Leukotriene-B4 derivatives, process for their production and their use as pharmaceutical agents

##STR1## Compounds of formula (I) in which the residues have the following meanings: a is (II) or (III); R.sup.1 is CH.sub.2 OH, CH.sub.3, CF.sub.3, COOR.sup.5 with R.sup.5 or, A is a trans, trans--CH.dbd.CH--CH.dbd.CH--or tetramethylene group; B is an alkylene group with up to 10 C atoms; D is a direct bond, oxygen, sulphur, a --C.tbd.C--group or a --CH.dbd.CR.sup.7 --group, or (IV); B and D together are a direct bond; R.sup.2 and R.sup.3 are the same or different and denote hydrogen or an organic acid residue with 1 to 15 C atoms, R.sup.1 and R.sup.2 together are a carbonyl group; R.sup.4 is a hydrogen atom or C.sub.1-10 alkyl, and if R.sup.5 denotes a hydrogen atom, their salts with physiologically acceptable bases and their cyclodextrin clathrates.

The invention relates to new leukotriene-B.sub.4 derivatives, the process 
for their production as well as their use as pharmaceutical agents. 
Leukotriene B.sub.4 (LTB.sub.4) was discovered in 1979 by B. Samuelsson et 
al. as a metabolite of arachidonic acid. In the biosynthesis, leukotriene 
A.sub.4 is formed by the enzyme 5-lipoxygenase first as a central 
intermediate product, which then is converted by a specific hydrolase to 
the LTB.sub.4. 
KEY 
Arachidonsaeure=arachidonic acid 
Lipoxygenase=lipoxygenase 
Dehydrase=dehydrase 
Leukotrien A.sub.4 (LTA.sub.4)=leukotriene A.sub.4 (LTA.sub.4) 
Hydrolase=hydrolase 
Glutathion-S-transferase=glutathione-S-transferase 
Leukotrien B.sub.4 (LTB.sub.4)=leukotriene B.sub.4 (LTB.sub.4) 
Leukotrien C.sub.4 (LTC.sub.4)=leukotriene C.sub.4 (LTC.sub.4) 
##STR2## 
The nomenclature of the leukotrienes can be gathers from the following 
works: 
a) B. Samuelsson et al., Prostaglandins 19, 645 (1980); 17, 785 (1979). 
b. C. N. Serhan et al., Prostaglandins 34, 201 (1987). 
The physiological and especially the pathophysiological importance of 
leukotriene B.sub.4 is summarized in several more recent works: 1: The 
Leukotriene, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey, 
Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 
(1987). c) B. Samuelsson et al., Science 237, 1171 (1987). d) C. W. 
Parker, Drug Development Research 10, 277 (1987). It follows from the 
above that LTB.sub.4 is an important inflammation mediator for 
inflammatory diseases, in which leukocytes invade the affected tissue. 
It is known that LTB.sub.4 causes the adhesion of leukocytes on the blood 
vessel wall. LTB.sub.4 is chemotactically effective, i.e., it triggers a 
directed migration of leukocytes in the direction of a gradient of 
increasing concentration. Further, because of its chemotactic activity, it 
indirectly changes the vascular permeability, and a synergism with 
prostaglandin E.sub.2 is observed. LTB.sub.4 obviously plays a decisive 
role in inflammatory, allergic and immunological processes. 
Leukotrienes and especially LTB.sub.4 are involved in skin diseases, which 
accompany inflammatory processes (increased vessel permeability and 
formation of edemas, cell infiltration), increased proliferation of skin 
cells and itching, such as, for example, in eczemas, erythemas, psoriasis, 
pruritus and acne. Pathologically increased leukotriene concentrations are 
involved either causally in the development of many dermatitides or there 
is a connection between the persistence of the dermatitides and the 
leukotrienes. Clearly increased leukotriene concentrations were measured, 
for example, in the skin of patients with psoriasis or atopic dermatitis. 
Further, leukotrienes and LTB.sub.4 are involved especially in arthritis, 
chronic lung diseases (e.g., asthma), rhinitis and inflammatory intestinal 
diseases. 
Antagonists against LTB.sub.4 receptors or inhibitors of those enzymes, 
which are involved in the synthesis of the LTB.sub.4, should be effective 
as specific medications, especially against diseases which accompany 
inflammations and allergic reactions. 
Besides the therapeutic possibilities, which can be derived from an 
antagonizing of LTB.sub.4 with LTB.sub.4 analogs, the usefulness and 
potential use of leukotriene-B.sub.4 agonists for the treatment of fungus 
diseases of the skin was also able to be shown recently (H. Kayama, 
Prostaglandins 34, 797 (1988)). 
It has now been found that the incorporation of the chemically and 
metabolically labile cis-delta.sup.6,7 double bond of LTB.sub.4 in a 
cis-1,2-substituted cyclohexyl ring or a trans-1,2-substituted cyclohexyl 
ring results in a stabilization, and especially by further derivatizing of 
the functional groups, LTB.sub.4 derivatives are obtained which greatly 
antagonize the action of the natural LTB.sub.4. I.e., the invention 
comprises LTB.sub.4 analogs, which can act as antagonists. 
The invention relates to compounds of formula I, 
##STR3## 
in which the radicals have the following meanings: 
##STR4## 
R.sup.1 is CH.sub.2 OH, CH.sub.3, CF.sub.3, COOR.sup.5 with R.sup.5 meaning 
a hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical 
with 3-10 C atoms, an aryl radical with 6-10 C atoms optionally 
substituted by 1-3 chlorine, bromine, phenyl, C.sub.1-4 alkyl, C.sub.1-4 
alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy, a 
--CH.sub.2 --CO--aryl radical with 6-10 C atoms for an aryl or a 
5-6-member aromatic heterocyclic radical with at least 1 heteroatom, or 
R.sup.1 is CONHR.sup.6 with R.sup.6 meaning an alkanoyl radical or an 
alkanesulfonyl radical with 1-10 C atoms or radical R.sup.5 ; 
A is a trans, trans--CH.dbd.CH--CH.dbd.CH-- group or a tetramethylene 
group; 
B is a straight-chain or branched-chain, saturated or unsaturated alkylene 
group with up to 10 C atoms which can optionally be substituted by 
fluorine, or the group 
##STR5## 
with n=1-3; 
D is a direct bond, oxygen, sulfur, a --C.tbd.C group or a 
--CH.dbd.CR.sup.7 group with R.sup.7 as hydrogen, C.sub.1-5 alkyl, 
chlorine, bromine or 
##STR6## 
B and D together are a direct bond, 
R.sup.2 and R.sup.3 are the same or different and mean hydrogen or an 
organic acid radical with 1-15 C atoms; 
R.sup.1 and R.sup.2 together are a carbonyl group; 
R.sup.4 is a hydrogen atom, C.sub.1-10 alkyl, which can optionally be 
substituted by chlorine or bromine, cycloalkyl with 3-10 C atoms, an aryl 
radical with 6-10 C atoms optionally substituted by 1-3 chlorine, bromine, 
phenyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, chloromethyl, fluoromethyl, 
trifluoromethyl, carboxy or hydroxy or a 5-6-member aromatic heterocyclic 
radical with at least 1 heteroatom, and if 
R.sup.5 means a hydrogen atom, their salts with physiologically compatible 
bases and their cyclodextrin clathrates. 
Groups OR.sup.2 and OR.sup.3 can be in alpha-position or beta-position. 
Formula I comprises both racemates and the possible pure diastereomers and 
enantiomers. 
As alkyl groups R.sup.5, straight-chain or branched-chain alkyl groups with 
1-10 C atoms, such as, for example, methyl, ethyl, propyl, butyl, 
isobutyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, decyl, are 
suitable. The alkyl groups R.sup.5 can optionally be substituted one or 
more times by halogen atoms, alkoxy groups, optionally substituted aryl or 
aroyl groups with 6-10 C atoms (substitution s. under aryl R.sup.5), 
dialkylamino and trialkylammonium with 1-C atoms in the alkyl portion, in 
which case the simple substitution is to be preferred. As substituents, 
for example, there can be mentioned fluorine, chlorine or bromine, phenyl, 
dimethylamine, diethylamine, methoxy, ethoxy. As preferred alkyl groups 
R.sup.5, those with 1-4 C atoms can be mentioned. 
As aryl groups R.sup.5, both substituted and unsubstituted aryl groups with 
6-10 C atoms are suitable, such as, for example, phenyl, 1-naphthyl and 
2-naphthyl, which can be respectively substituted by 1-3 halogen atoms (F, 
Cl, Br), a phenyl group, 1-3 alkyl groups with 1-4 C atoms each, a 
chloromethyl group, fluoromethyl group, trifluoromethyl group, carboxyl 
group, hydroxy group or alkoxy group with 1-4 C atoms. Preferred 
substituents in 3- and 4-position in the phenyl ring are, for example, 
fluorine, chlorine, alkoxy or trifluoromethyl, but in 4-position hydroxy. 
The cycloalkyl group R.sup.5 can contain in the ring 3-10 carbon atoms, 
preferably 5 and 6 carbon atoms. The rings can be substituted by alkyl 
groups with 1-4 carbon atoms. For example, there can be mentioned 
cyclopentylhexyl, cyclohexyl, methylcyclohexyl. 
As heterocyclic groups R.sup.5, 5- and 6-member aromatic heterocycles, 
which contain at least 1 heteroatom, preferably nitrogen, oxygen or 
sulfur, are suitable. For example, there can be mentioned 2-furyl, 
2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, 
pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, 2-tetrazolyl, 
i.a. 
As acid radical R.sup.6. physiologically compatible acid radicals are 
suitable. Preferred acids are organic carboxylic acids and sulfonic acids 
with 1-15 carbon atoms, which belong to the aliphatic, cycloaliphatic, 
aromatic, aromatic-aliphatic and heterocyclic series. These acids can be 
saturated, unsaturated and/or polybasic and/or substituted in the usual 
way. As examples for the substituents, there can be mentioned C.sub.1-4 
alkyl groups, hydroxy groups, C.sub.1-4 alkoxy group, oxo groups or amino 
groups or halogen atoms (F, Cl, Br). For example, the following carboxylic 
acids can be mentioned: formic acid, acetic acid, propionic acid, butyric 
acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, 
enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic 
acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, 
trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, 
cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, 
cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic 
acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, 
di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, 
piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, 
adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, 
Br) or trifluoromethyl groups, hydroxy groups, C.sub.1-4 alkoxy groups or 
carboxy groups, nicotinic acid, isonicotinic acid, 2-furancarboxylic acid, 
cyclopentylpropionic acid. As especially preferred acyl radicals and 
alkanesulfonyl radicals, those with up to 10 carbon atoms are suitable. As 
sulfonic acids, for example, methanesulfonic acid, ethanesulfonic acid, 
isopropanesulfonic acid, beta-chloroethanesulfonic acid, butanesulfonic 
acid, cyclopentanesulfonic acid, cyclohexanesulfonic acid, benzenesulfonic 
acid, p-toluenesulfonic acid, p-chlorobenzenesulfonic acid, 
N,N-dimethylaminosulfonic acid, N,N-diethylaminosulfonic acid, 
N,N-bis(beta-chloroethyl)aminosulfonic acid, N,N-diiosbutylaminosulfonic 
acid, N,N-dibutylaminosulfonic acid, pyrrolidino-, piperidino-, 
piperazino-, N-methylpiperazino- and morpholino-sulfonic acid are 
suitable. 
As alkyl groups R.sup.4, straight-chain and branched-chain, saturated and 
unsaturated alkyl radicals, preferably saturated, with 1-14, especially 
1-10 C atoms are suitable, which optionally can be substituted by 
optionally substituted phenyl (substitution see under aryl R.sup.5). For 
example, there can be mentioned the methyl, ethyl, propyl, butyl, 
isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, 
propenyl, pentenyl, benzyl, m- and p-chlorobenzyl groups. If alkyl groups 
R.sub.4 are halogen-substituted, fluorine, chlorine and bromine are 
suitable as halogens. 
As an example for halogen-substituted alkyl groups R.sup.4, alkyls with 
terminal trifluoromethyl groups are suitable. 
The cycloalkyl group R.sup.4 can contain in the ring 3-10 carbon atoms, 
preferably 3-6 carbon atoms. The rings can be substituted by alkyl groups 
with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl. 
As substituted or unsubstituted aryl groups R.sup.4 for example, phenyl, 
1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen 
atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a 
chloromethyl group, fluoromethyl group, trifluoromethyl group, carboxyl 
group, C.sub.1 -C.sub.4 alkoxy group or hydroxy group, are suitable. The 
substitution in 3- and 4-position in the phenyl ring is preferred, for 
example, by fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position 
by hydroxy. 
As heterocyclic aromatic groups R.sup.4, 5- and 6-member heterocycles that 
contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur, are 
suitable. For example, there can be mentioned 2-furyl, 2-thienyl, 
2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, 
pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a. 
As alkylene group B, straight-chain or branched-chain, saturated or 
unsaturated alkylene radicals, preferably saturated with 1-10 C atoms, 
especially with 1-5 C atoms, which optionally can be substituted by 
fluorine atoms, are suitable. For example, there can be mentioned: 
methylene, fluoromethylene, difluoromethylene, ethylene, 1,2-propylene, 
ethylethylene, trimethylene, tetramethylene, pentamethylene, 
1,2-difluoroethylene, 1-fluoroethylene, 1-methyltetramethylene, 1-methyl 
trimethylene, 1-methylene-ethylene, 1-methylene-tetramethylene. 
Alkylene group B can further constitute group 
##STR7## 
in which case n=1-3, preferably 2-3. 
As acid radicals R.sup.2 and R.sup.3, physiologically compatible acid 
radicals are suitable. Preferred acids are organic carboxylic acids and 
sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, 
cycloaliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These 
acids can be saturated, unsaturated and/or polybasic and/or substituted in 
the usual way. As examples for the substituents, there can be mentioned 
C.sub.1-4 alkyl, hydroxy, C.sub.1-4 alkoxy, oxo or amino groups or halogen 
atoms (F, Cl, Br). 
For example, the following carboxylic acids can e mentioned: formic acid, 
acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, 
isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic 
acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic 
acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, 
tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, 
cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, 
methoxyacetic acid, ethoxyacetic acid, mono-, di- and tri-chloroacetic 
acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, 
morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic 
acid, benzoic acids substituted with halogen (F, Cl, Br), trifluoromethyl, 
hydroxy, C.sub.1-4 alkoxy or carboxy groups, nicotinic acid, isonicotinic 
acid, 2-furancarboxylic acid, cyclopentylpropionic acid. As especially 
preferred acid radicals R.sup.2 and R.sup.3, acyl radicals with up to 10 
carbon atoms are suitable. 
R.sup.2 as a C.sub.1-5 alkyl manes straight-chain or branched-chain alkyl 
radicals such as those which have already been mentioned for R.sup.4 and 
R.sup.5. Preferred alkyl radicals R.sup.7 are methyl, ethyl, propyl and 
isopropyl. 
Inorganic and organic bases are suitable for salt formation, as they are 
known to one skilled in the art for forming physiologically compatible 
salts. For example, there can be mentioned alkali hydroxides, such as 
sodium hydroxide and potassium hydroxide, alkaline earth hydroxides, such 
as calcium hydroxide, ammonia, amines, such as ethanolamine, 
diethanolamine, triethanolamine, n-methylglucamine, morpholine, 
tris(hydroxymethyl)methylamine, etc. 
Preferred compounds of this invention are compounds of formula I, in which 
the radicals have the following meaning: 
##STR8## 
R.sup.1 is CH.sub.2 OH, COOR.sup.5 with R.sup.5 meaning a hydrogen atom, an 
alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a 
phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, chloromethyl, fluoromethyl, 
trifluoromethyl, carboxy or hydroxy, or 
R.sup.1 is CONHR.sup.6 with R.sup.6 meaning an alkanoyl radical or an 
alkanesulfonyl radical with 1-10 C atoms or radical R.sup.5 ; 
A is a trans, trans--CH.dbd.CH--CH.dbd.CH-- group or a tetramethylene 
group; 
B is a straight-chain or branched chain, saturated or unsaturated alkylene 
group with up to 10 C atoms which can optionally be substituted by 
fluorine, or the group 
##STR9## 
with n=1-3; 
D is a direct bond, oxygen, sulfur, a --CH.tbd.C group or a 
--CH.dbd.CR.sup.7 group with R.sup.7 as hydrogen, C.sub.1-5 alkyl, 
chlorine, bromine or 
##STR10## 
B and D together are a direct bond, 
R.sup.2 and R.sup.3 are the same or different and mean hydrogen or an 
organic acid radical with 1-15 C atoms; 
R.sup.1 and R.sup.2 together are a carbonyl group; 
R.sup.4 is a hydrogen atom, C.sub.1-10 alkyl, cycloalkyl with 5-6 C atoms, 
a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, 
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, chloromethyl, fluoromethyl, 
trifluoromethyl, carboxy or hydroxy, and if 
R.sup.5 means a hydrogen atom, their salts with physiologically compatible 
bases and their cyclodextrin clathrates. 
Especially preferred compounds of this invention are compounds of formula 
I, in which the radicals have the following meaning: 
##STR11## 
R.sup.1 is CH.sub.2 OH, COOR.sup.5 with R.sup.5 meaning a hydrogen atom, an 
alkyl radical with 1-4 C atoms; 
A is a trans, trans--CH.dbd.CH--CH.dbd.CH-- group or a tetramethylene 
group; 
B is a straight-chain or branched-chain alkylene group with up to 5 C 
atoms; 
D is a direct bond or a --C.tbd.C group or a --CH.dbd.CR.sup.7 group with 
R.sup.7 as hydrogen or C.sub.1-5 alkyl or 
##STR12## 
B and D together are a direct bond, 
R.sup.2 and R.sup.3 are the same or different and mean hydrogen or an 
organic acid radical with 1-6 C atoms; 
R.sup.1 and R.sup.2 together are a carbonyl group; 
R.sup.4 is a hydrogen atom or a C.sub.1-10 alkyl, and if R.sup.5 means a 
hydrogen atom, their salts with physiologically compatible bases and their 
cyclodextrin clathrates. 
The invention further relates to a process for the production of the 
compounds of formula I according to the invention, which is characterized 
in that an aldehyde of formula II, 
##STR13## 
in which A, B, D, and R.sup.4 have the above-indicated meaning, and 
R.sup.3' means silyl protecting groups, as then are mentioned for R.sup.8, 
optionally after protection of free hydroxy groups with a magnesium 
organic compound of formula III, 
EQU X--Mg--CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --O--R.sup.8 (III), 
in which X means chlorine, bromine or iodine and R.sup.8 means an easily 
cleavable ether radical, is reacted and then optionally separated into any 
sequence of isomers, protected hydroxy groups are released and/or a free 
hydroxy group is esterified and/or the 1-hydroxy group is oxidized to 
carboxylic acid and/or double bonds are hydrogenated and/or an esterified 
carboxyl group (R.sup.1 =COOR.sup.5) is saponified and/or reduced and/or a 
carboxyl group R.sup.5 =H) is esterified and/or a free carboxy group 
(R.sup.5 .ltoreq.H) is converted to an amide (R.sup.1 =CONHR.sup.6) or a 
carboxyl group with a physiologically compatible base is converted to a 
salt. 
As ether radicals R.sup.8 and R.sup.3' in the compound of formulas II and 
III, the radicals familiar to one skilled in the art are suitable. Easily 
cleavable ether radicals, such as, for example, dimethyl-tert-butylsilyl, 
trimethylsilylethyl, tribenzylsilylethyl, diphenyl-tert-butylsilylethyl, 
tetrahydropyranylethyl, tetrahydrofuranylethyl and alpha-ethoxyethyl are 
preferred, to mention only a few. 
The reaction of the compound of formula II with an organometallic compound 
of formula III takes place in a way known in the art in an inert solvent 
or solvent mixture, such as, for example, diethyl ether, tetrahydrofuran, 
dioxane, toluene, dimethoxyethane, preferably diethyl ether or 
tetrahydrofuran. The reaction is performed at temperatures between 
-100.degree. C. and 60.degree. C., preferably at -78.degree. C. to 
0.degree. C. 
The production of the compound of formula III needed for this reaction 
takes place by the reaction of the corresponding hydroxyhalide by 
etherification with dihydropyran and p-toluenesulfonic acid and then 
reaction with magnesium. 
The reduction to the compounds of formula I with R.sup.1 meaning a CH.sub.2 
--OH group is performed with a reducing agent suitable for the reduction 
of esters or carboxylic acids, such as, for example, lithium aluminum 
hydride, diisobutyl aluminum hydride, etc. As solvents, diethyl ether, 
tetrahydrofuran, dimethoxyethane, toluene, etc. are suitable. The 
reduction is performed at temperatures of -30.degree. C. up to the boiling 
temperature of the solvent used, preferably 0.degree. C. to 30.degree. C. 
The esterification of the alcohols of formula I (R.sup.2 =H and/or R.sup.3 
=H) takes place in a way known in the art. For example, the esterification 
takes place in than an acid derivative, preferably an acid halide or an 
acid anhydride, is reacted in the presence of a base such as, for example, 
NaH, pyridine, triethylamine, tributylamine or 4-dimethylaminopyridine 
with an alcohol of formula I. The reaction can be performed without a 
solvent or in an inert solvent, preferably acetone, acetonitrile, 
dimethylacetamide, DMSO at temperatures above or below room temperature, 
for example between -80.degree. C. to 100.degree. C., preferably at room 
temperature. 
The oxidation of the 1-hydroxy group is performed according to methods 
known to one skilled in the art. As oxidizing agents, for example, 
pyridinium dichromate (Tetrahedron Letters, 1979, 399), Jones reagent (J. 
Chem. Soc., 1953, 2555) or platinum/oxygen (Adv. In carbohydrate Chem. 17, 
169 (1962)) or Collins oxidation and then Jones oxidation can be used. The 
oxidation with pyridinium dichromate is performed at temperatures of 
0.degree. C. to 100.degree. C., preferably 20.degree. C. to 40.degree. C. 
in a solvent inert toward the oxidizing agent, for example, 
dimethylformamide. 
The oxidation with Jones reagent is performed at temperatures of 
-40.degree. C. to +40.degree. C., preferably 0.degree. C. to 30.degree. C. 
in acetone as a solvent. 
The oxidation with platinum/oxygen is performed at temperatures of 
0.degree. C. to 60.degree. C. preferably 20.degree. C. to 40.degree. C. in 
a solvent inert toward the oxidizing agent such as, e.g. ethyl acetate. 
The saponification of the esters of formula I is performed according to 
methods known to one skilled in the art, such as, for example, with basic 
catalysts. The compounds of formula I can be separated by the usual 
separation methods into the optical isomers. 
The release of the functionally modified hydroxy groups takes place 
according to known methods. For example, the cleavage of hydroxy 
protecting groups, such as, for example, the tetrahydropyranyl radical, is 
performed in an aqueous solution of an organic acid, such as, e.g., oxalic 
acid, acetic acid, propionic acid, i.a., or in an aqueous solution of an 
inorganic acid such as e.g., hydrochloric acid. To improve the solubility, 
a suitably water-miscible inert organic solvent is added. Suitable organic 
solvent are, e.g., alcohols, such as methanol and ethanol, and ethers, 
such as dimethoxyethane, dioxane and tetrahydrofuran. Tetrahydrofuran is 
preferably used. The cleavage is performed preferably at temperatures 
between 20.degree. C. and 80.degree. c. The cleavage of the silyl ether 
protecting groups takes place, for example, with tetrabutylammonium 
fluoride or with potassium fluoride in the presence of a crown ether. As a 
solvent, for example, tetrahydrofuran, diethyl ether, dioxane, methylene 
chloride, etc., are suitable. The cleavage is performed preferably at 
temperatures between 0.degree. C. and 80.degree. C. 
The saponification of the acyl groups takes place, for example, with alkali 
or alkaline-earth carbonates or hydroxides in an alcohol or in the aqueous 
solution of an alcohol. As an alcohol, aliphatic alcohols are suitable, 
such as e.g., methanol, ethanol, butanol, etc., preferably methanol. As 
alkali carbonates and hydroxides, potassium salts and sodium salts can be 
mentioned. The potassium salts are preferred. 
As alkaline-earth carbonates and hydroxides, for example, calcium 
carbonate, calcium hydroxide and barium carbonate are suitable. The 
reaction takes place at -10.degree. C. to +70.degree. c., preferably at 
+25.degree. C. 
The introduction of the ester group 
##STR14## 
for R.sup.1, in which R.sup.5 represents an alkyl group with 1-10 C atoms, 
takes place according to methods known to one skilled in the art. The 
1-carboxyl compounds are reacted, for example, with diazohydrocarbons in a 
way known in the art. The esterification with diazohydrocarbons takes 
place, e.g., in that a solution of the diazohydrocarbon in an inert 
solvent, preferably in diethyl ether, is mixed with the 1-carboxy compound 
in the same or in another inert solvent, such as, e.g., methylene 
chloride. After completion of the reaction in 1 to 30 minutes, the solvent 
is removed and the ester is purified in the usual way. Diazoalkanes are 
either known or can be produced according to known methods [Org. Reactions 
Vol., 8, pages 389-394 (1954)]. 
The introduction of the ester group 
##STR15## 
for R.sup.1, in which R.sup.2 represents a substituted or unsubstituted 
aryl group, takes place according to methods known to one skilled in the 
art. For example, the 1-carboxy compounds with the corresponding 
arylhydroxy compounds in an inert solvent are reacted with 
dicyclohexylcarbodiimide in the presence of a suitable base, for example, 
pyridine, DMAP, triethylamine. As a solvent, methylene chloride, ethylene 
chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably 
chloroform, are suitable. The reaction is performed at temperatures 
between -30.degree. C. and +50.degree. C., preferably at 10.degree. C. 
If C.dbd.C double bonds contained in the primary product are to be reduced, 
the hydrogenation takes place according to methods known in the art. 
The hydrogenation of the delta.sup.8,10 -diene system is performed, in a 
way known in the art, at low temperatures, preferably at about -20.degree. 
C. to +30.degree. C. in a hydrogen atmosphere in the presence of a noble 
metal catalyst. As a catalyst, for example, 10% palladium on carbon is 
suitable. 
The leukotriene-B.sub.4 derivatives of formula I with R.sup.1 meaning a 
COOH group can be converted to a salt with suitable amounts of the 
corresponding inorganic bases with neutralization. For example, during 
dissolving of the corresponding acids in water, which contains the 
stoichiometric amount of the base, the solid inorganic salt is obtained 
after the evaporating off of the water or after the addition of a 
water-miscible solvent, e.g., alcohol or acetone. 
For the production of an amine salt, the LTB.sub.4 acid, e.g., is dissolved 
in a suitable solvent, for example, ethanol, acetone, diethyl ether, 
acetonitrile or benzene, and at least the stoichiometric amount of the 
amine is added to this solution. In this way, the salt usually accumulates 
in solid form or is isolated after evaporation of the solvent in the usual 
way. 
The introduction of the amide group 
##STR16## 
for R.sup.1 takes place according to methods known to one skilled in the 
art. The carboxylic acids of formula I (R.sup.5 =H) are first converted in 
the presence of a tertiary amine, such as, for example, triethylamine, 
with chloroformic acid isobutyl ester to the mixed anhydride. The reaction 
of the mixed anhydride with the alkali salt of the corresponding amide or 
with ammonia (R.sup.6 =H) takes place in an inert solvent or solvent 
mixture, such as, for example, tetrahydrofuran, dimethoxyethane, 
dimethylformamide, hexamethylphosphoric acid triamide, at temperatures 
between -30.degree. C. and +60.degree. C., preferably at 0.degree. C. to 
30.degree. C. 
Another possibility for the introduction of the amide group 
##STR17## 
for R.sup.1 is in the reaction of a 1-carboxylic acid of formula I 
(R.sup.5 =H), in which free hydroxy groups optionally are protected 
intermediately with compounds of formula IV, 
EQU O.dbd.C.dbd.N--R.sup.6 (IV), 
in which R.sup.6 has the above indicated meaning. 
The reaction of the compound of formula I (R.sup.5 .ltoreq.H) with an 
isocyanate of formula IV optionally takes place with the addition of a 
tertiary amine, such as, e.g., triethylamine or pyridine. The reaction can 
be performed without a solvent or in an inert solvent, preferably 
acetonitrile, tetrahydrofuran, acetone, dimethylacetamide, methylene 
chloride, diethyl ether, toluene, at temperatures between -80.degree. C. 
to 100.degree. C., preferably at 0.degree. C. to 30.degree. c. 
If the initial product contains OH groups in the leukotriene-B.sub.4 
radical, these OH groups are also reacted. Finally, if end products are 
desired which contain free hydroxyl groups, a start is suitably made from 
the initial products, in which these are intermediately protected by 
preferably easily cleavable ether or acyl radicals. 
The separation of enantiomers and/or diastereomers takes place according to 
methods known to one skilled in the art., e.g., by chromatographic 
methods, for example, high-pressure liquid chromatography on optically 
active supply materials. 
The compounds of formula II used as initial material can be produced, for 
example, by 2-hydroxymethylbenzyl alcohol being converted to the monosilyl 
ether of formula V in a way known in the art. 
##STR18## 
By oxidation, e.g., with Collins reagent or by the Swern process, the 
aldehyde of formula VI is obtained, 
##STR19## 
which is converted in a Wittig-Horner olefinization with the phosphonate 
of formula VII and a base and optionally subsequent hydrogenation to the 
ester of formula VIII, in which A 
##STR20## 
has the above-indicated meaning. As bases, for example, 
potassium-tert-butylate, diazabicyclononane or sodium hydride are 
suitable. The reduction of the ester group, for example, with DIBAH and 
then oxidation of the primary alcohol obtained, e.g., with manganese 
dioxide or Collins reagent, results in the aldehyde of formula IX 
##STR21## 
The organometallic reaction of the aldehyde of formula IX with a Grignard 
reagent of formula X, in which B, D 
EQU X--Mg--B--D--R.sup.4 (X) 
and R.sup.4 exhibit the above-indicated meanings and X means chlorine, 
bromine or iodine, results after protection of the hydroxy group and 
optionally diastereomer separation (for example by acylation) in the 
compounds of formula XI 
##STR22## 
The production of the compound of formula X needed for the organometallic 
reaction takes place by the reaction of the corresponding terminal halide 
with magnesium. By reaction of silyl ether XI with tetrabutylammonium 
fluoride, the alcohol of formula XII is obtained. 
##STR23## 
The oxidation of the primary alcohol group in XII, e.g., with Collins 
reagent or pyridinium dichromate, results in the aldehyde of formula II. 
In the compounds of formula XI, in which B means a CH.sub.2 group and D 
means a --C.tbd.C-- group or a CH.dbd.CR.sup.7 group, a propargyl halide 
can be attained, for example by an organometallic reaction, with the 
aldehyde of formula IX and subsequent alkylation with a corresponding 
alkyl halide and optionally subsequent Lindlar hydrogenation. 
The compounds of formula I act in an anti-inflammatory and anti-allergic 
manner. In addition, they have antimycotic properties. Consequently, the 
new leukotriene-B.sub.4 derivatives of formula I represent valuable 
pharmaceutical active ingredients. The compounds of formula I are 
especially suitable for topical application, since they exhibit a 
dissociation between desirable topical effectiveness and undesirable 
systemic side effects. 
The new leukotriene-B.sub.4 derivatives of formula 1 are suitable in 
combination with the auxiliary agents and vehicles usual in galenic 
pharmaceutics for topical treatment of contact dermatitis, eczemas of the 
most varied types, neurodermatoses, erythrodermia, burns, tinea, pruritus 
vulvae, pruritus ani, rosacea, lupus erythematosus cutaneus, psoriasis, 
lichen ruber planus and verrucosis and similar skin diseases. 
The production of pharmaceutical agent specialties takes place in the usual 
way, by the active materials with suitable additions being converted into 
the desired form of application such as, for example: solutions, lotions, 
ointments, creams or plasters. 
In the pharmaceutical agents thus formulated, the active ingredient 
concentration is dependent on the form of application. In lotions and 
ointments, an active ingredient concentration of 0.0001% to 1% is 
preferably used. 
Further, the new compounds optionally in combination with the usual 
vehicles and auxiliary agents are also very suitable for the production of 
inhalants, which can be used for the treatment of allergic diseases of the 
respiratory system such as, for example, bronchial asthma or rhinitis. 
Further, the new leukotriene-B.sub.4 derivatives also are suitable in the 
form of capsules, tablets or coated tablets, which preferably contain 0.1 
to 100 mg of active ingredient or are applied orally in the form of 
suspensions, which preferably contain 1-200 mg of active ingredient per 
dosage unit, and are also applied rectally to treat allergic diseases of 
the intestinal tract, such as colitis ulcerosa and colitis granulomatosa. 
The new leukotriene-B.sub.4 derivatives can also be used combined with, 
e.g., lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin 
agonists, thromboxane antagonists, leukotriene-D.sub.4 antagonists, 
leukotriene-E.sub.4 antagonists, leukotriene-F.sub.4 antagonists, 
phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.