WO1998022452A1 - Derives de benzofuranes - Google Patents

Derives de benzofuranes Download PDF

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Publication number
WO1998022452A1
WO1998022452A1 PCT/JP1997/004212 JP9704212W WO9822452A1 WO 1998022452 A1 WO1998022452 A1 WO 1998022452A1 JP 9704212 W JP9704212 W JP 9704212W WO 9822452 A1 WO9822452 A1 WO 9822452A1
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compound
meoh
chcl
colorless crystals
methoxy
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PCT/JP1997/004212
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English (en)
Japanese (ja)
Inventor
Etsuo Ohshima
Tohru Matsuzaki
Kyoichiro Iida
Michio Ichimura
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Kyowa Hakko Kogyo Co., Ltd.
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Priority to AU49677/97A priority Critical patent/AU4967797A/en
Publication of WO1998022452A1 publication Critical patent/WO1998022452A1/fr

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    • 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 has a phosphodiesterase (PDE) IV inhibitory effect and raises intracellular cAMP concentration to increase allergic diseases such as bronchial asthma, allergic rhinitis and nephritis, rheumatism, multiple sclerosis Autoimmune diseases such as Crohn's disease, psoriasis, systemic lupus erythematosus, central nervous system diseases such as depression, amnesia, and dementia; organs associated with ischemia reperfusion caused by heart failure, shock, cerebrovascular disorders
  • the present invention relates to a benzofuran derivative or a pharmacologically acceptable salt thereof, which is useful as a therapeutic agent for disorders, insulin-resistant diabetes, wounds, and AIDS.
  • cAMP adenosine 3,5'-cyclic monophosphate
  • guanosine 3,5,5-cyclic monophosphate It is known that the effect is exerted by increasing the concentration of cGMP.
  • the intracellular concentrations of cAMP and cGMP are controlled by their production and degradation, and these degradations are performed by PDEs. Therefore, inhibiting PDE will result in increased levels of these intracellular second messengers.
  • TNF tumor necrosis factor
  • IAM intercellular adhesion molecule
  • cAMP concentration in tracheal smooth muscle cells can suppress their contraction It is well known [TJ Torphy in Directions for New Anti-Asthma Drugs, eds SR O'Donell and CGA Persson, 37, Birkhauser-Verlag (1988)]. Contraction of the tracheal smooth muscle is the main condition of bronchial asthma. In ischemia-reperfusion organ damage such as myocardial ischemia, infiltration of inflammatory white blood cells such as neutrophils is found in the affected area. In these inflammatory cells and tracheal smooth muscle cells, it has been shown that mainly type IV PDE (PDE IV) is involved in cAMP degradation. Therefore, a PDE IV selective inhibitor can be expected to have a therapeutic or preventive effect on inflammatory diseases, airway obstructive diseases or ischemic diseases.
  • PDE IV type IV PDE
  • PDE IV inhibitors suppress the secretion of inflammatory site forces such as TNFa and interleukin (IL) -8 by increasing cAMP, and It is expected that the prolonged progress of the transmitted inflammatory response can be prevented.
  • TNFa reduces the phosphorylation mechanism of insulin receptors in muscle and fat cells and contributes to insulin-resistant diabetes [J. Clin. Invest., 94, 1543-1549 ( 1994)].
  • TNFa is involved in the development of autoimmune diseases such as rheumatism, multiple sclerosis, and Crohn's disease, suggesting that PDE IV inhibitors may be effective in these diseases. [Nature Medicine, 1, 211-214; 244-248 (1995)].
  • 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.
  • EP 0307 172 and US 4910193 disclose benzofuran derivatives having serotonin (5HT) 3 receptor antagonism.
  • the present invention provides a compound of the formula (I)
  • R 1 represents hydrogen or substituted or unsubstituted lower alkyl
  • R 2 , R 3 and R 4 are the same or different and are hydrogen, halogen, lower alkyl, cycloalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted aralkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkyl group, substituted or unsubstituted alkyl group alkyl group, lower alkoxy group Represents carbonyl or cyano
  • R 5a is hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Represents unsubstituted aralkyl or substituted or unsubstituted Aryl,
  • R 5b is a substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted R 5a and R 5b together represent a substituted or unsubstituted heterocyclic group formed containing N, and R 6a and R 6b are the same or different.
  • the lower alkyl moiety of lower alkyl and lower alkoxy, lower alkanoyloxy, lower alkanol, lower alkoxycarbonyl and heteroarylalkyl is preferably a straight-chain or branched carbon atom having 1 to 4 carbon atoms. 8 including, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • Cycloalkyl and the cycloalkyl portion of cycloalkylcarbonyl include those having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like.
  • Polycycloalkyl includes those having 4 to 12 carbon atoms, such as bicyclo [3.2.1] octyl, bicyclo [4.3.2] indesyl, adamantyl, noradamantyl and the like.
  • Aryl includes phenyl, naphthyl and the like, and aralkyl includes C7-C15, for example, benzyl, phenethyl, phenylpropyl, benzhydryl, naphthylmethyl and the like.
  • Heterocyclic groups formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • Halogen means atoms of fluorine, chlorine, bromine and iodine.
  • substituent in the substituted lower alkyl include the same or different substituents having 1 to 2 substituents, for example, cycloalkyl, and cycloalkyl has the same meaning as described above.
  • the substituents in the alkyl or substituted lower alkanoyl or substituted cycloalkylcarbonyl may be the same or different and have 1 to 3 substituents, for example, aryl, lower alkyl, hydroxy, lower alkoxy, lower alkanol, lower alkoxylity.
  • lower alkyl, lower alkoxy, lower alkanol, lower alkoxycarbonyl or the lower alkyl portion of mono- or di-lower alkyl-substituted amino, aryl and halogen have the same meanings as above.
  • Examples of the substituent in the substituted heterocyclic group formed containing N include the same or different and having 1 to 3 substituents such as lower alkyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, Lower alkoxy, lower alkyl, lower alkoxycarbonyl, lower alkoxy, lower bamoyl, aromatic heterocyclic groups and the like are included.
  • the lower alkyl portion of lower alkyl, lower alkoxy, lower alkanol or lower alkoxycarbonyl, cycloalkyl, aryl, aralkyl and aromatic heterocyclic group have the same meanings as described above.
  • the substituents of the substituted aryl and the substituted aralkyl have the same meanings as described above.
  • Substituents in the substituted lower alkoxy include the same or different and have 1 to 3 substituents, for example, halogen, and halogen has the same meaning as described above.
  • the pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, formate, acetate, benzoate, maleate, fumarate, and succinate.
  • organic acid salts such as tartrate, citrate, oxalate, metasulfonate and P-toluenesulfonate.
  • the metal salt examples include an alkali metal salt such as a lithium salt, a sodium salt, and a potassium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; an aluminum salt; a zinc salt; and the like.
  • Ammo Salts such as dimethyl and tetramethylammonium; organic amine addition salts such as morpholine and piperidine; amino acid addition salts such as glycine, phenylalanine, glutamic acid, lysine and aspartic acid; Addition salts.
  • Compound (I) can be produced by the following production method.
  • R 1 , RR 3 , R 4 , R 5a and R 5b each have the same meaning as described above
  • 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 starting compound (II) and amine (III). Many methods are known for this dehydration condensation reaction (see the fourth edition of Experimental Chemistry, Maruzen 1990, Vol. 22, p. 138), and can be applied.
  • compound (II) can be prepared in an inert solvent or in the absence of a solvent using 1 equivalent to a large excess of thionyl chloride, oxalyl chloride or phosphorus pentachloride, if necessary, in the presence of a catalytic amount to an excess of base.
  • Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, Potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorpholine , N-methylpiperidine, diazabicycloundecene (DBU), diazabicyclononene (DBN) and the like.
  • LDA lithium diisopropylamide
  • DBU diazabicycloundecene
  • DBN diazabicyclononene
  • Inert solvents include tetrahydrofuran (THF), dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, benzene, toluene, and dimethyl.
  • THF tetrahydrofuran
  • dioxane getyl ether
  • ethylene glycol triethylene glycol
  • glyme diglyme
  • methanol ethanol
  • butanol isopropanol
  • dichloromethane chloroform
  • benzene benzene
  • toluene dimethyl.
  • dimethyl dimethyl sulfoxide
  • Compound (V) can be produced by formylating compound (IV). Many methods are known for formylation of aromatic compounds (see the 4th edition Experimental Chemistry, Maruzen 1990, Vol. 21, p. 106), and are applicable.
  • compound (IV) can be prepared in an inert solvent, more preferably in a halogenated solvent such as dichloromethane, with one equivalent to a large excess of dichloromethyl methyl ether and one equivalent to an excess of an acid, more preferably
  • the desired compound (V) can be obtained by reacting in the presence of titanium tetrachloride at a temperature between 1501 and the boiling point of the solvent used for 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 solvents include THF, dioxane, getyl ether, ethylenedali Examples include coal, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.
  • RRR 3, RR 5a , R 5b , R 6a and R 6b each have the same meaning as described above
  • the desired compound (I) can be produced by reductive amination of compound (V).
  • Several methods are known for the reductive amination of aromatic aldehydes (see the 4th edition of Experimental Chemistry, Maruzen 1990, Vol. 20, p. 300), and are applicable.
  • compound (V) is mixed with 1 equivalent to a large excess of amine (VI) in an inert solvent, and if necessary, an appropriate acid or salt is added, and 1 equivalent to an excess of a reducing agent, more preferably a hydrogenated tria.
  • the desired compound (I) can be obtained by reacting at a temperature between 15 and the boiling point of the used solvent for 5 minutes to 48 hours in the presence of cetoxyboron.
  • the reducing agent sodium borohydride, sodium cyanoborohydride and the like can also be used.
  • Examples of the acid include acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.
  • Examples of the salt include ammonium acetate, ammonium chloride, ammonium sulfide and the like.
  • inert solvent examples include THF, dioxane, getyl ether, dichloromethane, chloroform, benzene, toluene, methanol, ethanol, isopropanol and the like.
  • NR 6a R 6b Compound number NR 5a R 5b NR 6a R 6b
  • Test Example 1 Recombinant human PDE IVA enzyme inhibition test
  • HSPDE4A Human phosphodiesterase cDNA
  • the predicted amino acid sequence is the sequence (HSPD4A5) reported by Bolger, G. et al. [Mol. Cell. Biol. 13, 6558-6571 (1993)] with 223 amino acids deleted at the N-terminal. This recombinant protein was expressed and purified using an E. coli expression plasmid. PDE activity was measured by the following two-step process according to the method of Kincaid, R., L. and Manganiello, V., C. [Method. Enzymol. 159, 457-470 (1988)].
  • the substrate is [ 3 H] cAMP
  • the compound showed an enzyme inhibitory activity of 50% or more at 10 ⁇ / L.
  • 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 can contain Compound (I) or a pharmacologically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient.
  • the pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals. It is desirable to use the most effective route for treatment, and it can be oral or parenteral, for example, oral, respiratory, rectal, subcutaneous, intramuscular and intravenous. .
  • Dosage forms include sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like.
  • Liquid preparations suitable for oral administration include water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil. It can be produced using oils such as soybean oil, preservatives such as P-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint.
  • Capsules, tablets, powders, granules and the like include excipients such as lactose, glucose, sucrose and mannitol; disintegrants such as starch and sodium alginate; lubricants such as magnesium stearate and talc; It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as daricerin.
  • excipients such as lactose, glucose, sucrose and mannitol
  • disintegrants such as starch and sodium alginate
  • lubricants such as magnesium stearate and talc
  • It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as daricerin.
  • Formulations suitable for parenteral administration comprise a sterile aqueous preparation containing the active compound which is preferably isotonic with the blood of the recipient.
  • 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 are prepared using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids and provided as suppositories.
  • Sprays are prepared using a carrier which does not irritate the active compound itself or the oral and respiratory mucosa of the recipient and which disperses the active compound as fine particles to facilitate absorption.
  • lactose, glycerin and the like are exemplified.
  • Formulations such as aerosols and dry powders are possible depending on the nature of the active compound and the carrier used.
  • parenteral preparations select from the glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for the oral preparation.
  • One or more auxiliary ingredients can also be added.
  • the effective amount and the number of administration of the compound (I) or a pharmaceutically acceptable salt thereof are as follows: Depending on the dosage form, the age and weight of the patient, the nature or severity of the condition to be treated, usually 0.01 mg to lg, preferably 1 to 50 Omg per day for an adult It is administered once or several times. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg per adult, preferably 0.01 to Omg is administered once or several times a day. However, these dosages vary depending on the various conditions described above.
  • Compound 5 was obtained as colorless crystals in the same manner as in Example 1 using Compound 1b and 2-propylamine.
  • Example 11 1 N-cyclohexyl-7-methoxy-4- (2,3-dimethylcyclohexylaminomethyl) benzofuran-2-kelpoxamide (Compound 11)
  • Compound 11 was obtained as colorless crystals using compound lb and 2,3-dimethylcyclohexylamine.
  • Example 17 N-cyclohexyl-17-methoxy-14- [1-1 (S) -phenylethylaminomethyl] benzofuran-2-caproloxamide (Compound 17)
  • the compound was prepared in the same manner as in Example 1.
  • Compound 17 was obtained as colorless crystals using lb and 1- (S) -phenethylamine.
  • Example 19 N-cyclohexyl-7-methoxy-4- [2- (2-pyridyl) ethylaminomethyl] benzofuran-2-carboxamide (Compound 19)
  • compound 19 was obtained as colorless crystals using and 2- (2-pyridyl) amine.
  • Example 21 4-Cyclobutylaminomethyl-7-methoxy-N- (3-phenylpropyl) benzofuran-1-carboxamide (Compound 21)
  • 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound and reacted with 3-phenylpropylamine to react with 7-methoxy-N- (3-phenylpropyl) benzofuran-2 —Caproloxamide (Compound 21a) and further formylation to give 7-methoxy-4-formyl-1-N— (3-phenylpropyl) benzofuran-1-carboxamide (Compound 2 lb), and then react with cyclobutylamine Compound 21 was obtained as colorless crystals.
  • Example 24 7-Methoxy-4-I- (4-methylpiperazinylmethyl) -N- (3-phenylpropyl) benzofuran-l-carboxamide (Compound 24)
  • Compound 24 was obtained as colorless crystals using compound 21b and 1-methylbiperazine.
  • Example 26 7-methoxy-4- (2-phenylethylaminomethyl) -N- (3-phenylpropyl) benzofuran-2-carboxamide (Compound 26)
  • Compound 2 was prepared in the same manner as in Example 21.
  • Compound 26 was obtained as colorless crystals using 1b and 2-phenethylamine.
  • Example 28 7-methoxy-N- (3-phenylpropyl) -4- (3-phenylpropylaminomethyl) benzofuran-1-carboxamide (Compound 28)
  • Compound 21 was prepared in the same manner as in Example 21.
  • Compound 28 was obtained as colorless crystals using b and 3-phenylpropylamine.
  • Example 30 7-Methoxy-N- (3-phenylpropyl) -1- (2-morpholinoethylaminomethyl) benzofuran-2-carboxamide (Compound 30)
  • a compound was prepared in the same manner as in Example 21.
  • Compound 30 was obtained as colorless crystals using 21b and 2-morpholinoethylamine.
  • Rf (CHCl 3 : MeOH 9: l); 0.39
  • Example 35 4-Monobutylaminomethyl-7-methoxy-N-phenylbenzofuran-2-carboxamide (Compound 35) By a method similar to that of Example 31, compound 35 was obtained as colorless crystals using compound 31b and n-butylamine.
  • Example 40 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) 1-N-phenylbenzofuran-2-carboxamide (Compound 40)
  • Compound 3 lb was prepared in the same manner as in Example 31.
  • Compound 40 was obtained as colorless crystals using 2,3-dimethylcycloamine. ⁇
  • Example 51 1 N-benzyl-1 7-methoxy-4 monomethylaminomethyl benzofuran 1-2-caproloxamide (compound 51)
  • Example 60 N-benzyl-4- (2,3-dimethylcyclohexylaminomethyl (Tyl)-1-methoxybenzofuran-2-force lipoxamide (Compound 60)
  • Compound 5 was obtained as colorless crystals using Compound 5 lb and 2,3-dimethylcyclohexylamine.
  • Compound 51b and 1-methylbiperazine were obtained in the same manner as in Example 51.
  • Compound 65 was obtained as colorless crystals.
  • Furan-2-carboxamide (compound 79) Compound 79 was obtained as colorless crystals using compound 71b and piperidine in the same manner as in Example 71.
  • Example 89 N-cyclopentyl-7-methoxy-14-piperidinomethylbenzofuran-12-force lipoxamide (Compound 89)
  • compound 89 was obtained as colorless crystals using compound 81b and piperidine.
  • Example 96 4-Cyclopentylaminomethyl-7-methoxy-2-pyrrolidylcarbanolpenzafuran (compound 96)
  • Example 91 the compound was synthesized using compound 91b and piperidine.
  • Compound 99 was obtained as colorless crystals.
  • Example 91 In the same manner as in Example 91, compound 100 was obtained as colorless crystals using compound 91b and morpholine.
  • Example 104 7-Methoxy-1- (2-propylaminomethyl) -2-piridinocarbonylcarbonylbenzofuran (Compound 104)
  • compound 104 was obtained as colorless crystals using compound 101b and 2-propylamine.
  • Example 1 13 7-Methoxy-4-propylaminomethyl-2-morpholino force Luponyl benzofuran (Compound 113)
  • Example 1 14 7-methoxy-41- (2-propyl) aminomethyl-2-mol holinocarborpenzafuran (compound 114)
  • Example 1 19 7-Methoxy-1-4-piberidinomethyl-2-morpholino-potanol Rilpenzofuran (Compound 119)
  • Compound 120 was obtained as colorless crystals using compound 111b and morpholine in the same manner as in Example 11-11.
  • Example 123 7-Methoxy-N- (2-phenylethyl) 1-41-propyla Minomethylbenzofuran-2-force lpoxamide (Compound 123)
  • Compound 123 was obtained as colorless crystals using Compound 121b and n-propylamine.
  • Example 124 7-Methoxy-N- (2-phenylethyl) 1-141 (2-propylaminomethyl) benzofuran-1-carboxamide (Compound 124)
  • Compounds 12 1b and 2 were prepared in the same manner as in Example 121.
  • Compound 124 was obtained as colorless crystals using propylamine.
  • Example 127 4-cyclopentylaminomethyl-N- (2-phenylethyl) —7-methoxybenzofuran-2-carboxamide (Compound 127)
  • compound 121b and cyclopentylamido were prepared.
  • Compound 127 was obtained as colorless crystals using the compound.
  • Example 130 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) -N- (2-phenylethyl) benzofuran-2-carboxamide
  • Example 138 7-Methoxy-N- (2-phenylethyl) -4-1 (3-phenylpropylaminomethyl) benzofuran-2-caproloxamide (Compound 138)
  • Compound 139 was obtained as colorless crystals using compound 12 lb and 2 _ (2-pyridyl) ethylamine in the same manner as in Example 121.
  • Example 140 7-Methoxy-N- (2-phenylethyl) -14- (2-morpholinoethylaminomethyl) benzofuran-1-carpoxamide (Compound 140)
  • Example 143 7-Methoxy-N- [1- (S) -phenylethyl] —4-heppyraminomethylpentazofuran-21-Lupoxamide (Compound 143)
  • Compound 141b was prepared in the same manner as in Example 141.
  • Compound 143 was obtained as colorless crystals using and n-propylamine.
  • Example 146 4-cyclobutylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-carpoxamide (Compound 146)
  • Compound 141b and cyclobutyla were prepared in the same manner as in Example 141. Min was used to obtain Compound 146 as colorless crystals.
  • Example 147 4-Cyclopentylaminomethyl_7-methoxy-N— [1- (S) -phenylethyl] benzofuran-1-carboxamide (Compound 147)
  • Compound 141b and cyclopentylamine were obtained in the same manner as in Example 141.
  • Compound 147 was obtained as colorless crystals by using.
  • Example 148 4-Cyclohexylaminomethyl-N- [1- (S) -phenyl-2-ethyl] _7-methoxybenzofuran-2-carboxamide (Compound 148)
  • Compound 141 was prepared in the same manner as in Example 141.
  • Compound 148 was obtained as colorless crystals using b and cyclohexylamine.
  • Example 149 4-Cyclooctylaminomethyl-7-methoxy-N-tl-CS) -phenylethyl] benzofuran-2-caproloxamide (Compound 149)
  • compound 141b and cyclohexane Compound 149 was obtained as colorless crystals using octylamine.
  • Example 150 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) —N— [1- (S) -phenylethyl] benzofuran—2-caproloxamide (Compound 150)
  • Example 15 5 1 4-benzylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-12-caproloxamide (Compound 151)
  • Compound 141b was prepared in the same manner as in Example 141.
  • Compound 151 was obtained as colorless crystals using benzylamine.
  • Rf (CHCl 3: MeOH 9 : l); 0.54
  • Example 1 55 N- [1-(S) -phenylethyl] —4- (4-methylpyrazinylmethyl) —7-methoxybenzofuran-1-carboxamide (Compound 155)
  • Example 1 56 7-Methoxy-N_ [1- (S) -phenylethyl] -1-4_
  • Example 141 By a method similar to that of Example 141, compound 160 was obtained as colorless crystals using compound 141b and 2-morpholinoethylamine.
  • Example 161 N- (4-cyclophenyl) -4-cyclobutylaminomethyl 1-71-Methoxybenzofuran-2-carboxamide (Compound 161)
  • N- (4-chlorophenyl) 17-methoxybenzofuran-12-carpoxamide compound 16 la
  • N- (4-chlorophenyl) —4-formyl—7-methoxybenzofuran—2-caproloxamide After the compound 161b) was obtained, it was reacted with cyclobutylamine to give compound 161 as colorless crystals.
  • Example 164 N- (4-chlorophenyl) -4- (4-methylbiperazinylmethyl) -1-7-methoxybenzofuran-2-carboxamide (Compound 164) Compound 164 was obtained as colorless crystals using 16 1b and 1-methylbiperazinamine.
  • Example 166 N- (4-chlorophenyl) -7-methoxy-41- (2-phenylethylmethyl) benzofuran-2-carboxamide (Compound 166)
  • Compound 16 1 was prepared in the same manner as in Example 161.
  • Compound 166 was obtained as colorless crystals using b and 2-phenethylamine.
  • Example 170 N- (4-chlorophenyl) -1-7-methoxy-4- (2-morpholinoethylaminomethylbenzofuran-2-force lipoxamide (compound 170)
  • compound 170 was obtained as colorless crystals using compound 161b and 2-morpholinoyl.
  • Example 172 N- (4-tert-butylphenyl) -4-cyclooctylaminomethyl-7-methoxybenzofuran-1-carboxamide (Compound 172)
  • compound 171b and Compound 172 was obtained as colorless crystals using cyclooctylamine.
  • Example 1 73 N- (4-t-butylphenyl) -17-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) benzofuran-2-force lipoxamide (Compound 173)
  • Example 1 74 N- (4-t-butylphenyl) -7-methoxy-4- (4-methylbiperazinylmethyl) benzofuran-1-carboxamide (Compound 174)
  • Example 175 N- (4-t-butylphenyl) -17-methoxy-41- (11-pyrrolidinylmethyl) benzofuran-12-carboxamide (Compound 175) A compound was prepared in the same manner as in Example 17-1. Compound 175 was obtained as colorless crystals using 17 1b and pyrrolidine.
  • Example 1 78 N- (4-t-butylphenyl) -17-methoxy-14- (3-phenylpropylaminomethyl) benzofuran-12-caproloxamide (compound 178)
  • Compound 178 was obtained as colorless crystals by using the compound 171b and 3-phenylpropylamine in the same manner as in Example 1771.
  • Example 180 N- (4-t-butylphenyl) -7-methoxy-4- (2-morpholinoaminomethyl) benzofuran-1-carpoxamide (Compound 180)
  • compound 171b and Compound 180 was obtained as colorless crystals using 2-morpholinoethylamine.
  • Example 181 4-cyclobutylaminomethyl-7-methoxy-1-N- (4-methoxyphenyl) benzofuran-1-carboxamide (compound 181)
  • Example 182 4-cyclooctylaminomethyl-7-methoxy-N- (4-methoxyphenyl) benzofuran-2-carpoxamide (Compound 182)
  • compound 18 1b and cycloalkyl Compound 182 was obtained as colorless crystals using octylamine.
  • Example 184 7-methoxy-N- (4-methoxyphenyl) 1-4- (4-methylpiperazinylmethyl) benzofuran-2-force lipoxamide (Compound 184) A compound was prepared in the same manner as in Example 181. Compound 184 was obtained as colorless crystals using 18 1b and 1-methylbiperazine.
  • Example 188 7-Methoxy-N- (4-methoxyphenyl) -4- (3-phenylpropylaminomethyl) benzofuran-1-2-propanolamide (Compound 188)
  • compound 1888 was obtained as colorless crystals using compound 181b and 3-phenylpropylamine.
  • Example 190 7-Methoxy-N- (4-methoxyphenyl) _4-1 (2-morpholinoethylaminoethyl) benzofuran-1-carboxamide (Compound 190)
  • Example 19 9 1 4-cyclobutylaminomethyl-7-methoxy-N- (2-methoxyphenyl) benzofuran-12-carpoxamide (compound 1991)
  • Example 192 4-Cyclooctylaminomethyl_7-methoxy-N- (2-methoxyphenyl) benzofuran-2-carpoxamide (Compound 192) Compound 19 in the same manner as in Example 19 1b and cyclooctylami Compound 192 was obtained as colorless crystals using the compound.
  • Example 194 7-methoxy-N- (2-methoxyphenyl) -4-1 (4-methylpiperazinylmethyl) benzofuran-2-carboxamide (Compound 194) A compound was prepared in the same manner as in Example 191. Compound 194 was obtained as colorless crystals using 191b and 1-methylbiperazine.
  • Example 195 7-Methoxy-1-N- (2-methoxyphenyl) -4- (1-pyrrolidinylmethyl) benzofuran-12-caproloxamide (Compound 195)
  • Compound 191 was obtained in the same manner as in Example 191.
  • Compound 195 was obtained as colorless crystals using b and pyrrolidine.
  • Compound 199 was obtained as colorless crystals in the same manner as in Example 191 using compound 191b and 2- (2-pyridyl) ethylamine.
  • the present invention has an inhibitory effect on phosphodiesterase (PDE) IV, and has an inflammatory and allergic disease such as bronchial asthma, allergic rhinitis and nephritis, an autoimmune disease such as rheumatism, multiple sclerosis, Crohn's disease, psoriasis, and systemic lupus erythematosus.
  • PDE phosphodiesterase
  • Central nervous system diseases such as depression, amnesia, and dementia; organ dysfunction due to ischemia reperfusion due to heart failure, shock, cerebrovascular disorder, etc., diabetes due to insulin resistance, wounds, AIDS, etc.

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

Abstract

Dérivés de benzofuranes représentés par la formule générale (I) et leurs sels pharmaceutiquement acceptables. Dans la formule (I), R1 représente hydrogène ou alkyle inférieur substitué ou non; R?2, R3 et R4¿ représentent indépendamment l'un de l'autre hydrogène ou similaire; R5a représente hydrogène, alkyle inférieur substitué ou non, cycloalkyle, polycycloalkyle, aryle substitué ou non ou similaire; et R5b représente alkyle inférieur substitué ou non, cycloalkyle, polycycloalkyle ou similaire; en variante R?5a et R5b¿ peuvent être réunis pour former un groupe hétérocyclique azoté substitué ou non; et R?6a et R6b¿ représentent indépendamment l'un de l'autre hydrogène, alkyle inférieur substitué ou non, hétéroarylalkyle substitué ou non, ou arylalkyle substitué ou non; en variante R?6a et R6b¿ peuvent être réunis pour former un groupe hétérocyclique azoté substitué ou non.
PCT/JP1997/004212 1996-11-19 1997-11-19 Derives de benzofuranes WO1998022452A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045002A1 (fr) * 1998-03-04 1999-09-10 Kyowa Hakko Kogyo Co., Ltd. Derives de benzofurane
WO2002016353A1 (fr) * 2000-08-17 2002-02-28 Celltech R & D Limited Derives heteroaromatiques bicycliques pour le traitement de troubles immunitaires et de troubles inflammatoires
EP1310488A1 (fr) * 2000-08-09 2003-05-14 Mitsubishi Pharma Corporation Composes amide bicycliques condenses et utilisations medicales associees
WO2006066879A2 (fr) * 2004-12-21 2006-06-29 Devgen N.V. Composes inter-reagissant avec des canaux ioniques, en particulier avec des canaux ioniques de la famille kv
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
WO2020002611A1 (fr) 2018-06-28 2020-01-02 Phenex-Fxr Gmbh Nouveaux modulateurs lxr à fraction noyau bicyclique
EP3704126A4 (fr) * 2017-11-03 2020-12-09 Université de Montréal Composés et leur utilisation dans l'expansion de cellules souches et/ou de cellules progénitrices

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 64, No. 12, 6 June 1966, (Columbus, Ohio, USA), Abstract No. 17518b, M. DESCAMPS et al., "The Benzofuran Series...."; & CHIM. THERAP., 1966, (2), 87-97 (Fr). *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999045002A1 (fr) * 1998-03-04 1999-09-10 Kyowa Hakko Kogyo Co., Ltd. Derives de benzofurane
US7112594B2 (en) 2000-08-09 2006-09-26 Mitsubishi Pharma Corporation Fused bicyclic amide compounds and medicinal use thereof
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
WO2002016353A1 (fr) * 2000-08-17 2002-02-28 Celltech R & D Limited Derives heteroaromatiques bicycliques pour le traitement de troubles immunitaires et de troubles inflammatoires
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
WO2006066879A2 (fr) * 2004-12-21 2006-06-29 Devgen N.V. Composes inter-reagissant avec des canaux ioniques, en particulier avec des canaux ioniques de la famille kv
WO2006066879A3 (fr) * 2004-12-21 2006-10-12 Devgen Nv Composes inter-reagissant avec des canaux ioniques, en particulier avec des canaux ioniques de la famille kv
EP3704126A4 (fr) * 2017-11-03 2020-12-09 Université de Montréal Composés et leur utilisation dans l'expansion de cellules souches et/ou de cellules progénitrices
US11696928B2 (en) 2017-11-03 2023-07-11 Universite De Montreal Compounds and use thereof in the expansion of stem cells and/or progenitor cells
WO2020002611A1 (fr) 2018-06-28 2020-01-02 Phenex-Fxr Gmbh Nouveaux modulateurs lxr à fraction noyau bicyclique
US11618747B2 (en) 2018-06-28 2023-04-04 Orsobio, Inc. LXR modulators with bicyclic core moiety
US11970484B2 (en) 2018-06-28 2024-04-30 Orsobio, Inc. LXR modulators with bicyclic core moiety

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