EP0656003A1 - Condensed indole derivatives as 5ht2c and 5ht2b antagonists - Google Patents

Condensed indole derivatives as 5ht2c and 5ht2b antagonists

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Publication number
EP0656003A1
EP0656003A1 EP93917699A EP93917699A EP0656003A1 EP 0656003 A1 EP0656003 A1 EP 0656003A1 EP 93917699 A EP93917699 A EP 93917699A EP 93917699 A EP93917699 A EP 93917699A EP 0656003 A1 EP0656003 A1 EP 0656003A1
Authority
EP
European Patent Office
Prior art keywords
indole
methyl
dihydropyrrolo
pyridylcarbamoyl
hydrogen
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
EP93917699A
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German (de)
English (en)
French (fr)
Inventor
Ian Thomson Smithkline Beecham Pharm. Forbes
Roger Thomas Smithkline Beecham Pharm. Martin
Peter Smithkline Beecham Pharmaceuticals Ham
Thomas Paul Smithkline Beecham Pharm. Blackburn
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Filing date
Publication date
Priority claimed from GB929217674A external-priority patent/GB9217674D0/en
Priority claimed from GB939306461A external-priority patent/GB9306461D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0656003A1 publication Critical patent/EP0656003A1/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

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.
  • 5HT2 receptor antagonists A structurally distinct class of compounds has now been discovered, which compounds have been found to have 5HT2 receptor antagonist activity. Certain compounds of the invention also show 5HT2B receptor antagonist activity, the 5HT2B receptor being previously known as the fundus 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, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, 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.
  • CNS disorders such as anxiety, depression, obsessive compulsive disorders, migraine, anorexia, Alzheimers disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol. nicotine and benzodiazepines,
  • the present invention provides a compound of formula (I) or a salt thereof:
  • P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
  • R 1 is hydrogen or C ⁇ . alkyl;
  • R 2 , R3, R!0 and R 11 are independently hydrogen or C g alkyl, or R ⁇ and R 11 together form a bond, or R 2 and RlO or R3 and R ⁇ together form a C2-6 alkylene chain;
  • R 4 is hydrogen, C g alkyl, halogen, NR 8 R 9 or OR 12 ) where R 8 , R 9 and R 12 are independently hydrogen or C g alkyl;
  • R-5 is hydrogen or C 1. alkyl;
  • R 7 is hydrogen, C ⁇ . alkyl, OR 12 or halogen, where R 12 is hydrogen or C g alkyl; and n is 2 or 3; and the groups R- ⁇ and R 14 are independently hydrogen or Cj.g alkyl.
  • C ⁇ _6 alkyl moieties can be straight chain or branched and are preferably C ⁇ 3 alkyl, such as methyl, ethyl, n- and iso- propyl.
  • Suitable R 4 and R 7 halogens include chloro and bromo.
  • R is hydrogen or C 1.5 alkyl such as methyl, ethyl or propyl.
  • R! is methyl or ethyl.
  • R 2 , R-, R 1 ⁇ and R 1 * are independently hydrogen or Cj.g alkyl, or R*0 and R 1 ! together form a bond, or R 2 and R ⁇ or R and R* together form a
  • R 2 is hydrogen or methyl.
  • R3 is hydrogen.
  • R*0 and R* - are preferably hydrogen. Most preferably RlO and R 1 * form a bond so as to give an indole structure.
  • R 4 is hydrogen, C ⁇ g alkyl, halogen, NR 8 R 9 or OR 12 ? where R 8 , R 9 and R I are independently hydrogen or C 1.5 alkyl.
  • R 4 is hydrogen or methyl.
  • R-- is hydrogen or C ⁇ . ⁇ alkyl.
  • R-5 is hydrogen.
  • R 7 is hydrogen, C ⁇ . ⁇ alkyl, OR 12 or halogen, where R* 2 is hydrogen or C ⁇ _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.
  • P represents a quinoline or isoquinoline residue, or a 5- or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur.
  • Suitable moieties when the ring P is a 5-membered aromatic heterocyclic ring include, for example, isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
  • Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl.
  • P is a quinoline or isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4-position.
  • P is a 4-quinoline or 3-pyridyl group.
  • the urea moiety can be attached to a carbon or any available nitrogen atom of the ring P, preferably it is attached to a carbon atom.
  • the group -(CR 1 3R 14 ) n - forms an ethylene or propylene group each of which can be substituted by C ⁇ galkyl.
  • the group -(CR 1 3R 14 ) n - can be attached to the 4- or 6-position of the indole or indoline ring, preferably it is attached to the 6-position.
  • the group -(CR 13 R 1 ) n - is ethylene.
  • Particularly preferred compounds of formula (I) include: 5-Methyl-l-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f] indole 6-Methyl-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 5,7-Dimethyl- l-(3-pyridylcarbamoyl)-2,3-dmydropyrrolo[2,3-f]indole l-(3-Pyridylcarbamoyl)-2,3-dihydropyrrolo[2,3-f] indole 6-Methyl-3-(4-pyridylcarbamoyl)-2,3-dihydropyrrolo[3,2-e]indole 6-Methyl-3-(2-pyridylcarbamoyl)-2,3-dihydropyr
  • the 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 N-oxides or 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 R 4 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-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- R 2 ', R 3 ', R ⁇ ', R l r R 13' t R 14' R 4' R 5' ⁇ R 7 ⁇ R l, R 2, R 3, R 10, R ll, R 13, R 14 R 4 md 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 13 ', R 14 ', R 4 ', R- ' and R 7 ' when other than R-, R 2 , R 3 , RlO, RU, R* 3 , R 14 , R 4 , R 5 , and R 7 respectively to R
  • R 4 ', R-', 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* , R 2 , R 3 ', R ⁇ ' and R -' as defined in formula (HI), and thereafter optionally and as necessary in any appropriate order, converting any R 1 ', R 2 ', R 3 ', R 10 ', R 1 , R 13 ', R 14 ', R 4 ', R 5 ' and R 7 ' when other than R 1 , R 2 , R 3 , R!0, Rll, Rl , R 14 R 4 , R- and R 7 , to R 1 , R 2 , R 3 , R 10 , R 1 1 , R 13 , R 14 , R 4 , R- and R 7 , interconverting R 1
  • Suitable examples of groups A and R ⁇ include:
  • A is -NR 5 'COL and R 6 is -H
  • A is -NHR 5 ' and R 6 is COL, or
  • A is halogen and R 6 is -CONHR 5 ', 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 dimethylformamide at ambient or elevated temperature.
  • an inert solvent such as dichloromethane at ambient temperature
  • a base such as triethylamine or in dimethylformamide at ambient or elevated temperature.
  • reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
  • an inert solvent such as toluene
  • the cyclisation of the compound of formula (IV) tp prepare indoles (R 0 and R* 1 are a bond) may be effected using standard methodology such as described in Comprehensive Heterocyclic Chemistry 19844, 313 et. seq. or J. Het. Chem. 1988 25 p.l et seq.
  • Examples of the more important routes include the Leimgruber synthesis, the Fischer synthesis, the Japp-Klingemann variation, the Madelung synthesis and the Nordlander synthesis.
  • (ix) C is NHCH2CR 3 '(OR)2 and D is H where R is a C i.galkyl group.
  • Indolines may also be prepared by reduction, e.g. with NaCNBH3, of indoles produced by variants (vi) to (ix) above.
  • reaction variant (v) (Leimgruber synthesis) the compound of formula (IV) is prepared from the 2-methylnitrophenyl urea by treatment with a dialkylacetal of the dialkylformamide OHCNZ2 with heating and the product of formula (IV) cyclised by hydrogenation over a suitable catalyst such as palladium and charcoal optionally under pressure to yield the compound of formula (I) where R- ⁇ R- ⁇ R- ⁇ H.
  • reaction variant (vi) Fischer synthesis
  • the compound of formula (TV) is prepared from the hydrazinophenyl urea by dehydration, preferably by heating, with the appropriate ketone R COCH2R and the product of formula (TV) cyclised by heating with an acid catalyst such as hydrochloric or sulphuric acid.
  • reaction variant (vii) Japp-Klingemann synthesis
  • the compound of formula (TV) is prepared from the aminophenyl urea by diazotisation followed by treatment for example with CH3COCH(CO2X)-CH2R 3 ' where X is Cj_6 alkyl under basic conditions in aqueous alcohol as solvent
  • the product of formula (TV) may then be cyclised as in the Fischer synthesis above.
  • reaction variant (viii) (Madelung synthesis) the compound of formula (IN) is cyclised with base in an inert solvent optionally with heating.
  • reaction variant (ix) (Nordlander synthesis), the compound of formula (IV) is cyclised by heating in a mixture of trifluoroacetic anhydride/acid.
  • R ' , R , 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.
  • 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 N-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_6 alkyl group at the R-5 position by conventional alkylation using 1 molar equivalent of a Cj_6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
  • Rl C ⁇ . ⁇ 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 ⁇ _6 acyl.
  • R 4 halo and R 7 halo may be introduced by selective halogenation of the ring P 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).
  • 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 ⁇ ' 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 triethylaraine.
  • Q is CR i3 Rl L, CR 3 O or CO2R where L is a leaving group and Rl 3 and R i4 are as defined in formula (I), m is 1 or 2, Rl', R 2 ', R 3' , R 7 ', Rl°', Rl -', R 1 -' and Rl 4 ' are as defined in formula (HI) above, R& is a group R! ⁇ as defined in formula (HO) and R is an aryl or C ⁇ alkyl group,
  • 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 (IN), above.
  • compositions 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
  • 5HT2C receptor antagonist activity and certain compounds show 5HT2B antagonist activity.
  • Compounds of formula (I) are therefore believed to be of potential use in the treatment or prophylaxis of anxiety, depression, migraine, anorexia, obsessive compulsive disorders, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • 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 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 20.0 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.
  • the following Examples illustrate the preparation of pharmacologically active compounds of the invention.
  • the following Descriptions illustrate the preparation of intermediates to compounds of the present invention.
  • N-(l-Acetyl-5-indolinyl)-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.
  • N-(l-Acetyl-5-indolinyl)-2-chloroallylamine (Dll) l-Acetyl-5-aminoindoline (Dl) (4.36g, 24.8 mmol), anhydrous potassium carbonate (5.1g, 37 mmol) and 2,3-dichloro-l-propene (4.5 ml, 48.9 mmol) were stirred in dry DMF (50 ml) at 70°C for 16 h. The mixture was then diluted with water (500 ml), and stirred for 10 min. Filtration and air drying then gave the title compound (5.7 lg, 92%) as a dark olive solid.
  • N-(l-Acetyl-5-indolinyl)-2-chloroallylamine (Dl l) (5.71g, 24.8 mmol) and triethylamine (3.8 ml, 27.3 mmol) were stirred in chloroform (100 ml), and trifluoroacetic anhydride (3.8 ml, 27.3 mmol) was added dropwise over 1 min.
  • the mixture was stirred for 1 h, when water (100 ml) was added. This mixture was stirred vigorously for 20 min, acidified with 5 M hydrochloric acid, and separated. The organic portion was dried (Na2S04) and evaporated to give the title compound as a dark oil (7.49 g, 95%), which solidified on standing.
  • N-(l-Acetyl-5-indolinyl)-2-chloro-N-trifluoroacetylallylamine (D12) (7.63 g, 22 mmol) was stirred in polyphosphoric acid (38 g) at 140° C for 1.5h. The mixture was cooled, dispersed in water (200 ml) and extracted with ethyl acetate. The extract was filtered through Kieselguhr, dried (Na2S04) and evaporated to give a dark gum (ca. 3g).
  • the title compound was prepared from l-acetyl-5-ethyl-2,3-dihydropyrrolo[2,3-f] indole (D17) in 100% yield using a procedure similar to that for D6.
  • Formaldehyde (40% aq. solution, 2.8 ml, 36 mmol) and 3M sulphuric acid (5ml, 15 mmol) were stirred in ice. To this was added portionwise a suspension of sodium borohydride (1.66g, 44 mmol) and N-(l-acetyl-5-indolinyl)-2-chloroallylamine (Dll) (3.08g, 12.2 mmol) in tetrahydrofuran (60 ml), maintaining temperature below 20° C. The mixture was then stirred at ambient temperature for 0.25 h, and basified with excess solid sodium hydroxide.
  • sodium borohydride (1.66g, 44 mmol)
  • Dll N-(l-acetyl-5-indolinyl)-2-chloroallylamine
  • N-(l-Acetyl-5-indolinyl)-2-chloro-N-methylallylamine (D21) (2.1g, 7.9 mmol) was stirred in polyphosphoric acid (44g) at 140° C for 24h, cooled, dispersed in water (200 ml), and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and evaporated to give a pink solid. Chromatography on silica gel, eluting with 0-20% ethyl acetate in dichloromethane, gave:
  • 6-Aminoquinoline (5.75g, 40 mmol) and triethylamine (6.7 ml, 48 mmol) were stirred in chloroform (100 ml), and trifluoroacetic anhydride (6.7 ml, 48 mmol) was added over 2 min. The mixture was stirred for 1 h., when water (100 ml) was added. After stirring for 5 min, the gummy precipitate was filtered off, washed with chloroform and water, and dried in vacuo at 50° C. This gave the title compound (7.68g, 80%) as a straw-coloured semi-solid, containing residual triethylamine (NMR).
  • N-(6-Quinolyl)trifluoroacetamide (D25) (6.84g, 28.5 mmol) and nickel chloride hexahydrate (1.36g, 5.71 mmol) were stirred in methanol (100 ml), and sodium borohydride (4.3g, 113 mmol) was added portionwise over 0.5h. After stirring for a further 0.5h, another portion of sodium borohydride (l.Og, 26 mmol) was added. After another 0.5 h, the mixture was evaporated to dryness, partitioned between 5M hydrochloric acid (25 ml) and ethyl acetate (100 ml), and stirred until clear. This mixture was neutralised with excess sodium hydrogen carbonate, and separated.
  • N-(l-Acetyl-1 ⁇ 2 - > 4-tetrahydro-6-quinolyl)trifluoroacetaniide (D27) N-(l,2,3,4-Tetrahydro-6-qumolyl)trifluoroacetamide (D26) (5.64g, 23.1 mmol) and acetyl chloride (2.0 ml, 28 mmol) were stirred in dichloromethane (100 ml) as pyridine (2.25 ml, 28 mmol) was added. The mixture was stirred for 0.5h, when water (100 ml) was added. After vigorous stirring for 0.25 h, it was acidified with 5M hydrochloric acid, and separated. The organic portion was washed with brine, dried (Na2SO4), and evaporated, giving the title compound (5.24 g, 79%) as a cream solid.
  • N-(l-Acetyl-l,2,3,4-tetrahydro-6-quinolyl)trifluoroacetamide (D27) (1.85g, 6.5 mmol) was stirred in ethanol (15 ml), and sodium hydroxide (0.52g, 13.0 mmol) was added in water (3ml). The mixture was stirred at ambient temperature for 0.5 h, and then heated to reflux over 0.25 h. After 0.5 h at reflux, the mixture was cooled, acidified with 5M hydrochloric acid, basified with solid sodium carbonate, diluted with water (100 ml), and extracted with chloroform. The extract was dried (Na2SO4) and evaporated to give the title compound (1.38g, >100%) as a brown oil containing residual chloroform (NMR).
  • Nicotinoyl azide (0.56g, 3.8 mmol) was stirred at reflux under nitrogen in dry toluene (20 ml) for 0.75h, and cooled to ambient temperature.
  • 5-Methyl-2,3-dihydropyrrolo[2,3- fjindole (D6) (0.59g, nominally 3.4 mmol) was added in dichloromethane (20 ml) was stirring, with immediate precipitation. The suspension was stirred for 2.5h, and the solid was then filtered off, washed with 1:1 dichloromethane/toluene, and thoroughly dried. This gave the title compound (0.60g, 60%) as a light grey powder.
  • Example 4 l-(3-PyridylcarbamoyI)-2.3-dihydropyrrolo[2 -f]indole (E4) This material was isolated by chromatography on silica gel, eluting with 0-5% methanol in chloroform, as an impurity in a sample of 5-methyl-l-(3-pyridylcarbamoyl)-2,3- dihydropyrrolo[2,3-f]indole (El). Recrystallisation from ethanol petroleum ether (b.p. 60- 80° C) gave the compound as fine grey needles, m.p. 207-8° C (dec), still containing ethanol of crystallisation. It can also be prepared by hydrolysing D4 and then coupling with 3-pyridylisocyanate.
  • the tide compound was prepared from 4-aminopyridine, l,l'-carbonyld ⁇ midazole, 6- methyl-(2,3-dihydropyrrolo[3,2-e]indole) hydrochloride (D10) and triethylamine in methylene chloride/dimethylformamide.
  • the reaction mixture was poured onto water to afford the title compound in 98% yield, m.p >230° C.
  • the tide compound was prepared from 2-aminopyridine, l,l'-carbonyldiimidazole and 5- methyl-(2,3-dihydropyrrolo[2,3-f]indole) (D7) using a procedure similar to that described for Example 5, in 75% yield, m.p 137-8° C.
  • the tide compound was prepared from 5-ethyl-2,3-dihydropyrrolo[2,3-f]indole (D18) and 3-pyridylisocyanate (prepared in situ from nicotinoyl azide) in 58% yield using a procedure similar to that for El, m.p. 202-203° C.
  • This material was prepared from l-med ⁇ yl-5,6,7,8-tetrahydro-lH-pyrrolo[2,3-g]quinoline (D33) (0.64g, 3.4 mmol), following the procedure of Example 1. This gave a pale orange solid, 0.64g (60%). Recrystallisation from ethanol/petroleum ether (b.p. 60-80° C) gave lustrous pale orange flakes (0.56g), m.p. 154.5-155.5° C.
  • the tide compound was prepared from 2-methyl-4-aminoquinoline, 1,1 -carbonyl d ⁇ midazole, 6-methyl-(2,3-dihydropyr ⁇ olo-[3,2-e]indole)hydrochloride (DIO) and triethylamine, in 76% yield, m.p. > 230° C.
  • the tide compound was prepared from 5-aminoquinoline, 1,1 -carbonyldiimidazole, 6- methyl-(2,3-dihydropyrrolo-[3,2-e]indole)hydrochloride (D10) and triethylamine, in 42% yield, m.p. >240° C.
  • the tide compound was prepared from 3-aminoquinoline, 1,1 -carbonyl d ⁇ midazole, 6- methyl-(2,3-dihydropyrrolo-[3,2-e]-indole hydrochloride (D10) and triethylamine in 53% yield, m.p. 222-4° C.
  • the tide compound was prepared from 2-methyl-4-aminoquinoline, 1,1 -carbonyl d ⁇ midazole and 5-methyl-(2,3-dihydropyrrolo[2,3-f]indole) (D6), in 57% yield, m.p.>240° C.
  • 6-Methyl-8-(N,N-d-m-iediylaminomeu ⁇ yl)-3-(3-pyridylcarbamoyl)-2,3-dihydropyrrolo [3,2- e] indole (D40) (0.5g, 0.0014 moles) was hydrogenated at STP in ethanol (50ml) over 10% palladium on charcoal catalyst (0.5g) for 24hrs then at 50p.s.i. for 4hrs.
  • the tide compound was prepared from 2-aminopyrazine anion (prepared using sodium hydride), l,r-carbonyld ⁇ midazole, and 5-methyl-2,3-dihydropyrrolo[ 2,3-fjindole in dimethylformamide using a procedure sim ⁇ ar to that described for Example 5, in 75% yield, m.p. 196-198°C.
  • the tide compound was prepared by the method of E23, using 5-amino-3- memylisothiazole hydrochloride (0.60g, 4 mmol), CDI (0.7 lg, 4.4 mmol), triethylamine (0.56ml, 4 mmol) and dihydropyrroloindole (D6) (0.69g, 4 mmol). Triethylamine was added only with die isothiazole hydrochloride. After pouring the final mixture into water and filtering off the product the crude material was recrystallised from dichloromethane/methanol petrol to give the tide compound (0.76g, 61%), m.p. 254-255°C.
  • the tide compound was prepared by die method of E23, using 5-aminoquinoline (0.58g, 4 mmol), CDI (0.7 lg, 4.4 mmol), and dihydropyrroloindole (D6) (0.69g, 4 mmol). No triethylamine was used, and the initial reaction mixture was stirred for lh at 0°C and 0.5h at room temperature. After pouring the final mixture into water and filtering off the product the crude material was recrystalUsed from dichloromethane/methane/petrol to give the tide compound (0.48g, 35%), m.p. 240-243°C.
  • the tide compound was prepared from 5-aminoisoquinoline, carbonyl diimidazole and 1- amino-5-methyl- 2,3-dihydropyrrolo [2,3-f]indole, using a procedure sim ⁇ ar to that described for Example 25, in 15% yield, m.p. 245-250°C.
  • Nicotinoyl azide (0.142g, 0.96 mmol) was stirred at reflux under Ar in dry toluene (40 ml) for lh, allowed to cool and 2-methyl-2,3-dihydropyrrolo[2,3-f]indole (D47) (0.15g, 0.87 mmol) in dry toluene (10 ml) was added. The solution was stirred for 1 h, die resulting precipitate filtered off, washed with a sma ⁇ quantity of Et2 ⁇ and dried thoroughly to afford the tide compound (E29) (70 mg, 28%).
  • Nicotinoyl azide (28.7 mg, 1.1 eq.) was stirred at reflux under Ar in dry toluene (40 ml) for lh, a ⁇ owed to cool and 2,5-dimethyl-2,3-dihydropyrrolo[2,3-f]indole (D49) (037g, 1.76 mmol) in dry toluene (10 ml) added.
  • the solution was stirred for lh, the solution evaporated to dryness, and purified by column chromatography (Si ⁇ 2, CHCl3/MeOH 9: 1) to afford the product as a pale yellow oil which was triturated witii Et2 ⁇ to give a pale yeUow so ⁇ d (170 mg).
  • the title compound was prepared from 2-methyl-4-aminopyridine anion (prepared using sodium hydride) 1 , 1 '-carbonyld ⁇ midazole, and 5-methyl-23-dihydropyrrolo[2,3-f]indole in dimediylformamide using a procedure sim ⁇ ar to that described for Example 5, in 45% yield.
  • compositions for oral administration may be prepared by combining the foUowing:
  • the mixture may be compressed to tablets, or filled into hard gelatin capsules.
  • the tablet may be coated by applying a suspension of film former (e.g. HPM ce ⁇ ulose), pigment (e.g. titamum dioxide) and plasticiser (e.g. diethyl phthalate) and drymg d e film by evaporation of the solvent
  • film former e.g. HPM ce ⁇ ulose
  • pigment e.g. titamum dioxide
  • plasticiser e.g. diethyl phthalate
  • drymg d e film by evaporation of the solvent
  • the film coat can comprise 2.0% to 6.0% of the tablet weight preferably about 3.0%.
  • the medicinal compound is dispersed or dissolved in the Uquid carrier, with a thickening agent added, if required.
  • the formulation is then enclosed in a soft gelatin capsule by suitable technology.
  • a pharmaceutical composition for parenteral administration may be prepared by combining the foUowing:
  • 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 ceUs (Ju ⁇ us 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" 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.
  • mCPP m-(chlorophenyl)piperazine
  • TFMPP l-(m-tr ⁇ luoromethylphenyl)piperazine
  • mCPP-induced hypolocomotion was measured in automated locomotion cages of dimensions 56 cm long x ⁇ 6V ⁇ cm wide x 25 cm high and made of black perspex. Two photobeams traversed the widtii of d e cages at either end at ground level. Sequential breaking of these beams aUowed d e measurement of cage transits.
  • mice Male Sprague Dawley rats (200-250g) (Charles River) were housed in groups of six. They were given drugs oraUy lh pretest and 40 mins later mCPP (7 mg kg i.p.). After a further 20 min they were placed in individual automated cages in groups of four under red ⁇ ght in an adjacent room. After 10 min the test was terminated. Reversal of mCPP-induced hypolocomotion was considered as evidence of in vrv ⁇ central 5-HT2C receptor antagonist properties.
  • the compound of Example 2 showed a significant increase in social interaction at doses of 10 mg kg.
  • Rats are trained on a variable interval 30 sec schedule (VT30) to press a lever in order to obtain food reward.
  • the 5 min sessions of the NI30 schedule alternate witii 2-5 min of a schedule (FR5) in which every 5th lever press is foUowed by presentation of a food peUet paired with a 0.5 sec m ⁇ d footshock.
  • the total study lasts approximately 30 mins.
  • Rats typicaUy respond witii high rates of lever pressing under die VD0 schedule and low response rates under die FR5 'conflict' session.
  • Anxiolytic drugs increase the suppressed response rates of rats in a 'conflict' session.
  • Drugs are administered intraperitoneaUy or oraUy to groups of 3-8 rats 30 min before testing. The results are expressed as the percentage increase in the square root of the total number of lever presses in the FR5 'conflict' session. Square root transformation is necessary to norma ⁇ se the data for statistical analysis using parametric
  • the compound of Example 2 showed a significant increase in responding in the 'conflict' session at dose levels in die range 5 mg kg p.o.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heat Sensitive Colour Forming Recording (AREA)
  • Indole Compounds (AREA)
EP93917699A 1992-08-20 1993-07-29 Condensed indole derivatives as 5ht2c and 5ht2b antagonists Ceased EP0656003A1 (en)

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GB9217674 1992-08-20
GB929217674A GB9217674D0 (en) 1992-08-20 1992-08-20 Novel compounds
GB9306461 1993-03-29
GB939306461A GB9306461D0 (en) 1993-03-29 1993-03-29 Novel compounds
PCT/EP1993/002031 WO1994004533A1 (en) 1992-08-20 1993-07-29 Condensed indole derivatives as 5ht2c and 5ht2b antagonists

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GB9306460D0 (en) * 1993-03-29 1993-05-19 Smithkline Beecham Plc Novel compounds
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GB9402542D0 (en) * 1994-02-10 1994-04-06 Smith Kline Beecham Plc Novel compounds
EP0757687A1 (en) * 1994-04-23 1997-02-12 Smithkline Beecham Plc Tricyclic derivatives as 5ht 2c? and 5ht 2b? antagonists
GB9420521D0 (en) * 1994-10-12 1994-11-30 Smithkline Beecham Plc Novel compounds
GB9420999D0 (en) * 1994-10-18 1994-12-07 Smithkline Beecham Plc Novel compounds
US5972937A (en) * 1995-02-02 1999-10-26 Smithkline Beecham P.L.C. Heterocyclic compounds possessing 5HT2C receptor antagonist activity
KR19980701879A (ko) * 1995-02-02 1998-06-25 피터 기딩스 5-히드록시트립타민 수용체 길항제로서의 인돌 유도체
GB9517559D0 (en) * 1995-08-26 1995-10-25 Smithkline Beecham Plc Novel compounds
GB9607219D0 (en) * 1996-04-04 1996-06-12 Smithkline Beecham Plc Novel compounds
GB9612885D0 (en) * 1996-06-20 1996-08-21 Smithkline Beecham Plc Novel compounds
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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
GB9724372D0 (en) * 1997-11-18 1998-01-14 Smithkline Beecham Plc Novel compounds
UA77650C2 (en) 1999-12-06 2007-01-15 Lundbeck & Co As H Use of serotonin reuptake inhibitor in combination with deramcyclane
FR2807754A1 (fr) * 2000-04-13 2001-10-19 Adir Nouveaux derives de cyclobuta-indole carboxamide, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2837823B1 (fr) * 2002-03-27 2005-04-08 Servier Lab Nouveaux derives d'indoline, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2004057338A1 (en) * 2002-12-23 2004-07-08 Bayer Healthcare Ag Diagnostics and therapeutics for diseases assosciated with 5-hydroxytryptamine (serotonin) receptor 2b (5-hteb)
GB0305553D0 (en) * 2003-03-11 2003-04-16 Glaxo Group Ltd Compounds
WO2014049153A1 (en) * 2012-09-28 2014-04-03 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonists of the 5-ht2b receptor for use in the prevention or treatment of spasticity
EP4175637A4 (en) * 2020-07-02 2024-08-07 Purdue Research Foundation Tetrahydro-3h-pyrazolo quinolone and tetrahydro-3h-pyrrolo[3,2-f]quinoline-containing compounds and uses thereof

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JPH08500580A (ja) 1996-01-23
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