The invention discloses certain substituted 2-furanyl- or 5-oxo-2-furanyl methoxy phosphoryl alkyl cyclimmonium salts useful as PAF inhibitors, pharmaceutical compositions containing said compounds as an active ingredient thereof and a method of using such compositions for inhibiting PAF-induced blood platelet aggregation, PAF-mediated bronchoconstriction and extravasation, PAF-induced hypotension and PAF-induced ischemic bowel disease.

The present invention relates to certain substituted 2-furanyl- or 
5-oxo-2-furanyl methoxy phosphoryl alkyl 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 afore-mentioned 
compounds as an active ingredient thereof and the method of using such 
compositions for inhibiting PAF-mediated bronchoconstriction and 
extravasation, PAF-indeuced hypotension and PAF-involved ischemic bowel 
disease. 
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 immunologically 
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. Further, the possible role of PAF in ischemic bowel 
disease, particularly necrotizing enterocolitis (NEC) has recently been 
described, thereby implicating PAF in the development of disorders leading 
to bowel necrosis. 
The existence of platelet activating factor was proposed in an article by 
Henson, P. M., Journal of Experimental Medicine 131, 287 (1970). However, 
due to the limited quantities of material available for study, great 
difficulty was encountered in defining the chemical structure and 
biochemical activity of PAF. 
One of the earlier reports on the chemical nature of PAF was that of 
Benveniste, J., Nature 249, 581 (1974), wherein the physiochemical 
characteristics of PAF were reported. A later study by Benveniste, J., et 
al., Nature 269, 170 (1977) reported on the purification of PAF isolated 
by successive thin layer chromatography. A more recent study by Hanahan, 
et al. in the J. of Biol. Chem. 225: 5514-5516 (June 1980) confirmed that 
the compounds, 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), 
and PAF are one and the same composition. Since that time, many research 
endeavors have been directed to the synthesis of compounds structurally 
related to that of PAF in an effort to uncover compounds useful in the 
inhibition of platelet activating factor. 
The essence of the present invention is the discovery that certain 
substituted 2-furanyl- or 5-oxo-2-furanyl methoxy phosphoryl alkyl 
cyclimmonium salts of formula I: 
##STR1## 
where R is n-C.sub.12 -C.sub.20 alkyl, alkenyl or alkynyl; or C.sub.12 
-C.sub.24 alkoxyalkyl; 
X is CH.sub.2 or C.dbd.O; 
Y is CH.sub.2 ; O; 
##STR2## 
A, together with the nitrogen atom, forms an unsubstituted 5- or 
6-membered, monocyclic ring which may optionally contain one further 
hetero atom selected from nitrogen and sulfur; a 5- or 6-membered, 
monocyclic ring which may optionally contain one further hetero atom 
selected from nitrogen and sulfur and which is either mono-, di- or 
trisubstituted by C.sub.1 -C.sub.4 alkyl or monosubstituted by CF.sub.3, 
halo, COOH or COOCH.sub.3 ; an unsubstituted 10-membered, bicyclic ring 
which may optionally contain one further nitrogen atom; or a 10-membered, 
bicyclic ring which may optionally contain one further nitrogen atom and 
which is either mono-, di- or trisubstituted by C.sub.1 -C.sub.4 alkyl or 
monosubstituted by CF.sub.3, halo, COOH or COOCH.sub.3 ; 
Z.sup..crclbar. is a pharmaceutically acceptable anion; 
m is an integer 1 or 2; 
n is an integer 2 to 8; and 
y is .crclbar. and q is O or y is H and 
q is 1; 
are useful as PAF receptor antagonists and as inhibitors of PAF-induced 
blood platelet aggregation. 
Included among the compounds of formula I are the compounds of subclass Ia: 
##STR3## 
where R, Y, A, Z.sup..crclbar., m, n, y and q are as defined above. 
The preferred compounds of subclass Ia are compounds of formula Ia': 
##STR4## 
where R' is n-C.sub.14 -C.sub.20 alkyl, alkenyl or alkynyl; or C.sub.12 
-C.sub.20 alkoxyalkyl; 
Y' is CH.sub.2 ; O; 
##STR5## 
A', together with the nitrogen atom, forms an unsubstituted thiazolium, 
pyridinium, pyridazinium, quinolinium or isoquinolinium ring, or a 
thiazolium, pyridinium, pyridazinium, quinolinium or isoquinolinium ring 
which is either mono-, di- or trisubstituted by C.sub.1 -C.sub.4 -alkyl or 
monosubstituted by CF.sub.3, halo, COOH or COOCH.sub.3 ; 
Z.sup..crclbar.' is chloride; bromide; iodide; phenylsulfonate; 
toluenesulfonate; C.sub.1 -C.sub.4 -alkylsulfonate; carboxylate or 
tetrafluoroborate; 
n' is an integer 2 to 6; 
and m, y and q are as defined above. 
The more preferred compounds of subclass Ia are compounds of formula Ia": 
##STR6## 
where R" is n-C.sub.16 -C.sub.20 alkyl, alkenyl or alkynyl; or C.sub.14 
-C.sub.18 alkoxyalkyl; 
Y" is O; 
##STR7## 
A", together with the nitrogen atom, forms an unsubstituted thiazolium, 
pyridinium or quinolinium ring, or a thiazolium, pyridinium or quinolinium 
ring which is either mono-, di- or trisubstituted by C.sub.1 -C.sub.4 
alkyl or monosubstituted by CF.sub.3, halo, COOH or COOCH.sub.3 ; 
Z.sup..crclbar." is chloride; bromide; C.sub.1 -C.sub.4 alkylsulfonate or 
carboxylate; 
n" is an integer 2 to 4; 
and m, y and q are as defined above. 
The even more preferred compounds of subclass Ia are compounds of formula 
Ia'": 
##STR8## 
where R'" is n-C.sub.16 -C.sub.18 alkyl, alkenyl or alkynyl; or C.sub.14 
-C.sub.18 -alkoxyalkyl; 
Y'" is O; 
##STR9## 
and A", Z.sup..crclbar.", m, y and q are as defined above. 
Also included among the compounds of formula I are the compounds of 
subclass Ib: 
##STR10## 
where R, Y, A, Z.sup..crclbar., m, n, y and q are as defined above. 
The preferred compounds of subclass Ib are compounds of formula Ib': 
##STR11## 
where R', Y', A', Z.sup..crclbar.', m, n', y and q are as defined above. 
The more preferred compounds of subclass Ib are compounds of formula Ib": 
##STR12## 
where R", Y", A", Z.sup..crclbar.", m, n", y and q are as defined above. 
The even more preferred compounds of subclass Ib are compounds of formula 
Ib'": 
##STR13## 
where R'", Y'", A", Z.sup..crclbar.", m, y and q are as defined above. 
The compounds of subclass Ia where Y is CH.sub.2 or O, y is .sup..crclbar. 
(q is O) and R, A, m and n are as defined above may be prepared by an 
eight-step reaction as set forth below: 
##STR14## 
where R.sub.1 is n-C.sub.14 -C.sub.23 alkyl, alkenyl or alkynyl, CH.sub.2 
OR or CH.sub.2 CH.sub.2 OR, Bn is benzyl, M is an alkali metal or an 
alkaline earth metal cation and R is as defined above. 
##STR15## 
where R.sub.1 and Bn are as defined above. 
##STR16## 
where M' is an alkali or alkaline earth metal and R.sub.1 and Bn are as 
defined above. 
##STR17## 
where R.sub.1 and Bn are as defined above. 
##STR18## 
where R.sub.1 and Bn are as defined above and R.sub.2 is n-C.sub.1 
-C.sub.4 alkyl. 
##STR19## 
where R.sub.1 and Bn are as defined above. 
##STR20## 
where R.sub.1 and n are as defined above. 
##STR21## 
where R, n and A are as defined above. 
With respect to the individual steps, Step 1 concerns the reaction of an 
epoxide of formula II with benzyl alcohol in the presence of an alkali 
metal or alkaline earth metal hydride, preferably an alkali metal hydride, 
more preferably sodium hydride, to yield an adduct of formula III. The 
reaction is conveniently carried out in an inert, organic solvent, e.g., a 
dialkyl amine such as dimethylformamide or dimethylacetamide, an aromatic 
hydrocarbon such as toluene, benzene or xylene, a cyclic ether such as 
tetrahydrofuran, or a mixture thereof. The reaction may be carried out at 
temperatures of from 30.degree. to 100.degree. C. for a period of 1 to 24 
hours. 
Step 2 involves the oxidation of a compound produced in Step 1, i.e., a 
compound of formula III, employing a chromium-based oxidant such as 
pyridinium chlorochromate to yield a compound of formula IV. The oxidation 
is carried out in an inert, organic solvent, e.g., a chlorinated 
hydrocarbon such as methylene chloride, at a temperature of from 
20.degree. to 40.degree. C. for a period of between 6 and 36 hours. 
Alternatively, the oxidation of a compound of formula III may be carried 
out employing an oxidant prepared by the action of an activating agent 
such as an anhydride, e.g., trifluoroacetic anhydride, or an acid 
chloride, e.g., oxalyl chloride, on a dialkyl sulfoxide, preferably 
dimethyl sulfoxide, in the presence of an inert, organic solvent, e.g., a 
chlorinated hydrocarbon such as methylene chloride or an aromatic 
hydrocarbon such as toluene or xylene, at a temperature of from 
-78.degree. to 25.degree. C., preferably -78.degree. to 0.degree. C., 
followed by reaction with a C.sub.1-3 trialkylamine, e.g., triethylamine, 
at a temperature of from 0.degree. to 25.degree. C. for a period of 
between 1 and 3 hours. 
As to Step 3, after the preparation of an organometallic reagent by the 
action of an alkali or alkaline earth metal, e.g. Li or Mg, on an 
appropriate haloalkene such as 4-bromo-1-butene, in the presence of an 
aliphatic ether or a cyclic ether such as tetrahydrofuran at a temperature 
of from 20.degree. to 65.degree. C. for a period of 30 minutes to 2 hours, 
the organometallic compound is reacted with a compound producted in Step 
2, i.e., a compound of formula IV, to yield an olefin of formula V. The 
reaction is conducted in the presence of the same solvent employed in 
preparing the organometallic reagent or a mixture of said solvent with a 
compatible inert organic solvent such as pentane, hexane and the like. The 
reaction is carried out at a temperature of -78.degree. to 20.degree. C. 
for a period of between 30 minutes and 18 hours. 
Step 4 involves subjecting a compound produced in Step 3, i.e., an olefin 
of formula V, to ozone in a stream of oxygen in the presence of an inert, 
organic solvent, e.g., a chlorinated hydrocarbon such as methylene 
chloride, at a temperature of from -78.degree. to -50.degree. C. until 
consumption of the olefin has been effected, after which time a reducing 
agent, preferably a trialkyl phosphite or dialkyl sulfide, e.g., 
dimethylsulfide, is added. The reduction is carried out at temperatures of 
from 20.degree. to 30.degree. C. for a period of between 1 and 24 hours to 
yield a compound of formula VI. 
In Step 5, a compound produced in Step 4, i.e., a compound of formula VI, 
is reacted with a lower trialkyl silane such as triethylsilane and a Lewis 
acid catalyst, preferably borontrifluoride etherate, to yield a compound 
of formula VII. The reaction is usually conducted in the presence of a 
neutral solvent, e.g., a chlorinated hydrocarbon such as dichloromethane, 
at temperatures of from -30.degree. to 0.degree. C. for a period of 
between 1 and 4 hours. 
Step 6 involves the hydrogenolysis of the benzyl ether group of a compound 
produced in Step 5, i.e., a compound of formula VII, by dissolving said 
compound in a lower alkanol, e.g., methanol, ethanol and the like, or a 
mixture of a lower alkanol and water (up to 15%), with palladium, 
palladium hydroxide or platinum on carbon and subjecting the resultant 
mixture to a pressure of between 15 and 65 lbs. of hydrogen gas at a 
temperature of from 20.degree. to 50.degree. C. for a period of between 5 
and 20 hours to yield a compound of formula VIII. 
Step 7 is directed to the reaction of a compound produced in Step 6, i.e., 
a compound of formula VIII, with a compound of formula IX, i.e., a 
bromoalkoxy-dichlorophosphate compound, e.g., 
2-bromoethoxy-dichlorophosphate, in the presence of an amine base, such as 
pyridine or triethylamine. The reaction is conveniently carried out in an 
inert, organic solvent, e.g., an aromatic hydrocarbon such as toluene, 
benzene or xylene, a halogenated aliphatic hydrocarbon, such as methylene 
chloride, chloroform or carbon tetrachloride, a halogenated aromatic 
hydrocarbon, e.g., chlorobenzene, or an ether such as diethyl ether. The 
reaction may be carried out at temperatures of from 20.degree. to 
70.degree. C. for a period of between 5 and 30 hours. 
The second reaction in Step 7 involves subjecting the product produced in 
the first reaction to basic hydrolysis, e.g., by suspending the product in 
water. The hydrolysis is conveniently carried out at a temperature of from 
20.degree. to 100.degree. C. for a period of from 15 minutes to about 6 
hours to yield a compound of formula X. 
The last step, viz., Step 8, is concerned with the conversion of a compound 
produced in Step 7, i.e., a compound of formula X, into its corresponding 
cyclimmonium salt by reaction with a compound of formula XI, i.e., an 
optionally substituted 5- or 6-membered monocyclic or 10-membered bicyclic 
compound. The reaction producing the cyclimmonium salt, i.e., a compound 
of formula XII, is optionally conducted in the presence of an aromatic 
hydrocarbon such as benzene or toluene, a lower alkyl nitrile such as 
acetonitrile or a polar aprotic solvent such as dimethyl formamide. As to 
reaction conditions, the reaction is generally carried out at a 
temperature of from 50.degree. to 100.degree. C. usually in a sealed 
reaction vessel, for a period of between 12 and 72 hours to yield a 
hydrobromide salt. 
In a second part, the hydrobromide salt prepared in the first part, is 
treated with a silver salt, e.g., silver carbonate, in the presence of a 
lower alkanol, e.g., methanol, at a temperature of from 0.degree. to 
40.degree. C. for a period of between 15 minutes and 3 hours to yield a 
compound of formula XII. If the compound of formula XII desired is an 
unsubstituted pyridinium salt, it is preferred to use pyridine itself as 
both the reactant and solvent in the first part, in which case the 
reaction can be carried out at a temperature of from about 20.degree. to 
85.degree. C. for a period of between 6 and 24 hours. 
When a compound of subclass Ia is desired where R is alkyl, alkenyl or 
alkynyl, Y is --O--, y is .sup..crclbar. (q is O) and A, m and n are as 
defined above, it has been found more convenient to employ a three-step 
reaction commencing with the following reaction: 
##STR22## 
where R.sup.IV is n-C.sub.12 -C.sub.20 alkyl, alkenyl or alkynyl, T is 
chloro, bromo or iodo and M and m are as defined above. In Step 1A, a diol 
of formula XIII is reacted with a halo (C.sub.14 -C.sub.18) alkane, alkene 
or alkyne, e.g., 1-bromooctadecane, in the presence of an alkali metal or 
alkaline earth metal hydroxide, preferably an alkali metal hydroxide, to 
yield a compound of formula VIII-A. The reaction is conveniently carried 
out in the presence of an inert, organic solvent, e.g., a dialkyl amide 
such as dimethylformamide or dimethylacetamide, an aromatic hydrocarbon 
such as toluene, benzene or xylene, or a mixture of a dialkylamide and an 
aromatic hydrocarbon. Alternatively, the inert, organic solvent employed 
may be dimethylsulfoxide, a cyclic ether such as tetrahydrofuran, or a 
mixture thereof. The reaction may be carried out at temperatures of from 
15.degree. to 50.degree. C. for a period of between 1 and 6 hours. 
Employing a compound produced in Step 1A, i.e., a compound of formula 
VIII-A, and carrying out the reactions described above in Steps 7 and 8, 
results in a compound having the formula 
##STR23## 
The compounds of subclass Ia where Y is 
##STR24## 
y is .sup..crclbar. (q is O) and R, A, m and n are as defined above may be 
prepared by the following reaction scheme: 
##STR25## 
where J is an isocyanate, isothiocyanate, chlorocarbonate or 
carboxychloride group, and R, Y and m are as defined above. 
##STR26## 
where Y, R, m and n are as defined above. 
##STR27## 
where Y, R, m, n and A are as defined above. 
Turning to the reactions individually, Reaction A involves the reaction of 
a diol compound of formula XIII with a compound of formula XIV, i.e., an 
appropriate isocyanate, isothiocyanate, chlorocarbonate or carboxychloride 
compound containing the residue, R, in the presence of an amine base, such 
as pyridine or triethylamine, to yield a compound of formula XV. The 
reaction may optionally be conducted in the presence of a cosolvent which 
may be an aromatic hydrocarbon such as benzene or toluene, an aromatic 
halohydrocarbon such as chlorobenzene, an aliphatic halohydrocarbon such 
as chloroform or dichloromethane, a dialkyl ether such as diethylether, a 
cyclic ether such as tetrahydrofuran or a dialkyl amide such as 
dimethylformamide. The reaction is typically carried out at a temperature 
of from 20.degree. to 100.degree. C. for a period of between 1 and 24 
hours. 
As to Reaction B and Reaction C for preparing a compound of formula XVI and 
XVII, respectively, they are conducted in essentially the same manner as 
set forth above in Steps 7 and 8. 
The compounds of subclass Ib where Y is CH.sub.2 or O, y is .sup..crclbar. 
(q is O) and R, A, m and n are defined above may be prepared essentially 
as described below employing a compound of formula VI as the starting 
material: 
##STR28## 
where R.sub.1 and Bn are as defined above. 
##STR29## 
where R.sub.1 and Bn are as defined above. 
##STR30## 
where R.sub.1 and n are as defined above. 
##STR31## 
where R.sub.1, n and A are as defined above. 
In considering the steps individually, Step A concerns the oxidation of a 
compound of formula VI to yield a compound of formula XVIII. The oxidation 
is carried out according to either of the procedures set forth in Step 2 
above with regard to the description for preparing the compounds of 
subclass Ia. 
Step B involves the hydrogenolysis of the benzyl ether group of a compound 
produced in Step A, i.e., a compound of formula XVIII, to yield a compound 
of formula XIX. The hydrogenolysis is conveniently carried out in 
accordance with the procedure set forth in Step 6 above with regard to the 
description for preparing the compounds of subclass Ia. 
As to Step C and Step D for preparing a compound of formula XX and XXI, 
respectively, they are conducted in an analogous manner to that set forth 
above in Steps 7 and 8 regarding the description for preparing the 
compounds of subclass Ia. 
The compounds of subclass Ib where Y is 
##STR32## 
y is .sup..crclbar. (q is O) and R, A, m and n are as defined above may be 
prepared by the following reaction scheme: 
##STR33## 
where R.sub.3 is (CH.sub.2 --OC(CH.sub.3).sub.2 OCH.sub.3, and m, Bn and M 
are as defined above. 
##STR34## 
where R.sub.3 and Bn are as defined above. 
##STR35## 
where R.sub.3, Bn and M' are as defined above. 
##STR36## 
where R.sub.3 and Bn are as defined above. 
##STR37## 
where R.sub.3 and Bn are as defined above. 
##STR38## 
where HX' is a organic acid or a mineral acid, and R.sub.3, Bn and m are 
as defined above. 
##STR39## 
where Bn, m, R, J and Y are as defined above. 
##STR40## 
where Bn, m, R and Y are as defined above. 
##STR41## 
where m, R, Y and n are as defined above. 
##STR42## 
where m, R, Y, n and A are as defined above. 
As to the individual reactions, Reaction AA concerns the reaction of an 
epoxide of formula XXII with benzyl alcohol in the presence of an alkali 
metal or alkaline earth metal hydride, preferably an alkali metal hydride, 
more preferably sodium hydride, to yield an adduct of formula XXIII. With 
regard to the reaction conditions, i.e., the reaction medium, temperatures 
employed and reaction times, this reaction is conducted in an analogous 
manner to that set forth in Step 1 above regarding the description for 
preparing the compounds of subclass Ia. 
Reaction BB involves the oxidation of a compound produced in Reaction AA, 
i.e., a compound of formula XXIII, to yield a compound of formula XXIV. 
The oxidation is carried out in accordance with either of the procedures 
set forth in Step 2 above with regard to the description for preparing the 
compounds of subclass Ia. 
In Reaction CC, a compound produced in Reaction BB, i.e., a compound of 
formula XXIV, is reacted with an organometallic compound to yield an 
olefin of formula XXV. As to the nature of the organometallic compound and 
the reaction conditions, this reaction is carried out in an identical 
manner to that set forth above in Step 3 directed to the preparation of 
compounds of subclass Ia. 
Reaction DD involves subjecting a compound produced in Reaction CC, i.e., 
an olefin of formula XXV, to ozone in a stream of oxygen in the presence 
of an inert, organic solvent, e.g., a chlorinated hydrocarbon at an 
extremely low temperature, e.g., -80.degree. to -50.degree. C., until the 
consumption of the olefin has been effected. A reducing agent is then 
added, preferably a trialkyl phosphite or dialkyl sulfide, and reduction 
is carried out at ambient temperatures, i.e., in the range of 20.degree. 
to 30.degree. C., for a period of between 1 and 24 hours to yield a 
compound of formula XXVI. 
In Reaction EE, a compound produced in Reaction DD, i.e., a compound of 
formula XXVI, is oxidized employing either of the procedures set forth in 
Step 2 above regarding the description for preparing the compounds of 
subclass Ia to yield a compound of formula XXVII. 
Reaction FF concerns the reaction of a compound produced in Reaction EE, 
i.e., a compound of formula XXVII, with a mineral acid such as 
hydrochloric or sulfuric acid, or an organic acid such as 
p-toluenesulfonic acid, in the presence of a cosolvent, e.g., a mixture of 
a cyclic ether such as tetrahydrofuran in water. The reaction is conducted 
at a temperature of from 0.degree. to 25.degree. C. for a period of 
between 30 minutes and 4 hours and yields a compound of formula XXVIII. 
Reaction GG involves the reaction of a compound produced in Reaction FF, 
i.e., a compound of formula XXVIII, with an appropriate isocyanate, 
isothiocyanate, chlorocarbonate or carboxylchloride compound containing 
the residue, R, in the presence of an amine base, such as pyridine or 
triethylamine to yield a compound of formula XXIX. The reaction is 
conducted in an analogous manner to that set forth in Reaction A above for 
preparing the compounds of subclass Ia. 
Reaction HH concerns the hydrogenolysis of the benzyl ether group of a 
compound produced in Reaction GG, i.e., a compound of formula XXIX. The 
hydrogenolysis is conducted in a similar manner to that set forth in Step 
6 above regarding the description for preparing the compounds of subclass 
Ia to yield a compound of formula XXX. 
As to Reaction II and Reaction JJ for preparing a compound of formula XXXI 
and XXXII, respectively, they are conducted in essentially the same manner 
as that set forth in Steps 7 and 8 regarding the description for preparing 
the compounds of subclass Ia. 
It should be understood that when any of the previously described processes 
involve the preparation of compounds where R is a functionality sensitive 
to hydrogenolysis, i.e., alkenyl or alkynyl, the debenzylation should be 
effected employing a trialkylsilyliodide compound. For example, in the 
preparation of compounds of subclass Ia where Y is CH.sub.2 or O, y 
is.sup..crclbar. (q is O) and m and n are as defined above, the 
debenzylation step may be conducted as depicted below: 
##STR43## 
where R.sub.1.sup.' is n-C.sub.14 -C.sub.23 alkenyl or alkynyl, CH.sub.2 
OR or CH.sub.2 CH.sub.2 OR where R is n-C.sub.12 -C.sub.20 alkenyl or 
alkynyl, and Bn and R.sub.2 are as defined above. 
As to the reaction conditions, Step 6-A involves the reaction of a compound 
of formula VII-A with a trialkylsilyliodide compound, preferably 
trimethylsilyliodide, to yield a compound of formula VIII-B. The reaction 
is optionally conducted in the presence of a cosolvent, e.g., an aromatic 
hydrocarbon such as benzene or toluene, or a lower alkyl nitrile such as 
acetonitrile, at a temperature of from 20.degree. to 110.degree. C. for a 
period of between 1 and 24 hours. 
The compounds of formulae II, IX, XI, XIII, XIV and XXII are either known 
and obtained by methods described in the literature, or where not known, 
may be obtained by methods analogous to those described in the literature. 
The product of each reaction may, if desired, be purified by conventional 
techniques such as recrystallization (if a solid), column chromatography, 
preparative thin layer chromatography, gas chromatography (if sufficiently 
volatile) or fractional distillation under high vacuum (if sufficiently 
volatile). Often, however, the crude product of one reaction may be 
employed in the following reaction without purification. 
As is evident to those skilled in the art, the compounds of formula I can 
exist in racemic or enantiomeric form and both forms are contemplated as 
being included within the scope of this invention. 
Moreover, and as is also evident to those skilled in the art from 
structural formula I, said formula not only embraces the inner salts, 
i.e., compounds of formula I where y is .sup..crclbar. (q is O), but also 
the pharmaceutically acceptable acid addition salts (i.e., those salts 
which do not significantly increase the toxicity of the base compound), 
i.e., compounds of formula I where y is H (q is 1). The compounds of 
formula I can be converted into acid addition salt form in conventional 
manner. In this connection, and with regard to the processes described 
above for preparing all of the compounds of formula I, it can be clearly 
seen that the hydrobromide salts of all of the end-products, described 
above, e.g., the hydrobromide salt of a compound of formula XII, can be 
prepared by omitting the second part of Step 8 and recovering the product 
produced in the first part. 
All of the compounds of formula I are useful as platelet activating factor 
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.times.g.) of 
freshly drawn blood, anti-coagulated with 0.38% sodium citrate (final 
concentration). Platelet count is adjusted to 250,000 per .mu.l using 
platelet poor plasma (PPP) obtained by a second centrifugation 
(700.times.g.) of the blood sample. An aliquot (0.38 ml.) of the PRP is 
dispensed into cuvettes and maintained at room temperature (22.degree. C.) 
until used (but for not more than two hours). The PRP-containing cuvettes 
are incubated at 37.degree. 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 .mu.M. 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 0.01M Tris-Tyrodes buffer with 0.25% bovine serum albumin (pH 7.4), is 
added to the PRP-containing cuvettes in an amount predetermined to give a 
consistent aggregation response (either 0.1 .mu.M or 0.01 .mu.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 then 50% inhibition at 100 .mu.M are evaluated at 
lower concentrations to generate an IC.sub.50 (50% inhibitory 
concentration) value. 
Moreover, it has been found that all of the compounds of formula I are 
useful as platelet activating factor receptor antagonists as indicated by 
their ability to inhibit specific binding of [.sup.3 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 trisodium citrate and 20 
.mu.g/ml of Prostaglandin I.sub.2 (PGI.sub.2) in a ratio of blood to 
anti-coagulant of 9:1. Platelet rich plasma (PRP) is prepared by 
centrifugation (250.times.g) of the blood for 20 minutes at room 
temperature. The PRP is then centrifuged (900.times.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.sub.2 at a final 
concentration of 0.3 g/ml. The platelets are resuspended at 350,000 .mu.l 
in TT/BSA containing 1.4 mM CaCl.sub.2.2H.sub.2 O and 0.7 mM 
MgCl.sub.2.6H.sub.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 .mu.M. For each determination, the following solutions are mixed: 
500 .mu.l of the above-described platelets; 
10 .mu.l of [.sup.3 H]-PAF (40,000 counts per minute (cpm) to a final 
concentration of 1.5 .mu.M); and 
either 
10 .mu.l of the test compound at 50.times. the desired final concentration, 
10 .mu.l of vehicle (total bound), or 
10 .mu.l of 1.85.times.10.sup.-5 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 .mu.l of ice 
cold TT/BSA and centrifugation (900.times.g) at 4.degree. 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.times.g) at 4.degree. 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 
therewith. The pellets are resuspended in 500 .mu.l of Scintiverse II and 
mixed well. An additional 2 ml. 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 [.sup.3 H]-PAF and 
non-specifically bound [.sup.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.sub.50 (50% 
inhibitory 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 (C.sub.18 
-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 hemoconcentration 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 compound is 
administered intraarterially at one to five minutes prior to the 
introduction of PAF. The PAF (C.sub.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 
hemoconcentration 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 .mu.l 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 induces 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. 
Yet still further, the compounds of formula I are useful as inhibitors of 
PAF-induced hypotension as measured by their ability to inhibit the 
lowering of blood pressure levels induced by PAF according to the 
following test (Test D): 
Male Wistar rats, weighing approximately 300 gm, are anesthetized and their 
carotid arteries cannulated to enable their diastolic and systolic 
arterial blood pressure measurements to be recorded. PAF is then 
administered intravenously at either 100 or 500 ng/kg, and the blood 
pressure drop (within 10 sec.) and recovery time required to reach the 
pre-injection blood pressure level are measured. At 100 ng/kg, a 30% 
decrease in blood pressure and a 3 to 4 minute recovery time are observed, 
whereas at 500 ng/kg, a 52% decrease in blood pressure and a 10 minute 
recovery time are observed. In order to measure the effectiveness of a 
compound for both the inhibition of blood pressure decreases and 
shortening of the recovery time, the test compound is administered 
intravenously over a range of between 5 and 7 dosage levels (1 or 2 test 
animals per dose) and between 1 and 5 minutes prior to the introduction of 
PAF to generate an ED.sub.50. 
Yet even still further, the compounds of formula I are useful as inhibitors 
of PAF-induced ischemic intestinal necrosis, which property was measured 
in accordance with the following test (Test E): 
Following essentially the procedure of F. Gonzalez-Crussi and W. Hsueh 
published in J. Amer. Pathol., 112, pgs. 127-135 (1983), male 
Sprague-Dawley rats, weighing approximately between 260 and 300 g, are 
anesthetized and their carotid arteries cannulated and connected to a 
blood pressure transducer and recorder. The test compound is introduced 
into a cannula inserted into the jugular vein at a time 10 minutes prior 
to the administration of PAF. The abdomen is then incised along the 
midline and 2 .mu.g of PAF or 20 .mu.g of LPS (lipopolysaccharide) 
immediately followed by 1 .mu.g of PAF are injected into the abdominal 
aorta at the level of the renal artery. The abdominal incision is then 
covered with saline-moistened gauze and the intestine exposed and examined 
periodically up to 2 to 3 hours prior to sacrifice. Into the jugular vein 
is then injected 5 ml of 2% Evans Blue to assess the degree of intestinal 
perfusion. Blocks of intestinal tissue are then taken for microscopic 
examination to determine either the extent of necrosis or to verify the 
absence of necrosis when inhibited by the test compound. Microscopic 
changes in the intestine are assessed by hematoxylin and eosin staining. 
The test compound is assessed for its ability to alleviate or prevent the 
development of gross and microscopic lesions and may be expressed in terms 
of the number of animals in which inhibition is observed relative to the 
control (taken to be 100%). 
The compounds of formula I may be combined with one or more 
pharmaceutically, acceptable carriers and, optionally, one or more other 
conventional pharmaceutical adjuvants and administered orally in the form 
of tablets, dispersible powders, granules, capsules, elixirs, suspensions 
and the like or parenterally in the form of sterile injectable solutions 
or suspensions. The compositions may be prepared by conventional means. 
The precise dosage of a compound of formula I to be employed for inhibiting 
platelet activating factor (PAF) depends upon several factors including 
the host, the nature and the severity of the condition being treated, the 
mode of administration and the particular compound employed. However, in 
general, satisfactory inhibition or antagonism of platelet activating 
factor is achieved when a compound of formula I is administered orally at 
a daily dosage of 0.05-100, preferably 0.1-30 mg/kg body weight or, for 
most larger primates, daily dosage of 1-500 mg, preferably 1-50 mg. A 
typical oral dosage is 5 mg, three times a day. 
As with the PAF inhibition use, the precise dosage of a compound of formula 
I to be employed in treating platelet activating factor mediated 
bronchoconstriction and extravasation, platelet activating factor induced 
hypotension and ischemic bowel disease depends upon several factors 
including the host, the nature and severity of the condition being 
treated, the mode of administration and the particular compound employed. 
However, in general, satisfactory inhibition or antagonism of platelet 
activating factor mediated bronchoconstriction and extravasation, platelet 
activating factor induced hypotension and ischemic bowel disease is 
achieved when a compound of formula I is administered orally at a daily 
dosage of 0.2-100, preferably 0.2-50 mg/kg body weight or, for most larger 
primates, a daily dosage of 10-2000 mg, preferably 10-350 mg. A typical 
oral dosage is 50 or 100 mg, two or three times a day. 
Regardless of use, a small dosage is gradually increased until the optimal 
dosage for the host under treatment is determined. For administration by 
injection, a dosage somewhat lower than would be used for oral 
administration of the same compound to the same host having the same 
condition is usually employed. 
The compounds of formula I may be formulated into such pharmaceutical 
compositions containing an amount of the active substance that is 
effective for inhibiting PAF, in treating PAF mediated bronchoconstriction 
and extravasation, in treating PAF-induced hypotension, or in treating 
ischemic bowel disease, such compositions in unit dosage form and such 
compositions comprising a solid pharmaceutically acceptable carrier. 
Tablets and capsules containing the ingredients indicated below may be 
prepared by conventional techniques and are useful as platelet activating 
factor inhibitors. The tablet may be administered once or twice a day 
whereas the capsule is suitably administered three times a day. 
______________________________________ 
Weight (mg) 
Ingredients tablet capsule 
______________________________________ 
compound of formula I, e.g. 
5 5 
the compound of Example 3 
tragacanth 10 -- 
lactose (spray-dried) 
257.5 95 
corn starch 15 -- 
talcum 10 -- 
magnesium stearate 2.5 -- 
Total 300.0 100 
______________________________________ 
The following are representative of tablets and capsules which may be 
prepared by conventional means and are useful in treating platelet 
activating factor mediated bronchoconstriction and extravasation, platelet 
activating factor induced hypotension and ischemic bowel disease. The 
tablet and the capsule may be suitably administered two or three times a 
day. 
______________________________________ 
Weight (mg) 
Ingredients tablet capsule 
______________________________________ 
compound of formula I, e.g., 
50 50 
the compound of Example 3 
tragacanth 10 -- 
lactose (spray-dried) 
212.5 100 
cornstarch 15 -- 
talcum 10 -- 
magnesium stearate 2.5 -- 
Total 300.0 150.0 
______________________________________

The following examples show representative compounds encompassed by this 
invention and their synthesis. However, it should be clearly understood 
that they are for purposes of illustration only. 
EXAMPLE 1 
3-[2-[(2-Octadecyloxy)ethyl-5-oxo-tetrahydrofuran-2-yl]methoxyhydroxyphosph 
inyloxy-ethane]thiazolium hydroxide-inner salt-4-oxide 
##STR44## 
(a) Preparation of 1-benzyloxy-4-octadecyloxy-butane-2-ol 
To 12.0 g of 60% sodium hydride in mineral oil (30 mmol, washed free of oil 
by the use of petroleum ether) was added 32.4 g (0.3 mol) of benzyl 
alcohol in 200 ml of dry dimethylformamide. The suspension was heated 
under a flow of nitrogen to 80.degree. C. and maintained at this 
temperature for 45 minutes, after which time 66.1 g (0.19 mol) of an 
epoxide (prepared by the peracid oxidation of octadecyl-3-butenyl ether) 
in 100 ml of dimethylformamide was added and the temperature maintained at 
80.degree. C. for 15 hours. The solvent was then removed in vacuo and the 
residue chromatographed on silica gel employing a mixture of petroleum 
ether and diethyl ether in a ratio of 3:2 as the eluent to yield a 
wax-like solid. 
(b) Preparation of 1-benzyloxy-4-octadecyloxy-2-butanone 
To a complex prepared at -60.degree. C. from the addition of 10.4 ml of dry 
dimethyl sulfoxide to 8.9 g (70 mmol) of oxalyl chloride in 150 ml of 
methylene chloride, was added, dropwise, 27.7 g (62.2 mmol) of the 
compound prepared in (a) above. After stirring the mixture under a 
nitrogen atmosphere for 1 hour, 50 ml of triethylamine in 50 ml of 
methylene chloride was added and the resultant mixture was allowed to warm 
to 0.degree. C. over a period of 30 minutes, after which time it was 
quenched with 75 ml of water. After the mixture was allowed to warm to 
room temperature, the organic layer was separated, washed with a saturated 
sodium chloride solution, dried over magnesium sulfate and concentrated in 
vacuo to afford an oil which solidified on standing. Flash chromatography 
on silica gel employing a mixture of petroleum ether and diethyl ether in 
a ratio of 7:3 as the eluent yielded a solid, m.p. 33.degree.-34.degree. 
C. 
(c) Preparation of 3-benzyloxymethyl-3-hydroxy-1-octadecyloxy-hept-6-ene 
1.12 g (8 mmol) of 4-bromo-1-butene in 15 ml of dry ether was reacted with 
200 mg of magnesium turnings at reflux under a nitrogen atmosphere for 1 
hour. The resulting Grignard reagent was cooled to -60.degree. C. and then 
treated with 2.22 g (5 mmol) of the compound prepared in (b) above in 30 
ml of ether. After 1 hour at -60.degree. C., the mixture was warmed 
overnight to room temperature and then quenched with a saturated aqueous 
ammonium acetate solution and partitioned. The organic layer was then 
washed twice with ammonium acetate, washed with a saturated sodium 
chloride solution and dried over magnesium sulfate, after which time the 
solvent was removed under reduced pressure. Purification of the crude 
product was effected on silica gel employing a mixture of petroleum ether 
and diethyl ether as the eluent to yield a low melting solid. 
(d) Preparation of 
5-benzyloxymethyl-2-hydroxy-5-(2-octadecyloxyethyl)-tetrahydrofuran 
6.15 g (12.3 mmol) of the compound prepared in (c) above in 100 ml of 
methylene chloride was treated with ozone at -60.degree. C. After 
consumption of the olefin, 25 ml of dimethyl sulfide was added and the 
mixture allowed to warm to room temperature. The solvent was removed in 
vacuo and the crude product was purified on silica gel employing a mixture 
of petroleum ether and diethylether in a ratio of 7:3 as the eluent to 
yield a colorless oil. 
(e) Preparation of 
5-benzyloxymethyl-5-(2-octadecyloxyethyl)-4,5-dihydro-2(3H)-furanone 
To a solution of 1.6 g (7.4 mmol) of pyridinium chlorochromate in 25 ml of 
methylene chloride under a nitrogen atmosphere, was added 13.5 g (6.5 
mmol) of the compound prepared in (d) above in 25 ml of methylene 
chloride. After 18 hours at 25.degree. C., the solution was diluted with 
150 ml of ether, filtered through silica gel and the filtrate evaporated 
to afford an oil. The oil was then flash chromatographed on silica gel 
employing a mixture of petroleum ether and diethyl ether in a ratio of 7:3 
as the eluent to yield colorless oil. 
(f) Preparation of 
5-hydroxymethyl-5-(2-octadecyloxyethyl)-4,5-dihydro-2(3H)furanone 
A mixture containing 10.2 g (21.83 mmol) of the compound prepared in (e) 
above, 300 ml of a mixture of ethyl alcohol and water in a ratio of 9:1 
and 1.5 g of 5% palladium on carbon (50% water content) was placed in a 
pressure bottle and hydrogenated at 40.degree. C. under a pressure of 50 
lbs. of hydrogen until uptake was complete. The catalyst was then filtered 
off and the filtrate concentrated in vacuo. The residue was crystallized 
from methanol to yield a solid. 
(g) Preparation of 
2-bromoethyl-[(2-octadecyloxyethyltetrahydro-5-oxo-furan-2-yl)-methyl]phos 
phoric acid diester 
To 14 g (33.9 mmol) of the compound prepared in (f) above in 60 ml of dry 
benzene was added 9.9 g (40.7 mmol) of 
2-bromoethyloxyphosphoro-dichloridate. The resultant solution was cooled 
on in ice-salt bath and treated dropwise, under a nitrogen atmosphere, 
with a solution of 3.5 ml of pyridine in 40 ml of benzene. After the 
ice-salt bath was removed, the mixture was allowed to warm to room 
temperature over a period of 6 hours. The volatiles were removed under 
reduced pressure and the residue was suspended in 500 ml of water and 
heated on a steam bath for 80 minutes. After cooling to room temperature, 
the mixture was extracted with chloroform. The extract was dried over 
magnesium sulfate, filtered and, after removal of the solvent, a white 
solid was obtained. 
Preparation of the title compound 
The compound prepared in (g) above was placed into a pressure bottle and 22 
g of thiazole in 20 ml of toluene was added. The resultant mixture was 
heated at 65.degree. C. for 50 hours, after which time it was cooled and 
evaporated in vacuo. The residue was then taken up with 500 ml of methanol 
and, after the addition of 10.5 g of silver carbonate, the mixture was 
stirred for 90 minutes. The solids were then removed by filtration and the 
filtrate evaporated under reduced pressure to yield the crude product as a 
brown residue. The crude product was then purified on silica gel and 
eluted successively with a 5% solution of methanol in methylene chloride, 
a 20% solution of methanol in methylene chloride and finally a solution of 
methylene chloride, methanol and water in a ratio of 10:5:1 to yield the 
title compound as a white solid, m.p. 200.degree.-205.degree. C. (dec.) 
PAIA test--IC.sub.50 --10.5 .mu.M 
TEST A--IC.sub.50 --1.8 .mu.M 
TEST C--ED.sub.50 --0.25 mg/kg (ia) 
EXAMPLE 2 
3-[2-[(2-Octadecyloxymethyltetrahydrofuran-2-yl-methoxy)-hydroxyphosphinylo 
xy]-ethane]-thiazolium hydroxide inner salt-4-oxide 
##STR45## 
(a) Preparation of 2-hydroxymethyl-2-octadecyloxymethyl tetrahydrofuran 
To a mixture of 2.64 g (20 mmol) of 2,2-bishydroxymethyl tetrahydrofuran 
and 2.20 g (6.6 mmol) of 1-bromooctadecane in 8 ml of a 
dimethylsulfoxide-tetrahydrofuran solution in a 1:1 ratio was added 1.84 g 
(26.4 mmol) of finely powdered potassium hydroxide and the resultant 
mixture was stirred at room temperature for 2 hours. The mixture was then 
poured into 100 ml of water, diluted with a saturated sodium chloride 
solution and extracted with ether. The ether extract was then washed with 
saturated sodium chloride and dried over sodium sulfate. The solvents were 
then removed to yield the crude product as a low-melting solid. The crude 
product was then chromatographed on silica gel employing methyl-t-butyl 
ether and hexane in a 3:1 ratio as the eluent to yield a white, waxy 
solid. 
(b) Preparation of 
2-bromoethyl-[(2-octadecyloxymethyltetrahydrofuran-2-yl)-methyl]phosphoric 
acid diester 
To 0.244 g of bromoethoxyphosphordichloridate in 2.5 ml of benzene was 
added 0.322 g (0.84 mmol) of the compound prepared in (a) above and, after 
cooling the resultant mixture on an ice bath, the cooled mixture was 
treated dropwise with 82 .mu.l of dry pyridine. The ice bath was then 
removed and the mixture stirred, under a nitrogen atmosphere, for 5 hours. 
The solvent was then removed in vacuo and to the residue was added 4 ml of 
water. The mixture was then heated on a steam bath for 15 minutes, then 
cooled to room temperature, diluted with water and extracted with ether. 
The ether extracts were then washed with water, dried over sodium sulfate 
and, after removal of the solvents, a foam was obtained. 
Preparation of the title compound 
To a pressure bottle containing 1 ml of a mixture of thiazole and toluene 
in a 1:1 ratio was added the compound prepared in (b) above and, after 
sealing the bottle, the mixture was heated for 6 days. The volatiles were 
then removed in vacuo and the residue was then taken up in ethanol. 0.5 g 
of silver carbonate was then added and the mixture stirred for 1 hour, 
after which time it was filtered through Celite and the filtrate 
evaporated to dryness. To the resultant residue was added 10 ml of 
methanol and 100 mg of activated charcoal and the mixture was then heated 
for 5 minutes at 50.degree. C. The solids were then removed by filtration 
and the filtrate evaporated under reduced pressure to yield the crude 
product. The crude product was then purified on silica gel in a manner 
analogous to that described above in Example 1 to yield the title compound 
as a solid, m.p.&gt;140.degree. C. (dec.) 
PAIA test--IC.sub.50 --81.5 .mu.M 
TEST A--IC.sub.50 --3.3 .mu.M 
TEST C--54% inh. at 2.8 mg/kg (ia) 
EXAMPLE 3 
3-[2-[(2-Octadecylaminocarbonyloxymethyl 
tetrahydrofuran-2-yl-methoxy)-hydroxyphosphinyloxy]-ethane]-thiazolium 
hydroxide inner salt-4-oxide 
##STR46## 
(a) Preparation of 2-hydroxymethyl-2-octadecylaminocarbonyloxy 
tetrahydrofuran 
To a mixture of 1.9 g (14.4 mmol) of 2,2-bishydroxymethyl tetrahydrofuran 
in 10 ml of pyridine was added, at room temperature and under a nitrogen 
atmosphere, a solution of 4.04 g (13.7 mmol) of n-octadecylisocyanate in 
15 ml of pyridine. The resultant mixture was heated to 60.degree. C. and 
maintained at this temperature for 3 hours, after which time the solvent 
was removed in vacuo to yield a residue which was partitioned in a mixture 
of methylene chloride and 2N hydrochloric acid. The organic layer was then 
washed successively with saturated sodium chloride, 2N hydrochloric acid, 
saturated sodium bicarbonate and saturated sodium chloride and dried over 
magnesium sulfate. The solvent was then removed and the residue 
chromatographed on silica gel employing methyl-t-butyl ether as the eluent 
to yield a white solid. 
(b) Preparation of 
2-bromoethyl-[(2-octadecylaminocarbonyloxymethyl-tetrahydrofuran-2-yl)meth 
yl]-phosphoric acid diester 
Following essentially the procedure of Example (1g), and using in place of 
the compound prepared in (1f), an approximately equivalent amount of the 
compound prepared in (a) above, the desired compound was obtained. 
Preparation of the title compound 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in place of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (b) 
above, a brown resin was obtained as the crude product. The crude product 
was then dissolved in a mixture of tetrahydrofuran and water in a ratio of 
19:1 and the resultant solution was then passed through a column of 
Amberlite MB-3 ion-exchange resin. The eluate was then evaporated in vacuo 
and chromatographed in essentially the manner described above in Example 1 
to obtain a product which was precipitated from methylene chloride with 
acetone to yield the title compound as a creamy-white solid, m.p. 
170.degree.-175.degree. C. (dec.). 
PAIA test--IC.sub.50 --3.5 .mu.M 
TEST A--IC.sub.50 --0.47 .mu.M 
TEST C--ED.sub.50 --0.3 mg/kg (ia) 
TEST D--ED.sub.50 --1.5 mg/kg (iv) 
EXAMPLE 4 
3-[2-[(2-Octadecylaminocarbonyloxymethyl 
tetrahydrofuran-2-yl-methoxy)-hydroxyphosphinyloxy]-ethane]-thiazolium 
hydroxide-4-oxide, bromide salt 
##STR47## 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, but omitting the use of silver carbonate, and using 
in place of the compound prepared in (1g), an approximately equivalent 
amount of the compound of Example (3b), the title compound was obtained as 
a tan-colored solid, m.p. 185.degree.-190.degree. C. (dec.) 
EXAMPLE 5 
2-[Hydroxy(tetrahydro)-2-(octadecyl-5-oxo-2-furanyl)methoxyphosphinyloxy]-e 
thane thiazolium hydroxide-inner salt-4-oxide 
##STR48## 
(a) Preparation of 1-benzyloxy-2-eicosanol 
Following essentially the procedure of Example (1a), and using in place of 
octadecyl-3-butenyl ether, an approximately equivalent amount of 
1-epoxyeicosane, a waxy solid was obtained. 
(b) Preparation of 1-benzyloxy-2-eicosanone 
Following essentially the procedure of Example (1b), and using in place of 
the compound prepared in (1a), an approximately equivalent amount of the 
compound prepared in (a) above, a white solid was obtained. 
(c) Preparation of 5-benzyloxymethyl-5-hydroxy-1-tricosene 
Following essentially the procedure of Example (1c) and using in place of 
the compound prepared in (1b), an approximately equivalent amount of the 
compound prepared in (b) above, a colorless oil was obtained. 
(d) Preparation of 5-benzyloxymethyl-2-hydroxy-5-octadecyl tetrahydrofuran 
Following essentially the procedure of Example (1d), and using in place of 
the compound prepared in (1c), an approximately equivalent amount of the 
compound prepared in (c) above, a colorless oil was obtained. 
(e) Preparation of 5-benzyloxymethyl-5-octadecyl-4,5-dihydro-2(3H)-furanone 
Following essentially the procedure of Example (1e), and using in place of 
the compound prepared in (1d), an approximately equivalent amount of the 
compound prepared in (d) above, a colorless oil was obtained. 
(f) Preparation of 5-hydroxymethyl-5-octadecyl-4,5-dihydro-2-(3H)-furanone 
Following essentially the procedure of Example (1f), and using in place of 
the compound prepared in (1e), an approximately equivalent amount of the 
compound prepared in (e) above, a white solid was obtained. 
(g) Preparation of 
2-bromoethyl-[(2-octadecyl(tetrahydro)-5-oxofuran-2-yl)methyl]-phosphoric 
acid diester 
Following essentially the procedure of Example (1g), and using in place of 
the compound prepared in (1f), an approximately equivalent amount of the 
compound prepared in (f) above, a white solid was obtained. 
Preparation of the title compound 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in place of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (g) 
above, a white solid was obtained, m.p.&gt;122.degree. C. (dec.) 
EXAMPLE 6 
2-[Hydroxy(tetrahydro)-2-(octadecyl-2-furanyl)-methoxyphosphinyloxy]-ethane 
thiazolium hydroxide-inner salt-4-oxide 
##STR49## 
(a) Preparation of 2-benzyloxymethyl-2-octadecyl-tetrahydrofuran 
11.5 g (26 mmol) of the compound prepared in 5d) above was dissolved in 120 
ml of dichloromethane containing 4.54 g (39 mmol) of triethylsilane and 
the reaction mixture was cooled under a nitrogen atmosphere to -20.degree. 
C. To the cooled mixture was added 4.26 g (30 mmol) of boron trifluoride 
etherate and, after 1 hour, a saturated aqueous sodium bicarbonate 
solution was added. The resultant mixture was then warmed to room 
temperature and after being submitted to extractive isolation, 
chromatography on silica gel yielded a colorless oil. 
(b) Preparation of 2-hydroxymethyl-2-octadecyl-tetrahydrofuran 
Following essentially the procedure of Example (1f), and using in place of 
the compound prepared in (1e), an approximately equivalent amount of the 
compound prepared in (a) above, a white solid was obtained. 
(c) Preparation of 
2-bromoethyl-[(2-octadecyl-tetrahydrofuran-2-yl)-methyl]-phosphoric acid 
diester 
Following essentially the procedure of Example (1g), and using in place of 
the compound prepared in (1f), an approximately equivalent amount of the 
compound prepared in (b) above, a white solid was obtained. 
Preparation of the title compound 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in place of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (c) 
above, a white solid was obtained, m.p. 198.degree.-204.degree. C. (dec.) 
EXAMPLE 7 
3-[2-[(2-octadecylaminocarbonyloxymethyl-tetrahydrofuran-2-yl-methoxy)-hydr 
oxyphosphinyloxy]-ethane]-quinolinium hydroxide-inner salt-4-oxide 
##STR50## 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in place of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (3b), 
and in place of the thiazole, an approximately equivalent amount of 
quinoline, the title compound was obtained as a solid, m.p.&gt;105.degree. C. 
(dec.) 
EXAMPLE 8 
3-[6-[(2-Octadecylaminocarbonyloxymethyl-tetrahydrofuran-2-yl-methoxy)-hydr 
oxyphosphinyloxy]-hexane]-thiazolium hydroxide-inner salt-8-oxide 
##STR51## 
(a) Preparation of 
6-bromohexyl-[(2-octadecylaminocarbonyloxymethyl-tetrahydrofuran-2-yl)-met 
hyl]-phosphoric acid diester 
Following essentially the procedure of Example (1g), and using in place of 
the compound prepared in (1f), an approximately equivalent amount of the 
compound prepared in (3a), and in place of the 
2-bromoethylphosphorodichloridate, an approximately equivalent amount of 
6-bromohexylphosphorodichloridate, a white solid was obtained. 
Preparation of the title compound 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in plate of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (a) 
above, the title compound was obtained as a solid, m.p. 
65.degree.-70.degree. C. (dec.) 
EXAMPLE 9 
3-[2-[(2-(9-Octadecenyl)aminocarbonyloxymethyl-tetrahydrofuran-2-yl-methoxy 
)-hydroxyphosphinyloxy]-ethane]-thiazolium hydroxide-inner salt-4-oxide 
##STR52## 
(a) Preparation of 2-hydroxymethyl-2-(9-octadecenyl)aminocarbonyloxy 
tetrahydrofuran 
Following essentially the procedure of Example (3a), and using in place of 
n-octadecylisocyanate, an equivalent amount of n-octadec-9-enylisocyanate, 
a white solid was obtained. 
(b) Preparation of 
2-bromoethyl-[(2-(9-octadecenyl)aminocarbonyloxymethyl-tetrahydrofuran-2-y 
l)-methyl]-phosphoric acid diester 
Following essentially the procedure of Example (1g), and using in place of 
the compound prepared in (1f), an approximately equivalent amount of the 
compound prepared in (a) above, a white solid was obtained. 
Preparation of the title compound 
Following essentially the last step of the procedure in preparing the 
compound of Example 1, and using in place of the compound prepared in 
(1g), an approximately equivalent amount of the compound prepared in (b) 
above, the title compound was obtained as a waxy solid.