Fluorinated arachidonic acid derivatives

Fluorinated arachidonic derivatives are 5-lipoxygenase inhibitors which have the useful pharmacologic activity as antiallergy and anti-inflammatory agents and are useful for treating, for example, asthma, anaphylaxis, allergy, rheumatoid arthritis, and psoriasis and cardiovascular diseases.

This invention relates to certain fluorinated arachidonic acid derivatives 
and their pharmaceutical uses. 
BACKGROUND OF THE INVENTION 
Lipoxygenases, which are found in various mammalian tissues including the 
lung, mast cells, platelets, and white cells, are enzymes which oxidize 
arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) which are 
in turn reduced to the corresponding hydroxyeicosatetra-enoic acids 
(HETEs). The lipoxygenases are classified according to the position in the 
arachidonic acid which is oxygenated. Platelets metabolize arachidonic 
acid to 12-HETE via a 12-lipoxygenase, while polymorphonuclear leukocytes 
contain 5- and 15-lipoxygenases which oxidize arachidonic acid to 5-HPETE 
and 15-HPETE, respectively. 
5-HPETE is the precursor of leukotriene A.sub.4, an unstable precursor of 
two distinct groups of leukotrienes. The first of these are the 
peptido-lipid leukotrienes LTC.sub.4 and LTD.sub.4 formed sequentially by 
reaction of LTA.sub.4 with glutathione followed by reaction with 
.gamma.-glutamyl trans-peptidase to form the cysteinylglycine adduct. 
These compounds account for the biologically active material known as the 
slow reacting substances of anaphylaxis (SRS-A). 
These leukotrienes are potent smooth muscle contracting agents, 
particularly effective on smooth muscle but also on other tissues. They 
also promote mucous production, modulate vascular permeability changes and 
are potent inflammatory agents in human skin. The leukotrienes are potent 
spasmogens of human trachea, bronchus and lung parenchymal strips. 
Administered as an aerosol to normal volunteers, leukotrienes have been 
found to be about 3800 times more potent than histamine itself. In vitro 
studies have shown that antigen challenge of human lung or human mast 
cells results in the production and release of significant amounts of 
leukotrienes. For these reasons leukotrienes are thought to be major 
contributors of the symptoms of asthma and anaphylaxis. The most important 
compound of the second group of leukotrienes is leukotriene B.sub.4, a 
dihydroxy fatty acid. This compound is a potent chemotactic agent for 
neutrophils and in addition may modulate a number of other functions of 
these cells. It also affects other cell types such as lymphocytes and, for 
example, is thought to inhibit the phytohemagglutinin-induced elaboration 
of leukocyte inhibitory factor in T-lymphocytes. Leukotriene B.sub.4 is 
also a potent hyperalgesic agent in vivo and can modulate vascular 
permeability changes through a neutrophil-dependent mechanism. 
Psoriasis is a human skin disease which affects from about 2 to 6 per cent 
of the population but fully adequate therapy remains unavailable. One of 
the earliest events in the development of psoriatic lesions is the 
recruitment of leukocytes to the skin site. In human psoriatic skin, 
abnormally high levels of free arachidonic acid and lipoxygenase products 
are found. Among these, leukotriene B.sub.4 has been identified in blister 
fluid from human psoriatic skin, and when injected into human skin, 
leukotriene B.sub.4 induces a pronounced accumulation of neutrophils at 
the site of injection. Moreover in humans with stable psoriasis, 
intralesional injection of 15-(S)-HETE, an inhibitor of 5- and 
12-lipoxygenases, produces considerable improvement of psoriatic plates. 
The leukotrienes are important mediators of inflammatory diseases through 
their ability to modulate leukocyte and lymphocyte functions. The presence 
of the leukotrienes is thought to be responsible for many of the symptoms 
observed in allergy and rheumatoid arthritis patients. 
Applicants have now discovered a novel class of fluorinated arachidonic 
acid derivatives which are potent inhibitors of 5-lipoxygenase, the enzyme 
responsible for the conversion of arachidonic acid to the leukotrienes. 
These new compounds are useful as antiallergic and anti-inflammatory 
agents in the treatment of asthma, anaphylaxis, allergy, rheumatoid 
arthritis, psoriasis, and cardiovascular diseases. 
SUMMARY OF THE INVENTION 
Fluorinated arachidonic derivatives of formula 1: 
##STR1## 
wherein one of R.sub.5 and R.sub.6 is a fluoro group and the other is a 
hydrogen or both R.sub.5 and R.sub.6 individually are a hydrogen; 
one of R.sub.8 and R.sub.9 is a fluoro group and the other is a hydrogen; 
X is a C(O)OR' group wherein R' is a hydrogen, a straight chain (C.sub.1 
-C.sub.6)alkyl group, or 
X is a group of the formula --C(O)OCH.sub.2 CH(OR")CH.sub.2 (OR'") wherein 
R" is a long chain fatty acid residue and wherein R"' is a hydrogen or a 
long chain fatty acid residue, or 
X is a --C(O)NH.sub.2 or --C(O)NH(OH) group, or 
X is a 1H-tetrazol-5-yl group; and 
R is a group of one of the structural formulae 
##STR2## 
wherein R.sub.3 is a hydrogen or a straight chain (C.sub.1 -C.sub.4)alkyl 
and R.sub.4 is a hydrogen or a straight chain (C.sub.1 -C.sub.6)alkyl and 
wherein a dotted line indicates an optional double or triple bond 
as well as where X is C(O)OR' and R' is a hydrogen and the pharmaceutically 
acceptable salts thereof are 5-lipoxygenase inhibitors which have the 
useful pharmacologic activity as antiallergy and anti-inflammatory agents 
and are useful for treating, for example, asthma, anaphylaxis, allergy, 
rheumatoid arthritis, psoriasis, and cardiovascular diseases. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of this invention may be described as 8-fluoro-, 
5,8-difluoro-, 9-fluoro-, and 5,9-difluoro-, and 6,9-difluoro- arachidonic 
acid derivatives. 
The R groups of the compounds of this invention may contain one or more 
double bonds. Any double bonds in the R group of this invention must have 
the cis configuration except for the double bond at the 13,14 position of 
the hydroxylated R groups which must be of the trans configuration. 
Moreover the carbon atom to which the hydroxy group is attached in the 
hydroxylated R groups, the 15 carbon atom, is chiral. Of those compounds 
having a hydroxylated R group, applicants prefer those with the S 
configuration at the carbon atom bearing the hydroxy group. 
As is true with many classes of pharmacologically active compounds, certain 
subclasses are preferred. In the compounds of this invention those of 
formula 1 wherein X is a CO.sub.2 H group and wherein X is a group of the 
formula --C(O)OCH.sub.2 CH(OR")CH.sub.2 (OR'") wherein R" is a long chain 
fatty acid residue and wherein R"' is a hydrogen or a long chain fatty 
acid residue are preferred. Also preferred are those compounds of formula 
1 wherein the R group is hydroxylated, especially those hydroxylated R 
groups having two double bonds. Additionally preferred are those R groups 
wherein R.sub.3 is an ethyl group, especially those having two or three 
double bonds and which correspond to 5,8,11,14-eicosatetraenoic acid and 
5,8,11,14,17-eicosapentaenoic acid. 
Those compounds of this invention wherein X is a group of the formula 
--C(O)OCH.sub.2 CH(OR")CH.sub.2 (OR"') are analogs of the naturally 
occuring arachidonic acid containing lipids from which arachidonic acid is 
released in mammals. The groups R" and R'" can be long chain, fatty acid 
residues. Suitable long chain, fatty acid residues are those of the 
naturally occuring saturated and unsaturated fatty acids as well as 
analogs of these naturally occuring fatty acids. The carbon chains of the 
naturally occuring fatty acids are usually unbranched, usually contain an 
even number of carbon atoms, and usually any double bonds are of the cis 
configuration. Additionally the double bonds of the naturally occuring 
unsaturated fatty acids are never conjugated. However, the long chain, 
fatty acids of this invention may be branched, may contain an odd number 
of carbon atoms, may contain conjugated double bonds, and may have trans 
configuration. Examples of suitable fatty acids are butyric, caproic, 
caprylic, capric, lauric, myristic, palmitic, stearic, araohidic, 
lignoceric, oleic, palmit-oleic, linoleic, .gamma.-linolenic, linolenic, 
arachidonic 5,8,11,14,17-eicosapentaenoic acids. 
The 8-fluoro and 5,8-difluoroarachidonic acid derivatives, that is those 
compounds of formula 1 wherein X is a COOH group and R.sub.8 is a fluoro 
group, can be prepared by the oxidation of an aldehyde of formula 2 
wherein R and R.sub.5 are as defined in formula 1. The oxidation can be 
accomplished by, for example, adding an excess of Jones 
##STR3## 
Reagent to a cooled (0.degree. C.) acetone solution of the aldehyde. The 
reaction mixture is then allowed to react for about 10 to 30 minutes. 
Isopropanol is then added to consume excess Jones Reagent nd the acetone 
solvent is removed by evaporation on the rotary evaporator. The residue is 
then mixed with water and the water mixture is extracted with ethyl 
acetate. After concentration of the ethyl acetate extracts, flash 
chromatography on silica gel eluting with a mixture of ethyl acetate and 
benzene (15:85) results in the isolation of the desired carboxylic acid. 
The formula 2 aldehydes are prepared by treatment of a bromo or chloro 
derivative of formula 3 
##STR4## 
wherein Hal is a chloro or bromo group and R and R.sub.5 are as defined in 
formula 1. This can be accomplished by treating a solution of 
N-allyl-N,N',N"-pentamethylphosphoramide in tetrahydrohydrofuran (THF) 
with one equivalent of n-butyllithium while maintaining a temperature of 
about -78.degree. C. for about 1 hour until anion formation is complete. 
The formula 3 halide is then added to the solution of anion and the 
temperature is allowed to rise to about 0.degree. C. The reaction is 
complete in about 2 hours and the resulting condensation product of 
formula 3a 
##STR5## 
wherein R and R.sub.5 are as defined in formula 1, in an ether solvent 
such as THF or diethyl ether is then subjected to acid catalyzed 
hydrolysis employing a mild acid such as a dilute mineral acid such as 
dilute hydrochloric acid. The hydrolysis is complete in about 1 to about 2 
hours at room temperature. Isolation by solvent removal and purification 
by chromatography on, for example, silica gel eluting with a 25:75 mixture 
of ethyl acetate and hexane afforded purified product. 
The halide of formula 3 is prepared from the allylic alcohol of formula 4 
##STR6## 
wherein R and R.sub.5 are as defined in formula 1 in any suitable art 
known procedure. Applicants have prepared the halide derivatives of 
formula 3 by treatment of the formula 4 alcohol with a slight (e.g. 20%) 
excess of 1-bromo-N,N,2-trimethylpropenylamine in a cooled (0.degree. C.) 
methylene chloride solution. The formula 3 halide derivatives can also be 
prepared by stepwise conversion of the alcohol, 4, to its mesylate 
derivative by treatment with methanesulfonic acid chloride in the presence 
of a proton acceptor such pyridine or triethylamine. Subsequent treatment 
of the mesyl derivative with a source of bromide or chloride ion such as a 
brominated or chlorinated ion exchange resin, for example, Amberlyst A26, 
Br.sup.- or Cl.sup.- form, results in the desired halide. The 
halogenation reaction utilizing Amberlyst A26 resin will take from 8 to 24 
hours when performed in refluxing benzene. 
The alcohol of formula 4 is prepared by reduction of the corresponding 
carboxylic ester of formula 5 
##STR7## 
wherein R and R.sub.5 are as defined in formula 1 and R" is an alkyl or 
benzyl group, for example, an ethyl group. The reduction can be carried 
out in any conventional manner readily known by those skilled in the art 
for reducing an ester in the presence of an olefinic bond. Applicants have 
performed this reduction by treating a solution of an ethyl ester of 
formula 5 (R" is ethyl) in an ethereal solvent such as THF with a aluminun 
hydride reducing agent such as diisobutylaluminun hydride (DIBAL). Such a 
reaction is typically carried out by adding a solution of DIBAL in hexane 
to a solution of the ester in the ethereal solvent. After stirring for 
from about 15 minutes to about 1 hour, preferably about 30 minutes, the 
reaction is allowed to continue at room temperature for from about 6 to 
about 24 hours. Addition of methanol to destroy excess reducing agent and 
ammonium chloride to precipitate the aluminum salts gives a solution of 
the reduced product. The product is isolated after solvent removal and is 
purified by flash chromatography on silica gel eluting with, for example, 
an 8:2 mixute of hexane and ethyl acetate. 
The formula 5 ester is prepared from the formula 6 aldehyde 
##STR8## 
wherein R is as defined in formula 1 by reaction with the ylid of 
triethylphosphono fluoroacetate. 
The ylid is formed from the optionally fluorinated phosphonate in the usual 
way by treatment of the phosphonate with about one molar equivalent of a 
strong, organic base, preferably lithium diisopropylamide (LDA) formed in 
situ by the reaction of n-butyl lithium and diisopropylamine, at low 
temperature, typically from about -78.degree. C. to about -25.degree. C., 
in a suitable solvent, preferably a solvent or solvent combination known 
to promote the Wittig reaction such as tetrahydrofuran (THF). 
Hexamethylphosphorictriamide (HMPA), which is known to promote the Wittig 
reaction by forming a chelate with the lithium counterion, can 
advantageously be added. The solution of ylid is then allowed to warm 
slightly to from about -30.degree. C. to about 0.degree. C. and the 
appropriate aldehyde is added, preferably dropwise, and allowed to react 
until formation of the desired condensation product of formula 5 is 
formed. The product can be isolated by quenching the reaction mixture with 
a saturated, aqueous solution of ammonium chloride and subsequent removal 
of the organic solvent by evaporation with a rotary evaporator. The 
mixture is then extracted with diethyl ether to give the isolated product 
upon evaporation of the ether solvent. The crude product can be purified 
by, for example, flash chromatography on silicagel eluting with a mixture 
of hexane and bezene (9:1). 
The structure 6 aldehyde is in turn prepared from the appropriate dithiane 
of structure 7 
##STR9## 
wherein R is as defined in formula 1 by hydrolysis in the usual manner. 
The dithiane is prepared from the appropriate bromo or chloro of structure 
8 
##STR10## 
wherein R is as defined in formula 1 and wherein Hal is a bromo or chloro 
group by reaction with the anion of 1,3-dithiane formed by treatment with 
n-butyl lithium in cooled (i.e., -30.degree. C.) tetrahydrofuran. 
The formula 8 halide is prepared from the corresponding alcohol of formula 
8a in any suitable art-known manner. Applicants have transformed the 
formula 8a alcohol to the formula 8 halide by reaction with one equivalent 
of 1-bromo-N,N,2-trimethylpropenylamine in a cooled (0.degree. C.) 
methylene chloride solution. Alternatively, the formula 7 dithiane 
derivative can be prepared from an activated derivative of the formula 8a 
alcohol such as the mesyl or tosyl derivative of the alcohol. 
The formula 8a alcohol can be prepared by reduction of the appropriate 
ester of formula 9 
##STR11## 
wherein R is as defined for formula 1 and wherein R" is a lower alkyl, 
phenyl, or benzyl group. This reduction can be accomplished in any 
suitable manner such as by treating a solution of an ethyl ester of 
formula 9 (R"=ethyl) in an ethereal solvent such as THF with an aluminum 
hydride reducing agent such as diisobutylaluminum hydride (DIBAL). Such a 
rection is typically carried out by adding a solution of DIBAL in hexane 
to a solution of the ester in the ethereal solvent. After stirring for 
from about 15 minutes to about 1 hour, preferably about 30 minutes, the 
reaction is allowed to continue at room temperature for from about 6 to 
about 24 hours. Addition of methanol to destroy excess reducing agent and 
ammonium chloride to precipitate the aluminum salts gives a solution of 
the reduced product. The product is isolated after solvent removal and is 
purified by flash chromatography on silica gel eluting with, for example, 
an 8:2 mixture of hexane and ethyl acetate. 
The formula 9 ester is prepared by the condensation of the ylid of the 
fluorinated phosphonate (C.sub.2 H.sub.5 O).sub.2 P(O)CHFCO.sub.2 (C.sub.2 
H.sub.5) with an aldehyde of the formula RCHO wherein R is also as defined 
as above in formula 1. The ylid is formed from the fluorinated phosphonate 
in the usual way by treatment of the phosphonate with about one molar 
equivalent of a strong, organic base, preferably lithium diisopropylamide 
(LDA) formed in situ by the reaction of n-butyl lithium and 
diisopropylamine, at low temperature, typically from about -78.degree. C. 
to about -25.degree. C., in a suitable solvent, preferably a solvent or 
solvent combination known to promote the Wittig reaction such as 
tetrahydrofuran (THF). Hexamethylphosphorictriamide (HMPA), which is known 
to promote the Wittig reaction by forming a chelate with the lithium 
counterion, can advantageously be added. The solution of ylid is then 
allowed to warm slightly to from about -30.degree. C. to about 0.degree. 
C. and the appropriate aldehyde is added, preferably dropwise, and allowed 
to react until formation of the desired condensation product of formula 9 
is formed. The product can be isolated by quenching the reaction mixture 
with a saturated, aqueous solution of ammonium chloride and subsequent 
removal of the organic solvent by evaporation with a rotary evaporator. 
The mixture is then extracted with diethyl ether to give the isolated 
product upon evaporation of the ether solvent. The crude product can be 
purified by, for example, flash chromatography on silicagel eluting with a 
mixture of hexane and benzene (9:1). 
The aldehydes of the formula RCHO, i.e., R is a C.sub.11 carbon chain used 
to prepare the compounds of this invention can be easily prepared from 
readily available materials, for example, from the corresponding alcohols 
by simple oxidation using pyridinium chlorochromate or Collin's reagent in 
methylene chloride. Many of the alcohols and aldehydes are known. 
6-Dodecyn-1-ol is known from J. Chem. Soc., 4363 (1963); (Z)-6-Dodecenal 
is known from U.S. Pat. No. 4,239,756, granted December 1980; 
(Z,Z)-3,6-dodecedienal is known from Agric. Biol. Chem., 41, 1481 (1977); 
and 1-hydroxy-3,6,9-dodecatriyne and (Z,Z,Z)-1-hydroxy-3,6,9-dodecatriene 
are known from Tetrahedron Letters, 22, 4729 (1981). Olefinic alcohols 
having the (Z) configuration, for example, can be prepared by Nickel 
boride with ethylene diamine in methanol or ethanol hydrogenation of the 
corresponding acetylenic alcohols by the procedure of C. A. Brown and V. 
K. Ahuja, Chemical Comm. 553 (1973). 
The optically active aldehyde (25) required to prepare those compounds of 
formula 1 wherein the R group has the structural formula: 
##STR12## 
can be prepared from D-arabinose as illustrated in Scheme 3. 
##STR13## 
The thioacetal (26) is first prepared from D-arabinose by the procedure 
described by M. Wong and G. Gray, J. Amer. Chem. Soc. 100, 3548 (1978). 
The silyloxy aldehyde (27) is then prepared by reaction of the 
dithioacetal (26) with mercuric oxide and calcium carbonate in refluxing 
aqueous acetonitrile. The silyloxy aldehyde (27) is then reacted with the 
ylid of n-propylbromide and triphenylphosphine (28) formed in the usual 
manner by reaction with a strong base such as n-butyllithium and potassium 
t-butoxide in a solvent such as tetahydrofuran. The resulting 
silyloxyolefin (29) is reduced catalytically with, for example, molecular 
hydrogen and a palladium on carbon catalyst in ethylacetate to form the 
silyloxy compound (30). The silyloxy compound (30) is converted to the 
unsaturated aldehyde (33) by the procedure described in G. Just and Z. 
Wang, Tet. Lett. 26, 2993 (1985) via the diol (31) and the aldehyde (32). 
Reaction of the unsaturated aldehyde (33) with the ylid of the acetone 
ketal of 3,4-dihydroxyiodobutane described by P. DeClercy and R. Mijnheen, 
Bull. Soc. chem. Belg. 87, 495 (1978) in the usual manner results in the 
diolefinketal (34). Hydrolysis and sodium metaperiodate oxidation in a 
manner analogous to that described for the conversion of (30) to (32) 
gives the silyl ether derivative (24a) which upon removal of the silyl 
group in the usual manner such as by treatment with fluoride ion gives the 
desired diunsaturated aldehyde (24) wherein the carbon atom bearing the 
hydroxy group is of the S configuration. Modification of this procedure or 
chemical modification of the diunsaturated aldehyde can give the other 
required optically active aldehydes. 
In the preparation of the 8-fluoro compounds embraced by formula 1, the 
synthesis is affected by the following reaction scheme using compounds 6 
as starting materials. 
##STR14## 
The 5,9-difluoroarachidonic acid derivatives, that is those compounds of 
formula 1 wherein X is a COOH group and R.sub.5 and R.sub.9 are both a 
fluoro group, can be prepared by the oxidation of the corresponding 
alcohol of formula 10 
##STR15## 
wherein R and R.sub.5 are as defined in formula 1. Such an oxidation can 
be accomplished by, for example, treatment of the alcohol with the Jones 
Reagent. Excess Jones Reagent is then added to a cooled (0.degree. C.) 
acetone solution of the alcohol and the reaction mixture is then allowed 
to react for about 10 to 30 minutes. Isopropanol is then added to consume 
excess Jones Reagent and the acetone solvent is removed by evaporation on 
the rotary evaporator. The residue is then mixed with water and the water 
mixture is extracted with ethyl acetate. After concentration of the ethyl 
acetate extracts, flash chromatography on silica gel eluting with a 
mixture of ethyl acetate and benzene (15:85) results in the isolation of 
the desired carboxylic acid. 
The formula 10 alcohol is in turn prepared from the silylated halide of 
formula 11 
##STR16## 
wherein R.sub.5 is as defined in formula 1 and Hal is a chloro or 
preferably a bromo group. The formula 11 halide is first reacted with 
triphenylphosphine in the usual manner to form the triphenylphosphonium 
salt. The ylid is formed from the corresponding phosphonium salt in the 
usual way by treatment of the phosphonium salt with about one molar 
equivalent of a strong, organic base, preferably lithium diisopropylamide 
(LDA) formed in situ by the reaction of n-butyl lithium and 
diisopropylamine, at low temperature, typically from about -78.degree. C. 
to about -25.degree. C., in a suitable solvent, preferably a solvent or 
solvent combination known to promote the Wittig reaction such as 
tetrahydrofuran (THF). Hexamethylphosphorictriamide (HMPA), which is known 
to promote the Wittig reaction by forming a chelate with the lithium 
counterion, can advantageously be added. The solution of ylid is then 
allowed to warm slightly to from about -30.degree. C. to about 0.degree. 
C. and the appropriate aldehyde is added, preferably dropwise, and allowed 
to react until formation of the desired condensation product is formed. 
The product can be isolated by quenching the reaction mixture with a 
saturated, aqueous solution of ammonium chloride and subsequent removal of 
the organic solvent by evaporation with a rotary evaporator. The mixture 
is then extracted with diethyl ether to give the isolated product upon 
evaporation of the ether solvent. The crude product can be purified by, 
for example, flash chromatography on silicagel eluting with a mixture of 
hexane and bezene (9:1). Removal of the diphenyl-t-butyl silyl protecting 
group in the usual manner such as by treatment with fluoride ion results 
in the desired formula 10 alcohol. 
The formula 11 silylated halide is prepared from the corresponding alcohol 
of formula 11a wherein R.sub.5 is as defined in formula 1. Applicants have 
transformed the alcohol to the halide by reaction with one equivalent of 
1-bromo-N,N,2-trimethylpropenylamine in a cooled (0.degree. C.) methylene 
chloride solution. The formula 11a alcohol is prepared from the 
corresponding halide of formula 12 
##STR17## 
wherein R.sub.5 is as defined in formula 1 and wherein Hal is a chloro 
group or preferably a bromo group. The formula 12 halide is treated with 
the anion of 1,3-dithiane formed by reaction of 1,3-dithiane with n-butyl 
lithium in cooled (i.e. -30.degree. C.) tetrahydrofuran to produce an 
intermediate dithialane compound which upon hydrolysis in the usual manner 
such as by addition of the dithialane derivative to a suspension of one 
equivalent of trimethyloxonium tetrafluoroborate in methylene chloride. 
After reaction for about one hour at room temperature, two equivalents of 
calcium carbonate in aqueous acetone suspension is added and allowed to 
react overnight. The intermediate aldehyde is isolated and reduced with, 
for example, sodium borohydride in the usual manner to yield the desired 
alcohol of formula 11a. 
The formula 12 halide is prepared from the corresponding alcohol of formula 
12a wherein R.sub.5 is as defined in formula 1 in any suitable art known 
procedure. Applicants have prepared the formula 12 bromide by treatment of 
the alcohol with one equivalent of 1-bromo-N,N-2-trimethylpropenylamine in 
a cooled (0.degree. C.) methylene chloride solution. Alternatively the 
formula 12 halide can be prepared by stepwise conversion of the formula 
12a alcohol to its mesylate (or tosyl) derivative by treatment with 
methanesulfonic acid chloride in the presence of a proton acceptor such 
pyridine or triethylamine. Subsequent treatment of the mesyl derivative 
with a source of bromide ion such as a brominated ion exchange resin, for 
example, Amberlyst A26, Br.sup.- form, results in the desired bromide 12. 
The bromination reaction utilizing Amberlyst A26 resin will take from 8 to 
24 hours when performed in refluxing benzene. Alternatively, the mesyl (or 
tosyl) derivative can be utilized directly in the reaction with the anion 
of 1,3-dithiane to produce the dithiane intermediate described above for 
the preparation of the formula 11 alcohol. 
The formula 12a alcohol is prepared from the ester of formula 13 
##STR18## 
wherein R.sub.6 is as defined in formula 1 and wherein R" is a lower 
alkyl, phenyl, or benzyl group such as an ethyl group. This reduction can 
be accomplished in any suitable manner such as by treating a solution of 
an ethyl ester of formula 13 (R"=ethyl) in an ethereal solvent such as THF 
with an aluminum hydride reducing agent such as diisobutylaluminum hydride 
(DIBAL). Such a reaction is typically carried out by adding a solution of 
DIBAL in hexane to a solution of the ester in the ethereal solvent. After 
stirring for from about 15 minutes to about 1 hour, preferably about 30 
minutes, the reaction is allowed to continue at room temperature for from 
about 6 to about 24 hours. Addition of methanol to destroy excess reducing 
agent and ammonium chloride to precipitate the aluminum salts gives a 
solution of the reduced product. The product is isolated after solvent 
removal and is purified by flash chromatography on silica gel eluting 
with, for example, an 8:2 mixute of hexane and ethyl acetate. 
The formula 13 ester is in turn prepared reacting the formula 14 aldehyde 
##STR19## 
wherein R.sub.5 is as defined in formula 1 with the ylid of the 
fluorinated phosphonate ester (C.sub.2 H.sub.5 O).sub.2 P(O)CHFCO.sub.2 
C.sub.2 H.sub.5. The ylid is formed from the corresponding phosphonium 
salt in the usual way by treatment of the phosphonium salt with about one 
molar equivalent of a strong, organic base, preferably lithium 
diisopropylamide (LDA) formed in situ by the reaction of n-butyl lithium 
and diisopropylamine, at low temperature, typically from about -78.degree. 
C. to about -25.degree. C., in a suitable solvent preferably a solvent or 
solvent combination known to promote the Wittig reaction such as 
tetrahydrofuran (THF). Hexamethylphosphorictriamide (HMPA), which is known 
to promote the Wittig reaction by forming a chelate with the lithium 
counterion, can advantageously be added. The solution of ylid is then 
allowed to warm slightly to from about -30.degree. C. to about 0.degree. 
C. and the appropriate aldehyde is added, preferably dropwise, and allowed 
to react until formation of the desired condensation product of structure 
3 is formed. The product can be isolated by quenching the reaction mixture 
with a saturated, aqueous solution of ammonium chloride and subsequent 
removal of the organic solvent by evaporation with a rotary evaporator. 
The mixture is then extracted with diethyl ether to give the isolated 
product upon evaporation of the ether solvent. The crude product can be 
purified by, for example, flash chromatography on silicagel eluting with a 
mixture of hexane and benzene (9:1). 
The formula 14 alcohols are prepared by addition of the 1,3-dithialane 
derivative of formula 15 to a suspension of one equivalent of 
trimethyloxonium tetrafluoroborate in methylene chloride. After reaction 
for about one hour at room temperature, two equivalents of calcium 
carbonate in aqueous acetone suspension is added and allowed to react 
overnight. The aldehyde is isolated by, for example, filtration and 
solvent removal. 
The silylated dithialanes of formula 15 wherein R.sub.5 is a fluoro group 
are prepared from the dithianyl alcohol of formula 19 as outlined in 
scheme 1. 
##STR20## 
The hydroxy group of the formula 19 butene is converted to a chloro group 
by reaction with, for example, 1-chloro-N,N-2-trimethylpropene. The 
chlorinated compound of formula 18 wherein R.sub.5 is as defined in 
formula 1 is transformed into the aldehyde of formula 17 by reaction with 
N-allyl-N,N',N"-pentamethylphsophoramide in tetrahydrofuran. Reduction in 
the usual manner with sodium borohydride results in formation of the 
alcohol of formula 16. Treatment of the alcohol with t-butyldiphenylsilyl 
chloride in the presence of a proton acceptor gives the desired compound 
of formula 15. The hydroxy, dithialane of formula 19 is prepared from a 
chloro, tetrahydropyranyloxy butene of formula 21 
##STR21## 
wherein R.sub.5 is a defined in formula 1. The dithialane derivative of 
formula 20 
##STR22## 
is first prepared by reaction of the formula 21 chloro derivative with the 
anion of 1,3-dithiane formed by reaction with n-butyl lithium in cooled 
(i.e. -30.degree. C.) tetrahydrofuran. Subsequent removal of the THP 
protecting group by treatment with methanol and pyridinium paratoluene 
sulfonate (PPTS) catalyst results in the desired formula 19 alcohol. The 
compound of formula 21 is readily prepared from the optionally fluorinated 
maleic acid, formula 24, as illustrated in scheme 2. 
##STR23## 
The optionally fluorinated maleic acid is converted to the corresponding 
dimethylester of formula 22 by reaction with diazomethane. Subsequent 
ester group reduction with excess diisobutylaluminun hydride (DIBAL) in 
THF at about 0.degree. C. results in formation of the di-alcohol 
derivative of formula 23. Selective conversion of one of the hydroxy 
groups can be accomplished using a slight (10%) molar excess of 
N-chlorosuccinimide (NCS) and dimethylsulfide. Protection of the other 
hydroxy group as the THP derivative can be accomplished in the usual 
manner by reaction with dihydropyran (DHP) and catalytic pyridinium 
paratoluene sulfonate (PPTS) results in formation of the desired formula 
21 compound. 
##STR24## 
To prepare the 6,9-difluoroarachidonic acids of formula 1, the alcohols of 
36 are treated with one equivalent of 1-bromo-N,N-2-trimethylpropenylamine 
in a cooled (0.degree. C.) methylene chloride solution to obtain the 
corresponding bromide. The bromide (35) is treated with the anion of 
1,3-dithiane with n-butyl lithium in cooled (-30.degree. C.) THF to 
produce an intermediate dithalane which upon hydrolysis in the usual 
manner (i.e., addition of trimethyloxonium tetrafluoroborate in CH.sub.2 
Cl.sub.2. After reaction for about 1 hour at room temperature, two 
equivalents of calcium carbonate in aqueous acetone suspension is added 
and allowed to react overnight.) gives the corresponding aldehyde. This 
so-produced 6-F aldehyde is isolated and may be used without purification. 
This 6-F aldehyde is converted to the corresponding 6,9-difluoro compounds 
in the analogous way that the corresponding 5-fluoro aldehyde is converted 
to the 5,9-difluoro compounds of formula 10. 
To prepare the 9-fluoro arachidonic acid derivatives of formula 1 the 
chemistry used and described herein may analogously be utilized. Starting 
with dehydro-2,3-delta valero lactone, 
##STR25## 
The lactone is reduced to the corresponding 2-diol with an excess of DIBAL 
in THF. The diol (HOCH.sub.2 CH.sub.2 CH.dbd.CHCH.sub.2 OH) is treated 
with one equivalent of N-chlorosuccinimide (NCS) in CH.sub.2 Cl.sub.2 in 
the presence of dimethylsulfide to yield the Z-1-chloro-5-OH-2-pentene, 
the alcohol of which is protected as a tetrahydropyranyl ether (OTHP) 
using an excess of dihydropyran in the presence of catalytic amounts of 
PPTS. The chloride (THPO-CH.sub.2 CH.sub.2 CH.dbd.CHCH.sub.2 Cl) is 
converted to its aldehyde using analogous chemistry as described for 
converting 3 to 2 (i.e., [(CH.sub.3)N]2P(O)N(CH.sub.3)(C.sub.3 H.sub.5) 
plus n-BuLi, (2) HCl and (3) reprotection of the alcohol with DHP/PPTS as 
in the conversion of 16 to 15. The aldehyde is reduced with NaBH.sub.4 
(analogously with 17 to 16). The alcohol is silylated using chemistry 
analogous to conversion of 16 to 15 and then the THP ether is cleaned as 
described on for converting copound 37 to 36. The resulting alcohol is 
oxidized with pyridinium chlorochromate in CH.sub.2 Cl.sub.2, as 
previously described, to yield the aldehyde which is treated with the ylid 
of a fluorinated phosphonate ester using the same chemistry analogously 
described for converting compound 14 to 13. Following this chemical step 
then the same chemistry used to convert 10 to the desired arachidonic 
acids may be used (i.e., the R.sub.5 would be H). 
The compounds of structure 1 wherein X is other than C(O)OH can be readily 
prepared from the carboxylic acids by any procedure generally known to 
those skilled in the art. For example, those compounds of formula 1 
wherein X is --C(O)NH.sub.2, are prepared from the corresponding compound 
wherein X is --CO.sub.2 H, by reaction with about 1 molar equivalent of 
carbonyldiimidazole in an aprotic organic solvent, preferably 
dichloromethane, for a period of 1 to 7 hours, preferably about 4 hours. 
Then the product is reacted with a large excess of ammonium hydroxide for 
from 24 to 64 hours, preferably for about 48 hours. Isolation of the 
desired compounds of formula those in the art. 
Alternatively, the compounds of formula 1 wherein X is CONH.sub.2 can be 
prepared by first converting the acid into an activated derivative such 
as, for example, by reaction of the carboxylic acid with an acyl halide, 
an anhydride, a mixed anhydride, an alkyl ester, a substituted or 
unsubstituted phenyl ester, a thioalkyl ester, a thiophenyl ester, an acyl 
imidazole, and the like. The activated derivative is then reacted with 
ammonia or aqueous ammonia with or without a suitable water-miscible or 
immiscible organic solvent, for example, methanol, ethanol, 
dichloromethane, and the like, so as to produce the amide. The reaction is 
conducted at from -30.degree. C. to the boiling point of the solvent or 
solvent mixture used, for from 1 to 96 hours. 
Alternatively, the amide can be made by heating together the appropriate 
compound of formula 1 wherein X is CO.sub.2 H and ammonia, or by heating 
the ammonium salt of a carboxylic acid of formula 1. The reaction is 
conducted either in the absence of a solvent, or in the presence of a 
solvent such as, for example, toluene, at a temperature of from 
100.degree. C. to 300.degree. C., for from 1 to 12 hours. 
Alternatively, the amide can be obtained by hydrolysis of a nitrile 
derivative (formula 1 wherein X is CN) using either inorganic or organic 
acids or bases, such as, for example, hydrochloric acid, sulphuric acid, 
p-toluenesulphonic acid, sodium hydroxide, potassium carbonate, or 
tetrabutylammonium hydroxide and the like. The reaction is conducted in 
water optionally containing from 1% to 95% of a cosolvent such as, for 
example, methanol, acetic acid or diglyme, at a temperature of from 
0.degree. C. to the boiling point of the solvent used, for from 1 to 96 
hours. Such procedures are well known to those skilled in the art and are 
described, for example, in Synthetic Organic Chemistry, John Wiley and 
Sons, Publ., New York, 565-590 (1953) and Compendium of Organic Synthetic 
Methods, Vol. 1, Wiley-Interscience, New York, 203-230 (1971). 
The compounds of formula 1 wherein X is a 1H-tetrazol-5-yl group can be 
prepared from the corresponding amide (I wherein X is CONH.sub.2) via an 
intermediate nitrile (I wherein X is CN) derivative. To a solution of an 
appropriate compound of formula 1 wherein X is CONH.sub.2 in a basic 
organic solvent, preferably pyridine, is added about 1 mole, or 
equivalent, of an organic sulphonyl halide, preferably p-toluenesulphonyl 
chloride. The mixture is reacted for 12-48 hours, preferably about 24 
hours, and the solution is poured into water. The nitrile is extracted 
from the aqueous phase with an organic solvent, preferably ethyl ether, 
and the extract is purified by procedures known in the art. 
The isolated nitrile is then reacted with an excess, preferably 3 moles, of 
an alkali metal azide, preferably sodium azide, and an excess, preferably 
3 moles, of an ammonium halide, preferably ammonium chloride, in an 
aprotic, polar solvent, preferably dimethylformamide, at a temperature of 
80.degree. C. to 120.degree. C., preferably 100.degree. C., for 16 to 48 
hours, preferably 24 hours optionally in the presence of a Lewis acid such 
as, for example, boron trifluoride. In this reaction, other sources of 
azide ion may be used, such as aluminium azide and the azide of 
tri-n-butyl tin. The product is then isolated by procedures known in the 
art. 
Alternatively, the compounds of formula 1 wherein X is a 1H-tetrazol-5-yl 
group can be prepared by the reaction between an iminoether derivative of 
formula 1 wherein X.dbd.C(NH)O(C.sub.1 -C.sub.6 alkyl) and hydrazoic acid 
as described in German Patent 521870. The iminoether derivative is 
obtained by treatment of a nitrile derivative (formula 1 wherein X.dbd.CN) 
with a (C.sub.1 -C.sub.6) alkanol and a strong acid such as, for example, 
hydrochloric acid or p-toluenesulphonic acid. The reaction between the 
iminoether and hydrazoic acid is conducted in the presence of a solvent 
such as, for example, chloroform or dimethylformamide, at from 0.degree. 
C. to 120.degree. C., for from 1 to 72 hours. Tetrazole derivatives can 
also be obtained by the reaction between an amidine derivative of an 
unsaturated fatty acid, prepared, for example, from the nitrile derivative 
as described in Synthetic Organic Chemistry, John Wiley and Sons, Publ., 
New York, 635 (1953) and nitrous acid, as described in Annalen, 263, 96 
(1981), and 208, 91 (1987). The reaction is conducted in water or a 
mixture of water and a suitable organic solvent such as, for example, 
methanol or dioxane, at from 0.degree. C. to 100.degree. C., for from 1 to 
24 hours. 
The esters of compounds of formula I, those wherein X is C(O)OR.sup.1 
wherein R.sup.1 is a straight chain (C.sub.1 -C.sub.6) alkyl group can be 
prepared in the usual manner by esterification of the corresponding 
carboxylic acid of formula 1 (X.dbd.CO.sub.2 H)by treatment with a 
solution of hydrogen chloride in the appropriate lower alkanol, preferably 
the esters are prepared from the carboxylic acids via the acid chloride 
derivative. The acid is reacted with a thionyl or phosphoryl halide or 
phosphorus pentahalide, preferably thionyl chloride, dissolved in an inert 
organic solvent, preferably benzene, containing a trace of a tertiary 
organic amide, preferably dimethylformamide. The mixture is reacted for 
8-32 hours, preferably for about 16 hours, at from 0.degree. C. to 
25.degree. C., then evaporated to dryness. The residue, the acid chloride, 
is dissolved in an inert organic solvent and the appropriate lower alkanol 
is added dropwise. 
The acylhydroxylamine derivatives, those compounds of formula I wherein X 
is CONHOH, are prepared in two ways. The acid is either first converted, 
as described above, into the acid chloride or into a lower alkyl ester, 
preferably the methyl ester. The acid chloride or the lower alkyl ester is 
then reacted with an excess of hydroxylamine in an aqueous organic 
solvent, preferably aqueous methanol, at a pH of between 7 and 10, 
preferably at about pH 9, for from 1/4 to 6 hours, preferably about 1 
hour. The acylhydroxylamine product is then isolated by means known in the 
art. 
Acylhydroxylamines can also be prepared by the reaction between 
hydroxylamine and an activated derivative of an unsaturated fatty acid 
such as, for example, an acyl halide, an anhydride, a mixed anhydride, an 
alkyl ester, a substituted or unsubstituted phenyl ester, a thioalkyl 
ester, a thiophenyl ester, an acyl imidazole, and the like. The reaction 
is conducted in an aqueous organic or organic solvent such as, for 
example, methanol, acetonitrile or acetone, at from 0.degree. C. to the 
reflux temperature of the solvent, for from 1 to 48 hours. Alternately, 
acylhydroxylamines can be prepared by acid-catalyzed rearrangement of a 
primary nitro derivative (formula 1, X.dbd.NO.sub.2) as described in 
Chemical Reviews, 32, 395 (1943). The reaction is conducted in an aqueous 
organic or organic solvent, such as, for example, methanol, ethanol and 
dioxan, at from 0.degree. C. to 100.degree. C., for from 1 to 24 hours, in 
the presence of a strong acid such as, for example, sulphuric acid or 
hydrochloric acid. Acylhydroxylamine derivatives of unsaturated fatty 
acids can also be obtained by the oxidation of the oxime derivative of 
formula 1 wherein X.dbd.CHNOH using, for example, hydrogen peroxide as 
described in Chemical Reviews, 33, 225 (1943). The reaction is conducted 
in a solvent such as methanol or dichloromethane and the like, at from 
0.degree. C. to 35.degree. C. for from 1 to 6 hours. 
The chloro derivative, 17, is first reacted with 
N-allyl-N,N',N"-pentamethylphosphoramide in tetra-hydrofuran. The 
intermediate product is isolated and then treated with concentrated 
hydrochloric acid. Finally the THP (tetrahydropyranyloxy) group is 
reformed by reaction of the product with dihydropyran (DHP) and catalytic 
pyridinium paratoluene sulfonate (PPTS) to produce the aldehyde, 16. 
Reduction in the usual manner with sodium borohydride results in alcohol 
15. Treatment of the alcohol with t-butyldiphenylsilyl chloride in the 
presence of a proton acceptor gives the desired 14. The THP protecting 
group is then removed by treatment with methanol and 
tetrabutyl-1,3-diisothiocyanotodistannoxane catalyst to give the alcohol 
13. The alcohol is converted to the corresponding bromide, 12, by reaction 
with 1-bromo-N,N',2-trimethylpropenylamine in methylene chloride solution. 
The silylated, dithialane, 7, is then produced by reaction of the bromide, 
12, with the anion of 1,3-dithiane formed by reaction with n-butyl lithium 
in cooled (i.e. -30.degree. C.) tetrahydrofuran. 
Isolation and purification of the compounds and intermediates described 
herein can be effected, if desired, by any suitable separation or 
purification procedure such as, for example, filtration, extraction, 
crystallization, column chromatography, thin-layer chromatography or thick 
layer chromatography, or a combination of these procedures. Specific 
illustrations or suitable separation and isolation procedures can be had 
by reference to the examples hereinbelow. However, other equivalent 
separation or isolation proceudres could, of course, also be used. 
The pharmaceutically acceptable salts of the compounds of this invention 
wherein X is CO.sub.2 H, C(O)NHOH or 1H-tetrazol-5-yl, are prepared by 
treating the carboxylic acid, acylhydroxylamine or tetrazole compound of 
formula 1 with at least one molar equivalent of a pharmaceutically 
acceptable base. Representative pharmaceutically acceptable bases are 
sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium 
hydroxide, metal alkoxides, for example, sodium methoxide, trimethylamine, 
lysine, caffeine, and the like. The reaction is conducted in water, alone 
or in combination with an inert, water-miscible organic solvent, or in a 
suitable organic solvent such as methanol, ethanol, and the like, at a 
temperature of from about 0.degree. C. to about 100.degree. C., preferably 
at room temperature. Typical inert, water-miscible organic solvents 
include methanol, ethanol, or dioxane. The molar ratios of compounds of 
Formula 1 to base used are chosen to provide the ratio desired for any 
particular salt. 
Salts derived from inorganic bases include sodium, potassium, lithium, 
ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, 
ferric, manganic salts and the like. Particularly preferred are the 
ammonium, potassium, sodium, calcium and magnesium salts. Salts derived 
from pharmaceutically acceptable organic non-toxic bases include salts of 
primary, secondary, and tertiary amines, substituted amines including 
naturally occurring substituted amines, cyclic amines and basic ion 
exchange resins, such as isopropylamine, trimethylamine, diethylamine, 
triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 
2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, 
histidine, caffeine, procaine, hydrabamine, choline, betaine, 
ethylenediamine, glucosamine, methylglucamine, theobromine, purines, 
piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. 
Particularly preferred organic non-toxic bases are isopropylamine, 
diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline and 
caffeine. 
The salt products are also isolated by conventional means. For example, the 
reaction mixtures may be evaporated to dryness, and the salts can be 
further purified by conventional methods. Salts of the compounds of 
formula 1 may be interchanged by taking advantage of differential 
solubilities of the salts, or by treating with the appropriately loaded 
ion exchange resin. 
The amount of a fluorinated arachidonic acid derivative of this invention 
necessary to control the biosynthesis of leukotrienes prophylacticly or to 
treat existing allergic or inflammatory states can vary widely according 
to the particular dosage unit employed, the period of treatment, the age 
and sex of the patient treated and the nature and extent of the disorder 
treated. The total amount of the active ingredient to be administered will 
generally range from about 1 mg/kg to 150 mg/kg and preferably from 3 
mg/kg to 25 mg/kg. For example, an average 70 kg human patient will 
require from about 70 mg to about 10 g of active compound per day. A unit 
dosage may contain from 25 to 500 mg of active ingredient, and can be 
taken one or more times per day. The active compound of formula 1 can be 
administered with a pharmaceutical carrier using conventional dosage unit 
forms either orally, parenterally, or topically. 
The preferred route of administration is oral administration. For oral 
administration the compounds can be formulated into solid or liquid 
preparations such as capsules, pills, tablets, troches, lozenges, melts, 
powders, solutions, suspensions, or emulsions. The solid unit dosage forms 
can be a capsule which can be of the ordinary hard- or soft-shelled 
gelatin type containing, for example, surfactants, lubricants, and inert 
fillers such as lactose, sucrose, calcium phosphate, and cornstarch. In 
another embodiment the compounds of this invention can be tableted with 
conventional tablet bases such as lactose, sucrose, and cornstarch in 
combination with binders such as acacia, cornstarch, or gelatin, 
disintegrating agents intented to assist the break-up and dissolution of 
the tablet following administration such as potato starch, alginic acid, 
corn starch, and guar gum, lubricants intented to improve the flow of 
tablet granulations and to prevent the adhesion of tablet material to the 
surfaces of the tablet dies and punches, for example, talc, stearic acid, 
or magnesium, calcium, or zinc stearate, dyes, coloring agents, and 
flavoring agents intented to enhance the aesthetic qualities of the 
tablets and make them more acceptable to the patient. Suitable excipients 
for use in oral liquid dosage forms include diluents such as water and 
alcohols, for example, ethanol, benzyl alcohol, and the polyethylene 
alcohols, either with or without the addition of a pharmaceutically 
acceptable surfactant, suspending agent, or emulsifying agent. 
The compounds of this invention may also be administered parenterally, that 
is, subcutaneously, intravenously, intramuscularly, or interperitoneally, 
as injectable dosages of the compound in a physiologically acceptable 
diluent with a pharmaceutical carrier which can be a sterile liquid or 
mixture of liquids such as water, saline, aqueous dextrose and related 
sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl 
alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol 
ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as 
poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or 
glyceride, or an acetylated fatty acid glyceride with or without the 
addition of a pharmaceutically acceptable surfactant such as a soap or a 
detergent, suspending agent such as pectin, carbomers, methylcellulose, 
hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying 
agent and other pharmaceutically adjuvants. Illustrative of oils which can 
be used in the parenteral formulations of this invention are those of 
petroleum, animal, vegetable, or synthetic origin, for example, peanut 
oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, 
petrolatum, and mineral oil. Suitable fatty acids include oleic acid, 
stearic acid, and isostearic acid. Suitable fatty acid esters are, for 
example, ethyl oleate and isopropyl myristate. Suitable soaps include 
fatty alkali metal, ammonium, and triethanolamine salts and suitable 
detergents include cationic detergents, for example, dimethyl dialkyl 
ammonium halides, alkyl pyridinum halides, and alkylamines acetates; 
anionic detergents, for example, alkyl, aryl, and olefin sulfonates, 
alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates; 
nonionic detergents, for example, fatty amine oxides, fatty acid 
alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric 
detergents, for example, alkyl-beta-aminopropionates, and 
2-alkylimidazoline quarternary ammonium salts, as well as mixtures. The 
parenteral compositions of this invention will typically contain from 
about 0.5 to about 25% by weight of the active ingredient in solution. 
Preservatives and buffers may also be used advantageously. In order to 
minimize or eliminate irritation at the site of injection, such 
compositions may contain a non-ionic surfactant having a 
hydrophile-lipophile balance (HLB) of from about 12 to about 17. The 
quantity of surfactant in such formulations ranges from about 5 to about 
15% by weight. The surfactant can be a single component having the above 
HLB or can be a mixture of two or more components having the desired HLB. 
Illustrative of surfactants used in parenteral formulations are the class 
of polyethylene sorbitan fatty acid esters, for example, sorbitan 
monooleate and the high molecular weight adducts of ethylene oxide with a 
hydrophobic base, formed by the condensation of propylene oxide with 
propylene glycol. 
Aerosol or spray compositions containing the compounds of this invention 
can be applied to the skin or mucous membranes. Such compositions may 
contain a micronized solid or a solution of a compound of formula 1 and 
may also contain solvents, buffers, surfactants, perfumes, antiumicrobial 
agents, antioxidants, and propellants. Such compositions may be applied by 
means of a propellant under pressure or may be applied by means of a 
compressible plastic spray bottle, a nebulizer, or an atomizer without the 
use of a gaseous propellent. A preferred aerosol or spray composition is a 
nasal spray. 
The active ingredient may also be administered by means of a sustained 
release system whereby the compound of formula 1 is gradually released at 
a controlled, uniform rate form an inert or bioerodible carrier by means 
of diffusion, osmosis, or disintegration of the carrier during the 
treatment period. Controlled release drug delivery systems may be in the 
form of a patch or bandage applied to the skin or to the buccal, 
sublingual, or intranasal membranes, an ocular insert placed in the cul de 
sac of the eye, or a gradually eroding tablet or capsule or a 
gastrointestinal reservoir administered orally. Administration by means of 
such sustained release delivery systems permits the tissues of the body to 
be exposed constantly for a prolonged time period to a therapeutically or 
prophylactically effective dosage of a compound of formula 1. The unit 
dosage of the compound administered by means of a sustained release system 
will approximate the amount of an effective daily dosage multiplied by the 
maximum number of days during which the carrier is to remains on or in the 
body of the host. The sustained release carrier may be in the form of a 
solid or porous matrix or reservoir and may be formed from one or more 
natural or synthetic polymers, including modified or unmodified cellulose, 
starch, gelatin, collagen, rubber, polyolefins, polyamides, polyacrylates, 
polyalcohols, polyethers, polyesters, polyurethanes, polysulphones, 
polysiloxanes, and polyimides as wells as mixtures and copolymers of these 
polymers. The compounds of formula 1 may be incorporated in the sustained 
release carrier in a pure form or may be dissolved in any suitable liquid 
or solid vehicle, including the polymer of which the sustained release 
carrier is formed.