WO2001029029A1 - Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists - Google Patents

Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists Download PDF

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Publication number
WO2001029029A1
WO2001029029A1 PCT/EP2000/010149 EP0010149W WO0129029A1 WO 2001029029 A1 WO2001029029 A1 WO 2001029029A1 EP 0010149 W EP0010149 W EP 0010149W WO 0129029 A1 WO0129029 A1 WO 0129029A1
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Prior art keywords
indol
benzo
tetrahydro
butyl
compound
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PCT/EP2000/010149
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French (fr)
Inventor
Steven Mark Bromidge
Andrew Derrick Gribble
Peter John Lovell
Jason Witherington
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Smithkline Beecham P.L.C.
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Priority claimed from GBGB9924628.2A external-priority patent/GB9924628D0/en
Priority claimed from GB0006168A external-priority patent/GB0006168D0/en
Priority claimed from GB0018952A external-priority patent/GB0018952D0/en
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to AU10256/01A priority Critical patent/AU1025601A/en
Priority to EP00971384A priority patent/EP1222185A1/en
Priority to JP2001531828A priority patent/JP2003512372A/en
Publication of WO2001029029A1 publication Critical patent/WO2001029029A1/en
Priority to HK02109226.5A priority patent/HK1049151A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
  • Kikuchi et al. J. Med. Chem., 1999, 42, 533 describes tetrahydrobenzindolone compounds as selective antagonists of the 5-HT7 receptor.
  • Patent applications WO 98/00400, WO 99/33804 and WO 99/54303 also disclose tetrahydrobenzindolone compounds as 5-HT ⁇ receptor antagonists. Such compounds are claimed to be useful in the treatment of various CNS diseases.
  • a structurally novel class of compounds has now been found which also possess 5-HT7 receptor activity.
  • the present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R.1 is halogen, C ⁇ alkyl, hydroxy, C galkoxy, Ci-galkylthio, Cj-galkylsulphinyl, C j -galkylsulphonyl, amino, mono- or di-Cj-galkylamino, carboxy, carboxamido, hydroxyC ⁇ -galkyl, mono- or di-Ci-galkylaminocarbonyl, sulphonamido, mono- or di-Ci-galkylaminosulphonyl or C j -6alkoxycarbonyl; R2 is hydrogen, C 1 -6 l yl or arylC ⁇ - alkyl; p is 0, 1, 2 or 3;
  • R3 is hydrogen or C ⁇ galkyl; n is 2, 3, 4, 5 or 6;
  • A is nitrogen, carbon or CH, is a single bond when A is nitrogen or CH or
  • R4 is halogen, Ci- ⁇ lkyl, cyano, CF3, C ⁇ - cycloalkyl, Cj-galkoxy, hydroxy, amino, mono- or di-C 1 -galkylamino, acylamino, nitro, C i-galkoxycarbonyl, Cj-galkylthio, Ci-galkylsulphinyl, Ci-galkylsulphonyl, sulphamoyl, mono- and di-C ⁇ -5alkylsulphamoyl, carbamoyl, mono- and di-Cj-galkylcarbamoyl,
  • C ⁇ alkyl groups whether alone or as part of another group may be straight chain or branched.
  • the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • the term 'aryl', whether alone or as part of another group, is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl. Such aryl groups may be optionally substituted by one or more C ⁇ alkyl, halogen, CF3 or C ⁇ -galkoxy.
  • R ⁇ is preferably halogen (particularly fluorine or chlorine) or a C ⁇ alkyl (particularly methyl).
  • R* may be the same or different.
  • p is 0 or 1, most preferably 0.
  • R ⁇ is hydrogen
  • n is 4 or 5, most preferably 4.
  • R ⁇ is hydrogen
  • X is N.
  • Y is O, S or NH;
  • R ⁇ is preferably halogen (particularly fluorine or chlorine), a C ⁇ alkyl (particularly methyl), C ⁇ _6 lkoxy (particularly methoxy), CF3 or hydroxy.
  • a preferred site for substitution of R ⁇ groups is at the 4, 5 or 6 position of the benzo fused heteroaryl ring.
  • R ⁇ may be the same or different.
  • m is 0 or 1.
  • Preferred compounds of this invention include examples El - E41 (as shown below) or a pharmaceutically acceptable salt thereof.
  • Particularly preferred compounds of this invention include: 2a- ⁇ 4-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-butyl ⁇ -2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one,
  • the compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
  • inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid
  • organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and 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 invention also extends to any tautomeric forms and mixtures thereof.
  • 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 coupling a compound of formula (II):
  • Suitable leaving groups L include halogen, preferably chlorine or bromine, and -OSO2Ar groups such as tosylate.
  • the reaction of a compounds of formulae (II) and (III) is preferably carried out in a solvent such as dichloromethane or acetonitrile optionally in the presence of sodium iodide and a base such as potassium carbonate.
  • a solvent such as dichloromethane or acetonitrile
  • compounds of formula (II) and formula (III) are reacted together in the presence of a polymer supported base in a solvent such as DMF.
  • 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 (I) and their pharmaceutically acceptable salts have 5- HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of CNS and other disorders such as anxiety, depression, obsessive compulsive disorder, schizophrenia, attention deficit disorders, sleep disorders (including disturbances of circadian rhythms), migraine, neurodegenerative disorders such as Parkinson's disease and Alzheimers disease, pain disorders, feeding disorders such as anorexia and bulimia, sexual dysfunction, ocular disorders, asthma, epilepsy, hypothalamic diseases, inflammation, renal disorders, hypotension, cardiovascular shock, stroke including neurodegeneration resulting from stroke, septic shock and gastrointestinal diseases such as spastic colon and IBS (irritable bowel syndrome).
  • CNS and other disorders
  • other disorders such as anxiety, depression, obsessive compulsive disorder, schizophrenia, attention deficit disorders, sleep disorders (including disturbances of circadian rhythms), migraine, neurodegenerative disorders such as Parkinson's disease and Alzheimers disease, pain disorders, feeding disorders such as anorexia
  • 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 provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof for use in the treatment or prophylaxis of depression, anxiety, migraine and/or sleep disorders.
  • the invention further provides a method of treatment or prophylaxis of disorders where an antagonist of the 5-HT receptor is beneficial, particularly the aforementioned disorders, which comprises administering to a patient in need thereof 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
  • 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.
  • the 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.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • 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 times a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
  • Triazabicyclo[4.4.0]dec-5-ene bound to polystyrene cross-linked with 2% DVB 500 mg, 1.3 mmol was added to a shaken solution of 4-benzimidazol-2-yl-piperidine (100 mg, 0.5 mmol) and 2a-(4-bromobutyl) 2a,3,4,5-tetrahydro-lH-benzo[c,d]indol- 2-one2 (200 mg, 0.6 mmol) in DMF (10 ml). After 3 days the solution was decanted onto SCX resin and eluted with methanol (20 ml) followed by IN methano lie- ammonia (20 ml).
  • Racemic 2a- ⁇ 4-[4-(lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl ⁇ -2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (El) was subjected to preparative ⁇ PLC on a Chiralpak AD column, eluting with 30% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 7.8 minutes.
  • Racemic 2a- ⁇ 4-[4-(benzoxazol-2-yl)-piperidin-l-yl]-butyl ⁇ -2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E3) was subjected to preparative ⁇ PLC on a Chiralpak AD column, eluting with 15% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 17 minutes.
  • Racemic 2a- ⁇ 4-[4-(6-fluorobenzoxazol-2-yl)-piperidin-l-yl]-butyl ⁇ -2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E39) was subjected to preparative ⁇ PLC on a Chiralpak AD column, eluting with 10% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 19 minutes.
  • Racemic 2a- ⁇ 4-[4-(6-fluorobenzoxazol-2-yl)-piperidin-l-yl]-butyl ⁇ -2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E39) was subjected to preparative ⁇ PLC on a Chiralpak AD column, eluting with 10% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 29.5 minutes.
  • reaction mixture was loaded onto an SCX cartridge and washed with methanol (50ml) and then 5% aqueous ammonia/methanol (25ml).
  • the ammonia/methanol washing was concentrated in vacuo and the residue purified by column chromatography (5% then 10% methanol/chloroform) to give the title compound as a pale yellow solid (0.020 g, 13.4 %).
  • the affinity of the compounds of this invention for the 5-HT ⁇ receptor binding site can be determined by methods described in WO 97/29097. All compounds tested had a pKi greater than 6.0. Preferred examples had a pKi in the range 8.0 - 9.2.

Abstract

The invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1 is halogen, C¿1-6?alkyl, hydroxy, C1-6alkoxy, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, amino, mono- or di-C1-6alkylamino, carboxy, carboxamido, hydroxyC1-6alkyl, mono- or di-C1-6alkylaminocarbonyl, sulphonamido, C1-6alkylsulphonylamino, aminoC1-6alkyl, mono- or di-C1-6alkylaminosulphonyl or C1-6alkoxycarbonyl; R?2¿ is hydrogen, C¿1-6?alkyl or arylC1-6alkyl; p is 0, 1, 2 or 3; R?3¿ is hydrogen or C¿1-6?alkyl; n is 2, 3, 4, 5 or 6; A is nitrogen, carbon or CH, ....., is a single bond when A is nitrogen or CH or ..... is a double bond when A is carbon; X is nitrogen or CH; Y is O, S, NH or N-C1-6alkyl, R?4¿ is halogen, C¿1-6?alkyl, cyano, CF3, C3-7cycloalkyl, C1-6alkoxy, hydroxy, amino, mono- or di-C1-6alkylamino, acylamino, nitro, C1-6alkoxycarbonyl, C1-6alkylthio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, mono- and di-C1-6alkylsulphamoyl, carbamoyl, mono- and di-C1-6alkylcarbamoyl, C1-6alkylsulphonamido, arylsulphonamido, aryl, arylC1-6alkyl, arylC1-6alkoxy, aryloxy and arylthio; m is 0, 1, 2 or 3, having 5-HT7 antagonist activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.

Description

TETRAHYDROBENZINDOLONE DERIVATIVES, THEIR PREPARATION AND THEIR USE AS 5-HT7 RECEPTOR ANTAGONISTS
This invention relates to novel compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.
Kikuchi et al. (J. Med. Chem., 1999, 42, 533) describes tetrahydrobenzindolone compounds as selective antagonists of the 5-HT7 receptor.
Patent applications WO 98/00400, WO 99/33804 and WO 99/54303 also disclose tetrahydrobenzindolone compounds as 5-HTγ receptor antagonists. Such compounds are claimed to be useful in the treatment of various CNS diseases.
A structurally novel class of compounds has now been found which also possess 5-HT7 receptor activity. The present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
(I) wherein: R.1 is halogen, C^alkyl, hydroxy, C galkoxy, Ci-galkylthio, Cj-galkylsulphinyl, Cj-galkylsulphonyl, amino, mono- or di-Cj-galkylamino, carboxy, carboxamido, hydroxyC \ -galkyl, mono- or di-Ci-galkylaminocarbonyl, sulphonamido,
Figure imgf000003_0002
mono- or di-Ci-galkylaminosulphonyl or C j -6alkoxycarbonyl; R2 is hydrogen, C 1 -6 l yl or arylC \ - alkyl; p is 0, 1, 2 or 3;
R3 is hydrogen or Cμgalkyl; n is 2, 3, 4, 5 or 6;
A is nitrogen, carbon or CH, is a single bond when A is nitrogen or CH or
==-~ is a double bond when A is carbon; X is nitrogen or CH; Y is O, S, NH or N-C ι_6alkyl;
R4 is halogen, Ci-β lkyl, cyano, CF3, Cβ- cycloalkyl, Cj-galkoxy, hydroxy, amino, mono- or di-C 1 -galkylamino, acylamino, nitro, C i-galkoxycarbonyl, Cj-galkylthio, Ci-galkylsulphinyl, Ci-galkylsulphonyl, sulphamoyl, mono- and di-Cι-5alkylsulphamoyl, carbamoyl, mono- and di-Cj-galkylcarbamoyl,
Ci-galkylsulphonamido, arylsulphonamido, aryl, arylC^-galkyl, arylCj-galkoxy, aryloxy and arylthio; m is 0, 1, 2 or 3.
C^alkyl groups whether alone or as part of another group may be straight chain or branched. The term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine. The term 'aryl', whether alone or as part of another group, is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl. Such aryl groups may be optionally substituted by one or more C^alkyl, halogen, CF3 or C^-galkoxy.
When p is one or more, R^ is preferably halogen (particularly fluorine or chlorine) or a C^alkyl (particularly methyl). When p is 2 or 3 the groups R* may be the same or different. Preferably p is 0 or 1, most preferably 0.
Preferably R^ is hydrogen.
Preferably n is 4 or 5, most preferably 4.
Preferably R^ is hydrogen.
Preferably X is N. Preferably Y is O, S or NH;
When m is one or more, R^ is preferably halogen (particularly fluorine or chlorine), a C^alkyl (particularly methyl), Cι_6 lkoxy (particularly methoxy), CF3 or hydroxy. A preferred site for substitution of R^ groups is at the 4, 5 or 6 position of the benzo fused heteroaryl ring. When m is 2 or 3 the groups R^ may be the same or different. Preferably m is 0 or 1.
Preferred compounds of this invention include examples El - E41 (as shown below) or a pharmaceutically acceptable salt thereof. Particularly preferred compounds of this invention include: 2a-{4-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one,
2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro- 1 H-benzo [c,d] indol-2-one, 2a-{4-[4-(Benzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d] indol-2-one,
2a-{4-[4-(Benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one, 2a-{4-[4-(lH-Benzimidazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one,
2a-{4-[4-(5-Fluoro-lH-benzimidazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one,
2a-{5-[4-(5-Fluoro-lH-benzimidazol-2-yl)-piperazin-l-yl]-pentyl}-2a, 3, 4, 5- tetrahydro- 1 H-benzo [c,d] indol-2-one,
2a-{4-[4-(Benzothiazol-2-y_)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one,
2a-{4-[4-(Benzoxazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one, 2a-{4-[4-(lH-Benzimidazol-2-yl)-3,6-dihydro-l(2H)-pyridinyl]-butyl}-2a,3,4,5- tetrahydro-lH-benzo[c, ]indol-2-one,
2a-{4-[4-(lH-Indol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and 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 invention also extends to any tautomeric forms and mixtures thereof. 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 coupling a compound of formula (II):
Figure imgf000006_0001
(II) in which R% R p and n are as defined in formula (I) and L is a leaving group with a compound of formula (II
Figure imgf000006_0002
(III) in which , R^, R4} A, X, m and Y are as defined in formula (I); and optionally thereafter if appropriate:
• removing any protecting groups;
• forming a pharmaceutically acceptable salt.
Suitable leaving groups L include halogen, preferably chlorine or bromine, and -OSO2Ar groups such as tosylate. The reaction of a compounds of formulae (II) and (III) is preferably carried out in a solvent such as dichloromethane or acetonitrile optionally in the presence of sodium iodide and a base such as potassium carbonate. Preferably, compounds of formula (II) and formula (III) are reacted together in the presence of a polymer supported base in a solvent such as DMF.
Those skilled in the art will appreciate that it may be necessary to protect certain groups. 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 formulae (II) and (III) can be prepared using methods described herein, are commercially available or may be prepared according to known methods or analogous to known methods. Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5- HT7 receptor antagonist activity and are believed to be of potential use for the treatment or prophylaxis of CNS and other disorders such as anxiety, depression, obsessive compulsive disorder, schizophrenia, attention deficit disorders, sleep disorders (including disturbances of circadian rhythms), migraine, neurodegenerative disorders such as Parkinson's disease and Alzheimers disease, pain disorders, feeding disorders such as anorexia and bulimia, sexual dysfunction, ocular disorders, asthma, epilepsy, hypothalamic diseases, inflammation, renal disorders, hypotension, cardiovascular shock, stroke including neurodegeneration resulting from stroke, septic shock and gastrointestinal diseases such as spastic colon and IBS (irritable bowel syndrome). Thus 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. In particular the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof for use in the treatment or prophylaxis of depression, anxiety, migraine and/or sleep disorders.
The invention further provides a method of treatment or prophylaxis of disorders where an antagonist of the 5-HT receptor is beneficial, particularly the aforementioned disorders, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, 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 of disorders in which an antagonist of the 5-HT receptor is beneficial, particularly the aforementioned disorders. In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. 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.
For parenteral administration, 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The 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. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide 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 times a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The following Examples illustrate the preparation of the compounds of the invention.
Example 1
2a-{4-[4-(lH-Benzimidazo_-2-y_)-piperidin-l-y_]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (El)
Figure imgf000009_0001
Triazabicyclo[4.4.0]dec-5-ene bound to polystyrene cross-linked with 2% DVB (500 mg, 1.3 mmol) was added to a shaken solution of 4-benzimidazol-2-yl-piperidine (100 mg, 0.5 mmol) and 2a-(4-bromobutyl) 2a,3,4,5-tetrahydro-lH-benzo[c,d]indol- 2-one2 (200 mg, 0.6 mmol) in DMF (10 ml). After 3 days the solution was decanted onto SCX resin and eluted with methanol (20 ml) followed by IN methano lie- ammonia (20 ml). The methanolic-ammonia fraction was concentrated and the residue was purified by column chromatography (5% methanol-dichloromethane) to afford the title compound as a white foam (125mg, 58%). LCMS (100%) Mass spectrum MΗ+429. 1H NMR: δ DMSO 0.8-1.4 (5H, m), 1.6-2.2 (13H, m), 2.5-2.6 (1H, m), 2.7-2.9 (4H, m), 6.6 (1H, d), 6.7 (1H, d), 7.0-7.2 (3H, m), 7.3-7.4 (1H, m), 7.5-7.6 (1H, m), 10.1 (1H, s), 12.1 (1H, s).
Example la Enantiomer 1 of 2a-{4-[4-(lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH-benzo [c,d] indoI-2-one (E 1 a)
Racemic 2a-{4-[4-(lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (El) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 30% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 7.8 minutes.
Example lb
Enantiomer 2 of 2a-{4-[4-(lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4,
5-tetrahydro-lH-benzo[c,d]indol-2-one (Elb) Racemic 2a-{4-[4-(lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (El) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 30% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 13.1 minutes.
Example 2
2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yI)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo [c,d] indol-2-one (E2)
Figure imgf000010_0001
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with 4-(5-methyl)benzimidazol-2-yl-piperidine3 the title compound was obtained as a white solid.
Mass spectrum MΗ+ 444. Η NMR: δ MeOD 1.0-1.5 (4H, m), 1.6-2.0 (4H, m), 2.1- 2.5 (6H, m), 2.6 (3H, s), 2.7-2.8 (IH, m), 2.8-3.0 (IH, m), 3.0-3.3 (4H, m), 3.6-3.9 (3H, m), 6.7 (IH, d), 6.8 (IH, d), 7.1 (IH, App t), 7.4 (IH, dd), 7.6 (IH, d), 7.7 (IH, d).
Example 2a Enantiomer 1 of 2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]- butyl}-2a, 3, 4, 5-tetrahydro-lH-benzo[c,d]indol-2-one (E2a)
Racemic 2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH-benzo[c,d]indol-2-one (E2) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 30% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 7.9 minutes.
Example 2b
Enantiomer 2 of 2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]- butyl}-2a, 3, 4, 5-tetrahydro-lH-benzo[c,d]indol-2-one (E2b) Racemic 2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lΗ-benzo[c,d]indol-2-one (E2) was subjected to preparative HPLC on a Chiralpak AD column, eluting with 30% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 16.6 minutes. Example 3
2a-{4-[4-(Benzoxazol-2-yl)-piperidin-l-yI]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E3)
Figure imgf000011_0001
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with 4-benzoxazol-2-yl-piperidine , the title compound was obtained as a white solid.
LCMS (100%) Mass spectrum MΗ+ 430. IH NMR: δ DMSO 0.7-1.3 (5H, m), 1.5- 2.1 (13H, m), 2.4-2.5 (IH, m), 2.6-2.9 (4H, m), 6.5 (IH, d), 6.6 (IH, d), 6.9 (IH, app t), 7.2-7.3 (2H, m), 7.5-7.6 (2H, m), 9.9 (IH, s).
Example 3a
Enantiomer 1 of 2a-{4-[4-(BenzoxazoI-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E3a)
Racemic 2a-{4-[4-(benzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E3) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 15% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 17 minutes.
Example 3b
Enantiomer 2 of 2a-{4-[4-(Benzoxazol-2-yl)-piperidin-l-yI]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E3b)
Racemic 2a-{4-[4-(benzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E3) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 15% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 30 minutes
Example 4 2a-{4-[4-(Benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E4)
Figure imgf000012_0001
By an analogous procedure to that described for Example 1, replacing 4- benzimidazol-2-yl-piperidine with 4-benzothiazol-2-yl-piperidine , the title compound was obtained as a white solid. LCMS (100%) MH+ 446. 'H NMR÷ δ CDCb 1.0-1.2 (IH, m), 1.2-1.5 (5H, m), 1.8- 2.3 (12H, m), 2.5-2.7 (IH, m), 2.8-3.1 (4H, m), 6.7 (IH, d), 6.8 (IH, d), 7.1 (IH, App t), 7.3 (IH, dd), 7.4 (IH, dd), 7.8 (IH, s), 7.8 (IH, d), 7.9 (IH, d).
Example 4a Enantiomer 1 of 2a-{4-[4-(benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E4a)
Racemic 2a-{4-[4-(benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- lH-benzo[c,d]indol-2-one (E4) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 15% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 21.5 minutes.
Example 4b
Enantiomer 2 of 2a-{4-[4-(Benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo [c,d] indol-2-one (E4b) Racemic 2a-{4-[4-(benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- lH-benzo[c,d]indol-2-one (E4) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 15% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 43 minutes.
Example 5
2a-{4-[4-(lH-Benzimidazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E5)
Figure imgf000013_0001
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with l-benzimidazol-2-yl-piperazine4, the title compound was obtained as a white foam. LCMS (100%) MH+ 430. Η NMR: δ DMSO 1.0-1.2 (3H, m), 1.6-2.0 (7H, m), 2.5- 3.8 (10H, m), 4.3-4.4 (2H, m), 6.6 (IH, d), 6.7 (IH, d), 7.0-7.1 (IH, App t), 7.2-7.3 (2H, m), 7.4-7.5 (2H, m), 10.1 (IH, s), 11.3 (IH, s).
Example 6 2a-{4-[4-(5-Fluoro-lH-benzimidazoI-2-yl)-piperazin-l-yl]-butyI}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E6)
Figure imgf000013_0002
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with l-(5-fluoro)benzimidazol-2-yl-piperazine^, the title compound was obtained as a white solid.
LCMS (100%) MΗ+ 448. 1H NMR: δ DMSO 0.9-1.3 (5H, m), 1.7-2.4 (11H, m), 2.5- 2.8 (2H, m), 3.4-3.5 (4H, m), 6.6 (6.7 (3H, m), 6.9-7.2 (3H, m), 10.1 (IH, s), 11.4 (IH, s).
Example 7
2a-{5-[4-(5-Fluoro-lH-benzimidazol-2-yl)-piperazin-l-yI]-pentyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indoI-2-one (E7)
Figure imgf000013_0003
By an analogous procedure to that described for Example 1, replacing 4- benzimidazol-2-yl-piperidine with l-(5-fluoro)benzimidazol-2-yl-piperazine^ and 2a- (4-bromobutyl) 2a, 3, 4, 5-tetrahydro- lH-benzo[c,d]indol-2-one with 2a-(5- bromopentyl) 2a, 3, 4, 5-tetrahydro-lH-benzo[c,d]indol-2-one2, the title compound was obtained as a white solid.
LCMS (100%) MΗ+ 462. 1H NMR: δ CDC13 1.1-1.8 (10H, m), 2.0-2.3 (4H, m), 2.5- 2.6 (4H, m), 2.6-2.9 (2H, m), 3.5-3.6 (4H, m), 6.6-7.5 (8H, m).
Example 8
2a-{4-[4-(Benzothiazol-2-yl)-piperazin-l-yI]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E8)
Figure imgf000014_0001
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with l-benzothiazol-2-yl-piperazine^, the title compound was obtained as a white solid.
LC/MS (97%) MΗ+ 447. Η NMR: δ DMSO 0.8-1.3 (5H, m), 1.6-1.8 (2H, m), 1.8- 2.3 (4H, ), 2.3-2.4 (4H, m), 2.5-2.6 (IH, m), 2.8-2.9 (2H, m), 3.4-3.6 (4H, m), 6.6 (IH, d), 6.7 (IH, d), 7.0 (2H, App t), 7.2 (IH, app t), 7.4 (IH, d), 7.7 (IH, d), 10.1 (IH, s).
Example 9 2a-{4-[4-(Benzoxazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E9)
Figure imgf000014_0002
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with l-benzoxazol-2-yl-piperazine^, the title compound was obtained as a white solid.
LC/MS (100%) MΗ+ 430. Η NMR: δ DMSO 0.8-1.4 (6H, m), 1.6-1.8 (2H, m), 1.8- 2.2 (4H, m), 2.3-2.4 (4H, m), 2.6-2.7 (IH, m), 2.7-2.9 (IH, m), 3.4-3.6 (4H, m), 6.6 (IH, d), 6.7 (IH, d), 6.9-7.1 (3H, m), 7.2 (IH, d), 7.3 (IH, d), 10.1 (IH, s). By analogous procedures to those described in Examples 1 - 9, using the appropriate piperidine or piperazine and 2a-(ω-bromoalkyl)-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one intermediates consistent with the final products, Examples 10 - 37 of Table 1 were prepared. Η NMR and mass spectra were consistent with the structures given in Table 1.
Table 1
Figure imgf000016_0001
Figure imgf000016_0002
Example 39
2a-{4-[4-(6-FluorobenzoxazoI-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- lH-benzo[c,d]indol-2-one (E39)
By an analogous procedure to that described for Example 1, replacing 4- benzimidazol-2-yl-piperidine with 4-(6-fluorobenzoxazol-2-yl)-piperidine, the title compound was obtained as a white solid.
LCMS (100%) Mass spectrum MΗ+ 448 IH NMR: δ DMSO 0.9 - 1.0 (IH, m), 1.1 - 1.4 (4H, m), 1.6 - 2.3 (8H, m), 2.5 - 2.6 (IH, m), 2.7 - 3.0 (4H, m), 6.6 (IH, d), 6.7 (IH, d), 7.0 (IH, t), 7.2 (IH, td), 7.6 - 7.7 (2H, m), 10.1 (IH, s)
Example 39a
Enantiomer 1 of 2a-{4-[4-(6-Fluorobenzoxazol-2-yl)-piperidin-l-yI]-butyl}-2a, 3, 4, 5-tetrahydro-lH-benzo [c,d] indol-2-one (E39a)
Racemic 2a-{4-[4-(6-fluorobenzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E39) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 10% ethanol-hexane, to afford the enantiomer 1 title compound as the faster running component with a retention time of 19 minutes.
Example 39b
Enantiomer 2 of 2a-{4-[4-(6-Fluorobenzoxazol-2-yl)-piperidin-l-yI]-butyl}-2a, 3,
4, 5-tetrahydro-lH-benzo[c,d]indol-2-one (E39b)
Racemic 2a-{4-[4-(6-fluorobenzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one (E39) was subjected to preparative ΗPLC on a Chiralpak AD column, eluting with 10% ethanol-hexane, to afford the enantiomer 2 title compound as the slower running component with a retention time of 29.5 minutes.
Example 40
2a-{4-[4-(lH-indol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one (E40)
Figure imgf000018_0001
By an analogous procedure to that described for Example 1 , replacing 4- benzimidazol-2-yl-piperidine with 4-(indol-2-yl)-piperidine, the title compound was obtained as an off-white solid. LCMS (100%) Mass spectrum MH+ 428 IH NMR: δ CDC13 1.0 - 1.2 (IH, m), 1.2 - 2.2 (15H, m), 2.2 - 2.4 (2H, m), 2.6 - 2.8 (2H, m), 2.8 - 2.9 (IH, m), 2.9 - 3.0 (2H, m), 6.2 (IH, s), 6.7 (IH, d), 6.8 (IH, d), 7.0 - 7.2 (3H, m), 7.2 - 7.4 (2H, m), 7.5 (IH, d), 8.0 (IH, s)
Example 41
2a-{4-[4-(lH-Benzimidazol-2-yl)-3,6-dihydro-l(2H)-pyridinyl]-butyl}-2a,3,4,5- tetrahydro-lH-benzo[c-/]indol-2-one (E41)
Figure imgf000018_0002
2-(l,2,3,6-tetrahydro-pyridin-4-yl)-lH-benzimidazole
Figure imgf000018_0003
(0.07 g, 0.35 mmol) was added to a solution of diisopropylethylamine (0.06 ml, 0.35 mmol), 1,5,7,- triazabicyclo[4.4.0]dec-5-ene bound to polystyrene crosslinked with 2% DVB (0.3 g, -2.6 mmol base/g resin, 0.78 mmol) and 2a-(4-bromo-butyl)-2a,3,4,5-tetrahydro-lH- benzo[c,<f]indol-2-one2 (0.12 g, 0.39 mmol), in dimethylformamide (3 ml) and dichloromethane (1.5 ml), and the mixture stirred for 72 h. The reaction mixture was loaded onto an SCX cartridge and washed with methanol (50ml) and then 5% aqueous ammonia/methanol (25ml). The ammonia/methanol washing was concentrated in vacuo and the residue purified by column chromatography (5% then 10% methanol/chloroform) to give the title compound as a pale yellow solid (0.020 g, 13.4 %). LCMS (96%) Mass spectrum MΗ+427 Η NMR δ CDC13 1.0 - 2.9 (21H, series of unassigned m's), 3.1 (2H, app br s), 6.5 (IH, m), 6.6 (IH, d), 6.8 (IH, d), 7.1 (IH, t), 7.2 (2H, m), 7.5 (2H, app br s), 8.4 (IH, s). References
1. Orjales et al., J Heterocyc Chem. 1995, 32, 707.
2. Kikuchi et al., J. Med. Chem. 1999, 42, 533. 3. Uisano et al, Chem.Pharm. Bull. 1982, 30, 2996.
4. Orjales et al., J. Med. Chem. 1997, 0, 586.
5. Prepared according to the general procedure of Orjales^
6. Herrin et al., J Med. Chem. 1975, 75, 1216.
7. Sato et al., J. e . CAem. 1998, 41, 3015. 8. Haworth et al., Bioorg. and Med. Chem. Lett., 1997, 7, 2211-2216.
Pharmacological Data
[3_H]-5-Carboxamidotryptamine binding to human 5-HT receptor clones expressed in HEK 293 cells in vitro.
The affinity of the compounds of this invention for the 5-HTγ receptor binding site can be determined by methods described in WO 97/29097. All compounds tested had a pKi greater than 6.0. Preferred examples had a pKi in the range 8.0 - 9.2.

Claims

Claims:
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000020_0001
(I) wherein:
R is halogen, C _6alkyl, hydroxy, Cμgalkoxy, Cj-galkylthio, Ci-galkylsulphinyl, Ci-galkylsulphonyl, amino, mono- or di-Ci-galkylamino, carboxy, carboxamido, hydroxyC^-galkyl, mono- or di-Ci-galkylaminocarbonyl, sulphonamido, Ci-galkylsulphonylamino, aminoCi^alkyl, mono- or di-Ci-galkylaminosulphonyl or C \ -galkoxycarbonyl; R2 is hydrogen, Ci.ζalkyl or arylCi^alkyl; p is 0, 1, 2 or 3;
R3 is hydrogen or C^.galkyl; n is 2, 3, 4, 5 or 6;
A is nitrogen, carbon or CH, is a single bond when A is nitrogen or CH or is a double bond when A is carbon;
X is nitrogen or CH;
Y is O, S, NH or N-Cι_6alkyl;
R4 is halogen, Cj^alkyl, cyano, CF3, C3-ycycloalkyl, Cj-βalkoxy, hydroxy, amino, mono- or di-Ci- alkylamino, acylamino, nitro, Ci-galkoxycarbonyl, Ci-galkylthio,
Ci-galkylsulphinyl, Ci-galkylsulphonyl, sulphamoyl, mono- and di-Ci-galkylsulphamoyl, carbamoyl, mono- and di-Ci-galkylcarbamoyl,
C^-galkylsulphonamido, arylsulphonamido, aryl, arylC^-galkyl, arylC 1 -galkoxy, aryloxy and arylthio; m is 0, 1, 2 or 3.
2. A compound according to claim 1 in which X is nitrogen.
3. A compound according to claim 1 or claim 2 in which R^ is hydrogen.
4. A compound according to any of the preceding claims in which n is 4 or 5.
5. A compound according to claim 1 which is a compound El - E41 (as described above) or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 which is
2a-{4-[4-(lH-Benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one,
2a-{4-[4-(5-Methyl-lH-benzimidazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one, 2a-{4-[4-(Benzoxazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one,
2a-{4-[4-(Benzothiazol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one,
2a-{4-[4-(lH-Benzimidazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one,
2a-{4-[4-(5-Fluoro-lH-benzimidazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5- tetrahydro- 1 H-benzo [c, d] indol-2-one,
2a-{5-[4-(5-Fluoro-lH-benzimidazol-2-yl)-piperazin-l-yl]-penryl}-2a, 3, 4, 5- tetrahydro-lH-benzo[c,d]indol-2-one, 2a-{4-[4-(Benzothiazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro-lH- benzo[c,d]indol-2-one,
2a-{4-[4-(Benzoxazol-2-yl)-piperazin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one,
2a- {4- [4-( lH-Benzimidazol-2-yl)-3 ,6-dihydro- 1 (2H)-pyridinyl] -butyl } -2a,3 ,4,5- tetrahydro-lH-benzo[c,c ]indol-2-one,
2a-{4-[4-(lH-Indol-2-yl)-piperidin-l-yl]-butyl}-2a, 3, 4, 5-tetrahydro- 1H- benzo[c,d]indol-2-one or a pharmaceutically acceptable salt thereof.
7. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises coupling a compound of formula (II):
Figure imgf000022_0001
(II) in which R , R p and n are as defined in formula (I) and L is a leaving group with a compound of formula (I
Figure imgf000022_0002
(HI) in which , R- , R4, A, m, X, and Y are as defined in formula (I); and optionally thereafter if appropriate:
• removing any protecting groups;
• forming a pharmaceutically acceptable salt.
8. A compound according to any one of claims 1 to 6 for use in therapy.
9. A compound according to any one of claims 1 to 6 for use in the treatment of depression, anxiety, migraine and/or sleep disorders.
10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or excipient.
11. A compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of the 5-HTγ receptor is beneficial.
12. The use of a compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of the 5- HT7 receptor is beneficial.
PCT/EP2000/010149 1999-10-18 2000-10-13 Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists WO2001029029A1 (en)

Priority Applications (4)

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AU10256/01A AU1025601A (en) 1999-10-18 2000-10-13 Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists
EP00971384A EP1222185A1 (en) 1999-10-18 2000-10-13 Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists
JP2001531828A JP2003512372A (en) 1999-10-18 2000-10-13 Tetrahydrobenzoindolone derivatives, their preparation and their use as 5-HT7 receptor antagonists
HK02109226.5A HK1049151A1 (en) 1999-10-18 2002-12-19 Tetrahydrobenzindolone derivatives, their preparation and their use as 5-ht7 receptor antagonists

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WO2008000495A1 (en) * 2006-06-29 2008-01-03 Laboratorios Del Dr. Esteve, S.A Use of 5-ht7 receptor agonists for the treatment of pain
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EP3576734A4 (en) * 2017-02-03 2020-12-09 Arizona Board of Regents on behalf of the University of Arizona Small molecule antagonists of sumo related modification of crmp2 and uses thereof

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EP1491212A1 (en) * 2002-03-29 2004-12-29 Mitsubishi Pharma Corporation Remedy for sleep disturbance
US8003669B2 (en) 2002-03-29 2011-08-23 Mitsubishi Tanabe Pharma Corporation Remedy for sleep disturbance
EP1491212B1 (en) * 2002-03-29 2012-08-08 Mitsubishi Tanabe Pharma Corporation Remedy for sleep disturbance
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US8883808B2 (en) 2005-08-04 2014-11-11 Janssen Pharmaceutica N.V. Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy
WO2008000495A1 (en) * 2006-06-29 2008-01-03 Laboratorios Del Dr. Esteve, S.A Use of 5-ht7 receptor agonists for the treatment of pain
WO2008013556A1 (en) 2006-07-27 2008-01-31 Janssen Pharmaceutical N.V. Combination 5-ht7 receptor antagonist and serotonin reuptake inhibitor therapy

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