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WO1995029906A1 - Derive de benzofurane et son utilisation - Google Patents

Derive de benzofurane et son utilisation Download PDF

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Publication number
WO1995029906A1
WO1995029906A1 PCT/JP1995/000325 JP9500325W WO9529906A1 WO 1995029906 A1 WO1995029906 A1 WO 1995029906A1 JP 9500325 W JP9500325 W JP 9500325W WO 9529906 A1 WO9529906 A1 WO 9529906A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
ethyl acetate
reaction
mixture
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.)
Ceased
Application number
PCT/JP1995/000325
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English (en)
Japanese (ja)
Inventor
Tomonori Kamiyama
Yoshio Sato
Naoki Taketomo
Itsuro Yokota
Manabu Nakajima
Yoshihiro Yoshiyama
Hideo Nemoto
Yasuo Fujimoto
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.)
Meiji Dairies Corp
Original Assignee
Meiji Milk Products Co Ltd
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 Meiji Milk Products Co Ltd filed Critical Meiji Milk Products Co Ltd
Publication of WO1995029906A1 publication Critical patent/WO1995029906A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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

Definitions

  • the present invention relates to a benzofuran derivative and a use thereof, and more particularly, to a benzofuran derivative having an inhibitory action on 5-lipoxygenase activity and effective for treatment and prevention of allergic diseases and various inflammations, and a use thereof.
  • PG and LT are involved in allergic diseases such as bronchial asthma and various inflammations.
  • PG and LT among these factors play a particularly important role in allergic diseases and various inflammatory reactions due to their diversity in number and bioactivity.
  • arachidonic acid metabolites such as PG LT TX are over- or under-produced in the cells, resulting in increased vascular permeability, bronchoconstriction, and platelet aggregation. This leads to allergic diseases and various inflammations.
  • anti-inflammatory drugs Many drugs that inhibit the action of various enzymes involved in the arachidonic acid metabolic pathway have been developed as anti-inflammatory drugs.
  • non-steroid anti-inflammatory agents such as aspirin and indomethacin are mentioned as agents which exhibit an anti-inflammatory effect by inhibiting cyclooxygenase activity and consequently suppressing PG production.
  • they are effective for inflammation involving the PG system, they have no inhibitory effect on inflammation caused by LT.
  • SRS-A The presence of a slow reacting substance of anaphyla is SRS-A is clearly evident as a potent mediator of bronchial asthma.
  • This SRS-A is a mixture of LTC 4 LTD 4 and LTE 4 .
  • LTB 4 has potent leukocyte attracting action, the leukocyte-activating effect, involvement of the inflammation has attracted attention. Therefore, compounds that inhibit the activity of 5-lipoxygenase, which is the first enzyme in producing LT, are expected to be effective in treating or preventing allergic diseases such as bronchial asthma and various inflammations. And like this From the viewpoint, compounds capable of inhibiting 5-lipoxygenase activity have been developed (for example, Japanese Patent Application Laid-Open Nos. H11-213276 and W091 Z07396). However, some of these compounds are inadequate in their action or safety and others are difficult to produce.
  • the present inventors have conducted intensive studies in view of such circumstances, and as a result, have found that the compound (1) described below has excellent antiallergic and anti-inflammatory effects and is excellent in safety, and has completed the present invention. I came to.
  • the present invention provides the following general formula (1)
  • R 1 represents a hydrogen atom, a hydroxyl group or an alkoxyl group having 1 to 5 carbon atoms
  • R 2 and R 3 represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or an alkenyl group having 2 to 5 carbon atoms
  • R 4 represents an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 2 to 8 carbon atoms, or a benzoyloxy group which may be substituted by 1 to 2 hydroxyl groups.
  • R 4 is not an n-pentyl group.
  • the present invention relates to an antiallergic agent comprising the benzofuran derivative (1) as an active ingredient.
  • the present invention relates to an anti-inflammatory agent comprising the derivative (1) as an active ingredient.
  • the present invention also relates to a pharmaceutical composition containing the derivative (1) and a pharmaceutical carrier.
  • the present invention relates to the use of the benzofuran derivative (1) as a medicament. You.
  • the present invention relates to a method for treating an allergic disease or an inflammatory disease, which comprises administering an effective amount of the benzofuran derivative (1).
  • the alkoxy group having 1 to 5 carbon atoms represented by R 1 includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an n-pentyloxy group and the like. Of these, a methoxy group is more preferred. In R 1 , a hydrogen atom, a hydroxyl group or a methoxy group is more preferred, and a hydroxyl group is particularly preferred.
  • Examples of the alkyl group having 1 to 5 carbon atoms represented by R 2 and R 3 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an n-pentyl group. An n-propyl group is particularly preferred.
  • Examples of the alkenyl group having 2 to 5 carbon atoms represented by R 2 and R 3 include a vinyl group, a 2-propenyl group, a 1-propenyl group, a 3-butenyl group and a 4-pentenyl group. However, a 2-propenyl group is particularly preferred. It is preferable that one of R 2 and R 3 is a hydrogen atom and the other is an alkyl group having 1 to 5 carbon atoms or an alkenyl group having 2 to 5 carbon atoms.
  • Examples of the alkyl group having 1 to 8 carbon atoms represented by R 4 include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n —Octyl group and the like, among which a straight-chain alkyl group having 2 to 8 carbon atoms, particularly a straight-chain alkyl group having 3 to 8 carbon atoms, particularly n-butyl group is preferable.
  • alkoxyl group having 1 to 8 carbon atoms examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, Among these, a straight-chain alkoxyl group having 2 to 8 carbon atoms, particularly a straight-chain alkoxyl group having 3 to 8 carbon atoms, and particularly an n-benzyloxy group are preferable.
  • Benzyl groups which may be substituted by one or two hydroxyl groups represented by R 4 include benzoyl, 0-hydroxybenzoyl, m-hydroxybenzoyl, p-hydroxy Benzoyl group, 2,3-dihydroxybenzoyl And a 3,4-dihydroxybenzyl group. Of these, a 2,3-dihydroxybenzoyl group and a 3,4-dihydroxybenzoyl group are preferred.
  • the benzofuran derivative (1) of the present invention includes an optical isomer based on an asymmetric carbon atom.
  • the compound in which R 4 is an alkyl group having 1 to 8 carbon atoms can be obtained by, for example, starting from mono- or dihydroxybenzaldehyde ( ⁇ ) as a raw material according to the following reaction formula (a), or Starting from 2- (1,3-pentene genyl) -2,3-dihydro-5,7-dihydroquinbenzofuran (K), the intermediate aldehyde compound (J-1 ) And then from this aldehyde compound (J-1) according to the following reaction formulas (c) to (f).
  • A represents a protecting group
  • R 5 represents a hydrogen atom or a hydroxyl group
  • R 6 represents a hydrogen atom or 1 OA
  • the hydroxyl group of the compound (K) is protected with a methoxymethyl group, a trialkylsilyl group, etc. to give the compound (L), which is then reacted with osmium tetroxide to oxidize two double bonds to form a tetraol compound.
  • an aldehyde compound (J-11) is obtained.
  • R 7 represents a hydrogen atom or an alkyl group having 1 to 7 carbon atoms.
  • an Aldehyde (J-12) is converted to an alkenyl group corresponding to the alkyl group of the target compound (1) of the present invention by a Zitztig reaction using an alkylidenephosphorane to obtain olefin (N ) Is obtained, and this is subjected to catalytic hydrogenation to obtain a compound (II), which is then deprotected to obtain the present compound (1-a).
  • the compound (11b) of the present invention can be obtained by reacting the above compound (II) with aryl bromide to give a compound (P) and then deprotecting the compound (P). [Reaction formula (d)] Aryl bromide
  • compound (Q) is obtained by reacting compound (0) obtained by the above-mentioned reaction or by another method with lithium methoxide to deprotect only the 7-position. After reacting with aryl bromide to allylate the hydroxy group at the 7-position to give compound (R), the Claisen rearrangement reaction gives the ortho rearrangement (S) and para rearrangement (T), each of which is further deprotected. By this, the compounds of the present invention (1-1b) and (1-1c) can be obtained strongly. (Reaction formula (e))
  • R 8 represents an alkyl group having 1 to 5 carbon atoms, and R 7 and A have the same meaning as described above. ]
  • Compound (II) is obtained by subjecting compound (II) to catalytic hydrogenation using palladium carbon as a catalyst in a stream of hydrogen gas to obtain compound (X) and then deprotecting the compound (X).
  • a compound in which R 4 is an alkoxyl group having 2 to 8 carbon atoms is, for example, a compound in which R 6 is OA in the compound (I).
  • reaction formula (g) reaction formula (g) or reaction formula (h) using () as a raw material.
  • compound (Y) is reacted with an alkyl halide or alkyl paratoluenesulfonate in a solvent such as anhydrous dimethylformamide in the presence of sodium hydride to form compound (Y), which is then deprotected.
  • Compound (Z) is obtained.
  • the compound (H) is reacted with aryl bromide to allylate the hydroxyl group at the 7-position to give a compound ().
  • the hydroxyl group at the 5-position is protected with a methoxymethyl group, a trialkylsilyl group, etc., to give the compound (S). obtain.
  • an ortho rearrangement (7-a) and a para rearrangement ( ⁇ /-1b) are obtained by the Claisen rearrangement reaction, and each is further deprotected, whereby R 4 in the general formula (1) has 2 to 8 carbon atoms.
  • alkoxyl groups der is, the present invention compounds wherein R 1 is a hydroxyl group (1 one h) and (1-i) is obtained, et al.
  • R 6 is hydrogen atom in the compound (I) (1 2) deprotection to give compound was the (I 3), this is reacted with bromide Ariru ⁇ Ariru body (5) And subjected to a Claisen rearrangement reaction to obtain a 6-position rearrangement (£ 1a) and a 4-position rearrangement (£ 1b).
  • R 4 is a benzoyl group which may be substituted with one or two hydroxyl groups in the general formula (1)
  • reaction formula (i) a compound in which R 4 is a benzoyl group which may be substituted with one or two hydroxyl groups in the general formula (1)
  • R '° and R 11 represents a hydrogen atom or a hydroxy Le group
  • R ie' and R 11 ' represents a hydrogen atom or a Benjiruokin group. That is, the compound ( ⁇ -1a) or ( ⁇ -1b) obtained by the reaction formula (h) may be substituted with one or two benzyloxy groups, and then reacted with benzoic acid to form an ester compound.
  • R 4 is a benzoyloxy group which may be substituted by 1 to 2 hydroxyl groups, and R 1 is a hydrogen atom.
  • the benzofuran derivative (1) of the present invention has a remarkable inhibitory effect on 5-lipoxygenase activity in the arachidonic acid cascade [50% inhibitory concentration (IC 5 .value)
  • (1) has the effect of suppressing anaphylaxis, a type of allergic reaction, because it suppresses the tracheal contraction caused by the addition of antigen to the tracheal specimen of sensitized guinea pigs. It is stronger than the benzofuran derivative described in WO 91/07396.
  • a drug containing the compound of the present invention as an active ingredient is useful for treatment and prevention of allergic diseases such as bronchial asthma, rheumatic diseases, psoriasis, and various inflammations. .
  • Pharmaceuticals containing the compound of the present invention as an active ingredient can be administered orally in the form of tablets, capsules, liquids, injections, suppositories, etc. using the compound of the present invention as it is or using known carriers and excipients. It can be administered topically or parenterally.
  • the dosage varies depending on the subject, the route, the symptoms, and the like. For example, when administered for bronchial asthma in adults, it is usually preferable to administer about 0.1 to 100 mg per day.
  • the extract was washed successively with 100% hydrochloric acid (100 Omt), saturated aqueous sodium hydrogen carbonate (100) and saturated saline (100 1 ⁇ ), and the ethyl acetate layer was dehydrated with anhydrous sodium sulfate.
  • the solvent in the ethyl acetate layer is concentrated under reduced pressure, and the mixture is subjected to silica gel column chromatography to obtain ⁇ -hexane: ethyl acetate.
  • reaction solution was poured into cold water 50 to terminate the reaction, and the aqueous solution was extracted three times with ethyl acetate 100, and the ethyl acetate layer was washed successively with 100% hydrochloric acid 100 and water 100, and then dried with anhydrous sulfuric acid.
  • ethyl acetate 19: 1 by silica gel gel column chromatography to give 2,3-dihydro-2-vinyl-5 , 7-Bis (t-butyldimethylsiloxane) benzofuran (40 Omg, 1.0 mg) was obtained.
  • Example 1 2,3-Dihydro-2-propyl-5 in the same manner as in Example 1 except that methyltriphenylphosphonium bromide was used instead of methyltriphenylphosphonium bromide. , 7-dihydroxybenzofuran [Compound
  • Example 1 2,3-Dihydro-2-butyl monobutylamine was prepared in the same manner as in Example 1 except that methylpyrrophenylphosphonium bromide was used in place of methyltriphenylphosphonium bromide in (2). 5,7-Dihydroxybenzofuran [compound (113)] was obtained.
  • Example 1 2,3-Dihydro-2-hexyl was prepared in the same manner as in Example 1 except that benzyltriphenylphosphonium bromide was used in place of methyltriphenylphosphonium bromide in (2).
  • Example 1 In the same manner as in Example 1 except that hexyltriphenylphosphonium bromide was used in place of methyltriphenylphosphonium bromide in (2), 2,3-dihydro-1-heptyl-5 , 7-Dihydroxybenzofuran [compound (115)] was obtained.
  • Example 1 2,3-Dihydro-2-octyl-5,7 in the same manner as in Example 1 except that heptyltriphenylphosphonium bromide was used instead of methyltriphenylphosphonium bromide in (2). —Dihydroxybenzofuran [Compound (116)] was obtained.
  • Example 1 (3) 2,3-Dihydro-2-nonyl-5,2- (3-methyl-2-phenyl) -5 in the same manner as in Example 1 except that octyltriphenylphosphonium bromide was used instead of methyltriphenylphosphonium bromide in (2). 7-Dihydroxybenzofuran [compound (117)] was obtained.
  • reaction solution was poured into 150 m of water and extracted three times with 150 mL of ethanol acetate.
  • the extract was washed successively with 10% hydrochloric acid 200 TO saturated sodium bicarbonate aqueous solution 200 and saturated saline 20 and the ethyl acetate layer was dehydrated with anhydrous sodium sulfate.
  • methoxymethyl chloride (96.2ml 1.27mo ⁇ ) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was extracted by adding dichloromethan (400 000 ⁇ , 200 OT ⁇ ) and water (400 ⁇ ). Organic layer is 10% hydrochloric acid (300 200 ⁇ ). Saturated aqueous sodium hydrogen carbonate solution
  • the obtained residue was dissolved in methanol (80 Omi), and 10% carbon dioxide (50 g, 0.1 g) was added. After the completion of the reaction, the solvent was distilled off, saturated ammonium chloride (500 ⁇ ) was added, and the mixture was extracted with dichloromethane (500 ml 300 ml 300 ⁇ ). After the solvent was distilled off, the obtained residue was subjected to silica gel column chromatography, and the title compound (59: 1) was eluted with n-hexane monoethyl acetate (2: 1). .5 g, 77%) as a colorless oil.
  • reaction mixture was washed with ethyl acetate (diluted with 50, 10% hydrochloric acid (40 ( ⁇ , 30 ⁇ ), saturated sodium bicarbonate (30, saturated saline (30 ⁇ ), and then sodium sulfate). After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography, and the title compound (105 g) was eluted from the elution portion of ⁇ -hexaneethyl acetate (19: 1). , 91%) as a colorless oil.
  • the title compound (1 16 g, 94%) was obtained as white crystals from the eluted portion of ethyl ethyl acetate (1: 1), and recrystallized from methanol. White crystals with a melting point of 70.5-72.5 ° C were obtained.
  • reaction solution was poured into water, extracted three times with ethyl acetate loo, washed with saturated saline 30 (washed with e, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated under reduced pressure to give 2-ethoxymethyl-5, 7-Bis (methoxymethyloxy) -2,3-dihydrobenzofuran was obtained.
  • the title compound was produced in the same manner as in Example 15 except that propyl iodide was used instead of iodide tyl.
  • the title compound was produced in the same manner as in Example 15 except that pentyl iodide was used instead of iodide tyl.
  • the title compound was produced in the same manner as in Example 15 except that heptyl iodide was used instead of thiol iodide.
  • the title compound was produced in the same manner as in Example 15 except that octyl iodide was used instead of octyl iodide.
  • Triaryloxy-4-tosyloxybenzene 17.628 (57.9 t0) was dissolved in! ⁇ -Dimethylylaniline 6 (1 ⁇ 2), and the mixture was heated and stirred at 200 to 210 ° C for 21 hours.
  • RBL-1 cells Ra t Basophilic Leuk emia, Dainippon Pharmaceutical purchased from. 2. 5 X 1 0 7 cells, 0. 1M Tris - disrupting the cells with ultrasound was washed twice with hydrochloric acid buffer solution (pH7 5). The obtained cell lysate is ultracentrifuged at 100,000 xg for 90 minutes, and the supernatant is used as a 5-lipoxygenase enzyme solution.
  • the concentration (IC 50 ) of the compound of the present invention that inhibits 5-lipoxygenase activity by 50 % is represented by the concentration of the compound of the present invention when inhibiting the production of 5-HETE by 50 % as compared with the control group. It is. Table 1 shows the results.
  • the compound of the present invention has a remarkable 5-lipoxygenase activity inhibitory activity.
  • the compound of the present invention was compared with the benzofuran derivative described in WO 91/07396, It was found to have a stronger inhibitory effect on 5-lipoxygenase activity.
  • Test Example 2 Stress-suppressing effect on isolated guinea pig trachea specimen
  • OVA Five Min
  • guinea pigs Hartley
  • the isolated trachea was cut into a spiral, and suspended in a Magnus tube (1031 ° C) with a load of 1.0 g connected to the isotonic transducer to record the change in tension.
  • the inhibition rate of the compound of the present invention on the tracheal contraction induced by ⁇ VA was determined at two points at the time of maximum contraction and at 60 minutes after the addition of OVA by comparing with the standard tension. The total inhibition rate for 60 minutes was also determined from the area under the shrinkage curve.
  • Ovalbumin (OVA) in 5 OmgZ saline was intraperitoneally administered to guinea pigs (Hart 1 ey, male and female, SLC, Shizuoka) LmZ was administered subcutaneously and used for the experiment after 2-4 weeks. Guinea pigs weigh 450-600 g at the time of the experiment.
  • Guinea pigs were anesthetized with tiopental, and force trachea was inserted into the trachea, jugular vein and carotid artery.
  • a ventilator was connected to the tracheal force neurator, and forced to breathe at a rate of 54 times / 3 ⁇ 4 ⁇ at a rate of 1 O ⁇ / kg.
  • the blood pressure, heart rate, and pulmonary ventilation pressure were recorded over time from a pressure transformer connected to the arterial and tracheal force neurons.
  • the vagus nerve is cut to remove the effects of the parasympathetic nervous system, and propranolol (lmgZkg) to remove the effects of the sympathetic nervous system, histamine, and prostaglandins.
  • Pyrilamine (2 mg / kg) and indomethacin (5 mg / kg) were administered from a venous power neura.
  • the compound of the present invention (1 OmgZkg) dissolved in polyethylene glycol 200: saline (2: 1) or a solvent thereof was taken from an intravenous gland for about 10 minutes using an infusion pump. Was administered. Five minutes later, atomized ovalbumin (1) using an ultrasonic nebulizer 3 was inhaled through the tracheal force neura for 10 seconds.
  • Table 5 shows the rates of increase in lung pressure after 5, 10, and 20 minutes, based on the lung ventilation pressure immediately after inhalation of OVA.
  • the increase in pulmonary ventilation pressure due to OVA inhalation was significantly suppressed at each time point as compared with the group administered with the solvent.
  • Pulmonary ventilation pressure rise rate (%): Average soil SD constant
  • a single-dose toxicity test of the compound of the present invention was performed using 5-week-old male ICR mice (purchased from Japan Charl River).
  • the approximate lethal dose of each compound was estimated to be 20 Og / kg or more for compound (1-2) and 15 OmgZkg for compounds (1-3), (114) and (115). Was done.
  • the approximate half-life lethal dose of compound (1-8) was estimated to be 50-6 OmgZkg.
  • the benzofuran derivative of the present invention has a remarkable 5-lipoxygenase activity inhibitory activity, has excellent antiallergic and anti-inflammatory activities, and has allergic diseases such as bronchial asthma, rheumatic diseases, psoriasis and other diseases. It is useful as a treatment and prevention drug for various inflammations.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un dérivé de benzofurane représenté par la formule générale (I) et à un médicament le contenant, formule dans laquelle R1 représente hydrogène, hydroxy ou alcoxy C¿2?-C5; R?4 et R5¿ représentent chacun hydrogène, alkyle C¿1?-C5 ou alcynyle C2-C5; et R?4¿ représente alkyle C¿1?-C8, alcoxy C2-C8, ou benzoyloxy qui peut être substitué par un ou deux groupes hydroxy, à condition que R?4¿ ne représente pas n-pentyle lorsque R1 représente hydroxy et R2 et R3 représentent tous les deux hydrogène. Ce composé a un effet remarquable dans l'inhibition de 5-lipoxygénase ainsi que d'excellents effets antiallergiques et anti-inflammatoires, et est utilisé comme remède ou en prévention dans les maladies allergiques, telles que l'asthme bronchique, les affections rhumatismales et les inflammations, y compris le psoriasis.
PCT/JP1995/000325 1994-04-28 1995-03-01 Derive de benzofurane et son utilisation Ceased WO1995029906A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP6/91312 1994-04-28
JP9131294 1994-04-28
JP20958194 1994-09-02
JP6/209581 1994-09-02
JP6/263472 1994-10-27
JP26347294 1994-10-27

Publications (1)

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WO1995029906A1 true WO1995029906A1 (fr) 1995-11-09

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PCT/JP1995/000325 Ceased WO1995029906A1 (fr) 1994-04-28 1995-03-01 Derive de benzofurane et son utilisation

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020187A3 (fr) * 1994-12-23 1996-12-12 Alcon Lab Inc Esters et amides d'acides carboxyliques anti-inflammatoires non steroidiens pouvant etre utilises comme anti-oxydants, inhibiteurs de la 5-lipoxygenase et produits anti-inflammatoires non steroidiens
US5607966A (en) * 1994-12-23 1997-03-04 Alcon Laboratories, Inc. Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory prodrugs
US5811453A (en) * 1994-12-23 1998-09-22 Alcon Laboratories, Inc. Viscoelastic compositions and methods of use
EP1490048A4 (fr) * 2002-03-29 2005-06-01 Chugai Pharmaceutical Co Ltd Composition pharmaceutique permettant d'empecher ou de traiter les maladies respiratoires

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0276870A (ja) * 1988-06-10 1990-03-16 Takeda Chem Ind Ltd 新規２―置換クマラン誘導体
EP0413668A2 (fr) * 1989-08-18 1991-02-20 Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. 2,3-Dihydro-5-oxy-4,6,7-trimethylbenzofurannes substitués en position 2-(RS) utiles comme médicaments antioxydants, à propriétés mucorégulatrice et anti-ischémique
EP0447189A1 (fr) * 1990-03-12 1991-09-18 Merck Frosst Canada Inc. Analogues de l'hydroxy-5 dihydro-2,3 benzofuranne en tant qu'inhibiteurs de la biosynthèse de leucotriène
WO1994008930A1 (fr) * 1992-10-16 1994-04-28 Chugai Seiyaku Kabushiki Kaisha DERIVE DE 4-ALCOXY-2,6-DI-t-BUTHYLPHENOL

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0276870A (ja) * 1988-06-10 1990-03-16 Takeda Chem Ind Ltd 新規２―置換クマラン誘導体
EP0413668A2 (fr) * 1989-08-18 1991-02-20 Biomedica Foscama Industria Chimico-Farmaceutica S.P.A. 2,3-Dihydro-5-oxy-4,6,7-trimethylbenzofurannes substitués en position 2-(RS) utiles comme médicaments antioxydants, à propriétés mucorégulatrice et anti-ischémique
EP0447189A1 (fr) * 1990-03-12 1991-09-18 Merck Frosst Canada Inc. Analogues de l'hydroxy-5 dihydro-2,3 benzofuranne en tant qu'inhibiteurs de la biosynthèse de leucotriène
WO1994008930A1 (fr) * 1992-10-16 1994-04-28 Chugai Seiyaku Kabushiki Kaisha DERIVE DE 4-ALCOXY-2,6-DI-t-BUTHYLPHENOL

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. J., 274, 287-92 (1991). *
J. MED. CHEM., 35, 1299-318 (1992). *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020187A3 (fr) * 1994-12-23 1996-12-12 Alcon Lab Inc Esters et amides d'acides carboxyliques anti-inflammatoires non steroidiens pouvant etre utilises comme anti-oxydants, inhibiteurs de la 5-lipoxygenase et produits anti-inflammatoires non steroidiens
US5607966A (en) * 1994-12-23 1997-03-04 Alcon Laboratories, Inc. Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory prodrugs
US5811438A (en) * 1994-12-23 1998-09-22 Alcon Laboratories, Inc. Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products
US5811453A (en) * 1994-12-23 1998-09-22 Alcon Laboratories, Inc. Viscoelastic compositions and methods of use
US6242480B1 (en) 1994-12-23 2001-06-05 Alcon Laboratories, Inc. Ophthalmic viscoelastic compositions
EP1490048A4 (fr) * 2002-03-29 2005-06-01 Chugai Pharmaceutical Co Ltd Composition pharmaceutique permettant d'empecher ou de traiter les maladies respiratoires

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