EP1047691A1 - Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d - Google Patents

Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d

Info

Publication number
EP1047691A1
EP1047691A1 EP98965729A EP98965729A EP1047691A1 EP 1047691 A1 EP1047691 A1 EP 1047691A1 EP 98965729 A EP98965729 A EP 98965729A EP 98965729 A EP98965729 A EP 98965729A EP 1047691 A1 EP1047691 A1 EP 1047691A1
Authority
EP
European Patent Office
Prior art keywords
quinolin
methylpiperazin
urea
formula
naphth
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.)
Withdrawn
Application number
EP98965729A
Other languages
German (de)
English (en)
Inventor
Laramie Mary Smithkline Beecham Pharm. Gaster
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9726364.4A external-priority patent/GB9726364D0/en
Priority claimed from GBGB9726905.4A external-priority patent/GB9726905D0/en
Priority claimed from GBGB9800317.1A external-priority patent/GB9800317D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1047691A1 publication Critical patent/EP1047691A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/24—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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/46—Nitrogen atoms attached in position 4 with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
    • 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
    • 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

  • the present invention relates to novel piperazine derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • 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-HTi j ⁇ receptor antagonist activity.
  • the 5-HT ⁇ rj) receptor was subsequently found to consist of a pair of gene products originally designated 5-HTi ) ⁇ and 5-HTj ) ⁇ receptors which have more recently been reclassified as 5-HTj ) and 5-HTJB receptors respectively.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • R a is selected from a group of formula (i), (ii) or (iii); Group of formula (i)
  • P' is phenyl, bicyclic aryl, a 5 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur;
  • R1 is hydrogen, halogen, C j .galkyi, C3_6cycloalkyl. C ⁇ galkoxy. hydroxy. hydroxyCi. galkyl, hydroxyC ⁇ . ⁇ alkoxy, Ci- ⁇ alkoxyCi- ⁇ alkoxy, C j _6alkanoyl, nitro, trifluoromethyl, cyano.
  • R 9 , R 10 and R* 1 are independently hydrogen or C ⁇ _6alkyl and c is 1 to 4; a is 0, 1 or 2; and
  • R- is halogen, C i.galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, C ⁇ alkoxy, Cj.galkanoyl, aryl, acyloxy, hydroxy, nitro, trifluoromethyl, cyano, CO R 10 , CONR ⁇ R 1 1 , NR 10 R! 1 where RlO and R ⁇ are as defined above;
  • P ⁇ and P ⁇ are independently phenyl, bicyclic aryl, a 5- to 7- membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or a bicyclic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
  • A is a bond or oxygen, S(O) m where m is 0 to 2, carbonyl, CH? or NR ⁇ where R ⁇ is hydrogen or C i .galkyl;
  • R! is as defined above for formula (i) or is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C ⁇ .
  • R- and R ⁇ are independently halogen, Ci .galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, C ⁇ _ galkoxy, C ⁇ .galkanoyl, aryl. acyloxy, hydroxy, nitro, trifluoromethyl, cyano. CO 2 RlO,
  • the ring E is a 5, 6 or 7 -membered carbocyclic ring optionally substituted by one or more C j. ⁇ alkyl groups, fused at the 2.3- or 3.4-positions of the adjacent phenyl ring, the ring E being optionally fused to a further phenyl ring optionally substituted by one or more substituents independently selected from C ⁇ galkyl and halo; a is 0. 1 or 2; and
  • R- is halogen, C ⁇ .galkyl, C3_6cycloalkyl, C3_6cycloalkenyl, C ⁇ alkoxy, C ⁇ .galkanoyl, aryl, acyloxy, hydroxy, nitro. trifluoromethyl, cyano, CO 2 R 10 , CONR 10 Rl 1 , NR 10 R! 1 where RI O and R ⁇ are as defined above;
  • L is a group of formula
  • D is nitrogen, carbon or a CH group
  • G is hydrogen or C ⁇ -. ⁇ alkyl providing that D is nitrogen or a CH group
  • R°l forms a group W where W is (CR ⁇ R ⁇ ) t where t is
  • X is nitrogen or carbon
  • R°l, Rb2 and R° are independently hydrogen, halogen, hydroxy, Cj.galkyl,
  • R c is hydrogen or Chalk 1
  • • — is a single bond when X is nitrogen or a single or double bond when X is carbon.
  • Ci .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 [.galkyl.
  • the term 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl or naphthyl.
  • 'halogen ' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • the bicyclic aryl group represented by ? P- .and or PJ which may be partially saturated, is preferably naphthyl.
  • examples of bicyclic heterocyclic rings represented by P J ? ⁇ and/or P ⁇ include isoquinoline. indole. benzofuran, benzothiophene. and most preferably quinoline.
  • Examples of 5 to 7 membered heterocyclic rings represented by pi , ? ⁇ and/or p3, include thienyl, furyl, pyrrolyl, triazolyl. imidazolyl. oxazolyl, thiazolyl. oxadiazolyl, isothiazolyl, isoxazolyl. thiadiazolyl, pyrimidyl, pyrazinyl. and most preferably pyridyl.
  • the heterocyclic and bicyclic heterocyclic groups listed above can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
  • P 1 is preferably a phenyl, naphthyl or quinoline group.
  • P ⁇ is preferably phenyl or naphthyl.
  • R! is preferably a halogen atom most preferably, fluorine, chlorine or bromine, and R2 and/or R ⁇ are each preferably a halogen atom preferably, chlorine or bromine, or a C j . galkyl group for example a methyl group.
  • A is preferably a bond or oxygen.
  • the ring E in addition to the keto group and the portion fused to the phenyl ring, is preferably formed from a straight chain alkylene grouping containing 2, 3 or 4 carbon atoms.
  • the ring E 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 E being preferably attached to the 3,4-positions of the latter phenyl ring.
  • the group L is preferably a group of formula:-
  • D is preferably nitrogen and G is preferably a hydrogen atom or together with R D * forms a group W, preferably -(CH 2 ) - or -(CH )3-.
  • Rb*, R°2 and R°3 are preferably hydrogen or a halogen atom most preferably bromine or chlorine, or a C ⁇ .galkoxy group for example methoxy, or R D 1 together with G forms a group W referred to above.
  • X is preferably nitrogen.
  • R c is preferably a C j.galkyl group for example methyl.
  • Particularly preferred compounds according to the invention include:- N-[3-Chloro-4-(pyridin-4-yl)phenyl]-N'-[4-(4-methylpiperazin-l-yl)quinolin-6-yl]-urea,
  • Preferred salts of the compounds of formula (I) are pharmaceutically acceptable salts. These include acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates. tartrates, citrates, oxalates, methanesulphonates and p- toluenesulphonates.
  • acid addition salts such as hydrochlorides, hydrobromides, phosphates, acetates, fumarates, maleates. tartrates, citrates, oxalates, methanesulphonates and p- toluenesulphonates.
  • R a , Rbl . Rb2 ⁇ Rb3 ? R C ⁇ d x are .as defined in formula (I) and L 1 and L ⁇ contain the appropriate functional groups which are capable of reacting together to form the L moiety; or
  • R a -NC( O) (IV) in which R a is as defined in formula (I) or a protected derivative thereof, with a compound of formula (V):
  • L l is COL and L 2 is NH 2
  • L 1 is NH 2
  • L 2 is COL a in which L a is an appropriate leaving group.
  • one of L.1 and L- is an activated carboxylic 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 carboxylic acid with a coupling agent such as dicyclohexylcarbodiimide. carbonyldiimidazole or diphenylphosphorylazide.
  • a coupling agent such as dicyclohexylcarbodiimide. carbonyldiimidazole or diphenylphosphorylazide.
  • Li or L 2 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 IJ 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.
  • 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.
  • Carboxylic 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 (5-hydroxytryptamine; 5HT) receptors have been implicated in a number of pharmacological effects including 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
  • 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 ofthe 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-HTJ D receptor antagonist in conjunction with a 5-HTIA 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-HTj A 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, + . 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.
  • the invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in the treatment or prophylaxis of depression.
  • 5-HT ⁇ g and 5-HT I Q receptors can be determined by the following radioligand binding assay.
  • HEK 293 cells expressing 5-HTJA. receptors (4 x 10 ⁇ /ml) are homogenised in Tris buffer and stored in lml aliquots.
  • CHO cells expressing 5-HTjg receptors (4 x 10 ⁇ cells/ml) are homogenised in Tris buffer and stored in 1.5 ml aliquots.
  • CHO cells expressing 5-HTi ) 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-HT ⁇ ⁇ receptors and CHO cell membranes stably expressing human 5-HT ⁇ g receptors are homogenised in HEPES/EDTA buffer and stored in lml aliquots, and [ 3 ⁇ S]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 MgCh (3 mM), NaCl (100 mM), GDP (10 ⁇ 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) /MgCl 2 (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 5HT ⁇ A , 5-HTj ⁇ and 5-HT J E) receptors. It has been found, using the [-°S]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 (Hover 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 5HT I A, 5-HTj ⁇ and 5-HTJ Q 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 compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, a selective serotonin reuptake inhibitor (SSRJ) antidepressant.
  • SSRJ selective serotonin reuptake inhibitor
  • 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 ofthe 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 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.
  • the title compound was prepared from 4-chloro-3-cyanoaniline (D9) and pyridin-4-ylboronic acid using a similar procedure to Description 3.
  • the crude product was purified by chromatography on silica gel eluting with ethyl acetate to give needles from ether (8%), mp
  • the mixture was stirred well at 0-5°C for 1 hour, then diluted with water (20ml) and extracted with dichloromethane. The extract was dried (Na 2 SO4) and cautiously concentrated under vacuum at room temperature to approx. 10ml volume. This solution was then treated with toluene (30ml) and gently heated under argon to reflux temperature and maintained for 0.5 hours. The reaction mixture was allowed to cool and the isocyanate solution used directly in the next step.
  • the title compound was prepared from 5-(2-methylpyridin-5-yl)-l-naphthoic acid (D29) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • the title compound was prepared from 5-(2-methylpyridin-3-yl)-l-naphthoic acid (D31) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • the title compound was prepared from 2-bromopyrimidine and 5-carboxynaphth-l-ylboronic acid (D26) using a similar procedure to Description 3 to afford the product as an off-white solid.
  • the title compound was prepared from 5-(pyrimidin-2-yl)-l-naphthoic acid (D33) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • the title compound was prepared from diethyl 1 -benzyl- 1,2.3, 4-tetrahydroquinolin-6- ylaminojmethylenemalonate (D47, 9Jg, 223mmol) following a similar procedure to Description 38 (3J 8g. 37%).
  • the title compound was prepared from l-benzyl-9-(4-methylpiperazin-l-yl)- 1,2,3,4- tetrahydropyrido[2,3-g]quinolin-8-ylcarboxylic acid (D50, 2.5g, ⁇ .Ommol) following a similar procedure to Description 41 (lJg, 76%).
  • Finely ground N-[2-bromophenyl]glyoxamide oxime (D53, 292g, 0J2mol) was added portionwise to well stirred cone. H 2 SO4 (64ml) at 50°C maintaining an internal temperature of 50-70°C during the addition. The mixture was then heated to 80-85°C for 10 minutes, cooled to room temperature and poured onto crushed ice (600g) with stirring. A red/brown precipitate ofthe title compound formed. This was filtered off, washed with water and dried in a vacuum oven (14.8g, 55%).
  • the title compound was prepared from 8-bromoquinolin-4-ylcarboxylic acid (D56) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • the title compound was prepared from 8-(2-fluorophenyl)quinolin-4-ylcarboxylic acid (D58) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • the title compound was prepared from 8-(2-methoxyphenyl)quinolin-4-ylcarboxylic acid (D60) using a similar procedure to Description 28.
  • the isocyanate was not isolated, but used in the next step as its toluene solution.
  • CDCI3 ⁇ (ppm): 9.1 (s, IH), 8.95 (s, IH), 8.65 (d, 2H), 8.55 (d, IH), 8.5 (s, IH), 7.8 (d, IH), 7.6 (s, IH), 7.45 (d, IH), 7.3 (d, 2H), 7.2 (d, 2H), 6.8 (d, IH), 3.25 (br s, 4H), 2.65 (br s, 4H), 2.35 (s, 3H).
  • the title compound was prepared from 6-aminoquinoline and 6-amino-4-(4-methypiperazin- l-yl)quinoline (D2) following a similar procedure to Example 1 as a yellow powder from ether (1 1%), m.p. 240 - 250°C (dec).
  • the title compound was prepared from 4-(pyridin-4-yl)-3-trifluoromethylaniline (D8) and 6- amino-4-(4-methylpiperazin- 1 -yl)quinoline (D2) following a similar procedure to Example 1 as a yellow powder (47%).
  • the title compound was prepared from 5-cyano-l-naphthylamine (EP 456090) and 6-amino- 4-(4-methylpiperazin-l-yl)quinoline (D2) using a similar procedure to Example 1 as a pale buff solid (50%).
  • Example 1 The hydrochloride salt was isolated as a green powder (34%). ⁇ NMR (HCl salt) (250MHz. d 6 DMSO) ⁇ (ppm): 11.36 (s, IH), 1 1.05 (s. I H). 9.80 (s, IH), 8.76 (d. IH), 8.68 (d, IH), 8.59 (s, IH). 8.18 (q, 3H), 7.96 (d, IH), 7.76-7.64 (m. 2H), 7.33 (d. I H). 4.22 (br s. 2H), 3.62 (br s. 4H). 2.90 (s. 3H), 2.75 (s, 3H). 2H obscurred by H O signal.
  • the title compound was prepared from 5-(pyrimidin-2-yloxy)-l-naphthylamine (D23) and 6- amino-4-(4-methylpiperazin-l -yl)quinoline (D2) using a similar procedure to Example 1 as a pale yellow solid (10%).
  • Example 27 The free base was converted to monohydrochloride salt as a yellow solid from acetone.
  • the title compound was prepared from 5-(pyrimidin-2-yl)naphth-l-yl isocyanate (D34) and 6-amino-4-(4-methylpiperazin-l -yl)quinoline (D2) using a similar procedure to that described for Example 27.
  • the free base was converted to monohydrochloride salt, as a yellow solid.
  • the title compound was prepared from 4-(pyridin-4-yl)-l-naphthylamine (D5) and 2,3- dihydro-8-(4-methylpiperazin-l-yl)pyrrolo[2,3-g]quinoline (D42) using a similar procedure to Example 1 as the hydrochloride salt, a yellow solid (67%).
  • the title compound was prepared from 5-(pyrimidin-2-yloxy)-l-naphthylamine (D23) and 23-dihydro-8-(4-methylpiperazin-l-yl)pyrrolo[2,3-g]quinoline (D42) using a similar procedure to Example 1 as the hydrochloride salt, a yellow solid (47%).
  • the title compound was prepared from 6-amino-3,4-dihydro-l(2H)-naphthalenone and 6- amino-4-(4-methylpiperazin-l-yl)quinoline (D2) using a similar procedure to Example 1 as a yellow foam (47%).
  • the title compound was prepared from 5-amino-l-indanone and 6-amino-4-(4- methylpiperazin-l-yl)quinoline (D2) using a similar procedure to Example 1 as a yellow foam (20%).
  • affinities of the compounds of this invention were determined by methods described above.
  • 5-HTJ A > 5-HTJ B and 5-HTJ D Receptor Binding

Landscapes

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

Abstract

L'invention concerne des composés représentés par la formule (I) ou un de leurs sels, dans laquelle Ra est sélectionné dans un groupe représenté par la formule (i), (ii) ou (iii); L représente un groupe de formule -Y-C(=O)-DG- ou -C(=O)-DG- ou -DG-C(=O)- dans lesquelles Y représente -NH-, NR5, R5 représentant alkyle C¿1?-C6, ou représente -CH2 ou -O-; D représente azote, carbone ou un groupe CH, G représente hydrogène ou alkyle C1-C6 à condition que D représente azote ou un groupe CH, ou G avec R?b1¿ constitue un groupe W dans lequel W représente (CR16R17)t dans laquelle t est 2, 3 ou 4 et R?16 et R17¿ représentent indépendamment hydrogène ou alkyle C¿1?-C6 ou W représente (CR?16R17)¿u-J dans laquelle u est 0, 1, 2 ou 3 et J représente oxygène, soufre, CR?16=CR17, CR16=N, =CR16O, =CR16¿S ou =CR16-NR17 à condition qu'u ne soit pas 0 quand J représente oxygène ou soufre; X représente azote ou carbone; R?b1, Rb2 et Rb3¿ représentent indépendamment hydrogène, halogène, hydroxy, alkyle C¿1?-C6, alkényle C2-C6, cycloalkyle C3-C6, trifluorométhyle, alkoxy C1-C6 ou aryle, ou R?b1¿ et G constituent un groupe W défini ci-dessus; Rc représente hydrogène ou alkyle C¿1?-C6 et représente une liaison simple quand X représente azote ou une liaison simple ou double quand X représente carbone, ces composés exerçant une activité pharmacologique, des procédés servant à les préparer, des compositions les contenant et leur utilisation afin de traiter des maladies du système nerveux central.
EP98965729A 1997-12-12 1998-12-02 Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d Withdrawn EP1047691A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB9726364 1997-12-12
GBGB9726364.4A GB9726364D0 (en) 1997-12-12 1997-12-12 Novel Compounds
GB9726905 1997-12-19
GBGB9726905.4A GB9726905D0 (en) 1997-12-19 1997-12-19 Novel compounds
GB9800317 1998-01-07
GBGB9800317.1A GB9800317D0 (en) 1998-01-07 1998-01-07 Novel compounds
PCT/EP1998/007804 WO1999031086A1 (fr) 1997-12-12 1998-12-02 Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d

Publications (1)

Publication Number Publication Date
EP1047691A1 true EP1047691A1 (fr) 2000-11-02

Family

ID=27269131

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98965729A Withdrawn EP1047691A1 (fr) 1997-12-12 1998-12-02 Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d

Country Status (4)

Country Link
EP (1) EP1047691A1 (fr)
JP (1) JP2002508366A (fr)
CA (1) CA2313125A1 (fr)
WO (1) WO1999031086A1 (fr)

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9827882D0 (en) * 1998-12-17 1999-02-10 Smithkline Beecham Plc Novel compounds
US6693202B1 (en) 1999-02-16 2004-02-17 Theravance, Inc. Muscarinic receptor antagonists
AU6314900A (en) * 1999-07-26 2001-02-13 Banyu Pharmaceutical Co., Ltd. Biarylurea derivatives
JP2001106673A (ja) * 1999-07-26 2001-04-17 Banyu Pharmaceut Co Ltd ビアリールウレア誘導体
GB9926303D0 (en) * 1999-11-05 2000-01-12 Smithkline Beecham Plc Novel compounds
ATE286883T1 (de) * 1999-11-05 2005-01-15 Smithkline Beecham Plc Isochinolin und chinazolinderivate mit kombinierter 5ht1a, 5ht1b und 5ht1d rezeptor aktivität
UA73543C2 (uk) * 1999-12-07 2005-08-15 Тераванс, Інк. Похідні сечовини, фармацевтична композиція та застосування похідного при приготуванні лікарського засобу для лікування захворювання, яке опосередковується мускариновим рецептором
DE60021282T2 (de) 1999-12-07 2006-05-18 Theravance, Inc., South San Francisco Carbamat-derivate als muscarin-rezeptor antonisten
DE10139416A1 (de) * 2001-08-17 2003-03-06 Aventis Pharma Gmbh Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
US7084156B2 (en) 2001-11-27 2006-08-01 Merck & Co., Inc. 2-Aminoquinoline compounds
CA2484340C (fr) 2002-04-26 2011-05-03 Ortho-Mcneil Pharmaceutical, Inc. Heterocycles a fusion 2-(quinolonyle) en tant que modulateurs du recepteur d'androgenes
BR0312204A (pt) 2002-06-27 2005-04-26 Schering Ag Antagonista de receptor ccr5 de quinolina substituìda
PE20040950A1 (es) 2003-02-14 2005-01-01 Theravance Inc DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS
GB0316915D0 (en) 2003-07-18 2003-08-20 Glaxo Group Ltd Compounds
JP4851937B2 (ja) 2003-11-21 2012-01-11 セラヴァンス， インコーポレーテッド β２アドレナリン作動性受容体作動薬活性およびムスカリン受容体拮抗薬活性を有する化合物
SV2005001973A (es) 2003-12-12 2005-11-04 Wyeth Corp Quinolinas utiles en el tratamiento de enfermedades cardiovasculares ref. wyth0090-504 (am101500)
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
EP1954696B1 (fr) 2005-01-19 2011-02-23 Bristol-Myers Squibb Company Dérivés 2-phénoxy-n-(1,3,4-thiadizol-2-yl)pyridin-3-amine et composés similaires en tant que inhibiteurs du récepteur p2y1 pour le traitement de maladies thromboemboliques
US8071768B2 (en) 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
US7825244B2 (en) 2005-06-10 2010-11-02 Janssen Pharmaceutica Nv Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis
ES2352796T3 (es) 2005-06-27 2011-02-23 Bristol-Myers Squibb Company Antagonistas cíclicos unidos a c del receptor p2y1 útiles en el tratamiento de afecciones trombóticas.
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
EP1896466B1 (fr) 2005-06-27 2011-04-13 Bristol-Myers Squibb Company Antagonistes heterocycliques a liaison n du recepteur p2y1, utiles pour traiter des etats pathologiques thrombotiques
WO2007002584A1 (fr) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company Mimetiques lineaires de l’uree antagonistes du recepteur p2y1, utilises dans le traitement des troubles thrombotiques
GB0602778D0 (en) 2006-02-10 2006-03-22 Glaxo Group Ltd Novel compound
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US9410947B2 (en) 2012-08-07 2016-08-09 University Of Washington Through Its Center For Commercialization Fluorescent dyes and related methods
SG11201700776XA (en) 2014-08-01 2017-02-27 Nuevolution As Compounds active towards bromodomains
WO2020183011A1 (fr) 2019-03-14 2020-09-17 Institut Curie Inhibiteurs de htr1d et leurs utilisations dans le traitement du cancer

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032967A1 (fr) * 1994-05-28 1995-12-07 Smithkline Beecham Plc Derives amide a activite antagoniste par rapport a 5ht1d
EP1019412A1 (fr) * 1995-08-11 2000-07-19 Smithkline Beecham Plc Derives de biphenyl(thio)amide et de biphenylethan(thi)one, leur preparation et leur utilisation comme antagonistes des recepteurs 5-ht 1d?
WO1999007700A1 (fr) * 1997-08-09 1999-02-18 Smithkline Beecham Plc Composes bicycliques servant de ligands pour les recepteurs 5-ht1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9931086A1 *

Also Published As

Publication number Publication date
CA2313125A1 (fr) 1999-06-24
WO1999031086A1 (fr) 1999-06-24
JP2002508366A (ja) 2002-03-19

Similar Documents

Publication Publication Date Title
WO1999031086A1 (fr) Derives de quinoleinepiperazine et de quinoleinepiperidine, leur preparation et leur utilisation en tant qu'antagonistes combines des recepteurs 5-ht1a, 5-ht1b et 5-ht1d
US10494371B2 (en) Bromodomain inhibitors
JP6918088B2 (ja) Ｇｐｒ１３９のモジュレーターとしての４−オキソ−３，４−ジヒドロ−１，２，３−ベンゾトリアジン
AU765020B2 (en) Piperazine derivatives as 5-HT1B antagonists
JP2007008816A (ja) 新規イソキノリン誘導体
CA2500083A1 (fr) Derives de tetrahydroquinoline antagonistes de crth2
JP2008507534A (ja) フラノピリジン誘導体および使用方法
WO1998047868A1 (fr) Derives d'uree contenant un heterocycle utilises comme antagonistes des recepteurs 5ht1a, 5ht1b et 5ht¿1d?
TW201035055A (en) Substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine compounds
TW200843777A (en) Inhibitors of the hedgehog pathway
NO313293B1 (no) Substituerte pyrido- eller pyrimido-holdige 6,6- eller 6,7- bicykliske derivater, anvendelse derav og farmasöytisk preparat
CA2355234A1 (fr) Composes
JP2002534508A (ja) Ｐｅｄ−ｉｖ阻害作用を有するフェニルフェナントリジン
US20090012056A1 (en) Quinoline Compounds Capable of Binding the Cb2 and/or the 5-Ht6 Receptor
US20100240648A1 (en) Hexahydro-pyrrolo-isoquinoline compounds
WO2013013614A1 (fr) 4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation
US6391891B1 (en) Bicyclic compounds as ligands for 5-HT1 receptors
JP2006517976A (ja) 新規化合物
US5472966A (en) Antidepressant heteroarylaminoalkyl derivatives of naphthyl-monazines
US4035368A (en) Substituted 3-(1H-tetrazol-5-yl)-quinoline compounds
US6031097A (en) 1-(N-(arylalkylaminoalkyl) aminoisoquinolines; a new class of dopamine receptor subtype specific ligands
EP1368337B1 (fr) Derives de la piperazine, leur utilisation comme ligands de 5-ht 1b
WO1999029666A1 (fr) 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
JP2001512491A (ja) １−（イソキノリン−１−イル）−４−（１−フェニメチル）ピペラジン；ドーパミン受容体サブタイプ特異的リガンド
US5972945A (en) 2-aminoalkylaminoquinolines; dopamine receptor subtype specific ligands

Legal Events

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

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000523

AK Designated contracting states

Kind code of ref document: A1

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

17Q First examination report despatched

Effective date: 20010705

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

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020116