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WO1992004349A1 - Agents therapeutiques - Google Patents

Agents therapeutiques Download PDF

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Publication number
WO1992004349A1
WO1992004349A1 PCT/EP1991/001669 EP9101669W WO9204349A1 WO 1992004349 A1 WO1992004349 A1 WO 1992004349A1 EP 9101669 W EP9101669 W EP 9101669W WO 9204349 A1 WO9204349 A1 WO 9204349A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
phenyl
pharmaceutically acceptable
methyl
Prior art date
Application number
PCT/EP1991/001669
Other languages
English (en)
Inventor
Kelvin Cooper
Michael Jonathan Fray
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 FI931071A priority Critical patent/FI931071A0/fi
Publication of WO1992004349A1 publication Critical patent/WO1992004349A1/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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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 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 aggregating activity, PAF exhibits a wide spectrum of biological activities elicited either directly or via the release of other powerful mediators such as thromboxane A 2 or the leukotrienes. In vitro, PAF stimulates the movement and aggregation of neutrophils 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. Thus, 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.
  • 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 lesioned 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.
  • PAF is released during atrial pacing and, in pigs, intracoronary injection of PAF induces a prolonged decrease in coronary flow while in guinea pig hearts it induces regional shunting and ischaemia.
  • PAF has also been shown to initiate thrombus formation in a mesentenic artery preparation both when administered exogenously and when released endogenously. Ifore recently PAF has been shown to play a role in brain ischaemia induced in animal models of stroke.
  • R is H or a group selected from C 1 -C 6 alkyl, hydroxymethyl, (C 1 -C 4 alkoxy) methyl, C 3 -C 7 cycloalkyl, pyridyl, thienyl, unsubstituted phenyl and phenyl substituted by from one to three substituents each selected from halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and CF 3 , and their pharmaceutically acceptable salts.
  • halo means fluoro, chloro, bromo or iodo.
  • Alkyl and alkoxy groups of 3 or more carbon atoms may be straight or branched-chain.
  • R are methyl, phenyl and cyclohexyl.
  • These compounds and their salts may exist as one tautomer or a mixture of tautomeric forms, which may be separated by physical methods such as fractional crystallisation or chromatography.
  • the invention includes all the tautomers whether separated or not.
  • Compounds in which R comprises a branched hydrocarbon chain of 4 or more carbon atoms may contain a chiral centre and therefore exist as a pair of isomers which may be separated by conventional means.
  • the invention includes all these 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 hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or acid phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, methanesulphonate and dimethanesulphonate,
  • the compounds of formula (I) may generally be prepared by the following synthesis:
  • aminopyrazole (III) is reacted with a nitrite, for example sodium nitrite in the presence of acetic acid, to yield the nitrosopyrazole (IV) which is then reduced with hydrogen, generally in the presence of a catalyst such as palladium on carbon, to produce the diaminopyrazole (V).
  • a nitrite for example sodium nitrite in the presence of acetic acid
  • nitrosopyrazole (IV) which is then reduced with hydrogen, generally in the presence of a catalyst such as palladium on carbon, to produce the diaminopyrazole (V).
  • the diaminopyrazole is then reacted with co mpound (VI), for example in the presence of silica gel and a suitable solvent such as toluene, to give the compound of formula (II).
  • a proportion of compound (IIA) is also produced.
  • the diaminopyrazole is reacted with compound (VI) in the presence of a catalytic quantity of zinc chloride in ethanol, preferably under reflux for 24 hours, followed by treatment of the cooled solution with sodium hydride at room temperature to give compound (II).
  • Compounds (II) and (IIA) may be separated by physical methods such as chromatography.
  • the appropriate 2-hydroxyimino acetonitrile derivative is reacted with the appropriate hydrazino alcohol, generally by heating in the presence of a suitable solvent such as ethanol.
  • the compounds of formula (I) may be made by the following synthesis:
  • X is chloro, bromo, or iodo and Q is a leaving group such as
  • trip-henylphosphine and diethyl azodicarboxylate This compound may then be reduced, for example by treatment with hydrazine and
  • ketoester (VI) preferably in the presence of a zinc chloride catalyst followed by treatment with a base such as sodium hydride, to yield the compound of formula (I).
  • This compound may be separated from other reaction products formed by
  • the activity of the compounds of the invention is shown by their ability to inhibit the platelet aggregating activity of PAF in vitro. Testing is performed as follows:
  • Blood 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 mM KH 2 PO 4 , 6mM Na 2 HPO 4 , 100 mM
  • 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
  • ком ⁇ онентs 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 example, 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.
  • the 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 inflammatory conditions in a human being.
  • triphenylphosphine (386 mg, 1.47 mmol) and diethyl
  • the dichloromethane solution was concentrated under reduced pressure and the residue was purified by flash chromatography (gradient elution with dichloromethane/ methanol) to give the title compound as a white solid, 806 mg (65%), m.p. 206-207°C (from dichloromethane/methanol).

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hematology (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 du facteur d'activation plaquettaire répondant à la formule (I), dans laquelle A représente -(CH2)n où n est compris entre 2 et 5, ou -CH2CH=CHCH2-; et R représente H ou un groupe sélectionné parmi alkyle en C1-6, hydroxyméthyle, (alcoxy en C1-4)méthyle, cycloalkyle en C3-7, pyridyle, thiényle, phényle non substitué et phényle substitué par de un à trois substituants sélectionnés indépendamment parmi halo, alkyle en C1-4, alcoxy en C1-4 et -CF3; ou leur sel pharmaceutiquement acceptable.
PCT/EP1991/001669 1990-09-11 1991-09-02 Agents therapeutiques WO1992004349A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI931071A FI931071A0 (fi) 1990-09-11 1991-09-02 Terapeutiska aemnen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909019833A GB9019833D0 (en) 1990-09-11 1990-09-11 Therapeutic agents
GB9019833.4 1990-09-11

Publications (1)

Publication Number Publication Date
WO1992004349A1 true WO1992004349A1 (fr) 1992-03-19

Family

ID=10682011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1991/001669 WO1992004349A1 (fr) 1990-09-11 1991-09-02 Agents therapeutiques

Country Status (8)

Country Link
EP (1) EP0551291A1 (fr)
JP (1) JPH06500108A (fr)
CA (1) CA2088777A1 (fr)
FI (1) FI931071A0 (fr)
GB (1) GB9019833D0 (fr)
IE (1) IE913167A1 (fr)
PT (1) PT98902A (fr)
WO (1) WO1992004349A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6165229A (en) * 1996-03-22 2000-12-26 L'oreal Imidazoloazole-containing compositions for dyeing keratin fibers; their use in dyeing as couplers; dyeing process
US6179882B1 (en) 1996-03-22 2001-01-30 L'oreal Keratin fibre dye composition containing pyrazolopyrimidinoxo compounds, use thereof as dye couplers, and dyeing methods
US6210447B1 (en) 1996-03-22 2001-04-03 L'oreal Compositions containing pyrazolin-3,5-dione couplers for use in keratin fiber dyeing methods and kits
US6231623B1 (en) * 1996-03-22 2001-05-15 L'oreal S.A. Methods of dyeing keratin fibers with compositions containing pyrazolo-azole couplers
US6238440B1 (en) 1996-03-22 2001-05-29 L'oreal S.A. Keratin fibre dye compositions containing pyrrolo-azole compounds, use thereof as couplers, and dyeing method
US6322775B1 (en) 1996-03-22 2001-11-27 L'oreal S.A. Cosmetic compositions containing pyrazolin-4,5-diones, novel pyrazolin-4,5-diones, preparation methods therefor and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3435972A1 (de) * 1984-10-01 1986-04-10 Boehringer Ingelheim KG, 6507 Ingelheim Diazepine enthaltende pharmazeutische zusammensetzungen mit paf-antagonistischer wirkung
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
DE3435972A1 (de) * 1984-10-01 1986-04-10 Boehringer Ingelheim KG, 6507 Ingelheim Diazepine enthaltende pharmazeutische zusammensetzungen mit paf-antagonistischer wirkung
EP0389189A2 (fr) * 1989-03-23 1990-09-26 Pfizer Limited Agents antiallergiques à base de diazépines

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6165229A (en) * 1996-03-22 2000-12-26 L'oreal Imidazoloazole-containing compositions for dyeing keratin fibers; their use in dyeing as couplers; dyeing process
US6179882B1 (en) 1996-03-22 2001-01-30 L'oreal Keratin fibre dye composition containing pyrazolopyrimidinoxo compounds, use thereof as dye couplers, and dyeing methods
US6210447B1 (en) 1996-03-22 2001-04-03 L'oreal Compositions containing pyrazolin-3,5-dione couplers for use in keratin fiber dyeing methods and kits
US6231623B1 (en) * 1996-03-22 2001-05-15 L'oreal S.A. Methods of dyeing keratin fibers with compositions containing pyrazolo-azole couplers
US6238440B1 (en) 1996-03-22 2001-05-29 L'oreal S.A. Keratin fibre dye compositions containing pyrrolo-azole compounds, use thereof as couplers, and dyeing method
US6322775B1 (en) 1996-03-22 2001-11-27 L'oreal S.A. Cosmetic compositions containing pyrazolin-4,5-diones, novel pyrazolin-4,5-diones, preparation methods therefor and uses thereof
US6379395B1 (en) 1996-03-22 2002-04-30 L'oreal S.A. Pyrazolopyrimidinoxo-containing compositions for dyeing keratin fibres; their use in dyeing as couplers; dyeing processes
US6551360B2 (en) 1996-03-22 2003-04-22 Laurent Vidal Pyrazoline-3,5-dione-containing compositions for dyeing keratin fibres; their use in dyeing as couplers; dyeing process

Also Published As

Publication number Publication date
JPH06500108A (ja) 1994-01-06
FI931071L (fi) 1993-03-10
CA2088777A1 (fr) 1992-03-12
IE913167A1 (en) 1992-03-11
PT98902A (pt) 1992-07-31
EP0551291A1 (fr) 1993-07-21
FI931071A7 (fi) 1993-03-10
GB9019833D0 (en) 1990-10-24
FI931071A0 (fi) 1993-03-10

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