EP0724580A1 - Benzanilide derivatives as 5ht-1d receptor antagonists - Google Patents

Benzanilide derivatives as 5ht-1d receptor antagonists

Info

Publication number
EP0724580A1
EP0724580A1 EP94930171A EP94930171A EP0724580A1 EP 0724580 A1 EP0724580 A1 EP 0724580A1 EP 94930171 A EP94930171 A EP 94930171A EP 94930171 A EP94930171 A EP 94930171A EP 0724580 A1 EP0724580 A1 EP 0724580A1
Authority
EP
European Patent Office
Prior art keywords
formula
methyl
compound
dihydro
methylpiperazin
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Withdrawn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
EP94930171A
Other languages
German (de)
French (fr)
Inventor
Graham Francis Joiner
Laramie Mary Gaster
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB939321490A external-priority patent/GB9321490D0/en
Priority claimed from GB939325866A external-priority patent/GB9325866D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0724580A1 publication Critical patent/EP0724580A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel amide derivatives, processes for their preparation, and pharmaceutical compositions containing them.
  • EPA 0533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HTID receptor antagonist activity. These compounds are said 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.1 is halogen, C3_6cycloalkyl, optionally substituted phenyl or an optionally substituted 5-7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
  • R2 is hydrogen, halogen, C ⁇ galkyl, C ⁇ .g-alkoxy, acyl, nitro, trifluoromethyl or cyano;
  • R3 is hydrogen or Ci.galkyl;
  • A is -(CR 4 R 5 ) m - or -O(CR 4 R 5 ) n - where R 4 and R 5 are independently hydrogen or Ci.galkyl, m is 2, or 3; n is 1, 2 or 3 and B is CONH or NHCO.
  • the group R can be an aromatic or saturated heterocyclic ring. When R is an aromatic heterocyclic ring, examples of such rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, 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 C3_6cycloalkyl groups include cyclohexyl.
  • the group R is attached to the 4-position of the phenyl ring, that is to say, para to the amide group.
  • Optional substituents for R include halogen, Ci.galkyl, C ⁇ _6alkoxy, hydroxy, cyano, nitro, amino, CO2R"
  • the group R can also be an optionally substituted phenyl group, in particular a phenyl group disubstituted by Ci.galkyl and an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur.
  • Preferred 5 to 7-membered heterocyclic rings include those listed above.
  • Preferred substituents for such rings include Ci.galkyl, in particular methyl.
  • R is halogen, pyridyl or a phenyl group disubstituted by a C .galkyl group and an optionally substituted 5-7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. More preferably R* is a phenyl group disubstituted by methyl and an optionally substituted oxadiazolyl group, in particular an oxadiazolyl group substituted by Ci.galkyl. Most preferably R* is a group of formula:
  • R ⁇ is hydrogen, halogen, Ci.galkyl, Ci.galkoxy or nitro.
  • R ⁇ is hydrogen, methyl or nitro, most preferably hydrogen.
  • R ⁇ is hydrogen or Ci.galkyl.
  • R ⁇ is hydrogen or methyl.
  • A is CH2CH2 or OCH2CH2.
  • B is CONH.
  • Particularly preferred compounds include:
  • Ci.galkyl groups may be straight chain or branched.
  • 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. 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. Tautomeric forms of compounds of formula (I) and mixtures thereof also form an aspect of the invention.
  • the present invention provides a process for the preparation of a compound of formula (I) which comprises.
  • R 1 , R 2 , R 3 and A are as defined in formula (I) and R 9 and R 10 contain the appropriate functional group(s) necessary to form the B moiety;
  • R 3 is as defined in formula (I) and Hal is halogen, or
  • R 2 , R 3 , A and B are as defined in formula (I) and Y is halogen or a group -OSO2CF3 with a compound of formula (VIII):
  • R 9 or R 1 ⁇ i an activated carboxylic acid derivative, such as an acyl halide or acid anhydride, and the other is an amine group.
  • Activated compounds of formulae (II) or (El) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazole.
  • R 9 or RlO is a group COL where L is halo, particularly chloro.
  • a compound of formulae (II) and (HI) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine, pyridine or aqueous sodium hydroxide.
  • Compounds of formulae (II) and (III) can be prepared from the corresponding carboxylic acids using standard procedures.
  • 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 (IV) with a nucleophile R ⁇ is preferably carried out in a suitable solvent such as dimethylformamide in the presence of a strong base such as sodium hydride.
  • a strong base such as sodium hydride.
  • the leaving group X is halo, in particular fluoro.
  • the group R 2 is an electron withdrawing group, for example nitro, COCH3 or cyano, in the ortho or para-positions relative to the group X.
  • Reaction of a compound of formula (V) with a compound of formula (VI) 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.
  • reaction of compounds of formula (VII) and (VIII) and reaction of compounds of formulae (IX) and (X) 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
  • (X) are commercially available or can be prepared using standard procedures. For example certain compounds can be prepared using similar procedures to those outlined in EPA 533266/7/8.
  • 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.
  • 5HTID 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.
  • Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive 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 the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for 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
  • SUBS ⁇ TUTE SHEET (RULE 26) 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. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.
  • Benzodioxan-5-carboxylic acid (prepared as described by E.A.Watts, in Azabicycloalkylbenzamides and pharmaceutical compositions containing them, EP 82-303057 June 1982) (15 g) was dissolved in a mixture of glacial acetic acid (67 ml) and acetic anhydride (67 ml). The solution was heated to 40° C and treated with a solution of fuming nitric acid (13 ml) in acetic acid (13 ml) at a rate such that the temperature was maintained at 45-50° C with occasional ice/water cooling. The mixture was stirred at 50°-53° C for 2 days, then cooled and filtered to give the title compound as a white powder (4.09 g, 22%).
  • the mixture was refluxed for 3h, cooled and filtered through a short neutral alumina column eluting widi dichloromethane, tiien ethyl acetate.
  • the solvent was evaporated under reduced pressure, and the residual carbamate dissolved in methanol (10 ml) and stood overnight The solvent was evaporated under reduced pressure to leave the tide compound as a white powder (38 mg, 22%) Mp 175-180° C.

Landscapes

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

Abstract

Amide derivatives of formula (I) or a salt thereof, in which R1 is halogen, C¿3-6?cycloalkyl, optionally substituted phenyl or an optionally substituted 5-7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R?2¿ is hydrogen, halogen, C¿1-6?alkyl, C1-6alkoxy, acyl, nitro, trifluoromethyl or cyano; R?3¿ is hydrogen or C¿1-6?alkyl; and A is -(CR?4R5)¿m- or -O(CR4R5)n- where R?4 and R5¿ are independently hydrogen or C¿1-6?alkyl, m is 2, or 3; n is 1, 2 or 3 and B is CONH or NHCO, processes for their preparation, and pharmaceutical compositions containing them.

Description

BENZANILIDE DERIVATIVES AS 5HT-1D RECEPTOR ANTAGONISTS
The present invention relates to novel amide derivatives, processes for their preparation, and pharmaceutical compositions containing them. EPA 0533 266/7/8 disclose a series of benzanilide derivatives which are said to possess 5HTID receptor antagonist activity. These compounds are said to be of use in the treatment of various CNS disorders.
A structurally distinct class of compounds have now been discovered and have been found to exhibit 5HTi£> antagonist activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a salt thereof:
in which
R.1 is halogen, C3_6cycloalkyl, optionally substituted phenyl or an optionally substituted 5-7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur; R2 is hydrogen, halogen, C^galkyl, C^.g-alkoxy, acyl, nitro, trifluoromethyl or cyano; R3 is hydrogen or Ci.galkyl; and
A is -(CR4R5)m- or -O(CR4R5)n- where R4 and R5 are independently hydrogen or Ci.galkyl, m is 2, or 3; n is 1, 2 or 3 and B is CONH or NHCO. The group R can be an aromatic or saturated heterocyclic ring. When R is an aromatic heterocyclic ring, examples of such rings include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrimidyl and pyrazinyl. When 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. Examples of R C3_6cycloalkyl groups include cyclohexyl.
Preferably the group R is attached to the 4-position of the phenyl ring, that is to say, para to the amide group. Optional substituents for R , of which more than one can be present, include halogen, Ci.galkyl, Cι_6alkoxy, hydroxy, cyano, nitro, amino, CO2R"
- 1 -
SUBST1TUTE SHEET RULE 26 where R^ is hydrogen or C .galkyl or CONR^Rδ where R? and R& are hydrogen or Cι_6alkyl.
The group R can also be an optionally substituted phenyl group, in particular a phenyl group disubstituted by Ci.galkyl and an optionally substituted 5 to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Preferred 5 to 7-membered heterocyclic rings include those listed above. Preferred substituents for such rings include Ci.galkyl, in particular methyl.
Preferably R is halogen, pyridyl or a phenyl group disubstituted by a C .galkyl group and an optionally substituted 5-7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. More preferably R* is a phenyl group disubstituted by methyl and an optionally substituted oxadiazolyl group, in particular an oxadiazolyl group substituted by Ci.galkyl. Most preferably R* is a group of formula:
Suitably R^ is hydrogen, halogen, Ci.galkyl, Ci.galkoxy or nitro. Preferably R^ is hydrogen, methyl or nitro, most preferably hydrogen.
Suitably R^ is hydrogen or Ci.galkyl. Preferably R^ is hydrogen or methyl. Preferably A is CH2CH2 or OCH2CH2. Preferably B is CONH. Particularly preferred compounds include:
4-bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide,
4-bromo-3-methyl-N-[7-(piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide, 4-bromo-3-methyl-N-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benzamide,
4-(4-pyridyl)-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yl]benzamide,
4-(4-pyridyl)-3-memyl-N-[5-(4-methylpipera-an-l-yl)-l,4-benzodioxan-7-yl]benzamide,
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5-yl]-2'-methyl-4'-(5- methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, or
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2'-methyl-4'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[7-(Piperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2'-medιyl-4,-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, 4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5- yl]benzamide, N-[7-(piperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5-yl]-2'-methyl-4'-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5- yl]benzamide, N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]-2'-methyl-4'-(5-methyl- 1 ,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[7-(Piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]-2,-methyl-4'-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, or a pharmaceutically acceptable salt thereof. Ci.galkyl groups, whether alone or as part of another group, may be straight chain or branched.
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.
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. Tautomeric forms of compounds of formula (I) and mixtures thereof also form an aspect of the invention.
In a further aspect the present invention provides a process for the preparation of a compound of formula (I) which comprises.
(a) reaction of a compound of formula (II):
(II) with a compound of formula (HI):
in which R1, R2, R3 and A are as defined in formula (I) and R9 and R10 contain the appropriate functional group(s) necessary to form the B moiety;
(b) reaction of a compound of formula (IV):
(IV) in which R2, R3, A and B are as defined in formula (I) and X is a leaving group with a nucleophile R* where R is as defined in formula (I); or
(c) reaction of a compound of formula (V):
(V) in which R*, R2, A and B are as defined in formula (I) with a compound of formula (VI):
R3N(CH2CΗ2Hal)2 (VI)
in which R3 is as defined in formula (I) and Hal is halogen, or
(d) reaction of a compound of formula (VII):
- 4 -
SUBSTITUΓE SHEET (RULE 26)
(vπ)
in which R2, R3, A and B are as defined in formula (I) and Y is halogen or a group -OSO2CF3 with a compound of formula (VIII):
R1B(OH)2
(VIII)
in which R is as defined in formula (I), or
(e) reaction of a compound of formula (IX):
(DC) in which R2, R3, A and B are as defined in formula (I) with a compound of formula (X):
R!γ
(X) in which R* is as defined in formula (I) and Y is as defined in formula (VII), and optionally thereafter:
• converting a compound of formula (I) into another compound of formula (I)
• forming a pharmaceutically acceptable salt. Suitably one of R9 or R1^ is an activated carboxylic acid derivative, such as an acyl halide or acid anhydride, and the other is an amine group. Activated compounds of formulae (II) or (El) can also be prepared by reaction of the corresponding carboxylic acid with a coupling reagent such as carbonyldiimidazole, dicyclohexylcarbodiimide or diphenylphosphorylazole. Preferably R9 or RlO is a group COL where L is halo, particularly chloro.
A compound of formulae (II) and (HI) are typically reacted together in an inert organic solvent such as DMF, THF or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine, pyridine or aqueous sodium hydroxide. Compounds of formulae (II) and (III) can be prepared from the corresponding carboxylic acids using standard procedures. For example 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 (IV) with a nucleophile R^ is preferably carried out in a suitable solvent such as dimethylformamide in the presence of a strong base such as sodium hydride. Preferably the leaving group X is halo, in particular fluoro. Preferably the group R2 is an electron withdrawing group, for example nitro, COCH3 or cyano, in the ortho or para-positions relative to the group X. Reaction of a compound of formula (V) with a compound of formula (VI) 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. Suitably, the reactions are carried out at ambient or elevated temperature, preferably at the reflux temperature of the reaction mixture. Reaction of compounds of formula (VII) and (VIII) and reaction of compounds of formulae (IX) and (X) 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. Intermediate compounds of formulae (III), (IV), (V), (VI), (VII), (VIII), (IX) and
(X) are commercially available or can be prepared using standard procedures. For example certain compounds can be prepared using similar procedures to those outlined in EPA 533266/7/8.
It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures, for example when the group R3 is a hydrogen atom. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. These groups can be removed by conventional
- 6 -
SUBST1TUTE SHEET (RULE 26) procedures.
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. 5HTID 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. Other CNS disorders include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, as well as other psychiatric disorders.
5HTID Antagonists, and in particular compounds of the present invention, 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.
Therefore, 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.
In another aspect the invention provides the use of a compound of general formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of the aforementioned disorders.
In a further aspect 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.
In particular 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
- 7 -
SUBSΠTUTE SHEET (RULE 26) 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.
For parenteral administration, 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. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, 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. Advantageously, 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. However, as a general guide 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. When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.
The following Examples illustrate the preparation of pharmacologically active compounds of the invention.
- 9 -
SUBST1TUTE SHEET (RULE 26) Description 1 2,3-dihydrobenzofuran-7-carboxylic acjd (Dl)
Following the procedure outlined in EP-A-307172, Example 15, 2,3-dihydrobenzofuran (10.73g) was converted to the title compound (Dl) (6g, 41%).
*H NMR 250 MHz (CDC13) δ : 8.76 (brs, 1H), 7.82 (d, 1H), 7.42 (d, 1H), 6.95 (t, 1H), 4.8 (t, 2H), 3.3 (t, 2H)
Description 2
7-(trifluoroacetyIamino)-2,3-dihydrobenzofuran (D2)
2,3-dihydrobenzofuran-7-carboxylic acid (Dl) (1.42g) was dissolved in a mixture of trifluoroacetic acid (50 ml) and trifluoroacetic anhydride (10 ml). After stirring at room temperature for 1.5 h, the mixture was cooled to 0° C and treated portionwise with sodium azide (1.4 eq = 788 mg), then stirred at room temperature for 2 days under argon. The mixture was evaporated under reduced pressure, and the residue partitioned between CHCI3 and water. The organic phase was washed with K2CO3 (aq), dried (Na2SO.j.) and the solvent evaporated under reduced pressure, to give the title compound (1.64g, 82%) as an off-white crystalline material.
1H NMR 250 MHz (CDCI3) δ : 7.85-8.2 (m, 2H), 7.05 (d, H), 6.89 (t, H), 4.65 (t, 2H), 3.28 (t, 2H)
Description 3
7-amino-2,3-dihydrobenzofuran (D3)
A solution of 7-(trifluoroacetylamino)-2,3-dihydrobenzofuran (D2) (1.6g) in methanol (30 ml) and 10% NaOH (3 ml) was heated to reflux for 24 h. The mixture was evaporated under reduced pressure and partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (900 mg, 96%) as a pale orange oil, which crystallised on standing.
H NMR 200 MHz (CDCI3) δ : 6.44-6.75 (m, 3H), 4.57 (t, 2H), 3.55 (br s, 2H), 3.2 (t, 2H) Description 4 7-(4-methylpiperazin-l-yI)-2,3-dihydrobenzofuran (D4)
A solution of 7-amino-2,3-dihydrobenzofuran (D3) (2g) in chlorobenzene (15 ml) was treated with mechlorethamine hydrochloride (2.85 g) and die mixture refluxed overnight under Argon. The solvent was evaporated under reduced pressure and die residue was dissolved in 1-butanol (30 ml) and treated with Na2CO3 (6.28 g). After refluxing under Argon for a further 24 h, the solvent was evaporated under reduced pressure and partitioned between ethyl acetate and water. Organic phase was dried (Na2SO4) and solvent evaporated under reduced pressure to give the title compound as a red oil (1.32 g, 41%).
!H NMR 250 MHz (CDCI3) δ :6.69-7.0 (m, 3H), 4.6 (t, 2H), 3.05-3.35 (m, 6H), 2.52- 2.73 (m, 4H), 2.35 (s, 3H)
Description 5 7-(4-methylpiperazin-l-yl)-5-nitro-2 -dihydrobenzofuran (D5)
Potassium nitrate (705 mg) was added portionwise over V i to a solution of 7-(4- methylpiperazin-l-yl)-2,3-dihydrobenzofuran (D4) (1.32 g) in concentrated sulphuric acid
(16 ml) at room temperature. The resulting solution was stirred for a further XA h, then added to ice (40 g), basified with 5N NaOH, and extracted into ethyl acetate. The organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure to give the title compound (847 mg, 53%) as an orange, crystalline solid.
!H NMR 250 MHz (CDCI3) δ :7.79 (s, 1H), 7.64 (s, 1H), 4.78 (t, 2H), 3.1-3.38 (m, 6H),
2.5-2.7 (m, 4H), 2.36 (s, 3H)
Description 6 7-(4-methylpiperazin-l-yl)-5-amino-2,3-dihydrobenzofuran (D6)
A solution of 7-(4-methylpiperazin-l-yl)-5-nitro-2,3-dihydrobenzofuran (D5) (845 mg) in ethanol (50 ml) was hydrogenated over 10% Palladium on charcoal (0.5 g) at atmospheric pressure and room-temperature for 1 h. The catalyst was removed by filtration through kieselguhr, and the filtrate evaporated under reduced pressure to give the title compound (741 mg, 99%).
!H NMR 250 MHz (CDCI3) δ : 6.25 (s, 1H), 6.1 (s, 1H), 4.53 (t, 2H), 2.5-3.3 (m, 12H), 2.35 (s, 3H).
Description 7 7-Nitro-l,4-benzodioxan-5-carboxylic acid (D7)
Benzodioxan-5-carboxylic acid (prepared as described by E.A.Watts, in Azabicycloalkylbenzamides and pharmaceutical compositions containing them, EP 82-303057 June 1982) (15 g) was dissolved in a mixture of glacial acetic acid (67 ml) and acetic anhydride (67 ml). The solution was heated to 40° C and treated with a solution of fuming nitric acid (13 ml) in acetic acid (13 ml) at a rate such that the temperature was maintained at 45-50° C with occasional ice/water cooling. The mixture was stirred at 50°-53° C for 2 days, then cooled and filtered to give the title compound as a white powder (4.09 g, 22%).
1H NMR 250 MHz (DMSO-d6) δ : 8.09 (s, IH), 7.85 (s, IH), 4.28-4.59 (m, 4H).
Description 8 7-amino-l,4-benzodioxan-5-carboxyIic acid (D8)
A solution of 7-nitro-l,4-benzodioxan-5-carboxylic acid (D7) (2.8 lg) in etiianol (100 ml) was hydrogenated over 10% Palladium on charcoal (750 mg) for 20 h. The catalyst was removed by filtration through kieselguhr and die filtrate evaporated under reduced pressure to give the title compound as a white solid (1.96 g, 81%)
1H NMR 200 MHz (DMSO-d6) δ : 6.5 (s, IH), 6.26 (s, IH), 4.03-4.3 (m, 4H), 3.4 (br s, 2H).
Description 9 4-bromo-3-methyl-N-[5-carboxy-l,4-benzodioxan-7-yI]benzamide (D9)
Following the method outlined in Example 1, 7-amino-l,4-benzodioxan-5-carboxylic acid (D8) (1.96 g) was converted to die tide compound as an off-white powder (3.19 g, 81%).
1H NMR 250 MHz (DMSO-d6) δ : 10.19 (s, IH), 7.96 (s, IH), 7.72 (s, 2H), 7.36 (s, IH), 7.30 (s, IH), 4.12-4.25 (m, 4H), 2.42 (s, 3H)
- 12 -
SUBST1TUTE SHEET (RULE 26) Description 10
4-Bromo-3-methyl-N-[5-(trifluoroacetylamino)-l,4-benzodioxan-7-yl]benzamide
(D10)
Following the method outlined in description 2, 4-bromo-3-methyl-N-[5-carboxy-l,4- benzodioxan-7-yl]benzamide (D9) (1.0 g) was converted to die tide compound (739 mg, 63%).
1H NMR 200 MHz (DMSO-d6) δ : 10.89 (s, IH), 10.23 (s, IH), 7.92 (s, IH), 7.56-7.8 (m, 2H), 7.42 (s, IH), 7.39 (s, IH), 4.19-4.46 (m, 4H), 2.42 (s, 3H)
Description 11 4-bromo-3-methyl-N-[5-amino-l,4-benzodioxan-7-yl]benzamide (Dll)
Following the method outlined in description 3, 4-bromo-3-methyl-N-[5-
(lrifluoroacetylamino)-l,4-benzodioxan-7-yl]benzamide (D10) (1.85 g) was converted to the title compound (137 mg).
iH NMR 250 MHz (CDC13) δ :7.7 (s, IH), 7.55-7.65 (m, 2H), 7.45 (d, IH), 6.8 (s, IH), 6.5 (s, IH), 4.2- 4.38 (m, 4H), 3.81 (br s, 2H), 2.44 (s, 3H).
Description 12 2 3-dihydro-2-methylbenzofuran-7-carboxylic acid (D12)
Following the procedure outlined in EP-A-307172, Example 15, 2,3-dihydro-2- methylbenzofuran (10.62g) was converted to the title compound (7.33g, 52%).
iH NMR 250MHZ (CDCI3) δ : 7.82 (d, IH), 7.38 (d, IH), 6.95 (t, IH), 5.3-5.1 (m, IH), 3.5-3.3 (m, IH), 3.0-2.8 (m, IH), 1.58 (d, 3H)
Description 13 7-(trifluoroacetylamino)-2,3-dihydro-2-methylbenzofuran (D13)
Following the procedure outlined in description 2, 2,3-dihydro-2-methylbenzofuran-7- carboxylic acid (D12) (7.33g) was converted to the tide compound (8.36g, 83%).
*H NMR 200 MHz (CDCI3) δ : 8.08-7.8 ( , 2H), 7.01 (d, IH), 6.87 (t, IH), 5.12-4.92 (m, IH), 3.46-3.29 (m, IH), 2.97-2.8 (m, IH), 1.5 (d, 3H). Description 14 7-amino-2,3-dihydro-2-ιnethylbεnzofuran (D14)
Following the procedure oudined in description 3, 7-(trifluoroacetylamino)-2,3-dihydro-2- methylbenzofuran (D13) (8.36g) was converted to the tide compound (4.83g, 95%)
ΪH NMR 200 MHz (CDC13) δ : 6.74-6.45 (m, 3H), 5.01-4.81 (m, IH), 3.76-3.2 (m, 3H), 2.9-2.71 (m, IH), 1.48 (d, 3H).
Description 15 7-(4-methylpiperazin-l-yI)-2 -dihydro-2-methylbenzofuran (D15)
A solution of 7-amino-2,3-dihydro-2-methylbenzofuran (D14) (4.83g) in 1-butanol (80 ml) was treated with mechlorethamine hydrochloride (12.5 g) and die mixture refluxed under argon for 24 h. Sodium carbonate (13.7 g) was added and reflux continued for 48h. The solvent was evaporated under reduced pressure and die residue was partitioned between 10% (aq) sodium hydroxide and dichloromethane. The organic phase was dried (Na2SO4) and die solvent removed under reduced pressure to give a residue which was chromatographed on silica, eluting with ethylacetate and n-pentane to give the tide compound as an orange oil (4g, 53%)
*H NMR 200 MHz (CDCI3) δ : 6.86-6.65 (m, 3H), 5.05-4.84 (m, IH), 3.37-3.0 (m, 5H), 2.9-2.73 (m, IH), 2.69-2.51 (m, 4H), 2.35 (s, 3H), 1.5 (d, 3H).
Description 16 7-(4-methylpiperazin-l-yI)-5-nitro-2,3-dihydro-2-methyIbenzofuran (D16)
Following the procedure outlined in description 5, 7-(4-methylpiperazin-l-yl)-2,3-dihydro- 2-methylbenzofuran (D15) (4g) was converted to the tide compound (2.81g, 59%)
1H NMR 250 MHz (CDCI3) δ : 7.75 (s, IH), 7.64 (s, IH), 5.25-5.04 (m, IH), 3.45-3.05 (5H), 2.94-2.8 (m, IH), 2.72-2.51 (m, 4H), 2.37 (s, 3H), 1.55 (d, 3H) Description 17 5-amino-7-(4-methyIpiperazin-I-yI)-2^-dihydro-2-methylbenzofuran (D17)
Following the procedure oudined in description 6, 7-(4-methylpiperazin-l-yl)-5-nitro-2,3- dihydro-2-medιylbenzofuran (D16) (2.8 lg) was converted to die tide compound (2.57g, quantitative).
1HNMR 250MHz (CDCI3) δ : 6.2 (s, IH), 6.1 (s, IH), 5.0-4.78 (m, IH), 3.54-2.89 (m, 7H), 2.81-2.49 (m, 5H), 2.35 (s, 3H), 1.46 (d, 3H)
Description 18 7-(4-methylpiperazin-l-yl)-2,3-dihydro-2 -dimethylbenzofuran (D18)
Following the procedure oudined in description 15, 2,3-dihydro-2,2-dimethyl-7- benzofuranamine (4.93g) was converted into die tide compound (2.48g, 33%)
l NMR 250 MHz (CDCI3) δ : 6.85-6.65 (m, 3H), 3.29-3.09 (m, 4H), 2.98 (s, 2H), 2.7- 2.51 (m, 4H), 2.34 (s, 3H), 1.49 (s, 6H).
Description 19
7-(4-methylpiperazin-l-yl)-5-nitro-2,3-dihydro-2,2-dimethyIbenzofuran (D19)
Following the procedure oudined in description 5, 7-(4-methylpiperazin-l-yl)-2,3-dihydro- 2,2-dimethylbenzofuran (D18) (2.48 g) was converted to die tide compound (1.46g, 50%)
*H NMR 200 MHz (CDCI3) δ : 7.72 (s, IH), 7.61 (s, IH), 3.29-3.14 (m, 4H), 3.05 (s, 2H), 2.65-2.52 (m, 4H), 2.35 (s, 3H), 1.52 (s, 6H)
Description 20 5-Amino-7-(4-methyIpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran (D20)
Following the procedure outlined in description 6, 7-(4-methylpiperazin-l-yl)-5-nitro-2,3- dihydro-2,2-dimethylbenzofuran (D19) (1.46g) was converted to the title compound (1.06g, 81%)
lϋ NMR 250 MHz (CDCI3) δ : 6.19 (s, IH), 6.11 (s, IH), 3.25-3.04 (m, 4H), 2.9 (s, 2H), 2.68-2.51 (m, 4H), 2.35 (s, 3H), 1.45 (s, 6H)
- 15 -
SUBST1TUTΕ SHEET RULE 26) Example 1
4-bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yljbenzamide (El)
4-bromo-3-methylbenzoic acid (690 mg) was refluxed for 1 h in thionyl chloride (10 ml), then cooled to room-temperature and evaporated under reduced pressure to leave die acid chloride. A solution of 7-(4-methylpiperazin-l-yl)-5-amino-2,3-dihydrobenzofuran (D6) (740 mg) in tetrahydrofuran (50 ml) was treated witii a solution of the acid chloride (749 mg) in tetrahydrofuran (10 ml) and sodium hydroxide (0.26 g) in water (4 ml). The mixture was stirred for three days under Argon at room temperature, then the solvent was evaporated under reduced pressure, and die residue partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4), the solvent evaporated under reduced pressure and the residue passed through a short silica (flash) column, eluting with methanol/ethyl acetate(l%-6%), to give the title compound (810 mg, 59%), mp 93-5° C.
1H NMR 250 MHz (CDCI3) δ :7.74 (s, 2H), 7.62 (d, IH), 7.5 (d, IH), 7.23 (s, IH), 6.86 (s, IH), 4.62 (t, 2H), 3.03-3.32 (m, 6H), 2.52-2.71 (m, 4H), 2.46 (s, 3H), 2.35 (s, 3H).
Example 2 4-bromo-3-methyI-N-[7-(piperazin-l-yl)-2,3-dihydrobenzofuran-5-yI]benzamide hydrochloride (E2)
A solution of 4-bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran- 5-yl]benzamide (El) (250 mg) in dry toluene (4 ml) was cooled to 0° C and treated with α-chloroethyl chloroformate (166 mg). The mixture was stirred at room temperature for lh, and filtered through kieselguhr. The filtrate was evaporated under reduced pressure and the residue dissolved in a mixture of dry toluene (5 ml) and metiianol (4 ml) and stirred at room temperature overnight. The solvents were evaporated under reduced pressure to leave the title compound as an orange solid (65 mg) mp 129-132° C°.
1H NMR 250 MHz (DMSO-d6) δ : 10.15 (s, IH), 9.25 (br s, 2H), 7.94 (s, IH), 7.65-7.77 (m, 2H), 7.4 (s, IH), 7.2 (s, IH), 4.54 (t, 2H), 3.05-3.32 (m, 10H), 2.42 (s, 3H).
Example 3 4-bromo-3-methyl-N-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benzamide
(E3)
A solution of 4-bromo-3-methyl-N-[5-amino-l,4-benzodioxan-7-yl]benzamide (Dl l) (128
- 16 -
SUBSΠTUΓE SHEET (RULE 26) mg) in 1-butanol (2 ml) was treated with mechlorethamine hydrochloride (136 mg) and die mixture refluxed under Argon overnight. Na2CO3 (150 mg) was added and the mixture refluxed for a further 24 h under Argon. The mixture was partitioned between dichloromethane and 10% NaOH, the organic phase dried (Na2SO4) and the solvent evaporated under reduced pressure. Purification on preparative tic plate (Si) eluting with 7.5% edianol/chloroform gave the title compound as a tan foam (90 mg, 57%) mp 70-73° C.
1H NMR 250 MHz (CDC13) δ :7.66-7.82 (m, 2H), 7.62 (d, IH), 7.5 (d, IH), 6.96 (s, IH), 6.8 (s, IH), 4.16-4.45 (m, 4H), 2.98-3.29 (m, 4H), 2.54-2.78 (m, 4H), 2.45 (s, 3H), 2.36 (s, 3H).
Example 4
4-(4-pyridyl)-3-methyI-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yl]benzamide (E4)
To a solution of 4-bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran- 5-yl]benzamide (El) (300 mg) in dimetiioxyetiiane (10 ml) was added successively, 4- pyridylboronic acid (146 mg), sodium carbonate (192 mg) in water (5 ml) and tetrakis(triphenylphospine)palladium (0) (50 mg). The mixture was stirred at reflux under argon for 40 h, diluted with water and extracted into chloroform. The organic phase was dried (Na2SO4) and evaporated under reduced pressure and the residue purified by column chromatography (silica) eluting witii methanol and chloroform (l%-4%), to give the title compound (204 mg, 68%), mp 90-3° C.
1H NMR 250 MHz (CDCI3) δ : 8.7 (d, 2H), 7.7-8 (m, 3H), 7.22-7.4 (m, 4H), 6.91 (s, 1 H), 4.64 (t, 2H), 3.05-3.35 (m, 6H), 2.52-2.77 (m, 4H), 2.26-2.49 (m, 6H)
Example 5 4-(4-pyridyl)-3-methyl-N-[5-(4-methylpiperazin-l-yl)-l,4-benzodioxan-7- yljbenzamide (E5)
Following the method outlined in example 4, 4-bromo-3-methyl-N-[5-(4-methylpiperazin- l-yl)-l,4-benzodioxan-7-yl]benzamide (E3) (73 mg) was converted to the title compound, and purified on preparative tic plate (Siθ2) eluting with 15% ethanol/chloroform (42 mg, 58%) mp 230° C+ (dec)
*H NMR 250 MHz (CDCI3) δ : 8.7 (d, 2H), 7.82 (s, 2H), 7.75 (d, IH), 7.21-7.37 (m, 3H), 7.01 (s, IH), 6.85 (s, IH), 4.2-4.38 (m, 4H), 3.01-3.25 (m, 4H), 2.55-2.78 (m, 4H), 2.38 (s, 3H), 2.34 (s, 3H).
Example 6 N-[7-(4-methylpiperazin-l-yl)-2 -dihydro-2-methylbenzofuran-5-yI]-2I-methyl-4'-(5- methyl-l,2,4-oxadiazoI-3-yI)biphenyl-4-carboxaπιide (E6)
2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-l,l,-biphenyl-4-carboxylic acid (EP 0533 268A1) (200 mg) was heated under reflux in excess tiiionyl chloride (5 ml) under argon for 1 hr, and die excess tiiionyl chloride evaporated under reduced pressure. The resulting acid chloride was dissolved in tetrahydrofuran (25 ml) and treated wid 5-amino-7-(4- methylpiperazin-l-yl)-2,3-dihydro-2-medιylbenzofuran (D17) (176 mg) in tetrahydrofuran (10 ml), and a solution of sodium hydroxide (57 mg) in water (1 ml). The mixture was stirred at room temperature overnight then the solvent was evaporated under reduced pressure. The residue was partitioned between water and dichlorometiiane, the organic phase was dried (Na2SO4) and the solvent evaporated under reduced pressure, to give the title compound as a brown foam (339 mg, 91%).
1H NMR 250 MHz (CDC13) δ : 8.06-7.86 (m, 4H), 7.8 (s, IH), 7.45 (d, 2H), 7.34 (d, IH), 7.25 (d, IH), 6.86 (s, IH), 5.06-4.88 (m, IH), 3.38-3.0 (m, 5H), 2.9-2.74 (m, IH), 2.69 (s, 3H), 2.65-2.51 (m, 4H), 2.39-2.26 (m, 6H), 1.5 (d, 3H).
Example 7
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2'-methyl- 4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E7)
Following the procedure oudined in example 6, 5-amino-7-(4-methylpiperazin-l-yl)-2,3- dihydro-2,2-dimedιylbenzofuran (D20) (186 mg) was converted to the tide compound (258 mg, 68%)
1H NMR 250 MHz (CDCI3) δ : 8.06-7.89 (m, 4H), 7.81 (s, IH), 7.45 (d, 2H), 7.35 (d, IH), 7.25 (d, IH), 6.84 (s, IH), 3.3-3.09 (m, 4H), 3.0 (s, 2H), 2.75-2.5 (m, 7H), 2.41-2.22 (m, 6H), 1.49 (s, 6H). Example 8
N-^^Piperazin-l-y ^^-dihydro^^-dimethylbenzofuran-S-ylT^'-methyl^'^S- methyl-l^,4-oxadiazol-3-yl)biphenyl-4-carboxamide hydrochloride (E8)
A solution of N-[7-(4-me ylpiperarin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2'- methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E7) (150 mg) in dichloromethane (20 ml) was cooled to 0° C and treated witii α-chloroethyl chloroformate (0.04 ml) and diisopropylethylamine (0.55 ml). The mixture was refluxed for 3h, cooled and filtered through a short neutral alumina column eluting widi dichloromethane, tiien ethyl acetate. The solvent was evaporated under reduced pressure, and the residual carbamate dissolved in methanol (10 ml) and stood overnight The solvent was evaporated under reduced pressure to leave the tide compound as a white powder (38 mg, 22%) Mp 175-180° C.
1H NMR 250 MHz (CD3OD) δ: 8.08-7.98 (m, 3H), 7.94 (d, IH), 7.57-7.47 (m, 2H), 7.39 (d, IH), 7.27 (s, IH), 7.19 (s, IH), 3.4 (s, 8H), 3.06 (s, 2H), 2.68 (s, 3H), 2.35 (s, 3H), 1.5 (s, 6H).
Example 9 4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethyI benzofuran-5-yl]benzamide (E9)
Following the procedure oudined in example 1, 5-amino-7-(4~methylpiperazin-l-yl)-2,3- dihydro-2,2-dimethylbenzofuran (D20) (300 mg) was converted to die tide compound (230mg, 44%) Mp 81-83° C.
1H NMR 200 MHz (CDCI3) δ: 7.72 (br s, 2H), 7.61 (d, IH), 7.50 (d, IH), 7.19 (s, IH), 6.8 (s, IH), 3.18 (br s, 4H), 2.99 (s, 2H), 2.67-2.51 (m, 4H), 2.45 (s, 3H), 2.35 (s, 3H), 1.49 (s, 6H).
Example 10
N-[7-(piperazin-l-yl)-2 -dihydro-2-methylbenzofuran-5-yI]-2'-methyl-4,-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide hydrochloride (E10)
Following the procedure outlined in example 8, N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro- 2-methylbenzofuran-5-yl]-2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)biphenyl-4- carboxamide (E6) (150 mg) was converted to the title compound (55 mg, 35%) Mp 150- 155° C.
- 19 -
SUBST1TUTE SHEET (RULE 26) 1H NMR 250 MHz (DMSO-d6) δ: 10.19 (s, IH), 9.22 (br s, 2H), 8.16-7.85 (m, 4H), 7.61-7.75 (m, 2H), 7.49-7.39 (m, 2H), 7.24 (s, IH), 5.04-4.85 (m, IH), 3.48-3.18 (m, 9H), 2.87-2.65 (m, 4H), 2.35 (s, 3H), 1.4 (d, 3H).
Example 11
4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5- yl]benzamide (Ell)
Following the procedure oudined in example 1, 5-amino-7-(4-methylpiperazin-l-yl)-2,3- dihydro-2-methylbenzofuran (D17) (230 mg) was converted to the title compound (399 mg, 97%) Mp 73-5° C.
1H NMR 250 MHz (CDCI3) δ: 7.84-7.44 (m, 4H), 7.2 (s, IH), 6.82 (s, IH), 5.08- 4.89 (m, IH), 3.39-3.02 (m, 5H), 2.92-2.75 (m, IH), 2.69-2.52 (m, 4H), 2.47 (s, 3H), 2.35 (s, 3H), 1.5 (d, 3H).
Example 12
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yI]-2'-methyl-4'-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (E12)
Following the procedure oudined in example 6, 7-(4-methylpiperazin-l-yl)-5-amino-2,3- dihydrobenzofuran (D6) (166 mg) was converted to the tide compound (358 mg, 98%) Mp 80-85° C.
ΪH NMR 250 MHz (CDCI3) δ: 8.08-7.89 (m, 4H), 7.82 (s, IH), 7.51-7.41 (m, 2H), 7.35 (d, IH), 7.3-7.24 (m, IH), 6.9 (s, IH), 4.64 (t, 2H), 3.3-3.08 (m, 6H), 2.75-2.5 (m, 7H), 2.35 (d, 6H).
Example 13
N-[7-(Piperazin-l-yl)-2^-dihydrobenzofuran-5-yl]-2'-methyl-4'-(5-methyI-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide hydrochloride (E13)
Following die procedure outlined in example 8, N-[7-(4-methylpiperazin-l-yl)-2,3- dihydrobenzofuran-5-yl]-2'-methyl-4'-(5-methyl- 1 ,2,4-oxadiazol-3-yl)biphenyl-4- carboxamide (El 2) (200 mg) was converted to the title compound (159 mg, 76%) Mp 159-162° C.
- 20 -
SUBST1TUTE SHEET (RULE 26) iH NMR 250 MHz (CD3OD) δ: 8.07-7.98 (m, 3H), 7.94 (d, 1H), 7.55-7.48 (m, H), 7.4 (d, IH), 7.25 (s, 2H), 4.62 (t, 2H), 3.5-3.2 (m, 10H), 2.68 (s, 3H), 2.36 (s, 3H).
- 21 -
SUBSΠTUTE SHEET (RULE 26)

Claims

CLAIMS:
1. A compound of formula (I) or a salt thereof:
(I) in which
Ri is halogen, C3_6cycloalkyl, optionally substituted phenyl or an optionally substituted 5-7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur;
R2 is hydrogen, halogen, C^galkyl, Ci.galkoxy, acyl, nitro, trifluoromethyl or cyano;
R3 is hydrogen or Ci.galkyl; and
A is -(CR4R5)m- or -O(CR4R5)n- where R4 and R5 are independently hydrogen or Cι_6alkyl, m is 2, or 3; n is 1, 2 or 3 and
B is CONH or NHCO.
2. A compound according to claim 1 in which R is halogen, pyridyl or a disubstituted phenyl group.
3. A compound according to claim 1 or 2 in which R is:
4. A compound according to any one of claims 1 to 3 in which R2 is hydrogen.
5. A compound according to any one of claims 1 to 4 in which R3 is hydrogen or methyl.
6. A compound according to any one of claims 1 to 5 in which A is CH2CH2 or OCH CH2 and B is CONH.
7. A compound according to claim 1 which is
- 22 -
SUBST1TUTE SHEET (RULE 26) 4-bromo-3-methyl-N-[7-(4-methylpiperazin- 1 -yl)-2,3-dihydrobenzofuran-5-yl] benzamide,
4-bromo-3-methyl-N-[7-(piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]benzamide,
4-bromo-3-methyl-N-[5-(4-medιylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benza-mide,
4-(4-pyridyl)-3-methyl-N-[7-(4-medιylpiperazin-l-yl)-2,3-dihydrobenzofuran-5- yljbenzamide,
4-(4-pyridyl)-3-medιyl-N-[5-(4-medιylpiperazin-l-yl)-l,4-benzodioxan-7-yl]benzamide,
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-medιylbenzofuran-5-yl]-2'-methyl-4'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide, or
N-[7-(4-medιylpiperazin-l-yl)-2,3-dihydro-2,2-dimedιylbenzofuran-5-yl]-2'-medιyl-4'-(5- methyl- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[7-(Piperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5-yl]-2'-methyl-4'-(5-methyl- l,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide,
4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2,2-dimethylbenzofuran-5- yl]benzamide, N-[7-(piperazin-l-yl)-2,3-dihydro-2-medιylbenzofuran-5-yl]-2'-methyl-4'-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
4-Bromo-3-methyl-N-[7-(4-methylpiperazin-l-yl)-2,3-dihydro-2-methylbenzofuran-5- yl] benzamide,
N-[7-(4-methylpiperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]-2'-methyl-4'-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide,
N-[7-(Piperazin-l-yl)-2,3-dihydrobenzofuran-5-yl]-2'-methyl-4'-(5-methyl-l,2,4- oxadiazol-3-yl)biphenyl-4-carboxamide, or a pharmaceutically acceptable salts thereof.
8. A process for the preparation of a compound of formula (I) which comprises
(a) reaction of a compound of formula (II):
with a compound of formula (III):
- 23 -
SUBST1TUTE SHEET (RULE 26)
(HI) in which R\, R2, R3 and A are as defined in formula (I) and R^ and R*0 contain the appropriate functional group(s) necessary to form the B moiety;
(b) reaction of a compound of formula (TV) :
(IV) in which R2, R3, A and B are as defined in formula (I) and X is a leaving group witii a nucleophile R* where R* is as defined in formula (I); or
(c) reaction of a compound of formula (V):
(V) in which R , R2, A and B are as defined in formula (I) with a compound of formula (VI):
R3N(CH2CH2Hal)2 (VI) in which R3 is as defined in formula (I) and Hal is halogen, or
- 24 -
SUBST1TUTE SHEET (RULE 26) (d) reaction of a compound of formula (VII):
(vπ)
in which R2, R3, A and B are as defined in formula (I) and Y is halogen or a group -OSO2CF3 with a compound of formula (VIII):
R1B(OH)
(VΠD
in which R is as defined in formula (I), or
(e) reaction of a compound of formula (IX):
(IX) in which R2, R3, A and B are as defined in formula (I) with a compound of formula (X):
R!γ
(X) in which R is as defined in formula (I) and Y is as defined in formula (VII),
- 25 -
SUBST1TUTE SHEET (RULE 26) and optionally tiiereafter:
• converting a compound of formula (I) into another compound of formula (I)
• forming a pharmaceutically acceptable salt.
9. A compound according to any one of claims 1 to 7 for use in therapy.
10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 7 in association with a pharmaceutically acceptable carrier or excipient.
- 26 -
SUBSTrrUTE SHEET (RULE 26)
EP94930171A 1993-10-19 1994-10-13 Benzanilide derivatives as 5ht-1d receptor antagonists Withdrawn EP0724580A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9321490 1993-10-19
GB939321490A GB9321490D0 (en) 1993-10-19 1993-10-19 Novel compounds
GB9325866 1993-12-17
GB939325866A GB9325866D0 (en) 1993-12-17 1993-12-17 Novel compounds
PCT/EP1994/003387 WO1995011243A1 (en) 1993-10-19 1994-10-13 Benzanilide derivatives as 5ht-1d receptor antagonists

Publications (1)

Publication Number Publication Date
EP0724580A1 true EP0724580A1 (en) 1996-08-07

Family

ID=26303698

Family Applications (1)

Application Number Title Priority Date Filing Date
EP94930171A Withdrawn EP0724580A1 (en) 1993-10-19 1994-10-13 Benzanilide derivatives as 5ht-1d receptor antagonists

Country Status (3)

Country Link
EP (1) EP0724580A1 (en)
JP (1) JPH09503773A (en)
WO (1) WO1995011243A1 (en)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9519033D0 (en) * 1995-09-18 1995-11-15 Smithkline Beecham Plc Treatment
SE9601110D0 (en) 1996-03-22 1996-03-22 Astra Ab Substituted 1,2,3,4-tetrahydronaphthalene derivatives
DZ2376A1 (en) * 1996-12-19 2002-12-28 Smithkline Beecham Plc New sulfonamide derivatives process for their preparation and pharmaceutical compositions containing them.
WO1998027058A2 (en) * 1996-12-19 1998-06-25 Smithkline Beecham Plc N-piperazin-1-ylphenyl-benzamide derivatives
SE9900190D0 (en) 1999-01-22 1999-01-22 Astra Ab New compounds
SE9702799D0 (en) 1997-07-25 1997-07-25 Astra Ab New compounds
AU768310B2 (en) 1999-07-29 2003-12-04 Eli Lilly And Company Benzofurylpiperazines and benzofurylhomopiperazines: serotonin agonists
JP2003506370A (en) 1999-07-29 2003-02-18 イーライ・リリー・アンド・カンパニー Benzofurylpiperazine serotonin agonist
PE20020506A1 (en) 2000-08-22 2002-07-09 Glaxo Group Ltd PIRAZOLE DERIVATIVES FUSED AS PROTEIN KINASE INHIBITORS
US7041280B2 (en) 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
US6858592B2 (en) 2001-06-29 2005-02-22 Genzyme Corporation Aryl boronic acids for treating obesity
DE60231507D1 (en) 2001-07-20 2010-07-01 Psychogenics Inc TREATMENT OF HYPERACTIVITY DISORDERS AND ATTENTION DEFICITS
GB0124933D0 (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
GB0124931D0 (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
GB0124938D0 (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
GB0124936D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
US7125898B2 (en) 2002-02-12 2006-10-24 Smithkline Beecham Corporation Nicotinamide derivatives useful as p38 inhibitors.
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
GB0308201D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308185D0 (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
WO2006062481A1 (en) * 2004-12-09 2006-06-15 Biovitrum Ab New benzofuran derivatives and their use in the treatment of obesity, type ii diabetes and cns disorders .
CN103896831A (en) * 2007-08-27 2014-07-02 Abbvie德国有限责任两合公司 4-(4-pyridinyl)-benzamides and their use as rock activity modulators
GB201002563D0 (en) 2010-02-15 2010-03-31 Cambridge Entpr Ltd Compounds
CN107108581B (en) * 2014-08-21 2020-06-23 百时美施贵宝公司 Tieback benzamide derivatives as potent ROCK inhibitors
WO2019036024A1 (en) 2017-08-17 2019-02-21 Bristol-Myers Squibb Company 2-(1,1 '-biphenyl)-1 h-benzo[d]imidazole derivatives and related compounds as apelin and apj agonists for treating cardiovascular diseases
WO2020183011A1 (en) 2019-03-14 2020-09-17 Institut Curie Htr1d inhibitors and uses thereof in the treatment of cancer

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9119920D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
GB9119932D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
ATE204262T1 (en) * 1991-09-18 2001-09-15 Glaxo Group Ltd BENZANILIDE DERIVATIVES AS 5-HT1D ANTAGONISTS

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9511243A1 *

Also Published As

Publication number Publication date
WO1995011243A1 (en) 1995-04-27
JPH09503773A (en) 1997-04-15

Similar Documents

Publication Publication Date Title
WO1995011243A1 (en) Benzanilide derivatives as 5ht-1d receptor antagonists
US5905080A (en) Amide and urea derivatives as 5HT1D receptor antagonists
EP0736025B1 (en) Dyhydrobenzofuranyl-biphenyl carboxamides having 5ht1d antagonistic activity
US5756496A (en) Amide derivatives having 5HT1D-antagonist activity
US5935951A (en) 1-acyl-4-aliphatylaminopiperidine compounds
US5834471A (en) Amide derivatives as 5HT1D receptor antagonists
US5696122A (en) Indole and indoline derivatives as 5HT1D receptor antagonists
JP3262333B2 (en) Piperazine derivatives as 5-HT1A antagonists
HU191643B (en) Process for preparing new n-phenyl-n'-cycloalkyl-alkanoyl-piperazine derivatives
SK287912B6 (en) 4-Phenylpyridine derivates, process for preparing thereof, pharmaceutically acceptable composition and use of the compound for the manufacture of medicaments
SK1142003A3 (en) Carboxamide compounds and their use as antagonists of a human 11CBY receptor
US5972937A (en) Heterocyclic compounds possessing 5HT2C receptor antagonist activity
JP2009544579A (en) Substituted benzylamine compounds
EP0716656A1 (en) Amide derivatives as 5ht1d receptor antagonists
KR20050095601A (en) Pyridine derivatives useful for inhibiting sodium/calcium exchange system
KR20050119194A (en) 1,3,4-substituted pyrazoles for use as 5-ht receptor antagonists in the treatment of psychoses and neurological disorders
US5952325A (en) Tricyclic spiro compounds process for their preparation and their use of 5HT1D receptor antagonists
US5889022A (en) Indole, indoline and quinoline derivatives with 5HT1D (anti-depressive) activity
JP2009542707A (en) Butyl and butynylbenzylamine compounds
KR20050119195A (en) Pyrazole compounds
WO1997034900A1 (en) Azaspiro derivatives
US6066644A (en) Azaspiro derivatives with 5HT1B activity
US5298503A (en) N-(isoquinolin-5-ylsulphonyl) azacycloalkanes
WO1998050343A2 (en) (hetero)aryl carboxamide derivatives, process for their preparation and their use in the treatment of cns disorders
EP0452850A1 (en) 4-[3-(4-Oxothiazoldinyl)]butynylamines, a process for their preparation and their use as medicaments

Legal Events

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

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19960412

AK Designated contracting states

Kind code of ref document: A1

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

17Q First examination report despatched

Effective date: 19970828

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

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

18D Application deemed to be withdrawn

Effective date: 19971108