WO1992017172A1 - Naphtalenes disubstitues - Google Patents

Naphtalenes disubstitues Download PDF

Info

Publication number
WO1992017172A1
WO1992017172A1 PCT/US1992/002742 US9202742W WO9217172A1 WO 1992017172 A1 WO1992017172 A1 WO 1992017172A1 US 9202742 W US9202742 W US 9202742W WO 9217172 A1 WO9217172 A1 WO 9217172A1
Authority
WO
WIPO (PCT)
Prior art keywords
naphthyl
compound
salt
reaction
hydroxynonyl
Prior art date
Application number
PCT/US1992/002742
Other languages
English (en)
Inventor
Robert A. Daines
William D. Kingsbury
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to JP4509604A priority Critical patent/JPH06506469A/ja
Publication of WO1992017172A1 publication Critical patent/WO1992017172A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic

Definitions

  • This invention relates to disubstituted napthalenes which are useful as leukotriene antagonists. More particularly, these napthalenes are 2,7-disubstituted compounds which have utility in treating diseases related to leukotriene B 4 wherein the treatment is affected by virtue of the antagonist activity of these 2,7-disubstituted naphthalenes.
  • the family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems.
  • the leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C 4 , D4 and E4) and the hydroxyleukotrienes (leukotriene B 4 ).
  • This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
  • the peptidoleukotrienes are implicated with the biological response associated with the "Slow Reacting Substance of Anaphylaxis" (SRS-A). This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses.
  • SRS-A Slow Reacting Substance of Anaphylaxis
  • the pharmacology of the peptidoleukotrienes include smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production.
  • LTB 4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs). It is critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
  • PMNs polymorphonuclear leukocytes
  • Leukotriene B4 (LTB 4 ) was first described by B orgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)-6,8,10,14-eicosatetraenoic acid ( Figure I).
  • LTB 4 It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB 4 has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB 4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity.
  • LTB 4 has been established as an inflammatory mediator in vivo. It has also been associated with airway hyper-responsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB 4 has been implicated in inflammatory bowel disease, rheumatoid arthritis, gout, and psoriasis.
  • the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor.
  • This invention relates to disubstituted napthalenes of formula I
  • R l is -CH(OH)(CH 2 ) n CH 3 where n is 3-20; and R2 is COX, or
  • n 0, 1 or 2
  • R3 is -COX and X is OH or a salt, ester or amide thereof.
  • this invention covers pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable excipient.
  • Treating diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ are within the scope of this invention.
  • This treatment can be effected by administering an effective amount of one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient.
  • this invention relates to methods for making a compound of formula I. These methods are illustrated in the Schemes given below and in the Examples set forth in this specification. Included in these methods are those comprising a.) forming a salt from an acid, or b) hydrolyzing an ester to a salt, or c) converting a salt to the free acid, or d) converting one salt to another salt, or e) forming an ester, or f) forming an amide, or g) inserting an R2 group at position 2 by means of a triflate intermediate.
  • lower alkyl means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form.
  • Lower alkoxy means the group lower alkyl-O-.
  • Halo means fluoro, chloro, bromo or iodo.
  • An ester-forming group is any group where an oxygen is covalently bonded to a carbonyl carbon and a second carbon atom wherein the resulting molecule is called an ester.
  • an amide-forming group is one where a nitrogen is bonded to a carbonyl carbon and otherwise is substituted by two hydrogens, a hydrogen and a carbon or two carbons where the resulting molecule is called an amide.
  • esters or amides within the scope of this invention will retain some useful activity in treating a disease relating to or caused by leukotrienes particularly LTB 4 , or for some other industrial application.
  • a pharmaceutically acceptable ester-forming group or “pharmaceutically acceptable amide forming group”
  • the preferred esters are those having the formula CH3(CH 2 ) u -0- where u is 0-6, a lower alkoxy group.
  • the most preferred amides are those where the nitrogen is substituted with just hydrogen or one or two lower alkyl groups.
  • the preparation of esters and amides diethylamide is particularly preferred.
  • this invention is intended to cover all salts which have industrial application. If the phrase "a pharmaceutically acceptable salt” is used, that is intended to cover salts which have use and application in the human and animal medicinal arts. Examples of pharmaceutically acceptable salts can be found in the review article by Merge, S.M., et al., /. Pharm Sc , Vol. 66, No. 1, January 1977/1.
  • Salts are prepared in a standard manner, in a suitable solvent.
  • the parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of a basic functionality, or an excess of organic or inorganic base where X is OH.
  • a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. These compounds may be used as a racemic mixture or the racemates may be separated and the individual enantiomer used alone.
  • these compounds can be used in treating a variety of disease associated with or attributing their origin or affect to leukotrienes, particularly hydroxyleukotrienes (LTB 4 ). It is expected that these compounds can be used to treat pulmonary and non-pulmonary allergic diseases. For example, these compounds can be useful in treating antigen-induced anaphylaxis. They will be useful also in treating asthma and allergic rhinitis, psoriasis, and inflammatory bowel disease. Ocular diseases such as uveitis, and allergic conjunctivitis will also be treated with these compounds.
  • the preferred compounds of this invention are those where Ri is -CH(OH)(CH2) n CH3 and n is 5-15. More preferred compounds are those where the n in Ri is 8 and R 2 is -COX, or group A where n is 0, 1 or 2 and R3 is in the 3 or 4 position, or R2 is B where R3 is in the 3 or 4 position or C where R3 is in the 3 or 4 position.
  • the most preferred compounds are:
  • Syntheses These compounds may be made from the starting materials and using the intermediates and reagents set out in the reaction flow charts below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are given to illustrate the general case and are not intended to limit the chemistries which can be used in making these compounds. All reagents, intermediates, temperatures, solvents, reaction times, and work-up procedures may be varied to accommodate differences in the processes used in making these compounds and may be varied to optimize the particular conditions or reagents for making any given compound.
  • the 2,7-dihydroxynapthalene starting material is a known compound available from a number of commercial chemical houses.
  • First protected is one of the hydroxyl groups, preferably by means of a silyloxy group as illustrated by 2.
  • a f-butyldimethyl- silyloxy protecting group is preferred.
  • the triflate 3 is prepared by treating 2 with trifluoromethanesulfonic anhydride under an inert atmosphere in a dry solvent such as methylene dichloride. Slightly reduced temperature, e.g. -10° to 10°C, is preferred; the reaction is run for between about 10 minutes and 2 hours.
  • An ester function is introduced at the 7 position by mixing 3 with dppp and the palladium catalyst Pd(OAc)2, then bubbling carbon monoxide through the solution to produce the ester (4).
  • the ester is then reduced to the alcohol (5) by means of a reducing agent such as 1-BU2AI-H.
  • This reaction is carried out at reduced temperature (e.g. -78°C) under an inert atmosphere, the reaction being completed in a relatively short time of about 5 to 25 minutes.
  • the aldehyde 6 is made by treating 5 with a mild oxidizing agent such as manganese dioxide.
  • a Grignard reagent is employed to add the alkyl chain to the carbonyl carbon of 6 resulting in the 1 -hydroxy alky 1 compound 7.
  • This 1 -hydroxy group is then protected, preferably employing the same protecting group used to protect the 2-position hydroxy group.
  • Conditions which are the same as or similar to those used to prepare 2 may be used to prepare 8.
  • the 2-position is selectively deprotected. This may be accomplished using a nucleophile such as an alkali metal alkoxide, e.g., potassium methoxide.
  • An inert atmosphere, methanol, and anhydrous potassium carbonate comprise the preferred reactants and conditions for this reaction.
  • An hour or so of stirring at about room temperature is sufficient to effect the reaction, giving 9.
  • Preparing 10 converting it to the ester 11 and reducing the ester to the alcohol 12 is accomplished using the same or similar reagents and conditions described for making 3, 4 and 5.
  • the alcohol 12 is converted to the bromo 13 using carbon tetrabromide and triphenylphosphine under an inert atmosphere and an inert solvent. Then a mercaptobenzene adduct is reacted with 13 in the presence of a weak base to form 14.
  • An anhydrous alkali metal carbonate is preferred for this reaction, for example potassium carbonate.
  • Dimethylformamide or a similar solvent may be used.
  • the reaction can be carried out at room temperature or thereabouts.
  • the 1 -hydroxy group on the 7-position substitution is deprotected by means of a fluoride source such as tetrabutylammonium fluoride giving (15).
  • a base such as an alkali metal base is used to hydrolyze the ester on the benzene ring. This is for the case where LiOH is used.
  • the free acid can be obtained by acidifying a solution of the salt obtained from the saponification process, or by some other process.
  • Scheme II illustrates the process schematically.
  • the sulfoxide 17 is obtained if one equivalent of the oxidizing agent is used. Two equivalents provide the sulfone 19.
  • base preferably an alkali metal base, can be used to hydrolyze the ester to the salts 18 and 20.
  • Z represents the cation of whatever base was used to effect the hydrolysis.
  • Ethers can be made by treating 13 (see Scheme I) or an analog thereof with an hydroxybenzoate as outlined in Scheme III.
  • Ether 21 is made by combining the appropriate hydroxybenzoate with 13 in the presence of a weak base.
  • alkali metal carbonate is preferred, particularly anhydrous potassium carbonate.
  • this reaction is carried out at a temperature between about 30° - 90° C under an inert atmosphere in a dry solvent such as DMF.
  • tetrabutylammonium fluoride is used to deprotect the hydroxyl group on Ri.
  • the ester 22 is then saponified, preferably using an alkali metal base which gives an alkali metal salt, though
  • Starting material 12 is prepared by the method set out in Scheme I.
  • the hydroxyl group is treated with an oxidizing agent, for example a chromium-based oxidizing agent exemplified by pyridinium dichromate.
  • an oxidizing agent for example a chromium-based oxidizing agent exemplified by pyridinium dichromate.
  • a preferred method is to treat 12 with an excess of pyridinium dichromate in DMF under an inert atmosphere for an extended period, e.g.. 18 hours at room temperature. This gives 24.
  • the protecting group may be removed by acid such as acetic acid.
  • An elevated temperature between about 30° - 90° C with stirring for 2-6 hours will hydrolyze the silyl ether. Basifying the solution provides 25 where X + represents a cation.
  • compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or a pharmaceutically acceptable salt, such as an alkali metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes.
  • compositions and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by inhalation.
  • examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrif uoroethane and compressed carbon dioxide.
  • the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
  • the compositions will be in a form suitable for administration by inhalation.
  • the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
  • the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container.
  • the compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
  • the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
  • the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.
  • topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose.
  • the pharmaceutical composition will be in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, • liquid, or emulsion.
  • a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a factor.
  • the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration.
  • equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 100 mg to about 5000 mg.
  • the pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
  • a disease mediated by leukotrienes particularly by LTB4.
  • a therapeutically effective amount of a compound of formula I preferably in the form of a pharmaceutical composition.
  • the administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth.
  • compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction.
  • Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines (diphenhydramine), ethylenediamines (pyrilamine), the alkylamines (chlorpheniramine), the piperazines (chlorcyclizine), and the phenothiazines (promethazine).
  • Hi blockers such as 2-[4- (5-bromo-3 -methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3- yl)methyl]-4-pyrimidone are particularly useful in this aspect of the invention.
  • the specificity of the antagonist activity of a number of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, histamine and PGF2.
  • the receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [ 3 H]-LTB 4 binding sites on human U937 cell membranes.
  • the LTB 4 antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB 4 elicited calcium transient measured with fura-2, the fluorescent calcium probe.
  • the methods employed were as follows: U937 Cell Culture Conditions U937 cells were obtained from Dr. John Bomalaski (Medical
  • the pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris- HCl, pH 7.4 at 25° C and aliquots were rapidly frozen and stored at -70°C. Binding of .-3-HI-LTB ⁇ to U397 Membrane Receptors
  • [ 3 H]-LTB 4 binding assays were performed at 25° C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCh, 10 mM MgCl 2 , [ 3 H]- LTB4 . U937 cell membrane protein (standard conditions) in the presence (or absence of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations.
  • Total and non-specific binding of [ 3 H] - LTB4 were determined in the absence or presence of 2 ⁇ M of unlabeled LTB 4 , respectively. Specific binding was calculated as the difference between total and non-specific binding.
  • the radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [ 3 H]-LTB 4 , 20-40 ⁇ g of U937 cell membrane protein, increasing concentrations of LTB 4 (0.1 nM to 10 nM) or other competing ligands (0.1 ⁇ M to 30 ⁇ M) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25° C.
  • the unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique.
  • the membrane bound radioactivity on the filters was determined by liquid scintillation spectrometry.
  • Biomedical Instrumentation Group Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37° C with constant mixing.
  • U937 cells were diluted with fresh buffer to a concentration of 1 x 10 6 cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 ⁇ l aliquots.
  • Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one minute 10 nM LTB4 (a near maximal effective concentration) was added and the maximal Ca 2+ mobilization [Ca 2+ ]i was calculated using the following formula:
  • F was the maximum relative fluorescence measurement of the sample. Fmax was determined by lysing the cells with 10 ⁇ l of 10% Triton X-100 (final Concentration 0.02%). After Fmax was determined 67 ⁇ l of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca 2+ and quench the fura-2 signal and obtain the Fmin.
  • the [Ca 2+ ]i level for 10 nM LTB 4 in the absence of an antagonist was 100% and basal [Ca 2+ ]i was 0%.
  • the IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced [Ca 2 +]i mobilization.
  • the EC50 for LTB4 induced increase in [Ca 2+ ]i mobilization was the concentration for half maximal increase.
  • the Ki for calcium mobilization was determined using the formula:
  • the LTB 4 concentration was 10 nM and the EC5 0 was 2 nM.
  • Several of the compounds of this invention were tested in one or more of the aforementioned assays. Results for those tests are given in Figure III; average results are given where more than one test was done.
  • Example 1 3- ⁇ -Thia-2-( , 7-d -hvdroxynonyl . -2-naphthyl ' )ethvnbenzoic acid. lithium salt 1A. 2-t-Butyldimethylsilyloxy-7-hydroxy naphthalene.
  • reaction mixture Upon cooling to room temperature the reaction mixture was filtered through Celite and the CH3OH was evaporated. The remaining solution was diluted with Et2 ⁇ and washed with H2O, 5% HCl, aqueous NaHC03, and brine and dried (MgS ⁇ 4).
  • n-octylmagnesium bromide was prepared from 1-bromooctane (2.7mL, 15.6mmol) and Mg (450mg, 18.5mmol) in dry tetrahydrofuran (40mL) under an argon atmosphere.
  • the cooled (0°C) solution containing the Grignard reagent was transferred via canula to a cooled (-25° C) solution of 2-t- butyldimethylsilyloxy-7-naphthalene carboxaldehyde (2.63g, 9.2mmol) in dry tetrahydrofuran (lOmL).
  • Tetrabutylammonium fluoride (ImL, l .Ommol; 1.0M solution in tetrahydrofuran) was added to a stirred solution of methyl 3-[ l -thia-2-(7-( l -t-butyldimethylsilyloxynonyl)-2-naphthyl)ethyl]- benzoate (156mg, 0.276mmol) in tetrahydrofuran (0.5mL) under an argon atmosphere. After 1.5 hours the reaction was diluted with Et 2 ⁇ and washed with aqueous NH 4 CI and brine and dried (MgS0 4 ). The product was purified by flash column chromatography (silica, 10% ethyl acetate in CH 2 CI 2 ) to give a colorless solid: H NMR
  • Methyl 3-ri -oxythia-2-f7-fl -hydroxynonyl -2-naphthyl)ethyl1-benzoate Methyl 3-[l-thia-2-(7-(l-hydroxynonyl)-2-naphthyl)- ethyljbenzoate (30mg, 0.067mmol) was dissolved in dry CH2CI2 (ImL) under an argon atmosphere and cooled to 0°C. To this was added 80% -chloroperoxy-benzoic acid (16mg, 0.074mmol); stirring was continued for 30 minutes.
  • Methyl 3-[l -thia-2-(7-(l -hydroxynonyl)-2-naphthyl)- ethyljbenzoate (29mg, 0.065mmol) was dissolved in dry CH2CI2 (ImL) under an argon atmosphere and cooled to 0°C. To this was added 80% m-chloroperoxy-benzoic acid (30mg, 0.14mmol); stirring was continued for 2 hours. The reaction was poured into aqueous NaHC ⁇ 3 and the product extracted into CH 2 CI2. The organic layer was washed with brine and dried (MgS ⁇ 4 ).
  • Methyl 3-[l -dioxythia-2-(7-(l -hydroxynonyl)-2-naphthyl)- ethyljbenzoate (27mg, 0.056mmol) was dissolved in tetrahydrofuran (0.40mL) and CH3OH (0.20mL) and treated with 1.0M LiOH (0.20mL, 0.20mmol). The reaction was stirred under an atmosphere of argon for 4 hours. The tetrahydrofuran and CH3O H were evaporated and the product purified by Reversed Phased MPLC (RP-18 silica, H 2 O-CH3OH gradient).
  • Tetrabutylammonium fluoride (ImL, l.Ommol; 1.0M solution in tetrahydrofuran) was added to a stirred solution of methyl 3-[l-oxa-2-(7-(l -t-butyldimethylsilyloxynonyl)-2-naphthyl)ethyl]- benzoate (155mg, 0.282mmol) in tetrahydrofuran (0.5mL) under an argon atmosphere. After 1.5 hours the reaction was diluted with Et2 ⁇ and washed with aqueous NH 4 CI and brine and dried (MgS ⁇ 4).
  • Methyl 3-[ l -oxa-2-(7-( l -hydroxynonyl)-2-naphthyl)- ethyl] benzoate (65mg, 0.15mmol) was dissolved in tetrahydrofuran (0.90mL) and CH 3 OH (0.45mL) and treated with 1.0M LiOH (0.45mL, 0.45mmol). The reaction was stirred under an atmosphere of argon for 6 hours. The reaction solution was diluted with E_2 ⁇ and washed with 5% HCl (aqueous phase pH ⁇ l). The organic phase was washed with H 2 O and brine and dried (MgS0 4 ).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Naphtalènes 2,7-disubstitués utiles comme antagonistes de leucotriène.
PCT/US1992/002742 1991-04-05 1992-04-04 Naphtalenes disubstitues WO1992017172A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4509604A JPH06506469A (ja) 1991-04-05 1992-04-04 二置換ナフタレン

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68215791A 1991-04-05 1991-04-05
US682,157 1996-07-17

Publications (1)

Publication Number Publication Date
WO1992017172A1 true WO1992017172A1 (fr) 1992-10-15

Family

ID=24738481

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1992/002742 WO1992017172A1 (fr) 1991-04-05 1992-04-04 Naphtalenes disubstitues

Country Status (4)

Country Link
EP (1) EP0579731A1 (fr)
JP (1) JPH06506469A (fr)
AU (1) AU1742492A (fr)
WO (1) WO1992017172A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752616A (en) * 1987-06-29 1988-06-21 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, compositions containing same and method of use
US4943651A (en) * 1988-03-07 1990-07-24 Mitsui Petrochemical Industries, Ltd. Novel substitued naphthalene compounds and liquid crystal compositions containing same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4073912A (en) * 1976-10-12 1978-02-14 Smithkline Corporation Piperidylidene derivatives of benzo-fused xanthenes, thioxanthenes and dibenzoxepins and antipsychotic use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4752616A (en) * 1987-06-29 1988-06-21 E. R. Squibb & Sons, Inc. Arylthioalkylphenyl carboxylic acids, compositions containing same and method of use
US4943651A (en) * 1988-03-07 1990-07-24 Mitsui Petrochemical Industries, Ltd. Novel substitued naphthalene compounds and liquid crystal compositions containing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0579731A4 *

Also Published As

Publication number Publication date
JPH06506469A (ja) 1994-07-21
EP0579731A4 (fr) 1993-12-07
EP0579731A1 (fr) 1994-01-26
AU1742492A (en) 1992-11-02

Similar Documents

Publication Publication Date Title
DE69212948T2 (de) Styrol-Derivate
US4656190A (en) Indene derivatives and their use as PAF-antagonists
JPH0684336B2 (ja) 殺生物性芳香族化合物、その合成および医薬としてのその使用
US4672066A (en) Derivatives of 4-acetyl-3-hydroxy-2-alkyl-phenoxycarboxylic acids
JP6310931B2 (ja) Ｇｐｒ１２０アゴニストとしてのチオアリール誘導体
NZ244371A (en) Pyridyl-substituted benzylsulphides and analogues and pharmaceutical compositions
HUT64747A (en) Process for producing benzoic acid derivatives and pharmaceutical preparatives containing them
CS9200024A3 (en) Sulfonamide derivatives, process of their preparation and pharmaceuticalcompositions comprising them
EP0296732B1 (fr) Antagonistes de leukotriène
JPS5982385A (ja) Ｎ−置換−２−（１−イミダゾリル）インド−ル、その製法および該化合物を含有する医薬製剤
US6277839B1 (en) Biphenylene lactams as prostaglandin receptor ligands
US5643914A (en) Pharmaceutical pyridine compounds
US5990314A (en) Pharmaceutical pyridine compounds
WO1992017172A1 (fr) Naphtalenes disubstitues
CA2083958A1 (fr) Derives d'acide benzoique pour le traitement de maladies associees aux leucotrienes
DE3302814A1 (de) Neue allylamine, verfahren zu ihrer herstellung und ihre verwendung
EP0532621A1 (fr) Derives d'acide pyridyle-benzoique a liaison amide utilises dans le traitement de maladies associees aux leucotrienes
AU610528B2 (en) Leukotriene antagonists
US5314918A (en) Leukotriene antagonists
DE2415867A1 (de) Phenoxyalkanolderivate und verfahren zu ihrer herstellung
EP0532634A1 (fr) Derives d'acide phtalamique utilises dans le traitement de maladies associees aux leucotrienes
EP0165897A2 (fr) Résorcinéthers
EP0575494A1 (fr) Antagonistes des leucotrienes
EP0639975A1 (fr) Composes de pyridine heterocyclique substituee et leurs utilisations
EP0379191B1 (fr) Acides 1,3-dioxolane benzoiques et dérivés de ces derniers

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref country code: US

Ref document number: 1993 122552

Date of ref document: 19930930

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1992910006

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1992910006

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWR Wipo information: refused in national office

Ref document number: 1992910006

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1992910006

Country of ref document: EP