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WO2004035544A1 - Derives de benzazepine pour le traitement de troubles neurologiques et psychiatriques - Google Patents

Derives de benzazepine pour le traitement de troubles neurologiques et psychiatriques Download PDF

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Publication number
WO2004035544A1
WO2004035544A1 PCT/EP2003/011421 EP0311421W WO2004035544A1 WO 2004035544 A1 WO2004035544 A1 WO 2004035544A1 EP 0311421 W EP0311421 W EP 0311421W WO 2004035544 A1 WO2004035544 A1 WO 2004035544A1
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Prior art keywords
alkyl
heterocyclyl
compound
aryl
heteroaryl
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PCT/EP2003/011421
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English (en)
Inventor
Thomas Daniel Heightman
David Matthew Wilson
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Glaxo Group Limited
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Priority to AU2003278084A priority Critical patent/AU2003278084A1/en
Publication of WO2004035544A1 publication Critical patent/WO2004035544A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel benzazepine derivatives having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.
  • WO 02/76925 (Eli Lilly) describes a series of compounds which are claimed to be histamine H3 antagonists.
  • WO 01/87834 (Takeda) describes a series of bicyclic heterocycles which are claimed to be melanin-concentrating hormone antagonists.
  • the histamine H3 receptor is predominantly expressed in the mammalian central nervous system (CNS), with minimal expression in peripheral tissues except on some sympathetic nerves (Leurs er a/., (1998), Trends Pharmacol. Sci. 19, 177-183).
  • Activation of H3 receptors by selective agonists or histamine results in the inhibition of neurotransmitter release from a variety of different nerve populations, including histaminergic and cholinergic neurons (Schlicker ef al., (1994), Fundam. Clin. Pharmacol. 8, 128-137).
  • H3 antagonists can facilitate neurotransmitter release in brain areas such as the cerebral cortex and hippocampus, relevant to cognition (Onodera et al., (1998), In: The Histamine H3 receptor, ed Leurs and Timmerman, pp255-267, Elsevier Science B.V.).
  • H3 antagonists e.g. thioperamide, clobenpropit, ciproxifan and GT-2331
  • rodent models including the five choice task, object recognition, elevated plus maze, acquisition of novel task and passive avoidance (Giovanni et al., (1999), Behav. Brain Res. 104, 147-155).
  • the present invention provides, in a first aspect, a compound of formula (I):
  • R 1 represents hydrogen, -C ⁇ _e alkyl, -C 3 . 8 cycloalkyl, aryl, heterocyclyl, heteroaryl, -C ⁇ alkyl-aryl, -C ⁇ _ 6 alkyl-heteroaryl, -C ⁇ alkyl-heterocyclyl, -aryl-aryl, -aryl-heter ⁇ aryl, -aryl- heterocyclyl,- heteroaryl-aryl, -fieteroaryl-heteroaryl, -heteroaryl-heterocyclyl, - heterocyclyl-aryl, -heterocyclyl-heteroaryl, -heterocyclyl-heteroaryl, -heterocyclyl-heteroaryl, -heterocyclyl-heterocyclyl, wherein R 1 may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consist
  • 6 alkyl pentafluoroethyl, C ⁇ . e alkoxy, C 2 . 6 alkenyl, arylC ⁇ . 6 alkoxy, d- 6 alkylthio, d-e alkoxyC ⁇ -6 alkyl, C 3 . 7 cycloalkyld-6 alkoxy, d-6 alkanoyl, d-e alkoxycarbonyl, C ⁇ _ 6 alkylsulfonyl, d. 6 alkylsulfinyl, C 1 - 6 alkylsulfonyloxy, d_6 alkylsulfonylC- ⁇ .
  • R 2 represents halogen, d_ 6 alkyl, C 1 - 6 alkoxy, cyano, amino or trifluoromethyl; n is 0, 1 or 2;
  • R 4 represents hydrogen or d. 6 alkyl, or together with R 1 may form a heterocyclyl group
  • R 3 represents -(CH 2 ) q -NR 11
  • R 11 and R 12 independently represent d. 6 alkyl or together with the nitrogen atom to which they are attached represent an N-linked nitrogen containing heterocyclic group optionally substituted by one or more R 17 groups;
  • R 13 represents hydrogen, d_ 6 alkyl, C 3 . 8 cycloalkyl, -d. 6 alkyl-aryl or heterocyclyl;
  • R 14 and R 17 independently represent halogen, d. 6 alkyl, haloalkyl, OH, did. 6 alkylamino, d-e alkoxy or heterocyclyl; f and k independently represent 0, 1 or 2; g is 0, 1 or 2 and h is 0, 1 , 2 or 3, such that g and h cannot both be 0; or a pharmaceutically acceptable salt thereof.
  • Alkyl groups may be straight chain or branched and the groups alkoxy and alkanoyl shall be interpreted similarly.
  • Alkyl moieties are more preferably C M alkyl, eg. methyl or ethyl.
  • the term 'halogen' is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
  • aryl includes phenyl and naphthyl.
  • heterocyclyl is intended to mean a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring or a 4-7 membered saturated or partially unsaturated aliphatic ring fused to a benzene ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Suitable examples of such monocyclic rings include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, diazepanyl, azepanyl, azocanyl and dioxolanyl. Suitable examples of benzofused heterocyclic rings include indolinyl, isoindolinyl, benzodioxolyl and dihydroisoquinolinyl.
  • nitrogen containing heterocyclyl is intended to represent any heterocyclyl group as defined above which contains a nitrogen atom.
  • heteroaryl is intended to mean a 5-7 membered monocyclic aromatic or a fused 8-11 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur.
  • monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl.
  • fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like.
  • benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzo
  • R 1 represents hydrogen, d- 6 alkyl (eg. methyl, i-propyl, t-butyl), C 3 . 8 cycloalkyl (eg. cyclopropyl or cyclohexyl), aryl, heteroaryl (eg. thienyl) or heterocyclyl (eg. benzodioxolyl or tetrahydrofuranyl), optionally substituted by one or more d. 6 alkoxy groups (eg. methoxy). More preferably, R 1 represents d-e alkyl (eg. methyl, i-propyl, t- butyl) or C 3 . 8 cycloalkyl (eg. cyclopropyl or cyclohexyl).
  • d- 6 alkyl eg. methyl, i-propyl, t-butyl
  • C 3 . 8 cycloalkyl eg. cyclopropyl or cycl
  • X represents a bond, d. 6 alkyl (eg. CH 2 ) or CO, more preferably bond or d. 6 alkyl (eg. CH 2 ).
  • R -X- represents hydrogen-
  • Ci- 6 alkyl- eg. methyl, i-butyl-, propyl- or ethyl-
  • halogen eg. fluorine
  • cyano eg. methoxy
  • CONR 15 R 16 eg. - CON(ethyl) 2
  • arylsulfonyl eg. -SO 2 -phenyl
  • C 3 . 8 cycloalkyl-CH 2 - (eg. cyclopropyl-CH 2 - or cyclohexyl-CH 2 -); aryl- (eg. phenyl) optionally substituted by one or more halogen (eg. chlorine) or C 2 - 6 alkenyl (eg. propenyl) groups; aryl-CH 2 - (eg. phenyl-CH 2 - or naphthyl-CH 2 -) optionally substituted by one or more halogen (eg. chlorine), cyano, NR 15 R 16 (eg. -N(Me) 2 ), NR 15 COR 16 (eg. NHCOMe) or .
  • halogen eg. chlorine
  • NR 15 R 16 eg. -N(Me) 2
  • NR 15 COR 16 eg. NHCOMe
  • 6 alkoxy groups (eg. methoxy); heterocyclyl-CH 2 - (eg. tetrahydrofuranyl-CH 2 - or dioxolanyl-CH 2 -); d. 6 alkyl-CO- (eg. methyl-CO- or t-butyl-CO-); aryl-CO- (eg. phenyl-CO- or naphthyl-CO-) optionally substituted by one or more halogen (eg. chlorine) or d. 6 alkoxy groups (eg. methoxy); heteroaryl-CO- (eg. thienyl-CO- or benzofuranyl-CO-); heterocyclyl-CO- (eg.
  • benzodioxolyl-CO- d. 6 alkyl-NR 4 CO- (eg. isopropyl-NH-CO- ); aryl-NR 4 CO- (eg. phenyl-NH-CO-) optionally substituted by one or more halogen (eg. chlorine) atoms;
  • halogen eg. chlorine
  • alkyl-SO 2 - eg. butyl-SO 2 -
  • aryl-SO 2 - eg. phenyl-SO 2 -
  • halogen eg. chlorine
  • R 1 -X- represents hydrogen-; d-e alkyl- (eg. methyl, i-butyl- or ethyl-) optionally substituted by one or more halogen (eg. fluorine), cyano, d. 6 alkoxy groups (eg. methoxy), CONR 15 R 16 (eg. -
  • C 3 _ 8 cycloalkyl-CH 2 - (eg. cyclopropyl-CH 2 - or cyclohexyl-CH 2 -); aryl- (eg. phenyl) optionally substituted by one or more C 2 . 6 alkenyl (eg. propenyl) groups; aryl-CH 2 - (eg. phenyl-CH 2 - or naphthyl-CH 2 -) optionally substituted by one or more halogen (eg. chlorine), cyano, NR 15 R 16 (eg. -N(Me) 2 ), NR 15 COR 16 (eg. NHCOMe) or d- 6 alkoxy groups (eg. methoxy); or heterocyclyl-CH 2 - (eg. tetrahydrofuranyl-CH 2 -).
  • aryl- eg. phenyl
  • C 2 - optionally substituted by one or more C 2 . 6 al
  • n 0 or 1 , more preferably 0.
  • R 2 is preferably an amino group.
  • R 3 represents ⁇ (CH 2 ) q -NR 11 R 12 .
  • q represents 2 or 3, more preferably 3.
  • R 11 and R 12 independently represent d-e alkyl (eg. methyl or ethyl).
  • NR 11 R 12 represents piperidinyl, pyrrolidinyl, morpholinyl, azepanyl or diazepanyl optionally substituted by one or more d. 6 alkyl (eg. methyl) or heterocyclic groups (eg. piperidine).
  • NR 11 R 12 represents unsubstituted piperidinyl, pyrrolidinyl or azepanyl.
  • R 3 represents a group of formula (i)
  • f represents 0 or 1
  • h represents 1
  • g represents 2
  • k represents 0
  • R 13 represents d. 6 alkyl (eg. isopropyl).
  • R 3 represents a group of formula (i)
  • more f represents 0, h represents 1 , g represents 2, k represents 0 and R 13 represents d. 6 alkyl (eg. isopropyl).
  • -O-R 3 is present at the 7-position of the benzazepine group.
  • Preferred compounds according to the invention include examples E1-E54 as shown below, or a pharmaceutically acceptable salt thereof.
  • Compounds of formula (I) may form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, sulphate, citric, lactic, mandelic, tartaric and methanesulphonic. Salts, solvates and hydrates of compounds of formula (I) therefore form an aspect of the invention.
  • 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 these compounds and the mixtures thereof including racemates. Tautomers also form an aspect of the invention.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
  • R 2 and n are as defined above and P 1 represents R 1 -X or a suitable protecting group such as t-butoxycarbonyl, wherein R 1 and X are as defined above, with a compound of formula R 3' -L ⁇ wherein R 3' is as defined above for R 3 or a group convertible thereto and L 1 represents a suitable leaving group such as a halogen atom (eg. bromine or chlorine) or an optionally activated hydroxyl group, followed as necessary by deprotection under acidic conditions and conversion of R 3' to R 3 ; or
  • process (a) typically comprises the use of a suitable base, such as potassium carbonate in an appropriate solvent such as 2- butanone optionally in the presence of a transfer reagent such as potassium iodide at an appropriate temperature such as reflux.
  • a suitable base such as potassium carbonate
  • an appropriate solvent such as 2- butanone
  • a transfer reagent such as potassium iodide
  • process (a) typically comprises an alkylation reaction using analogous conditions to those described above.
  • R 3 represents a group of formula (i) and L 1 represents an optionally activated hydroxyl group
  • process (a) typically comprises the use of a phosphine such as triphenylphosphine in a suitable solvent such as tetrahydrofuran, followed by addition of an azadicarboxylate such as diethylazaodicarboxylate at a suitable temperature such as room temperature.
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. acetyl, 2',2',2 , -trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl), which may be removed by hydrolysis (e.g.
  • amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation.
  • compounds of formula (I) wherein X is other than a bond and R 1 is other than hydrogen may be prepared by the above interconversion procedures.
  • compounds of formula (I) wherein -X-R 1 represents C 1 - 6 alkyl may be prepared by interconverting a compound of formula (I) wherein -X-R 1 represents hydrogen in the presence of an appropriate carboxaldehyde or ketone. Such interconversion may occur in the presence of a suitable reducing agent such as a borohydride in the presence of a suitable solvent. Reaction with an appropriate carboxaldehyde may also be performed in the presence of sodium triacetoxyborohydride in the presence of a suitable solvent such as dichloromethane at a suitable temperature (eg. room temperature).
  • a suitable reducing agent such as a borohydride
  • Reaction with an appropriate carboxaldehyde may also be performed in the presence of sodium triacetoxyborohydride in the presence of a suitable solvent such as dichloromethane at a suitable temperature (eg. room temperature).
  • Compounds of formula (I) wherein -X-R 1 represents d-e alkyl may also be prepared by interconverting a compound of formula (I) wherein -X-R 1 represents hydrogen in the presence of an appropriate d_ ⁇ alkyl group containing a suitable leaving group (such as chlorine, bromine, iodine, methanesuifonyloxy and trifluoromethanesulfonyloxy). Such interconversion may occur in the presence of a suitable base (such as potassium carbonate) and a suitable solvent (such as butan-2-one) optionally in presence of heat.
  • a suitable base such as potassium carbonate
  • a suitable solvent such as butan-2-one
  • Compounds of formula (I) wherein X represents CO may be prepared by interconverting a compound of formula (I) wherein -X-R 1 represents hydrogen in the presence of an acid halide. Such interconversion may occur in the presence of a suitable base (such as triethylamine) and a suitable solvent (such as dichloromethane) at a suitable temperature (such as room temperature).
  • a suitable base such as triethylamine
  • a suitable solvent such as dichloromethane
  • Compounds of formula (I) wherein X represents CO may also be prepared by interconverting a compound of formula (I) wherein -X-R 1 represents hydrogen in the presence of an appropriate carboxylic acid. Such interconversion may occur in the presence of a suitable coupling reagent (such as dicyclohexylcarbodiimide) in the presence of a suitable solvent (such as dichloromethane) at a suitable temperature
  • Compounds of formula (I) wherein X represents SO 2 may be prepared by interconverting a compound of formula (I) wherein -X-R 1 represents hydrogen in the presence of a sulfonyl chloride. Such interconversion may occur in the presence of a suitable solvent
  • a suitable solvent such as 2-butanone
  • Compounds of formula (I) wherein X represents CONR 4 may also be interconverted by reacting a compound of formula (I) wherein -X-R 1 represents hydrogen sequentially with phosgene in a solvent such as toluene followed by a compound of formula R 4 R 1 -NH, in a solvent such as dichloromethane and a suitable base, such as triethylamine, wherein R 1 and R 4 are as defined above.
  • Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for and are antagonists and/or inverse agonists of the histamine H3 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive dysfunction, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders including narcolepsy; psychiatric disorders including schizophrenia, attention deficit hypereactivity disorder, depression and addiction; and other diseases including obesity, asthma, allergic rhinitis, nasal congestion, chronic obstructive pulmonary disease and gastro- intestinal disorders.
  • neurological diseases including Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive dysfunction, epilepsy, neuropathic pain, inflammatory pain, migraine, Parkinson's disease, multiple sclerosis, stroke and sleep disorders including narcolepsy; psychiatric disorders including schizophrenia, attention deficit hypereactivity disorder, depression and addiction; and other diseases including obesity, asthma
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders, in particular cognitive impairments in diseases such as Alzheimer's disease and related neurodegenerative disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.
  • compounds of formula (I) When used in therapy, compounds of formula (I) are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
  • the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition which comprises the 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 in preparing solutions, 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 000 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.
  • Tetrakistriphenyphosphinepalladium(O) (2.30g, 2mmol) was added and the solution stirred at room temperature for 24 hours. Solvents were removed in vacuo and the residue was partitioned between 3M sodium hydroxide solution and diethyl ether. The organic phase was washed with 3M soidium hydroxide solution (x3), water (x3), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to a crude solid.
  • the title compound was prepared from 1,1 -dimethylethyl 7-[( ⁇ 1-[(2-propen-1- yloxy)carbonyl]-4-piperidinyl ⁇ methyl)oxy]-1 ,2,4,5-tetrahydro-3H-3-benzazepine-3- carboxylate (D7) in an analogous manner to that used in D5 to afford the title compound (1.06g, 59%); MS (ES+) m/e 361 [M+H] + .
  • the title compound was prepared from 1,1 -dimethylethyl 7-[(4-piperidinylmethyl)oxy]- 1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D8) in an analogous manner to that used in D6 to afford the title compound (283 mg, 70%); MS (ES+) m/e 403 [M+ ⁇ ] + .
  • the title compound was prepared from 7-Hydroxy-8-nitro-1 ,2,4,5-tetrahydro- benzo[d]azepine-3-carboxylic acid ferf-butyl ester (WO 0368752) and 1-(2- chloroethyl)piperidine hydrochloride in an analogous manner to that used in D3 except methyl ethyl ketone was used instead of dimethylformamide; MS (ES+), m/e 434 [M+H] + .
  • Step 2 7-Amino-8-(3-piperidin-1 -yl-propoxy)-1 ,2,4,5-tetrahydro-benzo[d]azepine-3- carboxylic acid ferf-butyl ester
  • Step 1 The product of Step 1 (1.54g, 3.55mmol) was dissolved in ethanol (50ml), treated with
  • Example 1 The crude product of Example 1 (200 mg, 0.7 mmol) and cyclopropanecarboxaldehyde (79 ⁇ L, 1.1 mmol) were stirred at room temperature for 2 hours in 5% acetic acid in dichloromethane. The solution was then treated with sodium triacetoxyborohydride (297mg, 1.4mmol) and the suspension stirred at room temperature for 16 hours. The resulting solution was applied directly to a SCX cartridge (Varian bond-elute, 10g) and eluted with methanol then a mixture of .880 ammonia:methanol (1 :9).
  • SCX cartridge Variarian bond-elute, 10g
  • Examples 3-11 Examples 3-11 (E3-E11) were prepared using an analogous method to that described in Example 2 (E2) by substituting cyclopropanecarboxaldehyde for the appropriate aldehyde indicated in the table.
  • Examples 13-17 Examples 13-17 (E13-E17) were prepared using an analogous method to that described in Example 12 (E12) by substituting acetyl chloride for the appropriate acid chloride indicated in the table.
  • Examples 19-26 were prepared from Description 1 (D1) in a two step procedure using an analogous method to that described in Description 2 (D2) followed by an analogous method described in Example 1 (E1) by substituting piperidine for the appropriate amine indicated in the table.
  • the title compound was prepared from 1 ,1 -dimethylethyl 7-( ⁇ [1-(1-methylethyl)-4- piperidinyl]methyl ⁇ oxy)-1 ,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D9) in an analogous manner to that used in E31 to afford the title compound (E35) (178 mg, 80%); MS (ES+) m/e 303 [M+Hf.
  • a membrane preparation containing histamine H3 receptors may be prepared in accordance with the following procedures:
  • the GeneSwitchTM system (a system where in transgene expression is switched off in the absence of an inducer and switched on in the presence of an inducer) was performed as described in US Patent nos: 5,364,791; 5,874,534; and 5,935,934.
  • Ligated DNA was transformed into competent DH5 ⁇ E. coli host bacterial cells and plated onto Luria Broth (LB) agar containing ZeocinTM (an antibiotic which allows the selection of cells expressing the sh ble gene which is present on pGene and pSwitch) at 50 ⁇ g ml "1 . Colonies containing the re-ligated plasmid were identified by restriction analysis.
  • DNA for transfection into mammalian cells was prepared from 250ml cultures of the host bacterium containing the pGeneH3 plasmid and isolated using a DNA preparation kit (Qiagen Midi-Prep) as per manufacturers guidelines (Qiagen).
  • CHO K1 cells previously transfected with the pSwitch regulatory plasmid (InVitrogen) were seeded at 2x10e6 cells per T75 flask in Complete Medium, containing Hams F12 (GIBCOBRL, Life Technologies) medium supplemented with 10% v/v dialysed foetal bovine serum, L-glutamine, and hygromycin (100 ⁇ g ml "1 ), 24 hours prior to use. Plasmid DNA was transfected into the cells using Lipofectamine plus according to the manufacturers guidelines (InVitrogen). 48 hours post transfection cells were placed into complete medium supplemented with 500 ⁇ g ml "1 ZeocinTM.
  • Vantage SE Flow Cytometer fitted with an Automatic Cell Deposition Unit. Control cells were non-induced cells treated in a similar manner. Positively stained cells were sorted as single cells into 96-well plates, containing Complete Medium containing 500 ⁇ g ml "1 ZeocinTM and allowed to expand before reanalysis for receptor expression via antibody and ligand binding studies. One clone, 3H3, was selected for membrane preparation.
  • the cells are then homogenised by 2 x 15 second bursts in a 1 litre glass Waring blender, followed by centrifugation at 500g for 20 minutes. The supernatant is then spun at 48,000g for 30 minutes. The pellet is resuspended in 4 volumes of buffer A2 by vortexing for 5 seconds, followed by homogenisation in a Dounce homogeniser (10-15 strokes). At this point the preparation is aliquoted into polypropylene tubes and stored at -70°C.
  • test compound or 10 ⁇ l of iodophenpropit (a known histamine H3 antagonist) at a final concentration of 10mM) diluted to the required concentration in 10% DMSO;
  • test compound or 10 ⁇ l of guanosine 5'- triphosphate (GTP) (Sigma) as non-specific binding control
  • assay buffer 20mM N- 2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) + 100mM NaCI + 10mM MgCI 2 , pH7.4 NaOH
  • HEPES N- 2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid
  • SPA scintillation proximity assay
  • the compounds of Examples E1-54 were tested in the histamine H3 functional antagonist assay and exhibited antagonism in the following range: 6.0.-10.0 pK b . More particularly, the compounds of Examples E1-11 , E13-19, E26, E29-34, E37, E40, E42-44 and E46-54 exhibited antagonism in the following range: 8.0-10.0 pK b . Yet more particularly, the compounds of Examples E2-11 , E18-19, E26, E29-34, E48 and E50-53 exhibited antagonism in the following range: 8.5-10.0 pK b .

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Abstract

L'invention concerne de nouveaux dérivés de benzazépine de formule (I). Ces dérivés présentent une activité pharmacologique. L'invention concerne des procédés pour la préparation de ces dérivés, des compositions les contenant et leur utilisation dans le traitement de troubles neurologiques et psychiatriques.
PCT/EP2003/011421 2002-10-16 2003-10-14 Derives de benzazepine pour le traitement de troubles neurologiques et psychiatriques WO2004035544A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2005097778A1 (fr) * 2004-04-08 2005-10-20 Glaxo Group Limited Tertrahydrobenzazepines en tant que ligands du recepteur h3 de l'histamine
WO2006097691A1 (fr) 2005-03-14 2006-09-21 Glaxo Group Limited Derives du thiazole fondus ayant une affinite pour le recepteur de l’histamine h3
JP2008502644A (ja) * 2004-06-18 2008-01-31 グラクソ　グループ　リミテッド ヒスタミンｈ３アンタゴニストとしての３−シクロアルキルベンズアゼピン
WO2008015125A1 (fr) * 2006-08-03 2008-02-07 F. Hoffmann-La Roche Ag Dérivés 1h-indol-6-yl-pipérazin-1-yl-méthanone utilisés en tant que modulateurs du récepteur h3
US7446103B2 (en) 2002-10-22 2008-11-04 Glaxo Group Limited Bicyclic benzamide compound as histamine H3 receptor ligand useful in the treatment of neurological diseases
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7888347B2 (en) 2005-07-06 2011-02-15 Glaxo Group Limited Pyrazolo [3,4-D]azepine derivatives as histamine H3 antagonists
WO2013151982A1 (fr) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Méthodes et composés utiles pour traiter le prurit, et procédés d'identification desdits composés

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WO1993003015A1 (fr) * 1991-08-05 1993-02-18 Smithkline Beecham Corporation Heteroalcoxy benzazepines
WO2000021951A1 (fr) * 1998-10-08 2000-04-20 Smithkline Beecham Plc Derives de tetrahydrobenzozepine utiles comme modulateurs des recepteurs de la la dopamine d3
EP1122252A1 (fr) * 1998-10-16 2001-08-08 Takeda Chemical Industries, Ltd. Composes azotes hererocycliques condenses; procede de fabrication et agents les renfermant
WO2002012190A2 (fr) * 2000-08-08 2002-02-14 Ortho Mcneil Pharmaceutical, Inc. Aryloxypiperidines non-imidazole
WO2002040471A2 (fr) * 2000-11-14 2002-05-23 Smithkline Beecham P.L.C. Derives de tetrahydrobenzazepine utiles en tant que modulateurs des recepteurs d3 de la dopamine (agents antipsychotiques)
WO2002076925A2 (fr) * 2001-03-23 2002-10-03 Eli Lilly And Company Composes d'aryl alkylamines non imidazole comme antagonistes des recepteurs h3 de l'histamine, preparation et applications therapeutiques

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7446103B2 (en) 2002-10-22 2008-11-04 Glaxo Group Limited Bicyclic benzamide compound as histamine H3 receptor ligand useful in the treatment of neurological diseases
US7696193B2 (en) 2002-12-20 2010-04-13 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7704994B2 (en) 2002-12-20 2010-04-27 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US7799773B2 (en) 2002-12-20 2010-09-21 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
US8207331B2 (en) 2002-12-20 2012-06-26 Glaxo Group Limited Benzazepine derivatives for the treatment of neurological disorders
WO2005097778A1 (fr) * 2004-04-08 2005-10-20 Glaxo Group Limited Tertrahydrobenzazepines en tant que ligands du recepteur h3 de l'histamine
JP2008502644A (ja) * 2004-06-18 2008-01-31 グラクソ　グループ　リミテッド ヒスタミンｈ３アンタゴニストとしての３−シクロアルキルベンズアゼピン
WO2006097691A1 (fr) 2005-03-14 2006-09-21 Glaxo Group Limited Derives du thiazole fondus ayant une affinite pour le recepteur de l’histamine h3
US7888347B2 (en) 2005-07-06 2011-02-15 Glaxo Group Limited Pyrazolo [3,4-D]azepine derivatives as histamine H3 antagonists
WO2008015125A1 (fr) * 2006-08-03 2008-02-07 F. Hoffmann-La Roche Ag Dérivés 1h-indol-6-yl-pipérazin-1-yl-méthanone utilisés en tant que modulateurs du récepteur h3
US7514433B2 (en) 2006-08-03 2009-04-07 Hoffmann-La Roche Inc. 1H-indole-6-yl-piperazin-1-yl-methanone derivatives
WO2013151982A1 (fr) 2012-04-03 2013-10-10 Arena Pharmaceuticals, Inc. Méthodes et composés utiles pour traiter le prurit, et procédés d'identification desdits composés

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