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WO1996011929A1 - Derives biheteroaryl-carbonyles et carboxamides possedant une activite antagoniste de 5ht 2c/2b - Google Patents

Derives biheteroaryl-carbonyles et carboxamides possedant une activite antagoniste de 5ht 2c/2b Download PDF

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Publication number
WO1996011929A1
WO1996011929A1 PCT/EP1995/003887 EP9503887W WO9611929A1 WO 1996011929 A1 WO1996011929 A1 WO 1996011929A1 EP 9503887 W EP9503887 W EP 9503887W WO 9611929 A1 WO9611929 A1 WO 9611929A1
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WO
WIPO (PCT)
Prior art keywords
pyrrolo
pyridylcarbonyl
methyl
formula
indole
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
PCT/EP1995/003887
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English (en)
Inventor
Frederick Cassidy
Ian Hughes
Shahzad Sharooq Rahman
David James Hunter
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of WO1996011929A1 publication Critical patent/WO1996011929A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

Definitions

  • This invention relates to compounds having pharmacological activity, to a process for their preparation, to compositions containing them and to their use in the treatment of mammals.
  • WO 95/01976 (SmithKline Beecham plc) describes indoline derivatives which are described as possessing 5HT 2C receptor antagonist activity.
  • a structurally distinct class of compounds has now been discovered, which have been found to have 5HT 2C receptor antagonist activity.
  • Certain compounds of the invention also exhibit 5HT 2B antagonist activity.
  • 5HT 2C/2B receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the present invention provides a compound of formula (I) or a salt, solvate or hydrate thereof:
  • A, B, C and D are all carbon atoms or one of A, B, C or D is nitrogen and the others are all carbon;
  • E is oxygen, sulphur, CH 2 or NR 1 where R 1 is hydrogen or C 1 -6 alkyl;
  • R 2 is hydrogen, halogen, C 1 -6 alkyl, C 1-6 alkylthio, nitro, CF 3 , cyano, NR 4 R 5 ,
  • R 3 is a group of formula (i) in which:
  • X and Y are both nitrogen, one is nitrogen and the other is carbon or a CH group or one is a CH group and the other is carbon or a CH group;
  • R 8 and R 9 groups are independently C 1-6 alkyl optionally substituted by one or more halogen atoms, C 2-6 alkenyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylC 1-6 alkoxy,
  • R 10 and R 1 1 are independently hydrogen or C 1-6 alkyl
  • R 3 is a group of formula (ii):
  • R 8 and R 9 are as defined in formula (i), X and Y are both nitrogen, one is nitrogen and the other is a CH group or X and Y are both CH groups;
  • R 12 is hydrogen or C 1-6 alkyl
  • R 3 is a group of formula (iii):
  • R 8 , R 9 , X and Y are as defined for formula (i) and Z is oxygen, sulphur, CH 2 or NR 13 where R 13 is hydrogen or C 1-6 alkyl.
  • C 1-6 alkyl moieties whether alone or as pan of another group can be straight chain or branched.
  • A, B, C and D are all carbon atoms giving an indole ring, or one of A, B, C or D is nitrogen and the others are all carbon giving an azaindole ring, that is to say, a 4-, 5-, 6- or 7-azaindole ring.
  • A, B and C are all carbon atoms and D is a nitrogen atom, giving a 7-azaindole ring, also known as a pyrrolo[2,3-b]pyridine ring
  • E is NR 1 where R 1 is hydrogen.
  • R 2 is hydrogen
  • R 3 is a group of formula (i).
  • X and Y form part of a phenyl ring, that is to say one of X or Y is carbon and the other is a CH group or both of X and Y are CH groups.
  • R 3 is an indoline ring, that is to say a group of formula (A):
  • R 8 and R 9 form part of an aromatic ring
  • suitable rings include thiophene, furan and pyrrole rings.
  • Preferred R 8 and R 9 groups which can be the same or different, include C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, halogen, CF3, and CO 2 R 6 where R 6 is hydrogen or C 1-6 alkyl.
  • R 8 is trifluoromethyl and R 9 is C 1-6 alkylthio, for example methylthio.
  • Particularly preferred compounds of formula (I) include:
  • N-(1-Methyl-5-indolyl)-1-methylpyrrolof2,3-b]pyridine-3-carboxamide 2,3-Dihydro-5-methyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-ethyl-1-(1-methyl-3-pyrrolo[2,3-b]pyridylcarbonyl)pyrrolo[2,3-f]indole, 2,3-Dihydro-5-methyl-1-(3-pyrrolo[3,2-b]pyridylcarbonyl)pyrrolor2,3-f]indole,
  • 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, ic and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, ic and methanesulphonic.
  • 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 the coupling of a compound of formula (II):
  • A, B, C, and D are as defined in formula (I)
  • E is as defined in formula (I) or is a group NR 1
  • L is a leaving group and X is hydrogen or a metal atom
  • the variables, R 1 ' , R 2' and R 3 are R 1 , R 2 and R 3 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, convening any R 1' , R 2' and R 3' when other than R 1 , R 2 and R 3 respectively to R 1 , R 2 and R 3 , interconverting R 1 , R 2 and R 3 and forming a pharmaceutically acceptable salt thereof.
  • L is a leaving group such as halogen, in particular chloro.
  • X is hydrogen or a metal atom such as lithium or magnesium.
  • R 1 is hydrogen
  • C 1 -6 alkyl group by conventional alkylation using 1 molar equivalent of a C 1 -6 alkyl halide and 1 molar equivalent of a suitable base in an inert solvent.
  • R 2 ' , A, B, C, D and E are as defined in formula (II) using standard procedures.
  • compositions may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT 2B/2C receptor antagonist activity and are believed to be of potential use fo the treatment or prophylasis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the invention 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 infusible 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.
  • aqueous or oily suspension solutions, emulsions, syrups or elixirs
  • a dry product for reconstitution with water or other suitable vehicle before use.
  • 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 colorants.
  • suspending agents such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • 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 sterilisation 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.
  • N-acetyl-5-nitroindoline (D1) (4 g), excess acetaldehyde (20 ml) and 5% Pd/C (0.5 g) in ethanol (150 ml) was hydrogenated at a pressure of 45 psi for 18 h.
  • the mixture was then filtered through Kieselguhr, and evaporated to dryness to afford crude N-acetyl-5-diethylaminoindoline as a white solid (4.3 g). This was dissolved in cone. HCl (5 ml) and heated over a steambath for 0.5 h.
  • the solution was then basified by dropwise addition of aqueous K 2 CO 3 and extracted with chloroform(3 ⁇ 20 ml).
  • the indole (D10) (67.63g, 0.315 mol) was treated with sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic acid (500 ml) using standard methodology to afford the title indoline (67.73g, 99%) as an off-white solid.
  • N-(1-Methyl-5-indolyl)pyrrolo[2,3-b]pyridine-3-carboxamide (E6) A suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid 1 (162 mg, 1 mmol) in thionyl chloride (2 ml) was heated under reflux for 2 h then kept at room temperature overnight. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (10 ml) was added in portions to a solution of 1-methyl-5-aminoindole (146 mg, 1 mmol) and triethylamine (0.28 ml, 2 mmol) in dichloromethane (10 ml).
  • N-(1-Methyl-5-indolyl)pyrrolo[2,3-c]pyridine-3-carboxamide (E14) A suspension of pyrrolo[2,3-c]pyridine-3-carboxylic acid 1 (118 mg, 0.73 mmol) in thionyl chloride (5 ml) was heated under reflux overnight at room temperature. The mixture was evaporated to dryness, then a suspension of the residue in dichloromethane (5 ml) was added in portions to a solution of 1-methyl-5-aminoindole (106 mg, 0.73 mmol) and triethylamine (221 mg, 2.2 mmol) in dichloromethane (10 ml).
  • 6-Chloro-5-methyl-1-(3-pyrrolo[2,3-b]pyridylcarbonyl)indoline E19
  • a suspension of pyrrolo[2,3-b]pyridine-3-carboxylic acid (109 mg, 0.67 mmol) in thionyl chloride (5 ml) was stined for 18 h at room temperature. Excess thionyl chloride was evaporated in vacuo and the residue dissolved in dichloromethane was added to a solution of 6-chloro-5-methylindoline (see WO 95/01976) (90 mg, 0.53 mmol) and triethylamine (16 mg, 1.6 mmol) in dichloromethane (5 ml).
  • the compounds of examples 1 to 20 have pKi values of 5.2 to 8.3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit des composés indoles et indolines possédant une activité pharmacologique, un procédé de préparation de ceux-ci, des compositions les contenant ainsi que leur utilisation dans le traitement de troubles du système nerveux central (antagonistes de 5HT 2C/2B).
PCT/EP1995/003887 1994-10-12 1995-10-02 Derives biheteroaryl-carbonyles et carboxamides possedant une activite antagoniste de 5ht 2c/2b Ceased WO1996011929A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9420521.8 1994-10-12
GB9420521A GB9420521D0 (en) 1994-10-12 1994-10-12 Novel compounds

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WO1996011929A1 true WO1996011929A1 (fr) 1996-04-25

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US6476034B2 (en) 2000-02-22 2002-11-05 Bristol-Myers Squibb Company Antiviral azaindole derivatives
WO2004094416A1 (fr) * 2003-04-24 2004-11-04 Elbion Ag 7-azaindoles et leur utilisation comme produits therapeutiques
US6825201B2 (en) 2001-04-25 2004-11-30 Bristol-Myers Squibb Company Indole, azaindole and related heterocyclic amidopiperazine derivatives
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WO2001058869A3 (fr) * 2000-02-11 2002-01-24 Bristol Myers Squibb Co Modulateurs de recepteurs aux cannabinoides, leurs procedes de preparation et utilisations de modulateurs de recepteurs aux cannabinoides pour le traitement de maladies respiratoires et non respiratoires
JP2004502642A (ja) * 2000-02-11 2004-01-29 ブリストル−マイヤーズ　スクイブ　カンパニー カンナビノイドレセプターモジュレーター、それらの製造方法、および呼吸系および非呼吸系疾患の処置のためのカンナビノイドレセプターモジュレーターの使用
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