WO1999045002A1 - Derives de benzofurane - Google Patents

Derives de benzofurane Download PDF

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Publication number
WO1999045002A1
WO1999045002A1 PCT/JP1999/000921 JP9900921W WO9945002A1 WO 1999045002 A1 WO1999045002 A1 WO 1999045002A1 JP 9900921 W JP9900921 W JP 9900921W WO 9945002 A1 WO9945002 A1 WO 9945002A1
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WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
lower alkyl
compound
hydrogen atom
Prior art date
Application number
PCT/JP1999/000921
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English (en)
Japanese (ja)
Inventor
Etsuo Ohshima
Kyoichiro Iida
Toshio Suda
Ichiro Miki
Original Assignee
Kyowa Hakko Kogyo 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 Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU26412/99A priority Critical patent/AU2641299A/en
Publication of WO1999045002A1 publication Critical patent/WO1999045002A1/fr

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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
    • C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7

Definitions

  • the present invention relates to a benzofuran derivative having an autoimmune disease suppressing effect.
  • benzofuran derivatives are industrially useful, and patents have been disclosed as intermediates for production raw materials, light-emitting elements, pesticides, anthelmintics, pharmaceuticals, and the like.
  • J. Med.Chem., 31, 84-91 (1988), JP-A-61-50977, JP-A-61-126061, JP-A-61-143371 and JP-A-62-230760 describe a carboxyl group or tetrazolyl.
  • Disclosed are a benzofuran derivative, a benzopyran derivative and a benzodioxole derivative having a group, and it is described that these have a leukotriene antagonism, a phospholipase inhibitory action, a 5 ⁇ -reductase inhibitory action, an aldose reductase inhibitory action, and the like.
  • WO92 / 01681 and W092 / 12144 disclose benzofuran derivatives and benzopyran derivatives having an inhibitory action on acyl-CoA acetyltransferase (ACAT). Also,
  • WO93 / 01169 discloses a benzofuran derivative having an antikinetic action.
  • EP307172 and US4910193 disclose benzofuran derivatives having serotonin 3 (5HT 3 ) receptor antagonism.
  • W096 / 36626, W096 / 36625, WO97 / 20833 include phosphodiesterase
  • a benzofuran derivative having (PDE) -IV inhibitory activity W096 / 36624, reports an oxygen-containing heterocyclic compound having PDE-IV inhibitory activity.
  • An object of the present invention is to provide a benzofuran derivative having an excellent autoimmune disease suppressing effect.
  • the present invention provides a compound of the formula (I) (I)
  • Ri represents a hydrogen atom, substituted or unsubstituted lower alkyl, lower cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted aralkyl
  • R 2 , R 3 , R 4 and R 5 represent Same or different hydrogen atom, lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyl, lower cycloalkanol, substituted Or unsubstituted arylo, lower alkoxyl, luponyl, cyano, carboxy, halogen, substituted or unsubstituted amino or substituted or unsubstituted carboxamide
  • R 6 is a hydrogen atom, lower alkyl or substituted or unsubstituted aryl.
  • R 7 and R 8 are taken the same or different hydrogen atom, a lower a Kill, substituted or unsubstituted Ariru, represents lower alkoxy or halogen, R 9 represents a substituted or unsubstituted lower alkyl, substituted or unsubstituted ⁇ re Ichiru, substituted or unsubstituted a Ararukiru or pyridyl alkyl, A represents lower alkyl, substituted or unsubstituted aryl or substituted or unsubstituted pyridyl) or a pharmaceutically acceptable salt thereof.
  • compound (I) the compound represented by the formula (I) is referred to as compound (I).
  • the lower alkyl moiety of lower alkyl, lower alkoxy, lower alkoxycarbonyl and lower alkanoyl may be a straight-chain or branched C1-C8 alkyl group such as methyl, Includes ethyl, propyl, isopropyl, butyl, isobutyl, isooctyl, see-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • the cycloalkyl moiety of lower cycloalkyl and lower cycloalkanoyl includes those having 3 to 10 carbon atoms, for example, cyclopropyl, cyclohexyl, cyclooctyl, cyclodecyl and the like. It is.
  • Aralkyl includes C7-C15, for example, benzyl, phenethyl, benzylhydryl, naphthylmethyl and the like.
  • aryl include phenyl, naphthyl, indenyl, biphenyl, anthryl and the like.
  • Benzoyl, toluoyl, naphthoyl, phthaloyl, etc. are included as aroyl.
  • the alkyl part of the pyridylalkyl has the same meaning as the lower alkyl.
  • Halogen includes fluorine, chlorine, bromine and iodine atoms.
  • Substituted lower alkyl, substituted aryl, substituted aralkyl, substituted lower alkoxy, substituted lower alkanol, substituted aroyl and substituted pyridyl have the same or different substituents, and have 1 to 3 substituents, for example, lower alkyl, lower alkoxy, halogen, etc. Is included.
  • the definitions of lower alkyl, lower alkoxy and halogen are as defined above.
  • Substituents of substituted amino and substituted lipoxamide include substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and 5 to 7 members formed including nitrogen atom. Or a substituted or unsubstituted heterocyclic group.
  • the substituted or unsubstituted lower alkyl, the substituted or unsubstituted aryl, the substituted or unsubstituted aralkyl are the same as those described above, and the substituted or unsubstituted substituted or unsubstituted aryl group containing a nitrogen atom and having 5 to 7 members is formed.
  • telocyclic group examples include morpholino, piperidino, piperazinyl, homopirazinyl, N-methylbiperazinyl, N-benzylhomopiperazinyl and the like.
  • Pharmaceutically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate, and tartaric acid.
  • Organic salts such as salts, etc .; pharmacologically acceptable alkali metal salts and alkaline earth metal salts include sodium salts, potassium salts, calcium salts, etc .; pharmacologically acceptable salts Ammonies Examples of the salt include ammonium, tetramethylammonium, etc., and pharmaceutically acceptable organic amine addition salts include morpholine, piperidine, etc., and pharmaceutically acceptable amino acids. Examples of the addition salt include addition salts such as lysine, daricin, and feniralanine.
  • intermediates and target compounds are isolated by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. It can be purified. Further, the intermediate can be subjected to the next reaction without purification.
  • compound (I) When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it can be purified as it is. It should be done.
  • Compound (I) and its pharmacologically acceptable salts may be present in the form of adducts with water or various solvents. These adducts are also usefully used for the purpose of the present invention. be able to.
  • Some of the compounds (I) may have geometrical isomers, optical isomers, etc. in terms of stereochemistry, but all possible stereoisomers of the compound (I) and mixtures thereof are also included in the present invention. It can be used as a compound.
  • Compound (I) can be produced by the following production method. However, it is not limited to the following production method.
  • R 1 , R 2 , R 3 , R 4, R 5, R 6, R 7, R 8 and R 9 are each as defined above. Is)
  • the starting compound (II) can be obtained according to a known method [J. Med. Chem., 30, 62-67 (1987)].
  • Compound (IV) can be obtained by a dehydration condensation reaction between raw material compound (II) and aniline (III). Many methods are known for this dehydration condensation reaction [Refer to Maruzen, 4th Edition, Experimental Chemistry, Vol. 22, p. 138 (1990)], and can be applied.
  • compound ( ⁇ ) can be prepared by adding 1 equivalent to a large excess of thionyl chloride, oxalyl chloride or phosphorus pentachloride in an inert solvent or in the absence of a solvent. ⁇ 5 minutes to 10 hours at a temperature between the boiling point of the solvent used to lead to the corresponding acid chloride, and then 1 equivalent to a large excess of aniline (III) in an inert solvent.
  • reaction can be carried out at a temperature between -50 ° C and the boiling point of the used solvent for 5 minutes to 10 hours in the presence of 1 equivalent to an excess of a base.
  • a mixed acid anhydride can be obtained instead of the acid chloride.
  • the corresponding mixed acid anhydride of compound (II) can also be reacted with aniline (III) in the same manner as acid chloride to lead to compound (IV).
  • the bases used in the reaction of thionyl chloride, oxalyl chloride or phosphorus pentachloride are triethylamine, diisopropylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiperidine, diazabicyclo Examples include undecene (DBU), diazabicyclononene (DBN), and pyridine.
  • Bases used in the reaction of aniline (III) include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium tert- Examples include butoxide, triethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DBN, pyridine and the like.
  • Inert solvents used in both reactions are tetrahydrofuran (THF), Examples include dioxane, getyl ether, ethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like.
  • THF tetrahydrofuran
  • Examples include dioxane, getyl ether, ethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like.
  • Compound (I) can be produced by acylating compound (IV). Many methods are known for the acylation of aromatic compounds [Refer to the fourth edition of Experimental Chemistry, Vol. 22, p. 278 (1990) Maruzen], and are applicable.
  • compound (IV) can be prepared by reacting compound (IV) in an inert solvent, preferably a halogen-based solvent such as dichloromethane, in the presence of 1 equivalent to a large excess of acid chloride (V) and 1 equivalent to a large excess of an acid.
  • the desired compound (I) can be obtained by reacting at a temperature between the boiling points of the solvents used in 50 to 5 minutes to 48 hours.
  • Examples of the acid include methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride, aluminum chloride, stannic chloride, titanium tetrachloride, zinc chloride, ferric chloride and the like.
  • inert solvent examples include THF, dioxane, getyl ether, ethylene dalicol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.
  • Test Example 1 Prophylactic effect on rat adjuvant arthritis
  • the preventive effect on rat adjuvant arthritis was measured by the following method.
  • Test compound 30 mg / kg was suspended in a 0.5% methylcellulose solution and administered intraperitoneally once a day on Day 0-4, Day 7-11 and Dayl4-16 on the day of adjuvant treatment as Day O .
  • the control group received a 0.5% methylcellulose solution intraperitoneally.
  • Cyclosporin A which is recognized as a typical immunosuppressant, was used as a comparative compound.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations.
  • the pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention comprises the compound (I) or its pharmacology as an active ingredient.
  • such pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmaceutically acceptable carriers and by any method well known in the technical field of pharmaceuticals.
  • the active ingredients to be mixed are: serotonin 3 (5HT 3 ) receptor antagonist, serotonin 4 (5HT 4 ) receptor antagonist, serotonin 1A (5HTIA) receptor agonist, dopamine 2 (D 2 ) receptor antagonist And histamine 1 receptor antagonist, muscarinic receptor antagonist, neurokinin 1 receptor antagonist, endothelin A (ET A ) receptor antagonist and the like.
  • the route of administration is preferably the one that is most effective in treatment, and may be oral administration or parenteral administration, for example, oral, respiratory, rectal, subcutaneous, intramuscular, intravenous, etc. .
  • Dosage forms include sprays, capsules, tablets, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like.
  • Liquid preparations suitable for oral administration include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, and oils such as sesame oil, olive oil and soybean oil. , P-hydroxybenzoic acid esters and the like, and preservatives such as strawberry flavor, peppermint and the like.
  • Capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch, sodium alginate, lubricating agents such as magnesium stearate, talc, etc.
  • a suitable formulation for parenteral administration can be prepared using a binder, a binder such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin. It consists of a sterile aqueous preparation containing the active compound which is isotonic.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a glucose solution.
  • Formulations for enteral administration include, for example, cocoa butter, hydrogenated fat or It is prepared using a carrier such as boric acid and provided as a suppository.
  • the propellant is prepared using a carrier or the like which does not irritate the active compound itself or the mucosa of the mouth and respiratory tract of the recipient and disperses the active compound as fine particles to facilitate absorption.
  • a carrier or the like which does not irritate the active compound itself or the mucosa of the mouth and respiratory tract of the recipient and disperses the active compound as fine particles to facilitate absorption.
  • Specific examples include lactose and glycerin.
  • Formulations such as aerosol and dry powder are possible depending on the nature of the active compound and the carrier used.
  • parenteral preparations one selected from the diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for the oral preparations Alternatively, more auxiliary components can be added.
  • the effective amount and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the form of administration, the age and weight of the patient, and the nature or severity of the condition to be treated.
  • O.Olmg ⁇ : lg, preferably l ⁇ 500mg per adult is administered once or several times a day.
  • parenteral administration such as intravenous administration
  • 0.001 to! OOmg, preferably 0.01 to! Omg per adult is administered once or several times a day.
  • these dosages vary depending on the various conditions described above.
  • FIG. 1 shows changes in right hind limb paw volume after adjuvant treatment.
  • the horizontal axis represents the number of days of drug administration (days), and the vertical axis represents the right hind paw volume (ml) of the rat.
  • Fig. 2 shows changes in left hind paw volume without adjuvant treatment.
  • the horizontal axis represents the number of days of drug administration (days), and the vertical axis represents the left hind paw volume (ml) of the rat.
  • reaction solution was diluted with 1N hydrochloric acid (400 ml), and the organic layer was extracted with ethyl acetate, and further washed with 1N hydrochloric acid. This was dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the residue was added chloroform, and trituration gave 7-methoxy-N-phenylbenzofuran-2-carboxamide (compound la) (12.4 g, 98%) as a colorless solid.
  • Second step The obtained compound 1a (I2.7 g) was dissolved in dichloromethane (240 ml), and acetyl chloride (6.4 ml) and titanium tetrachloride (19.9 ml) were added thereto, followed by stirring at room temperature for 2 hours. .
  • the reaction solution was poured into a cooled diluted hydrochloric acid solution, and the organic layer was extracted with ethyl acetate. This was dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (elution solvent: 1% methanol / monochrome form), and recrystallized from ethanol to obtain Compound 1 (3.86 g , 28%) as a colorless solid.
  • Finely pulverized Compound 1 is mixed with a molten suppository base, poured into a mold and cooled to obtain a suppository.
  • a finely powdered compound 1 is mixed with powdered potato starch, lactose, magnesium stearate, polyvinyl alcohol and tar pigment, and then compressed to form tablets.
  • Finely pulverized Compound 1 and powdered lactose are mixed to obtain a powder.

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

Abstract

L'invention concerne des dérivés de benzofurane de la formule (I) ou des sels pharmaceutiquement acceptables desdits dérivés. Dans ladite formule, R1 est hydrogène, alkyle inférieur éventuellement substitué, cycloalkyle inférieur, etc.; R?2, R3, R4 et R5¿ sont identiques ou différents et représentent chacun hydrogène, alkyle inférieur, aryle éventuellement substitué, aralkyle éventuellement substitué, etc.; R6 est hydrogène, alkyle inférieur, etc.; R7 et R8 sont identiques ou différents et représentent chacun hydrogène, alkyle inférieur, aryle éventuellement substitué, etc.; R9 est alkyle inférieur éventuellement substitué, etc.; et A est alkyle inférieur, aryle éventuellement substitué etc.
PCT/JP1999/000921 1998-03-04 1999-02-26 Derives de benzofurane WO1999045002A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU26412/99A AU2641299A (en) 1998-03-04 1999-02-26 Benzofuran derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/52117 1998-03-04
JP5211798 1998-03-04

Publications (1)

Publication Number Publication Date
WO1999045002A1 true WO1999045002A1 (fr) 1999-09-10

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WO (1) WO1999045002A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310488A1 (fr) * 2000-08-09 2003-05-14 Mitsubishi Pharma Corporation Composes amide bicycliques condenses et utilisations medicales associees
WO2006044821A1 (fr) * 2004-10-19 2006-04-27 Sb Pharmco Puerto Rico Inc. Antagonistes du recepteur du crf et procedes associes
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022452A1 (fr) * 1996-11-19 1998-05-28 Kyowa Hakko Kogyo Co., Ltd. Derives de benzofuranes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022452A1 (fr) * 1996-11-19 1998-05-28 Kyowa Hakko Kogyo Co., Ltd. Derives de benzofuranes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BACHELET J.-P., ET AL.: "SUR L'ORIENTATION DE L'ACETYLATION DES NITRILES ET AMIDES COUMARILIQUES BZ-METHOXYLES Ú1¾.", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 21., no. 01., 1 January 1984 (1984-01-01), US, pages 177 - 180., XP002033970, ISSN: 0022-152X, DOI: 10.1002/jhet.5570210135 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1310488A1 (fr) * 2000-08-09 2003-05-14 Mitsubishi Pharma Corporation Composes amide bicycliques condenses et utilisations medicales associees
EP1310488A4 (fr) * 2000-08-09 2005-08-10 Mitsubishi Pharma Corp Composes amide bicycliques condenses et utilisations medicales associees
US7112594B2 (en) 2000-08-09 2006-09-26 Mitsubishi Pharma Corporation Fused bicyclic amide compounds and medicinal use thereof
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
WO2006044821A1 (fr) * 2004-10-19 2006-04-27 Sb Pharmco Puerto Rico Inc. Antagonistes du recepteur du crf et procedes associes
JP2008517060A (ja) * 2004-10-19 2008-05-22 エスビー・ファルムコ・プエルト・リコ・インコーポレイテッド Ｃｒｆ受容体アンタゴニストおよびその製法
US7652035B2 (en) 2004-10-19 2010-01-26 Neurocrine Bioscience, Inc. CRF receptor antagonists and methods relating thereto

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Publication number Publication date
AU2641299A (en) 1999-09-20

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