EP0195016A1 - Cyclimmonium salts - Google Patents

Cyclimmonium salts

Info

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Withdrawn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)
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
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Withdrawn legal-status Critical Current

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    • 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.Compounds of formula (I) in which Q is C1-24alkyl, C2-24alkenyl or alkynyl, C12-24alkoxy-alkyl, phenyl or C7-9phenylalkyl; A is CH2, O, S or a group W in which W is equal to (II), D is C2-8alkenylene, CH2, O, S or a group W as defined under A, A and D which cannot be at the same time a group W; E and B are independently C1-8alkylene; or C2-8alkenylene or alkynylene; NG$(1,5)$ represents a 5 or 6 membered monocyclic closed chain containing an additional heteroatom selected from either nitrogen or sulfur; a 10-membered bicyclic closed chain optionally containing an additional nitrogen atom; each of these chains possibly being unsubstituted or mono-, di-, or tri-substituted by C1-4alkyl or mono-substituted by CF3, COOH or COOH3; R1 and R2 are independently hydrogen, C1-4alkyl, C2-4alkenyl or alkynyl, C1-3alkoxy, C3-4alkenyloxy or alkynyloxy, phenyl, phenoxy, C2-4alkoxyalkyl or C2-4alkoxyalkoxy; R3 is hydrogen or together with the nitrogen atom to which it is attached forms a 5- or 6-membered heterocyclic closed chain optionally containing one or two additional heteroatoms selected from nitrogen, oxygen and sulfur; 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 phenalalkyl, at least one of A, B, D and E is not alkylene, alkenylene or alkynylene. The invention also relates to their preparation for pharmaceutical purposes.

Description

CYCLIMMONIUM SALTS
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. Their participation in these processes involved the release of platelet activating factor (PAF) which in turn interacts with the platelets, inducing aggregation and secretion of granular constituents. As a further consequence of platelet activation, there may result a fatal reaction consisting of acute pulmonary hypertension, right heart dilation, systemic hypotension, significant increases in pulmonary vascular resistance, decrease in dynamic lung compliance and often complete pulmonary apnea.
More recently, evidence has been obtained which appears to implicate platelet activating factor in the formation of fibromuscular lesions of the arterial walls of the aorta and coronary arteries, thereby contributing to the development of atherosclerosis. More particularly the invention concerns compounds of formula I wherein Q is C1_24alkyl, C2_24alkenyl or alkynyl, C12-24alkoxyalkyl, phenyl or C7-9phenylalkyl; A is CH2, O, S or a group W whereby W is
3
D is C2-8alkenylene, CH2, 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 C1-8alkylene; or C2-8alkenylene 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 C1-4alkyl or mono-substituted by CF-, COOH or COOCH3; R1 and R2 are, independently, hydrogen, C1-4alkyl, C2 alkenyl or alkynyl, C1-3alkoxy, C3-4alkenyloxy or alkynyloxy, phenyl, phenoxy, C2-4alkoxyalkyl or
C2-7-alkoxyalkoxy;
R3 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 θ 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.
As will be clear to one skilled in the art and as is eviden from the process description hereinafter a) the point of attachment of groups W to the adjacent groups
Q or (E)z within the formula I will be as follows (↑)
' b) when forming a ring acts as a bridge i.e. the fixed nitrogen atom will attach to C and one of the remainin ring members to the rest of the molecule.
In the definition of Q above: 1) 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 CH2, O, S, ji £ where R3 is as defined above, more preferably CH2, , O, S, where R3 is as defined above, especially CH2, O, , where R 3 is hydrogen or with N a 5- or 6-membered R3 saturated heterocyclic ring.
When x is 1, 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.
When z is 1, 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. 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 C1-4alkyl or monosubstituted by CF3, COOH or COOCH3.
R1 and R2, independently, are preferably hydrogen, C1-4alkyl/ C2-4alkenyl or alkynyl, C1-3alkoxy or C2-4alkoxyalkyloxy. More preferably, R1 and R2 independently are hydrogen, C1-4alkyl, C1-3alkoxy or C2-4alkoxyalkoxy. R1 and R2 are especially hydrogen, C1-4alkyl or C1-3alkoxy.
R3 is preferably R 3 as defined above.
The anion ZΘ is preferably chloride, bromide, iodide, phenyrsulfonate, toluenesulfonate, C1-4alkyl sulfonate, carboxylate or tetrafluoroborate. More preferably, ZΘ is chloride, bromide, C1-4alkylsulfonate or carboxylate.
Examples of preferred compounds of formula I are for example those a) wherein Q is C6-24 alkyl, C2-12alkenyl or alkynyl, C12-20- alkoxyalkyl or benzyl, J i
RR
E is C2-6alkylene, alkenylene or alkynylene, is a thiazolium, pyridinium, pyridazinium, quinolinium or isoquinolinium ring which is unsubstituted or either mono-, di- or trisubstituted by C1-4alkyl or monosubstituted by CF3, COOH or COOCH3,
R1 and R2 are independently hydrogen, C1-4alkyl, C2-4- alkenyl or alkynyl, C1-3alkoxy or C2-4alkoxyalkox ZΘ is chloride, bromide, iodide, phenylsulfonate, toluenesulfonate, C1-4alkylsulfonate, carboxylate or tetrafluoroborate and the remaining substituents are as defined above (compounds la) ;
b) wherein Q is C8 -22alkyl, C2-6 balkenyl or alkynyl, C1 2 -18alkoxyalkyl or benzyl O O
J
E is C3-5alkylene, alkenylene or alkynylene, is a thiazolinium, pyridinium or quinolinium ring which is unsubstituted or either mono-, di- or trisubstituted by C1-4 alkyl or monosubstituted by CF3, COOH or COOCH3, R1 and R2 are independently hydrogen, C1-4alkyl,
C1-3alkoxy, C2-4alkoxyalkoxy, ZΘ is chloride, bromide, C1-4alkyl sulfonate or carboxylate and the remaining substituents are as defined above (compounds lb);
c) wherein Q is C12-20alkyl, C3-5alkenyl or alkynyl, C12-18alkoxyalkyl or benzyl.
A is CH2, O,
B is C1- 2 alkylene or C3 - 5 alkenylene or O alkynyl gene , D is C 3-5 alkenylene , CH2 , O,
E is C4alkylene, alkenylene or alkynylene,
R1 and R2 are independently hydrogen, C1-4alkyl or
C1-3alkoxy, and ZΘare as defined for compounds lb and the remaining substituents are as defined above (compounds Ic), d) is a ring of formula
wherein R is hydrogen, C1-4alkyl, CF3, COOH or COOCH3 and R4 and R5 are independently hydrogen, C1-4alkyl or one thereof is hydrogen and the other is CF3 and the remaining substituents are as defined above
(compounds P1),
e) compounds P1 wherein represents a group of formula (i) as defined therein (compounds P2), f) compounds of formula I as defined above with the exception that R1 and R2 do not represent C2-4alkoxyalkoxy (compounds p3) The definitions in the above mentioned compound groups are subject to the provisos given for formula I.
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°. According to the nature of it may be employed as both reactant and solvent (e.g. when pyridine).
The starting material of formula H may be prepared accordin to or analogously to the reactions shown in the following schemes.
LEGEND FOR REACTION SCHEMES
R
Rk = - Bn = Benzyl
X = Cl, Br, I, phenylsulfonate or toluenesulfonate
X' = Cl, Br, T X" = Br, I
M = alkali or alkaline earth metal M' = alkali metal
Ar = aryl
D' = O or CH2 R5 = C1-3alkyl, C3-4alkenyl or alkynyl or C2-4alkoxyalkyl
In the formulae II, Ila, llb, lle, lld and III the symbols in Rk have the meanings given for formula I unless otherwise stated.
Examples of conditions for the processes in the reaction schemes are given by way of illustration in the following tables or in the examples hereinafter.
ABREVIATIONS lO = inert organic
HC = hydrocarbon HalHC = halogenated hydrocarbon
THF = tetrahydrofuran
PA = polar aprotic
DMF = dimethylformamide
DMSO = dimethylsulfoxide DMA = dimethylacetamide
Intermediates containing substituents other than those described in the reaction schemes may be prepared analogously thereto or are either known or may be prepared analogously to known methods. Starting materials set forth above are either known and/or may be obtained analogously to known methods in conventional manner.
Final products and intermediates may be isolated and purified in conventional manner. Intermediates, where appropriat may be employed directly in the following step without purification.
When in formula I R1 ≠ R2 the carbon atom to which these substituents are attached is optically active. These compounds may thus exist in racemic or enantiomeric form and the invention is intended to cover all forms.
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:
Human subjects are kept aspirin free for one week and fasted overnight. Platelet rich plasma (PRP) 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 μl 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). 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 μM. Between one and two minutes after the addition of the test compound, 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 μM or 0.01 μM). 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 μM are evaluated at lower concentrations to generate an IC50 (50% inhibitory concentration) value.
Moreover, it has been found that the compounds of formula I are useful as platelet activating factor receptor antagonists as indicated by their ability to inhibit specific binding of [3H]-PAF to platelets according to the Human Platelet PAF Receptor Assay test (Test A) as follows:
Human blood is obtained by venipuncture of healthy, human donors into an anti-coagulant mixture containing 3.15% of trisodium citrate and 20 μg/ml of Prostaglandin I (PGI2) in a ratio of blood to anti-coagulant of 9:1. 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 PGI2 at a final concentration of 0.3 μg/ml. The platelets are resuspended at 350,000 μl in TT/BSA containing 1.4 mM CaCl2.2H2O and 0.7 mM MgCl2.6H2O. 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 μM. For each determination, the following solutions are mixed 500 μl of the above-described platelets; 10 μl of [3H]-PAF (40,000 counts per minute (cpm) to a final concentration of 1.5 uM); and either
10 μl of the test compound at 50x the desired final concentration, 10 μl of vehicle (total bound), or
10 μl of 1.85 x 10-5M cold PAF ( non-specifically bound). Each mixture is allowed to incubate at room temperature for one hour, after which time the reaction is terminated by the addition of 500 μl of ice cold TT/BSA and centrifugation (900 x g.) at 4°C) for 10 minutes. The resultant supernatant is aspirated into scintillation vials and the pellet is washed with 250 ml of ice cold TT/BSA and centrifuged (900 x g) at 4°C for 10 minutes. 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 μl 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 [3H]-PAF and non-specifically bound [3H]-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 IC50 (50% inhibitor concentration) value is generated by evaluating the test compound over the full concentration range.
Furthermore, in view of their usefulness as PAF receptor antagonists, the compounds of formula I have been found useful as inhibitors of PAF-mediated bronchoconstriction, which property was evaluated by the PAF-induced Pulmonary Inflation Pressure (PIP) Increase test (Test B) as follows:
Male guinea pigs, weighing between 300 and 400 gm, are anesthetized, after which time trachea tube, carotid and jugular catheters are inserted. The test animal is then force ventilated employing a small animal Harvard respirator and the resistance to lung inflation (PIP) is measured utilizing a pressure transducer and recorder. The test compound is administered either orally at 30 minutes prior to or intravenously (jugular) at 5 minutes prior to the introduction of PAF. The PAF (C18-Sandoz, Hanover) is dissolved in Tris-Tyrode' s bovine serum albumin buffer and 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. Still further, 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:
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
(C 18-Sandoz, Hanover) is dissolved in Tris-Tyrode' s bovine serum albumin buffer and administered intravenously (jugular) at 100 ng/kg.
To determine the 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, 'blood samples are collected in 50 μl heparinized hematocrit tubes. These samples are taken just prior to the injection of PAF, one minute subsequent to the injection of PAF and every two minutes thereafter until 15 minutes has lapsed subsequent to the injection of PAF. 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.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquidfilled capsules.
Such compositions also form part of the invention. The following Examples, in which all temperatures are in °C illustrate the invention. EXAMPLE 1
3-[4-(octadecyloxy)butyl] thiazolium iodide (cmpd. no. 1) (Q=n-ClgH37, A=0, Rk=(CH2)4, ZΘ = IΘ, = thiazolium) a) Preparation of [ 4-(octadecyloxy)butoxy] methyl benzene A mixture of 7.0 g of octadecylbromide and 2.7 g of 4-benzyloxy-1-butanol in 20 ml of 50% sodium hydroxide containing 0.5g of tetra-n-butylammonium sulfate was heated at 70°C for 20 hours, after which time it was cooled and diluted with diethyl ether. The ethereal extract was then washed with water, dried over sodium sulfate and evaporated to yield the desired compound. b) Preparation of 4-octadecyloxy-1-butanol
A solution of 8.2 g of the compound prepared in a) above in tetrahydrofuran was hydrogenated under an atmosphere of hydrogen with 5% palladium on carbon. The resultant mixture was then filtered through Celite and evaporated to yield the desired compound. c) Preparation of 4-iodobutoxyoctadecane
To a mixture of 1.0g of the compound prepared in b) above, 1.07g of triphenylphosphine, 0.56g of imidazole and toluene was added 1.04g of iodine. The resultant mixture was stirred at room temperature for 1 hour and then diluted with pentane and filtered. After the solvents were evaporated, pentane was added and the resultant mixture was filtered. The pentane was then removed and the residue was filtered through silica gel using a mixture of 10% ethyl acetate in petroleum ether as the eluent. Evaporation of the solvents yielded the desired product. d) Preparation of the title compound
To a solution of 4-iodobutoxyoctadecane in 5ml of toluene was added 2.0g of thiazole. The reaction mixture was heated at 60° for 3 days, after which time it was cooled and diluted with diethyl ether. The resultant mixture was then filtered and the precipitate washed with ether. The residue was recrystallized from methylene chloride to yield the title compound, m.p. 90° (dec.). The following compounds were prepared analogously from appropriate starting materials and intermediates. Cmpd. No.
2 3-[ 4-(decylocy)butyl] thiazolium iodide, m.p. 64°-66° (dec.)
3 3-[ 4-(hexyloxy)butyl] thiazolium iodide, oil
4 3-[ 4-(dodecyloxy)butyl] thiazolium iodide, m.p. 75°-77° (dec.)
5 3-[ 4-(hexadecyloxy)butyl] thiazolium iodide, m.p. 87°-90° (dec.)
6 3-[ 4-(eicosanyloxy)butyl] thiazolium iodide, m.p. 94°-97° (dec.)
7 3-[ 4-(octadecyloxy)butyl] thiazolium bromide, m.p. 83°-86° (dec.) 8 3-[ 4-(tetradecyloxy)butyl] thiazolium iodide, m.p. 80°-82° (dec.)
9 3-[ 4-(octyloxy)butyl] thiazolium iodide, wax
10 3-[ 4-(docosanyloxy)butyl] thiazolium iodide, m.p. 95°-97° (dec.) 11 3-[ 5-(octadecyloxy)ρentyl] thiazolium iodide, m.p. 78°-80° (dec.)
12 3-[ 6-(octadecyloxy)hexyl] thiazolium iodide, m.p. 73°-75° (dec.)
13 3-[ 2-eicosanyloxy)ethyl] thiazolium iodide, m.p. 101°-104° (dec.)
14 3-[3-(octadecyloxy)ρropyl] thiazolium iodide, m.p..92°-96° (dec.)
15 3-[ 4-(butyloxy)butyl] thiazolium iodide, oil
16 3-[ 4-(ethyloxy)butyl] thiazolium iodide, oil. EXAMPLE 2
3-[4-[(3-octadecyloxy)propoxy] butyl] thiazolium iodide (cmpd.no.17) a) Preparation of tetrahydro-2-[ 3-[ 4-(phenylmethoxy)butoxy]propoxy]-2H-pyran Analogous to Example la) using tetrahydro-2-( 4-bromobutyloxy)-2H-pyran. b) Preparation of 3-[(4-phenylmethoxy)butoxy]-1-propanol
A solution containing 1.0 g of the compound prepared in a) above in 10 ml of tetrahydrofuran to which was added 10 ml of 10% hydrochloric acid was allowed to react at room temperature for 72 hours. The resultant mixture was diluted with ether, washed successively with water and saturated sodium bicarbonate, dried over sodium sulfate and evaporated to dryness to yield the desired compound as a clear oil.
The reaction was then continued analogously to Example la)-d) to yield the title compound m.p. 69° (dec). EXAMPLE 3
3- [4-[( 3-octadecylaminocarbonyloxy)propoxy] butyl] thiazolium iodide (cmpd. no. 18) a) Preparation of N-octadecylcarbamic acid, 3-[ 4-phenylrnethoxy) butoxy ]propyl ester To a solution of 1.0g of 3-[( 4-phenylmethoxy) butoxy]-1-propanol in 10 ml of dry pyridine was added 1.6 ml of octadecylisocyanate. The reaction mixture was heated at 60° for 7 hours, after which time the solvents were evaporated. The residue was then diluted with ether, washed successively with 3N hydrochloric acid, saturated sodium bicarbonate and brine, and then dried over sodium sulfate. The solvent was then removed and the resultant residue was chromatographed on silica gel employing 20% ethyl acetate in petroleum ether as the eluent to yield the desired compound.
The reaction was then continued analogously to Example lb)-d) to yield the title compound m.p. 80° (dec). EXAMPLE 4
3-[ 4-[(3-hexadecyloxy-2-methoxy)propoxy] butyl] thiazolium iodide (compound no. 19) a) Preparation of 6-methoxy-3, 3-dimethyl-14-phenyl-2, 4, 8,13tetraoxadecane
To a suspension of 7.5 g of sodium' hydride in 200 ml of dry dimethylformamide at 80° was slowly added 20 g of 1-benzyloxy4-butanol. After hydrogen evolution had ceased, 15 g of (1-methoxy-1-methylethoxy) methyl oxirane was added and the resultant mixture was allowed to react at 80° for 2 hours, after which time it was cooled. To the cooled mixture was added 12.5 ml of methyl iodide and the mixture was then allowed to react for 30 minutes, after which time it was diluted with water and extracted with ethyl acetate. The organic fraction was dried over sodium sulfate, evaporated and the resultant residue was chromatographed on silica gel employing a 1:1 mixture of t-butylmethyl ether and hexane as the eluent to yield the desired compound. b) Preparation of 2-methoxy-3-[( 4-phenylmethoxy)butoxy]1-proρanol A solution of 10 g of the compound prepared in a) above in 200 ml of 10% aqueous tetrahydrofuran containing 0.1 g of p-toluenesulfonate was heated at reflux for 2 hours. The mixture was then cooled, diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine, and dried over sodium sulfate. Upon evaporation of the solvents, the desired compound was obtained.
The reaction was then continued analogously to Example la)-d) to yield the title compound m.p. 43-44° (dec). EXAMPLE 5 3-[ 4-[(3-octadecylaminocarbonyloxy-2-methoxy)propoxy]butyl]thiazolium iodide (compound no. 20)
Starting from 2-methoxy-3-[(4-phenylmethoxy)butoxy]-1-propanol (cf. Ex. 4b) and proceeding analogously to Examples 3a and Ib)-d) the title compound was obtained m.p. 58-60° (dec). EXAMPLE 6
3-[2-[1-(1-oxohexadecyl)-4-piperidinyl] ethyl]-thiazolium iodide (compound no. 21) a) Preparation of 1-( 1-oxohexadecyl)-4-piperidineethanol To a chilled solution (0°C) of 5.0g of 4-( 2-hydroxyethyl)piperidine and 11 ml of triethylamine in 100 ml of methylene chloride was slowly added 11 g of palmitoyl chloride. 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.
The reaction was then continued analogously to Example lc), d) to yield the title product m.p. 102-105° (dec). EXAMPLE 7 3- [2-[(3-octadecyloxy)-propyloxycarbamoyl]-ethyl] thiazolium iodide (compound no. 22) a) Preparation of 3-octadecyloxy-1-propanol
To a mixture of 14 g (0.25 mol) of powdered potassium hydroxide in 80 ml of a 1:1 solution of tetrahydrofuran and dimethylsulfoxide, was added 15 ml (0.20 mol) of 1, 3-propanediol To the resultant mixture was added, with stirring, 22 g (0.066 mol) of 1-bromooctadecane . After being allowed to react at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The combined extracts were then washed successively with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride and dried over magnesium sulfate. The solvent was then removed in vacuo to afford an oil which solidified on standing. The crude product was then recrystallized from cold petroleum ether to yield a white solid. b) Preparation of N-(2-chloroethyl)-(3-octadecyloxy-1-propyl)carbamate
A solution of 1.26 g (0.005 mol) of the compound prepared in a) above in 15 ml of pyridine was treated with 0.43 ml (0.005 mol) of 2-chloroethyl isocyanate and the resultant mixture was then reacted for 10 hours under a nitrogen atmosphere at 60°. The pyridine was then removed under reduced pressure and the residue was partitioned in a mixture of 2N hydrochloric acid and ether. The ethereal layer was then washed successively with saturated sodium bicarbonate and saturated sodium chloride and dried over magnesium sulfate. The solvent was removed in vacuo and the crude solid was recrystallized from ether to afford a white solid. c) Preparation of N-(2-iodoethyl)-( 3-octadecyloxy-l-propyl)carbamate
0.0019 mol of the compound prepared in b) above was dissolved in 20 ml of acetone and the resultant solution was heated at reflux with 0.425 g (0.0029 mol) of sodium iodide under a nitrogen atmosphere for 20 hours. After the solvent was removed in vacuo, the residue was partitioned in a mixture of ether and water. The ethereal layer was then washed with saturated sodium chloride, dried over magnesium sulfate and the solvent removed to yield a solid. d) Preparation of the title compound 0.388 g (0.00075 mol) of N—( 2-iodoethyl)-(3-octadecyloxy-1propyl)-carbamate, 2 ml of acetonitrile and 0.250 g (0.003 mol) of thiazole were heated in a sealed tube at 85° for 20 hours. Upon cooling to room temperature, the solid was removed by filtration and recrystallized from methanol to yield a white solid, m.p. 88°-89°. EXAMPLE 8
3-[2-[( 3-octadecyloxy)-propylaminocarbonyl]-ethyl] thiazolium iodide (compound no. 23) a) Preparation of 3-octadecyloxy-1-propanol-p-toluenesulfonic acid ester 7.86 g (0.030 mol) of the compound prepared in Example 7a) was dissolved in 80 ml of dichloromethane and 9..5 g of pyridine. To this solution was added, portionwise, 6.3 g (0.033 mol) of p-toluenesulfonyl chloride and the resultant mixture was stirred at room temperature for 8 hours. 500 ml of ethyl acetate was then added and the mixture was then extracted with 2N hydrochloric acid. The organic layer was then washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, after which time the solvent was removed in vacuo. The crude product was then chromatographed on silica gel employing, as the eluent, a mixture of petroleum ether and methyl-t-butyl ether in a ratio of 9:1 to yield a low melting solid. b) Preparation of 3-azidopropyl octadecyl ether
0.0122 mol of the compound prepared in a) above was dissolved in 45 ml of dimethylformamide. To this solution was added 0.877g (0.0135 mol) of sodium azide and the resultant mixture was heated at 85° for four hours, after which time it was allowed to cool to room temperature. After 16 hours at room temperature, 500ml of ether was added. This mixture was then washed successively with water and saturated sodium chloride, after which time the ethereal layer was dried over magnesium sulfate. Removal of the solvent in vacuo yielded the desired compound as an oil. c) Preparation of 3-aminopropyloctadecyl ether
To a mixture of 0.822 g (0.0216 mol) of lithium aluminum hydride in 10 ml of ether, was added, over a period of 15 minutes (0.01083 mol) of the compound prepared in b) above in 30 ml of diethyl ether. The resultant mixture was then allowed to react at room temperature, under a nitrogen atmosphere, for 2 hours, after which time it was quenched with aqueous sodium hydroxide. The mixture was then filtered and the filtrate concentrated in vacuo to yield the desired compound as an oil. d) Preparation of N-(3-octadecyloxypropyl)-3-chloropropionamide 0.522 g of the compound prepared in c) above was dissolved in 5 ml of tetrahydrofuran containing 0.43 ml (0.0025 ml) of N,N-diisopropyl ethyl amine. To this mixture was added 0.317 g (0.0025 mol) of 3-chloropropionyl chloride and the resultant mixture was stirred at room temperature, under nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue was partitioned in a mixture of ether and water. The organic layer was then washed successively with 2N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride, and dried over magnesium sulfate. The solvent was then removed and the crude product was recrystallized from a mixture of ether and methylene chloride as the eluent to yield the desired compound as an off-white solid. The reaction was then continued analogously to 7c) (acetonitrile replacing acetone) and 7d) to yield the title compound m.p. 65-66°. EXAMPLE 9
3-[3-[( 3-octadecyloxy)-propylaminosulfonyl]-propyl] thiazolium iodide (compound no. 24)
The compound was prepared analogously to Example 8d) onwards employing 3-chloropropylsulfonylchloride in place of 3-chloropropionylchloride. The product is obtained as a solid. EXAMPLE 10 4-[(3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl pyridinium bromide (compound no. 25) a) Preparation of [ 3-( 4-bromobutoxy)-2-methoxypropoxy] octadecyl carbamate To a stirred mixture of 0.84 g of triphenylphosphine dibromide in 30 ml of dry acetonitrile was added dropwise over a period of five minutes, 1.0 g of 4-[(3-octadecylaminocarbonyloxy)-2-methoxypropoxy]-1-butanol (cf. Ex.5) in 2.6 ml of dry acetonitrile containing 0.2 g of pyridine. The resultant mixture was stirred for five minutes at room tempera ture, heated to reflux for one minute and permitted to cool for ten minutes. The mixture was then further cooled in an icewater bath, filtered and the filtrate diluted with petroleum ether.
The mixture was again filtered and, after evaporation of the solvents, the resultant residue was filtered through silica gel employing a mixture of 30% methyl t_-butyl ether and 70% petroleum ether as the eluent. Upon evaporation of the solvents, the desired product was obtained. b) Preparation of the title compound. A solution of 1.0 g of [3-( 4-bromobutoxy)-2-methoxypropoxy]octadecyl carbamate in 6 ml of dry pyridine was heated at 60° for 20 hours, after which time the volatiles were removed at
15 mm mercury (atmospheric pressure), then at 5 mm mercury. The gummy residue was then recrystallized from a mixture of 10% methylene chloride and 90% diethyl ether. The resultant white solid was chromatographed through silica gel using a mixture of 12% methanol and 88% methylene chloride as the eluent. Upon evaporation of the solvents, the title compound was obtained, m.p. 55°-56° (dec). EXAMPLE 11
Proceeding essentially according to Examples 3a and Ib)-d) the following compounds were obtained
3-[4-[3-phenylaminocarbonyloxy-2-methoxy)propoxy] butyl] thiazolium iodide, oil; (compound no. 26) 3-[4-[3-ethylaminocarbonyloxy-2-methoxy)propoxy] butyl] thiazolium iodide, oil; (compound no. 27).
EXAMPLE 12
4-[(3-octadecylaminocarbonyloxy-2-methoxy)propoxyl butyl pyridinium chloride (compound no. 28) The reaction was carried out analogously to Example 10a) and b) employing the dichloride in place of the dibromide to yield the title compound m.p. 56-57° (dec). EXAMPLE 13
3-carboxy-1-[4-[( 3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl]pyridinium bromide (compound no. 29)
1.08 g of [3-(4-bromobutoxy)-2-methoxypropoxy]octadecylcarbamate (cf. 10a)) was dissolved in 3 ml of dimethyl formamide and to the resultant solution was added 0.250 g of nicotinic acid. The resultant mixture was then heated to 100° and maintained at this temperature, with stirring and under a nitrogen atmosphere, for 20 hours. The resultant light brown solid was chromatographed through silica gel using a mixture of 15 % methanol and 85% methylene chloride as the eluent. Upon evaporation of the solvents, the title compound was obtained, m.p. 54°-55°.
The following compounds were prepared analogously using appropriate heterocycles in place of nicotinic acid. Cmpd. No.
30 4-[( 3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl isoquinolinium bromide, m.p. 50°-51°
31 4-[ (3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl pyridazinium bromide, m.p. 76°-78°
32 4-[( 3-octadecylaminocarbonyloxy-2-methoxy) propoxy ] butyl quinolinium bromide , m.p . 52 ° -53 ° 33 4-[ (3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl pyrazinium bromide, m.p. 55°-56°. EXAMPLE 14
3-carboxymethyl-1-[4-[( 3-octadecylaminocarbonyloxy-2-methoxy)propoxy]butyl]pyridinium bromide (compound no. 34)
A solution of 1g of [3-( 4-bromobutoxy)-2-methoxypropoxy]octadecylcarbamate (cf. 10a)) in 5ml of methyl nicotinate was heated at 60° for 20 hours. The resultant product was then chromatographed through silica gel using a mixture of 10% methanol and 90% methylene chloride as the eluent. Upon evaporation of the solvents, the title compound was obtained, m.p. 49°-50°. The following compound may be prepared analogously: 2,4, 6-trimethyl-1-[4-[(3-octadecylaminocarbonyloxy-2-methoxy)- propoxy] butyl] pyridinium bromide, m.p. 48-50° (compound no. 35)

Claims

1. A compound of formula I
Q-A- (B) ZΘ I wherein Q is C1-24alkyl, C2-24alkenyl or alkynyl, C12-24alkoxyalkyl, phenyl or C7-9phenylalkyl; A is CH2, O, S or a group W whereby W is
D is C2-8alkenylene, CH2, 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 C1-8alkylene; or C2-8alkenylene 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-substituted by C1-4alkyl or mono-substituted by CF3, COOH or COOCH3; R1 and R2 are, independently, hydrogen, C1-4alkyl, C2-4alkenyl or alkynyl, C1-3alkoxy, C3-4alkenyloxy or alkynyloxy, phenyl, phenoxy, C2-4alkoxyalkyl or C2-4-alkoxyalkoxy;
R3 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 ZΘ 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.
2. 3-[4-[(3-octadecylaminocarbonyloxy-2-methoxy)propoxy]butyl] thiazolium iodide.
3. A pharmaceutical composition comprising a compound according to Claim 1 together with a pharmaceutically acceptable diluent or carrier.
4. A compound according to Claim 1 for use in inhibiting PAF induced blood platelet aggregation or treating platelet activating factor mediated bronchoconstriction and extravasation.
5. A process for preparing a compound according to
Claim 1 which comprises reacting a compound of formula C
R2 l with a compound of formula CC
wherein Q,A,B,D,E,G, Z,x,y and z are as defined in Claim 1.
6. A compound according to Claim 1 substantially as hereinbefore described.
EP85904111A 1984-08-23 1985-08-20 Cyclimmonium salts Withdrawn EP0195016A1 (en)

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ES2013834A6 (en) * 1989-01-30 1990-06-01 Uriach & Cia Sa J New 4-substituted 2-alkoxytetrahydrofuran derivatives.
ES2010145A6 (en) * 1989-03-02 1989-10-16 Uriach & Cia Sa J 2-picolylamine derivates.
US5128351A (en) * 1990-05-04 1992-07-07 American Cyanamid Company Bis-aryl amide and urea antagonists of platelet activating factor
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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 (en) * 1982-11-11 1984-05-22 Ono Pharmaceut Co Ltd Glycerol derivative, its production and agent containing said derivative
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