EP0743946A1 - Indoles condenses a titre d'antagonistes des recepteurs de 5ht 2b? - Google Patents

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

Info

Publication number
EP0743946A1
EP0743946A1 EP95909678A EP95909678A EP0743946A1 EP 0743946 A1 EP0743946 A1 EP 0743946A1 EP 95909678 A EP95909678 A EP 95909678A EP 95909678 A EP95909678 A EP 95909678A EP 0743946 A1 EP0743946 A1 EP 0743946A1
Authority
EP
European Patent Office
Prior art keywords
indole
pyrrolo
formula
methyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP95909678A
Other languages
German (de)
English (en)
Inventor
Ian Thomson SmithKline Beecham Phar. FORBES
Graham Elgin SmithKline Beecham Phar. JONES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0743946A1 publication Critical patent/EP0743946A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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 5HTJC receptor antagonist activity.
  • the 5HT ⁇ £ receptor has recently been reclassified as the 5HT2C receptor [P. Hartig et al., Trends in Pharmacological Sciences (TIPS) 1993].
  • 5HT2C 5HT2B 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! is hydrogen or C ⁇ _ alkyl
  • R 2 , R3 5 R10 anc i R11 are independently hydrogen or C ⁇ _ ⁇ alkyl, or RlO and R * together form a bond, or R 2 and R 0 or R3 and R* * together form a C2-6 alkylene chain;
  • R is hydrogen, C ⁇ _(_ alkyl, C ⁇ . alkoxy, C ⁇ . alkylthio, halogen, nitro, trifluoromethyl, cyano, CO2R 12 or CONR 15 R 16 wht e R 12 , R 15 and R 16 are independently hydrogen or C ⁇ _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 ⁇ _6 alkyl; R5 is hydrogen or C ⁇ _(. alkyl;
  • R 7 is hydrogen, Cj.g alkyl, OR 12 or halogen, where R* 2 is hydrogen or Cj.g alkyl; and n is 2 or 3; and the groups R ⁇ and R - ⁇ are independently hydrogen or C g alkyl.
  • C j .g alkyl moieties can be straight chain or branched and are preferably C1-.3 alkyl, such as methyl, ethyl, n- and iso- propyl.
  • R* is hydrogen or C ⁇ _(- alkyl such as methyl, ethyl or propyl.
  • R! is Ci.galkyl such as methyl.
  • R 2 , R ⁇ , R10 and R * are independently hydrogen or Cj.g alkyl, or R ⁇ and R! together form a bond, or R 2 and R*0 or R3 and R 1 together form a C2-6 alkylene chain.
  • R 2 is hydrogen.
  • R ⁇ is hydrogen.
  • R*0 and R ⁇ are preferably hydrogen.
  • R 4 is hydrogen, C ⁇ _ - alkyl, C _ alkoxy, Cj_6 alkylthio, halogen, nitro, trifluoromethyl, cyano, CO2R 12 or CONR 15 R 16 where R 12 , R 15 and R 16 are independently hydrogen or C .
  • R 4 is nitro, cyano, halo, carbamoyl, Cj-galkoxy or trifluoromethyl.
  • R ⁇ is hydrogen or Cj.g alkyl.
  • R ⁇ is hydrogen.
  • R 7 is hydrogen, Cj.g alkyl, OR 12 or halogen, where R* is hydrogen or Cj_6 alkyl.
  • the group 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 14) ⁇ _ forms an ethylene or propylene group each of which can be substituted by Cj.galkyl.
  • the group -(CR ⁇ Rl4) n _ can be attached to the 4- or 6-position of the indole or indoline ring, preferably it is attached to the 6-position.
  • Particularly preferred compounds of formula (I) include: 2,3-Dihydro-5-methyl-l-(3-nitrophenylcarbamoyl)-lH-pyrrolo [2,3-f]indole, l-(3-Cyanophenylcarbamoyl)-2,3-dihydro-5-methyl-lH-pyrrolo[2,3-f] indole, 5-Methyl-l-(3-nitrophenylcarbamoyl)-2,3,6,7-tetrahydro-lH-pyrrolo[2,3-flindole, l-(3-Cyanophenylcarbamoyl)-5-methyl-2,3,6,7-tetrahydro-lH-pyrrolo[2,3-f] indole, 2,3-Dihydro-5-methyl-l-(3-trifluoromethylphenylcarbamoyl)-lH-pyrrolo[2,3-f]indole
  • 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.
  • Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term 'compound of formula (I)' also includes these forms.
  • R! (in an indole) and/or R ⁇ are hydrogen or when R4 is hydroxy or NR 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 and R*> contain the appropriate functional group(s) necessary to form the moiety, -NR ⁇ CO when coupled, wherein R ⁇ ' is R ⁇ as defined in formula (I) or a group convertible thereto, n is as defined in formula (I), and the variables R*', R 2 , R , RIO , Rll', Rl3', Rl4', R 4' and R 7' are Rl, R 2 , R3, RIO, R11, R 13 f R 14 R4 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 ', R 2 ', R 3 , R 10 ', Rl l', R 13 ', R 14 ', R 4' , R5 " 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 respectively to R 1 , R 1
  • R 4 , R ⁇ , R 7 , R* 3 , and R ⁇ 4' 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 ' , R 2 , R 3 , R ⁇ O and R ⁇ ' 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 1 1 ' , R 13' , R 14' , R 4' , R 5' and R 7' when other than R 1 , R 2 R 3 , RlO, Rl 1, Rl 3 , Rl 4 R4 R5 and R 7, to R l, R 2 R 3, R 10, R 11, R 13, R14 R4 R5 and R 7 , interconverting R 1 , R 2 , R 3 , R 10 , R 1 1 , R 1
  • A is -NHR 5 ' and R 6 is COL, or wherein R ⁇ ' 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 dimethylforma ide at ambient or elevated temperature.
  • an inert solvent such as dichloromethane at ambient temperature
  • a base such as triethylamine or in dimethylforma ide at ambient or elevated temperature.
  • Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis, the Japp-Klingemann variation, the Madelung synthesis and the Nordlander synthesis.
  • Examples of the groups C and D in the preparation of indoles include:
  • C is NR ! ' COR 2' and D is CH 2 R 3' .
  • 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 COCH2R 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 CH3COCH(CO2X)-CH2R 3 where X is C 1.5 alkyl under basic conditions in aqueous alcohol as solvent.
  • the product of formula (IN) 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. It will be appreciated that when D is hydrogen, either or both indole isomers may be formed during the cyclisation process.
  • 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 hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be converted to hydrogen by hydrolysis and decarboxylation. When 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 - ⁇ which is convertible to Rl include typical
  • ⁇ -protecting groups such as alkoxycarbonyl, in particular t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl and para-methoxybenzyl which are converted to R ⁇ hydrogen using conventional conditions.
  • Suitable examples of a group R ⁇ ' which is convertible to R ⁇ > include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to R ⁇ is hydrogen using conventional conditions.
  • R*, R 2 and R 3 are C _ alkyl and R ⁇ is hydrogen it is possible to introduce a Cj.g alkyl group at the R ⁇ position by conventional alkylation using 1 molar equivalent of a C j.g alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
  • R* Cj. ⁇ alkyl groups may also be introduced by conventional alkylation, for example using a C ⁇ _(. alkyl halide and base such as sodium hydride, or by reduction of C ⁇ _ 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. It should be appreciated that it may be necessary to protect any R to R 2 hydrogen variables which are not required to be interconverted.
  • 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).
  • Compounds of formula (II) in which A is -NR ⁇ COL may be prepared by reacting a compound of formula (II) in which A is -NHR ⁇ ' 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.
  • R ⁇ ' , R 7 ', R ⁇ 3 ', R ⁇ 4' 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 5HT2 receptor antagonist activity, and certain compounds are potential 5HT2B 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 in preparing solutions, 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 accomplished by filtration.
  • 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.
  • no unacceptable toxicological effects are expected with the compounds of the invention.
  • N-(l-Acetyl-5-indoIinyl)-2,2-diethoxyethylamine (D2) l-Acetyl-5-aminoindoline (Dl) (9.33g, 53 mmol), bromoacetaldehyde diethyl acetal (6.0 ml, 40 mmol) and sodium hydrogen carbonate (4.58g, 54 mmol) was stirred at reflux under nitrogen for 64h. Further acetal (2.0 ml, 13 mmol) was then added, and reflux was continued for a further 24h. The mixture was cooled, filtered, and evaporated to near- dryness. Chromatography on silica gel using ethyl acetate/petroleum ether (b.p.
  • N-(l-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 acetate/chloroform (0-60% ethyl acetate) then gave the title compound (6.28, 89%) as a light cream solid which darkened slightly on standing.
  • the title compound was prepared by the procedure of Example 1, starting with 3- aminobenzonitrile (0.26g, 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). Chromatography as before gave the title compound (0.28g, 40%), m.p. 199-200° C.
  • the title compound was prepared in 85% yield from the indole E5 using a procedure similar to that for E3 followed by salt formation using maleic acid, m.p. 160°C (dec).
  • 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 title compound was prepared by the procedure of Example 1, starting with 3- chloroaniline (0.28g, 2.2 mmol), carbonyldiimidazole (0.36g, 2.2 mmol) and pyrrolo[2,3- f]indole (D6, 0.38g, 2.2 mmol), with no triethylamine. Chromatography in 2% methanol/dichloromethane and recrystallisation from methanol gave the title compound (0.44g, 61%), m.p. 156-167° C.
  • the methoxy compound (El 3) was reduced with sodium cyanoborohydride in acetic acid according to the procedure of Example 3. Chromatography in 2% methanol/dichloromethane and recrystallisation from dichloromethane/petrol gave the tide compound, m.p. 152-154° C.
  • the title compound was prepared by the procedure of Example 1 , starting with N,N- dimethyl-l,3-phenylenediamine dihydrochloride (0.46g, 2.2 mmol), carbonyldiimidazole (0.36g, 2.2 mmol), triethylamine (0.62 ml, 4.4 mmol) and pyrrolo [2,3-f]indole (D6, 0.38g, 2.2 mmol). Chromatography in 2% methanol/dichlorometfiane and recrystallisation from dichloromethane/petrol gave the title compound (0.24g, 33%), m.p. 167-170° C.
  • 5-HT2C 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-HT2C binding site can be determined by assessing their ability to displace [ 3 H]-mesulergine from 5-HT2C 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 HC1 buffer (pH 7.4) at 37°C for 30 minutes. Non-specific binding was measured in the presence of mianserin (lO' ⁇ M). Ten concentrations of test drug (3 x 10" 9 to 10" 4 M final concentration) were added in a volume of 50ml. The total assay volume was 500ml.
  • Kd Affinity of mesulergine for 5-HT2C binding sites.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Toxicology (AREA)
  • Pain & Pain Management (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

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.
EP95909678A 1994-02-10 1995-02-06 Indoles condenses a titre d'antagonistes des recepteurs de 5ht 2b? Ceased EP0743946A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9402542 1994-02-10
GB9402542A GB9402542D0 (en) 1994-02-10 1994-02-10 Novel compounds
PCT/EP1995/000427 WO1995021844A1 (fr) 1994-02-10 1995-02-06 Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b?

Publications (1)

Publication Number Publication Date
EP0743946A1 true EP0743946A1 (fr) 1996-11-27

Family

ID=10750154

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95909678A Ceased EP0743946A1 (fr) 1994-02-10 1995-02-06 Indoles condenses a titre d'antagonistes des recepteurs de 5ht 2b?

Country Status (4)

Country Link
EP (1) EP0743946A1 (fr)
JP (1) JPH09508637A (fr)
GB (1) GB9402542D0 (fr)
WO (1) WO1995021844A1 (fr)

Families Citing this family (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?
JP2001508767A (ja) * 1996-12-02 2001-07-03 藤沢薬品工業株式会社 ５―ｈｔ拮抗作用を有するインドール―ウレア誘導体
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
KR101062376B1 (ko) * 2008-04-10 2011-09-06 한국화학연구원 신규 인돌 카르복실산 비스피리딜 카르복사마이드 유도체,이의 제조방법 및 이를 유효성분으로 함유하는 조성물

Family Cites Families (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
NZ254785A (en) * 1992-08-20 1995-09-26 Smithkline Beecham Plc Heterocyclically-condensed indoles and medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9521844A1 *

Also Published As

Publication number Publication date
WO1995021844A1 (fr) 1995-08-17
GB9402542D0 (en) 1994-04-06
JPH09508637A (ja) 1997-09-02

Similar Documents

Publication Publication Date Title
US5508288A (en) Indole derivatives as 5HT1C antagonists
US6787535B2 (en) Indole derivatives with 5HT6 receptor affinity
US5834493A (en) Indole derivatives as 5-HT1A and/or 5-HT2 ligands
US5478934A (en) Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands
US5866586A (en) CNS-active pyridinylurea derivatives
KR20020030126A (ko) ５―ｈｔ１ｂ 길항제로서의 피페라진 유도체
US6391891B1 (en) Bicyclic compounds as ligands for 5-HT1 receptors
WO1994004533A1 (fr) DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?
NZ230068A (en) Indazole-3-carboxylic acid esters and amides of diaza compounds having 6,7, or 8 ring members: preparatory processes and pharmaceutical compositions
CA2157998A1 (fr) Composes pharmaceutiques
JPH09502177A (ja) ５ｈｔ１ｄレセプター拮抗薬用インドールおよびインドリン誘導体
WO1997008167A1 (fr) Antagonistes des recepteurs 5ht2c et 5ht¿2b?
US5563147A (en) Serotonerbic tetrahydropyridoindoles
CA1296730C (fr) Derives 6,7,8,9-tetrahydropyrido[1,2-a]indole
JP2002114789A (ja) アザビシクロアルカン誘導体とその治療的使用
SK130694A3 (en) 1-£2h-1-benzopyran-2-on-8-yl| pyperazine derivatives, method of their production, pharmaceutical agents containing these compounds as effective matters and their using
US20040053956A1 (en) Isoquinoline derivatives useful in the treatment of cns disorders
NZ205786A (en) Heterocyclic-substituted phenylindene derivatives and pharmaceutical compositions
WO1995021844A1 (fr) Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b?
AU725817B2 (en) Pharmaceutical composition containing a 5HT2c antagonist and a D2 antagonist
EP0220873B1 (fr) Imides bicycliques condensées à activité psychotrope
US6031097A (en) 1-(N-(arylalkylaminoalkyl) aminoisoquinolines; a new class of dopamine receptor subtype specific ligands
US20010053783A1 (en) Pharmaceutical compounds
WO2000006575A2 (fr) Nouveaux composes
JPH02502190A (ja) 精神作用薬活性を有する多環式アミン

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19960827

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB IT LI NL

17Q First examination report despatched

Effective date: 19970303

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 19970824