EP0716656A1 - Derives d'amide en tant qu'antagonistes du recepteur de 5ht1d - Google Patents

Derives d'amide en tant qu'antagonistes du recepteur de 5ht1d

Info

Publication number
EP0716656A1
EP0716656A1 EP94924865A EP94924865A EP0716656A1 EP 0716656 A1 EP0716656 A1 EP 0716656A1 EP 94924865 A EP94924865 A EP 94924865A EP 94924865 A EP94924865 A EP 94924865A EP 0716656 A1 EP0716656 A1 EP 0716656A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
methyl
halogen
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94924865A
Other languages
German (de)
English (en)
Inventor
David Malcolm Duckworth
Laramie Mary Gaster
Keith Raymond Mulholland
Paul Adrian Wyman
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 GB939318328A external-priority patent/GB9318328D0/en
Priority claimed from GB939318326A external-priority patent/GB9318326D0/en
Priority claimed from GB939325752A external-priority patent/GB9325752D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0716656A1 publication Critical patent/EP0716656A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to novel amide derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • EPA 0533266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HT- * j> receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders.
  • the present invention therefore provides a compound of formula (I) or a salt thereof:
  • R! is optionally substituted phenyl or an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur or
  • R3 is hydrogen, halogen, hydroxy, C ⁇ galkyl or Cj.galkoxy
  • R 4 is hydrogen or C- ⁇ alkyl
  • A is a bond or an acyclic hydrocarbon chain having 1 to 6 carbon atoms; and n is 1 or 2.
  • the group R* can be an aromatic or saturated heterocyclic ring.
  • R* is an aromatic heterocyclic ring
  • examples of such rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, isothiazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl.
  • R* is a saturated ring examples include piperidine, morpholine and piperazine rings.
  • the group R* can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom.
  • R* is attached to the 4-position of the phenyl ring, that is to say, para to the amide group.
  • Optional substituents for R heterocyclic rings include halogen, C ⁇ _6alkyl, Cj-galkoxy, hydroxy, cyano, nitro, amino, CO2R or CONR R ⁇ where R 5 and R-5 are independently hydrogen or C ⁇ _6alkyl.
  • R* phenyl groups can be mono or di-substituted.
  • Optional substituents for R* phenyl groups include halogen, C ⁇ _6alkyl, Cj.galkoxy, hydroxy, cyano, nitro, amino, CO2R or CONR R6 where R 5 and R ⁇ are independently hydrogen or Cj.galkyl as well as 5 to 7-membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. These heterocyclic rings can themselves be substituted, for example by Ci.galkyl.
  • R* is halogen, cyclohexyl, optionally substituted pyridyl or optionally substituted phenyl. More preferably R is phenyl disubstituted by a Ci.galkyl group and a l-2,4-oxadiazol-3-yl group, in particular disubstituted by a methyl and a 5-methyl- 1-2,4- oxadiazol-3-yl group. Most preferably R is a group of formula:
  • R ⁇ is hydrogen or Cj.galkyl, for example methyl.
  • R ⁇ is hydrogen, halogen, hydroxy, Cj.galkyl or Cj.galkoxy.
  • R3 is C- ⁇ alkoxy such as methoxy.
  • n 1
  • R 4 is hydrogen or Cj.galkyl.
  • R 4 is Ci.galkyl such as methyl.
  • the term 'chain of 1 to 6 carbon atoms' means carbon atoms extending in a branched or unbranched chain between the phenyl group and the amide group.
  • the hydrocarbon chain can be an alkylene chain, for example methylene or ethylene, or A can contain alkene or alkyne groups.
  • the group A can be methylene or ethylene.
  • A is a bond.
  • C ⁇ _6alkyl groups may be straight chain or branched.
  • Particularly preferred compounds include:
  • 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.
  • Certain compounds of formula (I) are capable of existing in stereoisomeric forms.
  • the present invention provides a process for the preparation of a compound of formula (I) which comprises.
  • R 4 is as defined in formula (I) and Hal is halogen, or
  • R ⁇ , R ⁇ , R 4 , A and n are as defined in formula (I) and Y is halogen or a group OSO2CF3 with a compound of formula (Nil):
  • R ⁇ , R 4 and n are as defined in formula (I) and R ⁇ is Cj ⁇ alkyl in the presence of a trialkylaluminium reagent; and optionally after any of the above processes:
  • Suitable activated carboxylic acid derivatives of formula (HT) include acyl halides and acid anhydrides. Activated compounds of formula (HT) can also be prepared by reaction of the corresponding carboxylic acid widi a coupling reagent such as carbonyld ⁇ midazole, dicyclohexylcarbodiimide or diphenylphosphorylazole.
  • a coupling reagent such as carbonyld ⁇ midazole, dicyclohexylcarbodiimide or diphenylphosphorylazole.
  • the group L is halo, particularly chloro.
  • a compound of formula (II) is typically reacted with a compound of formula (HT) in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as rriethylamine or pyridine.
  • a compound of formula (HT) can be prepared from a compound of formula (XI):
  • acid chlorides can be prepared by reaction with phosphorous pentachloride, oxalyl chloride or thionyl chloride.
  • Acid anhydrides can be prepared by reaction with a suitable acid anhydride, for example trifluoroacetic anhydride.
  • Reaction of a compound of formula (IN) with a compound of formula (N) is suitably carried out in an alcohol or nitrile solvent with an optional base or, alternatively, in a non-polar solvent such as chlorobenzene in the absence of base.
  • the reactions are carried out at ambient or elevated temperature, preferably at the reflux temperature of the reaction mixture.
  • Reaction of compounds of formula (VI) and (VII) and reaction of compounds of formulae (VET) and (DC) can be carried out in the presence of a transition metal catalyst such as Pd(PPh3)4 in a solvent such as an ether in the presence of a base such as an alkali metal carbonate or bicarbonate, for example sodium carbonate or bicarbonate, at ambient or elevated temperature.
  • a transition metal catalyst such as Pd(PPh3)4
  • a solvent such as an ether
  • a base such as an alkali metal carbonate or bicarbonate, for example sodium carbonate or bicarbonate
  • Antagonists and in particular the compounds of the present invention, are expected to be of use in the treatment of CNS disorders such as mood disorders, including depression, seasonal effective 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, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa.
  • CNS disorders include depression, seasonal effective 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, amnestic disorders and age-associated memory impairment; and disorders of eating behaviours, including anorexia nervosa and bulimia nervosa.
  • CNS disorders include depression, seasonal effective disorder and dysthymia; anxiety disorders, including generalised anxiety
  • Parkinson's disease dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and taidive dyskinesias, as well as other psychiatric disorders.
  • 5HTID Antagonists may also be of use in the treatment of endocrine disorders such as hyperprolactinaemia, in the treatment of vasospasm (particularly in the cerebral vasculature) and hypertension, as well as disorders in the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of sexual dysfunction.
  • the present invention provides a compound of general formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy.
  • 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.
  • the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
  • 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.
  • 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.
  • Methyl 4-hydroxy-3-nitrobenzoate (5.00g, 0.025mol), was dissolved in acetone (100 ml), and treated with anhydrous potassium carbonate (6.9 lg, O.OSOmol), followed by iodomethane (1.71 ml, 0.0275mol). The mixture was then heated to reflux with stirring. After 16h, more iodome ⁇ ane (1.71 ml, 0.0275mol) was added and reflux was maintained for a further 3h. The reaction mixture was then filtered and the filtrate evaporated under reduced pressure to give an orange solid, which was dried in vacuo. The solid was then suspended in ethanol (200 ml), and was hydrogenated at atmospheric pressure in the presence of 5% PdC catalyst (0.5g).
  • reaction mixture was filtered through kieselguhr and evaporated under reduced pressure to give a pale yellow oily solid, which was dried in vacuo.
  • the oily solid was dissolved in chlorobenzene (50 ml), and mechloroethamine hydrochloride (14.44g, 0.075mol) was added.
  • the reaction mixture was then heated to reflux under argon. After 30h, the reaction mixture was allowed to cool, and was left for a further 24h at room temperature before being evaporated under reduced pressure and partitioned between potassium carbonate solution and dichloromethane.
  • the aqueous layer was then treated with aq. sodium bicarbonate until basic and then extracted with dichloromethane (2X).
  • the combined organic layers were then dried (Na2SO4), and evaporated under reduced pressure to give a pale brown solid.
  • the solid was the purified by silica-gel chromatography (6% MeOH/CH2Cl2) as eluant, to give the title compound as a cream coloured foam (0.2 lOg, 47%), which was converted to its oxalate salt.
  • n-Butyllithium (1.6M in hexanes) (8.36 ml, 0.013 mol) was added dropwise at -90 to - 100°C to a stirred solution of the product from Example 1 (0.450g, 1.11 mmol) in dry THF (20 ml) over 20 minutes.
  • the reaction mixture was the kept at -90°C for 0.5h, before being allowed to warm to -78°C, and was kept at -78°C for a further lh, before being allowed to warm to room temperature.
  • the reaction mixture was then stirred at room temperature overnight, before being treated with water (5 ml). After a further 2h stirring at room temperature, the reaction mixture was evaporated under reduced pressure and dried in vacuo.
  • the resultant yellow solid was then purified by silica-gel chromatography (10% MeOH/CH2 ⁇ 2) to give the derived phenylboronic acid (0.090g) as an off-white solid.
  • the phenylboronic acid (0.075g, 0.203mmol) was then dissolved in DME (5 ml) and treated with 3-(4-Bromo-3-methylphenyl)-5-methyl-l,2,4-oxadiazole (0.051g, 0.203mmol) (E.P. 0533 268 Al).
  • the mixture was then flushed with argon and Pd(PPh3)4 (10 mg) was added, the mixture was the heated to reflux under argon. After 20h, the reaction mixture was allowed to cool, and was partitioned between CH2CI2 and water.
  • the title compound was prepared from 4-cyclohexylaniline (0.19g, l.lmmol) and the product from description 1 (0.29g, l.lmmol) using the method described for example 2. Yield 0.13g, 29%.

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

Abstract

L'invention se rapporte à des nouveaux dérivés d'amide, à leurs procédés de préparation, aux compositions pharmaceutiques les contenant et à leur utilisation comme médicaments.
EP94924865A 1993-09-03 1994-08-09 Derives d'amide en tant qu'antagonistes du recepteur de 5ht1d Withdrawn EP0716656A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB9318328 1993-09-03
GB939318328A GB9318328D0 (en) 1993-09-03 1993-09-03 Novel compounds
GB939318326A GB9318326D0 (en) 1993-09-03 1993-09-03 Novel compounds
GB9318326 1993-09-03
GB9325752 1993-12-16
GB939325752A GB9325752D0 (en) 1993-12-16 1993-12-16 Novel compounds
PCT/EP1994/002661 WO1995006644A1 (fr) 1993-09-03 1994-08-09 Derives d'amide en tant qu'antagonistes du recepteur de 5ht1d

Publications (1)

Publication Number Publication Date
EP0716656A1 true EP0716656A1 (fr) 1996-06-19

Family

ID=27266837

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94924865A Withdrawn EP0716656A1 (fr) 1993-09-03 1994-08-09 Derives d'amide en tant qu'antagonistes du recepteur de 5ht1d

Country Status (2)

Country Link
EP (1) EP0716656A1 (fr)
WO (1) WO1995006644A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9507203D0 (en) * 1995-04-07 1995-05-31 Smithkline Beecham Plc Novel compounds
CA2338697A1 (fr) 1998-07-28 2000-02-10 Smithkline Beecham Corporation Composes et procedes
GB9827882D0 (en) * 1998-12-17 1999-02-10 Smithkline Beecham Plc Novel compounds
PE20020506A1 (es) 2000-08-22 2002-07-09 Glaxo Group Ltd Derivados de pirazol fusionados como inhibidores de la proteina cinasa
GB0124933D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124936D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124939D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
CA2474192C (fr) 2002-02-12 2011-06-21 Smithkline Beecham Corporation Derives de nicotinamide utiles comme inhibiteurs de p38
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
GB0308185D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308201D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308186D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0318814D0 (en) 2003-08-11 2003-09-10 Smithkline Beecham Corp Novel compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3063878D1 (en) * 1979-07-13 1983-07-28 Thomae Gmbh Dr K Derivatives of carboxylic acids, their preparation and medicaments containing them
DE3100535A1 (de) * 1981-01-10 1982-08-12 Dr. Karl Thomae Gmbh, 7950 Biberach "neue carbonsaeure-derivate, ihre herstellung und ihre verwendung als arzneimittel"
ES2162792T3 (es) * 1991-09-18 2002-01-16 Glaxo Group Ltd Derivados de benzanilida como antagonistas de 5-ht1d.
GB9119932D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
GB9119920D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9506644A1 *

Also Published As

Publication number Publication date
WO1995006644A1 (fr) 1995-03-09

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