CYCLIMMONIUM SALTS

Abstract: Compounds of formula (I) wherein Q is C1-24 alkyl, C2-24 alkenyl or alkynyl, C12-24 alkoxy-alkyl, phenyl or C7-9 phenylalkyl; A is CH2, O, S or a group W whereby W is formula (II), D is C2-8 alkenylene, 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 C1-8 alkylene; or C2-8 alkenylene or alkynylene; NG <SIGN> 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 C1-4 alkyl or mono-substituted by CF3, COOH or COOCH3; R1 and R2 are, independently, hydrogen, C1-4 alkyl, C2-4 alkenyl or alkynyl, C1-3 alkoxy, C3-4 alkenyloxy or alkynyloxy, phenyl, phenoxy, C2-4 alkoxyalkyl or C2-4-alkoxyalkoxy; R3 is hydrogen or together with the nitrogen atom to which it is attached forms a 5- or 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, and preparation for their use as pharmaceuticals.

Description: CYCLIM ONIUM SALTS The present invention relates to certain cyclimmonium salts and to their use as platelet activating factor (PAF) receptor antagonists and as inhibitors of PAF- induced 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 inhibit¬ ing 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 imπvunologically 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 con- stituents. As a further consequence of platelet activation, there may result a fatal reaction con¬ sisting 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. tar More particularly the invention concerns compounds of formula I Q-A-(B) χ -C-(CH 2 ) y -D-(E) P wherein Q is C 1 _ 24 alkyl, C 2 _ 24 alkenyl or alkynyl, C 12-24 alkOXY" alkyl, phenyl or C_ g phenylalkyl; A is CH-, 0, S or a group whereby is O N-SO„, N-C ? , N-C f , N- ?C-0 , N- fC-0 or 0-C-O , I 2 I I I I H R 3 H H H D is C , 0, S or a group as defined for A, whereby A and D may not simultaneously be a group ; E and B are independently C., -alkylene; or C 2 _ g alkeny- lene or alkynylene; NG 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 5 further nitrogen atom; each of which rings may be unsubstituted or either mono-, di-, or tri-substitute by C. .alkyl or mono-substituted by CF-, COOH or C00C I, and R 2 are, independently, hydrogen, C. .alkyl, C 2 alkenyl or alkynyl, C, alkoxy, C- .alkenyloxy 0 or alkynyloxy, phenyl, phenoxy, C- .alkoxyalkyl or C__.-alkoxyalkoxy; R- is hydrogen or together with the nitrogen atom to which it is attached forms a 5- or 6-membered heterocyclic ^ ring optionally containing 25 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. 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) within the formula I will be as follows (t) z - ϊC-0; b) -N- when forming a ring acts as a bridge i.e. the fixed &3 nitrogen atom will attach to -J- and one of the remainin 6 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 carb atoms and, especially 3 to 5 carbon atoms; 3) alkoxyalkyi is preferably of 12 to 20 carbon atoms, more preferably 12 to 18 carbon atoms; and 4)- phenylalky A i. preferably CH.,, 0, S, where R_ is as defined above, m or N-C-0, where R_ is as defined above, especially CH , 0, N- 0 C or N-C P-0, where R _ is hydrogen or with N a 5- or 6-membere ^ H 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. -4- more CH or 0- ?C-N. 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 C, .alkyl or monosubstituted by CF 3 , C00H or COOCH^. R-. and R_, independently, are preferably hydrogen, C, .alkyl/ C- .alkenyl or alkynyl, C. ..alkoxy or C 2 _.alkoxyalkyloxy. More preferably, R. and R_ independently are hydrogen, C. .alkyl, C,__alkoxy or C 2 _ 4 alkoxyalkoxy. R. and R 2 are especially hydrogen, C, .alkyl or C.^alkoxy. R^ is preferably R , as defined above. The anion Z^ is preferably chloride, bromide, iodide, pheny - sulfonate, toluenesulfonate, C. .alkyl sulfonate, carboxylate or tetrafluoroborate. More preferably, Z is chloride, bromide, C. .alkylsulfonate or carboxylate. Examples of preferred compounds of formula I are for example those a) wherein Q is C g _ 2 .alkyl, C ..alkenyl or alkynyl, c 12 -2 0 ~ alkoxyalkyi or benzyl, A is CH 2 , 0, S, N j ; ?_ 0 or 0 i- 0 , i 3 k B is C .alkylene or C alkenylene or alkynylene, D is C 2 _ 6 alkenylene, CH 2 , 0, S; N N _g Q _Ϊ. N or 0 - 0 ϊ- O , HH 3 HH E is C_ ..alkylene, alkenylene or alkynylene, is a thiazolium, pyridinium, pyridazinium, quinoliniu or isoquinolinium ring which is unsubstituted or either mono-, di- or trisubstituted by C. ,alkyl or monosubstituted by CF , COOH or COOCH , R. and R_ are independently hydrogen, C._ 4 alkyl, C__. alkenyl or alkynyl, C. alkoxy or C alkoxyalkox Z~ is chloride, bromide, iodide, phenylsulfonate, 5 toluenesulfonate, C. alkylsulfonate,carboxylate or tetrafluoroborate and the remaining substituen are as defined above (compounds la) ; b) wherein Q is C O 0 — Δ__Δalkyl, C_ —^ balkenyl or alkynyl, C.λ_ — η o Q alkox alkyl or benzyl, π 0 (1 ϊ A is CH.; 0; S; N-C or N-C-0 B is C, .alkylene or C alkenylene or alkynylene, D is C J — Z ς >alkenylene, CH , 0, S, oorr 0I --CC I--Ni ,, E is C ..alkylene, alkenylene or alkynylene, . ijc lis a thiazolinium, pyridinium or quinolinium ring 5 which is unsubstituted or either mono-, di- or tri substituted by C, . lkyl or monosubstituted by CF_, COOH or COOCH , R and R are independently hydrogen, C-^alkyl, C. alkoxy, C__.alkoxyalkoxy, Z is chloride, bromide, C, 4 alkyl sulfonate or carboxylate and the remaining substituents are as i defined above (compounds lb) ; c) wherein Q is C 12 _ 2Q alkyl, C 3 _ 5 alkenyl or alkynyl, C 12 _ 18 lko alkyl or benzyl. A is CH„, 0, -C if-0, B is C 1, -2 „ alkylene or C 3,-5.. alkenylene or O .alkynyl gene 0 D is C E is C.alkylene, alkenylene or alkynylene, R. and R are independently hydrogen, C, .alkyl or as defined for compounds lb and the remaining substituents are as defined above 5 (compounds Ic) r d) NG__ is a ring of formula wherein R is hydrogen, C ; ,_ alkyl, CF , COOH or COOCH and R and R are independently hydrogen, C, .alkyl or one thereof is hydrogen and the other is C , and 0 the remaining substituents are as defined above (compounds 'Pi), e) compounds Pi wherein NG ^ ) represents a group of formula (i) as defined therein (compounds P2), f) compounds of formula I as defined above with the exception 5 that R and R 2 do not represent C_ alkoxyalkoxy (compounds 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 £. R I 2 Q-A-(B)x-Cj-(CH-2)y-D-(E)z-Z £. 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 Q£m 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 scheme LEGEND FOR REACTION SCHEMES R 12 Rk = -(B) -C-(CH-) -D-(E) - x I Δ y ώ R l Bn = Benzyl X = Cl, Br, I, phenylsulfonate or toluenesulfonate X* = Cl, Br, T X" = Br, I M = alkali or alkaline earth metal ' M 1 = alkali metal Ar = aryl D* = 0 or CH 2 R- = C alkyl, C alkenyl or alkynyl or C 2 _ 4 alkoxyalkyl In the formulae II, Ila, lib, lie, lid 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 10 = inert organic HC = hydrocarbon HalHC = halogenated hydrocarbon THF = tetrahydrofuran PA = polar aprotic DMF = dimethylformamide DMSO = dimethylsulfoxide DMA = dimethylacetamide H REACTION SCHEME I REACTION SCHEME II - 10 - 3 to I > I I 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 purifi¬ cation. When in formula I R. ^ R_ 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 centrifuga- tion (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 PRP- containing 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 aggre¬ gation 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 IC.. (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 [ H]-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 tri- sodium citrate and 20 lg/ml of Prostaglandin I (PGI-) in a rati 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 PGI_ at a final concentration of 0.3 μg/ml. The platelets are resuspended at 350,000 μl in TT/BSA containing 1.4 iM CaCl 2 .2H 0 and 0.7 mM Cl 2< 6H 2 0. 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 mixe 500 μl of the above-described platelets; 10 μl of [ H]-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~ M 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 pi 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 [ H]-PAF and non-specifically bound [ 3 H]-PAF. The percent inhibition of specific binding is determined by dividing the cp 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% 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 propert 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 trans¬ ducer 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 (C. --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 trans- ducer 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 baselin A reading at 15 minutes after the administration of PAF is terme 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 plasm from the lumen of the blood vessels into the vessel wall and surrounding tissues) measured as a function of hemo-concentratio 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 intragastri- cally at one hour prior to the introduction of PAF. The PAF (C 1.0 0 -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 injectio ' n of PAF, one minute subse- quent 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 injec tion 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 hemo- concentration 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 g 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 dosage 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 inhibitin or antagonising platelet activating factor and of treating platelet activating factor mediated bronchoconstriction and extravasation which comprises administering to a subject in nee 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 extravasatio 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 steri injectable solutions or suspensions. The preferred pharmaceutical compositions from the stand- point of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid- 'filled 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-C lg H 37 , A=0, Rk=(CH 2 ) 4 , Z Θ = I®, NcQ = thiazolium) a) Preparation of [ 4-(octadecyloxy)butoxy]methyl benzene 5 A mixture of 7.0 g of octadecylbromide and 2.7 g of 4-benzy- loxy-1-butanol in 20 mi 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 10 sodium sulfate and evaporated to yield the desired compound. b) Preparation of 4-octadecyloxy-l-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 15 then filtered through Celite and evaporated to yield the desired compound. c) Preparation of 4-iodobutoxyoctadecane To a mixture of l.Og of the compound prepared in b) above, 1.07g of triphenylphosphine, 0.56g of imidazole and toluene was 20 added 1.04g of iodine. The resultant mixture was stirred at room temperature for 1 hour and then diluted with pentane and filtere 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 25 of 10% ethyl acetate in petroleum ether as the eluent. Evapora¬ tion 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 30 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-C 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. a) Preparation of tetrahydro-2-[ 3-C 4-(phenylmethoxy)butoxy]- propoxy] -2H-py an Analogous to Example la) using tetrahydro-2-(4-bromobutyl- oxy)-2H-pyran. b) Preparation of 3- C(4-phenylmethoxy)butoxy]-l-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) to yield the title compound m.p. 69° (dec). EXAMPLE 3 3- [4- C( 3-octadecylaminocarbonyloxy)propoxy] butyl] thiazolium iodide (cmpd. no. 18) a) Preparation of N-octadecylcarbamic acid, 3-C 4-phenylrnethoxy) butoxy]propyl ester To a solution ' of l.Og of 3- C(4-phenylmethoxy)butoxy]-1-pro- panol in 10 ml of dry pyridine was added 1.6 ml- of octadecyliso cyanate. 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 hydrochlor acid, saturated sodium bicarbonate and brine, and then dried over sodium sulfate. The solvent was then removed and the resul tant 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) to yield the title compound m.p. 80° (dec). EXAMPLE 4 3-C 4-C (3-hexadecyloxy-2-methoxy)propoxy]butyl] thiazolium iodide (compound no. 19) a) Preparation of 6-methoxy-3,3-dimethyl-14-phenyl-2,4, 8,13- tetraoxadecane 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-benzyloxy- 4-butanol. ' After hydrogen evolution had ceased, 15 g of (1-meth oxy-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 extract with ethyl acetate. The organic fraction was dried over sodium sulfate, evaporated and the resultant residue was chromatograph 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 mixtur was then cooled, diluted with ethyl acetate, washed successivel 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)- to yield the title compound m.p. 43-44° (dec). EXAMPLE 5 3-C 4- C ( 3-octadecylaminocarbonyloxy-2-methoxy)propoxy]butyl]thia zolium iodide (compound no. 20) Starting from 2-methoxy-3-C (4-phenylmethoxy)butoxy]-1-pro- panol (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- [l-(l-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 resul¬ tant 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 succes¬ sively 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-l-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-l-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 andthe 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 dis- - solved 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-l propyl)-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-C2- [( 3-octadecyloxy)-propylaminocarbonyl] -ethyl] thiazolium iodide (compound no. 23) a) Preparation of 3-octadecyloxy-l-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 hydro¬ chloric 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 dis¬ solved in 45 ml of dimethylformamide. To this solution was added 0.877 g (0.0135 mol) of sodium azide and the resultant mixture was heated at 85° for four hours', after which time it was allowe to cool to room temperature. After 16 hours at room temperature, 500ml of ether was added. This mixture was then washed succes¬ sively with water and saturated sodium chloride, after which time the ethereal layer was dried over magnesium sulfate. Remova 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 minute (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-chloropropionami 0.522 g of the compound prepared in c) above was dissolve 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 resultan mixture was stirred at room temperature, under nitrogen atmos phere 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 hydrochlor 0 acid, saturated sodium bicarbonate and saturated sodium chlor and dried over magnesium sulfate. The solvent was then remove and the crude product was recrystallized from a mixture of et and methylene chloride as the eluent to yield the desired com pound as an off-white solid. 5 The reaction was then continued analogously to 7c) (aceto nitrile replacing acetone) and 7d) to yield the title compoun > - m.p. 65-6 ' β°. EXAMPLE 9 3- C3- C(3-octadecyloxy)-propylaminosulfonyl]-propyl]thiazolium 0 iodide. (compound no. 24) The compound was prepared analogously to Example 8d) onwa employing 3-chloropropylsulfonylchloride in place of 3-chloro propionylchloride. The product is obtained as a solid. EXAMPLE 10 5 4-C (3-octadecylaminocarbonyloxy-2 ' -methoxy)propoxy]butyl pyri¬ dinium bromide (compound no. 25) a) Preparation of C 3-(4-bromobutoxy)-2-methoxypropoxy]octadec carbamate To a stirred mixture of 0.84 g of triphenylphosphine 0 dibromide in 30 ml of dry acetonitrile was added dropwise ove a period of five minutes, 1.0 g of 4-[ (3-octadecylaminocarbon oxy)-2-methoxypropoxy]-l-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 temper 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% petrole 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-C4- C3-phenylaminocarbonyloxy-2-methoxy)propoxy] butyl] thiazoli iodide, oil; (compound no. 26) 3-[4- [3-ethylaminocarbonyloxy-2-methoxy)propoxy] butyl] thiazoliu iodide, oil; (compound no. 27). EXAMPLE 12 4- C(3-octadecylaminocarbonyloxy-2-methoxy)propoxyl butyl pyridinium chloride (compound no. 28) The reaction was carried out analogously to Example 10a) and employing the dichloride in place of the dibromide to yield the title compound m.p. 56-57° (dec). EXAMPLE 13 3-carboxy-l- [4- [(3-octadecylaminocarbonyloxy-2-methoxy)propoxy] butyl]pyridinium bromide (compound no. 29) 1.08 g of C3-(4-bromobutoxy)-2-methoxypropoxy]octadecyl- carbamate (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 main¬ tained 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 evapora¬ tion 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- C(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- C (3-octadecylaminocarbonyloxy-2-methoxy)propoxy ] butyl pyrazinium bromide, m.p. 55°-56°. EXAMPLE 14 3-carboxymethyl-l- C4- C(3-octadecylaminocarbonyloxy-2-methoxy)- propoxy]butyl]pyridinium bromide (compound no. 34) A solution of lg 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 evapora¬ tion of the solvents, the title compound was obtained, m.p. 49°-50°. The following compound may be prepared analogously: 2,4,6-trimethyl-l-[4- [(3-octadecylaminocarbonyloxy-2-methoxy)- propoxy]butyl] pyridinium bromide, m.p. 48-50° (compound no. 35)

Claims: . CLAIMS 1. A compound of formula I Q-A- (B) -C- (CH ) -D- ( E) z -NG w h erein Q is C 1 _ 24 al yl, C 2 _ 24 alkenyl or alkynyl, C 12 _ 24 al oxy- alkyl, phenyl or C 7 _ 9 phenylalkyl; A is CH_, 0, S or a group whereby W is 0 S 0 S 0 r, ■■ n » «» N-SO„, N-C , N-C , ' N-C-0 , N-C-0 or O-C-0 , I 2 1 I I ' H H H H D is C, Q alkenylene, CH_, 0, S or a group as defined 2—8 Z for A; whereby A and D may not simultaneously be a group W; E and B are independently C 1 _ g alkylene; or C 2 _ g alkeny- lene or alkynylene; N_G J 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 C, .alkyl or mono-substituted by CF , COOH or COOCH. R. and R- are, independently, hydrogen, C, .alkyl, C__.alkenyl or alkynyl, C._-^alkoxy, C^_ alkenyloxy or alkynyloxy, phenyl, phenoxy, C__ .alkoxyalkyi or C_ -alkoxyalkoxy; R 3 is hydrogen or together with the nitrogen atom to which it is attached forms a 5- or 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. 2. 3-C4-C (3-octadecylaminocarbony.loxy-2-methoxy)propoxy]- butyl]thiazolium iodide. 3. A pharmaceutical composition comprising a compound according to Claim 1 together with a pharmaceutically accept- able 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 extra¬ vasation. 5. process for preparing a compound according to Claim 1 which comprises reacting a compound of formula C R 2 Q-A-(B) -C-(CH-) -D-(E) -Z C x , 2 y z — R 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.

Inventors: ANDERSON ROBERT C, LEE MARK L, TOMESCH JOHN C, ANDERSON, ROBERT, C., LEE, MARK, L., TOMESCH, JOHN, C.
Applicants: SANDOZ AG
Application year: 1985
Main classification: C07D277
IPC codes: C07D211, C07D213, C07D215, C07D217, C07D237, C07D241, C07D277, C07D309, C07D417