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WO1992004354A1 - 6,7-dihydroimidazo(1,5,4-ef)(1,5)benzodiazepine-6-ones substitues, leur preparation et compositions pharmaceutiques - Google Patents

6,7-dihydroimidazo(1,5,4-ef)(1,5)benzodiazepine-6-ones substitues, leur preparation et compositions pharmaceutiques Download PDF

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Publication number
WO1992004354A1
WO1992004354A1 PCT/EP1991/001671 EP9101671W WO9204354A1 WO 1992004354 A1 WO1992004354 A1 WO 1992004354A1 EP 9101671 W EP9101671 W EP 9101671W WO 9204354 A1 WO9204354 A1 WO 9204354A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
formula
integer
compound
phenyl
Prior art date
Application number
PCT/EP1991/001671
Other languages
English (en)
Inventor
Kelvin Cooper
Michael Jonathan Fray
John Steele
Original Assignee
Pfizer Limited
Pfizer Inc.
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 Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to FI930967A priority Critical patent/FI930967A0/fi
Publication of WO1992004354A1 publication Critical patent/WO1992004354A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to diazepine derivatives which are potent, orally active antagonists of platelet activating factor and as such have clinical utility for treating allergic and inflammatory conditions such as asthma and arthritis respectively.
  • Platelet activating factor (PAF, 1-0-alkyl-2-acetyl-sn- glyceryl-3-phosphorylcholine) is an ether phospholipid whose structure was first elucidated in 1979. It is produced by, released from and interacts with many pro-inflammatory cells, platelets and the kidney. In addition to potent platelet
  • PAF aggregating activity
  • PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thrcmb ⁇ xane A 2 or the leukotrienes.
  • PAF stimulates the movement and aggregation of neutrqphils and the release therefrom of tissue-damaging enzymes and oxygen radicals. These activities contribute to actions of PAF in vivo consistent with it playing a significant role in inflammatory and allergic responses.
  • intradermal PAF has been shown to induce an inflammatory response, with associated pain
  • PAF has been implicated as being involved in a number of other medical conditions.
  • circulatory shock which is characterised by systemic hypotension, pulmonary hypertension and increased lung vascular permeability
  • the symptoms can be mimicked by infusion of PAF.
  • This coupled with evidence shewing that circulating PAF levels are increased by endotoxin infusion indicate that PAF is a prime mediator in certain forms of shock.
  • Intravenous infusion of PAF at doses of 20-200 pmol kg -1 min -1 into rats results in the formation of extensive haemorrhagic erosions in the gastric mucosa and thus PAF is the most potent gastric ulcerogen yet described whose
  • Psoriasis is an inflammatory and
  • PAF proliferative disease characterised by skin lesions.
  • PAF is pro-inflammatory and has been isolated from lesi ⁇ ned scale of psoriatic patients indicating PAF has a role in the disease of psoriasis.
  • increasing evidence supports a potential pathophysiological role for PAF in cardiovascular disease.
  • shew PAF is released during atrial pacing and, in pigs, intcracoronary injection of PAF induces a prolonged decrease in coronary flow while in guinea pig hearts it induces regional shunting and ischaeraia.
  • PAF has also been shewn to initiate thrombus formation in a mesentenic artery preparation both when administered exogenously and when released endogenously. More recently PAF has been shewn to play a role in brain ischaemia induced in animal models of stroke.
  • European Patent Application No. 0258033 we disclose a series of 2-substituted 1,4-dihydropyridine derivatives as PAF antagonists.
  • European Patent Application 0310386 we disclose a further series of dihydropyridine PAF antagonists in which the 2-position substituent may be a 2-methyl-imidazo[4,5-c]- pyrid-1-phenyl group.
  • R 1 is either H or C 1 -C 4 alkyl optionally substituted by a substituent selected from phenyl, halophenyl, pyridyl, (C 1 -C 4 alkoxy) carbonyl and di-(C 1 -C 4 alkyl) amino, or C 2 -C 4 alkyl substituted by hydroxyl or by one or two C 1 -C 4 alkoxy groups or is (CH 2 ) n CONR 7 R 8 where n is an integer from 1 to 4 and R 7 and R 8 are each independently H or C 1 -C 4 alkyl, and R 2 is selected from H, OH and
  • R 3 is selected from halo or C 1 -C 4 alkyl;
  • R 4 is methyl; p is 0-3 and m is 0-3; and their
  • R 1 are H, CH 3 and ethoxycarbonylmethyl.
  • R 2 may be selected from H, OH and CH 3 .
  • Particularly preferred compounds are 7-methyl-4-[4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-
  • Such compounds and their salts may exist as one tautomer or as a mixture of tautomers, which may generally be separated by physical means such as fractional crystallisation or
  • the invention includes all tautcmers whether separated or not.
  • R 1 , R 2 or R 3 comprises a branched alkyl or alkoxy group having 4 carbon atoms
  • the compound may contain a chiral centre and exist as a pair of isomers which may be separated by conventional means.
  • the invention includes all such enantiomers, whether separated or not.
  • the pharmaceutically acceptable salts of the compounds of formula (I) are those formed from acids which form non-toxic addition salts, for example the hydrcchloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methane-sulphonate and dimethane-sulphonate,
  • R 1 is H and R 2 is H or C 1 -C 4 alkyl
  • the compounds of formula (I) may be made by the following method.
  • R 4 reacts with an orthoester of the appropriate carboxylic acid in the presence of that acid and compound (I) may be isolated by conventional means.
  • the compound (I) in which R 2 is OH may be made from compound
  • substituted alkyl may be prepared from the corresponding compounds in which R 1 is H by reaction of the latter with compound R 1 -X when
  • X is chloro, bromo or iodo.
  • the reaction is generally conducted in the presence of a base such as sodium hydride.
  • the activity of the compounds of the invention is shewn by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is performed as follows:
  • Elood samples are taken from either rabbit or man into 0.1 vol disodium ethylenediamine tetraacetic acid buffer and the samples centrifuged for 15 minutes to obtain platelet rich plasma. The plasma is further centrifuged to give a platelet pellet which is washed with a buffer solution (4 nM KH 2 PO 4 , 6mM Na 2 HPO 4 , 100 mM NaCl, 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of
  • the activity of the compounds of formula (I) is also demonstrated in vivo by their ability to protect mice from the lethal effect of an injection of PAF.
  • a mixture of PAF (50 ⁇ g/kg) and DL-propranolol (5 mg/kg) in 0.9% w/v sodium chloride is injected (0.2 ml) via a tail vein into mice.
  • the compounds under test are either injected into the tail vein immediately prior to the PAF/propranolol injection or administered orally by gavage two hours earlier.
  • the compounds are tested at several doses in groups of 5 mice and the dose which reduces mortality to 50% is recorded as the PD 50 value.
  • the compounds of the formula (I) will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of
  • compositions for example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for exanple, enough salts or glucose to make the solution isotonic with blood.
  • oral dosages of the compounds will generally be in the range of from 2-1000 mg daily for an average adult patient (70 kg).
  • individual tablets or capsules contain from 1 to 500 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier.
  • administration would typically be within the range 1 to 10 mg per single dose as required.
  • inhalation via a nebuliser or aerosol may be the preferred route of drug administration.
  • Dose levels by this route would be within the range 0.1 to 50 mg per single dose as required.
  • physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient.
  • the above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the invention provides a
  • composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.
  • the invention also includes a compound of the formula (I) or a pharmaceutically acceptable salt thereof, for use in medicine, in particular in the treatment of allergic and
  • reaction mixture On cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate such that the aqueous phase had pH8.
  • the organic extract was washed with water, dried over magnesium sulphate and the drying agent filtered off.
  • Pre-adsorption silica Karlgel 60, 70-230 mesh, 1g was added to the filtrate which was concentrated to dryness under reduced pressure. The residue was purified by flash
  • This compound was prepared by the method of Example 1 substituting teiethylorthoacetate and acetic acid for
  • Example 1 (0.51g, 1.3mmol) in anhydrous dimethylformamide (10ml) under nitrogen. After being stirred under reflux for 1 hour, the reaction inixture was cooled to room temperature, whereupon ethyl bromoacetate (0.166ml, 1.5mmol) was added and the solution stirred for an additional 36 hours at room temperature. The dimethylformamide was evaporated off under reduced pressure. The residue was diluted with water, hydrochloric acid (2M) added to give pH1, followed by sodium hydrogen carbonate to give pH8 and product extracted with ethyl acetate. The organic extract was washed three times with water, dried over magnesium sulphate and the drying agent filtered off. Pre-adsorption silica (Kieselgel 60,70-230 mesh, 2g) was added to the filtrate which was evaporated to dryness under reduced pressure.
  • ethyl bromoacetate (0.166ml, 1.5mmol
  • Example 4 The procedure of Example 4 was followed, using methyl iodide instead of ethyl bromoacetate, to yield the title compound, (30mg, 13%).
  • Step (b) belcw, m.p. 200°C (broad).
  • Ethyl 4'-(2-mtethylimidazo[4,5-c]-pyrid-1-yl)benzoylacetate may be prepared as described in European Patent Application No. 0310386A.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Antagonistes de facteurs d'activation plaquettaire de formule (I), où R1 représente H ou alkyle C¿1?-C4 éventuellement substitué par un susbtituant choisi à partir de phényle, halophényle, pyridyle, carbonyle (alcoxy C1-C4) et di-(alkyle C1-C4) amino, ou représente alkyle C2-C4 substitué par un hydroxyle ou par un ou deux groupes alcoxy ou représente (CH2)nCONR?7R8¿ où n est un nombre entier compris entre 1 et 4 et R7 et R8 représentent chacun indépendamment H ou alkyle C¿1?-C4, R?2¿ est choisi à partir de H, OH, et alkyle C¿1?-C4, R?3¿ est choisi à partir de halo et alkyle C¿1?-C4, R?4¿ représente méthyle et p est un nombre entier compris entre 0 et 3 et m est un nombre entier compris ente 0 et 3; ou un sel pharmaceutiquement acceptable de ces composés.
PCT/EP1991/001671 1990-09-05 1991-09-02 6,7-dihydroimidazo(1,5,4-ef)(1,5)benzodiazepine-6-ones substitues, leur preparation et compositions pharmaceutiques WO1992004354A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI930967A FI930967A0 (fi) 1990-09-05 1991-09-02 Substituerade 6,7-dihydroimidazo(1,5,4-ef)(1,5)bensodiazepin-6-oner, deras framstaellning och farmaceutiska kompositioner

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909019409A GB9019409D0 (en) 1990-09-05 1990-09-05 Therapeutic agents
GB9019409.3 1990-09-05

Publications (1)

Publication Number Publication Date
WO1992004354A1 true WO1992004354A1 (fr) 1992-03-19

Family

ID=10681724

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/001671 WO1992004354A1 (fr) 1990-09-05 1991-09-02 6,7-dihydroimidazo(1,5,4-ef)(1,5)benzodiazepine-6-ones substitues, leur preparation et compositions pharmaceutiques

Country Status (8)

Country Link
EP (1) EP0548125A1 (fr)
JP (1) JPH06500091A (fr)
CA (1) CA2091057A1 (fr)
FI (1) FI930967A0 (fr)
GB (1) GB9019409D0 (fr)
IE (1) IE913102A1 (fr)
PT (1) PT98851A (fr)
WO (1) WO1992004354A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5965535A (en) * 1997-09-12 1999-10-12 Ludwig Institute For Cancer Research Mage-3 peptides presented by HLA class II molecules
US6130052A (en) * 1997-04-25 2000-10-10 Ludwig Institute For Cancer Research Leukemia associated genes
US7252825B2 (en) 1997-09-12 2007-08-07 Ludwig Institute For Cancer Research MAGE-3 peptides presented by HLA class II molecules

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310386A2 (fr) * 1987-09-30 1989-04-05 Pfizer Limited 4-Aryl-5-carbamoyl-1,4-dihydropyridines
EP0389189A2 (fr) * 1989-03-23 1990-09-26 Pfizer Limited Agents antiallergiques à base de diazépines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0310386A2 (fr) * 1987-09-30 1989-04-05 Pfizer Limited 4-Aryl-5-carbamoyl-1,4-dihydropyridines
EP0389189A2 (fr) * 1989-03-23 1990-09-26 Pfizer Limited Agents antiallergiques à base de diazépines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY.CHIMICA THERAPEUTICA. vol. 13, no. 1, 1978, CHATENAY-MALABRY FR pages 53 - 59; P. GENESTE ET AL.: 'Recherches en série de l'imidazo- (4,5,1-jk)- benzodiazépine- 1,4 et de l'imidazo- (1,5,4- ef)- benzodiazépine- 1,5' *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6130052A (en) * 1997-04-25 2000-10-10 Ludwig Institute For Cancer Research Leukemia associated genes
US5965535A (en) * 1997-09-12 1999-10-12 Ludwig Institute For Cancer Research Mage-3 peptides presented by HLA class II molecules
US7252825B2 (en) 1997-09-12 2007-08-07 Ludwig Institute For Cancer Research MAGE-3 peptides presented by HLA class II molecules

Also Published As

Publication number Publication date
CA2091057A1 (fr) 1992-03-06
PT98851A (pt) 1992-07-31
EP0548125A1 (fr) 1993-06-30
FI930967A7 (fi) 1993-03-04
IE913102A1 (en) 1992-03-11
FI930967L (fi) 1993-03-04
GB9019409D0 (en) 1990-10-17
JPH06500091A (ja) 1994-01-06
FI930967A0 (fi) 1993-03-04

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