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WO1992002500A1 - Derive de 2-phenylindole - Google Patents

Derive de 2-phenylindole Download PDF

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Publication number
WO1992002500A1
WO1992002500A1 PCT/JP1991/001000 JP9101000W WO9202500A1 WO 1992002500 A1 WO1992002500 A1 WO 1992002500A1 JP 9101000 W JP9101000 W JP 9101000W WO 9202500 A1 WO9202500 A1 WO 9202500A1
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WO
WIPO (PCT)
Prior art keywords
group
lower alkyl
hydrochloride
formula
alkyl group
Prior art date
Application number
PCT/JP1991/001000
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English (en)
Japanese (ja)
Inventor
Yukio Hasegawa
Yasushi Suzuki
Michitaka Sato
Norio Yamamoto
Kohichi Hasumi
Kazuhiro Shitara
Katsuhiko Miyasaka
Takashi Mikami
Katsuhiko Miyazawa
Motohiro Kobayashi
Masafumi Hagiwara
Original Assignee
Teikoku Hormone Mfg. 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 Teikoku Hormone Mfg. Co., Ltd. filed Critical Teikoku Hormone Mfg. Co., Ltd.
Priority to JP3512380A priority Critical patent/JP2988723B2/ja
Publication of WO1992002500A1 publication Critical patent/WO1992002500A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to a novel 2-phenylindole derivative having lipoxygenase inhibitory activity, and more particularly to a compound of the formula
  • R 2 represents a hydrogen atom or a C 1 -C 3 alkyl group
  • R 3 represents a hydrogen atom or a lower alkyl group and R 4 represents a lower alkyl group or an acyl group, or R 3 and R 4 represent such with bind nitrogen atom connexion 0, S and NR 7 (wherein, R 7 is a hydrogen atom or a lower alkyl group and represents) further comprise Idei which may be heterocyclic group the heteroatom selected from Represent;
  • R 5 and Re are the same or different and are each a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkanoyloxy group, an aralkyloxy group, a lower alkylthio group, a lower haloalkyl group,
  • R 9 is the same or different and each represents a hydrogen atom, a lower alkyl group, an aralkyl group or an acyl group, or R 5 and R 6 together represent a lower alkylenedioxy group;
  • Polyunsaturated fatty acids are constituents of phospholipids present in biological membranes, and are released from biological membranes by various stimuli [eg, inflammatory stimuli, antigen-antibody reactions (immune stimuli), etc.]. Released in The released arachidonic acid is usually metabolized by cyclooxygenase and lipoxygenase, of which slow reacting, substance, substance, ob, and naphylaxis are metabolically produced by 5-lipoxygenase. substance of anaphylaxis (SRS-A)] is believed to be one of the causative agents of allergic symptoms involved in the allergic reaction.
  • SRS-A anaphylaxis
  • Arakidon acid - has a lipoxygenase metabolite is a product mouth Ikotoryen B 4 leukocyte migration activity, Roikotoryen C 4, D 4 Contact and E 4 has vascular permeability enhancing effect, the various inflammatory reactions Is also involved.
  • fatty acid peroxide, a lipoxygenase metabolite of polyunsaturated fatty acids has an adverse effect on the living body, such as inhibiting the production of prostazaicrin, which plays an important role in the defense of living tissues.
  • lipoxygenase inhibitors are useful for controlling various physiological effects that are undesirable to the living body caused by the involvement of lipoxygenase-based metabolites.
  • JP-A Japanese Patent Application Laid-Open
  • JP-A Japanese Patent Application Laid-Open
  • 51-17662 US Patent No. 4,024,155
  • 2- (3,5- Dimethyl-4-hydroxyphenyl indole has been disclosed as being useful as a stabilizer for vinyl chloride polymers, and has been disclosed by Y. Isomera et al., Chemical and Pharmaceutical Viuretin (Y. Isomura).
  • Y. Isomura Chem. Pharin. Bull.
  • Vol. 31, 3168-31, 78 (1983) describes certain 2- (3,5-di-tert-butyl) -4-hydroxyhydrindine derivatives. It is disclosed that it has an anti-inflammatory effect.
  • indole derivative having 5-lipoxygenase inhibitory activity the present inventors have previously substituted the 2-position with a 3,5-di-C, -C 3 alkyl-4-hydroxyhydrenyl group. Certain indole derivatives have been disclosed [JP-A-61-60648 and JP-A-62-53962 (US Patent No. 4695581)].
  • the 2-phenylindole derivative represented by the above formula (I) is a novel compound which has not been published in the conventional literature, and is a lipoxygenase of polyunsaturated fatty acids, particularly 5 -It specifically inhibits lipoxygenase, has good absorption, and is not easily metabolized, especially when administered orally. Effectively inhibits allergic reactions and various inflammatory reactions such as atopic dermatitis, allergic rhinitis, and food allergies, and suppresses the production of Z or peroxide fatty acids to protect living tissues from these peroxides.
  • the present invention was found to be extremely useful, and the present invention was completed.
  • the term "lower” means that the group or compound to which this term is attached has at most 6, preferably at most 4, carbon atoms.
  • the “lower alkyl group” may be linear or branched, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n- Pentyl, n-hexyl group, etc.
  • the “lower alkoxy group” is a lower alkyl-10-group in which the lower alkyl moiety has the above-mentioned meaning.
  • lower alkanoyloxy group is a lower alkyl-C00- group in which the lower alkyl moiety has the above-mentioned meaning, and examples thereof include acetyloxy and propionyloxy groups, and the like.
  • aralkyloxy group is an aralkyl group in which the aralkyl moiety has the above-mentioned meaning.
  • the “lower alkylthio group” is a lower alkyl-1S— group in which the lower alkyl moiety has the above-mentioned meaning, and includes, for example, methylthio, ethylthio group, n-butylthio group and the like, and “lower haloalkyl group” Include a trifluoromethyl group, etc.
  • the “lower alkanoyl group” is a lower alkyl-CO— group in which the lower alkyl moiety has the above-mentioned meaning, for example, acetyl, propionyl, butyryl and the like.
  • group "is a lower alkyl one S 0 2 have the meanings lower alkyl moiety is the - group, for example Metanzuruhoniru, ethanesulfonyl group, and the like.
  • [Ashiru group include mono - or polycarboxylic acid, a least residue portion obtained by removing one 0 H from organic acids such as organic sulfonic acids, in particular wherein one COR 1 0 or one S 0 Groups such as 2 R n are included.
  • R 10 is a hydrogen atom; a halogen atom, an amino group, a carboxyl group, a lower alkoxy A carbonyl group, a lower alkanoyloxy group, a lower alkyl group optionally substituted with a carbamoyl group or an aryl group; a lower alkenyl group optionally substituted with an aryl group; a lower cycloalkyl group; RH represents a lower alkyl group; a lower haloalkyl group; or an aryl group which may be substituted with a lower alkyl group.
  • acyl groups include formyl, acetyl, propionole, butyryl, trifluoroacetyl, glycyl, aranyl, ⁇ -ylanyl, leucyl, isoleucyl, nokril, lysyl, aspartyl, glucil Tamyl, asparaginyl, glutaminyl, 3-carboxypropionyl, 4-carboxybutanoyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutanoyl, acetoxacetyl, acetooxypropionyl, 3-caprolvamoylpropionyl, phenylacetyl, phe N-propionyl, acryloyl, methacryloyl, cinnamoyl, cyclohexancarbonyl, benzoyl, naphthyl, methanesulfonyl, trifluorome
  • Examples of the 1 N group in the above formula (I) include the following.
  • 3-caproluvyl propionylamino phenylacetylamino, acryloylamino, cinnamoylamino, cyclohexanecarbonylamino, benzoylamino, methanesulfonylamino, trifluoromethanesulfonylamino, P-toluene Sulfonylamino group and the like.
  • halogen atom includes fluorine, chlorine and bromine atoms.
  • R 5 and R 6 together represent a “lower alkylenedioxy group” examples of the lower alkylenedioxy group include a methylenedioxy, ethylenedioxy or propylenedioxy group.
  • R 3 and R 4 may further comprise a heteroatom selected from 0, S and NR 7 together with the nitrogen atom to which they are attached, wherein R 7 represents a hydrogen atom or a lower alkyl group.
  • heterocyclic group when representing ⁇ a heterocyclic group which may be contained '' include: pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylbiperazinyl,
  • Examples thereof include 5- to 6-membered heterocyclic groups such as a 4-ethylpyperazinyl group.
  • R 2 is C! ⁇ C 3 alkyl group, in particular compound represents a methyl group.
  • R 3 represents a lower alkyl group
  • R 4 represents a lower alkyl group, a lower alkanol group, or a lower alkanesulfonyl group.
  • R 5 is a lower alkyl group present in the 5-position of and R 6 is indole ring represents a hydrogen atom, a lower alkoxy group, and - NHR 81 (where R 81 is a hydrogen atom, a lower Arukanoiru group or lower alk force Nsuruho Or a substituent selected from the group consisting of R 5 and R e, and preferably represents a 5, 6 _ lower alkylenedioxy group.
  • R ei represents a methyl group, a methoxy group, an amino group, an acetylamino group or a methanesulfonylamino group
  • Compounds of formula (I) may exist as salts, examples of such salts include metal salts such as sodium and potassium, or hydrochloric acid. And salts with inorganic acids such as acetic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid and citric acid. Among them, pharmaceutically acceptable salts are preferable.
  • the compounds of the formula (I) are known from Fisher-indole It can be produced according to a synthesis method. Specifically, for example, the formula
  • R 5 and R 6 have the above-mentioned meaning
  • R !, R 2, R 3 and R 4 are as defined above.
  • R 2, R 3, R 4, R 5 and R E may be prepared by cyclizing a compound of as defined above.
  • the reaction between the compound of the formula (II) or a salt thereof and the compound of the formula (ffl) or a salt thereof is usually carried out in a suitable solvent, for example, methanol,
  • a suitable solvent for example, methanol
  • the reaction can be carried out in alcohols such as tanol, propanol and isopropanol; ethers such as tetrahydrofuran and dioxane; or in a mixed solvent of two or more of these solvents.
  • the reaction temperature may be varied widely s depending on the critical the type of the starting material of the type and the solvent used rather like the reflux temperature of generally from room temperature to the reaction mixture, favored properly is 5 0 ° C to the reaction mixture It is desirable to carry out the reaction at a temperature within the range of the reflux temperature.
  • the above reaction can be appropriately performed in the presence of an acid catalyst.
  • the acid catalyst examples include organic acids such as trifluoroacetic acid and glacial acid; and inorganic acids such as hydrochloric acid and sulfuric acid. These catalysts are generally used in an amount of 1 Z 10 per mole of the compound of the formula ( ⁇ ). 0 to: L 0, preferably about 110 to 1 mol can be used.
  • the acid catalyst is not particularly required.
  • the use amount of the compound of the formula (m) or the salt thereof with respect to the compound of the formula ( ⁇ ) or a salt thereof is not particularly limited, either.
  • the compound of the formula (BI) per mole of the compound of the formula ( ⁇ ) or a salt thereof is used.
  • the above reaction produces the compound of the formula (IV), which can be subjected to a cyclization reaction as it is or once separated from the reaction mixture according to a conventional method.
  • the cyclization of the compound of formula (IV) may be carried out in the absence of a solvent or in a suitable solvent, for example, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, or the like.
  • a suitable solvent for example, a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, or the like.
  • Polyphosphoric acid including a mixture of phosphorus pentoxide and phosphoric acid in any ratio
  • an organic ester thereof eg, lower alkyl ester of polyphosphoric acid such as polyethyl phosphate, trialkylsilyl ester of polyphosphoric acid such as trimethylsilyl ester of polyphosphoric acid
  • Lewis acid such as tin tetrachloride, titanium tetrachloride, etc.
  • the former treatment with polyphosphoric acid or its organic ester or Lewis acid can be carried out generally at a temperature of 40 to 150 ° C., preferably 60 to 120 ° C.
  • Treatment with an alcohol solvent is generally performed at room temperature to the reflux temperature of the reaction mixture, preferably at room temperature.
  • the reaction can be performed at 50 ° C. to the reflux temperature of the reaction mixture.
  • the amount of the polyphosphoric acid or its organic ester or Lewis acid to be used is not critical, but is usually at least approximately equal to the weight of the compound of the formula (W), preferably 5 to 50 times by weight. It is advantageous to use it.
  • the acidic alcohol solvent can be used in an amount of at least about 1 equivalent, preferably a large excess, per mole of the compound of the formula (IV) as an equivalent of the acid in the alcohol solvent.
  • the compound of formula (I) of the present invention can be obtained in a good yield by the above cyclization reaction.
  • the compound of formula (I) thus obtained can be separated from the reaction mixture by a method known per se, for example, by extraction, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, or the like. Z or can be purified.
  • the compound of the formula (in) is a novel compound and can be synthesized, for example, according to the following reaction formula A.
  • R In each of the above formulas, R !, R 2 , R 3 and R 4 have the above-mentioned meanings.
  • nitration of the compound of the formula (V) can be performed, for example, by treatment with nitric acid in anhydrous dianhydride.
  • Reduction of the resulting compound of the formula ( ⁇ ) can be performed, for example, using methanol, ethanol, or the like.
  • the reaction can be carried out by treating with hydrogen in a solvent such as in the presence of a catalyst such as Raney-Nigel.
  • the conversion of the compound of the formula (VII) thus obtained into the compound of the formula (no) can be carried out by various methods known per se, depending on the type of the groups R 3 and R 4 . ,
  • R 3 and R 4 each represent a lower alkyl group, for example, by reacting a lower alkyl halide in the presence of a base such as triethylamine,
  • R 3 is a hydrogen atom and R 4 represents a lower alkyl group
  • R 4 represents a lower alkyl halide is reacted in the presence of a base such as triethylamine, or R 4 is a secondary alkyl group.
  • a base such as triethylamine
  • R 4 is a secondary alkyl group.
  • R 3 is a hydrogen atom and R 4 is an acyl group, for example, by reacting an acyl halide in pyridine,
  • R 3 and R 4 together with the nitrogen atom to which they are attached represent a heterocyclic group, for example, 0, S and NR 7 may be included in the alkane chain 1, ⁇ -Dihaloalkane is reacted in the presence of a base such as triethylamine, or by treatment with 1, ⁇ -dihydroxyalkane and hydrogen chloride gas.
  • a base such as triethylamine
  • the compound of the formula (I) of the present invention may be obtained by combining the compound of the formula (VII) or a salt thereof with the phenylhydrazine compound of the formula (II) or a salt thereof as described above in the Fischer fundole.
  • R 2 , R 5 and R 6 have the above-mentioned meaning
  • the amino group at the 5-position of the phenyl group of the 2-phenylindole compound represented by the formula is converted by the same method as described for the conversion of the compound of the formula (VII) to the compound of the formula (m). Can also be produced.
  • the compound of formula (VIII-a) The compound is represented by the following formula, which can be produced by reacting the compound of the formula ( ⁇ ) with the phenylhydrazine compound of the formula ( ⁇ ) or a salt thereof according to the above-mentioned Fishhindole synthesis method.
  • Y represents a nitro group or an amino group
  • the compound of the formula (VIII) wherein Y represents an amino group in the above formula (VIII), that is, the compound of the formula ( ⁇ -a) is not only useful as a synthetic intermediate, but also has excellent lipoxygena itself. It also has an inhibitory effect on the enzyme.
  • R 5 or R 6 is a bromine atom
  • the bromine atom is a known one. Reactions [eg Tetrahedron, 23 3823 - 3827, see page 1967], can be converted into Shiano group by treatment with cyanide (I).
  • the amino group on the indole ring of the compound of the formula (I) can be obtained by a conventional alkylation method of an amino group [for example, Annalenlen del Hemi-1 (Ann. :), Vol. 598, pp. 174-185 ( 1956)], the amino group can be converted to a mono- or di- (lower alkyl or aralkyl) amino group, and the usual method for acylating an amino group (for example, Berichte ' ⁇ Hemisin Deutschen (Ber.), Vol. 71, pp. 1480-1481 (1938)]. It can be changed to a group.
  • a conventional alkylation method of an amino group for example, Annalenlen del Hemi-1 (Ann. :), Vol. 598, pp. 174-185 ( 1956)
  • the amino group can be converted to a mono- or di- (lower alkyl or aralkyl) amino group
  • the usual method for acylating an amino group for example, Berichte
  • the amino group is protected by a known protecting group such as a benzyloxycarbonyl group or a t-butoxycarbonyl group in advance. After the acylation reaction, it is desirable to release the protecting group.
  • R 5 or R e is an acylamino group
  • it may be prepared according to a conventional method [for example, Organic Synthesis Collective Volume I (Org. Synth. Coll. Vol. 1), 111-113 (1932) )]. It is also possible to convert the acylamino group to a free amino group by hydrolysis.
  • the compound of the formula (I) produced by the method described above can be converted to a salt thereof, if necessary.
  • the conversion of the compound of the formula (I) into a salt can be carried out by a method known per se, for example, by treatment with an acid or an inorganic base in the absence of a solvent or in a suitable inert solvent according to a conventional method. Can be done.
  • the compound of the above formula (I) provided by the present invention described above is a lipoxygenase for polyunsaturated fatty acids present in a biological membrane, particularly
  • the compound of the formula (I) of the present invention is useful for controlling various physiological actions that are undesirable for a living body caused by the involvement of lipoxygenase metabolites.
  • the compound of the present invention has a remarkable feature that it is well absorbed when administered orally and is not easily metabolized (and therefore hardly inactivated in a living body), and is extremely useful. Further, the compound of the formula (I) of the present invention has a unique feature that it also has an action of eliminating active oxygen in a living body.
  • the compounds of the formula (I) provided by the present invention include anti-asthmatic agents, anti-allergic agents (prevention and treatment of allergic dermatitis, allergic rhinitis, urticaria, gastrointestinal allergy, food allergy, etc.), Anti-inflammatory agent, anti-rheumatic agent, anti-thrombotic agent, therapeutic agent for arteriosclerosis, therapeutic agent for vasospasm during subarachnoid hemorrhage, therapeutic agent for improving cerebral circulation, therapeutic agent for improving coronary blood vessels, therapeutic agent for coronary heart disease ischemic myocardial infarction It can be used as a therapeutic agent for ischemic cerebral infarction, an immunomodulator, a therapeutic agent for ulcerative colitis, a therapeutic agent for skin psoriasis, a transplant rejection inhibitor, and the like.
  • the following animal experiments can prove that the compound of the formula (I) of the present invention has a selective polyunsaturated fatty acid lipoxygenase inhibitory action.
  • leukocytes (more than 90% are polymorphonuclear leukocytes and contain a large amount of 5-lipoxygenase) in the exudate collected from the pleural cavity of rats with induced phylagenin pleurisy
  • the cells were suspended in 5 O mM Tris-HCl buffer (pH 7.4) containing mM sodium chloride.
  • the radioactivity of each fraction was measured by a liquid scintillation counter, and the radioactivity of each fraction relative to the total radioactivity was determined (production rate). Using this production rate as an index, the inhibition rate of the test drug on the synthesis ability of each fraction was determined.
  • the 5-LO activity was determined to be 5 S-hydroxy-6, 8, 11, 14-eicosate traenoic acid (5-HETE) and 53,12 shaku-dihydroxy-6, 8, 10, 14-eicosatetraene.
  • the production of acid (5,12-diHETE) was used as an index, and the CO activity was used as an index for the production of 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT).
  • test drugs were dissolved in 10% dimethyl sulfoxide solution.
  • the final concentration of dimethyl sulfoxide in the Atsushi system is 2.5%.
  • the 5-LO inhibitory activity is represented by the concentration (IC 5 ) that inhibits the production of 5-HETE and 5,12-diHETE by 50%. It should be noted that, in the present assay, none of the compounds of the formula (I) of the present invention showed a CO inhibitory effect at a concentration showing a 5-LO inhibitory effect (the production of HHT was not inhibited at all).
  • the compound of formula (I) of the present invention is useful in humans and other warm-blooded animals for the treatment or prevention of various diseases caused by the involvement of lipoxygenase metabolites. It can be administered orally, parenterally (eg, intramuscularly, intravenously, subcutaneously, rectally, etc.) or topically.
  • the compound of formula (I) of the present invention can be formulated into various forms suitable for oral, parenteral or topical administration.
  • the compounds of the present invention may be used in non-toxic excipients, binders, lubricants, disintegrants, preservatives, isotonic agents, stabilizers, dispersants, antioxidants, which are commonly used in this class of drugs. It can be formulated using additives such as agents, coloring agents, flavoring agents, buffers, propellants, and surfactants.
  • Such drugs may be any of tablets, capsules, granules, powders, fine granules, pills, troches, suppositories, ointments, patches, injections, syrups, aerosols, etc. Can be prepared.
  • non-toxic additives which may be used include, for example, starch, gelatin, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, Gum arabic, polyethylene glycol, p-hydroxybenzoic acid alkyl ester, syrup, ethanol, propylene glycol Recall, glycerin, carboxyl, glycerin, sodium chloride, sodium nitrite, sodium phosphate, citric acid, dichlorodifluoromethane, 1,2-dichlorotetrafluoroethane, sorbitan trioleate and the like.
  • the agent may also contain other therapeutically useful agents.
  • the dose of the compound of the formula (I) of the present invention can be varied widely depending on the kind of the target human or other warm-blooded animals, the administration route, the severity of the symptoms, the diagnosis of a doctor, and the like.
  • the above dose can be administered once or several times.
  • 3-Methyl-4-hydroxy-5-aminopropyl is synthesized by the primary alkylation of 5-aminopropiophenone with aceton and sodium cyanoborohydride 3-methyl-4-hydroxy-5-isopropyl
  • Aminopropiophenone hydrochloride 94 Omg and p-methoxyphenylhydrazine hydrochloride 740 mg were treated in the same manner as in the step (d) of Example 1 to give 2- (3-methyl-4-hydroxy-5-isobutyric acid). 1.14 g of propylaminophenyl) -5-methoxy-3-methylindole hydrochloride was obtained.
  • step (b) Treating thiophenol and 3-methyl-4-hydroxy-15-nitro-2- ⁇ -promoacetophenone in the same manner as in step (c) of Example 30 to give 3-methyl-14-hydroxy-15 —Nitro- ⁇ -phenylthioacetophenone was obtained.
  • the compound of the formula (I) and a salt thereof of the present invention are useful in the prevention and treatment of diseases caused by involvement of lipoxygenase metabolites, for example, asthma, allergic dermatitis, allergic rhinitis and the like. .

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un composé inhibiteur de lipoxygénase représenté par la formule générale (I), à une composition pharmaceutique contenant ce composé et à un intermédiaire de ce composé. Dans la formule (I), R1 représente un alkyle inférieur, un alkylthio ou phénylthio inférieur; R2 représente un hydrogène ou un alkyle C1 à C3; R3 représente un hydrogène ou un alkyle inférieur et R4 représente un alkyle ou un acyle inférieur, ou, dans une variante R3 et R4 peuvent être combinés ensemble avec l'atome d'azote pour former un hétérocycle qui peut en outre contenir des atomes choisis parmi l'oxygène, le soufre et NR7, où R7 représente un hydrogène ou un alkyle inférieur; et R5 et R6 représentent chacun un hydrogène, un halogène, un alkyle inférieur, un alkoxy inférieur, un alcanoyloxy inférieur, un aralkyloxy, un alkylthio inférieur, un haloalkyle inférieur, un cyano, un nitro ou NR8R9, où R8 et R9 représentent chacun un hydrogène, un aralkyle, un acyle ou un alkyl inférieur, ou, dans une variante, R5 et R6 peuvent être combinés pour former un alkylènedioxy inférieur.
PCT/JP1991/001000 1990-07-31 1991-07-25 Derive de 2-phenylindole WO1992002500A1 (fr)

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JP2/233094 1990-09-05

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
US7256287B2 (en) 2002-09-12 2007-08-14 Avanir Pharmaceuticals Phenyl-aza-benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US7282518B2 (en) 2001-03-12 2007-10-16 Avanir Pharmaceuticals Benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US7375118B2 (en) 2002-09-12 2008-05-20 Avanir Pharmaceuticals Phenyl-indole compounds for modulating IgE and Inhibiting cellular proliferation
WO2018153893A1 (fr) * 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures aryle (ahr)
EP2178870B1 (fr) * 2007-08-17 2018-09-19 LG Chem, Ltd. Composés d'indole et d'indazole en tant qu'inhibiteurs de nécrose cellulaire
US10981908B2 (en) 2017-02-01 2021-04-20 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (AHR) modulator compounds
US11376241B2 (en) 2017-02-01 2022-07-05 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (AhR) modulator compounds

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* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 104, No. 13, (1986), Abstract No. 101983u. *
CHEMICAL ABSTRACTS, Vol. 89, No. 19, (1978), Abstract No. 163338t. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502187A (en) * 1992-04-03 1996-03-26 The Upjohn Company Pharmaceutically active bicyclic-heterocyclic amines
US7282518B2 (en) 2001-03-12 2007-10-16 Avanir Pharmaceuticals Benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US7256287B2 (en) 2002-09-12 2007-08-14 Avanir Pharmaceuticals Phenyl-aza-benzimidazole compounds for modulating IgE and inhibiting cellular proliferation
US7375118B2 (en) 2002-09-12 2008-05-20 Avanir Pharmaceuticals Phenyl-indole compounds for modulating IgE and Inhibiting cellular proliferation
EP2178870B1 (fr) * 2007-08-17 2018-09-19 LG Chem, Ltd. Composés d'indole et d'indazole en tant qu'inhibiteurs de nécrose cellulaire
US10981908B2 (en) 2017-02-01 2021-04-20 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (AHR) modulator compounds
US11376241B2 (en) 2017-02-01 2022-07-05 Phenex Pharmaceuticals Ag Aryl hydrocarbon receptor (AhR) modulator compounds
WO2018153893A1 (fr) * 2017-02-21 2018-08-30 Phenex Pharmaceuticals Ag Composés modulateurs du récepteur des hydrocarbures aryle (ahr)

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