WO1986001507A1 - Sels cyclimmoniques - Google Patents

Sels cyclimmoniques Download PDF

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Publication number
WO1986001507A1
WO1986001507A1 PCT/EP1985/000426 EP8500426W WO8601507A1 WO 1986001507 A1 WO1986001507 A1 WO 1986001507A1 EP 8500426 W EP8500426 W EP 8500426W WO 8601507 A1 WO8601507 A1 WO 8601507A1
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alkyl
compound
alkynyl
alkenylene
alkenyl
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PCT/EP1985/000426
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English (en)
Inventor
Robert C. Anderson
Mark L. Lee
John C. Tomesch
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Sandoz Ag
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    • 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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composés de formule (I) dans laquelle Q est C1-24alcoyle, C2-24alkényle ou alkynyle, C12-24alkoxy-alcoyle, phényle ou C7-9phénylalcoyle; A est CH2, O, S ou un groupe W dans lequel W est égal à (II), D est C2-8alkénylène, CH2, O, S ou un groupe W comme défini sous A, A et D ne pouvant pas être en même temps un groupe W; E et B sont indépendamment C1-8alkylène; ou C2-8alkénylène ou alkynylène; NG$(1,5)$représente une chaîne fermée monocyclique à 5 ou 6 membres contenant un hétéroatome supplémentaire sélectionné soit de l'azote ou du soufre; une chaîne fermée bicyclique à 10 membres contenant facultativement un atome d'azote supplémentaire; chacune de ces chaînes pouvant être non-substituée ou mono-, di-, ou tri-substituée par C1-4alcoyle ou mono-substituée par CF3, COOH ou COOH3; R1 et R2 sont indépendamment hydrogène, C1-4alcoyle, C2-4alkényle ou alkynyle, C1-3alkoxy, C3-4alkényloxy ou alkynyloxy, phényle, phénoxy, C2-4alkoxyalcoyle ou C2-4alkoxyalkoxy; R3 est de l'hydrogène ou forme avec l'atome d'azote auquel il est attaché une chaîne fermée hétérocyclique à 5 ou 6 membres contenant facultativement un ou deux hétéroatomes supplémentaires sélectionnés entre l'azote, l'oxygène et le soufre; X et Z sont indépendamment égaux à 0 ou 1; y est égal à 0, 1 ou 2; et Z- est un anion pharmaceutiquement acceptable, à la condition générale que lorsque Q est alcoyle, alkényle, alkynyle, phényle ou phénalcoyle, au moins un élément parmi A, B, D et E ne soit pas alkylène, alkénylène ou alkynylène. L'invention concerne également leur préparation à des fins pharmaceutiques.
PCT/EP1985/000426 1984-08-23 1985-08-20 Sels cyclimmoniques WO1986001507A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US64383784A 1984-08-23 1984-08-23
US643,837 1984-08-23
US67257784A 1984-11-16 1984-11-16
US71084785A 1985-03-12 1985-03-12
US710,847 1985-03-12
US672,577 1991-03-20

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WO1986001507A1 true WO1986001507A1 (fr) 1986-03-13

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

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0304244A2 (fr) * 1987-08-18 1989-02-22 Takeda Chemical Industries, Ltd. Dérivés de propanediol leur production et utilisation
US4980362A (en) * 1989-01-30 1990-12-25 J. Uriach & Cia. S.A. 4-substituted-2-alkoxytetrahydrofuran derivatives
EP0458037A1 (fr) * 1990-05-04 1991-11-27 American Cyanamid Company Bis-aryl-amides et urées à action antagoniste du facteur d'activation des plaquettes
US5134151A (en) * 1989-03-02 1992-07-28 J. Uriach & Cia 2-picolylamine derivatives
US5420131A (en) * 1993-03-23 1995-05-30 J. Uriach & Cia, S.A. Cyanomethylpyridine derivatives
CN110041291A (zh) * 2018-01-15 2019-07-23 北京采瑞医药科技研究院有限公司 一种新型玛咖酰胺衍生物及其制备方法

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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
FR2276289A1 (fr) * 1974-06-24 1976-01-23 Inter Research Corp Sels d'ammonium quaternaires
EP0094586A2 (fr) * 1982-05-13 1983-11-23 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109255A2 (fr) * 1982-11-11 1984-05-23 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0147768A2 (fr) * 1983-12-30 1985-07-10 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés du glycérol

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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
FR2276289A1 (fr) * 1974-06-24 1976-01-23 Inter Research Corp Sels d'ammonium quaternaires
EP0094586A2 (fr) * 1982-05-13 1983-11-23 Ono Pharmaceutical Co., Ltd. Dérivés de glycérol, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0109255A2 (fr) * 1982-11-11 1984-05-23 Ono Pharmaceutical Co., Ltd. Dérivés du glycérol
EP0147768A2 (fr) * 1983-12-30 1985-07-10 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés du glycérol

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Tetrahedron Letters, Volume 24, Nr. 27, 1983, Pergamon Press, Oxford, (GB) R.C. ANDERSON et al.: "Synthesis of a Novel Platelet Activating Factor Congener from Diacetane Glucose", see pages 2741-2744 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0304244A2 (fr) * 1987-08-18 1989-02-22 Takeda Chemical Industries, Ltd. Dérivés de propanediol leur production et utilisation
EP0304244A3 (fr) * 1987-08-18 1990-01-10 Takeda Chemical Industries, Ltd. Dérivés de propanediol leur production et utilisation
US4980362A (en) * 1989-01-30 1990-12-25 J. Uriach & Cia. S.A. 4-substituted-2-alkoxytetrahydrofuran derivatives
US5134151A (en) * 1989-03-02 1992-07-28 J. Uriach & Cia 2-picolylamine derivatives
EP0458037A1 (fr) * 1990-05-04 1991-11-27 American Cyanamid Company Bis-aryl-amides et urées à action antagoniste du facteur d'activation des plaquettes
AU639325B2 (en) * 1990-05-04 1993-07-22 American Cyanamid Company Bis-aryl amide and urea antagonists of platelet activating factor
US5420131A (en) * 1993-03-23 1995-05-30 J. Uriach & Cia, S.A. Cyanomethylpyridine derivatives
CN110041291A (zh) * 2018-01-15 2019-07-23 北京采瑞医药科技研究院有限公司 一种新型玛咖酰胺衍生物及其制备方法

Also Published As

Publication number Publication date
EP0195016A1 (fr) 1986-09-24
PT80999B (en) 1987-06-26
PT80999A (en) 1985-09-01
AU4727085A (en) 1986-03-24
IL76166A0 (en) 1985-12-31
GR852036B (fr) 1985-12-18
ES546350A1 (es) 1986-04-16

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