WO1994024151A1 - 1,5 benzodiazepine derivatives having cck and/or gastrin antagonistic activity - Google Patents

1,5 benzodiazepine derivatives having cck and/or gastrin antagonistic activity Download PDF

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Publication number
WO1994024151A1
WO1994024151A1 PCT/EP1994/001130 EP9401130W WO9424151A1 WO 1994024151 A1 WO1994024151 A1 WO 1994024151A1 EP 9401130 W EP9401130 W EP 9401130W WO 9424151 A1 WO9424151 A1 WO 9424151A1
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Prior art keywords
formula
phenyl
compound
compounds
cck
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PCT/EP1994/001130
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English (en)
French (fr)
Inventor
Harry Finch
Pritom Shah
Robin Arthur Carr
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Glaxo Inc.
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Filing date
Publication date
Priority claimed from GB939307833A external-priority patent/GB9307833D0/en
Priority to US08/525,659 priority Critical patent/US5646140A/en
Priority claimed from GB9406037A external-priority patent/GB9406037D0/en
Application filed by Glaxo Inc. filed Critical Glaxo Inc.
Priority to AU65675/94A priority patent/AU688316B2/en
Priority to JP6522733A priority patent/JPH08508743A/ja
Priority to SK1254-95A priority patent/SK125495A3/sk
Priority to US08/522,363 priority patent/US5585376A/en
Priority to EP94913579A priority patent/EP0694040A1/en
Publication of WO1994024151A1 publication Critical patent/WO1994024151A1/en
Priority to FI954852A priority patent/FI954852A/fi
Priority to NO954091A priority patent/NO954091L/no

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0821Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06139Dipeptides with the first amino acid being heterocyclic
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08Tripeptides
    • C07K5/0827Tripeptides containing heteroatoms different from O, S, or N
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • This invention relates to novel 1 ,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxy terminal octapeptide, CCK-8 (also a naturally- occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14- amino acid forms, with the miniumum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH 2 (CCK-4), which is the common structual element shared by both CCK and gastrin.
  • CCK-4 Trp-Met-Asp-Phe-NH 2
  • CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body.
  • CCK-A and CCK-B are found in the periphery and in the central nervous system.
  • CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal and central nervous systems of animals, and more particularly humans.
  • R 2 represents a 5-7 membered saturated heterocylic ring which may be substituted by one or two methyl groups
  • R 3 is C h al y I, C 3 . 6 cycloalkyl or phenyl optionally substituted by 1 or 2 halogen atoms
  • R is phenyl or phenyl substituted by one or two groups selected from halogen, C ⁇ _ 4 alkyl, trifluoromethyl, trifluoromethoxy or (CH 2 ) n R 5 wherein n is zero or 1 and R 5 represents C ⁇ alkoxy, hydroxy, nitro, cyano, C0 2 R 6 , S(0) p CH 3 , NR 7 R 8 , CONR 7 R 8 , S0 2 NR 7 CO(C 1 . 4 alkyl), tetrazolyl, carboxamidotetrazolyl, or a 3- trifluoromethyl 1 ,2,4-triazolyl;
  • R 6 is hydrogen, C 1 . 4 alkyl or benzyl
  • R 7 is hydrogen or C- ⁇ alkyl
  • R 8 is hydrogen, C 1 . 4 alkyl, S0 2 CH 3 or S0 2 CF 3
  • X represents hydrogen, C-,_ 4 alkyl or halogen; m is zero, 1 or 2, and p is zero, 1 or 2.
  • the compounds of the invention possess at least one asymmetric carbon atom and the compounds of the invention include both enantiomers and mixtures thereof including the racemate.
  • alkyl refers to both straight chain and branched chain alkyl groups.
  • Chalky! includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or hexyl.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • R 5 represents a tetrazolyl, carboxamidotetrazolyl or 3-trifluoromethyl 1 ,2,4-triazolyl group these are linked to the rest of the molecule via a carbon atom therein and the invention includes all tautomers thereof and the C-,_ 4 alkyl -N substituted derivatives thereof.
  • Examples of such groups include (1 H) tetrazol-5-yl, carboxamido-1 H-tetrazol-5-yl, 2-methyltetrazol-5-yl and (3- trifluoromethyl-1 ,2,4-triazol-5-yl.
  • the group NR 1 R 2 is linked to the rest of the molecule via the nitrogen thereof examples of such groups include pyrrolidino, piperidino, hexamethylenimino-, 2,5-dimethylpyrrolidino, 3,3-dimethylpiperidino, 2,6-dimethylpiperidino or 4,4- dimethylpiperidino.
  • R 3 represents phenyl optionally substituted by halogen examples of such groups include phenyl optionally substituted by fluorine e.g. phenyl or 2- fluorophenyl, or 4-fluorophenyl.
  • R 3 represents C 3 . 6 cycloalkyl examples of such groups include cyclopropyl, cyclopentyl or cyclohexyl.
  • R 3 represents C ⁇ alkyl examples of such groups include methyl, ethyl, propyl, butyl, 3-methylbutyl or 3,3-dimethylbutyl.
  • R 4 examples include phenyl optionally substituted by halogen e.g. fluorine, alkyl e.g. methyl, alkoxy e.g. methoxy, nitro, cyano, thiomethyl, carboxamido, carboxyl, dimethylamino, cyanomethyl, 1 H-tetrazol-5-yl, carboxy methyl, or N-methanesulphonylcarboxamido.
  • halogen e.g. fluorine
  • alkyl e.g. methyl
  • alkoxy e.g. methoxy
  • carboxamido carboxyl
  • dimethylamino cyanomethyl
  • 1 H-tetrazol-5-yl carboxy methyl
  • N-methanesulphonylcarboxamido examples include phenyl optionally substituted by halogen e.g. fluorine, alkyl e.g. methyl,
  • a preferred class of compound according to the invention are those wherein the group NR-
  • the group NR-,R 2 is conveniently pyrrolidino, piperidino, or 3,3- dimethylpiperidino.
  • the group X is conveniently halogen e.g. bromine, fluorine or fluorine or more particularly hydrogen.
  • a further preferred class of compounds of formula (I) are those wherein R 3 is phenyl, 2-fluorophenyl or cyclohexyl and more particularly 2-fluorophenyl or cyclohexyl.
  • R 4 is phenyl or phenyl substituted by methyl e.g. 3-methylphenyl or 3,5- dimethylphenyl, 3-dimethylaminophenyl, phenyl substituted by fluorine e.g. 4- fluorophenyl, phenyl substituted by methoxy e.g. 3-methoxyphenyl or 4- methoxyphenyl, 3-nitrophenyl, 3-cyanomethylphenyl, 3-carboxamidophenyl, 3- carboxyphenyl, 3-carboxymethylphenyl, or 3-(1 H)-tetrazol-5-ylphenyl.
  • a particularly preferred group of compounds according to the invention are those wherein NR-
  • particularly preferred compounds include those wherein R 4 is phenyl, 4-fluorophenyl, 3-dimethylaminophenyl, 3-carboxyphenyl, 3-carboxymethylphenyl or 3-(1 H)-tetrazolyl-5-yl-phenyl.
  • a particularly preferred compound of the invention is:-
  • physiologically acceptable salts of the compounds of formula (I) include conventional salts formed for example from pharmaceutically acceptable inorganic or organic acids as well as quaternary ammonium acid addition salts.
  • Suitable salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulphonic, methanesulphonic, naphthalene-2-sulphonic, benzenesulphonic and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • references hereinafter to a compound according to the invention includes both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
  • Compounds of the invention modulate the effect of gastrin and/or CCK in mammals.
  • compounds of the invention are antagonists of gastrin and/or CCK.
  • Compounds of the invention have been shown to be antagonists of CCK, particularly at CCK-B receptors as demonstrated for example by the compound's ability to inhibit the contractile actions of CCK-4 in the presence of a CCK-A antagonist, in the guinea-pig isolated ileum longitudinal muscle- myenteric plexus.
  • Compounds of the invention have also been shown to have a greater affinity for the CCK-B receptor than for the CCK-A receptor. This may be determined using the CCK receptor binding assays described by Fornos et al J. Pharmacol Exp. Ther., 201 1056-1063, 1992. Alternatively the binding affinity of compounds of the invention for CCK-A and CCK-B receptors may be determined using HeLa cell membranes that are transfected with the human CCK-B receptor or, COS-M6 cell membranes that are transiently transfected with the human CCK-A receptor.
  • the compounds of the invention are therefore useful for the treatment and/or prevention of disorders in mammals, especially humans, where modification of the effects of gastrin or CCK is of therapeutic benefit.
  • the compounds of the invention are useful for the treatment of gastrointestinal disorders especially those where there is an advantage in lowering gastric acidity.
  • Such disorders include peptic ulceration, reflux oesophagitis and Zollinger Ellison syndrome.
  • They may also be useful for the treatment of gastrointestinal disorders such as irritable bowel syndrome, excess pancreatic secretion, acute pancreatitis, motility disorders, antral G cell hyperplasia, fundic mucosal hyperplasia or gastrointestinal neoplasms.
  • the compounds of the invention are also useful for the treatment of central nervous system disorders where CCK and/or gastrin are involved.
  • anxiety disorders including panic disorder, agoraphobia, social phobia, simple phobia, obsessive compulsive disorders, post traumatic stress disorder, and general anxiety disorder
  • depression tardive dyskinesia
  • Parkinson's disease or psychosis They may also be useful for the treatment of dependency on drugs or substances of abuse and withdrawal, Gilles de la Tourette syndrome, or dysfunction of appetite regulatory systems; as well as the treatment of certain tumours of the lower oesophagus, stomach, intestines and colon.
  • Compounds of the invention are also useful for directly inducing analgesia, or enhancing opiate or non-opiate mediated analgesia, as well as anaesthesia or loss of the sensation of pain.
  • the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of conditions where modification of the effects of gastrin and/or CCK is of therapeutic benefit.
  • a method for the treatment of a mammal including man, in particular in the treatment of conditions where modification of the effects of gastrin and/or CCK is of therapeutic benefit which method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to the patient.
  • a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however doses employed for adult human treatment will typically be in the range of 1-2000mg per day e.g 10-500mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • Compounds of the invention which antagonise the function of CCK in animals may also be used as feed additives to increase the food intake in animals in daily dosages of around 1 mg/kg to 10mg/kg. While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation.
  • the invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, implant, or rectal administration. Oral administration is preferred.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline celluiose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p.- hydroxybenzoates or ascorbic acid.
  • the compositions may also be formulated as suppositories, e
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • composition according to the invention may be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • composition according to the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3- 50% for liquid preparations.
  • compounds of formula (I) may be prepared by the reaction of an amine of formula (II) wherein R 1 f R 2 , R 3 , X and m have the meanings defined in formula (I).
  • R 4 Y is an isocyanate of formula (III), carbamoyi chloride of formula (IV), imidazolide of formula (V), or an optionally substituted phenyl carbamate of formula (VI) wherein R a is an optionally phenxoy group.
  • the reaction conveniently takes place in the presence of a suitable solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran) or nitrile (e.g. acetronitrile) or a mixture thereof at a temperature in the range of 0°-80°C.
  • a suitable solvent such as a halohydrocarbon (e.g. dichloromethane), an ether (e.g. tetrahydrofuran) or nitrile (e.g. acetronitrile) or a mixture thereof at a temperature in the range of 0°-80°C.
  • Isocyanates of formula (III) may be purchased or prepared by the reaction of amines H 2 N-R 4 with phosgene or triphosgene in a suitable solvent such as methylene chloride.
  • Carbamoyi chlorides of formula (IV) are also prepared by the reaction of amines H 2 NR 4 with phosgene or triphosgene in a suitable solvent such as methylene chloride.
  • Imidazolides of formula (VI) are prepared by treatment of amines H 2 N-R 4 with carbonyl diimidazole in a suitable solvent (dichloromethane, ether, tetrahydrofuran) at a temperature ranging from 0-80° C (conveniently at room temperature).
  • Optionally substituted phenyl carbamates of formula (VI) are prepared by the reaction of amines H 2 N-R 4 with the appropriate chloroformate R a COCI in the presence of a base (pyridine, triethylamine) in a suitable solvent (dichloromethane) and at a temperature of 0 - 50° C.
  • compounds of formula (I) may be prepared by reaction of an intermediate of formula (VII).
  • Y is the group -NCO, -NHCOCI or NHCOR a wherein R a is an optionally substituted phenoxy group or a 1-imidazole group with an amine (VIII)
  • a base such as a tertiary amine (e.g. triethylamine).
  • the reaction conveniently takes place in a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) or an amide (e.g. N,N-dimethyl formamide) optionally at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) or an amide (e.g. N,N-dimethyl formamide) optionally at a temperature ranging from room temperature to the reflux temperature of the solvent.
  • the compound of formula (VII) are prepared in situ from the amine (II).
  • the imidazolide (VII) may be formed in situ in which case the amine of formula (VIII) will be mixed with the compound of formula (II) in the presence of carbonyidiimidazole under the aforementioned conditions.
  • reaction with the primary amine (VIII) is preferably carried out in the presence of a base such as a tertiary amine e.g. triethylamine.
  • reaction with the primary amine (VIII) is preferably carried out in an aprotic solvent such as a halohydrocarbon e.g. methylene chloride.
  • a halohydrocarbon e.g. methylene chloride.
  • the isocyanate is generated in situ prior to the addition of the primary amine (VIII).
  • the compounds of formula (VII) wherein R a is an optionally substituted phenoxy group may be prepared from the primary amine (II) by reaction with the corresponding optionally substituted phenyl chloroformate in the presence of a base such as pyridine.
  • the reaction may be carried out in a solvent such as a halohydrocabon e.g. dichloromethane and at a temperature from 0-50°.
  • Compounds of formula (VII) wherein R a is a 1-imidazole group may be prepared by reacting a compound of formula (II) with carbonyidiimidazole in the presence of a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) at a temperature ranging from 0° to 80° (conveniently at room temperature).
  • a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane) or an ether (e.g. tetrahydrofuran) at a temperature ranging from 0° to 80° (conveniently at room temperature).
  • reaction is conveniently carried out by treating the compound of formula (IX) with a strong base such as sodium hydride in a polar aprotic solvent such as N,N-dimethylformamide followed by reaction with the alkylating agent F ⁇ RgNCOCHgZ.
  • a strong base such as sodium hydride
  • a polar aprotic solvent such as N,N-dimethylformamide
  • Compounds of formula (X) wherein W is CH-N3 may be reduced to a compound of formula (II) by hydrogenation in the presence of a suitable catalyst such as palladium, on a support such as carbon or calcium carbonate, or platinum (IV) oxide.
  • a suitable catalyst such as palladium, on a support such as carbon or calcium carbonate, or platinum (IV) oxide.
  • the reaction conveniently takes place in the presence of a solvent such as an alkanol (e.g. ethanol) an ester (e.g. ethyl acetate) or acetic acid.
  • Compounds of formula (X) wherein W is CHN3 may be prepared from a compound of formula (X) wherein W is CH2 by treatment with a strong base such as sodium hydride or potassium tert-butoxide followed by tri-isopropyl benzenesulphonyl azide.
  • a strong base such as sodium hydride or potassium tert-butoxide followed by tri-isopropyl benzenesulphonyl azide.
  • the reaction conveniently takes place in a solvent such as an ether (e.g. tetrahydrofuran) at a temperature in the range of -78° to 20°.
  • amine (XIV) may be reacted with the compound R-
  • the compounds of formula (III), (IV), (V) and (VI) are either known compounds or may be prepared according to methods simlar to those used for the preparation of known compounds,
  • a compound of formula (I) may be prepared from the compound of formula (XV) wherein R is hydrogen
  • reaction of an activated derivative thereof with the amine R 1 R 2 NH is carried out using the acid in the presence of a diimide such as dicyclohexyl carbodimide and hydroxybenzotriazole in a solvent such as dichloromethane or in the presence 2-ethoxy-1-ethoxycarbonyl-1 ,2- dihydroquinoline in a solvent such as dimethoxyethane.
  • a diimide such as dicyclohexyl carbodimide and hydroxybenzotriazole
  • solvent such as dichloromethane
  • 2-ethoxy-1-ethoxycarbonyl-1 ,2- dihydroquinoline in a solvent such as dimethoxyethane.
  • the compounds of formula (XV) wherein R b is a hydrogen may be prepared by hydrolysis of the corresponding compound of formula (XV) wherein R b is a t- butyl group, for example by reaction with trifluoroacetic acid.
  • the compound of formula (XV) wherein R b is t-butyl may be prepared by alkylation of the corresponding compound of formula (IX) with the halo ester Z-CH 2 C0 2 R b wherein Z is halogen.
  • the compound (XV) wherein R b is t-butyl may be prepared using the general processes A and B described above for preparing the compounds of formula (I) but starting with the appropriate N- substituted benzodiazepine derivative.
  • a compound of formula (I) may be converted into another compound of formula (I) using conventional techniques.
  • Compounds of formula (IX) may be prepared from the diamine (XIV), in which the primary amino group is protected as an p-methoxybenzyl derivative thereof, using the general procedures described above for preparing the compounds of formula (I) from the corresponding orthophenylenediamine (XI) followed by removal of the N-protecting group p-methoxybenzyl using conventional procedures.
  • Compounds of formula (I) contain at least one asymmetric carbon atom, namely the carbon atom of the diazepine ring to which the substituted urea grouping is attached.
  • Specific enantiomers of the compounds of formula (I) may be obtained by resolution of the racemic compound using conventional procedures such as chiral HPLC.
  • the required enantiomer may be prepared from the corresponding enantiomeric amine of formula (II) using any of the processes described above for preparing compounds of formula (I) from the amine (II).
  • the enantiomers of the amine (II) may be prepared from the racemic amine (II) using conventional procedures such as salt formation with a suitably optically active acid such as R- camphorsulphonic acid or by preparative chiral HPLC.
  • EA ethyl acetate
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • DE diethyl ether
  • DCM dichloromethane
  • MeOH methanol
  • AcOH acetic acid
  • ee enantiomeric excess
  • R ⁇ retention time.
  • Example 2 The compound of Example 1 (1.7g) was separated into its 2 enantiomers (Isomer 1 and Isomer 2) by chiral HPLC.
  • Tablets a. Active ingredient 50mg Lactose anhydrous USP 163mg Microcrystallme Cellulose NF 69mg Pregelatinised starch Ph. Eur. 15mg Magnesium stearate USP 3m ⁇ Compression weight 300mg
  • the active ingredient, microcrystalline cellulose, lactose and pregelatinised starch are sieved through a 500 micron sieve and blended in a suitable mixer.
  • the magnesium stearate is sieved through a 250 micron sieve and blended with the active blend.
  • the blend is compressed into tablets using suitable punches.
  • the active ingredient, lactose and pregelatinised starch are blended together and granulated with water.
  • the wet mass is dried and milled.
  • the magnesium stearate and Crospovidone are screened through a 250 micron sieve and blended with the granule.
  • the resultant blend is compressed using suitable tablet punches.
  • Active ingredient 50mg Pregelatinised Starch Ph. Eur. 148mg Magnesium stearate USP 2mg Fill weight 200mg
  • the active ingredient and pregelatinised starch are screened through a 500 micron mesh sieve, blended together and lubricated with magnesium stearate (meshed through a 250 micron sieve).
  • the blend is filled into hard gelatin capsules of a suitable size.
  • the active ingredient and lactose are blended together and granulated with a solution of Povidone.
  • the wet mass is dried and milled.
  • the magnesium stearate and Crospovidone are screened through a 250 micron sieve and blended with the granule.
  • the resultant blend is filled into hard gelatin capsules of a suitable size.
  • CCK-B receptor binding studies were carried out using HeLa cell membranes which had been stabily transfected with the human CCK-B receptor cloned from temporal cortex cDNA library.
  • the transfected HeLa cell membranes were incubated with 30pM [ 125 I]BH- sCCK-8 in the presence of various concentrations of the test compound (1 pM to 1 ⁇ M). All experiments were performed in an assay volume of 250 ⁇ l. Membranes were harvested onto GF/C glass fibre filter paper (Whatman, UK) by rapid filtration using a Cell Harvester (Brandel model M-24R) and washed three times with HEPES Wash buffer chilled to 4°C. The radioactivity trapped on individual filter discs was counted over 60 seconds using a gamma counter (Mini Gamma counter, LKB, Wallac, Finland) at a counting efficiency of 77%. A control experiment was also carried out in the absence of a test compound.
  • CCK-A receptor binding studies were carried out using COS-M6 cell membranes which have been transiently transfected with human gall bladder CCK-A receptor cDNA.
  • the clone was transiently transfected into COS-M6 cells grown to 80% confluency using the dimethylaminoethyl - dextran method based on the method of Seed and Araffo. Proc. Natl, Acad, Sci. USA 84, 3365 1987. The required transfected cell membranes were then isolated in a conventional manner.
  • the affinity of compounds of the invention for the CCK-A receptor was determined using the procedures described above for the CCK-B receptor however, in these experiments the test compound was tested at concentrations in the range 10pM to 10 ⁇ M.
  • the compounds of the invention are essential non-toxic a theraapeutically active doses. Thus no untoward effects were observed when the compound of Example 1 (isomer 1) was administered to the gastrin fistula rat of doses of 0.3 and 1 mg/kg iv at these doses gastric acid secretion was significally inhibited.

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PCT/EP1994/001130 1993-04-15 1994-04-13 1,5 benzodiazepine derivatives having cck and/or gastrin antagonistic activity WO1994024151A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
US08/525,659 US5646140A (en) 1993-04-15 1994-01-04 1,5-benzodiazepine derivatives having CCK antagonistic or agonistic activity
AU65675/94A AU688316B2 (en) 1993-04-15 1994-04-13 1,5 benzodiazepine derivatives having CCK and/or gastrin antagonistic activity
JP6522733A JPH08508743A (ja) 1993-04-15 1994-04-13 Cckおよび/またはガストリン拮抗作用を有する1,5−ベンゾジアゼピン誘導体
SK1254-95A SK125495A3 (en) 1993-04-15 1994-04-13 1,5-benzodiazepine derivatives, manufacturing process, their use and pharmaceutical compositions containing them
US08/522,363 US5585376A (en) 1993-04-15 1994-04-13 1,5-benzodiazepine derivatives having CCK and/or gastrin antagonistic activity
EP94913579A EP0694040A1 (en) 1993-04-15 1994-04-13 1,5 benzodiazepine derivatives having cck and/or gastrin antagonistic activity
FI954852A FI954852A (fi) 1993-04-15 1995-10-12 1,5-bentsodiatsepiinijohdannaisia, joilla on CCK- ja/tai gastriiniantagonistinen aktiivisuus
NO954091A NO954091L (no) 1993-04-15 1995-10-13 1,5-Benzodinazepinderivater med CCK- og/eller gastrinantagonistisk aktivitet

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9307833.5 1993-04-15
GB939307833A GB9307833D0 (en) 1993-04-15 1993-04-15 Modulators of cholecystokinin and gastrin
GB9406037A GB9406037D0 (en) 1994-03-29 1994-03-29 1,5 Benzodiazepine derivatives
GB9406037.3 1994-03-29

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CA (1) CA2158972A1 (ja)
CZ (1) CZ267695A3 (ja)
FI (1) FI954852A (ja)
HU (1) HUT74091A (ja)
NO (1) NO954091L (ja)
NZ (1) NZ265271A (ja)
OA (1) OA10236A (ja)
PL (1) PL311083A1 (ja)
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0728748A1 (en) * 1993-12-28 1996-08-28 Shionogi & Co., Ltd. Novel benzodiazepine derivative
WO1998025911A1 (fr) * 1996-12-10 1998-06-18 Zeria Pharmaceutical Co., Ltd. Derives de 1,5-benzodiazepine
WO2000037434A1 (fr) * 1998-12-22 2000-06-29 Mitsubishi Chemical Corporation Derives d'amide
US6344452B1 (en) 1998-06-05 2002-02-05 Zeria Pharmaceuticals Co., Ltd. 1,5-benzodiazepine derivatives
US6444849B1 (en) 1997-06-25 2002-09-03 Mitsubishi Chemical Corporation Amide derivatives
US10308627B2 (en) 2014-08-08 2019-06-04 Trio Medicines Ltd Benzodiazepine derivatives as CCK2/gastrin receptor antagonists
US10570102B2 (en) 2015-08-07 2020-02-25 Trio Medicines Limited Synthesis of benzodiazepine derivatives
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0376849A1 (fr) * 1988-12-29 1990-07-04 Roussel-Uclaf Nouveaux dérivés de la 2,4-dioxo 2,3,4,5-tétrahydro 1H-1,5-benzodiazépine, leur procédé et les intermédiaires de préparation, leur application comme médicaments et les compositions les renfermant
WO1991013862A1 (fr) * 1990-03-13 1991-09-19 Rhone-Poulenc Rorer S.A. Derives de l'uree, leur preparation et les medicaments les contenant
EP0487207A1 (en) * 1990-10-22 1992-05-27 Merck & Co. Inc. Benzolactam analogs as antagonists of CCK
WO1993014074A1 (en) * 1992-01-21 1993-07-22 Glaxo Spa 1,5-benzodiazepine derivatives and their use in medicine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0376849A1 (fr) * 1988-12-29 1990-07-04 Roussel-Uclaf Nouveaux dérivés de la 2,4-dioxo 2,3,4,5-tétrahydro 1H-1,5-benzodiazépine, leur procédé et les intermédiaires de préparation, leur application comme médicaments et les compositions les renfermant
WO1991013862A1 (fr) * 1990-03-13 1991-09-19 Rhone-Poulenc Rorer S.A. Derives de l'uree, leur preparation et les medicaments les contenant
EP0487207A1 (en) * 1990-10-22 1992-05-27 Merck & Co. Inc. Benzolactam analogs as antagonists of CCK
WO1993014074A1 (en) * 1992-01-21 1993-07-22 Glaxo Spa 1,5-benzodiazepine derivatives and their use in medicine

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0728748A1 (en) * 1993-12-28 1996-08-28 Shionogi & Co., Ltd. Novel benzodiazepine derivative
EP0728748A4 (en) * 1993-12-28 1997-03-19 Shionogi & Co NEW BENZODIAZEPINE DERIVATIVE
US5776929A (en) * 1993-12-28 1998-07-07 Shionogi & Co., Ltd. Benzodiazepine derivative
WO1998025911A1 (fr) * 1996-12-10 1998-06-18 Zeria Pharmaceutical Co., Ltd. Derives de 1,5-benzodiazepine
US6444849B1 (en) 1997-06-25 2002-09-03 Mitsubishi Chemical Corporation Amide derivatives
US6344452B1 (en) 1998-06-05 2002-02-05 Zeria Pharmaceuticals Co., Ltd. 1,5-benzodiazepine derivatives
WO2000037434A1 (fr) * 1998-12-22 2000-06-29 Mitsubishi Chemical Corporation Derives d'amide
US10308627B2 (en) 2014-08-08 2019-06-04 Trio Medicines Ltd Benzodiazepine derivatives as CCK2/gastrin receptor antagonists
US10906884B2 (en) 2014-08-08 2021-02-02 Trio Medicines Ltd Benzodiazepine derivatives as CCK2/gastrin receptor antagonists
US10570102B2 (en) 2015-08-07 2020-02-25 Trio Medicines Limited Synthesis of benzodiazepine derivatives
US11447454B2 (en) 2015-08-07 2022-09-20 Trio Medicines Limited Synthesis of benzodiazepine derivatives
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists

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AU6567594A (en) 1994-11-08
FI954852A0 (fi) 1995-10-12
CA2158972A1 (en) 1994-10-27
JPH08508743A (ja) 1996-09-17
AU688316B2 (en) 1998-03-12
NO954091L (no) 1995-12-13
PL311083A1 (en) 1996-02-05
OA10236A (en) 1997-10-07
SK125495A3 (en) 1996-06-05
NZ265271A (en) 1997-06-24
NO954091D0 (no) 1995-10-13
CN1120845A (zh) 1996-04-17
CZ267695A3 (en) 1996-04-17
EP0694040A1 (en) 1996-01-31
FI954852A (fi) 1995-10-12
HUT74091A (en) 1996-11-28
HU9502977D0 (en) 1995-12-28

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