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EP0551291A1 - Therapeutic (paf antagonists) agents - Google Patents

Therapeutic (paf antagonists) agents

Info

Publication number
EP0551291A1
EP0551291A1 EP91915535A EP91915535A EP0551291A1 EP 0551291 A1 EP0551291 A1 EP 0551291A1 EP 91915535 A EP91915535 A EP 91915535A EP 91915535 A EP91915535 A EP 91915535A EP 0551291 A1 EP0551291 A1 EP 0551291A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
phenyl
pharmaceutically acceptable
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP91915535A
Other languages
German (de)
English (en)
French (fr)
Inventor
Kelvin Pfizer Central Research Cooper
Michael Jonathan Pfizer Central Research Fray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
Pfizer Inc
Original Assignee
Pfizer Corp Belgium
Pfizer Ltd Great Britain
Pfizer Corp SRL
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 Corp Belgium, Pfizer Ltd Great Britain, Pfizer Corp SRL, Pfizer Inc filed Critical Pfizer Corp Belgium
Publication of EP0551291A1 publication Critical patent/EP0551291A1/en
Ceased legal-status Critical Current

Links

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

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Hematology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP91915535A 1990-09-11 1991-09-02 Therapeutic (paf antagonists) agents Ceased EP0551291A1 (en)

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
EP0551291A1 true EP0551291A1 (en) 1993-07-21

Family

ID=10682011

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91915535A Ceased EP0551291A1 (en) 1990-09-11 1991-09-02 Therapeutic (paf antagonists) agents

Country Status (8)

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

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2746310B1 (fr) 1996-03-22 1998-06-12 Oreal Compositions de teinture des fibres keratiniques contenant des pyrazolin-3,5-dione ; leur utilisation pour la teinture comme coupleurs, procede de teinture
FR2746307B1 (fr) 1996-03-22 1998-04-30 Oreal Compositions de teinture des fibres keratiniques contenant des pyrrolo-azoles ; utilisation comme coupleurs ; procede de teinture
FR2746308B1 (fr) * 1996-03-22 1998-04-30 Oreal Compositions de teinture des fibres keratiniques contenant des imidazolo-azoles ; leur utilisation en teinture comme coupleurs ; procede de teinture
FR2746309B1 (fr) 1996-03-22 1998-04-17 Oreal Composition de teinture des fibres keratiniques contenant des pyrazolopyrimidineoxo ; leur utilisation pour la teinture comme coupleurs, procedes de teinture
FR2746391B1 (fr) 1996-03-22 1998-04-17 Oreal Compositions cosmetiques a base de pyrazolin-4,5-diones, nouvelles pyrazolin-4,5 diones, procedes de preparation et utilisations
FR2746306B1 (fr) * 1996-03-22 1998-04-30 Oreal Compositions de teinture des fibres keratiniques contenant des pyrazolo-azoles ; leur utilisation pour la teinture comme coupleurs, procede de teinture

Family Cites Families (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
DK0389189T3 (da) * 1989-03-23 1994-06-20 Pfizer Diazepin antiallergimidler

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9204349A1 *

Also Published As

Publication number Publication date
IE913167A1 (en) 1992-03-11
CA2088777A1 (en) 1992-03-12
WO1992004349A1 (en) 1992-03-19
FI931071A (fi) 1993-03-10
PT98902A (pt) 1992-07-31
GB9019833D0 (en) 1990-10-24
JPH06500108A (ja) 1994-01-06
FI931071A0 (fi) 1993-03-10

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Legal Events

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PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

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