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WO1995021844A1 - Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b? - Google Patents

Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b? Download PDF

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Publication number
WO1995021844A1
WO1995021844A1 PCT/EP1995/000427 EP9500427W WO9521844A1 WO 1995021844 A1 WO1995021844 A1 WO 1995021844A1 EP 9500427 W EP9500427 W EP 9500427W WO 9521844 A1 WO9521844 A1 WO 9521844A1
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Prior art keywords
indole
pyrrolo
formula
methyl
alkyl
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PCT/EP1995/000427
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English (en)
Inventor
Ian Thomson Forbes
Graham Elgin Jones
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Smithkline Beecham Plc
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Priority to JP7520951A priority Critical patent/JPH09508637A/ja
Priority to EP95909678A priority patent/EP0743946A1/fr
Publication of WO1995021844A1 publication Critical patent/WO1995021844A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
  • WO 92/05170 describes certain urea derivatives which are described as possessing 5HT 1C receptor antagonist activity.
  • the 5HT 1C receptor has recently been reclassified as the 5HT 2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993].
  • 5HT 2C /5HT 2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the present invention provides a compound of formula (I) or a salt thereof:
  • R 1 is hydrogen or C 1-6 alkyl
  • R 2 , R 3 , R 10 and R 11 are independently hydrogen or C 1 -6 alkyl, or R 10 and R 11 together form a bond, or R 2 and R 10 or R 3 and R 11 together form a C 2-6 alkylene chain;
  • R 4 is hydrogen, C 1 -6 alkyl, C 1 -6 alkoxy, C 1 -6 alkylthio, halogen, nitro, trifluoromethyl, cyano, CO 2 R 12 or CONR 15 R 16 where R 12 , R 15 and R 16 are independently hydrogen or C 1 -6 alkyl, S(O) n R 17 or S(O) n NR 18 R 19 where n is 1 or 2 and R 17 , R 18 and R 19 are independently hydrogen or C 1 -6 alkyl;
  • R 5 is hydrogen or C 1 -6 alkyl
  • R 7 is hydrogen, C 1 -6 alkyl, OR 12 or halogen, where R 12 is hydrogen or C 1 -6 alkyl; and n is 2 or 3; and
  • R 13 and R 14 are independently hydrogen or C 1 -6 alkyl.
  • C 1 -6 alkyl moieties can be straight chain or branched and are preferably C 1-3 alkyl, such as methyl, ethyl, n- and iso- propyl.
  • R 1 is hydrogen or C 1 -6 alkyl such as methyl, ethyl or propyl.
  • R 1 is C 1 -6 alkyl such as methyl.
  • R 2 , R 3 , R 10 and R 11 are independently hydrogen or C 1 -6 alkyl, or R 10 and R 11 together form a bond, or R 2 and R 10 or R 3 and R 11 together form a
  • R 2 is hydrogen.
  • R 3 is hydrogen.
  • R 10 and R 11 are preferably hydrogen.
  • R 4 is hydrogen, C 1 -6 alkyl, C 1 -6 alkoxy, C 1 -6 alkylthio, halogen, nitro, trifluoromethyl, cyano, CO 2 R 12 or CONR 15 R 16 where R 12 , R 15 and R 16 are
  • R 4 is nitro, cyano, halo, carbamoyl, C 1 -6 alkoxy or trifluoromethyl.
  • R 5 is hydrogen or C 1 -6 alkyl.
  • R 5 is hydrogen.
  • R 7 is hydrogen, C 1 -6 alkyl, OR 12 or halogen, where R 12 is hydrogen or
  • R 7 can be attached to any vacant position in the phenyl part of the indole or indoline rings, that is to say, the 4-, 6- or 7-positions of the indole or indoline rings.
  • R 7 is hydrogen.
  • the group -(CR 13 R 14 ) n - forms an ethylene or propylene group each of which can be substituted by C 1 -6 alkyl.
  • the group -(CR 13 R 14 ) n _ can be attached to the 4- or 6-position of the indole or indoline ring, preferably it is attached to the
  • the group -(CR 13 R 14 ) n - is ethylene.
  • Particularly preferred compounds of formula (I) include:
  • Certain compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • R 1 (in an indole) and/or R 5 are hydrogen or when R 4 is hydroxy or NR 8 R 9 and at least one of R 8 and R 9 are hydrogen the compounds of formula (I) may exist tautomerically in more than one form.
  • the invention extends to these and any other tautomeric forms and mixtures thereof.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises (a) the coupling of a compound of formula (II); with a compound of formula (III); wherein A and R 6 contain the appropriate functional group(s) necessary to form the moiety, -NR 5 CO when coupled, wherein R 5' is R 5 as defined in formula (I) or a group convertible thereto, n is as defined in formula (I), and the variables R 1 ' , R 2' , R 3 ' , R 10' , R 11' , R 13' , R 14' , R 4' and R 7' are R 1 , R 2 , R 3 , R 10 , R 11 , R 13 , R 14 R 4 and R 7 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R 1' , R 2' , R 3' , R 10' , R 11 '
  • R 4' , R 5' , R 7 ' , R 13' , and R 14' are as defined in formulae (II) and (III), n is as defined in formula (I), and C and D contain the appropriate functional group(s) necessary to form the indole or indoline ring substituted by R 1 ' , R 2' , R 3' , R 10' and R 11' as defined in formula (III), and thereafter optionally and as necessary in any appropriate order, converting any R 1 ' , R 2' , R 3' , R 10' , R 11 ' , R 13' , R 14' , R 4' , R 5' and R 7' when other than R 1 , R 2 R 3 , R 10 , R 11 , R 13 , R 14 R 4 R 5 and R 7 , to R 1 , R 2 , R 3 , R 10 , R 11 , R 13 , R 14 , R 4 , R 5 and R 7 , interconverting R 1
  • A is -NHR 5' and R 6 is COL, or
  • R 5' is as defined above and L is a leaving group.
  • suitable leaving groups L include imidazole, halogen such as chloro or bromo or phenoxy or phenylthio optionally substituted for example with halogen.
  • reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient temperature.
  • reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in
  • Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis, the Japp-Klingemann variation, the Madelung synthesis and the
  • Indolines may also be prepared by reduction, e.g. with NaCNBH3, of indoles produced by variants (vi) to (ix) above.
  • reaction variant (vi) Fischer synthesis
  • the compound of formula (IV) is prepared from the hydrazinophenyl urea by dehydration, preferably by heating, with the appropriate ketone R 2' COCH 2 R 3' and the product of formula (IV) cyclised by heating with an acid catalyst such as hydrochloric or sulphuric acid.
  • reaction variant (vii) Japp-Klingemann synthesis
  • (IV) is prepared from the aminophenyl urea by diazotisation followed by treatment for example with CH 3 COCH(CO 2 X)-CH 2 R 3' where X is C 1-6 alkyl under basic conditions in aqueous alcohol as solvent.
  • the product of formula (IV) may then be cyclised as in the Fischer synthesis above.
  • reaction variant (viii) (Madelung synthesis) the compound of formula (IV) is cyclised with base in an inert solvent optionally with heating.
  • reaction variant (ix) ( ⁇ ordlander synthesis)
  • the compound of formula (IV) is cyclised by heating in a mixture of trifluoroacetic anhydride/acid.
  • Suitable examples of groups R 2' , R 3' , R 4' , and R 7' which are convertible to R 2 , R 3 , R 4 , and R 7 alkyl groups respectively, include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventional reduction, such as using sodium borohydride in an inert solvent followed by
  • Hydrogen substituents may be obtained from
  • alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis
  • R 4 is hydroxy it is preferably protected in the compound of formula (II) as, for example, benzyl which is removed by hydrogenation.
  • Suitable examples of a group R 1' which is convertible to R 1 include typical
  • ⁇ -protecting groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxybenzyl which are converted to R 1 hydrogen using conventional conditions.
  • Suitable examples of a group R 5' which is convertible to R 5 include
  • alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R 5 is hydrogen using conventional conditions.
  • R 1 , R 2 and R 3 are C 1-6 alkyl and R 5 is hydrogen it is possible to introduce a C 1 -6 alkyl group at the R 5 position by conventional alkylation using 1 molar equivalent of a C 1-6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
  • R 1 C 1-6 alkyl groups may also be introduced by conventional alkylation, for example using a C 1-6 alkyl halide and base such as sodium hydride, or by reduction of C 1-6 acyl.
  • R 4 halo and R 7 halo may be introduced by selective halogenation of the benzene ring or indole/indoline ring respectively using conventional conditions.
  • Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T.W. 'Protective groups in organic synthesis' New York, Wiley (1981).
  • A is amino, with phosgene or a phosgene equivalent, in the presence of excess base in an inert solvent.
  • A is acylazide (i.e. CON 3 ), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70 262).
  • A is CONH 2 , via the nitrene intermediate using conventional conditions.
  • Compounds of formula (II) in which A is -NR 5 COL may be prepared by reacting a compound of formula (II) in which A is -NHR 5' with phosgene or a phosgene equivalent, in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as triethylamine.
  • Q is CR 13 R 14 L, CR 13 O or CO 2 R where L is a leaving group and R 13 and R 14 are as defined in formula (I), m is 1 or 2, R 1' , R 2' , R 3' , R 7' , R 10' , R 11' , R 13' and R 14' are as defined in formula (III) above, R ⁇ ' is a group R 6 as defined in formula (III) and R is an aryl or
  • R 6' , R 7' , R 13' , R 14' and n are as defined in formula (V) and C and D are as defined in formula (IV) above.
  • the cyclisation of a compound of formula (V) may be suitably carried out in an inert solvent at ambient or elevated temperatures, optionally in the presence of a base. Reduction may be carried out using conventional reduction techniques.
  • the cyclisation of a compound of formula (VI) may be suitably carried out using the procedures outlined for the cyclisation of a compound of formula (IV), above.
  • Novel intermediates of formulae (III) and (IV) also form part of the invention.
  • salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT 2C receptor antagonist activity, and certain compounds are potential 5HT 2B antagonists.
  • Compounds of the invention are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis the above disorders.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 70.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.01 to 100 mg; and such therapy may extend for a number of weeks or months.
  • N-(1-Acetyl-5-indolinyl)-2,2-diethoxyethylamine (D2) (6.5 lg, 22 mmol) was added to an ice-cold, stirred mixture of trifluoroacetic acid (25 ml) and trifluoroacetic anhydride (25 ml). The mixture was stirred at 0°C under nitrogen for 0.5h, after which time further trifluoroacetic acid (40 ml) was added. The mixture was then heated at reflux for 64h, cooled, and evaporated to dryness. Chromatography on silica gel using ethyl
  • the title compound was prepared in 55% yield from 2,3-dihydro-5-methyl-1H-pyrrolo[2,3-f]indole (D6) and3-trifluoromethylphenyl isocyanate.
  • the title compound was prepared by the procedure of Example 1, starting with ethyl 3-aminobenzoate (0.375g, 2.3 mmol), carbonyldiimidazole (0.38g, 2.3 mmol), triethylamine (0.32 ml, 2.3 mmol) and pyrrolo[2,3-flindole (D6, 0.39g, 2.3 mmol). Crude product was recrystallised from dichloromethane/petrol to give the title compound (0.55g, 66%) m.p. 190-191° C
  • the title compound was prepared by the procedure of Example 1, starting with 3-aminobenzamide (0.30g, 2.2 mmol), carbonyldiimidazole (0.36g, 2.2 mmol), triethylamine (0.31 ml, 2.2 mmol) and pyrrolo [2,3-fjindole (D6, 0.38g, 2.2 mmol). Recrystallisation from dichloromethane/methanol gave the title compound (0.29, 39%), m.p. 230-235° C.
  • the methoxy compound (E13) was reduced with sodium cyanoborohydride in acetic acid according to the procedure of Example 3. Chromatography in 2%
  • 5-HT 2C antagonists may have a number of therapeutic indications including the treatment of anxiety, migraine, depression, feeding disorders and obsessive compulsion disorders. (Curzon and Kennett, 1990; Fozard and Gray, 1989) and Alzheimer's Disease (Lawlor, 1989, J. Arch. Gen. Psychiat. Vol. 46 p.542).
  • the affinity of test drugs for the 5-HT 2C binding site can be determined by assessing their ability to displace [ 3 H]-mesulergine from 5-HT 2C clones expressed in 293 cells (Julius et al, 1988). The method employed was similar to that of Pazos et al, 1984.
  • the cells suspension 400ml was incubated with [ 3 H]-mesulergine (0.5nM) in Tris HCl buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (10 -6 M). Ten concentrations of test drug (3 ⁇ 10 -9 to 10 -4 M final concentration) were added in a volume of 50ml. The total assay volume was 500ml. Incubation was stopped by rapid filtration using a Brandel cell harvester and radioactivity measured by scintillation counting. The IC 50 values were determined using a four parameter logistic program (DeLean 1978) and the pK i (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where:
  • Kd Affinity of mesulergine for 5-HT 2C binding sites.

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Abstract

Composés répondant à la formule (I), dans laquelle R?2, R3, R10 et R11¿, indépendamment les uns des autres, représentent hydrogène ou alkyle, ou R?10 et R11¿, pris ensemble, forment une liaison, ou R?2 et R10 ou R3 et R11¿, pris ensemble, forment une chaîne alkylène C¿2-6?; et n ¸ 5 2 ou 3. Les composés de la formule (I) présentent une activité antagoniste des récepteurs de 5HTC2C, et certains composés sont des antagonistes potentiels de 5HT2B. Lesdits composés seraient susceptibles d'être utilisés dans le traitement des affections du système nerveux central telles que l'angoisse, la dépression, l'épilepsie, les troubles obsessionnels compulsifs, la migraine, la maladie d'Alzheimer, les troubles du sommeil, les troubles de l'alimentation tels que l'anorexie et la boulimie, les crises de panique, le sevrage d'une drogue telle que la cocaïne, l'éthanol, la nicotine et les benzodiazépines, la schizophrénie, ainsi que les troubles associés aux traumatismes rachidiens et/ou aux traumatismes crâniens tels que l'hydrocéphalie. On s'attend également à ce que les composés précités soient utilisables dans le traitement de certains troubles gastro-intestinaux tels que le côlon irritable, et des maladies touchant les vaisseaux de petit calibre, par exemple la rétinopathie à ÷dème maculaire.
PCT/EP1995/000427 1994-02-10 1995-02-06 Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b? WO1995021844A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7520951A JPH09508637A (ja) 1994-02-10 1995-02-06 ５ｈｔ２ｂレセプタ拮抗薬縮合インドール
EP95909678A EP0743946A1 (fr) 1994-02-10 1995-02-06 Indoles condenses a titre d'antagonistes des recepteurs de 5ht 2b?

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GB9402542A GB9402542D0 (en) 1994-02-10 1994-02-10 Novel compounds
GB9402542.6 1994-02-10

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023769A2 (fr) * 1995-02-02 1996-08-08 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
WO1998024785A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht
WO2006044762A2 (fr) * 2004-10-15 2006-04-27 Bayer Pharmaceuticals Corporation Derives tetrahydro-5h-pyrimido[4,5-d]azepine convenant pour le traitement de maladies associees au recepteur 5-ht2c
KR100843352B1 (ko) * 2007-01-30 2008-07-03 한국과학기술연구원 세로토닌 수용체 5-ＨＴ2ａ 또는 5-ＨＴ2ｃ의 길항제로활성을 갖는 1,2-다이하이드로-1-옥소프탈라지닐 피페라진화합물 및 이의 제조방법
WO2009125923A3 (fr) * 2008-04-10 2009-12-03 Korea Reserach Institute Of Chemical Technology Nouveaux dérivés de bispyridyl carboxamide d'acide indole carboxylique, leurs sels pharmaceutiquement acceptables, procédé de préparation et composition les contenant en tant d'ingrédient actif

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
P. FLUDZINSKI ET AL.: "2,3-Dialkyl(dimethylamino)indoles: Interaction with 5HT1, 5HT", and rat stomach fundal serotonin receptors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 111, WASHINGTON US, pages 2415 - 2418 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023769A2 (fr) * 1995-02-02 1996-08-08 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
WO1996023769A3 (fr) * 1995-02-02 1996-10-24 Smithkline Beecham Plc Composes heterocycliques possedant une activite antagoniste vis-a-vis du recepteur de 5ht¿2c?
US5972937A (en) * 1995-02-02 1999-10-26 Smithkline Beecham P.L.C. Heterocyclic compounds possessing 5HT2C receptor antagonist activity
WO1998024785A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht
WO2006044762A2 (fr) * 2004-10-15 2006-04-27 Bayer Pharmaceuticals Corporation Derives tetrahydro-5h-pyrimido[4,5-d]azepine convenant pour le traitement de maladies associees au recepteur 5-ht2c
WO2006044762A3 (fr) * 2004-10-15 2006-08-03 Bayer Pharmaceuticals Corp Derives tetrahydro-5h-pyrimido[4,5-d]azepine convenant pour le traitement de maladies associees au recepteur 5-ht2c
KR100843352B1 (ko) * 2007-01-30 2008-07-03 한국과학기술연구원 세로토닌 수용체 5-ＨＴ2ａ 또는 5-ＨＴ2ｃ의 길항제로활성을 갖는 1,2-다이하이드로-1-옥소프탈라지닐 피페라진화합물 및 이의 제조방법
WO2009125923A3 (fr) * 2008-04-10 2009-12-03 Korea Reserach Institute Of Chemical Technology Nouveaux dérivés de bispyridyl carboxamide d'acide indole carboxylique, leurs sels pharmaceutiquement acceptables, procédé de préparation et composition les contenant en tant d'ingrédient actif

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GB9402542D0 (en) 1994-04-06
JPH09508637A (ja) 1997-09-02
EP0743946A1 (fr) 1996-11-27

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