EP0195016A1 - Cyclimmonium salts - Google Patents

Cyclimmonium salts

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Publication number
EP0195016A1
EP0195016A1 EP85904111A EP85904111A EP0195016A1 EP 0195016 A1 EP0195016 A1 EP 0195016A1 EP 85904111 A EP85904111 A EP 85904111A EP 85904111 A EP85904111 A EP 85904111A EP 0195016 A1 EP0195016 A1 EP 0195016A1
Authority
EP
European Patent Office
Prior art keywords
compound
alkyl
alkynyl
phenyl
independently
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.)
Withdrawn
Application number
EP85904111A
Other languages
German (de)
English (en)
French (fr)
Inventor
Robert C. Anderson
Mark L. Lee
John C. Tomesch
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.)
Novartis Pharma GmbH Austria
Sandoz AG
Original Assignee
Sandoz Erfindungen Verwaltungs GmbH
Sandoz AG
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 Sandoz Erfindungen Verwaltungs GmbH, Sandoz AG filed Critical Sandoz Erfindungen Verwaltungs GmbH
Publication of EP0195016A1 publication Critical patent/EP0195016A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C07D213/20—Quaternary compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/10—Quaternary compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/10—Quaternary compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to certain cyclimmonium salts and to their use as platelet activating factor (PAF) receptor antagonists and as inhibitors of PAFinduced blood platelet aggregation.
  • the invention also relates to pharmaceutical compositions containing the aforementioned compounds as an active ingredient thereof and to the method of using such compositions for inhibiting PAF-mediated bronchoconstriction and extravasation.
  • Blood platelets also called thrombocytes, are well recognized as important cellular elements that circulate in the blood. Their role is to staunch bleeding by forming clots in broken blood vessels, i.e., they are nature's corks. They have, however, been implicated in a variety of immuunologically mediated forms of tissue injury.
  • PAF platelet activating factor
  • the invention concerns compounds of formula I wherein Q is C 1 _ 24 alkyl, C 2 _ 24 alkenyl or alkynyl, C 12-24 alkoxyalkyl, phenyl or C 7-9 phenylalkyl; A is CH 2 , O, S or a group W whereby W is
  • D is C 2-8 alkenylene, CH 2 , O, S or a group W as defined for A, whereby A and D may not simultaneously be a group W;
  • E and B are independently C 1-8 alkylene; or C 2-8 alkenylene or alkynylene; represents a 5- or 6- membered mono-cyclic ring optionally containing one further heteroatom selected from nitrogen or sulphur; or a 10-membered bicyclic ring optionally containing one further nitrogen atom; each of which rings may be unsubstituted or either mono-, di-, or tri-substitute by C 1-4 alkyl or mono-substituted by CF-, COOH or COOCH 3 ;
  • R 1 and R 2 are, independently, hydrogen, C 1-4 alkyl, C 2 alkenyl or alkynyl, C 1-3 alkoxy, C 3-4 alkenyloxy or alkynyloxy, phenyl, phenoxy, C 2-4 alkoxyalkyl
  • R 3 is hydrogen or together with the nitrogen atom to which it is attached forms a 5or 6-membered heterocyclic ⁇ ring optionally containing one or two further heteroatoms selected from nitrogen oxygen and sulphur; x and z are independently 0 or 1; y is 0, 1 or 2; and ⁇ Z is a pharmaceutically acceptable anion, with the general proviso that when Q is alkyl, alkenyl, alkynyl, phenyl or phenalkyl, at least one of A, B, D and E is other than alkylene, alkenylene or alkynylene.
  • alkyl is preferably of 6 to 24 carbon atoms, more preferably 8 to 22 carbon atoms and, especially 12 to 20 carbon atoms; 2) alkenyl and alkynyl are preferably of 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms and, especially 3 to 5 carbon atoms; 3) alkoxyalkyl is preferably of 12 to 20 carbon atoms, more preferably 12 to 18 carbon atoms; and 4) phenylalkyl is preferably benzyl.
  • A is preferably CH 2 , O, S, ji £ where R 3 is as defined above, more preferably CH 2 , , O, S, where R 3 is as defined above, especially CH 2 , O, , where R 3 is hydrogen or with N a 5- or 6-membered R 3 saturated heterocyclic ring.
  • alkylene in the definition of B is preferably of 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms and especially 1 or 2 carbon atoms.
  • Alkenylene or alkynylene in the definition of B is preferably of 2 to 6 carbon atoms, more preferably of 3 to 5 carbon atoms.
  • alkylene in the definition of E is preferably of 2 to 6 carbon atoms, more preferably 3 to 5 carbon atoms, especially 4 carbon atoms.
  • Alkenylene or alkynylene in the definition of E is preferably of 2 to 6 carbon atoms, more preferably 3 to 5 carbon atoms, especially 4 carbon atoms.
  • thiazolium is preferably a thiazolium, pyridinium, pyridazinium, quinolinium or isoquinolinium ring or more preferably a thiazolium, pyridinium or quinolinium ring, said rings in each case being unsubstituted or either mono-, di- or trisubstituted by C 1-4 alkyl or monosubstituted by CF 3 , COOH or COOCH 3 .
  • R 1 and R 2 are preferably hydrogen, C 1-4 alkyl/ C 2-4 alkenyl or alkynyl, C 1-3 alkoxy or C 2-4 alkoxyalkyloxy. More preferably, R 1 and R 2 independently are hydrogen, C 1-4 alkyl, C 1-3 alkoxy or C 2-4 alkoxyalkoxy. R 1 and R 2 are especially hydrogen, C 1-4 alkyl or C 1-3 alkoxy.
  • R 3 is preferably R 3 as defined above.
  • the anion Z ⁇ is preferably chloride, bromide, iodide, phenyrsulfonate, toluenesulfonate, C 1-4 alkyl sulfonate, carboxylate or tetrafluoroborate. More preferably, Z ⁇ is chloride, bromide, C 1-4 alkylsulfonate or carboxylate.
  • Examples of preferred compounds of formula I are for example those a) wherein Q is C 6-24 alkyl, C 2-12 alkenyl or alkynyl, C 12-20 - alkoxyalkyl or benzyl, J i
  • E is C 2-6 alkylene, alkenylene or alkynylene, is a thiazolium, pyridinium, pyridazinium, quinolinium or isoquinolinium ring which is unsubstituted or either mono-, di- or trisubstituted by C 1-4 alkyl or monosubstituted by CF 3 , COOH or COOCH 3 ,
  • R 1 and R 2 are independently hydrogen, C 1-4 alkyl, C 2-4 - alkenyl or alkynyl, C 1-3 alkoxy or C 2-4 alkoxyalkox Z ⁇ is chloride, bromide, iodide, phenylsulfonate, toluenesulfonate, C 1-4 alkylsulfonate, carboxylate or tetrafluoroborate and the remaining substituents are as defined above (compounds la) ;
  • E is C 3-5 alkylene, alkenylene or alkynylene, is a thiazolinium, pyridinium or quinolinium ring which is unsubstituted or either mono-, di- or trisubstituted by C 1-4 alkyl or monosubstituted by CF 3 , COOH or COOCH 3 , R 1 and R 2 are independently hydrogen, C 1-4 alkyl,
  • Q is C 12-20 alkyl, C 3-5 alkenyl or alkynyl, C 12-18 alkoxyalkyl or benzyl.
  • A is CH 2 , O,
  • B is C 1- 2 alkylene or C 3 - 5 alkenylene or O alkynyl gene
  • D is C 3-5 alkenylene , CH 2 , O,
  • E is C 4 alkylene, alkenylene or alkynylene
  • R 1 and R 2 are independently hydrogen, C 1-4 alkyl or
  • R is hydrogen, C 1-4 alkyl, CF 3 , COOH or COOCH 3 and R 4 and R 5 are independently hydrogen, C 1-4 alkyl or one thereof is hydrogen and the other is CF 3 and the remaining substituents are as defined above
  • the compounds according to the invention may be prepared by reacting a compound of formula with a compond of formula wherein Q, A,B,D,E,G, Z,x,y and z are as defined above.
  • the reaction is suitably carried out in the presence of an inert solvent such-as an aromatic hydrocarbon e.g. benzene or toluene, a lower alkyl nitrile e.g. acetonitrile or a polar aprotic solvent e.g. dimethylformamide at a temperature e.g. of 20° to 100° especially 50°-100°.
  • an inert solvent such-as an aromatic hydrocarbon e.g. benzene or toluene, a lower alkyl nitrile e.g. acetonitrile or a polar aprotic solvent e.g. dimethylformamide
  • an inert solvent such-as an aromatic hydrocarbon e.g. benzene or toluene, a lower alkyl nitrile e.g. acetonitrile or a polar aprotic solvent e.g. dimethylformamide
  • the starting material of formula H may be prepared accordin to or analogously to the reactions shown in the following schemes.
  • M alkali or alkaline earth metal
  • M' alkali metal
  • D' O or CH 2
  • R 5 C 1-3 alkyl, C 3-4 alkenyl or alkynyl or C 2-4 alkoxyalkyl
  • PA polar aprotic
  • Enantiomeric forms may be recovered in conventional manner e.g. by resolution of end or intermediate products or by employing optically active starting materials.
  • the compounds of formula I are useful as platelet activating inhibitors as indicated by their ability to inhibit platelet activating factor (PAF) -induced human platelet aggregation in vitro according to the Platelet Aggregation Inhibition Assay test (PAIA test) as follows:
  • Platelet rich plasma is prepared by centrifugation (200 x g.) of freshly drawn blood, anti-coagulated with 0.38% sodium citrate (final concentration). Platelet count is adjusted to 250,000 per ⁇ l using platelet poor plasma (PPP) obtained by a second centrifugation (700 x g.) of the blood sample. An aliquot (0.38 ml) of the PRP is dispensed into cuvettes and maintained at room temperature (22°C) until used (but for not more than two hours).
  • PPP platelet poor plasma
  • the PRP-containing cuvettes are incubated at 37°C and stirred at 900 rpm within a Payton Aggregometer which is activated to follow the light deflection pattern prior to the addition of the test compound.
  • the test compound (dissolved in a suitable solvent mixture which does not influence platelet aggregation) is then added to a PRPcontaining cuvette in an amount sufficient to provide a final concentration of 100 ⁇ M.
  • the aggregation inducing agent (C-16 PAF-Sandoz-Hanover), dissolved in a buffer consisting of 0.01 M tris-tyrodes buffer with 0.25% bovine serum albumin (pH 7.4), is added to the PRP-containing cuvettes in an amount pre-determined to give a consistent aggregation response (either 0.1 ⁇ M or 0.01 ⁇ M). All aggregations are allowed to proceed for 6 minutes from the addition of the inducing agent. The aggregation response is quantitated by determining the area under the curve (AUC). The AUC calculated for the inducing agent alone is considered to be one hundred percent.
  • the potential percent inhibition of the aggregation response is determined by dividing the AUC generated in the presence of the compound by the AUC of the inducing agent alone, multiplying by 100 and then subtracting from 100.
  • the compounds demonstrating greater than 50% inhibition at 100 ⁇ M are evaluated at lower concentrations to generate an IC 50 (50% inhibitory concentration) value.
  • Human blood is obtained by venipuncture of healthy, human donors into an anti-coagulant mixture containing 3.15% of trisodium citrate and 20 ⁇ g/ml of Prostaglandin I (PGI 2 ) in a ratio of blood to anti-coagulant of 9:1.
  • PKI 2 Prostaglandin I
  • Platelet rich plasma (PRP) is prepared by centrifugation (250 x g.) of the blood for 20 minutes at room temperature.
  • the PRP is then centrifuged (900 x g.) for 10 minutes at room temperature and the platelet pellet is washed two times with Tris-tyrode's (TT) solution having a pH of 7.4 and containing 0.25% bovine serum albumin (BSA), and to which has been added PGI 2 at a final concentration of 0.3 ⁇ g/ml.
  • TT Tris-tyrode's
  • BSA bovine serum albumin
  • the platelets are resuspended at 350,000 ⁇ l in TT/BSA containing 1.4 mM CaCl 2 .2H 2 O and 0.7 mM MgCl 2 .6H 2 O. All of the tests are conducted in duplicate and each of the test compounds is evaluated at concentrations of 100, 50, 1 and 0.1 ⁇ M. For each determination, the following solutions are mixed 500 ⁇ l of the above-described platelets; 10 ⁇ l of [ 3 H]-PAF (40,000 counts per minute (cpm) to a final
  • the supernatants are then aspirated into the same scintillation vials as before and 10 ml of Scintiverse II (a liquid scintillation cocktail) is added to and mixed therewit The pellets are resuspended in 500 ⁇ l of Scintiverse II and mixe well. An additional 2ml of Scintiverse II is then added to the vials and, after mixing, the vials are counted for 1 minute in a liquid scintillation spectrometer. The amount of specific binding is calculated as the difference in cpm between the total bound [ 3 H]-PAF and non-specifically bound [ 3 H]-PAF.
  • the percent inhibition of specific binding is determined by dividing the cpm specifically bound in the presence of the test compound by the cpm specifically bound in total,----------------------------------------------- multiplying by 100 and then subtracting from 100.
  • An IC 50 (50% inhibitor concentration) value is generated by evaluating the test compound over the full concentration range.
  • PAF-induced Pulmonary Inflation Pressure (PIP) Increase test Test B
  • test compound is administered either orally at 30 minutes prior to or intravenously (jugular) at 5 minutes prior to the introduction of PAF.
  • PAF C 18 -Sandoz, Hanover
  • Tris-Tyrode' s bovine serum albumin buffer is administered intravenously (jugular) at 100 ng/kg.
  • any blood pressure measurements taken are recorded from a transducer attached to the carotid catheter.
  • Two responses are noted in the PIP recordings after the PAF is administered: 1) an immediate response which, in PAF-only treated test animals, averages out to between 70% and 80% more than the baseline PIP values. (This early response is also the greatest response and is, therefore, termed maximal PIP); and 2) the long term (at least 30 minutes) PIP response which slowly decreases to baseline.
  • a reading at 15 minutes after the administration of PAF is termed the endpoint PIP.
  • the effect of the test compound on the PIP response is determined by the difference between the percent increase in maximal PIP over baseline for the test animal to which has been administered PAF and the test compound compared to the test animal to which only PAF has been administered.
  • the compounds of formula I are useful as inhibitors of PAF-mediated extravasation (the extrusion of plasma from the lumen of the blood vessels into the vessel wall and surrounding tissues) measured as a function of hemo-concentration according to the PAF-induced Extravasation test (Test C) as follows:
  • test compounds Male guinea pigs, weighing between 300 and 400 gm, are anesthetized, after which time a femoral catheter is inserted.
  • the test compounds is administered either orally or intragastrically at one hour prior to the introduction of PAF.
  • the PAF is administered either orally or intragastrically at one hour prior to the introduction of PAF.
  • hematocrit value which is employed to index hemo-concentration and is defined as the percent of packed red blood cells in a sample of blood which is centrifuged to separate plasma from the cellular components.
  • hematocrit a percent of packed red blood cells
  • the tubes are then centrifuged and the percent of packed red blood cells (hematocrit) is measured (PAF induced a maximal increase in hematocrit at 5 to 7 minutes subsequent to the injection of PAF). The percent increase in hematocrit over the value prior to the injection of PAF is calculated.
  • the hematocrit values obtained with the test compound are compared to the hemoconcentration values obtained with PAF alone and are expressed as percent inhibition of percent increase in hematocrit.
  • the compounds are thus indicated for use in inhibiting or antagonising PAF and an indicated suitable daily dosage for this use is from about 1 to 500 mg preferably 1 to 50 mg suitably administered in divided dosages of 0.25 to 500 mg preferably 0.25 to 50 mg one to four times daily or in controlled release form.
  • a typical oral dosage is 5 mg three times a day.
  • the compounds are further indicated for use in treating PAF mediated bronchoconstriction and extravasation and an indicated suitable daily dosage for this use is from about 10 to 2000 mg preferably 10 to 350 mg suitably administered in divided dosages of 0.25 to 500 mg (esp. 0.25 to 350 mg) one to four times daily or in controlled release form.
  • a typical oral dosage is 50 or 100 mg two or three times a day.
  • the invention therefore also concerns a method of inhibiting or antagonising platelet activating factor and of treating platelet activating factor mediated bronchoconstriction and extravasation which comprises administering to a subject in need of such treatment a compound of formula I, as well as such compounds for use as pharmaceuticals e.g. in inhibiting or antagonising platelet activating factor and treating platelet activating factor mediated bronchoconstriction and extravasation.
  • the compounds may be administered alone, or in admixture with a pharmaceutically acceptable diluent or carrier, and, optionally other excipients, and administered orally in such forms as tablets, dispersible powders, granules, elixirs, capsules or suspensions or parenterally in such forms as sterile injectable solutions or suspensions.
  • compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquidfilled capsules.
  • the resultant mixture was then cooled, stirred for 30 minutes, warmed to room temperature and stirred for an additional 30 minutes, after which time it was diluted with ether, and washed successively with 3N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over sodium sulfate, the solvent was removed and the resultant residue was chromatographed on silica gel employing ethyl acetate as the eluent to yield the desired compound as a clear oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP85904111A 1984-08-23 1985-08-20 Cyclimmonium salts Withdrawn EP0195016A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US64383784A 1984-08-23 1984-08-23
US643837 1984-08-23
US67257784A 1984-11-16 1984-11-16
US672577 1984-11-16
US71084785A 1985-03-12 1985-03-12
US710847 1985-03-12

Publications (1)

Publication Number Publication Date
EP0195016A1 true EP0195016A1 (en) 1986-09-24

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EP85904111A Withdrawn EP0195016A1 (en) 1984-08-23 1985-08-20 Cyclimmonium salts

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EP (1) EP0195016A1 (enrdf_load_stackoverflow)
AU (1) AU4727085A (enrdf_load_stackoverflow)
ES (1) ES546350A1 (enrdf_load_stackoverflow)
GR (1) GR852036B (enrdf_load_stackoverflow)
IL (1) IL76166A0 (enrdf_load_stackoverflow)
PT (1) PT80999B (enrdf_load_stackoverflow)
WO (1) WO1986001507A1 (enrdf_load_stackoverflow)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0304244A3 (en) * 1987-08-18 1990-01-10 Takeda Chemical Industries, Ltd. Propanediol derivatives, their production and use
ES2013834A6 (es) * 1989-01-30 1990-06-01 Uriach & Cia Sa J Procedimiento para la obtencion de derivados 4-sustituidos de 2-alcoxitetrahidrofurano.
ES2010145A6 (es) * 1989-03-02 1989-10-16 Uriach & Cia Sa J Procedimiento para la obtencion de derivados de la 2-picolilamina.
US5128351A (en) * 1990-05-04 1992-07-07 American Cyanamid Company Bis-aryl amide and urea antagonists of platelet activating factor
ES2062943B1 (es) * 1993-03-23 1995-11-16 Uriach & Cia Sa J Nuevos derivados de la (2-metil-3-piridil) cianometilpiperazinas.
CN110041291B (zh) * 2018-01-15 2021-02-26 北京采瑞医药科技研究院有限公司 一种玛咖酰胺衍生物及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH375838A (de) * 1958-10-21 1964-03-15 Ruson Lab Inc Verfahren zur Herstellung von Komplexverbindungen aus quaternären Acyloxyäthylaminocarbonylmethylaminsalzen und Jod
GB1030372A (en) * 1963-03-19 1966-05-25 Wander S A A Vasodilators comprising nicotinoyl derivatives
US3998815A (en) * 1974-06-24 1976-12-21 Interx Research Corporation 1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts
EP0094586A3 (en) * 1982-05-13 1984-06-06 Ono Pharmaceutical Co., Ltd. Glycerol derivatives, process for preparing same and pharmaceutical composition containing same
JPS5988447A (ja) * 1982-11-11 1984-05-22 Ono Pharmaceut Co Ltd グリセリン誘導体、その製造方法及びその誘導体を含有する薬剤
DK160818C (da) * 1983-12-30 1991-10-07 Hoffmann La Roche N-ring-holdige glycerolderivater, fremgangsmaade til fremstilling deraf, anvendelse deraf til fremstilling af et blodpladeaktiveringsfaktorhaemmende middel samt laegemidler indeholdende en saadan forbindelse

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8601507A1 *

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AU4727085A (en) 1986-03-24
WO1986001507A1 (en) 1986-03-13
ES546350A1 (es) 1986-04-16
IL76166A0 (en) 1985-12-31
GR852036B (enrdf_load_stackoverflow) 1985-12-18
PT80999A (en) 1985-09-01
PT80999B (en) 1987-06-26

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