EP0595980A1 - Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique - Google Patents

Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique

Info

Publication number
EP0595980A1
EP0595980A1 EP92916391A EP92916391A EP0595980A1 EP 0595980 A1 EP0595980 A1 EP 0595980A1 EP 92916391 A EP92916391 A EP 92916391A EP 92916391 A EP92916391 A EP 92916391A EP 0595980 A1 EP0595980 A1 EP 0595980A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
formula
cck
compounds
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Withdrawn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
EP92916391A
Other languages
German (de)
English (en)
Inventor
Stephen Robert 10 Clipped Hedge Fletcher
Graham Andrew Showell
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.)
Organon Pharma UK Ltd
Original Assignee
Merck Sharp and Dohme 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
Application filed by Merck Sharp and Dohme Ltd filed Critical Merck Sharp and Dohme Ltd
Publication of EP0595980A1 publication Critical patent/EP0595980A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to benzodiazepine compounds which are useful as antagonists of cholecystokinin and gastrin receptors.
  • Cholecystokinins (CCK) and gastrin are structurally related neuropeptides which exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones, G.B.J. Green, Ed., Raven Press, N.Y., p.169 and G. Nission, ibid. p.127).
  • Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form (see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (also a naturally- occurring neuropeptide and the minimum fully active sequence), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with the minimum active sequence being the C-terminal
  • Trp-Met-Asp-Phe-NH 2 which is the common structural element shared by both CCK and gastrin.
  • CCKs are believed to be physiological satiety hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eating and Its
  • gastrin The primary role of gastrin, on the other hand, appears to be stimulation of the secretion of water and electrolytes from the stomach and, as such, is involved in control of gastric acid and pepsin secretion. Other physiological effects of gastrin then include increased mucosal blood flow and increased antral motility. Rat studies have shown that gastrin has a positive trophic effect on the gastric mucosa, as evidenced by increased DNA, RNA and protein synthesis.
  • CCK-A and CCK-B cholecystokinin receptors
  • CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal (GI) and central nervous (CNS) systems of animals, especially mammals, and more especially those of humans.
  • GI gastrointestinal
  • CNS central nervous
  • antagonists also tend to have affinity for both CCK-B receptors and gastrin receptors.
  • Other antagonists have activity at the CCK-A subtype.
  • Selective CCK antagonists are themselves useful in treating CCK-related disorders of appetite regulatory systems of animals as well as in potentiating and
  • Selective CCK and gastrin antagonists are useful in the modulation of behaviour mediated by dopaminergic and serotonergic neuronal systems and thus have utility in the treatment of schizophrenia and depression (Rasmussen et. al., 1991, Eur. J. Pharmacol., 209, 135-138; Woodruff et. al., 1991, Neuropeptides, 19, 45-46; Cervo et. al., 1988, Eur. J. Pharmacol., 158, 53-59), as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the
  • CCK antagonists are useful anxiolytic agents and can be used in the treatment of panic and anxiety disorders.
  • CCK has been reported to evoke the release of stress hormones such as adrenocorticotrophic hormone, ⁇ - endorphin, vasopressin and oxytocin, CCK may function as a mediator of responses to stress and as part of the arousal system.
  • stress hormones such as adrenocorticotrophic hormone, ⁇ - endorphin, vasopressin and oxytocin
  • CCK-A receptors are now known to be present in a number of areas of the CNS and may be involved in modulating all of the above.
  • CCK may be involved in the regulation of stress and its relationship with drug abuse e.g. alleviation of the benzodiazepine withdrawal syndrome (Singh et. al., 1992, Br. J. Pharmacol., 105, 8-10%) and neuroadaptive
  • CCK antagonists may also be effective in neuroprotection.
  • CCK receptor antagonists have been found to inhibit the contractile effects of CCK on iris sphincter and ciliary muscles of monkey and human eyes (Eur. J.
  • European patent application no. 0 167 919 discloses benzodiazepine CCK and gastrin antagonists substituted in the 3-position by, inter alia, a phenyl urea and at the 5-position by an optionally substituted phenyl or pyridyl group.
  • British patent application no. 1,034,872 discloses benzodiazepines substituted at the 3-position by an unsubstituted amino group or a substituted amino group containing up to eight carbon atoms, and at the 5- position by a monocyclic aryl moiety.
  • the only 5- substituents specifically disclosed are phenyl
  • benzodiazepines substituted at the 5-position by, inter alia, a heterocyclic group, and at the 3-position by H, alkyl, alkoxy, alkylthioalkyl, phenyl, benzyl or
  • the present invention provides benzodiazepine compounds of formula (I):
  • one of W, X, Y or Z represents a nitrogen atom
  • another of W, X, Y or Z is a nitrogen, oxygen or sulphur atom or a group NR 8 where R 8 is H or C 1-6 alkyl, and the other two of W, X, Y and Z each independently represent nitrogen atoms or groups CR 8 , and the dotted circle represents two double bonds;
  • R 1 represents C 1-6 alkyl, C 3 -7 cycloalkyl,
  • R2 represents C 1-6 alkyl, halo, (CH 2 ) r tetrazolyl, optionally substituted in the tetrazole ring by
  • R 3 represents H, C 1-6 alkyl or halo
  • n 0, 1 or 2;
  • n 0, 1, 2 or 3;
  • formula (I) is intended to embrace all possible isomers, including optical isomers, and mixtures thereof, including racemates.
  • the present invention includes within its scope prodrugs of the compounds of formula I above.
  • prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I.
  • alkyl means linear or branched chain alkyl.
  • suitable alkyl groups include methyl, ethyl, isopropyl and
  • R 1 represents cycloalkyl
  • suitable cycloalkyl groups include cyclopropyl
  • Halo includes fluoro, chloro and bromo.
  • halo will be fluoro or chloro.
  • R 1 represents C 1-6 alkyl, C 3-7 cycloalkyl,
  • R 6 and R 7 each independently represents a hydrogen atom or a C 1-4 alkyl group, or R 6 and R 7 together form a chain (CH 2 ) p where p is 4 or 5); R 2 represents C 1-6 alkyl, halo, (CH 2 ) s tetrazolyl,
  • R 1 is C 1-6 alkyl, more preferably methyl or iso-butyl.
  • Suitable values for R 9 include methyl, ethyl, i- propyl, t-butyl, phenyl and trifluoromethyl.
  • R 9 is optionally substituted aryl, this will preferably be optionally substituted phenyl.
  • Suitable substituents include C 1-4 alkyl, C 1-4 alkoxy, halo and trifluoromethyl.
  • R 9 is C 1-6 alkyl, it will preferably represent C 1-4 alkyl. Particularly preferred are methyl and iso- propyl.
  • R 10 When R 2 is SO 2 NHR 10 , suitable values of R 10 include, for example, thiazole, thiadiazole and pyrazine.
  • R 2 is tetrazolyl, methyl or COOH, more preferably 5-tetrazolyl.
  • a is 1.
  • n is zero.
  • q is 1.
  • r is zero.
  • Z is a sulphur atom or a group NR 18 , where R 18 is H or methyl;
  • R 20 is C 1-6 alkyl
  • R 21 is C 1-6 alkyl, tetrazolyl or CO 2 H, preferably tetrazolyl.
  • the salts of the compounds of formula (I) are pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be used for the preparation of pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts of the compounds of formula (I) include the conventional non-toxic salts or the quaternary ammonium salts of the compounds from formula (I) formed, e.g., from inorganic or organic acids or bases.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, steric, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compound of formula (I) which contain a basic or acidic moiety by
  • the salts are prepared by reacting the free base or acid with
  • an acid of formula (I) may be reacted with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g. dibenzylethylenediamine,
  • a base such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium
  • an organic base such as an amine, e.g. dibenzylethylenediamine
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a salt or prodrug thereof and a
  • the compounds of formula (I) and their salts and prodrugs may be administered to animals, preferably to mammals, and most especially to a human subject either alone or, preferably, in combination with
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having pharmaceutical practice.
  • the compounds can be any organic compound having
  • the selected compounds may be any organic compound having the selected compounds.
  • the selected compounds may be any organic compound.
  • aqueous solution or suspension administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • a compound of formula (I) may be formulated as, for example, a
  • pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers.
  • the pharmaceutical preparation may also contain non-toxic auxiliary substances such as
  • emulsifying, preserving, wetting agents, bodying agents and the like as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates,
  • gluconate buffers and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol,
  • the compounds of formula (I) antagonise CCK and/or gastrin and are useful for the treatment and prevention of disorders including central nervous system disorders wherein CCK and/or gastrin may be involved.
  • diseases include gastrointestinal diseases, including gastrointestinal ulcers, such as peptic and duodenal ulcers, irritable bowel syndrome,
  • central nervous system disorders including central nervous system disorders caused by CCK
  • dopamine neuroleptic disorders, tardive dyskinesia, Parkinson's disease, psychosis or Gilles de la Tourette syndrome; depression; schizophrenia;
  • the compounds of formula (I) are particularly useful in the treatment or prevention of neurological disorders involving anxiety disorders and panic disorders, wherein CCK and/or gastrin is involved. Examples of such
  • disorders include panic disorders, anxiety disorders, panic syndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronic anxiety and endogenous anxiety.
  • the compounds of formula (I) are also useful for directly inducing analgesia, opiate or non-opiate
  • the compounds of formula (I) may further be useful for preventing or treating the withdrawal response produced by chronic treatment or abuse of drugs or alcohol.
  • drugs include, but are not limited to benzodiazepines, cocaine, alcohol and nicotine.
  • the compounds of formula (I) may further by useful in the treatment of stress and its relationship with drug abuse.
  • the compounds of formula (I) may further be useful in the treatment of oncologic disorders wherein CCK may be involved.
  • oncologic disorders include small cell adenocarcinomas and primary tumours of the central nervous system glial and neuronal cells.
  • tumours examples include, but are not limited to, tumours of the lower oesophagus, stomach, intestine, colon and lung, including small cell lung carcinoma.
  • the compounds of formula (I) may also be useful as neuroprotective agents, for example, in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease,
  • Olivo-ponto-cerebellar atrophy anoxia such as from drowning, spinal cord and head injury, and poisoning by neurotoxins, including environmental neurotoxins.
  • the compounds of formula (I) may further be used to induce miosis for therapeutic purposes after certain types of examination and intraocular surgery.
  • An example of intraocular surgery would include cateract surgery with implantation of an artificial lens.
  • antagonist compounds of this invention can be used to prevent miosis occuring in association with crizotis, ureitis and trauma.
  • the present invention therefore provides a compound of formula (I) or a salt or prodrug thereof for use in the preparation of a medicament.
  • the present invention also provides a compound of formula (I) for use in therapy.
  • antagonising amount of a compound of formula (I) When a compound according to formula (I) is used as an antagonist of CCK or gastrin in a human subject, the daily dosage will normally be determined by the
  • an effective daily dosage wll be in the range from about 0.005mg/kg to about 100mg/kg of body weight, and
  • 0.05mg/kg to about 50mg/kg such as from about 0.5mg/kg to about 20mg/kg of body weight, administered in single or divided doses.
  • dosages outside these limits.
  • animal experiments have indicated that doses as low as lng may be effective.
  • preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist may be administered orally (p.o.), administered in single or divided doses per day (b.i.d.).
  • Other routes of administration preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist may be administered orally (p.o.), administered in single or divided doses per day (b.i.d.).
  • Other routes of administration preferably about 0.05 mg/kg to about 0.5 mg/kg of CCK antagonist may be administered orally (p.o.), administered in single or divided doses per day (b.i.d.).
  • the effective dosage preferably ranges from about 100 ng/kg to about lmg/kg by intravenous administration.
  • Oral administration is an alternative route, as well as others.
  • CCK antagonist In the treatment or irritable bowel syndrome, preferably about 0.1 to 10 mg/kg of CCK antagonist is administered orally (p.o.), administered in single or divided doses per day (b.i.d.).
  • Other routes of administration preferably about 0.1 to 10 mg/kg of CCK antagonist is administered orally (p.o.), administered in single or divided doses per day (b.i.d.).
  • an effective dosage of preferably about 0.1 to about 10 mg/kg administered one- to-four times daily is indicated.
  • the effective dosage preferably ranges from about 0.5mg/kg to about 20mg/kg.
  • these compounds may also be used as feed additives to increase the food intake of animals in daily dosage of preferably about 0.05mg/kg to about 50mg/kg of body weight.
  • the compounds of formula (I) may be prepared by processes analogous to those described in European Patent Specification No. 0167919.
  • a compound of formula (I) may be prepared from an intermediate of formula (III)
  • R 2 and m are as defined for formula (I).
  • reaction is preferably conducted in a suitable organic solvent, such as an ether, for example,
  • the isocyanate of formula (IV) may be generated in situ from the corresponding amine by treatment with triphosgene.
  • W, X, Y, Z, R 3 and n are as defined for formula (I) and G is a protecting group; by reaction with a reagent suitable to introduce the group R 1 , for example a halide of formula R 1 Hal where Hal represents halo such as bromo or iodo, followed by deprotection.
  • the reaction is carried out in the presence of a base, such as an alkali metal hydride or an alkaline earth metal carbonate, for example sodium hydride or caesium carbonate.
  • a base such as an alkali metal hydride or an alkaline earth metal carbonate, for example sodium hydride or caesium carbonate.
  • G is as defined above, in the presence of a base, such as a tertiary amine, for example triethylamine or N- methyl morpholine, and a coupling reagent.
  • a base such as a tertiary amine, for example triethylamine or N- methyl morpholine
  • a coupling reagent Any of the coupling reagents commonly used in peptide synthesis are suitable, for example, 1,3-dicyclohexylcarbodiimide (DCC) or isobutyl chloroformate.
  • novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the novel compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-L- tartaric acid and/or (+)-di-p-toluoyl-D-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
  • enantiomers of the novel compounds may be separated by HPLC using a chiral column.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wutts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • Step 2 1,3-Dihydro-3(R,S)-(benzyloxycarbonylamino)-1- niethyl-5-(1-methylimidazol-2-yl)-2H-1,4-benzodiazepin-2-one T o a s tirre d s olu ti o n o f 1 , 3 - dihydro - 3 (R , S )- (benzyloxycarbonylamino)-5-(1-methylimidazol-2-yl)-2H-1,4- benzodiazepin- 2-one (348mg) in anhydrous dimethylformamide (5ml), at ambient temperature, was added sodium hydride (40mg of a 55% oil dispersion).
  • Step 3 N- [3 (R,S )-2 , 3 -Dihydro- 1-methyl- 5-( 1- methylimidazol-2-yl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[3- methylphenyl]urea
  • Step 2 1,3-Dihydro-3(R,S)-(benzyloxycarbonylamino)-1-(2- methylpropyl)-5-(thiazol-2-yl)-2H-1,4-benzodiazepin-2-one
  • Step 3 N-[ 3(R,S)-2,3-Dihydro-1-(2-methylpropyl)-2-oxo-5- (thiazol- 2-yl)- 1H- 1 ,4-benzodiazepin-3- yl]-N'- [ 3- methylphenyl]urea
  • Step 3 N-[ 3 (R,S)-2,3-Dihydro-1-(2-methylpropyl)-2-oxo-5- (thiazol-2-yl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(tetrazol-5- yl)phenyl]urea
  • Triethylamine (193mg) was added to a stirred, cooled (0°C) suspension of 5-(3-aminophenyl)tetrazole hydrochloride (188mg) in anhydrous tetrahydrofuran (2ml).
  • Triphosgene (93mg) was added followed by a further quantity of triethylamine (96mg) ensuring the pH > 7.
  • the reaction mixture was stirred at ambient temperature for 30 minutes.
  • the compound of formula (I), cellulose, lactose and a portion of the corn starch are mixed and granulated with
  • the resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing
  • the sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water.
  • the compound of formula (I) is dissolved or suspended in the solution and made up to volume.
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the compound of formula (I) is added and stirring continued until dispersed. The mixture is then cooled until solid.
  • CCK-8 sulphated was radiolabelled with 125 I-Bolton Hunter reagent (2000 Ci/mmole). Receptor binding was performed according to Chang and Lotti (Proc. Natl. Acad. Sci. 83, 4923-4926, 1986) with minor modifications.
  • Pellets were resuspended in 10 volumes of binding assay buffer (20mM (HEPES)), 1mM ethylene glycol-bis-( ⁇ - aminoethylether-N,N'-tetraacetic acid) (EGTA), 5mM MgCl 2 , 150 mM NaCl, bacitracin 0.25 mg/ml, soya bean trypsin inhibitor 0.1 mg/ml, and bovine serum albumin 2 mg/ml pH 6.5 at 25°C) using a Teflon (trademark) homogenizer, 15 strokes at 500 rpm. The homogenate was further diluted in binding assay buffer to give a final concentration of 0.5 mg original wet weight/1 ml buffer.
  • HEPES ethylene glycol-bis-( ⁇ - aminoethylether-N,N'-tetraacetic acid)
  • EGTA ethylene glycol-bis-( ⁇ - aminoethylether-N,N'-tetraacetic acid
  • CCK-8 sulphated was radiolabelled and the binding was performed according to the description for the pancreas method with minor modifications.
  • the preferred compounds of Formula I are those which produced dose-dependent inhibition of specific 125 I-CCK-8 binding as defined as the difference between total and non-specific (i.e. in the presence of 1 ⁇ M CCK) binding.
  • IC 50 refers to the concentration of the compound required to inhibit 50% of specific binding of 125 I-CCK-8.

Abstract

Composés répondant à la formule (I), leurs sels et leurs promédicaments, dans laquelle, l'un parmi W, X, Y ou Z représente N, un autre parmi W, X, Y ou Z représente un atome de N, O ou S ou NR8, et les deux restants parmi W, X, Y et Z représentent N ou CR8, et le cercle en pointillés représente deux liaisons doubles; R' représente alkyle C1-6 éventuellement substitué, ou cycloalkyle C3-7; R2 représente alkyle C1-6 éventuellement substitué, halo, CONR6R7, SO (alkyle C1-6), SO2 (alkyle C1-4), CONHSO2R9, SO2NHCOR9, SONHR10, cyano ou B(OH)2; R3 représente H, alkyle C1-6 ou halo; m vaut 0, 1 ou 2; n vaut 0, 1, 2 ou 3; ces composés servant d'antagonistes de CCK et/ou de gastrine. De ce fait, lesdits composés, ainsi que les compositions qui les contiennent, sont utilisés en thérapeutique.
EP92916391A 1991-07-25 1992-07-23 Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique Withdrawn EP0595980A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB919116113A GB9116113D0 (en) 1991-07-25 1991-07-25 Therapeutic agents
GB91161133 1991-07-25
PCT/GB1992/001366 WO1993002078A1 (fr) 1991-07-25 1992-07-23 Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique

Publications (1)

Publication Number Publication Date
EP0595980A1 true EP0595980A1 (fr) 1994-05-11

Family

ID=10698996

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92916391A Withdrawn EP0595980A1 (fr) 1991-07-25 1992-07-23 Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique

Country Status (5)

Country Link
EP (1) EP0595980A1 (fr)
JP (1) JPH06509337A (fr)
CA (1) CA2112561A1 (fr)
GB (1) GB9116113D0 (fr)
WO (1) WO1993002078A1 (fr)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2282595A (en) * 1993-08-25 1995-04-12 Yamanouchi Pharma Co Ltd Benzodiazepine derivatives
US5438055A (en) * 1993-11-22 1995-08-01 Merck & Co., Inc. Antiarrhythmic benzodiazepines
US5426185A (en) * 1993-11-22 1995-06-20 Merck & Co., Inc. Antiarrhythmic benzodiazepines
US5428157A (en) * 1993-11-22 1995-06-27 Merck & Co., Inc. 3-acylaminobenzodiazepines
US5633251A (en) * 1994-08-18 1997-05-27 Merck & Co., Inc. N-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1h-1,4-benzodiazepines
SK282019B6 (sk) * 1994-08-18 2001-10-08 Merck & Co., Inc. 2,3-dihydro-1-(2,2,2-trifluóretyl)-2-oxo-5-fenyl-1h-1,4- benzodiazepínové deriváty, farmaceutický prostriedok s ich obsahom a ich použitie
US5556969A (en) * 1994-12-07 1996-09-17 Merck Sharp & Dohme Ltd. Benzodiazepine derivatives
JPH11506760A (ja) * 1995-06-07 1999-06-15 メルク エンド カンパニー インコーポレーテッド 新規なｎ−（２，４−ジオキソ−２，３，４，５−テトラヒドロ−１ｈ−１，５−ベンゾジアゼピン−３イル）−３−アミド
US5691331A (en) * 1995-06-07 1997-11-25 Merck & Co., Inc. N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3yl) -3- amides
US5700797A (en) * 1995-06-07 1997-12-23 Merck & Co, Inc. N-(2,4-dioxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl)-3-amides
US5726171A (en) * 1995-06-07 1998-03-10 Merck & Co Inc N-(1-alkyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo B! 1,4!diazepin-3yl)-acetamides
US5631251A (en) * 1995-06-07 1997-05-20 Merck & Co., Inc. 5-cyclopropyl-1,4 benzodiazepine-2-ones
ES2400208T3 (es) * 2008-08-18 2013-04-08 The Gillette Company Dispositivo afeitador y recortador combinado

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL39413A0 (en) * 1971-05-13 1972-07-26 Sparamedica Ag Benzodiazepine derivatives,their preparation and pharmaceutical compositions containing them
US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9302078A1 *

Also Published As

Publication number Publication date
CA2112561A1 (fr) 1993-02-04
GB9116113D0 (en) 1991-09-11
JPH06509337A (ja) 1994-10-20
WO1993002078A1 (fr) 1993-02-04

Similar Documents

Publication Publication Date Title
US5681833A (en) Benzodiazepine derivatives
US5597915A (en) Benzodiazepine derivatives, compositions containing them and their use in therapy
US5360802A (en) Benzodiazepine derivatives, compositions containing them and their use in therapy
US5556969A (en) Benzodiazepine derivatives
US5451582A (en) Benzodiazepine derivatives, compositions containing them and their use in therapy
US5410049A (en) Benzodiazepine derivatives, compositions containing them and their use in therapy
US5302591A (en) Benzodiazepine derivatives
EP0514133A1 (fr) Dérivés de benzodiazépine, compositions les contenant et leur utilisation en thérapie
US5478933A (en) Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
US5220018A (en) Cholecystokinin antagonists
US5521175A (en) Benzodiazepine derivatives
AU667690B2 (en) Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
EP0595980A1 (fr) Derives de benzodiazepine, compositions les contenant, et leur utilisation therapeutique
EP0508796B1 (fr) Antagonistes de cholecystokinine
US5218115A (en) Cholecystokinin antagonists
WO1994005673A1 (fr) Derives de la thienodiazepine comme antagonistes de la cholecystokinine et de la gastrine
US5696110A (en) Benzodiazepine derivatives and their use as antagonists of cholecystokinin and/or gastrin receptors
GB2271991A (en) N-(2-oxo-1H-1,4-benzodiazepin-3-yl)-ureas
GB2266528A (en) Benzodiazepine derivatives

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: 19931203

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

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: 19970201