptable salt thereof with a base.
2. A compound according to claim 1, wherein Y is R1 0 or -C6H4R 10.
3. A compound according to claim 1 or 2, wherein Z is -(O)y-(CR5R6)s-R10 or R1 0.
4. A compound according to any one of claims 1-3, wherein R1 and R3 are aryl and R2 and R4 are hydrogen.
5. A compound according to any one of claims 1-4, wherein Y is S(O)uR8, OR9 or R10, and Z is-(O)y-(CR5R6)s-R10 or -(O)y-(CR5R6)v-OR9.
6. A compound according to any one of claims 1-5, wherein Y is R10, Z is -(O)y-(CR5R6)v-OR9 or -(O)y-(CR5R6)s-R10, R7 is hydroxy, R9 is hydrogen, and R10 is -COR7.
7. A compound according to claim 6, wherein X is O, z is zero, t is 1, n is 3-5, y is zero and s or v is 2-6.
8. A compound according to any one of claims 1-5, wherein Y is S(O)uR8 or OR9, Z is -(O)y-(CR5R6)s-R10, R7 is hydroxy, R8 is lower alkyl, R9 is hydrogen and R10 is -COR7.
9. A compound according to claim 8, wherein X is O, z is zero, t is 1, n is 3-5, y is zero and s is 2-6.
10. A compound according to claim 1 , wherein the compound of formula I is selected from the group consisting of 2-(3-carboxypropoxy)-6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]-hexyl]-benzenepropanoic acid; 2-[6-[(4,6-diphenyl-2-pyridinyl)- oxy] hexyl] -6- [(4-hydroxy-4-methylpentyl)-oxy]benzenepropanoic acid; 2-[6-[4,6-diphenyl-2-pyridinyl)oxy]hexyl]-6-[4-(methylsulfonyl)butoxy]-benzenepropanoic acid; 4-[3-[6-[(4,6-diphenyl-2-pyridinyl)oxy] hexyl] -2-(3 -hydroxy-3 -methylbutyl)phenoxy]butanoic acid; 3-(2-carboxyethyl)-4-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]-benzenepentanoic acid; and 5-(3 -carboxypropoxy)-2-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl] -benzenepropanoic acid.
1 1. A compound according to claim 1 , wherein the compound of formula I is selected from the group consisting of 2-[3-(2-carboxyphenyl)propoxy] -6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid; 2-[3-(3-carboxyphenyl)propoxy] -6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl] -benzenepropanoic acid; 2-(3-carboxypropoxy)-6-[5-[(4,6-diphenyl-2-pyridinyl)oxy]pentyloxy]benzenepropanoic acid; 2-(3-carboxypropoxy)-6-[6- [(4-phenyl-6-(4-fluorophenyl)-2-pyridinyl)oxy]hexyl]benzenepropanoic acid; 2-(3-carboxypropoxy)-6- [6-[(4-phenyl-6-(2-thienyl)-2-pyridinyl)oxy] -hexyl]benzenepropanoic acid; 2-[(4-carboxyphenyl)methoxy]-6- [6-[(4,6-diphenyl-2-pyridinyl)oxy]- hexyl]benzenepropanoic acid; 2-[(2-carboxyphenyl)methoxy]-6-[6-[(4,6-diphenyl-2-pyridinyl)oxy]hexyl]benzenepropanoic acid; and 2-[(3-carboxyphenyl)methoxy] -6- [6- [(4,6-diphenyl-2-pyridinyl)oxy] -hexyl]benzenepropanoic acid.
12. A pharmaceutical composition especially for the treatment or prevention of inflammatory diseases such as psoriasis, rhinitis, chronic obstructive pulmonary disese, 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/perfusion injury and traumainduced inflammation which contains an effective amount of a compound in accordance with any one of claims 1-11 or a pharmaceutically acceptable salt thereof with a base, and an inert carrier.
13. A process for the manufacture of compounds according to any one of claims 1-11 , which process comprises a) reacting a compound of the general formula
with a compound of the general formula
wherein L is a leaving group, R1, R2, R3, R4, R5, R6, X, m, n, z and t are as defined in claim 1 and Y' and Z' are Y and Z as defined in claim 1 with the proviso that in any COR7 R7 is lower alkoxy,
or b ) saponifying a compound of the general formula I, wherein Y and/or Z contain(s) a -COR7 group and R7 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 HNR5R13 wherein R5 is as defined in claim 1 and R13 is hydrogen, lower alkyl or a group -SO2R8 and R8 is as defined in claim 1, to the corresponding mono- or disubstituted amides or sulfonamides,
or d ) reacting a compound of the general formula I, wherein Y is -CN with a metal azide to a compound of the formula I, wherein Y is 1H-tetrazol-5-yl, and e) if desired, converting a compound of the general formula I into a pharmaceutically acceptable salt.
14. Compounds in accordance with any one of claims 1-11 whenever prepared according to the process as claimed in claim 13 or by an obvious chemical equivalent thereof.
15. Compounds according to any one of claims 1-11 for use as therapeutically active substances especially for the treatment or prevention 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/perfusion injury and traumainduced inflammation.
16. The use of compounds according to any one of claims 1 -11 in the control or prevention of inflammatory diseases 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/perfusion injury and traumainduced inflammation, or for the manufacture of active pharmaceutical preparations.
17. The invention such hereinbefore particularly described.
***
EP95915853A 1994-04-13 1995-04-06 Substituted pyridine leukotriene b 4 antagonists Withdrawn EP0755381A1 (en)

Applications Claiming Priority (5)

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US22824694A 1994-04-13 1994-04-13
US228246 1994-04-13
US39509295A 1995-03-06 1995-03-06
PCT/EP1995/001262 WO1995028386A1 (en) 1994-04-13 1995-04-06 Substituted pyridine leukotriene b4 antagonists
US395092 1999-09-13

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US8093253B2 (en) * 2008-03-06 2012-01-10 Hoffmann-La Roche Inc. Leukotriene B4 inhibitors
CN118745145A (en) * 2024-06-24 2024-10-08 湖南大学 A class of 2-hydroxypyridine derivatives and their synthesis method and use

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KR930700445A (en) * 1990-06-07 1993-03-15 원본미기재 Benzoic acid derivatives for the treatment of leukotrienes-related diseases
FR2665159B1 (en) * 1990-07-24 1992-11-13 Rhone Poulenc Sante NEW PYRIDINE AND QUINOLEIN DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.

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AU2256995A (en) 1995-11-10
CA2186252A1 (en) 1995-10-26
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BR9507459A (en) 1997-11-11
NZ284069A (en) 1997-10-24

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