WO1995006041A1 - 3-phenylureido-1,4-benzodiaxepines utiles comme antagonistes selectifs de la cck-b - Google Patents

3-phenylureido-1,4-benzodiaxepines utiles comme antagonistes selectifs de la cck-b Download PDF

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Publication number
WO1995006041A1
WO1995006041A1 PCT/GB1994/001858 GB9401858W WO9506041A1 WO 1995006041 A1 WO1995006041 A1 WO 1995006041A1 GB 9401858 W GB9401858 W GB 9401858W WO 9506041 A1 WO9506041 A1 WO 9506041A1
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WO
WIPO (PCT)
Prior art keywords
rgrr
phenyl
benzodiazepin
cck
oxo
Prior art date
Application number
PCT/GB1994/001858
Other languages
English (en)
Inventor
Graeme Semple
Hamish Ryder
Michael Szelke
Masato Satoh
Mitsuaki Ohta
Keiji Miyata
Akito Nishida
Original Assignee
Yamanouchi Pharmaceutical Co. Ltd.
Ferring Research 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 Yamanouchi Pharmaceutical Co. Ltd., Ferring Research Ltd. filed Critical Yamanouchi Pharmaceutical Co. Ltd.
Priority to AU74660/94A priority Critical patent/AU7466094A/en
Publication of WO1995006041A1 publication Critical patent/WO1995006041A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C07D243/24—Oxygen atoms

Definitions

  • This invention relates to benzodiazepine derivatives which are useful as drugs exhibiting antagonism at the gastrin and/or CCK-B receptor, and to their production.
  • benzodiazepine derivatives have been described in the course of development of psychotropic drugs which act as agonists at the "benzodiazepine receptor" in the central nervous system. More recently benzodiazepine derivatives have been described which act as antagonists at the CCK-A (cholecystokinin-A) and CCK-B receptors. It was further repo ⁇ ed that those compounds which were selective antagonists for the CCK-B receptor were able to reduce the secretion of gastric acid in response to the administration of pentagastrin (V J Lotti & R S L Chang, Eur J Pharmacol 1989, 162, 273-280). Examples of benzodiazepine derivatives which act as antagonists at the CCK-B receptor are disclosed in, for example, U.S. Patent No. 4,820,834.
  • the compounds of the present invention are novel. They differ from the compounds described in U.S. Patent No. 4,820,834, particularly in the nature of the substituent at position 1 of the benzodiazepine nucleus.
  • the present invention includes compounds of superior pharmacological characteristics than those described in U.S. Patent No. 4,820,834; preferred compounds of the invention have a higher affinity for the CCK-B receptor and/or discriminate more selectively between the CCK-B and CCK-A receptors than the previously described compounds.
  • the present invention provides a benzodiazepine derivative of formula I, or a pharmaceutically acceptable salt thereof:.
  • R 1 is selected from alkyl and cycloalkyl groups.
  • R 2 is a tertiary cyclic amino substituent of structure II, HI or IV,
  • alkyl and cycloalkyl groups are preferably of up to 8 carbon atoms.
  • alkyl and cycloalkyl groups include rerr-butyl, cyclopentyl and cyclohexylmethyl.
  • R 1 is rerr-butyl.
  • R 2 is azetidinyl, pyrroiidinyl or piperidinyl.
  • the compounds of this invention all have at least one stereogenic centre and so can exist as optical isomers. It should be understood that these isomers, either separately or as mixtures, are included within the scope of this invention.
  • the absolute configuration at the 3-position of the benzodiazepine ring is R (as shown in V).
  • the compounds of this invention can form salts with inorganic or organic acids or, in some cases, bases.
  • examples of such salts would include chlorides, sulphates and acetates, or sodium and potassium salts. These salts should be understood to be included within the scope of this invention.
  • Compounds according to the invention act as CCK-B and gastrin receptor antagonists. They may be used as drugs for the treatment of diseases induced by the failure of a physiological function controlled by gastrin, such as gastric and duodenal ulcers, gastritis, reflux esophagitis, gastric and colon cancers, and Zollinger-Ellison syndrome; there may be no side effects arising from CCK-A receptor interaction. They may be used as drugs for the treatment of diseases induced by the failure of physiological function controlled by the central CCK-B receptor (e.g. for the reduction of anxiety or for appetite regulation).
  • the compounds of the invention can be prepared according to the route outlined in Scheme 1 below.
  • the starting material VI is prepared according to procedures described in Intemational Patent Application No. PCT/GB 93/00404.
  • Example 1 N-((3R)-l-rgrr-Butylcarbonylmethyl-2.3-dihvdro-2-oxo-5-(2-Pyridyl')-lH- l,4-benzodiazepin-3-yl-N'-(3-(l-pyrrolidinyl)phenyl ' ) urea
  • the tide compound was prepared as described previously in Intemational Patent Application No. PCT/GB 93/00404.
  • Example 2 N-(3R)-l-rgrr-Butylcarbonylmethyl-2.3-dihvdro-2-oxo-5-phenyl-lH-1.4- benzodiazepin-3-yl-N'-(3-(l-pyrrolidinyl'.phenyl') urea.
  • 3-(l-pyrrolidi ⁇ yi)phenyl isocyanate was prepared as described in example ID and treated widi the benzodiazepine of example 2A (280 mg, 0.8 mmol).
  • the crude product was evaporated and chromatographed (eluant CHCl 3 EtOAc, 1/1, v/v) to provide the tide compound as a white solid (276 mg, 64%).
  • the compounds of the present invention are potent and selective antagonists at the CCK-B receptor and inhibit gastric acid secretion stimulated by pentagastrin. The methods of measuring these activities are described below:
  • the precipitate thus obtained was dispersed in 50 mM Tris-HCl buffer (pH 7.4) containing 0.08% Triton X-100, this suspension was allowed to stand for 30 minutes and again centrifuged for 15 minutes at 11500 g, the precipitate thus obtained was washed twice with 5 mM Tris-HCl buffer and twice with 50 mM Tris-HCl buffer in that order with centrifugal separation, the washed precipitate- was suspended in 50 mM Tris-HCl buffer, and the suspension thus obtained was stored at -80°C until d e membrane preparation was required.
  • the membrane preparations were warmed to room temperature, diluted witii 10 mM HEPES buffer (containing 130 mM NaCl, 5 mM MgCl 2 , 1 mM EGTA and 0.25 mg/ml bacitracin; pH 6.5) and incubated at 25°C for 120 minutes in the presence of [ 1 5 I]BH-CCK-8 and the test compound, ti en separated by suction filtration.
  • Non-specific binding was determined in d e presence of 1 ⁇ M CCK-8.
  • the amount of labelled ligand bound to die receptor was measured by d e use of a ⁇ -counter, IC 50 values were determined, being that concentration of test compound required to inhibit specific binding by 50%.
  • pancreas of an SD rat was homogenized in a 20- fold volume of 50 mM Tris-HCl buffer (pH 7.7) by the use of a Polytrone-type homogenizer, the homogenate was twice centrifuged for 10 minutes at 50000 g by the use of an ultra-centrifuge, the precipitate thus obtained was suspended in a 40-fold volume of 50 mM Tris-HCl buffer (containing 0.2% BSA, 5 mM MgCl 2 , 0.1 mg/ml bacitracin and 5 mM DTT; pH 7.7), and d e suspension was stored at -80°C until the membrane preparations were required.
  • 50 mM Tris-HCl buffer pH 7.7
  • the membrane preparations were d en warmed to room temperature, diluted 1:10 witii die buffer and incubated at 37°C for 30 minutes in the presence of [ 3 H]L-364,718 and die test compound d en separated by suction filtration. Non-specific binding was determined in d e presence of 1 ⁇ M L-364,718. The amount of labelled ligand bound to d e receptor was measured by the use of a liquid scintillation counter, IC 50 values were determined, being that concentration of test compound required to inhibit specific binding by 50%.
  • a high affinity for the CCK-A receptor in a CCK-B/gastrin antagonist is thought to be undesirable as it may lead to side-effects such as cholestasis and gall stone formation during dierapy. Therefore it is preferable for the therapeutic agent to be selective for the CCK-B receptor.
  • This selectivity is expressed by the ratio I Q (CCK-Ayi o (CCK-B); the higher the value of this ratio die better is the selectivity.
  • Example 2 0.17 160 940 Measurement of inhibition of pentagastrin-stimulated gastric acid secretion in rat
  • a cannula was inserted into the trachea of a rat anaesthetised wid ur ⁇ thane (intraperitoneally administered, 1.25 g/Kg), its abdominal wall was incised to expose the gastric and duodenal portions, and a polyethylene cannula was set in the anterior stomach after ligation of the cardia.
  • the duodenum was men subjected to slight section, a polyediylene cannula was inserted from the incised portion toward the stomach, and d e pylorus was ligated to fix the cannula.
  • Physiological saline (with pH adjusted to 7.0) was perfused from the anterior stomach toward die pylorus at a rate of 3 ml/min, and the gastric-acid secretion was measured by continuous titration of die perfusate by the use of a pH-stat (AUT-201; product of Toa Electronics, Ltd.). The continuous titration was carried out by using 25 mM NaOH solution until me pH reached 7.0, and die result was expressed as die amount of gastric acid secreted for every 10 minutes ( ⁇ E q /10 min.). Pentagastrin was intravenously administered at a rate of 15 ⁇ g/Kg/hr.
  • the secretion of gastric acid increased upon administration of pentagastrin, reaching the maximum level after 60 minutes and stably maintaining tiiis level after diat.
  • a test drug was dien intravenously administered, and the secretion of gastric acid was measured. The effect of each drug was calculated as d e percentage inhibition of stimulated acid ou ⁇ ut at 0.1 ⁇ mol/kg dose of drug. The table below shows the maximum inhibition observed for representative examples. Each result is a mean for 3 - 5 animals.
  • d e compounds of d e present invention are potent and selective CCK-B antagonists and tiiat they inhibit the stimulation of gastric acid release due to pentagastrin. They are therefore useful in the treatment of disease states in which the CCK-B or gastrin receptor is implicated as a mediating factor.
  • disease states would include disorders of d e gastro-intestinal system, for example gastric and duodenal ulceration, gastritis, reflux esophagitis, Zollinger-EUison syndrome, gastrin- sensitive pancreas, and gastrin-sensitive tumors.
  • disorders of d e central nervous system such as anxiety and psychoses would also be amenable to treatment with d e compounds of this invention.
  • the compounds can also be used in the control of appetite and pain.
  • the compounds of this invention and salts thereof can be administered orally (including sublingual administration) or parenterally in the form of tablets, powders, capsules, pills, liquids, injections, suppositories, ointments and adhesive plasters.
  • the carrier and excipient for pharmaceutical manufacturing can be a solid or liquid, non-toxic medicinal substance, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and odier commonly employed materials.
  • non-toxic medicinal substance such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and odier commonly employed materials.
  • Hydroxypropylcellulose 4 5 Carboxymethylcellulose Ca 4 4.2 Mg Stearate 0.6 0.8
  • the granules were filtered through a 20-mesh sieve, 20 g of carboxymethylcellulose Ca and 3 g of magnesium stearate were then added, and die mixture was treated in a rotary tablet machine equipped with a,pesde of 7 mm x 8.4 R (product of Hata Tekkosho), tiius producing tablets each weighing 120 mg.
  • the clinical dosage of the compounds of this invention will be determined by die physician taking into account the precise illness, and the body weight, age, sex, medical history and other factors of the patient to be treated. In general the dosage when administered orally will be between 1 and 1000 mg day in either a single dose or sub-divided into smaller multiple doses.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Dérivé de benzodiazépine de la formule (I), ou sel pharmaceutiquement acceptable de celui-ci. Dans la formule, (a) R1 est sélectionné dans les groupes alkyle et cycloalkyle; (b) R2 est un substituant aminé cyclique tertiaire de la structure (II), (III) ou (IV), dans lesquelles a est 1-6; (c) X est soit CH, soit N. Ces composés sont des antagonistes des récepteurs de la gastrine et/ou de la CCK-B.
PCT/GB1994/001858 1993-08-25 1994-08-25 3-phenylureido-1,4-benzodiaxepines utiles comme antagonistes selectifs de la cck-b WO1995006041A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74660/94A AU7466094A (en) 1993-08-25 1994-08-25 3-phenylureido-1,4-benzodiazepines useful as selective cck-b antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9317692A GB2282594A (en) 1993-08-25 1993-08-25 Benzodiazepine derivatives
GB9317692.3 1993-08-25

Publications (1)

Publication Number Publication Date
WO1995006041A1 true WO1995006041A1 (fr) 1995-03-02

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AU (1) AU7466094A (fr)
GB (1) GB2282594A (fr)
IL (1) IL110782A0 (fr)
WO (1) WO1995006041A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010846A2 (fr) * 1999-08-05 2001-02-15 Igt Pharma Inc. Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
WO2004106310A1 (fr) * 2003-05-30 2004-12-09 Aston University Nouvelles 1,4-benzodiazepines 3-substituees
WO2005111001A1 (fr) * 2004-05-19 2005-11-24 Astrazeneca Ab Heterocycles fusionnes et utilisations
CN106715411A (zh) * 2014-08-08 2017-05-24 特里奥医药有限公司 苯并二氮杂*衍生物
US10570102B2 (en) 2015-08-07 2020-02-25 Trio Medicines Limited Synthesis of benzodiazepine derivatives

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs
EP0538945A1 (fr) * 1991-10-24 1993-04-28 Glaxo Group Limited Dérivés de benzodiazepine et leur utilisation comme antagonistes de la gastrine et/ou de la cholecystokinine
WO1993016999A1 (fr) * 1992-02-27 1993-09-02 Yamanouchi Pharmaceutical Co. Ltd. Derives de benzodiazepine utiles comme antagonistes recepteurs de cck
WO1994000438A1 (fr) * 1992-06-24 1994-01-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de benzodiazepine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2264492B (en) * 1992-02-27 1996-09-25 Yamanouchi Pharma Co Ltd Benzodiazepine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4820834A (en) * 1984-06-26 1989-04-11 Merck & Co., Inc. Benzodiazepine analogs
EP0538945A1 (fr) * 1991-10-24 1993-04-28 Glaxo Group Limited Dérivés de benzodiazepine et leur utilisation comme antagonistes de la gastrine et/ou de la cholecystokinine
WO1993016999A1 (fr) * 1992-02-27 1993-09-02 Yamanouchi Pharmaceutical Co. Ltd. Derives de benzodiazepine utiles comme antagonistes recepteurs de cck
WO1994000438A1 (fr) * 1992-06-24 1994-01-06 Yamanouchi Pharmaceutical Co., Ltd. Nouveau derive de benzodiazepine

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001010846A2 (fr) * 1999-08-05 2001-02-15 Igt Pharma Inc. Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
WO2001010846A3 (fr) * 1999-08-05 2001-11-08 Igt Pharma Inc Nouveaux composes de 1,4-benzodiazepine et derives de ces derniers
WO2004106310A1 (fr) * 2003-05-30 2004-12-09 Aston University Nouvelles 1,4-benzodiazepines 3-substituees
WO2005111001A1 (fr) * 2004-05-19 2005-11-24 Astrazeneca Ab Heterocycles fusionnes et utilisations
CN106715411A (zh) * 2014-08-08 2017-05-24 特里奥医药有限公司 苯并二氮杂*衍生物
US10308627B2 (en) 2014-08-08 2019-06-04 Trio Medicines Ltd Benzodiazepine derivatives as CCK2/gastrin receptor antagonists
CN106715411B (zh) * 2014-08-08 2020-06-23 特里奥医药有限公司 苯并二氮杂*衍生物
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

Also Published As

Publication number Publication date
GB2282594A (en) 1995-04-12
GB9317692D0 (en) 1993-10-13
AU7466094A (en) 1995-03-21
IL110782A0 (en) 1994-11-11

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