WO2000044737A1 - Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) - Google Patents

Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) Download PDF

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Publication number
WO2000044737A1
WO2000044737A1 PCT/US2000/001342 US0001342W WO0044737A1 WO 2000044737 A1 WO2000044737 A1 WO 2000044737A1 US 0001342 W US0001342 W US 0001342W WO 0044737 A1 WO0044737 A1 WO 0044737A1
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alkyl
hydrogen
mmol
halo
aminopropane
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PCT/US2000/001342
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English (en)
Inventor
Karin Briner
Joseph Paul Burkhart
Timothy Paul Burkholder
Matthew Joseph Fisher
William Harlan Gritton
Daniel Timothy Kohlman
Sidney Xi Liang
Shawn Christopher Miller
Jeffrey Thomas Mullaney
Yao-Chang Xu
Yanping Xu
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Eli Lilly And Company
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Priority to CA002361516A priority Critical patent/CA2361516A1/fr
Priority to JP2000595993A priority patent/JP2002535396A/ja
Priority to AU26198/00A priority patent/AU2619800A/en
Priority to EP00904438A priority patent/EP1149085A1/fr
Priority to US09/890,311 priority patent/US7045545B1/en
Publication of WO2000044737A1 publication Critical patent/WO2000044737A1/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
    • C07D307/79—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si

Definitions

  • the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has a rich pharmacology arising from a heterogeneous population of at least seven receptor classes.
  • the serotonin 5-HT2 class is further subdivided into at least three subtypes, designated 5-HT2a' 5_HT 2b' and 5-HT2 c .
  • the 5-H 2c receptor has been isolated and characterized (Julius, et al . , U.S. Patent No. 4,985,352), and transgenic mice lacking the 5-HT2 c receptor have been reported to exhibit seizures and an eating disorder resulting in increased consumption of food (Julius, et al . , U.S. Patent No. 5,698,766).
  • Compounds selective for the 5-HT2 c receptor would provide useful therapies for the treatment of seizure and eating disorders without the side effects associated with current therapies.
  • the present invention provides aminoalkylbenzofurans of Formula I :
  • A is -CHR 13 - or a bond
  • R is hydrogen, halo, cyano, -C(0)NR ⁇ R 7 , C ⁇ _-C6 alkyl, C1-C4 alkoxycarbonyl , carboxy, or phenyl optionally substituted with one or two substituents selected from the group consisting of halo, C1-C4 alkyl, and C1-C4 alkoxy;
  • R! is hydrogen, halo, cyano, carboxamido, formyl, trimethylsilyl, trifluoromethyl, pentafluoroethyl, or C ⁇ _-Cg alkyl ;
  • R 2 and R 3 are independently hydrogen, halo, amino, nitro, C . -C4 alkoxy, cyano, carboxamido, -C(0)NR8R9,
  • R 4 and R 4 ' are independently hydrogen, C1-C4 alkyl, or benzyl; or R 4 and R 4 ' together with the carbon atom to which they are attached form a cyclopropyl moiety;
  • R5 is hydrogen, C ⁇ _-C alkyl, or benzyl;
  • R 5 ' is hydrogen, or R ⁇ and R5 ' together with the carbon atom to which they are attached form a cyclopropyl moiety;
  • R6 and R 7 are independently hydrogen or C1-C4 alkyl;
  • R8 is hydrogen or C ⁇ _-C4 alkyl;
  • R9 is C ⁇ _-Cg alkyl where the alkyl chain is optionally substituted with a substituent selected from the group consisting of carboxy, phenyl, or pyridyl, said phenyl or pyridyl substituent optionally substituted with one or two substituents selected from the group consisting of halo, C ⁇ _- C4 alkyl, or C1-C4 alkoxy;
  • R!0 is hydrogen or C1-C4 alkyl
  • R 11 is C1-C4 alkyl or C1-C4 acyl
  • R 12 is hydrogen, halo, or C1-C4 alkyl; R!3 i s hydrogen, C1-C4 alkyl, or benzyl; R!4 i s hydrogen, C ⁇ _-C4 alkyl, or phenyl optionally substituted with a substituent selected from the group consisting of halo, C ⁇ -CA alkyl, and C1-C4 alkoxy; or pharmaceutically acceptable acid addition salts thereof .
  • This invention also provides a pharmaceutical formulation which comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I .
  • the present invention provides a method for increasing activation of the 5-HT2C receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
  • a further embodiment of this invention is a method for increasing activation of the 5-HT2C receptor for treating a variety of disorders which have been linked to decreased neurotransmission of serotonin in mammals. Included among these disorders are depression, obesity, bulimia, premenstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of aging, social phobia, attention deficit hyperactivity disorder, disruptive behavior disorders, impulse control disorders, borderline personality disorder, obsessive compulsive disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, anxiety, seizure disorders, and mutism. Any of these methods employ a compound of Formula I .
  • This invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of obesity. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of obesity containing a compound of Formula I. Furthermore, this invention includes a method for the treatment of obesity which comprises administering an effective amount of a compound of Formula I .
  • alkyl includes such groups as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, and the like.
  • alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • acyl includes such groups as formyl, acetyl, propionyl, b tyryl, 2-methylpropionyl, and the like.
  • halo includes fluoro, chloro, bromo and iodo.
  • the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature.
  • Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like.
  • Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyro-phosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1 , 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxy- benzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
  • variable A is -CHR 13 - anc : R13 i s other than hydrogen
  • R 4 ' and R 4 are not the same
  • the compounds of the invention exist, are formulated, and are used as single enantiomers or diastereomers
  • the present invention also contemplates the compounds of the invention existing in racemic form and as mixtures of the individual enantiomers and diastereomers .
  • the methods and formulations of the invention also contemplate the use and formulation of the compounds of the invention in their racemic form and as mixtures of the individual enantiomers and diastereomers.
  • the individual enantiomers and diastereomers may be prepared by chiral chromatography of the racemic or enantiomerically or diastereomerically enriched free amine, or fractional crystallization of salts prepared from racemic or enantiomerically or diastereomerically enriched free amine and a chiral acid.
  • the free amine may be reacted with a chiral auxiliary and the enantiomers or diastereomers separated by chromatography followed by removal of the chiral auxiliary to regenerate the free amine.
  • separation of enantiomers or diastereomers may be performed at any convenient point in the synthesis of the compounds of the invention.
  • the compounds of the invention may also be prepared by the use of chiral syntheses.
  • A is a bond; ab) A is attached at the 4-position of the benzofuran ring; ac) A is attached at the 5-position of the benzofuran ring; ad) A is attached at the 6-position of the benzofuran ring; ae) A is attached at the 7-position of the benzofuran ring; af) R is hydrogen; ag) R is halo; ah) R is cyano; ai) R is -C(0)NR 6 R 7 ; aj ) R is C ⁇ -Cg alkyl; ak) R is C .
  • R is carboxy; am) R is phenyl optionally substituted with one or two substituents selected from the group consisting of halo, C1-C alkyl, and C1-C4 alkoxy; an) R 1 is hydrogen; ao) R! is halo; ap) R! is cyano; aq) R!
  • R 1 is carboxamido; ar) R 1 is trifluoromethyl; as) R 1 is C1-C4 alkyl; at) R2 is hydrogen; au) R 2 is halo; av) R 2 is fluoro; aw) R 2 is amino; ax) R 2 is C1-C4 alkoxy; ay) R 2 is C ⁇ _-C4 alkyl optionally substituted with a substituent selected from the group consisting of C ⁇ _-C4 alkoxy, hydroxy, phenoxy, and phenyl; az) R 2 is -C(0)NR 8 R 9 ; ba) R 2 is -NR 10 -* 11 ; bb) R 2 is trifluoromethyl; be) R3 is hydrogen; bd) R 3 is halo; be) R3 is fluoro; bf) R 3 is trifluoromethyl ; bg) R 3 is C ⁇ _-C4 alkyl optionally substituted with a substituent selected from
  • the present invention also provides a method for increasing activation of the 5-HT2C receptor in mammals by administering to a mammal in need of such activation a pharmaceutically effective amount of a compound of Formula I.
  • the preferred mammal is human.
  • variable A is a bond
  • variables R, R 1 , R 2 , R 3 , R 4 . R4 ' r anc ; R 5 are as previously defined:
  • the bromobenzofuran is coupled with an appropriate enol acetate in the presence of palladium( II) chloride, tri (o- tolyl)phosphine, and tributyl tin methoxide to provide the corresponding ketone.
  • This ketone is then reductively aminated under standard conditions, such as treatment of the ketone with ammonium acetate and sodium cyanoborohydride in the presence of acid, to provide the primary amines of the present invention.
  • the bromobenzofuran may be treated with magnesium to prepare the corresponding Grignard reagent. This compound is then reacted with copper (I) bromide followed by an appropriate N-protected aziridine to provide the corresponding N-protected amine. Deprotection of the amine then provides the compounds of the present invention.
  • protecting groups which may be conveniently removed. Commonly the protecting group employed is the tert-butoxycarbonyl group, which is then removed by treatment with acid, typically hydrochloric acid.
  • variable A is -CHR13- are prepared as described in the following scheme where * variables R, R- 1 -, R 2 , R 3 , R 4 , R ⁇ R ⁇ 2 , and R ⁇ 3 are a s previously defined:
  • the bromobenzofuran is coupled with an appropriate allylic alcohol in the presence of palladium(II) acetate and an appropriate triarylphosphine such as triphenylphosphine or tri (o-tolyl)phosphine to provide the corresponding ketone.
  • This ketone is then reductively aminated under standard conditions to provide the compounds of the present invention.
  • R 4 ' moiety may be introduced by reacting the ketone prepared above with an appropriate alkylating agent under standard conditions .
  • the requisite benzofuran intermediates are either commercially available or may be prepared from an appropriately substituted phenol by methods well known in the art as illustrated in the following scheme where variables R , R 3 , and R ⁇ - 2 are as previously defined:
  • Bases useful for this reaction include hydride sources, such as sodium or potassium hydride, or carbonates, such as sodium or potassium carbonate.
  • the phenoxide solution is then reacted with a chloro- or bromoacetaldehyde which is protected as a cyclic or dialkyl acetal .
  • Bromoacetaldehyde diethyl acetal is particularly useful for this reaction.
  • the phenoxyacetaldehyde acetal prepared by this procedure is reacted with a source of acid in a suitable solvent to provide the desired benzofuran.
  • Suitable solvents include aromatic solvents such as toluene, xylene, benzene, and halobenzenes such as chlorobenzene .
  • Suitable acids include concentrated sulfuric acid, polyphosphoric acid, and acidic resins such as Amberlyst 15TM.
  • the phenoxide solution is treated with an allyl bromide or allyl chloride to provide, after standard isolation and purification procedures, the corresponding allyl ether.
  • This purified ether is heated at a temperature sufficient to effect an ortho-Claisen rearrangement to provide the corresponding o-allylphenol. It is critical that the allyl ether employed in this rearrangement is substantially free of residual dimethyl- formamide.
  • the rearrangement can provide a mixture of two isomeric products. These isomers may be separated at this stage or later in the synthetic sequence as is convenient or desired.
  • the separation may be effected by chromatography, distilla-tion, or crystallization.
  • the o-allylphenol is then treated with an excess of ozone in an appropriate solvent, dichloromethane and methanol are useful solvents for this step.
  • the reaction mixture is then purged of ozone and the ozonide is treated under reducing conditions, typically by treatment with triphenylphosphine or dimethyl- sulfide, to provide the corresponding phenylacetaldehyde .
  • triphenylphosphine or dimethyl- sulfide to provide the corresponding phenylacetaldehyde .
  • a solution of this equilibrium mixture in a suitable solvent, such as toluene is treated with a catalytic amount of an appropriate acid, such as sulfuric acid, to provide the desired benzofuran.
  • benzofurans substituted in the 2- and/or 3-position may be prepared by modification of the chemistry described in Synthetic Scheme III.
  • the phenol may be alkylated with a suitable haloketone and then cyclized to provide a substituted benzofuran.
  • the benzofuran moiety may be substituted in the 2- or 3-position at any convenient point in the synthesis of the compounds of the present invention by methods known to those skilled in the art .
  • benzofurans may also be prepared from an appropriately substituted phenol as illustrated in the following scheme where variables R , R 3 , and R ⁇ 2 are as previously defined:
  • a mixture of an appropriate phenol and hexamethylenetetra- mine are treated with an appropriate acid, such as trifluoroacetic acid, to provide upon aqueous workup the corresponding o-formylphenol .
  • This o-formylphenol is then treated with (bromomethyl) triphenylphosphonium bromide followed by an appropriate base such as potassium tert- butoxide to provide the desired benzofuran.
  • bromobenzofuran is treated with either magnesium metal to provide the corresponding Grignard reagent, or with an alkyllithium at low temperature to effect halogen metal exchange. Either of these reagents is then reacted with an appropriate reagent, for example dimethyIformamide, to provide the corresponding formylbenzofuran.
  • This formylbenzofuran is reduced under standard hydride reducing conditions, for example sodium borohydride in ethanol, to provide the corresponding alcohol.
  • the alcohol is then converted to the corresponding nitrile by either converting first to the corresponding halide and displacing with a source of cyanide anion, or by directly converting the alcohol to the nitrile by reaction with trimethylsilylchloride and sodium cyanide in a mixture of dimethylformamide and acetonitrile in the presence of catalytic sodium iodide as described by dans et al . (Journal of Organic Chemistry, 46, 2985 (1981)).
  • the requisite nitrile may also be prepared beginning with an appropriate benzofurylacetate ester, such as ethyl benzofurylacetate.
  • the benzofurylacetate ester is reacted with formamide in the presence of an appropriate base, such as sodium methoxide, to prepare the corresponding benzofur- ylacetamide.
  • This acetamide is then dehydrated to provide the desired nitrile by reaction with an appropriate dehydrating agent, such as trifluoroacetic anhydride in the presence of pyridine as described by Campagna, et al . (Tetrahedron Letters, 1813 (1977)).
  • the cyclopropyl moiety is introduced by reacting this nitrile with 1,2-dibromoethane and aqueous sodium hydroxide in the presence of a phase-transfer catalyst such as benzyltriethylammoniu chloride under the conditions described by Sychkova and Shabarov (Zh. Org . Khim. , 16, 2086 (1980) ) .
  • a phase-transfer catalyst such as benzyltriethylammoniu chloride under the conditions described by Sychkova and Shabarov (Zh. Org . Khim. , 16, 2086 (1980) ) .
  • Reduction of the corresponding cyclopropylamide with an appropriate hydride reducing agent, for example lithium aluminum hydride or borane dimethylsulfide complex, provides the compound of the present invention.
  • benzofurylacetate ester may be reacted with 1,2-dibromoethane in the presence of an excess of an appropriate base, such as lithium diisopropylamide, to provide the corresponding ester of 1-benzofuryl-l-carboxycy- clopropane.
  • an appropriate base such as lithium diisopropylamide
  • the resulting tert- butyl ester is subjected to standard Curtius rearrangement conditions to provide the corresponding N-tert- butoxycarbonyl 1-amino-l- (benzofuryl) methylcyclopropane .
  • This compound is deprotected by treatment with acid to provide the compounds of the present invention. If necessary or desired, the starting aldehyde may be reduced to the corresponding alcohol and then converted to the corresponding bromomethylbenzofuran.
  • This reagent is then reacted with 1-1ert-butoxycarbony1eyelopropy11ithium essentially as described by Haener, to provide 1-tert- butoxycarbonyl-1- (benzofuryl) methylcyclopropane which is then subjected to the Curtius rearrangement/deprotection sequence described supra to provide the compounds of the present invention.
  • the starting bromobenzofuran may be reacted with magnesium metal under standard conditions to prepare the corresponding Grignard reagent, benzof rylmag- nesium bromide.
  • This Grignard reagent is then reacted with the Weinreb amide, N-methyl N-methoxy 1- (tert-butoxycarbon- ylamino) cyclopropane-1-carboxamide, to provide 1- ( tert- butoxycarbonylamino) -1- (benzofurylcarbonyl ) cyclopropane.
  • This ketone is then reduced under standard conditions, typically with sodium borohydride in methanol or ethanol, to provide 1- (tert-butoxycarbonylamino) -1- (benzofuryl (hydroxy- methyl) ) cyclopropane.
  • This alcohol is then converted to the corresponding acetate and reduced to the corresponding methylene by treatment with samarium iodide as previously described.
  • the requisite Weinreb amide, N-methyl N-methoxy 1- ( tert-butoxycarbonylamino) cyclo- propane-1-carboxamide may be prepared from the commercially available 1-amino-l-carboxycyclopropane by standard methods well known in the art.
  • alkoxy groups may be cleaved to provide the corresponding phenols, and primary amines may be diazotized and displaced to provide the corresponding halogenated compounds .
  • the following Preparations and Examples are illustrative of methods useful for the synthesis of the compounds of the present invention.
  • This oil was subjected to silica gel chromatography, eluting with a gradient system of hexane containing from 0- 30% ethyl acetate. Fractions containing the fastest eluting compound were combined and concentrated under reduced pressure to provide 18.1 gm (28%) of 2-bromo-5-methoxyphenol as a clear liquid.
  • the aqueous phase was extracted with three 100 mL portions of diethyl ether.
  • the organic phases were combined and extracted well with 5 N sodium hydroxide.
  • These basic aqueous extracts were combined and cooled in an ice/water bath.
  • the pH of this aqueous solution was adjusted to about 1 with 5 N hydrochloric acid and then extracted with three 100 mL portions of diethyl ether.
  • These ether extracts were combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
  • the resulting residue was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0 to 10% ethyl acetate.
  • reaction mixture was stirred at 0°C for about one hour.
  • the reaction mixture was washed twice with 200 mL portions of water, once with 200 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was subjected to silica gel chromatography, eluting with 1:1 hexane : ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure.
  • the reaction mixture was concentrated under reduced pressure and the residue dissolved in water. This aqueous solution was washed with ethyl acetate and the organic phase discarded. The remaining aqueous phase was made acidic by the addition of aqueous potassium hydrogen sulfate. The aqueous phase was again extracted with ethyl acetate. This organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from a mixture of chloroform and hexane to provide 0.300 gm (92%) of the title compound as a white crystalline solid in two crops.
  • Preparation XXIV 3 isopropy1-5-fluoro-7-bromobenzofuran Beginning with 4-methylpent-2-en-l-yl 2-bromo-4- fluorophenyl ether, the title compound was prepared essentially as described in Preparation XX.
  • Preparation XXV 3 4-dimethyl-5-fluoro-7-bromobenzofuran Beginning with but-2-en-l-yl 2-bromo-4-fluoro-5- methylphenyl ether, the title compound was prepared essentially as described in Preparation XX.
  • the resulting mixture was cooled to 0°C and was then treated with 15 mL 20% aqueous sodium thiosulfate.
  • the resulting slurry was stirred for about 1 hour and then the phases separated.
  • the organic phase was washed sequentially with 3 x 20 mL 20% aqueous sodium thiosulfate followed by 3 x 20 mL saturated aqueous sodium chloride.
  • 3-bromo-4-fluorophenyl allyl ether was placed in a sealed tube and was deoxygenated by bubbling nitrogen through the liquid. The tube was sealed and then heated at 230°C for 3 hours. After cooling to room temperature, the mixture is subjected to silica gel chromatography, eluting with 8:1 hexane: diethyl ether. The faster eluting product isomer was 2-allyl-4-fluoro-5-bromophenol . The slower eluting isomer was 2-allyl-3-bromo-4-fluorophenol . The isomers were isolated in a ratio of 3:2 respectively.
  • reaction mixture was stirred without cooling for two hours.
  • the reaction mixture was then diluted with 500 mL water and the resulting solid collected by filtration.
  • the solid was washed with water until the wash was neutral (pH about 7) .
  • the solid was dried under reduced pressure and was then subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-2% ethyl acetate. Fractions containing the desired compound were combined and concentrated under reduced pressure to provide 57 gm (62%) 2-hydroxy-3-bromo-5-fluoro- 6-chlorobenzaldehyde .
  • the reaction mixture was diluted with 700 mL of hexane and the resulting precipitate removed by filtration.
  • the recovered solid was slurried in 300 mL hexane and filtered 4 times.
  • the combined filtrates were washed with 2 x 500 mL water followed by 500 mL saturated aqueous sodium chloride.
  • the remaining organics were dried over sodium sulfate and concentrated under reduced pressure to provide a residual solid.
  • This solid was slurried and filtered with 4 x 300 mL diethyl ether to remove triphenylphosphine oxide.
  • the filtrate was separated and the organic phase was extracted with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride. The remaining organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane containing 20% ethyl acetate. This solid was subjected to silica gel chromatography, eluting with a gradient of hexane containing from 0-20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from hexane to provide 13.5 gm (56%) of the desired compound.
  • This ketone was converted to 0.082 gm (32%) of l-(7- fluorobenzofur-5-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the hydrochloride salt to provide the title compound.
  • reaction mixture was diluted with 200 mL ethyl acetate, washed sequentially with 100 mL of water and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residual solid was slurried in diethyl ether and filtered, providing 0.14 gm (60%) of the desired compound in two crops .
  • reaction mixture was then stirred for 3 hours at which point 0.03 mL (0.77 mMol) ammonium hydroxide were added. After stirring about 20 hours at room temperature the reaction mixture was concentrated under reduced pressure. The residue was diluted with 300 mL ethyl acetate and washed with sequentially with 100 mL 2 N sodium hydroxide, 200 mL saturated aqueous ammonium chloride, 100 mL water, and 100 mL saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 1:1 hexane: ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.055 gm (28%) of the desired compound.
  • the reaction mixture was partitioned between 300 mL ethyl acetate and 300 mL water. The phases were separated and the aqueous phase was extracted twice with 200 mL ethyl acetate. The organic phases were combined and washed sequentially with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (69%) of the desired compound as a yellow solid.
  • reaction mixture was quenched by addition of 2 mL saturated aqueous ammonium chloride and was then allowed to warm to room temperature.
  • EXAMPLE 29 1- ( 5-fluorobenzofur-7-yl ) -3-aminobutane hydrochloride Nitrogen was bubbled through a mixture of 1.0 gm (4.65 mMol) 5-fluoro-7-bromobenzofuran, 0.61 mL (6.98 mMol) 3- buten-2-ol, 0.057 gm (0.186 mMol) tri (o-tolyl) phosphine, and 0.47 gm (5.58 mMol) sodium bicarbonate in 35 mL N- methylpyrrolidinone for 10 minutes.
  • N-tert-butoxycarbonyl 1- (5- [N' -tert-butoxycarbonyl j amino- benzofur-7-yl) -2-aminopropane
  • the reaction mixture was diluted with 25 mL ethyl acetate and stirred vigorously. The organic phase was decanted off and the process was repeated. The combined organic extracts were combined and concentrated under reduced pressure. The residual oily solid was subjected to flash silica gel chromatography eluting with dichloromethane containing 4% methanol . Fractions containing the desired product were combined and concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in diethyl ether and the solution was then concentrated under reduced pressure to provide 0.121 gm (78%) of the desired compound as an off- white foam.
  • reaction mixture was then allowed to stir at room temperature for about 18 hours at which point it was heated at reflux for 9 hours followed by about 18 hours at room temperature.
  • To this mixture were then added 0.5 mL 50% aqueous sodium hydroxide and 2 mL dioxane and the resulting mixture was stirred at room temperature for about 18 hours.
  • the reaction mixture was then partitioned between 2 mL of water and 25 mL diethyl ether. The organic phase was separated, dried over sodium sulfate, and concentrated under reduced pressure.
  • the residual oil was subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.042 gm (60%) of the desired compound as a colorless oil.
  • EXAMPLE 38 1- (5-hydroxybenzofur-7-yl) -2-aminopropane hydrochloride A mixture of 0.73 gm (2.38 mMol) N-tert-butoxycarbonyl 1- ( 5-methoxybenzofur-7-yl) -2-aminopropane and 3.30 gm (28.52 mMol) pyridine hydrochloride were heated at 170°C in a sealed tube for 15 hours . The mixture was cooled and the residue was dissolved in dichloromethane containing 10% methanol and 1% ammonium hydroxide. The solution was concentrated under reduced pressure and the pyridine remaining in the residue was removed azeotropically by diluting the residue with water and concentrating three times.
  • reaction mixture was allowed to warm to room temperature and was then stirred at room temperature for 30 minutes.
  • the reaction mixture was diluted with 20 volumes of ethyl acetate and was washed sequentially with IN hydrochloric acid, water, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 30% ethyl acetate. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.894 gm (80%) of the desired compound.
  • reaction mixture was then diluted with ethyl acetate and the resulting solution washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
  • the remaining organic phase was concentrated under reduced pressure and the residue subjected to flash silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.723 gm (62%) of the desired compound.
  • This ketone was converted to 0.38 gm (75%) of l-(5- (methoxycarbonyl) benzofur-7-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the oxalate salt to provide the title compound.
  • reaction mixture was then washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was subjected to silica gel chromatography, eluting with dichloromethane containing 1% methanol saturated with ammonia. Fractions containing the desired product were combined and concentrated under reduced pressure to provide 0.164 gm (70%) of the desired compound as a white solid.
  • EXAMPLE 48 1- (N' - [1- (pyridin-4-yl) eth-2-yl] 5-carboxamidobenzofur-7- yl) -2-aminopropane dihydrochloride Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur- 7-yl) -2-aminopropane and 4- (2-ethylamino) pyridine, the title compound was prepared essentially as described in EXAMPLE 46.
  • EXAMPLE 49 1- (N* - [carboxymethyl] 5-carboxamidobenzofur-7-yl) -2- aminopropane trifluoroacetate Beginning with N-tert-butoxycarbonyl 5-carboxybenzofur- 7-yl) -2-aminopropane and glycine tert-butyl ester hydrochloride, the title compound was prepared essentially as described in EXAMPLE 46.
  • This ketone was converted to 1- (4-trifluoromethylbenzo- fur-7-yl) -2-aminopropane essentially as described in Example 1. This amine was converted to the hydrochloride salt to provide 0.13 gm (39%) of the title compound.
  • This ketone was converted to 1- (4-chloro-5-fluoro- benzofur-7-yl) -2-aminopropane essentially as described in Example 1.
  • This amine was converted to the hydrochloride salt to provide 0.080 gm (49%) of the title compound as a white solid.
  • EXAMPLE 68 1- (3-isopropyl-5-fluorobenzofur-7-yl) -2-aminopropane oxalate Beginning with 3-isopropyl-5-fluoro-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
  • EXAMPLE 74 2- (5-fluorobenzofur-7-yl) -1-aminobutane oxalate Beginning with 5-fluoro-7-bromobenzofuran, 2- (5- fluorobenzofur-7-yl) -1-aminobutane was prepared essentially as described in EXAMPLE 39. This amine was treated with oxalic acid to provide the title compound.
  • reaction mixture was quenched by the addition of 0.13 mL (2.13 mMol) iodomethane.
  • the reaction mixture was allowed to warm to room temperature and was diluted with ethyl acetate. This mixture was then washed sequentially with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The remaining organics were concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.16 gm (90%) of the desired compound.
  • EXAMPLE 90 1- (3-pentyl-5-fluorobenzofur-7-yl) -2-aminopropane oxalate Beginning with 3-pentyl-5-fluoro-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
  • EXAMPLE 92 1- (5-fluoro-6-methylbenzofur-7-yl) -2-aminopropane Beginning with 5-fluoro-6-methyl-7-bromobenzofuran, the title compound was prepared essentially as described in EXAMPLE 1.
  • Membrane Preparation AV12 cells stably transfected with the human 5-HT2 c receptors were grown in suspension and harvested by centrifugation, resuspended in 50 mM tris-HCl, pH 7.4, and frozen at -70°C. On the day of assay, an aliquot of cells was thawed, resuspended in 40 mL of 50 mM tris-HCl, pH 7.4, and centrifuged at 39,800 x g for 10 minutes at 4°C . The resulting pellet was resuspended, incubated at 37°C for 10 minutes to remove endogenous serotonin, then centrifuged twice more.
  • Nonlinear regression analysis was performed on the concentration response curves using a four parameter logistic equation described by DeLean (DeLean, et al . , Molecular Pharmacology, 21, 5-16 (1982)). IC50 values were converted to K-j_ values using the Cheng-Prusoff equation (Cheng, et al . , Biochem. Pharmacol., 22, 3099-3108 (1973)). Representative compounds of the present invention were found to have affinity for the 5-HT2 c receptor as measured essentially by the procedure described supra .
  • the 5-HT2c receptor is functionally coupled to a G- protein. Agonist activation of G-protein-coupled receptors results in the release of GDP from the -subunit of the G- protein and the subsequent binding of GTP . The binding of the stable analog [35s]-GTP ⁇ S is an indicator of this receptor's activation.
  • Representative compounds of the present invention were tested in the [35s]-GTP ⁇ S assay and were found to be agonists of the 5-HT2 c receptor.
  • Representative compounds of the present invention were tested in the feeding assay and were found to reduce food consumed by fasting rats.
  • compositions comprising a pharmaceutically acceptable excipient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal .
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e.g. , REMINGTON'S PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols
  • ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art .
  • the compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg/kg.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • Quantity Ingredient (mg/tablet)
  • the active ingredient, starch and cellulose are passed through a No . 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No . 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows :
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No . 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows :
  • a topical formulation may be prepared as follows:
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s) , and the state of the patient .

Abstract

La présente invention concerne des aminoalkylbenzofurannes sérotoninergiques de formule (I), dans laquelle R, R?1, R2, R3, R4, R4', R5, R5' et R12¿ sont tels que définis dans le mémoire descriptif.
PCT/US2000/001342 1999-01-27 2000-01-19 Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c)) WO2000044737A1 (fr)

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CA002361516A CA2361516A1 (fr) 1999-01-27 2000-01-19 Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c))
JP2000595993A JP2002535396A (ja) 1999-01-27 2000-01-19 セロトニン（５−ｈｔ（２ｃ））アゴニストとしてのアミノアルキルベンゾフラン類
AU26198/00A AU2619800A (en) 1999-01-27 2000-01-19 Aminoalkylbenzofurans as serotonin (5-ht(2c)) agonists
EP00904438A EP1149085A1 (fr) 1999-01-27 2000-01-19 Aminoalkylbenzofurannes faisant office d'agonistes de la serotonine (5-ht(2c))
US09/890,311 US7045545B1 (en) 1999-01-27 2000-01-19 Aminoalkylbenzofurans as serotonin (5-HT(2c)) agonists

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US60/117,385 1999-01-27

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US6593330B2 (en) 2000-11-20 2003-07-15 Biovitrum Compounds and their use
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
WO2004019874A2 (fr) * 2002-08-30 2004-03-11 Alcon, Inc. Composes de 5-chroman-5-yl-ethylamine substitues et leur utilisation dans le traitement du glaucome
WO2005044812A1 (fr) * 2003-10-24 2005-05-19 Wyeth A Corporation Of The State Of Delaware Derives de dihydrobenzofuranyle alcanamine servant d'agonistes de 5ht2c
WO2006000902A1 (fr) * 2004-06-25 2006-01-05 Pfizer Products Inc. Composes dihydrobenzofurane et leurs utilisations
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WO2006116150A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives de dihydrobenzofurane et utilisations associees
WO2007030150A1 (fr) * 2005-04-22 2007-03-15 Wyeth Dérivés d’alkanamine de dihydrobenzofuranyle comme agonistes 5ht2c
WO2007132841A1 (fr) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Composé hétérocyclique fusionné et utilisation
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
WO2009063992A1 (fr) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Dérivé de pyridine condensé et son utilisation
EP2108649A1 (fr) 2008-04-10 2009-10-14 Korea Research Institute of Chemical Technology Nouveaux dérivés de bispyridyl carboxamide de l'acide carboxylique de l'indole comme antagonistes du récepteur 5-HT2c
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
WO2011071136A1 (fr) 2009-12-11 2011-06-16 アステラス製薬株式会社 Agent thérapeutique pour la fibromyalgie
WO2012030953A1 (fr) 2010-09-01 2012-03-08 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c dans traitement de troubles améliorés par réduction du taux de noradrénaline
WO2015066344A1 (fr) 2013-11-01 2015-05-07 Arena Pharmaceuticals, Inc. Agonistes du récepteur 5-ht2c et compositions et procédés d'utilisation
WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
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US7247633B2 (en) 2000-11-20 2007-07-24 Biovitrum Ab Pyrimidine compounds and their use
AU2002346671B2 (en) * 2001-12-14 2005-08-11 Alcon, Inc. Aminoalkyl-benzofuran-5-OL compounds for the treatment of glaucoma
WO2003051352A1 (fr) * 2001-12-14 2003-06-26 Alcon, Inc. Composes d'aminoalkyl-benzofuran-5-ol pour le traitement du glaucome
US7005448B2 (en) 2001-12-14 2006-02-28 Alcon, Inc. Aminoalkyl-benzofuran-5-ol compounds for the treatment of glaucoma
WO2004000830A1 (fr) 2002-06-19 2003-12-31 Biovitrum Ab Nouveaux composes, leur utilisation et leur preparation
WO2004019874A3 (fr) * 2002-08-30 2004-07-01 Alcon Inc Composes de 5-chroman-5-yl-ethylamine substitues et leur utilisation dans le traitement du glaucome
WO2004019874A2 (fr) * 2002-08-30 2004-03-11 Alcon, Inc. Composes de 5-chroman-5-yl-ethylamine substitues et leur utilisation dans le traitement du glaucome
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US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
EP2277513A2 (fr) 2003-04-25 2011-01-26 Pfizer Inc. Traitement de l'incontinence avec des 5ht2c agonistes
WO2005044812A1 (fr) * 2003-10-24 2005-05-19 Wyeth A Corporation Of The State Of Delaware Derives de dihydrobenzofuranyle alcanamine servant d'agonistes de 5ht2c
WO2006000902A1 (fr) * 2004-06-25 2006-01-05 Pfizer Products Inc. Composes dihydrobenzofurane et leurs utilisations
EP2248524A2 (fr) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Agents préventifs/remèdes pour l'incontinence de stress et procédé de séléction de ceux-ci
US7507732B2 (en) 2005-03-31 2009-03-24 Pfizer Inc. Cyclopentapyridine and tetrahydroquinoline derivatives
WO2006116151A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives d’alcanamine de benzofuranyle et leurs utilisations comme agonistes 5-ht2c
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WO2006116150A1 (fr) * 2005-04-22 2006-11-02 Wyeth Derives de dihydrobenzofurane et utilisations associees
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US8324246B2 (en) 2008-04-10 2012-12-04 Korea Research Institute Of Chemical Technology Indol carboxylic acid bispyridyl carboxamide derivatives, pharmaceutically acceptable salt thereof, preparation method and composition containing the same as an active ingredient
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WO2019131902A1 (fr) 2017-12-27 2019-07-04 武田薬品工業株式会社 Agent thérapeutique pour incontinence urinaire de stress et incontinence fécale
CN110684000A (zh) * 2019-10-18 2020-01-14 上海皓元医药股份有限公司 苯并呋喃衍生物的制备方法
CN110684000B (zh) * 2019-10-18 2021-08-31 上海皓元医药股份有限公司 苯并呋喃衍生物的制备方法

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