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WO1999029666A1 - Derives d'arylpiperazine et d'arylpiperidine, leur mise au point et leur utilisation en tant qu'antagonistes des recepteurs de 5-ht1a, 5-ht1b et 5-ht1d combines - Google Patents

Derives d'arylpiperazine et d'arylpiperidine, leur mise au point et leur utilisation en tant qu'antagonistes des recepteurs de 5-ht1a, 5-ht1b et 5-ht1d combines Download PDF

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Publication number
WO1999029666A1
WO1999029666A1 PCT/EP1998/007803 EP9807803W WO9929666A1 WO 1999029666 A1 WO1999029666 A1 WO 1999029666A1 EP 9807803 W EP9807803 W EP 9807803W WO 9929666 A1 WO9929666 A1 WO 9929666A1
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Prior art keywords
formula
compound
methylpiperazin
indoline
group
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Ceased
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PCT/EP1998/007803
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English (en)
Inventor
Laramie Mary Gaster
Paul Adrian Wyman
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group

Definitions

  • the present invention relates to novel piperazine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • WO 95/04729, WO 95/06044 and WO 95/06637 all disclose a series of piperazine derivatives which are said to possess 5HTi£) receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression.
  • EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5-HTID receptor antagonist activity.
  • the 5-HTJD receptor was subsequently found to consist of a pair of gene products originally designated 5-HTjj) ⁇ and 5-HTjj) ⁇ receptors which have more recently been reclassified as 5-HTi ) and 5-HT ⁇ g receptors respectively (Hartig, P.R. et al., Trends in Pharmacological Sciences 1992, Vol. 13, page 152, Hartig, P.R. et al., Trends in Pharmacological Sciences, 1996, Vol. 17, page 103).
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • the ring A is 5, 6 or 7 -membered carbocyclic ring optionally substituted by one or more C ⁇ _6alkyl groups, fused at the 2,3- or 3,4-positions of the adjacent phenyl ring, the ring A being optionally fused to a further phenyl ring optionally substituted by one or more substituents independently selected from C ⁇ _6alkyl and halo;
  • R 2 is halogen, Cj.galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, C ⁇ alkoxy, C ⁇ galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO2 10 , CON 1°R11, NR1°R11 where R O and Ri 1 are independently hydrogen or
  • L is a group of formula
  • D is nitrogen, carbon or a CH group
  • G is hydrogen or C ⁇ galkyl providing that D is nitrogen or a CH group
  • Rbl forms a group W where W is (CR ⁇ R ⁇ )t where t is
  • X is nitrogen or carbon
  • Rbl and R 2 are independently hydrogen, halogen, hydroxy, Cj. ⁇ alkyl,
  • R c is hydrogen or C 1 _6alkyl; and is a single bond when X is nitrogen or a single or double bond when X is carbon.
  • Cj.galkyl groups whether alone or as part of another group may be straight chain or branched.
  • the term 'acyloxy' is used herein to describe a group -OC(O)C ⁇ _6alkyl.
  • the term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl.
  • the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • the ring A is preferably formed from a straight chain alkylene grouping containing 2, 3 or 4 carbon atoms.
  • the ring A is preferably a 5 or 6-membered ring in which the oxo group is advantageously attached to a carbon atom adjacent to the phenyl ring, the ring A being preferably attached to the 3,4-positions of the latter phenyl ring, a is preferably 0 or 1 ;
  • R 2 is preferably halogen for example a chloro group or a Cj. ⁇ alkyl group for example a methyl group;
  • the group L is preferably a group of formula: -
  • Y is preferably -NH
  • D is preferably nitrogen and G is preferably a hydrogen atom or together with Rbl forms a group W, preferably -(CH2)2->
  • Rbl and Rb2 are preferably hydrogen or a halogen atom for example bromine or chlorine, or a C ⁇ . ⁇ a ⁇ koxy group for example methoxy, or Rbl together with G forms the group W referred to above.
  • Rb2 has a para relationship with respect to the group L.
  • X is preferably nitrogen.
  • R c is preferably a C ⁇ _6alkyl group for example methyl.
  • Particularly preferred compounds according to the invention include:-
  • Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydro bromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p- toluenesulphonates.
  • acid addition salts such as hydrochlorides, hydro bromides, phosphates, acetates, fumarates, maleates, tartrates, citrates, oxalates, methanesulphonates and p- toluenesulphonates.
  • R -NC( O) (IV) in which R a is defined in formula (I) or a protected derivative thereof, with a compound of formula (V):
  • R a _ ⁇ _ ( 0) - L 3 (VH) in which R a is as defined in formula (I), and L 3 is an appropriate leaving group, with a compound of formula (V):or
  • L,l and L2 include:-
  • L is COL a and L 2 is NH 2 .
  • Li is NH2 and L2 is COL a in which L a is an appropriate leaving group.
  • L a is an appropriate leaving group.
  • one of Ll and L is an activated carboxyhc acid derivative such as an acyl chloride or acid anhydride, and the other is an amine group.
  • Activated compounds of formulae (II) and (III) can also be prepared by reaction of the corresponding carboxyhc acid with a coupling agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or diphenylphosphorylazide.
  • L.1 or L is a group COL a where L a is halo particularly chloro.
  • reaction in process (b) is conveniently effected in an organic solvent such as dichloromethane.
  • the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • the leaving group L 3 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • the leaving group L 3 may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • an inert organic solvent such as tetrahydrofuran or dichloromethane
  • a base such as triethylamine or pyridine.
  • Intermediate compounds of formula (II) to (VET) can be prepared using standard procedures known in the art. It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional procedures well known in the art. Carboxyhc acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection is achieved using standard conditions.
  • Serotonin receptors have been implicated in pharmacological effects such as mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of Circadian rhythm), motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • mood disorders including depression, seasonal affective disorder and dysthymia
  • anxiety disorders including generalised anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder
  • memory disorders including dementia, amnesic disorders and age-associated memory impairment
  • disorders of eating behaviours including an
  • Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction and hypothermia.
  • WO 95/31988 refers to the use of a 5-HT ⁇ rj receptor antagonist in conjunction with a 5-HT ⁇ receptor antagonist to treat CNS (central nervous system), endocrine and GI (gastrointestinal) disorders
  • K. Rasmussen Annual Reports in Medicinal Chemistry, (1995) 30, 1) describes the utility of 5-HTJA receptor agonists and partial agonists in the treatment of various CNS disorders
  • P. Trouillas Progress in Brain Research, C.I. de Zeeuw, P. Stara and J. Voogd, Eds. 1997, 144, 589) and G. Maura (J.
  • the present invention also provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment of the aforementioned disorders.
  • the invention provides a method of treating the aforementioned disorders which comprises administering an effective amount to a patient in need of such treatment of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
  • the affinities of the compounds of this invention for the 5HTIA > 5-HTJB nd 5-HTID receptors can be determined by the following radioUgand binding assay.
  • HEK 293 cells expressing 5-HT ⁇ A receptors (4 x 10 7 /ml) are homogenised in Tris buffer and stored in lml aliquots.
  • CHO cells expressing 5-HTJB receptors (4 x 10 7 cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots.
  • CHO cells expressing 5-HTID receptors (0.563 x 10 ⁇ /ml) are homogenised in Tris buffer and stored in 1 ml aliquots.
  • the intrinsic activity of the compounds of this invention can be determined according to the following procedure.
  • HEK293 cell membranes stably expressing human 5-HTj x_ receptors and CHO cell membranes stably expressing human 5-HTJB receptors are homogenised in HEPES/EDTA buffer and stored in 1ml aliquots, and [ 3 5S]GTP ⁇ S binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications.
  • Membranes from 10 ⁇ cells are pre-incubated at 30°C for 30 min in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl2 (3 mM), NaCl (100 mM), GDP (lO ⁇ M) and ascorbate (0.2 mM), with or without compounds.
  • the reaction is started by the addition of 10 ⁇ l of [ 3 ⁇ S]GTP ⁇ S (100 pM, assay concentration) followed by a further 30 minutes incubation at 30°C.
  • Non-specific binding was determined using non- radiolabelled GTP ⁇ S (20 ⁇ M) added prior to the membranes.
  • the reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5 x 1 ml washes with ice cold HEPES (20 mM) /MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [ ⁇ S]GTP ⁇ S functional assay.
  • the compounds of formula (I) show high affinity for the 5HTIA > 5-HTIB and 5-HTjr) receptors. It has been found, using the [ 3 5s]GTP ⁇ S functional assay, that certain compounds of formula (I) show varying levels of intrinsic efficacy, which is defined by a scale ranging from 1.0 to 0 (1 defines the maximum response elicited by the agonist 5-HT, 0 defines antagonism).
  • the difficulties in describing intrinsic activity of drugs acting at G protein coupled receptors is recognised in the art (Hoyer and Boddeke, Trends in Pharmacological Sciences, July 1993, [Vol. 14], page 270-275).
  • the compounds of this invention will be useful antidepressants in vivo. It is believed that the preferred compounds of this invention will display 5HTj A> -HTJB and 5-HTij) antagonist activity in vivo and that such compounds will have a rapid onset of action.
  • a rapid onset of action is particularly advantageous for antidepressant compounds: by 'rapid onset of action' we mean that a therapeutic response is seen within 7 days from first administration of the compound, as opposed to a period of about 21 days or more which is typical of SSRI's, tricyclic antidepressants and buspirone.
  • 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.
  • 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 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.
  • 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.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.
  • Example 3 5-Bromo-6-(4-methylpiperazin-l-yl)-l-[(l-oxoindan-5-yl)aminocarbonyl]indoIine (E3)
  • the title compound was prepared from 5-amino-l-indanone and 5-bromo-6-(4- methylpiperazin-l-yl)indoline (D7) using a similar method to Example 1.
  • the title compound was prepared from 7-amino-l -tetralone (EP 0275131) and 5-bromo-6-(4- methylpiperazin-l-yl)indoline (DI) using a similar method to Example 1. This was isolated as its hydrochloride salt.
  • the title compound was prepared from 7-amino-l -tetralone (EP 0275131) and 5-chloro-6-(4- methylpiperazin-l-yl)indoline (D5) using a similar method to Example 1. This was isolated as its hydrochloride salt.
  • the title compound was prepared from 2-amino-9H-fluoren-9-one and 5-chloro-6-(4- methylpiperazin-l-yl)indoline (D5) using a similar procedure to Example 1, as an orange solid (46%).
  • the title compound was prepared from 3-amino-9H-fluoren-9-one and 5-chloro-6-(4- methylpiperazin-l-yl)indoline (D5) using a similar procedure to Example 1, as a yellow/orange solid (66%).
  • the title compound was prepared from 5-amino-l -tetralone (D9) and 5-chloro-6-(4- methylpiperazin-l-yl)indoline (D5) using a similar method to Example 1, as the hydrochloride salt, a buff solid (30%).
  • the title compound was prepared from 5-amino-l -tetralone (D9) and 5-methoxy-6-(4- methylpiperazin-l-yl)indoline (Intermediate 3 in WO 95/06627) using a similar method to Example 1, as the hydrochloride salt, a buff solid (33%).
  • affinities of the compounds of this invention were determined by methods described above.
  • 5-HT ⁇ A > 5-HT ⁇ B a nd 5-HTID Receptor Binding
  • Examples 1, 2, 3, 4, 9, 10, 11 and 14 had pKi values > 7.5 at 5-HT ⁇ A, 5-HTIB and 5-HTID receptors.

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

Abstract

Cette invention a trait à des composés correspondant à la formule (I) ou à l'un de leurs sels ayant une activité pharmacologique, formule dans laquelle Ra représente le groupe (1) dans lequel le noyau A représente un noyau carbocyclique à 5, 6 ou 7 ramifications éventuellement substitué par un ou plusieurs groupes alkyles comportant de 1 à 6 atomes de carbone, avec fusion sur les positions 2,3 ou 3,4 du noyau phényle adjacent, ce noyau A étant éventuellement fusionné à un autre noyau phényle éventuellement substitué par un ou plusieurs substituants sélectionnés, de manière indépendante, entre un alkyle comportant de 1 à 6 atomes de carbone et un halo, R2 représente un halogène, un alkyle comportant de 1 à 6 atomes de carbone, un cycloalkyle comportant de 3 à 6 atomes de carbone, un cycloalcényle comportant de 3 à 6 atomes de carbone, un alcoxy comportant de 1 à 6 atomes de carbone, un alcanoyle comportant de 1 à 6 atomes de carbone, un aryle, un hydroxy, un nitro, un trifluorométhyle, un cyano, CO¿2?R?10, CONR10R11, NR10R11 où R10 et R11¿ représentent, de manière indépendante, un hydrogène ou un alkyle comportant de 1 à 6 atomes de carbone, a valant 0, 1 ou 2, L représente un groupe correspondant à la formule: -Y-C(=O)-DG- ou C(=O)-DG ou -DG-C(=O)-, formule dans laquelle Y représente -NH-, NR5 où R5 représente un alkyle comportant de 1 à 6 atomes de carbone, ou bien Y représente -CH¿2?- ou -O-, D représente un azote, un carbone ou un groupe CH, G représente un hydrogène ou un alkyle comportant de 1 à 6 atomes de carbone, à condition que D représente un azote ou un groupe CH ou bien G et R?11¿ constituent un groupe W dans lequel W représente (CR16R17) où t vaut 2, 3 ou 4 et R?16 et R17¿ représentent, de manière indépendante, un hydrogène ou un alkyle comportant de 1 à 6 atomes de carbone ou bien W représente (CR16R17)u-J où u vaut 0, 1, 2 ou 3 et où J représente un oxygène, un soufre, CR?16=R17, CR16=N, =CR16O, =CR16¿S ou =CR16-NR17, à condition que la valeur de u ne soit pas 0 lorsque J représente un oxygène ou un soufre, X représente un azote ou un carbone, R?b1 et Rb2¿ représentent, de manière indépendante, un hydrogène, un halogène, un hydroxy, un alkyle comportant de 1 à 6 atomes de carbone, un alcényle comportant de 2 à 6 atomes de carbone, un cycloalkyle comportant de 3 à 6 atomes de carbone, un trifluorométhyle, un alcoxy comportant de 1 à 6 atomes de carbone ou bien Rb1 et G forment un groupe W tel que défini ci-dessus, Rc représente un hydrogène ou un alkyle comportant de 1 à 6 atomes de carbone et ........ représente une liaison unique lorsque X représente un azote ou bien une liaison unique ou double lorsque X représente un carbone. Cette invention concerne également des procédés de mise au point de ces composés, des compositions les renfermant et leur utilisation dans le traitement d'affections du système nerveux central.
PCT/EP1998/007803 1997-12-05 1998-12-01 Derives d'arylpiperazine et d'arylpiperidine, leur mise au point et leur utilisation en tant qu'antagonistes des recepteurs de 5-ht1a, 5-ht1b et 5-ht1d combines Ceased WO1999029666A1 (fr)

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WO2002074764A3 (fr) * 2001-03-15 2002-11-14 Smithkline Beecham Plc Derives de la piperazine, leur preparation et leurs applications therapeutiques
WO2004110994A1 (fr) * 2003-06-18 2004-12-23 Pfizer Products Inc. Nouveaux lactames de piperazinyl-aryloxy et de piperazinyl-heteroaryloxy-n-aryle
WO2020048043A1 (fr) * 2018-09-06 2020-03-12 中国科学院上海药物研究所 Composé d'aniline pour la prévention ou le traitement d'un trouble mental
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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO2001023374A1 (fr) * 1999-09-25 2001-04-05 Smithkline Beecham P.L.C. Derives de piperazine utilises en tant qu'antagonistes de 5-ht1b
US6747030B1 (en) 1999-09-25 2004-06-08 Smithkline Beecham P.L.C. Piperazine derivatives as 5-HT1B antagonists
WO2002074764A3 (fr) * 2001-03-15 2002-11-14 Smithkline Beecham Plc Derives de la piperazine, leur preparation et leurs applications therapeutiques
US7109201B2 (en) 2001-03-15 2006-09-19 Smithkline Beecham Plc Piperazine derivatives, their preparation and uses in therapy
WO2004110994A1 (fr) * 2003-06-18 2004-12-23 Pfizer Products Inc. Nouveaux lactames de piperazinyl-aryloxy et de piperazinyl-heteroaryloxy-n-aryle
US7101885B2 (en) 2003-06-18 2006-09-05 Pfizer Inc Piperazinyl-aryloxy and piperazinyl-heteroaryloxy-n-aryl lactams
WO2020048043A1 (fr) * 2018-09-06 2020-03-12 中国科学院上海药物研究所 Composé d'aniline pour la prévention ou le traitement d'un trouble mental
WO2020183011A1 (fr) 2019-03-14 2020-09-17 Institut Curie Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer

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