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WO1998050346A2 - Derives d'acetamide et d'uree, procede de preparation et utilisation de ces derives dans le traitement des troubles du systeme nerveux central - Google Patents

Derives d'acetamide et d'uree, procede de preparation et utilisation de ces derives dans le traitement des troubles du systeme nerveux central Download PDF

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Publication number
WO1998050346A2
WO1998050346A2 PCT/EP1998/002263 EP9802263W WO9850346A2 WO 1998050346 A2 WO1998050346 A2 WO 1998050346A2 EP 9802263 W EP9802263 W EP 9802263W WO 9850346 A2 WO9850346 A2 WO 9850346A2
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WO
WIPO (PCT)
Prior art keywords
dimethylaminoethoxy
pyridin
dihydro
indole
iodophenyl
Prior art date
Application number
PCT/EP1998/002263
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English (en)
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WO1998050346A3 (fr
Inventor
Laramie Mary Gaster
Paul Adrian Wyman
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Smithkline Beecham Plc
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Publication date
Priority claimed from GBGB9707874.5A external-priority patent/GB9707874D0/en
Priority claimed from GBGB9801632.2A external-priority patent/GB9801632D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU75267/98A priority Critical patent/AU7526798A/en
Publication of WO1998050346A2 publication Critical patent/WO1998050346A2/fr
Publication of WO1998050346A3 publication Critical patent/WO1998050346A3/fr

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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C275/36—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • 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
    • 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
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel aryl compounds processes for their preparation, and pharmaceutical compositions containing them.
  • WO 95/15954, WO 95/17398, WO 95/26328 and WO 96/06079 disclose a series of biphenyl amide derivatives which are said to possess 5HTI D 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-HT ⁇ ⁇ j receptor antagonist activity.
  • a structurally distinct class of compounds have now been found to exhibit comb i ned 5HT ⁇ A, 5HTIB and 5 HTID receptor antagonist activity. It is expected that such compounds will be useful for the treatment and prophylaxis of various CNS disorders with the advantage of a relatively fast onset of action.
  • the present invention therefore provides a compound of formula (I) or a salt thereof: 5
  • R a is a group of formula (i)
  • P 1 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;
  • 5 R 1 is hydrogen, halogen, C _ 6 alkyl, C 3 .
  • R9, RlO and RI are independently hydrogen or Ci .galkyl and c is 1 to 4;
  • R2 is hydrogen, halogen, Cj.galkyl, C3_6"cycloalkyl,
  • 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, or CH 2 or NR ⁇ where R ⁇ is hydrogen or Ci .galkyl;
  • RI is as defined above for formula (i) or RI is a 5 to 7-membered heterocyclic ring, containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur, optionally substituted by C ⁇ _6 alkyl, halogen or Ci _6 alkanoyl;
  • R2 and R-* are independently hydrogen, halogen, C ⁇ galkyl, C .gcycloalkyl,
  • B is CH 2 , oxygen, S(O) p where p is 0, 1 or 2, NR ⁇ where R ⁇ is hydrogen or Ci . ⁇ alkyl or
  • R c and R are independently hydrogen or Cj.galkyl;
  • RY is a 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur, or
  • Ry is a group of formula - NR e R in which R e and R* are independently hydrogen, Ci .galkyl or aralkyl;
  • Rbl and R°2 are independently hydrogen, halogen, hydroxy, C ⁇ alkyl, trifluoromethyl, Ci .galkoxy or aryl, or R°l together with G forms a group W as defined above; and n is 0, 1, 2, 3 or 4.
  • Cj-galkyl groups whether alone or as part of another group may be straight chain or branched.
  • acyloxy' is used herein to describe a group -OC(O)C ⁇ .galkyl.
  • 'aryl' is used herein to describe, unless otherwise stated, a group such as phenyl.
  • 'aralkyl' is used herein to describe, unless otherwise stated, a group such as benzyl.
  • the bicyclic aryl group represented by pi, P ⁇ and or P- , which may be partially saturated, is preferably naphthyl.
  • bicyclic heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur include quinoline, isoquinoline, indole, benzofuran and benzothiophene rings.
  • the heterocyclic groups can be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
  • Examples of 5 to 7 membered heterocyclic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur represented by P ⁇ , P ⁇ and/or P ⁇ include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl, preferably pyridyl.
  • RI is preferably a halogen atom for example, fluorine, chlorine or bromine
  • R2 and or R ⁇ are each preferably hydrogen, halogen for example a chloro group or a C ⁇ . galkyl group for example a methyl group.
  • a and b are each preferably 1 or 2.
  • A is preferably a bond or oxygen, most preferably a bond.
  • Y is preferably -NH-.
  • V is preferably oxygen.
  • D is preferably nitrogen and G is preferably a hydrogen atom or together with R°l forms group W, preferably -(CH 2 ) 2 -.
  • the groups R ⁇ and R°2 are preferably hydrogen or a halogen atom for example iodine, or R°l together with G forms group W referred to above.
  • B is preferably CH 2 or oxygen, most preferably oxygen.
  • R c and Rd are preferably hydrogen.
  • Ry is a 5- to 7-membered heterocyclic ring such groups can be linked to the rest of the molecule by a carbon atom or, when present, a suitable nitrogen atom. Suitable examples of 5- to 7-membered heterocyclic rings include pyrrolidine, piperidine, piperazine, morpholine, optionally substituted by C j .galkyl, such as methyl.
  • Ry is preferably a piperidinyl group or a dialkylamino (e.g. dimethylamino) group.
  • n is preferably 2.
  • the group B-(CR c Rd) n -Ry has a meta relationship with respect to the group R a L.
  • the group R°2 has a para relationship with respect to the group R a L.
  • Particularly preferred compounds according to the invention include:-
  • 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. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and the mixtures thereof including racemates.
  • R a _NC( V) (II) in which R a and V are as defined in formula (I) or a protected derivative thereof with a compound of formula (III).
  • Y is -CH 2 - or -O- and L ⁇ is an appropriate leaving group, with a compound of formula (III)
  • reaction in process (a) 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, tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • the leaving group O- may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • the leaving group O- may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofiiran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
  • an inert organic solvent such as tetrahydrofiiran or dichloromethane
  • a base such as triethylamine or pyridine.
  • Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques.
  • Intermediate compounds of formula (II), (III), (IV), (V), (VI) and (VII) can be prepared using standard procedures known in the art.
  • 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.
  • 5HT ⁇ A/IB/ID receptor antagonists are expected to be of use in the treatment of CNS disorders 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, amnestic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa ;and sleep disorders.
  • CNS disorders include motor disorders such as Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
  • 5HT ⁇ pj ⁇ B/1D receptor 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 and hypothermia.
  • 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. It will be appreciated by those skilled in the art that 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.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 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 mixture was then concentrated in vacuo to a gum, which was partitioned between 2N sodium hydroxide solution and dichloromethane.
  • the aqueous layer was separated, adjusted to pH 0 with 6N hydrochloric acid and washed with dichloromethane; then adjusted to pH 7 by addition of aqueous potassium carbonate solution and extracted with dichloromethane.
  • the dichloromethane extract was dried (Na 2 SO4) and concentrated in vacuo to give the title compound, which crystallised from ether as needles mp 210-215°C (465mg, 46%).
  • the reaction was then concentrated in vacuo to a gum and partitioned between 5N HCl and dichloromethane.
  • the aqueous solution was separated and basified with 2N sodium hydroxide solution.
  • the product was recovered by extraction into dichloromethane, the organic layer separated, dried (Na SO4) and concentrated in vacuo to afford the title compound as a gum (1.2g, 89%).
  • 2,3-Dihydro-6-nitro-l H-indole (15.63g, 0.095 mol) was refluxed for 0.25h in acetic anhydride (100ml), cooled, and the precipitate filtered and washed with water, before drying in vacuo.
  • This material (16.6g, 0.08 mol) was hydrogenated in ethanol (500ml) over 10% palladium on charcoal (3.4g of 50% paste in water). The catalyst was removed by filtration and the filtrate was evaporated to leave the title compound as an off- white/cream powder (12.59g, 89%).
  • Tetrakis (triphenylphosphine) palladium (0) (0.260g) was added, a condenser attached and the mixture was heated at 100°C under argon for 10 h, then cooled.
  • the DMF was removed in vacuo and the residue partitioned between ethyl acetate (50ml) and 2M HCl (aq) (140ml).
  • the ethyl acetate layer was washed with 2M HCl (2x50ml), then the aqueous extracts were combined, basified to pHIO with K 2 CO 3 (s) and extracted with CH 2 C1 2 (3x100ml).
  • the title compound was prepared from 2-chloro-5-nitrophenol and 4-hydroxy-l -methyl piperidine using a similar procedure to description 41 to give the title compound in 26% yield.
  • the title compound was prepared from 4-bromo-3-hydroxyacetanilide and 2- dimethylaminoethyl chloride hydrochloride using a similar procedure to description 13 to afford the title compound in 46% yield.
  • the title compound was prepared from 5-bromo-l-butyryl-2,3-dihydro-6-hydroxy-lH- indole (D50) and (l-methylpiperidin-4-yl)methanol following a similar procedure to description 41 to give the title compound as cubes (m.p. 114-115°C) in 75% yield.
  • the compound was prepared from 4-bromo-3-methylphenylisocyanate (D2) using a similar procedure to Example 1.
  • Naphth-1 -ylacetic acid 250mg, 1.34 mmole was dissolved in dichloromethane (10ml) and treated with oxalyl chloride (338mg, 2.68 mmole) and dimethylformamide (1 drop) at room temperature and stirred under an atmosphere of argon for 2h. The reaction was then concentrated in vacuo to a gum which was azeotroped with dry toluene to remove the last traces of oxalyl chloride.
  • the gum was dissolved in dichloromethane (30ml) and treated at room temperature with 3-(2-dimethylaminoethoxy)-4-iodoaniline (410mg, 1.34 mmole, D50 in WO 95/15954) and triethylamine (270mg, 2.68 mmole). After 2h the reaction was washed with aqueous potassium carbonate solution, dried (Na 2 SO 4 ) and concentrated in vacuo to a gum, which was crystallised from ether to give the title compound as needles m.p. 135 - 137°C (410mg, 64%).
  • Example 6 N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-N'-[(4-fluoro-3-nitro)phenyl]urea
  • the title compound was prepared from 4-fluoro-3-nitrophenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to
  • Example 12 N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-N'-[2-nitrophenyl]urea
  • the title compound was prepared from 2-nitrophenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to
  • Example 16 N-[3-Chloro-2-methylphenyl]-N'-[3-(2-dimethylaminoethoxy)-4-iodophenyl]urea
  • the title compound was prepared from 3-chloro-2-methylphenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to Example 1.
  • MS: m/z 474 (MH + )
  • Example 18 N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-N'-[2-fluoro-5-nitrophenyl]urea
  • the title compound was prepared from 2-fluoro-5-nitrophenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to
  • Example 20 N-[3-(2-Dimethylaminoethoxy)-4-iodophenyl]-N'-[2,3-dimethylphenyl]urea
  • the title compound was prepared from 2,3-dimethylphenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to Example 1.
  • MS: m/z 454 (MH + )
  • Example 22 N-[3-n-Butoxyphenyl]-N'-[3-(2-dimethyIaminoethoxy)-4-iodophenyl]urea
  • the title compound was prepared from 3-n-butoxyphenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to
  • Example 28 N-[4-n-Butyl-3-(dimethylaminoethoxy)phe ⁇ yl]-4-(pyridin-4-yl)naphth-l-ylacetamide
  • the title compound was prepared from 4-(pyridin-4-yl)naphth-l -ylacetic acid (D9) and 4- butyl-3-(2-dimethylaminoethoxy)aniline (D14) following a similar procedure to Example 3 to give the title compound as needles from ether mp 92 - 94°C (62%).
  • the title compound was prepared from 4-butyl-3-(2-dimethylaminoethoxy)aniline (D14) and 2,3-dichlorophenylacetic acid (D17) following a similar procedure to Example 3 to give the title compound as crystals from ether/petrol mp 106 - 108°C (49%).
  • the title compound was prepared from 4-(pyridin-4-yl)naphth-l-ylamine (D3) and 3-(3- dimethylaminopropoxy)-4-iodoaniline (D26) using a similar procedure to Example 9 as a pale yellow oil (36%). This material was converted to its hydrochloride salt as a yellow solid from acetone.
  • the title compound was prepared from 5-(pyridin-4-yl)naphth-l-ylamine (D22) and 3-(2- dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to Example 9 as a yellow oil (29%). This material was converted to its hydrochloride salt as a yellow solid from acetone.
  • the title compound was prepared from 5-(pyridin-4-yl)naphth-l -ylacetic acid (D24) and 3-(2-dimethylaminoethoxy)-4-iodoaniline (D50 in WO95/15954) using a similar procedure to Example 3 as a yellow oil. This material was converted to its hydrochloride salt as a white solid from acetone.
  • the title compound was prepared from 2,3-dichlorophenyl isocyanate and 2,3-dihydro-6- (2-dimethylaminethoxy)-5-iodo-l H-indole (D31) using a similar procedure to Example 1 as a pale yellow oil (17%). This material was converted to its hydrochloride salt as a white solid from acetone.
  • the title compound was prepared from 4-(pyridin-4-yl)naphth-l-ylamine (D3) and 2,3- dihydro-6-(2-dimethylaminoethoxy)-5-iodo-l H-indole (D31) using a similar procdure to Example 9 as a pale yellow oil (33%). This material was converted to its hydrochloride salt as a yellow solid from acetone.
  • the title compound was prepared from 4-(pyridin-4-yl)naphth-l -ylacetic acid (D9) and 2,3-dihydro-6-(2-dimethylaminoethoxy)-5-ethyl-lH-indole (D39) using a similar procedure to Example 3 as a yellow oil (82%). This material was converted to its hydrochloride salt as a yellow solid from acetone.
  • the title compound was prepared from 3-chloro-4-(pyridin-4-yl)aniline (D23) and 5- bromo-2,3-dihydro-6-(l-methylpiperidin-4-yloxy)-lH-indole (D52) as described in Example 49 in 64% yield.
  • the title compound was prepared from 4-(pyridin-4-yl)-3-trifluoromethylaniline (D54) and 4-chloro-3-(l-methylpiperidin-4-yloxy)aniline (D43) as described in Example 49 in 81% yield.
  • the title compound was prepared from 4-(pyridin-4-yl)-3-trifluoromethylaniline (D54) and 4-chloro-3-(2-dimethylaminoethoxy)aniline (D56) as described in Example 49 in 44% yield.
  • the title compound was prepared from 3-chloro-4-(pyridin-4-yl)aniline (D23) and 5- bromo-2,3-dihydro-6-[(l-methylpyrrolidin-2-yl)methoxy]-lH-indole (D60) following a similar procedure to Example 9 to give the title compound as colourless needles 35%, (m.p. 210-213°C).
  • the title compound was prepared from 4-(4-pyridyl)-l-naphthylamine (D3) and (5- bromo-6-[(l-methyl-4-piperidinyl)oxy]indoline (D52) following a similar procedure to Example 9 to give the title compound as a yellow solid (55%) (m.p. 1 19-123°C).
  • the title compound was prepared from 5-bromo-2,3-dihydro-6-[(l-methylpiperidin-4- yl)methoxy]-l H-indole (D63) and 3-chloro-4-(pyridin-4-yl)aniline (D23) following a similar procedure to Example 9 to give the title compound as needles from ether (m.p. 236-240°C).
  • Example 61 N-[3-AcetylphenyI]-N'-[3-(2-dimethylaminoethoxy)-4-iodophenyl]urea
  • the title compound was prepared from 3- acetylphenyl isocyanate and 3-(2- dimethylaminoethoxy)-4-iodoaniline (Description 50 in WO 95/15954) using a similar method to Example 1 ( 66%).
  • Example 66 N- [2,3-Dichloro-4-(pyridin-4-yl)phenyI] -N'- [3-(2-dimethy laminoethoxy)-4- iodophenyl]urea
  • the title compound was prepared from 2,3-dichloro-4-(pyridin-4-yl)aniline (D72) and 3- (2-dimethylaminoethoxy)-4-iodoaniline (D50 in WO 95/15954) using a similar procedure to Example 9 as a gum (27%).
  • the title compound was prepared from 4-(pyridin-4-yl)naphth-l -ylamine (D3) and 5- bromo-2,3-dihydro-6-[2-(l-methylpiperidin-2-yl)ethyl]-l H-indole (D92), using a similar procedure to Example 9, as a pale brown solid (50%).
  • HEK 293 cells expressing 5-HTIA receptors (4 x l ⁇ 7/ml) were homogenised in Tris buffer and stored in 1ml aliquots.
  • CHO cells expressing 5-HTJB receptors (4 x 10 7 cells/ml) were homogenised in Tris buffer and stored in 1.5 ml aliquots.
  • CHO cells expressing 5-HT ⁇ rj) receptors (0.563 x 10 ⁇ /ml) were homogenised in Tris buffer and stored in 1 ml aliquots.

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Abstract

Composés ayant la formule (I), leurs procédés de préparation et leur utilisation en tant qu'agents CNS, formule dans laquelle Ra est un groupe ayant la formule (i) dans laquelle P1 représente phényle, aryle bicyclique, un anneau hétérocyclique de 5 à 7 membres et contenant de 1 à 3 hétéroatomes sélectionnés parmi oxygène, azote et soufre, ou un anneau hétérocyclique bicyclique contenant de 1 à 3 hétéroatomes sélectionnés parmi oxygène, azote et soufre; ou Ra est un groupe de formule (ii); L est un groupe de formule -Y-C(=V)-DG-, dans laquelle Y représente -NH-, NR5 où R5 représente C¿1-6? alkyle, ou Y représente -CH2-, ou -O-; V représente oxygène ou soufre; B représente azote, carbone ou un groupe CH, G représente hydrogène ou C1-6 alkyle à condition que D soit azote ou un groupe CH, ou G forme avec R?b1¿ un groupe W qui est (CR16R17)t, t valant 2, 3 ou 4 et R?16 et R17¿ représente indépendamment hydrogène ou C¿1-6? alkyle ou W représente (CR?16R17)¿u-J où u vaut 0, 1, 2 ou 3 et J représente oxygène, soufre, CR?16=CR17, CR16=N, =CR16O, =CR16¿S ou =CR16-NR17; B représente CH¿2?, oxygène, S(O)p où p vaut 0, 1 ou 2, NR?6 où R6¿ est hydrogène ou C¿1-6? alkyle ou B est CR?7=CR8 où R7 et R8¿ sont indépendamment hydrogène ou C¿1-6? alkyle; R?c et Rd¿ représentent indépendamment hydrogène ou C¿1-6? alkyle; R?y¿ est un anneau hétérocyclique ayant de 5 à 7 membres et contenant de 1 à 3 hétéroatomes sélectionnés parmi oxygène, azote et soufre, ou Ry est un groupe ayant la formule NReRf dans laquelle Re et Rf représentent indépendamment hydrogène, C¿1-6? alkyle ou aralkyle; R?b1 et Rb2¿ représentent indépendamment hydrogène, halogène, hydroxy, C¿1-6? alkyle, trifluorométhyle, C1-6 alcoxy ou aryle, ou R?b1¿ forment ensemble avec G un groupe W tel que défini ci-dessus; et n représente 0, 1, 2, 3 ou 4.
PCT/EP1998/002263 1997-04-18 1998-04-14 Derives d'acetamide et d'uree, procede de preparation et utilisation de ces derives dans le traitement des troubles du systeme nerveux central WO1998050346A2 (fr)

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JP4820488B2 (ja) * 1999-03-12 2011-11-24 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド 抗炎症薬として有用な化合物
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CN1293073C (zh) * 2001-04-20 2007-01-03 惠氏公司 作为5－羟色胺－6配体的杂环基烷氧基－、－烷硫基－和－烷基氨基吲哚衍生物
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WO2003016274A3 (fr) * 2001-08-21 2003-10-16 Sepracor Inc Piperidines 2-substitue, ligands pour des recepteurs et des transporteurs de monoamines
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US7056925B2 (en) 2002-08-13 2006-06-06 Abbott Laboratories Urea kinase inhibitors
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