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WO1994005638A1 - Composes de trans 1,4-diethercyclohexane utilises en tant qu'inhibiteurs de la 5-lipoxygenase - Google Patents

Composes de trans 1,4-diethercyclohexane utilises en tant qu'inhibiteurs de la 5-lipoxygenase Download PDF

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Publication number
WO1994005638A1
WO1994005638A1 PCT/US1993/008036 US9308036W WO9405638A1 WO 1994005638 A1 WO1994005638 A1 WO 1994005638A1 US 9308036 W US9308036 W US 9308036W WO 9405638 A1 WO9405638 A1 WO 9405638A1
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Prior art keywords
phenyl
ylmethyloxy
dimethoxy
cyclohexane
napth
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PCT/US1993/008036
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English (en)
Inventor
Joseph F. Dellaria
Lawrence A. Black
Dee W. Brooks
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Abbott Laboratories
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
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    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/21—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing rings other than six-membered aromatic rings
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Ari is optionally substituted phenyl or naphthyl
  • Ai is Ci-C ⁇ alkylene, C3-C6 alkenylene, C3-C 6 alkynylene, or C3-C6 cycloalkylene
  • a ⁇ 2 is optionally substituted phenylene or a 6-membered heterocyclene moiety containing up to three nitrogen atoms
  • Ri is hydrogen, C 1 -C 6 alkyl, C3-C 6 alkenyl, C3-C 6 alkynyl, cyano-substituted C1-C4 alkyl or C2-C4 alkanoyl, or optionally substituted benzoyl
  • R 2 and R 3 together form a C3-C6 alkylene group which defines an optionally substituted alkylene ring having 4 to 7 ring atoms, which ring may bear one or two substituents, which may be the same or different, selected from hydroxy, C 1 -C 4 alkyl, C1-C 4
  • EPA 409414 discloses a leukotriene inhibitor of structure
  • the present invention provides certain trans 1,4- diether cyclohexyl compounds which inhibit 5-lipoxygenase enzyme activity and are useful in the treatment of allergic and inflammatory disease states.
  • the compounds of this invention have the structure
  • R2 and R3 are independently hydrogen or alkyl of from one to four carbon atoms.
  • the group A is selected from 1-propynyl or methylene.
  • the group X is selected from oxy, thio, sulfonyl, or NH.
  • the group R5 is hydrogen or alkyl of from one to four carbon atoms.
  • compositions which comprise a therapeutically effective amount of the compound as defined above in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting leukotriene biosynthesis in a host mammal in need of such treatment comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined above.
  • alkyl refers to a monovalent group derived from a straight or branched chain saturated hydrocarbon by the removal of a single hydrogen atom. Alkyl groups are exemplified by methyl, ethyl, n- and -s ⁇ -propyl, n-, sec-, iso- and tert- butyl, and the like.
  • carbocyclic aryl denotes a monovalent carbocyclic ring group derived by the removal of a single hydrogen atom from a monocyclic or bicyclic fused or non-fused ring system obeying the "4n + 2 ⁇ electron” or Huckel aromaticity rule.
  • Examples of carbocyclic aryl groups include phenyl, 1-, and 2-naphthyl, biphenyl and the like.
  • 5- or 6-membered heterocyclic aryl denotes a monovalent heterocyclic ring group derived by the removal of a single hydrogen atom from a monocyclic heterocyclic ring system obeying the "4n + 2 ⁇ electron” or Huckel aromaticity rule.
  • Examples of 5, or 6-membered heterocycUc aryl groups include pyridinyl, furyl, thienyl, thiazolyl, imidazolyl, and pyrimidinyl.
  • 10-membered bicyclic heterocycUc aryl containing one or two nitrogen atoms refers to a group selected from quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, and quinoxalinyl .
  • 9- or 10-membered heterocycUc aryl containing one or two nitrogen and optionally containing a further heteroatom selected from nitrogen or oxygen, and one oxo or thioxo substituent refers to a group selected from 2- oxo-l,2-dihydroquinolinyl, 2-oxo-l,2,3,4-tetrahydroquinolinyl, 3-oxo-2,3- dihydro-4H- 1 ,4-benzoxazinyl, oxindolinyl, 3-oxo- 1 ,2-dihydro-3H-indazolyl, 2-oxo-2,3-dihydrobenzothiazolyl, 2-oxo-2,3-dihydrobenzimid__zolyl, 3-thioxo- 2,3-dihydro-4H- 1 ,4-benzoxazinyl, and 2-thioxo- 1 ,2,3,4-tetrahydroquionlinyl
  • oxo denotes a carbonyl oxygen atom
  • thioxo denotes an oxo group as defined above in which the oxygen atom is replaced by a sulfur atom.
  • propynyl refers to a straight chain, three-carbon group containing a carbon-carbon triple bond.
  • alkoxy and alkoxyl denote an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom.
  • Representative alkoxy groups include methoxyl, ethoxyl, propoxyl, butoxyl, and the like.
  • alkylene denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1 -ethylene, 1,3-propylene, 2,2- dimethylpropylene, and the like.
  • Preferred compounds of the present invention are those having the generic structure given above in which A is methylene, X is oxy, and the values of Ar, Y, Rj, R2, R3, R4, and R5 are as defined above.
  • Particular compounds falUng within the scope of the present invention include, but are not limited to:
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • parenteral administration refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intraste nal, subcutaneous and intraarticular injection and infusion.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycoUde. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile soUd compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • SoUd dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylceUulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain siUcates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cety
  • SoUd compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as weU as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, piUs, and granules can be prepared with coatings and shells such as enteric coatings and other coatings weU known in the pharmaceutical formulating ait They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentiaUy, in a certain part of the intestinal tract, optionaUy, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert dUuents commonly used in the art such as, for example, water or other solvents, solubUizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert dUuents commonly used in the art such as, for example, water or other solvents, solubUizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystaUine cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but Uquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phosphoUpids or other lipid substances. Liposomes are formed by mono- or multi-lameUar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologicaUy acceptable and metabolizable lipid capable of forming Uposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phosphoUpids and the phosphatidyl cholines (lecithins), both natural and synthetic.
  • Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceuticaUy acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compourid(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration.
  • dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
  • 3-bromophenol (I) is converted to an O-protected intermediate (II or VI) by standard methodology.
  • MetaUation of the 3-bromo group with n-butyl Uthium and quenching of the resulting aryl anion with the mono-ethylene ketal of cyclohex__ne-l,4-dione provides intermediates HI and VH which are methylated by exposure to sodium hydride and methyl iodide.
  • Subsequent deprotection with aqueous hydrochloric acid in acetone provides the ketones V or IV.
  • Step 1 4-hydroxy-4-r3-(naphth-2-ylmethyloxy)phenyllcyclohexan-l-one ethylene glycol ketal.
  • the reaction was stirred for 1.5 hours at -78°C and judged to be complete by tic at that point.
  • the reaction was quenched by adding excess saturated aqueous ammonium chloride.
  • the resulting biphasic mixture was extracted with ether.
  • the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a colorless oil which was crystaUized with ethyl acetate/hexanes.
  • the product was collected by filtration and dried in vacuo to provide 0.28 g (36 %) as a colorless solid (mp 128-129°C).
  • Step 2 4-methoxy-4-r3-(naphth-2-ylmethyloxy phenyllcyclohexan- 1 -one ethylene glycol ketal.
  • ethylene glycol ketal (2.4 g, 6.15 mmol) prepared in step 1 was dissolved in freshly dried THF (50 mL) and sodium hydride (0.16 g, 6.76 mmol) was added portionwise to the mixture. After gas evolution ceased methyl iodide (0.5 mL, 7.99 mmol) was added and the reaction was stirred for 17 hours at ambient temperature. The reaction was quenched by adding excess saturated aqueous ammonium chloride. The resulting biphasic mixture was extracted with ether.
  • Example 1 step 2, except substituting tr ⁇ n_.-4-methoxy-4-[3-(napth-2- ylmethyloxy)phenyl]cyclohexan-l-ol (0.10 g, 0.28 mmol), prepared as in Example 2, for 4-hydroxy-4-[3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l- one ethylene glycol ketal, and adding 2% dry DMF to achieve an acceptable reaction rate.
  • the title compound was purified by chromatography on sUica gel (5% ethyl acetate/hexanes) and recrystalUzation from methanol (8 mg, 8%). mp 76-77°C.
  • the title compound is prepared by treatment of 4-methoxy-4-(3-[napth- 2-ylmethyloxy)phenyl]cyclohexan-l-one, prepared as in Example 1, with methylmagnesium bromide.
  • Example 6 The title compound is prepared according to the method of Example 1, step 2, except substituting tr ⁇ ns-4-methoxy-l-methyl-4-[3-(napth-2- y_methyloxy)phenyl] cyclohexanol, prepared as in Example 4, for 4-hydroxy-4- [3-(naphth-2-ylmethyloxy)phenyl]cyclohexan-l-one ethylene glycol ketal.
  • the title compound is prepared according to the method of Example 2, except substituting cis- and tra/w-4-methoxy-2-methyl-4-[3-(napth-2- ylmethyloxy)phenyl] cyclohexanone, prepared as in Example 6, for 4-methoxy- 4-[3-(napth-2-ylmethyloxy)phenyl]cyclohexan-l-one.
  • the title compound is prepared by treatment of tr ⁇ /w-4-methoxy-4-[3- (napth-2-ylmethyloxy)phenyl]cyclohexan- 1 -ol, prepared as in Example 2, with chloromethyl methylether (MOM-C1, 1.5 eqiuv) in the presence of NN- d sopropylethylamine (2 equiv) in dichloromethane.
  • MOM-C1 chloromethyl methylether

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Abstract

L'invention concerne des composés présentant la structure suivante (I) dans laquelle Ar représente aryle carbocyclique ou hétérocyclique; A propynyle ou méthylène; X représente oxygène, soufre, sulfonyle ou NH; Y représente hydrogène, alkyle comprenant un à six atomes de carbone, haloalkyle comprenant un à six atomes de carbone, alcoxy avec un à six atomes de carbone, ou halogène; R1 représente alkyle avec un à quatre atomes de carbone; R2 et R3 représentent hydrogène ou alkyle avec un à quatre atomes de carbone; R4 représente hydroxyle ou -OR1 où R1 est tel que défini ci-avant; et R5 représente hydrogène ou alkyle avec un à quatre atomes de carbone. Ces composés constituent des inhibiteurs de la biosynthèse des leucotriènes et sont utiles dans le traitemen de pathologies inflammatoires et allergiques.
PCT/US1993/008036 1992-09-02 1993-08-25 Composes de trans 1,4-diethercyclohexane utilises en tant qu'inhibiteurs de la 5-lipoxygenase Ceased WO1994005638A1 (fr)

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US93950592A 1992-09-02 1992-09-02
US07/939,505 1992-09-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090821A (en) * 1998-06-30 2000-07-18 E. I. Dupont De Nemours And Company Substituted quinolin-2 (1H)-ones useful as HIV reverse transcriptase inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375457A2 (fr) * 1988-12-23 1990-06-27 Imperial Chemical Industries Plc Dérivés d'éthers cycliques
EP0385663A2 (fr) * 1989-02-28 1990-09-05 Zeneca Limited Cycloalcanes hétérocycliques comme inhibiteurs de 5-lypoxygénase
EP0409412A2 (fr) * 1989-07-18 1991-01-23 Imperial Chemical Industries Plc Ethers cycliques de diaryléther

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375457A2 (fr) * 1988-12-23 1990-06-27 Imperial Chemical Industries Plc Dérivés d'éthers cycliques
EP0385663A2 (fr) * 1989-02-28 1990-09-05 Zeneca Limited Cycloalcanes hétérocycliques comme inhibiteurs de 5-lypoxygénase
EP0409412A2 (fr) * 1989-07-18 1991-01-23 Imperial Chemical Industries Plc Ethers cycliques de diaryléther

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. MEDICINAL CHEMISTRY, Vol. 35, No. 14, issued 1992, CRAWLEY et al., II, "Methoxytetrahydropyrans. A New Series of Selective and Orally Potent 5-Lipoxygenase Inhibitors", pages 2600-2609. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6090821A (en) * 1998-06-30 2000-07-18 E. I. Dupont De Nemours And Company Substituted quinolin-2 (1H)-ones useful as HIV reverse transcriptase inhibitors

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