DD243697A5 - ALIPHATIC THIOETHER - Google Patents

Abstract

The invention relates to a process for the preparation of novel unsymmetrical aliphatic thioethers for use as medicaments. The object of the invention is to provide novel compounds which are effective as leukotriene antagonists, by eliminating the smooth muscle contractions caused by leukotrienes, and which are therefore suitable for the treatment of allergic, especially of asthmatic conditions. According to the present invention, novel unsymmetrical thioethers of the formula wherein R1 is a C1-3 alkyl or a C1-3 hydroxyalkyl whose hydroxy group may be in esterified form, R2 is an unsubstituted aliphatic radical of 5-15 C atoms, R3 is hydroxyl, alkoxy or an optionally substituted amino group, and X represents a single bond, a methylene group or an optionally N-acylated primary aminomethylene group, wherein the O atom of the hydroxyl group with the S atom to each other are in the relative trans configuration.

Description

in which R ^{1 is} a C 1-3 -alkyl or C 3-3 -hydroxaalkyl whose hydroxyl group may be in esterified form, R ^{2 is} a saturated or unsaturated aliphatic radical having 5-15 C atoms, R ^{3 is} hydroxyl, alkoxy or an optionally substituted amino group, and

X represents a single bond, a methyl group or an optionally N-acylated primary aminomethylene group, wherein the O atom of the hydroxyl group with the S atom to each other in the relative trans configuration, or a salt of such compound having salt-forming properties and / or optionally a pharmaceutical composition, characterized in that a trans-epoxide of the formula

0-C-CCH ₂ ) ₂ -E

H-CH = CH-C. - ^(II)

wherein R ¹ and R ^{2 have} the meanings given above and in which an optionally present hydroxyl group can be present in a protected form, with a mercaptoalkanecarboxylic acid derivative of the formula

HS-CH ₂ -X-CO-R ³ - (III)

wherein R ³ and -X- have the abovementioned meanings and in which an optionally present amino group may be present in a protected form, and if necessary or desired, the protective group (s) of the hydroxyl and / or amino group (s) split off and or esterifying a compound present as an ester to the free acid or a salt and / or converting a resulting free compound having salt-forming properties into a salt and / or liberating a compound from a corresponding salt form and / or optionally a resulting compound with at least one pharmaceutically acceptable Carrier material is mixed into a non-chemical pharmaceutical composition and, when a finished pharmaceutical form is desired, filled into suitable containers in metered quantities.

2. The method according to item!, Characterized in that one prepares a compound of formula I, wherein R ¹ and C-i_ ₃ alkyl or a corresponding ω-hydroxyalkyl whose hydroxyl group is free or esterified by a carboxylic acid having at most 12 carbon atoms can be represents.

3. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{1 is} ethyl or / 3-hydroxyethyl, which can be esterified by an alkanoic acid having 1-4C atoms.

4. Process according to item 1, characterized in that a compound of the formula I is prepared in which R ^{1 is} ethyl, / 8-hydroxyethyl and β-acetoxethyl.

5. The method according to item 1, characterized in that one prepares a compound of formula I wherein R ^{2 represents} a C5_i ₅ alkyl or a corresponding radical having one, two or three double bonds.

6. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{2 represents} a linear alkyl having 5-15 carbon atoms.

7. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{2 represents} a linear I-alkenyl having 5-12 C-atoms.

8. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{2 represents} a linear 1,3-alkadienyl having 5-12 C-atoms.

9. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{2 represents} a linear 1,3,6-alkatrienyl having 8-12 carbon atoms.

10. The method according to item!, Characterized in that one prepares a compound of formula I wherein R ^{3 is} hydroxyl, Ci_7-alkoxy or an optionally substituted amino group of the partial formula

i- ^a 3 · (Ri

-33H-OH-CO-EJ

in which R ³ , hydrogen or a C ₁ -S-AlkYl and R ³ , hydroxyl, C ^ alkoxy or the primary amino group.

11. The method according to item 1, characterized in that one prepares a compound of formula I, wherein R ^{3 represents} hydroxyl or methoxy.

12. The method according to item 1, characterized in that one prepares a compound of formula I wherein R ^{3 is} an optionally esterified by a C ^ alkanol, bound by its N-atom glycine residue.

13. The method according to item!, Characterized in that one prepares a compound of formula I, wherein -X-a single bond, the methylene group or an optionally N-acylated aminomethylene group of the partial formula

R ⁴ -NH-CH- (-X ₀ -)

wherein R ^{4 is} hydrogen or the acyl radical of a carboxylic acid having at most 12 C atoms, which may optionally be substituted by halogens, or a corresponding amino acid.

14. The method according to item 1, characterized in that one prepares a compound of formula I wherein -X- represents the single bond or the methylene group.

15. The method according to item!, Characterized in that one prepares a compound of formula I, wherein -X- represents the group -X ₀ -, in which R ^{4 is} hydrogen or trifluoroacetyl.

16. The method according to item!, Characterized in that a compound of the forms! Wherein X represents the group X ₀ -, in which R ^{4 represents} the acyl radical of a naturally occurring mono- or di-basic α-amino acid.

17. The method according to item!, Characterized in that one prepares a compound of formula I, wherein -X- stands for the group X ₀ - in which R ^{4 represents} the y-glutamyl radical, optionally in the form of a salt ,

18. The method according to item!, Characterized in that one prepares a compound of formula I, wherein R ^{1 is} methyl, ethyl, propyl or an optionally by a C ₁ - ^ - Al kansäureverestertes / 3-hydroxyethyl, R ^{2 is} a linear C 15 -alkyl or a corresponding radical having 1-3 double bonds, R ³ is hydroxyl, C ₁ ^ -alkoxy or the radical of partial formula -NH-CH ₂ -CORb (where R ³ b-hydroxyl or C ^ -alkoxy is _7), and -X- is a single bond, the methylene group or the group of the partial formula

R ⁴ -NH-CH-

wherein R ^{4 is} hydrogen or the acyl radical of an optionally halogenated carboxylic acid having at most 12 C atoms or an amino acid, and salts of compounds having salt-forming properties.

19. The method according to item 18, characterized in that one prepares a compound of formula I wherein R ¹ and R ^{2 have} the meanings given there and the grouping -S-CH ₂ -X-CO-R ³ a by the S Represents atomically bound residue of mercaptoacetic acid or its methyl ester.

20. The method according to item 18, characterized in that one prepares a compound of formula I wherein R ¹ and R ^{2 have} the meanings given there and the grouping -S-CH ₂ -X-CO-R ³ a by the S Atom-bound residue of / 3-mercaptopropionic acid or N- (β-mercaptopropionyl) -glycine, or a corresponding methyl ester thereof.

21. The method according to item 18, characterized in that one prepares a compound of formula I wherein R ¹ and R ² have the meanings given there have the grouping -S-CH ₂ -X-CO-R ^{3 is} an optionally N-acylated L. -Cysteinyl radical of the formula

R ⁴ -Cys-R ³ ,

in which R ³ is hydroxyl or C ₁ ^ -alkoxy and R ⁴ is hydrogen, trifluoroacetyl or y-glutamyl, represents.

22. The method according to item 18, characterized in that one prepares a compound of formula I wherein R ¹ and R ^{2 have} the meanings given there and the grouping -S-CH ₂ -X-CO-R ^{3 is} an optionally N-acylated N- (LCysteinyl) -glycyl radical of the formula

R ⁴ -Cys-Gly-R ³

in which R ³ is hydroxyl or C ₁ ^ -alkoxy and R ⁴ is hydrogen, trifluoroacetyl or y-glutamyl, represents.

23. A method according to item 1, characterized in that N-is -S-tSIRSLefSRl-ö-hydroxy ^^ - trans-li-cis-eicosatrien-eyl-N-trifluoroacetyl-cysteinylj-glycine in the form of methyl ester, free acid or an alkali metal salt manufactures.

24. Method according to item I, characterized in that N- {S- [5 (S), 6 (R) -5-hydroxy-7,9-trans-11-cis-eicosatrien-6-yl] -N- trifluoroacetyl-cysteinyl-glycine in the form of methyl ester, free acid or an alkali metal salt.

25. The method according to item 1, characterized in that N- {S- [5 (R), 6 (S) -5-hydroxy-7,9-trans-1 l-cis-eicosatrien-6-yl] - N-trifluoroacetyl-cysteinyl} -glVcin in the form of methyl ester, free acid or an alkali metal salt.

26. The method according to item 1, characterized in that one produces N-fS-tBfRSLölSRJ-ö-hydroxy ^ trans-ii ^ -ciseicosatetraen-e-ylj-cysteinylj-glycine in the form of methyl ester, free acid or an alkali metal salt.

27. The method according to item 1, characterized in that one N- {S- [5 (S), 6 (R) -5-hydroxy-7,9-trans-11,14-ciseicosatetraen-e-yll-cysteinylj glycine in the form of methyl ester, free acid or an alkali metal salt.

28. The method according to item 1, characterized in that N-i

6-yl] -cysteinyl} -glycine in the form of methyl ester, free acid or an alkali metal salt.

29. The method according to item 1, characterized in that N- {S- [5 (RS), 6 (SR) -1,5-dihydroxy-7,9-trans-11,14-ciseicosatetraen-e-yl] cysteinyl-glycine in the form of methyl ester, free acid or an alkali metal salt.

30. The method according to item 1, characterized in that N- {S- [5 (S), 6 (R) -1,5-dihydroxy-7,9-trans-11,14-ciseicosatetraen-e-ylj- cysteinyl-glycine in the form of methyl ester, free acid or an alkali metal salt.

31. The method according to item 1, characterized in that one produces N-is-ISIRhBfSM / S-dihydroxy ^ -trans-H ^ -ciseicosatetraen-6-yl] -cysteinyl} -glycine in the form of methyl ester, free acid or an alkali metal salt ,

32. The method according to item!, Characterized in that one produces a physiologically acceptable salt of one of the compounds according to any one of claims 1-31, if it has at least one free carboxyl group.

33. The method according to item 1, characterized in that one prepares a compound according to item 1, which is described in any one of examples 1-75.

34. The method according to item 1, characterized in that one prepares a pharmaceutical composition in a finished pharmaceutical form.

35. The method according to item!, Characterized in that one prepares a pharmaceutical composition suitable for administration by inhalation.

Field of application of the invention

The invention relates to a process for the preparation of unsymmetrical aliphatic thioethers with valuable pharmacological properties, in particular with activity as leukotriene antagonists.

The compounds according to the invention are used as medicaments, for example for the treatment of allergies of various kinds, especially asthmatic conditions.

Characteristic of the known technical solutions

Several years ago it was demonstrated that isolates of biological material of various origins known as SRS (slow-reacting substance of anaphylaxis) from immunological studies, cf. H.R. Morris et al. Nature 285, 1045-106 (May 1980) and L. Oerning, S.Hammarström and B.Samuelsson: Proc. Natl. Acad. USA 77 (4), 2014-2017 (1980), are identical to the so-called leukotrienes known from the study of arachidonic acid metabolism. So goes z. For example, it is clear from the latter two papers that the drug termed SRS-A, which is most likely responsible as a primary mediator of immediate onset hypersensitivity reactions to bronchoconstriction in asthma, is identical to the so-called leukotriene D (see below Formula LTD). Equally effective is leukotriene C, whose spatial structure has recently been [E.J.Corey et al., J. Am. Soc. 102 (4), 1436-1439 (1980)] was also confirmed by the total synthesis.

The structural backbone of leukotrienes general is formed by a polyunsaturated, linear eicosanoic acid bearing characteristic substituents in the 1-, 5-, and 6-positions, as shown in the formulas for the main constituents mentioned:

20 ^: U 11 9 - 7 6 - 5 4 3 2 1

GO

- < H S-OH ₂ "

R ¹ -IH-GH-CO-R ²

LTC-4: R ¹ = HOCOCH (NH ₂ ) CH ₂ Ch ₂ CO-; R ² = -NHCH ₂ COOH LTD-4: R ¹ = H-; R ² = -NHCH ₂ COOH LTE-4: R ¹ = H-; R ² = -OH

(Here the spatial representation is to be understood that the entire olefinic chain lies in the representation plane and the valence lines indicated by arrow are above the representation plane, whereas the dotted ones are below the plane.) In their physiological properties, leukotrienes are generally distinguished by that they cause a marked contraction of smooth muscles of various kinds. From the standpoint of health, such an effect is mostly undesirable, and accordingly, the search for suitable leukotriene antagonists is at the forefront of research in the field.

Object of the invention

The aim of the invention is the provision of compounds which can be used as leukotriene antagonists.

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, novel unsymmetrical aliphatic thioethers are prepared, derived from the radical (A) of a mercaptoalkanecarboxylic acid, such as mercaptoacetic acid, / 3-mercaptoacetic acid, an optionally acylated cysteine or cysteine peptide on the nitrogen atom, or a salt or a carboxyl-modified derivative of such an acid, its sulfur atom is substituted with an olefinic radical (B) having at least 12 carbon atoms, which carries in α position to the sulfur atom on one side of its chain a relative to the S atom trans-oriented hydroxyl, on the other side a double bond

 In particular, compounds of the formula

H OH '

R ² -GH _Ä GH-GG- (GH ₂₎ p-R '

II "(D.

, , SE

Gho-X-GQ-R

manufactured, in which --- .. ά

R ^{1 is} a C 1-3 -alkyl or C _1-3 -hydroxyalkyl whose hydroxyl group may be in esterified form, R ^{2 is} an optionally unsaturated aliphatic radical having 5-15 C atoms, R ^{3 is} hydroxyl, alkoxy or an optionally substituted amino group, and X represents a single bond, a methylene group or an optionally N-acylated primary aminomethylene group, wherein the O atom of the hydroxyl group with the S atom are in the relative trans configuration relative to one another, and salts of such compounds having salt-forming properties.

The spatial representation in formula I above is to be understood as meaning that the symbols of the first row above, and those of the third row are then below the representation plane (or vice versa), which for the mapped formula of the mutual configuration (RS) - (SR) of both corresponds to central carbon atoms according to the Kahn-Ingold-Prelog convention.

The invention relates not only to processes for the preparation of the compounds of the invention as defined above, but also to pharmaceutical compositions which contain these compounds as active ingredient and to corresponding preparation processes by means of which such compositions are prepared by non-chemical means. - Another object of the invention is the therapeutic use of the above-defined compounds and pharmaceutical compositions, especially in alleviating and remedy such pathological conditions in which the pronounced leukotriene antagonizing activity of the compounds of the invention comes into their own, as in allergies of various kinds, especially in asthma.

Surprisingly, it has now been found that the compounds of the formula I according to the invention, although they have several structural features in common with known leukotrienes, exert a pronounced antagonistic effect on them. Thus, in different test arrangements they have a markedly leukotriene-antagonizing effect in vitro.

That's how they stop. B. in the concentration range tested of about 0.1-25μ, ΜοΙ / Ι inhibited by Leuktorien-D ₄ (LTD ₄ - see above) induced smooth muscle contraction. This so-called LTD4 antagonism is experimentally z. B.

In segments taken from the lumbar of a guinea pig weighing 300-400 g and in an organ bath in Tyrode's solution at 38 ° C and gassed with a mixture of 95% oxygen and 5% carbon dioxide at a load of 1 g were incubated be with synthetic leukotriene D ₄ is triggered (as potassium salt) contractions and registered isotonically. the extent of inhibition by the test substance is determined after a pre-incubation of 2 minutes and as _IC50, ie the concentration which reduces the test contraction by 50% The LTD ₄ antagonism can also be detected in vivo by standard guinea pig bronchoconstriction assay with aerosol administration. (The description of the test method is given in the appendix to the US Pat

Examples).

In another assay, compounds of formula I in the tested concentration range of about 1 μΜΜ / Ι inhibit the aggregation of rat peritoneal leukocytes induced by leukotriene B ₄ (LTB _4. When experimentally performed, Wistar rats (400-60 og) 24 Hours after ip injection of 16ml of 12% sodium caseinate solution killed, cells are washed out from the peritoneum with buffered Eagle's minimal essential medium (E-MEM), 0.5 ml each of cell suspension (10 ⁷ cells in 1 ml of E-MEM) placed in the cuvette of a platelet aggregometer and heated with constant stirring (800-900 rpm) to 37 ⁰ C. Four minutes after addition of the test substance (2μ.Ι), the aggregation is triggered by 2 μΙ LTB ₄ (1 ng / ml final concentration) and The concentration of the test substance which reduces control aggregation (LTB ₄ alone) by 50% is referred to as IC ₅₀ .

Surprisingly, compounds of formula I also exert a pronounced inhibitory effect on other physiologically important enzyme systems. Thus, the inhibition of phospholipase A ₂ from human leukocytes was observed in the tested concentration range of about 0.5-50 μΜοΙ / Ι. (The experimental arrangement for this determination is described in more detail in the appendix to the examples. (The inhibition of phospholipase C from human thymocytes was also observed in the tested concentration range of about 1-μΙΟΟοΙ / ((for experimental arrangement see the appendix to the examples). ,

The antiallergic or antiinflammatory properties indicated by these methods in vitro are also confirmed in vivo in animal experiments. Thus, for example, the local anti-inflammatory efficacy can be demonstrated by the method developed by G.Tonelli and LThibault (Endocrinology 77, 625 [1965]) by inhibiting crotonoil-induced rat ear edema in the normal rat in the dose range of about 1 to about 100 mg / ml.

Thanks to these valuable pharmacological properties, the compounds of the formula I according to the invention can find therapeutic use everywhere where the allergogenic action of the leukotrienes leads to pathological conditions and is to be alleviated or eliminated. Accordingly, they can be used, for example, for the treatment of allergic conditions and diseases, such as, in particular, asthma, but also hay fever and obstructive pulmonary diseases, including cystic fibrosis. Also, thanks to their anti-inflammatory efficacy, they are anti-inflammatory agents, particularly as external (topical) skin phlogistatics for the treatment of inflammatory dermatoses of any genesis, such as mild skin irritation, contact dermatitis, rashes and burns, and as mucous membrane phlogostatics for the treatment of mucositis, e.g. the eyes, nose, lips, mouth and genital or anal region. Further, they can be used as a sunscreen. The high inhibitory activity on various blood factors also indicates the possibility of therapeutic use of the compounds of formula I in the indications thrombosis and blood coagulation.

As already mentioned above, the structural structure of the compounds of the formula I and leukotrienes according to the invention has general analogy, in particular in the obligatory trans configuration of the vicinal S and O atoms discussed at the outset and the overall structure of the mercaptoalkanoic acid residue A (in particular in its typical form of a cysteine peptide). On the other hand, they differ substantially from leukotrienes in that they lack the characteristic terminal carboxyl group in the olefinic residue (B). In contrast to leukotrienes, the number, character and spatial arrangement of the multiple bonds as well as the total length of the olefinic radical (B) are largely irrelevant for the effectiveness, and even the absolute configuration of the asymmetric C atoms discussed above is not critical to the efficacy , as exemplified by the highly potent N- [S-5 (R), 6 (S) -5-hydroxy-7,9-trans-1-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] glycine sodium salt, which has the opposite absolute configuration of the leukotrienes of the carbon atoms 5 and 6 of the hydrocarbon chain.

In the formula I defined above, R ¹ preferably represents an alkyl, such as methyl, propyl and especially ethyl, or else a corresponding hydroxyalkyl, preferably ω-hydroxyalkyl, in particular / 3-hydroxyethyl, where the hydroxyl group is not only available in may be free, but also in esterified form. The esterified hydroxyl group is preferably esterified by the radical of an aliphatic or aromatic carboxylic acid having at most 12 C atoms, such as benzoic acid or, in particular, a C 1-7 -alkanoic acid, especially acetic acid.

The aliphatic radical represented by symbol R ² is preferably a linear radical, e.g. B. an alkyl radical consisting of 5-15, preferably 7-12 carbon atoms, in particular heptyl, nonyl, undecyl and dodecyl, or a corresponding mono- or polyunsaturated radical having one, two or three multiple bonds, such as triple bonds and especially double bonds in arbitrary ice or trans configuration, in any combination wears. These multiple bonds are preferably as close as possible to the sulfur atom, ie conjugated to the first double bond, which is in position to the sulfur-bearing carbon atom. Preferred radicals R ^{2 of} this type are, for example, 1-alkenyl, 1,3-alkadienyl and 1,3,6-alkatrienyl radicals, in particular 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1 Undecenyl and 1-dodecenyl or 1,3-octadienyl, 1,3-decadienyl, 1,3-dodecadienyl and 1,3,6-dodecatrienyl, in which all the double bonds are individually in cis or trans configuration and any Combinations can form.

The symbol R ³ defined in formula I given at the beginning forms together with the adjacent carbonyl group-CO-a free or functionally modified carboxyl radical; If R ^{3 is} hydroxyl, it forms with the carbonyl group the carboxyl radical of a free carboxylic acid, if it is an alkoxy, in particular one with at most 7 C atoms, especially methoxy, it adds a carboxylic acid ester, and if it stands for an amino group, it belongs for the amidine bond of a carboxamide or, if the amino group is suitably substituted, for a peptide. In the latter case, the substituted amino group is the basic element of an amino acid, such as an α-aminocarboxylic acid and especially an α-amino-C2-7-alkanoic acid, preferably one found in nature, such as leucine, valine, alanine (especially in the US Pat The carboxyl of these amino acids may in turn be present as free carboxyl or may be functionally modified in the manner defined above as an ester group, such as in particular a C _1-7 alkoxycarbonyl, or the carboxamido group -CONH ₂ Such preferred meanings of the symbol R ³ then correspond to the partial formula

" f

-NH-CH-CO-I

(R ³ ,

wherein R ^{3 is} a Ci-s-alkyl or preferably hydrogen and R ^{3 is} hydroxyl, Ci_ ₇ alkoxy or the primary amino group NH ₂ .

The symbol -X- defined at the outset can, on the one hand, represent a simple C-C bond and thus together with the adjacent groups form the remainder of the MBrCaPtOeSSIgSaUTe-S-CH ₂ -CO-R ³ ; in this case, among the above meanings R ^3, hydroxyl is particularly preferred. On the other hand, -X-may represent an aminomethylene group which may be acylated on the nitrogen atom, which may be the partial formula

R ⁴ -NH-CH- (-X ₀ -)

in which R ^{4 is} hydrogen or the acyl radical of a carboxylic acid, such as an aliphatic or aromatic carboxylic acid having at most 12 C atoms, in particular an unsubstituted or substituted, preferably linear, C, _i 5-alkanoic acid. Examples of substituted alkanoic acids of this type include, on the one hand, mono- or preferably poly-halogenated, in particular chlorinated or fluorinated, Ci_s-alkanoic acids, such as trifluoroacetic acid, on the other hand, mono- and dibasic amino acids, including monoamides of the latter, in particular .alpha.-amino acids of Type of those which occur as building blocks of peptides and in particular in L-form in nature; Among these, for example, the glutamic acid is emphasized, which acylates preferably with its -y-carboxyl, the amino group. Symbol R ⁴ preferably represents hydrogen, trifluoroacetyl or-glutamyl of the formula HOCOCH (NH ₂ ) Ch ₂ CH ₂ CO-, in which case its free carboxyl may be present in a salt form. Preferably, the above-characterized aminomethylene group forms, together with the adjacent symbols, an optionally acylated cysteine residue of the partial formula

-S-CH ₂ R * -NH-CH-CO-R ³ k ^zw '' ⁿ short form R ⁴ -Cys-R ³ ,

wherein R ³ and R ^{4 have} the abovementioned general and preferred meanings, with the L-cysteinyl radical having the naturally occurring configuration being preferred at the asymmetric C atom. In this case, R ^{3 is} preferably hydroxyl, C 1-4 -alkoxy or a nitrogen-bonded, optionally esterified by a C 1-4 -alkanol, glycine residue, and R ^{4 is} in particular hydrogen, Trifiuoracetyl or y-glutamyl {also in salt form). Most compounds of the formula I can, according to their individual character, also be present in the form of salts. Those which have a sufficient acidity, in particular those with free carboxyl groups, may form salts with bases, in particular inorganic bases, preferably physiologically compatible alkali metal salts, especially sodium and potassium salts. Those of the compounds of formula I which have sufficient basicity, such as esters and amides of amino acids, may be present as acid addition salts, in particular as physiologically acceptable salts, with customary pharmaceutically acceptable acids; of inorganic acids are the hydrogen halides, such as hydrochloric acid, and sulfuric acid and phosphoric or pyrophosphoric particular, of the organic acids, it is primarily the sulfonic acids, eg. As the aromatic, such as benzene or p-toluenesulfonic acid, embonic acid and sulfanilic acid, or lower alkanesulfonic acids, such as methanesulfonic, ethanesulfonic, hydroxyethanesulfonic and ethylenedisulfonic acid, or else aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids, such as ants, Acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyracene, phenylacetic, benzoic, p-aminobenzoic, Anthranil, p-hydroxybenzoic, salicylic and p-aminosalicylic acids, as well as ascorbic acid. Compounds of formula I which contain both basic and acidic functional groups, such as free carboxyl and amino groups, may also be present as internal salts.

Of particular note are compounds of the formula I, in which all the radical (A) of the mercaptoalkanecarboxylic acid mentioned in the beginning is represented by one of the following formulas, the amino acid radicals of the "natural" L-series being preferred:

HOCO-CH (NH ₂ ) -CH ₂ -CH ₂ -CO-NH-CH-CO-NH-CH ₂ -COOH (AI),

or in short form

r-Cys-Gly-OH H-Glu-OH

-S-CH ₂ . .

CF ₃ -CO-NH-CH-CO-NH-CH ₂ -COOh or in short form CP ₃ CO-CyS-Gly-OH (A-2),

-S-CH ₂ ,

Cr ₃ -CO-NH-CH-COOH or in short form CF ₃ CO-CyS-OH (A-3),

-S-CH ₂ ,

_f NH ₂ -CH-CO-NH-CH ₂ -COOh or in short H-Cys-Gly-OH (A-4),

-S-CH ₂ ,

NH ₂ -CH-COOH or in short form H-Cys-OH (A-5)

and -S-CH ₂ -COOH (A-6).

Also included are corresponding compounds wherein the carboxyl groups are in the form of a primary amide or C 1-6 alkyl ester, or more particularly a salt, preferably an alkali metal salt. In the first place, the compounds of formula I described in the examples are to be emphasized.

The thioethers according to the invention can be prepared in a manner known per se, for example by carrying an unsaturated aliphatic trans-epoxide of at least 12 carbon atoms which corresponds to the radical (B) defined above and which bears a double bond at least in the α-position relative to the epoxy moiety , especially one of the formula

CO- (CH ₂ ) aR ¹ R ² -CH = CH- (X ^(II)

wherein R ¹ and R ^{2 have} the abovementioned meanings and both hydrogens are oriented transversely to one another on the oxirane ring, and in which an optionally present hydroxyl group may be present in a protected form, with a mercaptoalkanecarboxylic acid corresponding to the radical (A) defined above, in particular one of the formula

HS-CH ₂ -X-CO-R ³ (III)

wherein R ³ and -X-have the abovementioned meanings, in which acid an optionally present amino group may be present in a protected form, or with its salt or derivative having a converted carboxyl group and, if necessary or desired, the protective groups of the hydroxyl and / or or amino group, and / or saponifies an esterified compound to the free acid or a salt thereof and, if desired, converts a free compound having salt-forming properties into a salt thereof or a salt obtained into a free compound. The conversion is carried out under conditions known per se at temperatures of about -20 ⁰ C to about + 5O ⁰ C, preferably at room temperature, and especially in a basic medium, for example in the presence of an amine, especially a tertiary aliphatic, araliphatic or saturated heterocyclic amine such as trialkylamine (eg triethylamine, or ethyldiisopropylamine), dialkylbenzylamine (eg N, N-dimethylbenzylamine), Ν, Ν-dialkylaniline (eg N, N-dimethylaniline) or N-methyl- or N-ethyl piperidine or Ν, Ν'-dimethylpiperazine. Usually, the reaction is carried out in an inert organic solvent such as a lower alkanol, e.g. For example, methanol or ethanol.

If a free hydroxyl is present in the starting material, in particular in the substituent R ^{1 of} the formula II, it may be in a protected, etherified form during the reaction. Preference is given to easily removable, in particular acidolytically removable, hydroxyl-protecting groups, as are generally known, in particular from peptide and steroid chemistry; In this case, protecting groups of Typtert-butyl and especially tetrahydropyranyl ether (THP ether) are particularly preferred. These protective groups can after the main reaction (ie condensation of the epoxide with the mercaptocarboxylic acid) in atigemein known manner, for. By treatment with an organic acid such as formic acid, acetic acid, oxalic acid or trifluoroacetic acid, or a mixture thereof, and optionally in the presence of water and / or inert organic solvents such as lower alkanols (e.g., methanol or ethanol) and cyclic ethers (Such as tetrahydrofuran or dioxane) are removed to release the hydroxyl.

If the mercaptocarboxylic acids used as starting material contain a free amino group, this may preferably be present in a protected, in particular an acylated form during the main reaction. Preferably, particularly acidolytic cleavable amino-protecting groups are used, as they are generally well known, especially in peptide chemistry, including conditions for their removal. Among the amino-protecting groups, however, the trifluoroacetyl group is particularly noteworthy: after the main reaction has taken place, it can remain in the end product according to the invention or, if desired, be split off subsequently. The cleavage of the N-trifluoroacetyl group is carried out, as known, preferably by hydrolysis, in particular under basic conditions, such as with alkali metal carbonates z. Sodium or potassium carbonate) or diluted caustic solutions (e.g., sodium or potassium hydroxide) in the presence of water in a water-miscible organic solvent such as a lower alkanol (e.g., methanol or ethanol) or cyclic ether (e.g. for example, tetrahydrofuran or dioxane) at temperatures of about 0-80 ⁰ C, preferably at a slightly elevated temperature of about 50-60 ⁰ C. When ester groups are present in the product to be hydrolyzed, such as an acylated hydroxyl group in the hydroxyalkyl radical R ¹ or an esterified carboxyl group in the mercapto acid residue (A), then they are mitsubstituted simultaneously under these conditions.

In the main reaction (condensation with epoxide), the mercaptocarboxylic acid is used primarily in the form of its ester, preferably a C 1-4 -alkyl ester (such as methyl or ethyl ester); if the end product of the present invention is desired as the free acid or its salt, then the resulting ester must be hydrolyzed. The hydrolysis is carried out under the usual conditions, for. For example, those described above for the base-catalyzed hydrolytic cleavage of the N-trifluoroacetyl group. However, under milder conditions, in particular at low temperature (preferably at room temperature), with an equivalent stoichiometric amount of alkali and by a shortened reaction time, optionally under analytical control, e.g. For example, by thin layer chromatography, the ester group selectively split off with the preservation of the N-Trifluoracetylgrup ^ e, but an acylated hydroxyl group is cleaved at the same time most of the same time. Starting materials for the condensation process according to the invention are either known per se or obtainable by known analogy methods in a manner known per se. - So are z. B. the important mercaptocarboxylic acids of the formula III described (see, for example, E.J. Corey et al .: Tetrahedron Letters 1980,3143), other analogous acids are accessible in the same way starting from corresponding known starting materials. For the preparation of cysteine derivatives, analogously known analogous cystine compounds are used and subjected to the usual reductive cleavage of the disulfide bond or else suitable as cysteine derivatives, eg. B. processed by trityl or acetylaminomethyl, protected mercapto group.

The unsaturated trans-epoxide used as starting material, eg. As that of formula II defined above, can be prepared mainly by the same method, which are also used in the synthesis of Leukotrieneri. In a typical general synthetic route, e.g. B. of a saturated aliphatic aldehyde (alkanal) of the formula

O = CH- (CH ₂ J ₂ -R ¹ (IV)

assumed, wherein R ^{1 has} the meanings given above, wherein an optionally present in the radical R ¹ free hydroxyl group in a protected as ether, z. B. one of the above-described form is present. This compound is condensed with formylmethylenetriphenylphosphorane (or an equivalent reagent) to give the corresponding α, β- unsaturated aldehyde, 2-trans-alkenal, of the formula

O = CH. / CE

is formed, wherein R ^{1 has} the meanings given above and one in the radical R ¹ optionally present free hydroxyl group is protected as an ether. This compound is then epoxidized in a manner known per se, preferably under weakly alkaline conditions (for example in the presence of alkali metal carbonates) with aqueous hydrogen peroxide, whereby a trans-epoxide, 2- (RS), 3 (SR) -epoxy-alkanal of the formula

- (Vl)

CH Z) ₂ -R ¹

results, wherein R ^{1 has} the meanings given above and one in the radical R ¹ optionally present free hydroxyl group is protected as an ether. This epoxy aldehyde can be added to the desired unsaturated epoxide, e.g. Example, the formula II defined above, wherein an optionally present in the radical R ¹ free hydroxyl group in protected, etherified form are condensed by condensation with a corresponding known Alkylidentriphenylphosphoran. For polyunsaturated epoxides, e.g. For example, those of formula II wherein R ^{2 has} one or more double bonds, offers an indirect alternative: instead of the Wittig reaction with an unsaturated in its chain ylidene-phosphorane, the epoxy aldehyde Vl first with formylmethylenetriphenylphosphorane ory-Triphenylphosphoranylidencrotonaldehyd Triphenylphosphoranylidene-2-trans-butenal) by 2 or 4 carbon atoms (1 or 2 double bonds) extended, and only the resulting 4 (RS), 5 (RS) -epoxy-2-alkenal or 6 (RS), 7 (RS) -epoxy-2,4-alkadienal condensed with a simple, saturated Alkylidentriphenylphosphoran or a less complicated Aikenylidentriphenylphosphoran to the desired polyunsaturated epoxide (eg one of the formula II).

If individual diastereomers are desired, an individual diastereomer of a starting material can advantageously be used at any stage, or a diastereomer can preferably be formed from a racemic or optically inactive starting material by stereoselective reaction conditions or optically active reagents, or racemic diastereomer mixtures by physical separation methods, optionally with application optically active excipients, are separated into optically individual diastereomers.

In stereochemical terms, however, both the inventive condensation of the formation components II and III, as well as the preparation of the starting materials primarily carried out so that each stereochemically uniform starting materials used, the reactions if possible steroselective, z. B. by the use of optically active reagents and / or auxiliaries, performs and isolated stereochemically uniform products from reaction mixtures immediately after the reaction. So z. B. in the production of unsaturated starting materials optionally formed isomers with cis and trans double bonds immediately separated, including the usual physical separation methods, in particular chromatography, are suitable. In the main reactions, primarily the epoxide of formula II is used as an individual trans stereoisomer but in racemic form (as normally formed by the epoxidation of an olefin); the mercaptoalkanoic acid of the formula IM, if it is optically active, is preferably used as an individual optical antipode (which is the usual case in particular for cysteine and its derivatives) - this measure allows the two optically active diastereomers formed to be readily prepared by common physical methods, such as Chromatography, to separate from each other; If an optically inactive mercaptoalkanoic acid is used, it is inevitable to obtain individual optically active products, the methods of cleavage in antipode by means of optically active Hijfsstoffe such. As the formation of salts with optically active bases apply. All suitable separation methods are known per se and can also be repeated or combined with each other appropriately. Due to the close relationships between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood in the preceding and following among the free compounds or their salts, mutatis mutandis.

The invention also relates to those embodiments of the process according to which one starts from an intermediate obtainable at any stage of the process and carries out the missing steps or uses a starting material in the form of a salt or forms it under the reaction conditions. The novel starting materials and intermediates occurring in the novel processes and their precursors likewise form the subject of the invention.

Preferably, such starting materials are used, and the reaction conditions are selected so that one arrives at the compounds listed above as being particularly preferred.

The present invention also relates to pharmaceutical compositions and pharmaceutical compositions containing one of the compounds of the formula I according to the invention or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the invention are in particular those which are suitable for local administration and especially for inhalation administration, eg. Example, in the form of an aerosol, micropowdered powder or a finely sprayed solution, are intended to suckers and contain the active ingredient alone or together with a pharmaceutically acceptable carrier material.

Pharmaceutical preparations for topical and local use are e.g. For the treatment of skin lotions and creams containing a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative). For the treatment of the eyes are eye drops containing the active compound in aqueous or oily solution, and eye ointments, which are preferably prepared in sterile form. For the treatment of the nose are aerosols and sprays (similar to those described below for the treatment of the respiratory tract), coarse powders which are administered by rapid inhalation through the nostrils, and especially nasal drops containing the active compound in aqueous and oily solution , suitable; for local treatment of the oral cavity are also lozenges, which contain the active compound in a generally formed from sugar and gum arabic or tragaganth mass to which flavors may be added, and lozenges containing the active ingredient in an inert mass, for. As gelatin and glycerol or sugar and gum arabic included.

As pharmaceutical compositions for administration in the form of aerosols or sprays are suitable z. B. Solutions, suspensions or emulsions of the active compound of the formula I according to the invention with a suitable pharmaceutically acceptable solvent, in particular ethanol and water, or a mixture of such solvents. If desired, they may also contain other pharmaceutical auxiliaries, such as nonionic or anionic surfactants, emulsifiers and stabilizers, as well as other active ingredients, and more particularly suitably with a propellant, such as an inert gas under elevated pressure or, in particular, with a volatile, preferably lower normal atmospheric pressure below the usual room temperature (eg between about -30 and +10 ⁰ C) boiling liquid, such as an at least partially fluorinated polyhalogenated lower alkane, or a mixture of such liquids, is mixed. Such pharmaceutical compositions, which are used predominantly as intermediates or storage mixtures for the preparation of the corresponding medicaments in finished form, usually contain the active substance in a concentration of about 0.1 to about 10, in particular from about 0.3 to about 3, 3% by weight. , For the preparation of medicaments in the finished form, such a pharmaceutical composition is filled into suitable containers, such as bottles and pressure bottles, which are provided with a suitable spraying device or valve for such purposes. The valve is preferably constructed as a metering valve which upon actuation releases a predetermined amount of the liquid corresponding to a predetermined dose of the active ingredient. In the preparation of the finished pharmaceutical form can also proceed so that appropriate amounts of the present as a stock solution pharmaceutical composition and the blowing agent are filled separately into the container and come there only for mixing. The dosage of the active compound of formula I to be administered and the frequency of administration depend on the respective efficacy or length of action of each individual of these compounds, on the severity of the disease or symptoms to be treated, and on sex, age, weight and individual responsiveness of the mammal to be treated. On average, the recommended daily dose of a compound of formula I according to the invention in a 75kg mammal (primarily humans) will be in the range of about 10 to about 500, preferably between about 25 to about 250mg, which administration will be appropriate as needed can be done several times a day.

The invention also relates to the use of the active compounds of the formula I according to the invention for alleviating or eliminating pathological states and / or symptoms of the body of a mammal, in particular of humans, which are attributable to the allergogenic action of leukotrienes and which occur in particular in asthma. This application or the corresponding healing method is characterized by the treatment of the suffering body or body part with an antiallergically effective amount of a compound of the formula I alone or in the form of a pharmaceutical, in particular a pharmaceutical composition intended for inhalation. By the term "an anti-allergic effective amount" is meant an amount of the active ingredient sufficient to significantly inhibit the contractions caused by leukotrienes.

embodiment

The following examples further illustrate the present invention without limiting its scope. All temperatures are in degrees Celsius. The amino acids as the formation components of the described compounds are in the "natural" L-form.

Example 1:

and the individual 5 (S), 6 (R) and 5 (R), 6 (S) diastereomers

A solution of 103 mg (0.36 mmol) of 5 (S, R), 6 (S, R) -5,6-epoxy-7-trans, 9-trans, 1-cis-cis-eicosatetraene, 154 mg ( 0.54 mmol) of N-IN'-trifluoroacetylcysteinyl-O-glycine methyl ester and 145 mg (1.44 mmol) of triethylamine in 0.5 ml of methanol is stirred in an argon atmosphere for 4 hours at room temperature and diluted with 2 ml of methanol. Reverse-phase chromatography in the acetonitrile / water (2: 1) system gives 212 mg (100%) of a diate isomer mixture which is approximately equal in proportions by subsequent high pressure chromatography on a Zorbax ODS RP column with methanol / water (85:15) both diastereomers is separated. The 5 (S), 6 (R) diastereomer has a shorter retention time under these conditions than the 5 (R), 6 (S) diastereomers

UV (in methanol): 5 (S), 6 (R) -isomer: A _max = 271,281,290 nm

(ε ₂₈₁ = 40 600)

5 (R), 6 (S) -isomer: K _msx = 271,280,290 nm IR (CH 2 Cl 2) is virtually identical for both diastereomers:

3570 (wide), 3370 (wide), 3000, 2950, 2920, 2850,1742,1720,1 680,1 518,1 460,1 435,1 380-1 350,1 208,1165,1000cm " ¹ . [a] § ° [5 (S), 6 (R) -isomer]: + 59 ° ± 1 ° (1.4% in CHCl ₃ ).

The racemic 5 (S, R), 6 (S, R) -5,6-epoxy-7-trans, 9-trans, 11-cis, 14-cis-eicosatetraene used as starting material can be prepared as follows:

A solution of 51.4 ml of pentanal and 147 g Triphenylphosphoranylidenacetaldehyd in 480 ml of chloroform is heated for 5 days under reflux, the solvent was distilled off under reduced pressure and the residue obtained with 400 ml of a

evaporated in vacuo and the residue distilled in vacuo. This gives 24.5 g (42.5%) of 2-trans-heptenal as a colorless oil, bp. 60-65 ° C / 24mbar.

To a solution of 2,24g 2-trans-heptenal in 24ml of methylene chloride and methanol 44ml 2,04ml 30% aqueous H, followed by 100 mg of solid potassium carbonate at 0 ⁰ C with stirring for ₂ O2 solution was added. The resulting reaction mixture is stirred at 0 ⁰ C for 3 hours. Finally, it is mixed with 100 ml of methylene chloride and washed twice with 25 ml of phosphate buffer of pH 8.0. The aqueous portions are back-extracted with 50 ml of methylene chloride. The combined organics are dried over magnesium sulfate and evaporated under reduced pressure. Chromatography of the crude product thus obtained on 85 g of Merck silica gel 60 with methylene chloride as the eluent gives a total of 1.59 g (62%) of 2 (R, S), 3 (S, R) -2,3-epoxyheptanal aisillose oil [R _f , (silica gel Toluene-ethyl acetate 4: 1): 0.59; IR (CH ₂ Cl ₂ ): 2950, 2925, 2850, 2820, 1721, 1463, 430, 178, ¹ 210, 850 cm ^-1 ]

To a solution of 640 mg of 2 (R, S), 3 (S, R) -2,3-epoxyheptanal in 10 ml of methylene chloride is added dropwise at room temperature within 1 hour, a solution of 1.65 g of y-Triphenylphosphoranylidencrotonaldehyd in 15 ml of methylene chloride and the resulting reaction mixture stirred for a further hour at room temperature. For work-up, the reaction mixture is evaporated under reduced pressure and the residue is chromatographed on a column of 40 g of silica gel in toluene / ethyl acetate (19: 1). This gives a cis, trans and trans, trans-isomer mixture, which is dissolved in 5 ml of methylene chloride with a few crystals of iodine for isomerization and allowed to stand at room temperature for 4 hours. The solution is then evaporated in vacuo and chromatographed as mentioned above. This gives 511 mg (57%) of 6 (S, R), 7 (S, R) -6,7-epoxy-2-trans, 4-transundecadienal as a yellowish oil. [UV (ethanol): X _max = 276nm; ε = 29900; IR (CH ₂ Cl ₂ ): 2950.2920, 2850, 2800, 2720, 1678, ¹ 640, 16, 16, 16, 16, 11, 11, 11, 11, 17, 17, cm 2 ""¹; R _f [silica gel; Toluene-ethyl acetate (4: 1)] = 0.56.

A solution of S-cis -nonen-i-yl-triphenyl-phosphonium-toluene-sulfonate [I. Ernest, AJMain, R.Menasse, Tetrahedron Letters 23, 167 (1982)] (378 mg) in 4.2 ml of tetrahydrofuran and 1 , 26 ml of hexamethylphosphoric triamide is added dropwise at -78 ° C under argon with 0.31 ml of a 20% solution of butyllithium in hexane and the resulting solution at -78 ° C for a further 30 min. Stirred. To the obtained solution of triphenylphosphoranylidene-3-cis-nonene, is at -78 ⁰ C a solution of 110 mg 6 (S, R), 7 (S, R) -6,7-epoxy-2-trans-4-trans- Undecadienal added dropwise in 1.0 ml of tetrahydronfuran and the resulting reaction mixture was stirred for 30 min. At -78 ° C. For work-up, the reaction mixture is partitioned between 100 ml of ether and 30 ml of phosphate buffer of pH 8.0, and both phases are back-extracted with ether or buffer solution. The combined ethereal portions are dried over magnesium sulfate and evaporated in vacuo to give 421 mg of oily crude product. This is triturated with 2-3 ml hexane-ether mixture 3: 1, the crystalline precipitated Triphenylphsphinoxid separated and evaporated the Fi Itrat. The resulting residue (195 mg) is chromatographed on an alumina column (10 g) prepared in hexane with 0.5% triethylamine, with the same eluent. This gives 90.6 mg (57%) of 5 (S, R), 6 (S, R) -5,6-epoxy-7-trans, 9-trans, 1 i-cis.U-cis-eicosatetraen as viscous , yellowish oil. [UV (methanol): X _max = 270, 280.291 nm; S ₂₈₀ = 59,600; IR (CH ₂ Cl ₂ ): 3000, 2900, 2850, 1445.1, 370, 992, 963 cm " ¹ ].

Example 1A:

N- {S- [5 {S), 6 (R) -5-hydroxy-7-trans, 9-trans, 11-cis, 14-cis eicosatetraen-6-yl] -N-trifluoracetylcysteinyl} -Glycine methyl ester [from optically individualized epoxy olefin].

A solution of 130 mg (0.45 μmol) 5 (S), 6 (S) -5,6-epoxy-7-trans, 9-trans, 11-cis, 14-cis-eicosatetraene, 260 mg (0.902 mmol) N- fN-trifluoroacetylcysteinyl-O-glycine methyl ester and 250 ml (1.8 mmol) triethylamine in 1.0 ml of methanol are stirred under argon at room temperature for 3.5 hours and then, after dilution with a little methanol, onto 12RP plates (Opti-UPC.RTM. ANTECHAG, Bennwil, Switzerland, 20 x 20 cm) in the system acetonitrile: water (1: 1) chromatographed. The title compound (216mg) thus obtained is rechromatographed on a high pressure RP column (ZorbaxODS) in methanol: water = 87:13. This gives 122 mg of pure title compound, which is identical in all respects with the diastereomer with the shorter retention time (see Example 1).

The optically active starting material, d. H. 5 (S), 6 (S) -5,6-epoxy-7-trans, 9-trans, 11-cis-cis-eicosatetraene, is prepared in the following manner:

To a solution of 10 g of lithium aluminum hydride in 400 ml of ether are added dropwise at 0 ⁰ C 16.9 g of 2-heptynol in 200 ml of ether within 30 minutes with stirring, and the resulting reaction mixture is refluxed overnight. The excess of LiAlH ₄ is destroyed by cooling in an ice-water bath by addition of 40 ml of ethyl acetate, and the resulting reaction mixture is taken up between ether and cold 1N sulfuric acid. The acidified (pH 2) aqueous layer is back-extracted with ether, the combined organic extracts are dried over magnesium sulfate and evaporated in vacuo. Distillation of the residue (18 g) under reduced pressure gives 13.2 g of 2-trans-heptenol as a colorless oil, bp. 71.5-72 ° C / 13mbar.

A solution of 2.28 g (20 mM) 2-trans-heptenol in 10 mL of methylene chloride is added at -20 ° C to a solution of 5.94 mL of tetraisopropyl orthotitanate and 4.12 g of L - (+) - tartaric acid diethyl ester in 210 mL of methylene chloride of 9.75 ml of a 4.1 M solution of tert-butyl hydroperoxide in 1,2-dichloroethane. The resulting reaction mixture is allowed to stand at -20 ⁰ C overnight. After addition of 8 ml of dimethyl sulfide at -2O ⁰ C is gerühn to -23 ⁰ C for 45 minutes, then rr) it50ml of a 10% aqueous solution of L - (+) - tartaric acid was added and 30min. at -20 ° C and 60min. stirring continued without cooling. The organic phase is separated off, washed with 100 ml of water and dried after drying over magnesium sulfate under reduced pressure. The residue, dissolved in 150 ml of ether, is stirred at 0 ° C with 60 ml of 1N NaOH for 30 minutes, the aqueous phase separated, back-extracted with ether, and the combined organic extracts are shaken with brine. After drying the organic portion over magnesium sulfate and distilling off the solvent under reduced pressure gives 2.3 g of 2 (S), 3 (S) -2,3-epoxyheptanol as a colorless, unstable oil. It will be processed immediately. A solution of 1.2 g of 2 (S), 3 (S) -2,3-epoxyheptanol in 28 ml of methylene chloride is added at room temperature to a freshly prepared solution of 5.5 g of chromium trioxide and 8.76 g of pyridine in 70 ml of methylene chloride and the resulting Reaction mixture further stirred for 30 minutes. The dark colored reaction mixture is decanted from the precipitated material, the latter washed with 160 ml of methylene chloride, and the combined organic portions are washed with 80 ml of phosphate buffer of pH 8.0. After drying over magnesium sulfate and evaporation under reduced pressure, the crude product to be left is chromatographed on 90 g of Merck Kieselgel 60 with toluene / ethyl acetate (4: 1 (464 mg of 2 (R), 3 (S) -2,3-epoxyheptanal) . as a colorless oil [a] = +101 g ° C ± 1 ^{0 0} C (1.225% in CHCI _3); IR (CH ₂ CI _2): 2950,2925,2860,2815,2730, 1722.1 462.1432 , 1 380,1 360,1 230,1156, 850cm " ^1. ]

A solution of 804 mg-y-Triphenylphosphoranylidencrotonaldehyd in 10 ml of methylene chloride is added dropwise at room temperature within 1 hour with a solution of 260 mg of 2 (R), 3 (S) -2,3-Epoxyheptanal in 10 ml of methylene chloride and the resulting reaction mixture then 1 Stirred for 5 hours. The solution is then concentrated under reduced pressure to about 2 ml and immediately chromatographed on a column of 20 g silica gel 60 with toluene / ethyl acetate (19: 1). This gives 120 mg of a cis, trans and trans / trans isomer mixture, which, dissolved in 2 ml of methylene chloride with 2 mg of iodine, is allowed to stand for isomerization at room temperature. After 2.5 hours, the solution is concentrated in vacuo and rechromatographed as described above to give 103 mg of pure, optically active 6 (S), 7 (S) -6,7-epoxy-2-trans, 4- trans-undecadienal as a yellow, at -2O ⁰ C crystalline solidifying oil. Hd = ⁰ -28 ⁰ C ± 1 ⁰ C (0.735% in CHCI _3).

The condensation of 90 mg of the latter compound, dissolved in 2 ml abs. Tetrahydrofuran at -78 ⁰ C with a solution of Triphenylphosporanyliden-3-cis-nonene, prepared from 338 mg of the corresponding phosphonium toluene sulfonate in tetrahydrofuran / hexamethylphosphoric triamide by adding butyllithium in hexane, and working up in the manner described for the racemic product (see Example 1), 132 mg (91%) of 5 (S), 6 (S) -5,6-epoxy-7-trans, 9-trans, 11-cis, 14-ciseicosatetraen are obtained as a yellowish oil

[a] § ° = -23 ° C ± 1X (0.81% in CHCl ₃ ).

Example 1 B: N- {5- [5 (S), 6 (R) -5-hydroxy-7-trans, 9-trans, 11-cis, 14-cis-eicosatetraene-6-yl] -cysteinyl) glycine potassium salt A solution of 84 mg of N- {S- [5 (S), 6 (R) -5-hydroxy-7-trans, 9-trans, 11-cis, 14-cis-eicoratetraen-6-yl] - N-trifluoroacetylcysteinyl} -glycine methyl ester in 3.8 ml of tetrahydrofuran and 3.8 ml of methanol is treated with a solution of 276 mg of potassium carbonate in 11.5 ml of water and the resulting mixture is stirred at room temperature under argon for 44 hours. Finally, it is concentrated under reduced pressure to about 3 ml and applied to reverse phase plates. Chromatography in the system acetonitrile / water (1: 1 (gives 40 mg of the title compound, which is stored in 5.0 ml of ethanol at -78 ° C; UV (ethanol): A _max = 271, 280.290nm; 8 _2S0 = 48600.

Example 1C: N- {S- [5 (R), 6 {S) -5-hydroxy-7-trans, 9-trans, 11-cis, 14-cis-eicosatetraen-6-yl] -cysteinyl} -glycine Potassium salt Analogously to the process described in the preceding Example 1B, from 32 mg of N- {S- [5 {R), 6 (S) -5-hydroxy-7-trans, 9-trans, 11-cis, 14-cis- eicosatetraen-6-yl] -N-trifluoroacetylcysteinyl} -glycine methyl ester 8.5 mg of the title compound, which is stored in ethanolic solution at -78 ° C; UV (ethanol): A _max = 270,280,290 nm; ε ₂₈ ο = 49000.

General procedure Example 2: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-heptadecene-6-yl-N-trifluoracetylcysteinyl] -glycine methylester

To a solution of 480 mg of 5 (RS), 6 (RS) -5,6-epoxy-7-cis-heptadecene (E 1) and 660 mg of N-t-N-trifluoroacetylcysteinyl-1-glycine methyl ester [E. J. Corey et al., Tetrahedron Lett. 1980,3143] in 6 ml of methanol are added 0.78 ml of triethylamine. The solution is stirred for 16 hours at room temperature under argon, the solvent evaporated in vacuo and the residue purified by chromatography on silica gel with dichloromethane / ethyl acetate (85:15). The title compound is obtained as a colorless

IR (CH ₂ Cl ₂ ): 3400, 2940, 2870, 1755, 1740, 16, 15, 15 cm " ¹ .

In an analogous way are obtained ':

Example 3: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-undecen-6-yl-N-trifluoroacetylcysteinyl] -glycine methyl ester, on 67mg 5 (RS), 6 ( RS) -5,6-epoxy-7-cis-undecene (E2) and 486 mg of N-IN-trifluoroacetylcysteinyl-J-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400.2960, 2940, 2880.1 750.1730.1 640.1 525 cm ^-1 .

Example 4: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-tridecen-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.5 g of 5 (RS ), 6 (RS) -5,6-epoxy-7-cis-tridecene (E3) and 0.8 g of N-dN-trifluoroacetylcysteinyD-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400.2980, 2940, 2870.1 760.1740.1 700.1 535cm " ¹ .

Example 5: S-.alpha.RSRS ^ fSRJ-S-hydroxy-cis-tridecen-e-yl-cysteine methyl ester from 0.5 g of 5 (RS), 6 (RS) -5,6-epoxy-7-cis-tridecene (E3) and 0.87 g of cysteine-methylester hydrochloride.

IR (CH ₂ Cl ₂ ): 3600.3400, 2970, 2950, 2880.1, 750.1, 445cm " ¹ .

Example 6 Methyl S-SfRSLeiSRi-S-hydroxy-cis-tridecen-6-yl-mercaptoacetic acid, from 0.72 g of 5 (RS), 6 (RS) -5,6-epoxy-7-cis-tridecene ( E3) and 0.43 g of mercaptoacetic acid methyl ester.

IR (CH ₂ Cl ₂ ): 3600, 2980, 2940, 2880, 1745, 1475, 1445 cm ^-1 .

Example 7: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis -pentadecen-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.5 g of 5 (RS ), 6 (RS) -5,6-epoxy-7-cis-pentadecene (E4) and 0.71 g of N-fN-trifluoroacetylcysteinyl-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400, 2970, 2950, 2870.1 760.1740.1 695.1 530cm ^-1 .

Example 7a: S-5 (RS), 6 (SR) -5-hydroxy-7-cis-pentadecen-6-yl-N-trifluoroacetyl-cysteine methyl ester, from 0.5 g of 5 (RS), 6 (RS) 5,6-epoxy-7-cis-pentadecene (E4) and 0.58 g of N-trifluoroacetylcysteine methyl ester.

Example 8: S-SiRSl ^ fSRJ-S-hydroxy-cis-pentadecen-e-yl-cysteine methyl ester, from 0.5 g of 5 (RS), 6 (RS) -5,6-epoxy-7-cis-pentadecene ( E4) and 0.77 g of cysteine methyl ester hydrochloride.

IR (CH ₂ Cl ₂ ): 3600.3400, 2970, 2940, 2870.1 750.1 475.1 445cm " ¹ .

Example 9: Methyl S-SfRShefSRI-S-hydroxy-cis-pentadecen-S-yl-mercaptoacetic acid, from 0.9 g of BiRSWiRSl-epoxy-cis-pentadecene (E4) and 0.47 g of 2-mercaptoacetic acid methyl ester. IR (CH ₂ Cl ₂ ): 3600, 2970, 2990, 2870.1 750, 1475.1 445 cm ^-1 .

Example 10: S-SIRS1 / 1SRj-B-hydroxy ^ -cis-heptadecen-e-yl-cysteinyl-methyl ester, from 1 g of 5 (RS), 6 (RS) -5,6-epoxy-7-cis-heptadecene (E 1) and 1.4 g of cysteine methyl ester hydrochloride.

IR (CH ₂ Cl ₂ ): 3600, 3400, 2940, 2870.1, 750, 475cm " ¹ .

Example 11: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-eicosene-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 1 g 5 (RS) , 6 (SR) -S, 6-epoxy-7-cis-eicosene (E5) and 1 g of N-fN-trifluoroacetylcysteinyl-1-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400, 2930, 2860.1, 750.1, 735, 6.190, ¹ 530 cm ^-1 ,

Example 12: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-tricosene-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.6 g of 5 (RS ), 6 (SR) -5,6-epoxy-7-cis-tricosene (E6) and 0.58 g of N-IN-trifluoroacetylcysteinyl-1-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400, 2940, 2870, 175560, 740, 171, ¹ , 5, 5Cm " ¹ .

Example 13: N-iS-iRSJ ^ iSRl ^ -hydroxy-e-cis-tetradecen-S-yl-thiol-propionyl-1-glycine methyl ester, from 300mg4 (RS), 5 (RS) -4,5-epoxy-6 cis-tetradecene (E7) and 275 mg of N-.beta.-mercaptopropionyU-glycine methylesteriS.Okuyama et al., Chem. Pharm. Bull. 30, 2453 [1982]). IR (CH ₂ Cl ₂ ): 3450,2970,2940,2870,1760,1 690,1525cm " ¹ .

Example 14: N- [S-4 (RS), 5 (SR) -4-Hydroxy-6-cis-tetradecen-5-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.7 g of 4 (RS ), 5 (RS) -4,5-epoxy-6-cis-tetradecene (E7) and 1.2 g of N-fN-trifluoroacetylcysteinyl-O-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400.2980, 2940, 2870, 1760, ¹ 740, ^1, 7, 5, 5, 5cm " ¹ .

Example 15: N-IS-iRSi ^ fSRM-hydroxy-e-cis-nonadecen-6-yl-thioJ-propionyl-1-glycine methyl ester, from 250mg4 (RS), 5 (RS) -4,5-epoxy-6- cis-nonadecene (E8) and 175mg N-fS-mercaptopropionyl-D-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3450, 2980, 2940, 2870.1, 760.1, 690.1, 530 cm ^-1 .

Example 16: N- [S-4 (RS), 5 (SR) -4-hydroxy-6-cis-nonadecen-5-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 500 mg 4 (RS), 5 (RS) -4,5-epoxy-6-cis-nonadecene (E8) and 620 mg of N-fN-trifluoroacetylcysteinyl-O-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400.2970, 2940, 2870.1 760.1 740.1 700.1 530cm ^-1 .

Example 17: N- [S-4 (RS), 5 (SR) -4-hydroxy-6-cis-eicosen-5-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 680 mg 4 (RS), 5 (RS) -4,5-epoxy-6-cis-eicosene (E9) and 8'30 mg of N-fN-trifluoroacetylcysteinyl-1-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400.2940, 2870.1 760.1740, 1700.1, 530 cm ^-1 .

Example 17a: N- {3-t4 (RS), 5 (SR) -4-hydroxy-6-cis-eicosene-5-yl-thio] -propionyl} -glycine methyl ester, from 680 mg 4 (RS), 5 ( RS) -4,5-epoxy-6-cis-eicosene (E9) and 720g N-Fβ-mercaptopropionyl-D-glycine methyl ester.

Example 17b: S-MRShBiSRM-hydroxy-e-cis-eicosene-B-yH-N-trifluoroacetyl-cysteine methyl ester, from 680 mg 4 (RS), 5 (RS) -4,5-epoxy-6-cis-eicosene (E9) and 620 mg of N-trifluoroacetylcysteine methyl ester.

Example 18: N- [S-6 (RS), 7 (SR) -6-hydroxy-8-cis-eicosene-7-yl-N-trifluoroacetylcysteinyl] -glycine methyl ester, from 0.54 g 6 (RS), 7 ( RS) -6,7-epoxy-8-cis-eicosene (E 10) and 0.53 g of N-fN-trifluoroacetylcysteinyl-O-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400, 2940, 2870.1, 760.1, 740, 1700, ¹ 530 cm ^-1 .

Example 18a: N- {2- [6 (RS), 7 (SR) -6-hydroxy-8-cis-eicosene-7-yl-thio] -propionyl} -glycine, from 0.54 g 6 (RS), 7 (RS) -6,7-epoxy-8-cis-eicosene (E 10) and 0.45 g N-fa-mercaptopropionyD-glycine.

Example 18b: S-iefRSl ^ fSRi-e-hydroxy-S-cis-eicosen ^ -yl-1-cysteine methyl ester, from 0.54 g 6 (RS), 7 (RS) -6,7-epoxy-8- cis-eicosene (E 10) and 0.45 g of cysteine methyl ester.

Example 19: N-tS-SfRSl ^ fSRI-S-hydroxy-i-tetrahydropyranyloxy-cis-octadecene-e-yl-N-trifluoroacetyl-cysteinyl-glycine ethyl ester, from 'O ^ g SIRSl.efRSl-ö ^ -epoxy -i-tetrahydropyranyloxy-cis-octadecene (E11) and 0.6 g of N (N-trifluoroacetylcysteinyl-1-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400, 2940, 2870.1, 740.1, 700.1, 530 cm ^-1 .

Example 19a: Methyl S-SiRSl.efSRl-S-hydroxy-i-tetrahydropyranyloxy-cis-octadecene-e-yl-mercaptoacetic acid, from 0.7 g of BiRSI ^ IRSJ-S ^ -epoxy-i-tetrahydropyranyloxy) -cis octadecene (Eil) and 0.35 g of mercaptoacetic acid methyl ester.

Example 20: N-IS-δRSRS ^ fSRI-S-hydroxy-i-tetrahydropyranyloxy-cis-eicosene-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester.

from 0.8 g of SfRSi ^ fRSJ-B ^ -epoxy-i-tetrahydropyranyioxy ^ cis-eicosene (E 12) and 0.64 g of N-IN-trifluoroacetylcysteinyD-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400, 2940, 2860.1 760.1 740.1 700.1 530cm ^-1 .

Example 20a: Methyl S-BiRSjlSRJ-B-hydroxy-i-tetrahydropyranyloxy-T-cis-eicosen-e-yl-mercaptoacetic acid, from 0.8 g of 5 (RS), 6 (RS) -5,6-epoxy 1-tetrahydropyranyloxy-7-cis-eicosene (E 12) and 0.4 g methyl mercaptoacetate.

Example 21: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-trans-9-cis-nonadecadien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0, 55 g of εRSi ^ iRSi-ö ^ -epoxy-y-trans-S-cis-nonadecadiene (E 13) and 0.62 g of N-iN-trifluoroacetylcysteinyl-1-glycine methyl ester.

Example 21 a: N-f-S-ISfRSlefSRJ-S-hydroxy ^ -trans-S-cis-nonadecadien-e-yl-thiol-propionyl-glycine methyl ester, from 0.55 g

(E13) and 0.53 g of N-O-mercaptopropionyl-1-glycine methyl ester.

Example 21b: S-ISfRSi ^ iSRj-S-hydroxy-y-trans-S-cis-nonadecadien-e-yl-J-cysteine methyl ester, from 0.55g of 5 (RS), 6 (RS) -5.6 -Epoxy-7-trans-9-cis-nonadecadiene (E 13) and 0.40 g of cysteine methyl ester.

Example 21c: S-tBiRSl.eiSi-B-hydroxy-T-trans-S-cis-nonadecadien-e-yl-1-mercaptoacetic acid methyl ester, from 0.55 g

(E 13) and 0.32g mercaptoacetic acid methyl ester.

Example 21d: S-ISiRSl ^ iSRI-S-hydroxy-y-trans-S-cis-nonadecadien-e-yl-1-mercaptoacetic acid, from 0.55 g of 5 (RS), 6 (RS) -5,6- Epoxy-T-trans-egg-cis-nonadecadiene (E 13) and 0.30 g mercaptoacetic acid.

Example 21 e: N-IS-S-hydroxy ^ -trans-g-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester; Diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B] (by chromatography):

from 0.6 g of racemic öfRSi ^ fRSi-S ^ -epoxy-T-trans-S-cis-eicosadiene (E13a) and 0.52 g of N-tN-trifluoroacetyl-cysteinyD-glycine methyl ester in a mixture of both diastereomers in the ratio of about 1: 1 which is separated into individual forms [A] and [B] of the title compound by chromatography on silica gel with hexane-ethyl acetate (7: 3).

Example 21 f: N- [S-4 (RS), 5 (SR) -4-hydroxy-6-trans-8-cis-nonadecadien-5-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester; from 0.6 g of 4 (RS), 5 (RS) -epoxy-6-trans-8-cis-nonadecadiene (E13b) and 0.52 g of N-fN-trifluoroacetyl-cysteinyl-glycine methyl ester.

Example 22: N-tS-S-hydroxy-i-tetrahydropyranyloxy-trans-g-cis-octadecadiene-e-yl-N-trifluoroacetyl-cysteinyl-1-glycine methyl ester; Diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B] (by chromatography):

from 0.6 g of racemic SiRSl ^ iRSl-ö ^ -epoxy-i-tetrahydropyranyloxy ^ -trans-cis-octadecadiene (E 14) and 0.52 g of N- (N-trifluoroacetyl-cysteinyO-glycine methyl ester is a mixture of both diastereomers in the ratio of about 1: 1, which is separated into individual forms [A] and [B] of the title compound by chromatography on silica gel with hexane-ethyl acetate (1: 1) Both compounds have a virtually identical spectrum: IR (CH ₂ Cl ₂ ): 3400, 2940, 2870, 1760, 1740, 1695, 1530 cm " ¹ .

Example 22a: S- [5 (RS), 6 (SR S -hydroxy-i-tetrahydropranyloxy) trans-g-cis-octadecadiene-e-yl-methylmercaptoacetic acid methyl ester: from 0.9 g of BiRSl.sub.rst.S.sup.-1-epoxy-i tetrahydropyranyloxy-trans-S-cis-octadecadiene (E14) and O, 45g mercaptoacetic acid methyl ester.

Example 23: N-tS-S-hydroxy-i-tetrahydropyranyloxy-trans-g-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester: diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B] (by chromatography).

From 0.5 g of racemic olfactoryiRSJ-S ^ -epoxy-i-tetrahydropyrariyloxy-trans-g-cis-eicosadiene (E15) and 0.4 g of N- (N-trifluoroacetylcysteinyl-glycine methyl ester is a mixture of both diastereomers in the ratio of about 1 1, which is separated into individual forms [A] and [B] of the title compound by chromatography on silica gel with hexane-ethyl acetate (1: 1) Both compounds have a virtually identical spectrum: IR (CH ₂ Cl ₂ ): 3400, 2940, 2870, 1760, 1740, 1700, 1530 cm " ¹ .

Example 23a: S-IsofRSl-tSRl-S-hydroxy-i-tetrahydropyranyloxy-trans-g-cis-eicosadien-e-yl-mercaptoacetic acid methyl ester

from 0.91 g of SfRSl1-lRSl-o ^ -epoxy-i-tetrahydropyranyloxy-trans-g-cis-eicosadiene (E15) and 0.45 g of methyl mercaptoacetate.

Example 24: N- [S-5 (RS), 6 (SR) -5-hydroxy-7,9-trans-1-cis-hexadecatrien-e-yl-N-trifluoroacetyl-cysteinyl-1-glycine methyl ester, from 1.1 g of 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11-cis-hexadecatriene (E16) and 1.3 g of N-iN-trifluoroacetyl-cysteino-O-glycine methyl ester

IR (CH ₂ Cl ₂ ): 3400.2980, 2950,? 880, 1740.1, 700.1, 530 cm ^-1 .

This mixture of diastereomers is separated by chromatography on silica gel with hexane-ethyl acetate (4: 1) in both optically uniform forms: first the 5 (S), 6 (R) -diastereomer is eluted, followed by the 5 (R), 6 ( S) diastereomers.

Example 25: N-IS-SfRSl-iSRI-S-hydroxy ^ JI-cis-g-trans-hexadecatrien-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine methyl ester, from

0.5 g of OISRSlirRSi-S ^ -epoxy ^ n-cis-g-trans-hexadecatriene (E17) and 0.62 g of N-iN-trifluoroacetyl-cysteinyl-O-glycine methyl ester; IR (CH ₂ Cl ₂ ): 3400.2970, 2950, 2880.1, 740.1, 700.1, 530 cm ^-1 .

This mixture of diastereomers is separated by chromatography on silica gel with hexane-ethyl acetate (2: 1) in both optically uniform forms: first, the 5 (S), 6 (R) -diastereomers,

Ho ⁰ = +102.2 ± 4.4 ⁰ C, eluted, followed by 5 (R), 6 (S) diastereomers, Hd ⁰ = -41.4 ± 2.9 ° C; both values are measured in chloroform solution of concentration 0.255% (w / v) and 0.35% (w / v), respectively.

Example 25a: N- [S-5 (RS), 6 (SR) -5-hydroxy-7,9-trans-11-cis-octadecatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.5 g of SiRSl ^ RSl-S ^ -epoxy ^^ - trans -H-cis-octadecatriene (E17a) and 0.62 g of N-fN-trifluoroacetyl-cysteinyU-glycine methyl ester.

Example 26: N- [S-5 (RS), 6 (SR) -5-hydroxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, from 0.54 g of oilRSKetRSl-B ^ -epoxy ^ -trans-H-cis-eicosatriene (E18) and 0.58 g of N-fN-trifluoroacetyl-cysteine-glycine methyl ester.

IR (CH ₂ Cl ₂ ): 3400, 2970, 2940, 2870, 1760, 740, 1700, 1530 cm ^-1 .

Chromatography on silica gel with hexane-ethyl acetate (3: 2) separates this mixture of diastereomers into individual optically uniform forms; in the former fractions, the 5 (S), 6 (R) -diastereomer is eluted, followed by N- [S-5 (R), 6 (S) -5-hydroxy-7,9-trans-11-cis-eicosatriene 6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, which, as well as its diastereomer, has analog spectral properties such as the mixture of diastereomers.

Both mentioned optically indidipeullen compounds can also be obtained from corresponding optically uniform 5,6-epoxides by condensation with N-lN-trifluoroacetyl-cysteinyO-glycine methyl ester as follows:

Example 26A: N- [S-5 (R), 6 (S) -5-Hydroxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester: A Solution of 2.35 g of 5 (R), 6 (R) -5,6-epoxy-7,9-trans-11-cis-eicosatriene in 28 ml of methanol under argon with 2.48 g of triethylamine and 2.53 g of N- fN-trifluoroacetyl-cysteinylJ glycine methylester and stirred for 16 hours at 2O ⁰ C. Volatile components are removed in a water-jet vacuum and the residue is chromatographed on silica gel. Elution with hexane-ethyl acetate (3: 2) affords the title compound as a colorless oil which is identical to the product characterized above.

The optically active epoxide component can be prepared using the method of Example 1A as follows:

Under anhydrous conditions a stirred solution of 66.3 ml of tetraisopropyl orthotitanate and 38.51 ml of D - (-) - Weinsäurediethylesterin 1.11 methylene chloride at -23 ⁰ C in succession with 25.7 g of 2-trans-heptanol (see example 1A) and 140ml of a 3.2 M solution of tert-butylhydroperoxide in toluene for 16 hours maintained at 2O ⁰ C and treated at-23 ° C and 56ml of 10% aqueous L-tartaric acid solution dropwise. After a further 30 minutes, the mixture is allowed to warm to + 2O ⁰ C and stirring is continued until the organic layer can be clearly separated. This is stirred with 11 1% aqueous sodium sulfite solution for 1 hour, separated, washed with water over sodium sulfate and concentrated in a water-jet vacuum. The residue is dissolved in 1.61 diethyl ether, cooled to 0 ⁰ C, treated dropwise with 675 ml of sodium hydroxide solution and stirred at 0 ⁰ C for 30 minutes. The separated organic phase is washed with saturated sodium chloride solution, dried and concentrated to give 2 (R), 3 (R) -2,3-epoxyheptanol as a colorless, unstable liquid, which is processed immediately in the next step.

A solution of 13.3 g of the latter compound in 100 ml of methylene chloride is added dropwise within 30 minutes to a stirred suspension of 110.1 g of pyridinium chlorochromate and 41.9 g of sodium acetate in 500 ml of methylene chloride, the temperature is maintained at 25 ° C by gentle cooling , After 3 hours, the reaction mixture is diluted with 500 ml of diethyl ether and filtered through silica gel. The filtrate is washed with pH 8 phosphate buffer, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with a mixture of petroleum ether (b.p. 30-45 ° C) and diethyl ether (3: 2) gives 2 (S), 3 (R) -2,3-epoxy-heptanal as a colorless liquid; the product has analog spectral properties such as its 2 (R), 3 (S) antipode (see Example 1 A). ·

A solution of 6.7 g of 2 (S), 3 (R) -2,3-Epoxyheptanal in 250 ml of methylene chloride is added dropwise at 20 ⁰ C for 1 hour with a solution of 20.85 g of γ-Triphenylphosphoranylidencrotonaldehyd in 200 ml of methylene chloride dropwise and a stirred at 20 ⁰ C for a further hour. The reaction mixture is diluted with 240 ml of hexane and 120 ml of ethyl acetate, filtered through silica gel and concentrated. The residue is taken up in equal volumes of hexane and ethyl acetate, stirred for 15 minutes, filtered again through silica gel and concentrated. The resulting oily mixture of cis, trans and trans / trans isomers is dissolved in 200 ml of methanol for the purpose of isomerization, treated with 220 mg of iodine and allowed to stand at 20 ° C for 3 hours. After washing with an aqueous sodium thiosulfate solution and water and drying over sodium sulfate, the solution is concentrated and the residue is chromatographed on silica gel. Elution with hexane-ethyl acetate (4: 1) gives the desired 6 (R), 7 (R) -6,7-epoxy-2,4-trans-undecadienal as a yellowish oil,

Hd ⁰ = -21.1 ± 1.3 ° C (0.75G / V% in chloroform), whose spectral properties are not those of the 6 (S), 7 (S) antipodes (see Example 1A) differ.

To a cooled to -78 ° C, stirred solution of 5.15 g Nonyltriphenylphosphoniumbromid in 50 ml of tetrahydrofuran is added under argon, 6.85 ml of a 1.6 M solution of butyllithium in toluene. After 30 minutes at -78 ⁰ C, the mixture is successively by the dropwise addition of 15.1 g of hexamethylphosphoric triamide and a solution of 1.52 g (6 (R), 7 (R) -6,7-epoxy-2,4-trans -undecadieneal in 10 ml of tetrahydrofuran, held for a further 15 minutes at -78 ⁰ C and allowed to warm to 0 ⁰ C. The reaction mixture is treated with phosphate buffer (pH 8) and extracted with ether The combined ether extracts are stabilized with a few drops of triethylamine dried over sodium sulphate and freed from volatile constituents in vacuo at 20 ^° C. The residue is stirred with small amounts of ether and freed from the precipitated solid triphenylphosphine oxide by filtration.From the filtrate, the last portions of triphenylphosphine oxide are removed by filtration through a silica gel column, which was prepared by washing with a mixture (4: 1) of ether-hexane with a 2% admixture of triethylamine, after distilling off the solvents The filtrate gives the desired 5 (R), 6 (R) -5,6-epoxy-7,9-trans-11-cis-eicosatriene as slightly yellow crystals, mp 31-32 ° C.

Example 26B: N- [S-5 (S), 6 (R) -5-hydroxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester is obtained in an analogous manner as in Example 26 A, but starting from 5 (S), 6 (S) -5,6-epoxy-7,9-trans-11-cis-eicosatrien. The title compound is identical to the product obtainable by chromatography of the diastereomeric mixture (see above).

The 5 (S), 6 (S) -5,6-epoxy-7,9-trans-11-cis-eicosatriene required as starting material can be obtained in an analogous manner as its 5 (R), 6 (R) -antipod by reacting the 6 (S), 7 (S) -6,7-epoxy-2,4-transundecadienal (see Example 1 A) with a Wittig reagent prepared in situ from nonyltriphenylphosphonium bromide and butyllithium according to the last paragraph of Example 26A. The spectral properties of this compound correspond to those of the 5 (R), 6 (R) antipodes characterized in Example 26A.

Example 27: N-tS-BfRSl-iSRi-S-hydroxy ^^ cis-S-trans-eicosatrien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester, from 0.94 g of 5 (RS), 6 (RS) -5,6-epoxy-7,11-cis-9-trans-eicosatriene (E19) and 1.0 g of N-fN-trifluoroacetyl-cysteinyD-glycine methyl ester. IR (CH ₂ Cl ₂ ): 3400,2970,2940,2870,1740,1700,1 535cm " ¹

The diastereomer mixture can be separated by chromatography analogous to Example 25 into individual optically uniform diastereomers (eluent: hexane-ethyl acetate 7: 3).

Example 28: N- [S-5 (RS), 6 (SR) -5-hydroxy-1-tetrahydropyranyloxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester, individual diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B]. .

From 0.78 racemic 5 (RS), 6 (RS) -5,6-epoxy-1-tetrahydropyranyloxy-7,9-trans-11-cis-eicosatriene (E20) and 0.63 g of N- (N-trifluoroacetyl) cysteinyl-O-glycine methyl ester gives a mixture of diastereomers [A] and [B] in the ratio of about 1: 1, from which individual forms of the title compound are isolated by chromatography on silica gel with hexane: ethyl acetate (1: 1) spectrum

IR (CH ₂ Cl ₂ ): 3400, 2940, 2870, 1 740, ¹ 695, 1 530 cm ^-1 .

Example 28a: N-IS-SlRSI-iSRI-i-acetoxy-S-hydroxy ^^ trans-ii-cis-eicosatrien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester, individual diastereomers 5 (R), 6 ( S) - [A] and 5 (S), 6 (R) - [B].

From 0.78 racemic 5 (RS), 6 (RS) -1-acetoxy-5,6-epoxy-7,9-trans-11-cis-eicosatriene (E20a), and 0.63 g N- (N-trifluoroacetylcysteinyl) glycine methyl ester gives a mixture of diastereomers [A] and [B] in the ratio of about 1: 1, from which individual forms of the title compound are isolated by chromatography on silica gel with hexane-ethyl acetate (1: 1).

Example 29: N-tS-BfRSi ^ iSRI-S-hydroxy ^^ trans -H.M-cis-eicosatetraen-e-yl-N-t-fluoro-acetyl-cysteinyl-1-glycine methyl ester;

individual diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B].

From 103mg of racemic SfRSKefRSKMS-epoxy ^ g-trans-H ^ -cis-eicosatetraen (E21) and 154mg of N- (N-trifluoroacetylcysteinyD-glycine methyl ester.), A mixture of diastereomers [A] and [B] in the ratio of about 1 : 1, from which individual forms of the title compound are isolated by chromatography on silica gel with hexane-ethyl acetate.

Both show analog spectrum.

IR (CH ₂ Cl ₂ ): 3360, 2920, 2850, 1740.1, 720, 16, 60, 520 cm ^-1 .

Example 29a: Methyl S-SfRSheiSRi-α-hydroxy-g-trans-H-cis-eicosatetraen-e-yl-mercaptoacetic acid

from 103mg of 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11,14-cis-eicosatetraene (E21) and 54mg of methyl mercaptoacetate.

Example 30: N- [S-5 (RS), 6 (SR) -5-hydroxy-1-tetrahydropyranyloxy-7,9-trans-11,14-cii-eicosatetraen-e-yl-N-trifluoroacetylcysteinyl-glycine methylester; individual diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B]. From 0.5 g of racemic 5 (RS), 6 (RS) -5,6-epoxy-tetrahydropyranyloxy-7,9-trans-11,14-cis-eicosatetraene (E22) and 0.42 g of N-fN-trifluoroacetyl-cysteinyD glycine methyl ester gives a mixture of diastereomers [A] and [B] in the ratio of about 1: 1, from which individual forms of the title compound are isolated by chromatography on silica gel with hexane-ethyl acetate (1: 1). Both show analog spectrum

IR (CH ₂ Cl ₂ ): 3400, 2940, 2880, 1 760.1, 740, ¹ , 7, 5, 5, 5cm " ¹ .

Example 31: N-tS-SiRSi ^ fSRI-i-acetoxy-S-hydroxy ^ .i ^ M-cis-g-trans-eicosatetraen-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester; individual diastereomers 5 (R), 6 (S) - [A] and 5 (S), 6 (R) - [B]. From 490 mg of racemic 5 (RS), 6 (RS) -1-acetoxy-5,6-epoxy-7,11,14-cis-9-trans-eicosatetraene (E23) and 400 mg of N-fN-trifluoroacetyl-cysteinyl-J-glycine methyl ester, a mixture of diastereomers [A] and [B] is obtained in the ratio of about 1: 1, from which individual forms of the title compound are isolated by chromatography on silica gel with hexane-ethyl acetate (1: 1). Both show analog spectrum. IR (CH ₂ Cl ₂ ): 3400, 2940, 2870.1, 740.1, 700.1, 530 cm ^-1 .

Diastereomes [A]: [α] § ° = -36.6 ± 2 ° C (0.5G / V% in chloroform) Diastereomer [B]: [a] § ° = +63.0 ± 2 ° C ( 0.5G / V% in chloroform)

Subsequent elimination of the hydroxyl-protecting group

Example 32: N-tS-BiRSl ^ tSRf-i ^ -dihydroxy-y-cis-eicosene-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine methyl ester. The solution of 1.2 g of 1-tetrahydropyranyl ether of the title compound (see Example 20) in 70 ml of a mixture consisting of 4 volumes of acetic acid, 2 tetrahydrofuran and 1 of water is stirred for 6 hours at 45 ⁰ C. The solvent is evaporated in vacuo, the residue is extracted several times in toluene, and the extracts are concentrated in vacuo. Chromatography of the residue on silica gel with dichloromethane / hexane (15: 1) gives the title compound. IR (CH ₂ Cl ₂ ): 3620.3400, 2940, 2870, 1 760/1 740, 1700, ¹ 130, 220, 1180 cm " ¹ .

Example 33: N-tS-SiRSl-1SRJ-i ^ -dihydroxy-cis-octadecene-e-yl-N-trifluoroacetyl-cysteinyU-glycine methyl ester. By the method of Example 32, the title compound is obtained from 0.7 g of its corresponding 1-tetrahydropyranyl ether (see Example 19)

IR (CH ₂ Cl ₂ ): 3620, 3400, 2940, 2870.1, 760.1, 740.1, 700.1, 535.1, 220, 1180cm " ¹ .

Example 33a: Methyl S-5 (RS), 6 (SR) -1,5-dihydroxy-7-cis-octadecene-6-yl-mercaptoacetic acid. By the method of Example 32, the title compound is prepared from 0.7 g of its corresponding 1 Tetrahydropyranylethers (see Example 19a).

Example 33b: S-OisRSlefSRI-I.S-dihydroxy-cis-eicosene-e-yl-mercaptoacetic acid methyl ester. By the method of Example 32, the titer compound is obtained from 0.7 g of its corresponding 1-tetrahydropyranyl ether (see Example 19b).

Example 34: N-iS-SfSi ^ iRl-I.S-dihydroxy ^ -trans-g-cis-octadecadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester. By the method of Example 32, the titer compound is obtained from 0.39 g of its corresponding 1-tetrahydropyranyl ether (see Example 22, diastereomer [B]

IR (CH ₂ Cl ₂ ): 3620.3400, 2940, 2870, 1760, 1740, 1700, 1530, 120, 1180 cm " ¹ .

Example 35: N-iso-α-di-i-di-dihydroxy-trans -cis-octadecadien-e-yl-N-trifluoroacetyl-cysteine-glycine methyl ester. By the method of Example 32, the titanium compound is obtained from 0.33 g of its corresponding 1-tetrahydropyranyl ether (see Example 22, Diastereomer [A]

IR (CH ₂ Cl ₂ ): 3620.3400, 2940, 2870, 1760, 1740.1, 700, 15, 110, 220, 1180 cm " ¹ .

Example 35a: S-SfRSl ^ iSRl-i ^ -dihydroxy ^ -trans-g-cis-octadecadien-e-yl-mercaptoacetic acid methyl ester. By the method of Example 32, the title compound is obtained from 0.33 g of its corresponding 1-tetrahydropyranyl ether (see Example 22a).

Example 36: N-IS-SiSl ^ iRi-i ^ -dihydroxy ^ -trans-g-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteino-O-glycine methyl ester. By the method of Example 32, the titer compound is obtained from 0.25 g of its corresponding 1-tetrahydropyranyl ether (see Example 23, diastereomer [B]

IR (CH ₂ Cl ₂ ): 3640.3420, 2940, 2880.1, 760.1740, 1700.1, 535.1, 220, 1180 cm " ¹ .

Example 37: N- [S-5 (R), 6 (S) -1,5-Dihydroxy-7-trans-9-cis-eicosadien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester. By the method of Example 32, the titer compound is obtained from 0.24 g of its corresponding 1-tetrahydropyranyl ether (see Example 23, diastereomer [A])

IR (CH ₂ Cl ₂ ): 3620.3400, 2940, 2870.1, 760.1740, 1700.1, 535.1, 220.1, 180 cm " ¹ .

Example 37a: S-O-Fe-S-tSRl-i-dihydroxy-trans-g-cis-eicosadien-e-yl-mercaptoacetic acid methyl ester. By the method of Example 32, the titer compound is obtained from 0.25 g of its corresponding 1-tetrahydropyranyl ether (see Example 23a, diastereomer [B]).

Example 38: N-IS-SiSi ^ iRl-i ^ -Dihydroxy ^^ - trans -H-cis-eicosatrien-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine methyl ester. By the method of Example 32, the titanium compound is obtained from 0.56 g of its corresponding 1-tetrahydropyranyl ether (see Example 28, diastereomer [B])

IR (CH ₂ Cl ₂ ): 3620, 3400, 2940, 2860.1, 740.1, 695.1, 535.1, 220, 1180cm " ¹ .

Example 39: N- [S-5 (R), 6 (S) -1,5-Dihydroxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -ghicin-methyl 'ester. By the method of Example 32, the titanium compound is obtained from 49 mg of its corresponding 1-tetrahydropyranyl ether (see Example 28, Diastereomer [A])

IR (CH ₂ Cl ₂ ): 3620, 3400, 2940, 2860, 1760.1, 740.1, 695.1, 535.1, 220, 1180 cm ^-1 .

Example 40: N-IS-SiSi ^ tRi-i ^ -dihydroxy ^^ trans-II.W-cis-eicosatetraen-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester. By the method of Example 32, the titer compound is obtained from 140 mg of its corresponding 1-tetrahydropyranyl ether (see Example 30, diastereomer [B])

IR (CH ₂ Cl ₂ ): 3610, 3400, 2930, 2880.1 750.1725.1 685.1 525.1 215.1170 cm ^-1 .

Example 41: N-tS-SfRi ^ tSi-i ^ -Dihydroxy ^^ - trans-I ^ W-cis-eicosatetraen-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester. By the method of Example 32, the titer compound is obtained from 140 mg of its corresponding 1-tetrahydropyranyl ether (see Example 30, diastereomer [A]).

Subsequent saponification of the terminal ester group

Example 42: N-tS-iSiRSl.eiSRi-S-hydroxy ^ -cis-heptadecen-e-yl-N-trifluoroacetyl-cysteinyO-glycine sodium salt. The dissolution of 800 mg of methyl ester of the title compound (see Example 2) in 70 ml of methanol is mixed with 22 ml of 0.1 N aqueous sodium hydroxide solution and 16h. stirred at room temperature. The methanol is evaporated in vacuo at 20 ° C and the aqueous residue is mixed with 80 ml of acetonitrile. The solution is filtered over a small amount of silica gel and freed from the solvent in vacuo at 20 ° C. The residue is extracted several times with chloroform and the extracts are concentrated in vacuo. After drying in a high vacuum, the residue, consisting of the title compound, can be pulverized. IR (CH ₂ Cl ₂ ): 3320, 2980, 2940, 2870, 1730, ¹ 675, ¹ 400 cm ^-1 .

Example 43: N-IS-BfRSl-tSRl-S-hydroxy-y-cis-undecen-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt. According to the procedure described in Example 41, the title compound is recovered from 1.74 g of the corresponding methyl ester (see Example 3).

IR (CH ₂ Cl ₂ ): 3320.2980, 29.0, 2880, 1730, 1675, 1610, 1400 cm ^-1 .

Example 44: N-IS-SfRSI-tSRl-B-hydroxy-cis-tridecen-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 800 mg of the corresponding methyl ester (see Example 4).

IR (CH ₂ Cl ₂ ): 3300, 2980, 2940, 2870.1 730.1 670.1 600.1400cm ^-1 .

Example 45: S-SIRS1-tSRi-S-hydroxy-cis-tridecen-6-yl-cysteine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 300 mg of the corresponding methyl ester (see Example 5).

IR (CH ₂ Cl ₂ ): 2970, 2940, 2860.1 740.1 620.1 430 cm ^-1 .

Example 46: S-OISOLIPL-S-hydroxy-cis-tridecen-e-yl-mercaptoacetic acid sodium salt. According to the procedure described in Example 41, the title compound is obtained from 700 mg of the corresponding methyl ester (see Example 6). IR (CH ₂ Cl ₂ ): 3300.2960, 2930, 2860.1 600.1400 cm ^-1 .

Example 47: N-tS-SiRSi ^ fSRI-S-hydroxy-cis-pentadecene-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine sodium salt. According to the procedure described in Example 41, the title compound is obtained from 710 mg of the corresponding methyl ester (see Example 7).

IR (CH ₂ Cl ₂ ): 3300, 2970, 2940, 2860, 1730, 1 670, 610, 1400 cm ^-1 .

Example 47a: S-BfRSl-fSRI-B-hydroxy-cis-pentadecen-e-yl-N-trifluoroacetyl-cysteine potassium salt.

According to the procedure described in Example 41, the title compound is obtained from 710 mg of the corresponding methyl ester (see Example 7a).

Example 48: S-BfRSLefSRi-ö-hydroxy ^ -cis-pentadecen-e-yl-cysteine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 250 mg of the corresponding methyl ester (see Example 8).

IR (CH ₂ CI _2): 2970, 2940, 2870.1 740.1 640.1 590,1410cm ^'1.

Example 49: S-SiRSl-ISOL-B-hydroxy-cis-pentadecen-e-yl-mercaptoacetic acid sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 950 mg of the corresponding methyl ester (see Example 9).

IR (CH ₂ Cl ₂ ): 3300, 2960, 2930, 2860.1 600.1400 cm ^-1 .

Example 50: S-SfRSheiSRJ-S-hydroxy ^ -cis-heptadecen-e-yl-cysteine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 500 mg of the corresponding methyl ester (see Example 10).

IR (CH ₂ Cl ₂ ): 3300.2940, 2870.1 600.1 410 cm ^-1 .

Example 51: N-IS-BfRSl-iSRi-S-hydroxy-cis-eicosene-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt.

According to the procedure described in Example 41, the title compound is recovered from 1.64 g of the corresponding methyl ester (see Example 11).

IR (CH ₂ Cl ₂ ): 3300, 2930, 2860.1 730.1 670.1 600.1 400 cm ^-1 .

Example 52: N-IS-SIRS-iSRJ-B-hydroxy-cis-tricosene-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 950 mg of the corresponding methyl ester (see Example 12).

Example 53: N-iS-MRSLSfSRM-hydroxy-e-cis-tetradecene-S-yl-thiol-propionyl-glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 200 mg of the corresponding methyl ester (see Example 13).

Example 54: N-fS ^ fRSLBiSRM-hydroxy-e-cis-tetradecen-S-yl-N-trifluoroacetyl-cysteine-glycine-sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 600 mg of the corresponding methyl ester (see Example 4).

IR (CH ₂ Cl ₂ ): 3300, 2980, 2940, 2870.1 720.1 660.1 610.1 560 cm ^-1 .

Example 54a: N-IS ^ RSLSfSRM-hydroxy-e-cis-nonadecene-S-yl-N-trifluoroacetyl-cysteine-glycine sodium salt

 According to the procedure described in Example 41, the title compound, mp 69-73 ° C, is obtained from 600 mg of the corresponding methyl ester (see Example 16).

Example 55: N- [S-4 (RS), 5 (S-R) -4-hydroxy-6-cis-eicosene-5-N-trifluoroacetyl-cysteinyl] -glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 420 mg of the corresponding methyl ester (see Example 17).

Example 55a: N - ^ - WiRSLBiSRM-hydroxy-e-cis-eicosene B ^ 'l-thiol-propionyl-J-glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 420 mg of the corresponding methyl ester (see Example 17a).

Example 55b: S ^ IRSLSfSRM-hydroxy-e-cis-eicosen-B-yl-N-trifluoroacetyl-cysteine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 420 mg of the corresponding methyl ester (see Example 17b).

Example 56: N-IS-efRSUISRJ-e-hydroxy-S-cis-eicosyl-1-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 570 mg of the corresponding methyl ester (see Example 18).

IR (CH ₂ Cl ₂ ): 3300, 2940, 2870, 1730, ¹ 675, 620, 1400 cm ^-1 .

Example 56a: S-5 (RS), 6 (SR) -1,5-dihydroxy-7-cis-octadecene-6-yl-mercaptoacetic acid sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 570 mg of the corresponding methyl ester (see Example 33a).

Example 56b: N-IS-BfRSI-iSRI-i-dihydroxy-cis-eicosene-e-yl-N-trifluoroacetyl-cysteinyl-glycine potassium salt

 According to the procedure described in Example 41, the title compound is obtained from 570 mg of the corresponding methyl ester (see Example 32).

Example 56c: S-SfRSi ^ iSRJ-I.B-dihydroxy-cis-eicosene-e-yl-mercaptoacetic acid sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 570 mg of the corresponding methyl ester (see Example 33b).

Example 57: N-tS-SfRSl ^ fSRi-S-hydroxy ^ -trans-S-cis-nonadecadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt. According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 21).

IR (CH ₂ Cl ₂ ): 3300, 2940, 2860, 1730, 1 670, 610, ¹ , 400 cm -1.

Example 57a: N- {3- [5 (RS), 6 (SR) -5-hydroxy-7-trans-9-cis-nonadecadien-6-yl-thio] -propionyl} -glycine sodium salt

 According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 21a).

Example 57b: N-tS-BiRi ^ iSJ-B-hydroxy ^ -trans-S-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine potassium salt

 According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 21e, diastereomer [A]).

Example 57c: N- [S-5 (S), 6 (R) -5-hydroxy-7-trans-9-cis-eicosadien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine potassium salt

 According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 21e, diastereomer [B].

Example 57d: N-tS ^ RSLSiSRM-hydroxy-e-trans-S-cis-nonadecadien-S-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt. According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 21 f). Smp.52-54 ° C.

Example 57e: S-5 (RS), 6 (SR) -1,5-dihydroxy-7-trans-9-cis-octadecadien-6-yl-mercaptoacetic acid sodium salt.

According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding ×

Methyl ester (see Example 35a).

Example 57f: N-tS-BiSl ^ fRl-i ^ -dihydroxy ^ -trans-g-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteinyl-glycine potassium salt. According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 36).

Example 57g: N-tS-SiRLefSi-i ^ -dihydroxy ^ -trans-S-cis-eicosadien-e-yl-N-trifluoroacetyl-cysteinyn-giycin potassium salt. According to the procedure described in Example 41, the title compound is obtained from 410 mg of the corresponding methyl ester (see Example 37).

Example 58: N-tS-SiRSi ^ iSRI-S-hydroxy ^^ trans-ii-cis-hexadecatrien-e-yl-N-trifluoroacetyl-cysteinyl-glycine-sodium salt. According to the procedure described in Example 41, the title compound is obtained from 1.17 g of the corresponding methyl ester (see Example 24).

IR (CH ₂ Cl ₂ ): 3300, 2970, 2940, 2880, 1 730, 670, 620, 1, 410 cm " ¹ .

Example 59: N-IS-BfRSJBfSRI-B-Hydroxy-TJI-cis-g-trans-hexadecatrien-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt. According to the procedure described in Example 41, the title compound is obtained from 730 mg of the corresponding methyl ester (see Example 25).

IR (CH ₂ Cl ₂ ): 3300, 2970, 2940, 2880, 1 730, ¹ 675, 625, 1410 cm ^-1 .

Example 60: N-IS-SiRSl ^ fSRJ-S-hydroxy ^ .g-trans-H-cis-eicosatrien-e-yl-N-trifluoroacetyl-cysteinyl-glycine sodium salt. According to the procedure described in Example 41, the title compound is obtained from 230 mg of the corresponding methyl ester (see Example 26).

IR (CH ₂ Cl ₂ ): 3350, 2960, 2930, 2860.1 720.1 675.1 540crrT ¹ .

Analogously, starting from corresponding optically individual diastereomers (see Examples 26A and 26B), optically individual products can be obtained:

Example 6OA: N-tS-SIRijeiSl-S-hydroxy ^ .s-trans-H-cis-eicosatriene-S-yf-N-trifluoroacetyl-cysteinyl-glycine-sodium salt:

A solution of 3.1 g of N- [S-5 (R), 6 (S) -5-hydroxy-7,9-tans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine Methyl ester (see Example 26A) in 50 ml of methanol is added dropwise under argon at 0-5 ⁰ C with 26.8 ml of 0.2 N sodium hydroxide solution, stirred at 20 ⁰ C for 20 hours and concentrated at this temperature in vacuo. By reversed-phase chromatography on adsorbent Merck RP 8 with methanol-water (3: 1) and distilling off the solvents in vacuo, the title compound results as a white amorphous powder.

Example 6OB: N- [S-5 (S), 6 (R) -5-Hydroxy-7,9-trans-11-cis-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine sodium salt: Sub the reaction conditions of Example 60 A and with analogous amounts of reactants and auxiliary chemicals, but starting from N- [S-5 (S), 6 (R) -5-hydroxy-7,9-trans-11-cis-eicosatrien-6 -yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester (see Example 26B), the title compound is obtained in the form of a white amorphous powder.

Example 61: N-IS-SIRSJ ^ fSRI-S-hydroxy ^ jH-cis-g-trans-eicosatrien-e-yl-N-t-fluoro-acetyl-cysteine-glycine-sodium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 27).

IR (CH ₂ Cl ₂ ): 3300, 2960, 2430, 2860, 1720, 1 660, 620, 1400 cm ^-1 .

Analogously, starting from corresponding optically individual diastereomers (see the chromatographic separation in Example 27), optically individual products, i. 5 (S), 6 (R) -diastereomers [A] and 5 (R), 6 (S) -diastereomers [B] are obtained.

Example 61a: N- [S-5 (S), 6 (R) -1-acetoxy-5-hydroxy-7,11-cis-9-trans-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine Potassium salt and N- [S-5 (S), 6 (R) -1,5-dihydroxy-7,11-cis-9-trans-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine potassium salt , According to the procedure described in Example 41, the corresponding optically individual methyl ester 1-acetate (see Example 28) is reacted and the crude reaction mixture is separated by reverse phase chromatography (eluting with methanol: water 3: 1). First, the diol compound is eluted, followed by the 1-acetate.

Example 61b: N- [S-5 (R), 6 (S) -1-acetoxy-5-hydroxy-7,11-cis-9-trans-eicosatrien-6-yl-N-trifluoroacetyl-cysteinyl] -glycine Potassium salt and N-IS-SfRJieiSl-i ^ -dihydroxy ^ JI-cis ^ -trans-eicosatrien-e-yl-N-trifluoroacetyl-cysteinyn-glycine potassium salt. According to the procedure described in Example 41, the corresponding optically individual methyl ester 1-acetate (see Example 28) is reacted and the crude reaction mixture is separated by reverse phase chromatography (eluting with methanol: water 3: 1). First, the diol compound is eluted, followed by the 1-acetate.

Example 61c: N-tS-SfRl-1Si-S-hydroxy ^^ trans-II.M-cis-eicosatetraen-e-yl-N-t-butylacetyl-cysteinyl-J-glycine potassium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 29, Diastereomer [A]).

Example 61d: N-IS-SfSi ^ fRI-S-hydroxy ^^ trans -I ^ M-cis-eicosatetraen-e-yl-N-trifluoroacetyl-cysteinyl-J-glycine potassium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 29, diastereomer [B]).

Example 61 e: S-5 (RS), 6 (SR) -5-hydroxy-7,9-trans-1!, M-cis-eicosatetraene-e-yl-mercaptoacetic acid potassium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 29a).

Example 61 f: N-IS-StSJ.efRI-I.S-dihydroxy-iH.M-cis-g-trans-eicosatetraene-e-yl-N-trifluoroacetyl-cysteinyl-glycine potassium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 31, Dioastereomeres [B]).

Example 61g: N-tS-SiRJ.eiSl-i.o-dihydroxy ^ J ^ M-cis-g-trans-eicosatetraen-e-yl-N-trifluoroacetyl-cysteine-glycine quinium salt. According to the procedure described in Example 41, the title compound is obtained from 370 mg of the corresponding methyl ester (see Example 31, diastereomer [A]).

Subsequent elimination of the N-trifluoroacetyl group

Example 62: N-tS-BfRSl-1SRI-S-hydroxy-T-cis-heptadecen-e-yl-cysteinyl-J-glycine sodium salt.

To the solution of 590 mg of N ^{cys -trifluoroacetyl} derivative of the title compound (see Example 41) in 15 ml of methanol is added a solution of 1.7 g of sodium carbonate in 15 ml of water. The resulting suspension is 20h. stirred at 60 ° C. The reaction mixture is filtered and the filtrate evaporated in vacuo. The residue is dissolved in methanol / dichloromethane (1: 1) and filtered again, and the filtrate is freed from the solvent in vacuo. The residue gives by reversed phase chromatography on silica gel with methanol / water (3: 1) the desired title compound. IR (CH ₂ Cl ₂ ): 3300, 2940, 2870.1 680.1 600.1400 cm ^-1 .

Example 63: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-undecene-6-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 1.74 g of the corresponding N-trifluoroacetyl derivative (see Example 42).

IR (CH ₂ Cl ₂ ): 3300, 2980, 2940, 2880.1 730.1 670.1 610.1 400 cm ^-1 .

Example 64: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-tridecen-6-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 320 mg of the corresponding N-trifluoroacetyl derivative (see Example 43).

IR (CH ₂ Cl ₂ ): 3400, 2960, 2930, 2860.1 600.1400 cm ^-1 .

Example 65: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis -pentadecen-6-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 400 mg of the corresponding N-trifluoroacetyl derivative (see Example 46).

IR (CH ₂ Cl ₂ ): 3380, 2960, 2930, 2860.1 650.1 600.1 400crrT ¹ .

Example 66: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-eicosene-6-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 1.64 g of the corresponding N-trifluoroacetyl derivative (see Example 50).

IR (CH ₂ Cl ₂ ): 3300.2930, 2860.1 730, T670.1 600.1 400 cm ^-1 .

Example 67: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-tricosen-6-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 960 mg of the corresponding

N-trifluoroacetyl derivative (see Example 51). , * '

IR (CH ₂ Cl ₂ ): 3250.2940, 2870.1 680.1 600.1 400 cm ^-1 .

Example 67a: N- [S-4 (RS), 5 (SR) -4-hydroxy-6-cis-nonadecen-5-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 54a); Mp 182 ° C.

Example 68: N- [S-4 (RS), 5 (SR) -4-hydroxy-6-cis-eicosen-5-yl-cysteinyl] -glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 54).

IR (CH ₂ Cl ₂ ): 3420, 2940, 2860.1 720.1 670.1 620.1 400 cm ^-1 .

Example 68a: S ^ iRSLSfSRM-hydroxy-e-cis-eicosene-S-yl-cysteine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 55a); M.p. 153-156 ⁰ C.

Example 68b: N- [S-6 (RS), 7 (SR) -6-hydroxy-8-cis-eicosene-7-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 56).

Example 68c: S-SiRSJJiSRJ-e-hydroxy-S-cis-eicosenic ^ -yl-cysteine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 18b).

Step Example! 68d: N-IS-SiRSl.eiSRi-S-hydroxy ^ -trans-g-cis-nonadecadien-e-yl-cysteinyl-glycine-sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 57).

Example 68e: N-IS-ethyl-t-S-hydroxy-trans-g-cis-eicosadien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 57b).

Example 68f: N-tS-SiSLeiRl-S-hydroxy ^ -trans-S-cis-eicosadien-e-yl-cysteinyn-giycin potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 57c).

Example 68g: N-iS ^ RSl-ISrM-hydroxy-e-trans-S-cis-nonadecadien-S-yl-cysteinyl-glycine sodium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 57d); Mp. 98-102 ⁰ C.

Example 68h: N-IS-BIS-1-IL-B-hydroxy-T ^ -trans-H-cis-eicosatrieno-S-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 60B).

Example 68i: N-fS-BIRi-isl-S-hydroxy-T ^ -trans-H-cis-eicosatrien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 60A).

Example 68j: N-IS-BISi.lRJ-B-hydroxy-T-cis-S-trans-ii-cis-eicosatrien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 61).

Example 68k: N-IS-BiRl ^ fSl-B-hydroxy-V-cis-S-trans-H-cis-eicosatrien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 61).

Examples: N-tS-SISi ^ iRJ-i ^ -dihydroxy-V ^ -trans-ii-cis-eicosatrien-e-yl-cysteinyl-J-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 61a).

Example 68m: N-fS-BfRl ^ fSl-i ^ -dihydroxy-y ^ -trans-H-cis-eicosatrien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 62, the title compound is obtained from 200 mg of the corresponding N-trifluoroacetyl derivative (see Example 61b).

Subsequent simultaneous cleavage of the N-trifluoroacetyl group and saponification of the terminal ester group

Example 69: N- [S-5 (S), 6 (R) -1,5-dihydroxy-7,9-trans-1!, M-cis-eicosatetraene-e-yl-cysteinyl-glycine potassium salt.

To a solution of 50 mg of N ^cys trifluoroacetyl methyl ester of the title compound [see Example 39, diastereomer 5 (S), 6 (R)] in 4 ml of methanol is added the solution of 170 mg of potassium carbonate in 10 ml of water. The reaction solution is stirred under argon for 3 days and evaporated in vacuo at room temperature. The residue is repeatedly taken up in chloroform and evaporated in vacuo. After reversed phases, chromatography on silica gel in the methanol-water system (3: 1), the title compound is obtained.

Example 69a: N- [S-5 (RS), 6 (SR) -1,5-dihydroxy-7-cis-octadecene-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 33).

Example 69b: N- [S-5 (RS), 6 (SR) -1,5-dihydroxy-7-cis-eicosene-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 32).

Example 69c: N- [S-5 (S), 6 (R) -1,5-dihydroxy-7-trans-9-cis-octadecadien-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 34).

Example 69d: N- [S-5 (S), 6 (R) -5-hydroxy-7,9-trans-11-cis-hexadecatrien-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetylmethyl ester (see Example 24).

Example 69e: N-tS-BiRi ^ iSi-B-hydroxy ^^ - trans -H-cis-hexadecatrien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 24).

Example 69f: N- [S-5 (S), 6 (R) -5-hydroxy-7,11-cis-S-trans-hexadecadien-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 25).

-i

Example o9g: N- [S-5 (R), 6 (S) -5-hydroxy-7,11-cis-9-trans-hexadecadien-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 25).

Example 70: N- [S-5 (R), 6 (S) -1,5-Dihydroxy-7,9-trans-11,14-cis-eicosatetraen-6-yl-cysteinyl] -glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 30 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 40, diastereomer [5 (R), 6 (S)].

Example 71: N-IS-oleSi.eiRi-S-hydroxy ^^ - trans -H.M. cis-eicosatetraene-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 33 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 29, diastereomer [B]).

UV (CH ₃ OH): \ _max = 280 nm (ε = 48600).

Example 72: N-IS-SIRJ-ISl-B-hydroxy-yl-trans-II-cis-eicosatetraene-e-yl-cysteinyl-glycine potassium salt.

According to the general procedure described in Example 69, the title compound is obtained from 8 mg of the corresponding N-trifluoroacetyl methyl ester (see Example 29, diastereomer [A]),

UV (CH ₃ OH): \ _max = 280 nm (ε = 48600).

Example 73: N-IS-SIShefRM ^ -dihydroxy ^ ii -cis-g-trans-eicosatetraen-e-yl-cysteinyl-glycine potassium salt. (Simultaneous cleavage of 3 protecting groups).

A solution of 160 mg of N- [S-5 (S), 6 (R) -1-acetoxy-5-hydroxy-7,11,14-cis-9-trans-eicosatetraen-6-yl-trifluoroacetyl-cysteinyl] - Glycinmethylester is mixed with a solution of 700 mg of potassium carbonate in 50 ml of water, stirred for 3 days under argon at room temperature and evaporated in vacuo at room temperature. The residue is taken up in several portions of chloroform and the extract is evaporated in vacuo. After filtration through silica gel in a solution in dichloromethane / methanol (1: 3), the desired title compound is obtained

IR (CH ₂ Cl ₂ ): 3400, 2940.1 690.1 600.1 440.1 220.1190 cm ^-1 .

Example 74: N- [S-5 (R), 6 (S) -1,5-Dihydroxy-7,11,14-cis-9-trans-eicosatetraen-6-yl-cysteinyl] -glycine potassium salt. (Simultaneous cleavage of 3 protective groups)

In an analogous manner as in the preceding example, 160 mg of N-tS-SiRheiSl-i-acetoxy-δ-hydroxy ^ H ^ -cis-g-transeicosatetraen-6-yl-N-trifluoroacetyl-cysteinyl] -glycine methyl ester is hydrolyzed to the title compound ,

IR (CH ₂ Cl ₂ ): 3420, 2940.1 685.1 615.1420.1 220.1190 cm ^-1 .

Example 74a: N-tS-αiRheiSM ^ -dihydroxy ^ -trans-g-cis-eicosadien-e-yl-cysteinyn-glycine potassium salt. (Simultaneous cleavage of 3 protecting groups).

In an analogous manner as in Example 73 is 160mg N-tS-SfRl ^ lSl-i-acetoxy-S-hydroxy ^ -trans-g-cis-eicosaien-e-yl-N-trifluoroacetyl-cysteinyl-glycine methyl ester of Example 23a hydrolyzed to the title compound.

Example 75: N- [S-5 (RS), 6 (SR) -5-hydroxy-7-cis-heptadecen-6-yl-cysteinyl] -glycine.

The solution of 250 mg of sodium salt of the title compound (see Example 62) in 15 ml of dichloromethane is shaken vigorously with 15 ml of 5% aqueous acetic acid for 10 minutes at room temperature. The organic phase is separated, washed with water, dried over sodium sulfate and freed from the solvent in vacuo. There remain 220mg of the title compound as an amorphous residue.

IR (CH ₂ Cl ₂ ): 3300.2960, 2870.1 680.1 620.1 410 cm ^-1

Appendix: The starting materials used in Examples 2-74 can be prepared as follows:

A. Unsaturated aldehydes: A1. 2-trans-heptenal:

The solution of 44.81 valeraldehyde and 6.3 g formylmethylenetriphenylphosphorane (S.Trippett and D.M. Walker,

J. Chem. Soc. 1961, 12666) in 400 ml of tetrahydrofuran and 150 ml of chloroform under argon for 24h. refluxed.

The red solution is freed from the solvent in vacuo at room temperature and the residue is stirred with ether / hexane (1: 1). The solid portion is filtered off and washed four times with ether / hexane (1: 1). The filtrate is evaporated in vacuo and the residue is distilled in vacuo. The title compound is obtained as a colorless liquid

(Bp. = 55-57 ° C / 22mbar.)

 The following are obtained in an analogous manner: A 2. 2-trans-hexenal! = 33 ° C / 14mbar)

from 30.2 ml of butyraldehyde and 51 g of formylmethylenetriphenylphosphorane. A3. 2-trans-octenal (bp. = 65-69 ° C / 16m bar)

from 20 mg capronaldehyde and 42.6 g Formy Imethylentriphenylphosphoran, A4. 7-Tetrahydropyranyloxy-2-trans-heptenal (bp = 106 ° C / 5mbar)

from 16 g of 5-tetrahydropyranyloxypentanal [E. J. Corey et al, J. Am. Chem. Soc. 92, 6635 (1970)] and 26.1 g

formylmethylenetriphenylphosphorane

 A 5. 7-acetoxy-2-trans-heptenal (oil),

from 3.9 g of 5-acetoxypentanal [H. C. Brown et al., Synthesis 1980,151] and 8.2 g of formylmethylenetriphenylphosphorane, after chromatography of the crude product on silica gel with hexane / ethyl acetate (3: 1).

B. epoxy aldehydes

B1. 2 (RS), 3 (SR) -2,3-Epoxyheptanal

The solution of 9 g of 2-trans-heptenal (Al) in 200 ml of dichloromethane / methanol (1: 1) is mixed with 28 ml of 30 percent strength. aqueous hydrogen peroxide and treated with 800 mg of potassium carbonate and stirred for 6 hrs. At room temperature. Add 100 ml of phosphate buffer (pH = 8) and the organic phase is separated off. The aqueous phase is extracted three more times with 50 ml dichloromethane. The combined organic phases are washed with 20 ml of phosphate buffer and dried over magnesium sulfate. The solution is filtered through a little Florisil and evaporated in vacuo. The title compound is obtained as a colorless liquid

IR (CH ₂ Cl ₂ ): 2950,2920,2850,1 720,1 460,850cm " ¹ .

In analogous ways are obtained:

B 2. 2 (RS), 3 (SR) -2,3-epoxyhexanal

from 16.2 g of 2-trans-hexenal (A 2) as OeI,

IR (CH ₂ Cl ₂ ): 2980.2950, 2890, 1740, 1475, 860 cm ^-1 .

B 3. 2 (RS), 3 (SR) -2,3-Octanal

from 9.0 g of 2-trans-octenal (A3) as OeI,

IR (CH ₂ Cl ₂ ): 2970, 2950, 2870, ¹ 740, ¹ 475, 1025 cm ^-1 .

B 4. 2 (RS), 3 (SR) -2,3-epoxy-7-tetrahydropyranyloxyheptanal

from 8.1 gy-tetrahydropyranyloxy-trans-heptenal (A 4) by chromatography of the crude product on silica gel with hexane / ethyl acetate (2: 1) as OeI,

IR (CH ₂ Cl ₂ ): 2950, 2880, 1735, 1140, 130, 120, 040 cm ^-1

 B 5. 2 (RS), 3 (SR) -7-acetoxy-2,3-epoxyheptanal

from 2.2 g of 7-acetoxy-2-trans-heptenal (A 5) after chromatography of the crude product on silica gel with dichloromethane /

Ethyl acetate (93: 7) as Oel, IR (CH ₂ Cl ₂ ): 2960, 1740, 1375, 1250, 1060, 860 cm ^-1 .

C. Monounsaturated epoxy aldehydes

C1. 4 (RS), 5 (RS) -4,5-epoxy-2-trans-nonenal

The solution of 7.4 g of 2 (RS), 3 (SR) -epoxyheptanal (B 1) and 17.6 g of formylmethylenetriphenylphosphorane in 250 ml of tetrahydrofuran and 100 ml of chloroform is refluxed under argon for 1.5 hours. The cooled solution is freed from the solvent in vacuo at room temperature and the residue is stirred with ether / hexane (4: 1). The suspension is filtered through a little silica gel and washed with ether / hexane (4: 1) The filtrate is concentrated in vacuo and the residue is chromatographed on silica gel with hexane / ethyl acetate (5: 1, with 1% triethylamine) to give the title compound as colorless oil, IR (CH ₂ Cl ₂ ): 2970.2 940.2 870.1 690.1 650.1115.990 cm ^-1 .

In an analogous manner is obtained:

C1 a. 4- (RS), 5 (RS) -4,5-epoxy-2-trans-octenal

from 2 (RS), 3 (SR) -2,3-epoxyhexanal (B 2) as OeI.

C 2. 4 (RS), 5 (RS) -4,5-epoxy-9-tetrahydropyranyloxy-2-trans-nonenal

from 2 g of 2 (RS), 3 (SR) -2,3-epoxy-7-tetrahydropyranyloxyheptanal (B 4) as OeI, IR (CH ₂ Cl ₂ ): 2 950.2 880.1 700.1 125.1 040 cm " ¹ .

C 2 a. 4 {RS), 5 (RS) -9-acetoxy-4,5-epoxy-2-trans-nonenal

from 2 (RS), 3 (SR) -7-acetoxy-2,3-epoxy-heptanal (B 5) as OeI.

D. Double Unsaturated Epoxy Aldehydes

D1. 6 (RS), 7 (RS) -6,7-epoxy-2,4-undecadienal: 2-trans-4-trans-isomer (D 1 a) and 2-trans-4-cis isomer (D 1 b ).

To a solution of 1.75 g of 2 (RS), 3 (SR) -2,3-epoxyheptanal (B 1) in 40 ml of dichloromethane is added dropwise with stirring and under argon, the solution of 4.6 g of 4-Triphenylphosphoranyliden-2 trans-butenal [MJ Berenguer et al., Tetrahedron Lett. 1971, 495] within 1 hour at room temperature. The mixture is stirred for a further 1 hour and the solvent is evaporated off in vacuo at room temperature. The residue is stirred with ether / hexane (4: 1), filtered through a little silica gel and washed with ether / hexane (4: 1). After evaporation of the solvent in vacuo, the residue is chromatographed on silica gel with hexane / ethyl acetate (4: 1, with 1% triethylamine). Approximately equal amounts of the 2-trans-4-cis- (D 1 b) and 2-trans-4-trans (D 1 a) isomers of the title compound are obtained as bright yellows, both having spectral maxima: IR (CH ₂ CI ₂ ): 2950,2920,1 680,1 640,1 110,990cm " ¹ .

In an analogous way we get:

D 2. 6 (RS), 7 (RS) -6,7-epoxy-11-tetrahydropyranyloxy-2,4-trans-undecadienal

A mixture of isomers is obtained from 1.4 g of 2 (RS), 3 (SR) -2,3-epoxy-7-tetrahydropyranyl-oxyheptanal (B4), which is then treated with iodine in dichloromethane solution until it becomes permanent and then stirred for 5 hours at room temperature. After filtering through silica gel, the solvent is distilled off and the title compound is isolated as OeI: IR (CH ₂ Cl ₂ ): 2960.2880.1 690.1 650.1 580.1 120.1 040 cm ^-1 .

D 3. efRSlJfRSMI-Acetoxy-ej-epoxy-aAundecadienal:

2-trans-4-trans isomer (D 3 a) and 2-trans-4-cis isomer (D 3 b). A mixture of both isomers is prepared from 0.54 g of 2 (RS), 3 (SR) -7-acetoxy-2,3-epoxy-heptanal (B 5) in the ratio of about 1: 2 (D 3 a: D 3 b ) and separated by chromatography.

E. Epoxy olefins of the formula II

E2. 5 (RS), 6 (RS) -5,6-epoxy-7-cis-heptadecene

To a cooled to -30 ⁰ C solution of 9.4 g of n-Decyltriphenylphosphoniumbromid (CT EylesundS.Trippett, J. Chem. Soc. (C) 1966.67) in 50 ml of tetrahydrofuran is added dropwise 12.2 ml of a 1.6 molar solution of n-Bu.tyllithium in hexane under stirring and under an argon atmosphere, the temperature between -25 and -30 ⁰ C is maintained. The red solution is allowed to thaw to room temperature and stirred for 10 minutes at this temperature. After cooling to -78 ⁰ C is added dropwise, the solution of 2 g of 2 (RS), 3 (SR) -2,3-epoxy-heptanal (B 1) in 10 ml of tetrahydrofuran within 15 minutes. The solution is allowed to warm to room temperature and stirred for 1 hour. The solvent is evaporated in vacuo at 40 ° C and the residue dissolved in dichloromethane. The solution is mixed with silica gel (so much that all the solvent is absorbed), then slurried with ether and filtered. It is washed four times with ether / hexane (1: 1) and the filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel with hexane / ethyl acetate (30: 1, with 1% triethylamine). The title compound is obtained as a colorless oil. IR (CH ₂ Cl ₂ ): 2 980.2 940.2 870.1 475.875 cm ^-1 .

In an analogous way we get:

E 2. 5 (RS), 6 (RS) -5,6-epoxy-7-cis-undecene

from 1.3 g of 2 (RS), 3 (SR) -2,3-epoxy-heptanal (B1) and 5.5 g of n-butyltriphenylphosphonium bromide (R.Mechoulam and F. Sondheimer, J. Am. Chem. Soc. 80, 4386 [1958])

IR (CH ₂ Cl ₂ ): 2970, 2940, 2880, 1440, 875 cm " ¹ .

E 3. 5 (RS), 6 (RS) -5,6-epoxy-7-cis-tridecene

from 1,2,22 (RS), 3 (SR) -2,3-epoxy-heptanal (B1) and 5-n-hexyltriphenylphosphonium bromide (C F. Hauser et al., J. Org.

Chem. 28,372 [1963]).

IR (CH ₂ Cl ₂ ): 2970, 2940, 2870, 475, 875 cm " ¹ .

E 4 5 {RS) 6 (RS) -5,6-epoxy-7-cis-pentadecene

from 1.25 g 2 (RS), 3 (SR) -2,3-epoxy-heptanal (B 1) and 5.6 g n-octyltriphenylphosphoniumbronnide (CT, Eyles and S.Trippett,

J. Chem. Soc. [C] 1966, 67).

IR (CH ₂ Cl ₂ ): 2970, 2930, 2870, 475, 875 cm ^-1, E 5 5 (RS), 6 (RS) -5,6-epoxy-7-cis-eicosene from 2 g 2 (RS), 3 (SR) -2,3-epoxy-heptanal (B 1) and 12.3 g of n-tridecyltriphenylphosphonium bromide (J.Gigg et al., J. Chem.

Soc. 1966.1872).

IR (CH ₂ Cl ₂ ): 2970, 2940, 2860, 1475, 875 cm " ¹ E 6 5 (RS), 6 {RS) -5,6-epoxy-7-cis-tricosene from 1 g 2 (RS) , 3 (SR) -2,3-epoxy-heptanal (B 1) and 5.5 g of n-hexadecyltriphenylphosphonium bromide (D. Jerchel and

J. Kimmig, Chem. Ber. 83,277 [1950]).

IR (CH ₂ Cl ₂ ): 2970.2935, 2870, 1470, 875 cm- ^1, E 7 4 (RS), 5 (RS) -4,5-epoxy-6-cis-tetradecene from 2 g 2 (RS), 3 ( SR) -2,3-epoxy-hexanal (B2) and 10g of n-octyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): 2990, 2960, 2880, 1440, 910 cm " ¹ E 8 4 (RS), 5 (RS) -4,5-epoxy-6-cis-nonadecene from 1 g 2 (RS) , 3 (SR) -2,3-epoxy-hexanal (B2) and 3,6g of n-tridecyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): 2980, 2940, 2870, 1475, 995 cm ^-1, E 9 4 (RS), 5 (RS) -4, 5-epoxy-6-cis-eicosene from 0.58 g 2 ( RS), 3 (SR) -2,3-epoxy-hexanal (B 2) and 3.8 g of n-tetradecyltriphenylphosphonium bromide (EJ Reist and PH Christie, J. Org. Chem. 35, 3521 [1970]).

IR (CH ₂ Cl ₂ ): 2940, 2870, 1470, 955 cm ^-1 . E10 6 (RS), 7 (RS) -6,7-epoxy-8-cis-eicosene from 1 g 2 (RS), 3 ( SR) -2,3-epoxy-octanal (B3) and 4.1 g of n-dodecyltriphenylphosphonium bromide (D. Jerchel and J. Kimmig, Chem. Ber. 83,277 [1950]).

IR (CH ₂ Cl ₂ ): 2940, 2870, 1465, 875 cm ^-1 . E11 5 (RS), 6 (RS) -5,6-epoxy-1-tetrahydropyranyloxy-cis-octadecene from 1 g 2 (RS) , 3 (SR) -2,3-epoxy-7-tetrahydropyranyloxyheptanal (B4) and 6.6 g of n-undecyltriphenylphosphonium bromide (prepared analogously to n-decyltriphenylphosphonium bromide).

IR (CH ₂ Cl ₂ ): 2930.2860, 1465, 1040 cm ^-1, E11 a 5 (RS), 6 (RS) -1-acetoxy-5,6-epoxy-7-cis-octadecene under the same conditions as in the preceding example, but from 2 (RS), 3 (SR) -7-acetoxy-2,3-epoxy-heptanal

(B5) instead of the THP derivative B4: OeI. E12 5 (RS), 6 (RS) -5,6-epoxy-1-tetrahdropyranyloxy-7-cis-eicosene from 1 g 2 (RS), 3 (SR) -2,3-epoxy-7-tetrahydropyranyloxy-heptanal (B4) and 6.6 g of n-tridecyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): 2930.2860, 1465, 1040 cm ^-1 . E12 a 5 (RS), 6 (RS) -1 -acetoxy-Be-epoxy-cis-eicosene under the same conditions as in the preceding example but from 2 (RS), 3 (SR) -7-acetoxy-2,3-epoxy-heptanal

(B5) instead of the THP derivative B4: oil. E13 5 (RS), 6 (RS) -5,6-epoxy-7-trans-9-cis-nonadecadiene

from 1g4 (RS), 5 (RS) -4,5-epoxy-2-trans-nonenal (CilundSjSgn-decyltriphenylphosphonium bromide, E13 a otRSI.SiRSJ-B ^ -Epoxy ^ -trans-g-cis-eicosadiene

from 1g4 (RS), 5 (RS) -4,5-epoxy-7-trans-nonenal (Cil and Sn-undecyltriphenylphosphonium bromide: oil E13b4 (RS), 5 (RS) -4,5-epoxy-6-trans -8-cis-nonadecadien

from 1g4 (RS), 5- (RS) -4,5-epoxy-7-transocteno (C1 al and Sn1-undecyltriphenylphosphonium bromide) E145 (RS), 6 (RS) -5,6-epoxy-1-tetrahydropyranyloxy ^ -trans-g-cis-octadecadiene from 0.8 g of 4 (RS), 5 (RS) -4,5-epoxy-9-tetrahydropyranyloxy-2-trans-nonenal (C2) and 2.2 g of n-nonyltriphenylphosphonium bromide (G. Ohloff et al HeIv. Chim. Acta 60,1161 [1977])

IR (CH ₂ Cl ₂ ): 2940.2870.1 585.1460.1 040cm ^-1 . E 14a 5 (RS), 6 (RS) -1-acetoxy-5,6-epoxy-7-trans-9- cis-octadecadiene under the same conditions as in the preceding example, but from 4 (RS), 5 (RS) -9-acetoxy-4,5-epoxy-2-trans-

nonenal (C2a) instead of the THP derivative C2: oil. E15 5 (RS), 6 (RS) -5,6-epoxy-1-tetrahydropyranyloxy-trans-cis-eicosadiene from 0.8 g of 4 (RS), 5 (RS) -4,5-epoxy-9-tetrahydropyranyloxy 2-trans-nonenal (C2) and 2,4g n-undecyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): 2940.2870.1 585.1450.1 040cm ^-1 . E15 a 5 {RS), 6 (RS) -1 -acetoxy-Se-epoxy ^ -trans-g-cis-eicosadiene under the same conditions as in the preceding example, but from 4 (RS), 5 (RS) -9-acetoxy-4,5-epoxy-2-trans-

nonenal (C2a) instead of the THP derivative C2: oil. E16 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11-cis-hexadecatriene from 0.95 g 6 (RS), 7 (RS) -6,7-epoxy-2,4 trans-undecadienal (D 1a) and 2.8 g of n-pentyltriphenylphosphonium bromide (Jaenicke et al., Liebigs Ann. Chem. 1973, 125c).

IR (CH ₂ Cl ₂ ): 2980, 2940, 2880, 1470, 1000, 870 cm ^-1 . E17 5 (RS), 6 (RS) -5,6-epoxy-7,11-cis-9-trans-hexadecatriene from O ^ SgefRSi ^ tRSJ-ej-epoxy ^ -trans ^ -cis-undecadiena KDI b) and 2,3gn-pentyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): 2975,2940,2880,1470,1000,870 cm ^-1 . E17a SfRSJ ^ IRSl-Se-epoxy ^^ - trans-H-cis-octadecatriene under the same conditions as in the preceding example but from Heptyltriphenylphosphonium bromide instead of pentyl derivative: oil.

E18 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11-cis-eicosatriene

consisting of 0.65 g of 6 (RS), 7 (RS) -6,7-epoxy-2,4-transundecadienal (D 1 a) and 4.65 g of n-nonyltriphenylphosphonium bromide. Egg 9 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11-cis-eicosatriene

from O, iRSi ^ TRSl-e ^ -Epoxy ^ -trans ^ -cis-undecadienaliDI b) and 4.65g n-nonyltriphenylphosphonium bromide.

IR (CH ₂ Cl ₂ ): E 20 5 (RS), 6 (RS) -5,6-epoxy-1-tetrahydropyranyloxy-7,9-trans-11-cis-eicosatriene from 0.66g 6 (RS), 7 (RS) -6,7-epoxy-11-tetrahydroranyloxy-2,4-transundecadienal (D2) and 2.8g

n-Nonyltriphenylphosphonium bromide E 20 a 5 (RS); 6 {RS) -1-acetoxy-S ^ -epoxy ^^ - trans-i1-cis-eicosatriene

under the same conditions as in the preceding example, but from 6 (RS), 7 (RS) -11-acetoxy-6,7-epoxy-2,4-trans

undecadienal (D3a) instead of the THP derivative D2: oil

 E21 5 (RS), 6 (RS) -5,6-epoxy-7,9-trans-11,14-cis-eicosatetraene

from 125 mg of 6 (RS), 7 (RS) -6,7-epoxy-2,4-trans-undecadienal (D 1 a) and 435 mg of 3-cis-nonenyltriphenylphosphonium iodide (EJCorey, et al., J. Am. Chem.Soc.101,6748 [1970])

IR (CH ₂ Cl ₂ ): 2910, 2840, 1450, 990 cm " ¹

 E22BtRSl ^ tRSJ-ö ^ -epoxy-i-tetrahydropyranyloxy ^^ - trans -HU-cis-eicosatetraene from 0.5 g6 (RS), 7 (RS) -6,7-epoxy-11-tetrahydropyranylosy-2,4-trans -undecadienal (D2) und2,1g3-cis-Nonenyltriphenyl-

phosphonium

 E23 StRSl.etRSJ-i-acetoxy-S ^ -epoxy ^ i ^^ - cis-g-transeicosatetraen

aus0,3g6 (RS), 7 (RS) -11-acetoxy-6,7-epoxy-2-trans-4-cis-undecadienal (D3b) und0,8g3-cis-Nonenyltriphynylphosphoniumjodid.

Examples of the pharmaceutical compositions

and corresponding finished drug forms.

The term "active ingredient" is understood below to mean a compound of the formula I according to the invention, in particular one which is described as a product in Examples 1-75, such as, for example,

S-IBiRSi ^ ö Isri-hydroxy ^ -cis-pentadecene e-YLJ-cysteine-methylester; N-fS-ISiRSt ^ FSRL-ö-hydroxy ^ -cis-heptadecene-e-yn-N-trifluoroacetyl-cysteinylj-glycine-methylester; N-fS-IöiRSLeiSRJ-S-hydroxy ^ -trans ^ -cis-nonadecadien-e-yll-N-trifluoracetylcysteinylj-glycine, sodium salt; N-fS-tStRSl ^ Isri-B-hydroxy ^^ - trans-ii-cis-eicosatriene-e-YLJ-N-trifluoroacetyl-cysteinylJ-glycine methyl ester;

N- {S- [5 (RS), 6 (SR) -5-hydroxy-7,9-trans-11,14-cis-eicosatetraen-6-yl] -cysteinyl} -glycine (also in optical active form) ; and N- {S- [5 (RS), 6 (SR) -1,5-dihydroxy-7,9-trans-11,14-cis-eicosatetraen-6-yl] -cysteinyl} -glycine potassium salt (also in optically active form).

Example A: A propellant-containing, solid-aerosol-forming inhalable suspension containing 0.1% by weight of active ingredient. Composition:% by weight

Active ingredient, micronized 0.1

Sorbitan trioleate 0.5

Propellant A

(Trichlorotrifluoroethane) 4.4

Propellant B

(Dichlorodifluoromethane and 15.0

1,2-dichlorotetrafluoroethane) 80.0

Production: The material is suspended under exclusion of moisture with the aid of a conventional homogenizer with addition of the sorbitan trioleate in trichlorotrifluoroethane, the suspension is filled into a metered-dose aerosol container; this is closed and filled with the blowing agent B under pressure.

Example B: A suitable for inhalation, about 2% aqueous solution of an active ingredient in the form of its sodium or potassium salt.

composition

Active substance (K or Na salt) 2,000 mg

Ethylenediaminetetraacetic acid disodium salt 10 mg

Benzalkonium chloride 10 mg

Water, freshly distilled ad 100 ml

Preparation: The active ingredient is dissolved in about 60 ml of freshly distilled water and the stabilizer (ethylenediaminetetraacetic acid disodium salt) and the preservative (benzalkonium chloride) are added. After complete dissolution of all components, the resulting solution is made up to 100 ml, filled into pressure vials and sealed gas-tight. The propellant is added in gaseous form as needed under pressure or in liquid form. ANNEX - PHARMACOLOGICAL TEST METHODS Guinea pig bronchoconstriction test (in vivo, aerosol):

Male guinea pigs, 400-700 g, are anesthetized intraperitoneally with 1.4 g / kg urethane and injected with a polyethylene cannula into the jugular vein. A second polyethylene cannula is inserted into the trachea. By means of a cannula inserted in the esophagus, which is connected to a Statham pressure transducer, the pressure in the esophagus is recorded. The animal is placed in an airtight sealable plexiglass chamber connected to a Fleisch # 03 tube and a Validyne MP 45-1 transducer. With this arrangement, the flow is measured. After the surgical preparation of the test animals one waits for a certain time for the pulmonary functions to stabilize. The compound to be tested is then administered according to the following protocol. The test animals are exposed for 1 minute to a 1% aerosol solution of the test compound (w / v) or distilled water (for control purposes). All test compounds administered by inhalation use a Monaghan Model 670 Ultrasonic Sprayer whose particle size ranges from 1 to 8 microns, with a major portion of 3 microns.

Aqueous solutions are each made fresh and introduced with an on-stream drug vial in the chamber of the sprayer. The produced spray is administered to the experimental animals via a 65 ml glass chamber connected to the trachea with a cannula. At the end of the treatment period, LTD ₄ (0.3 μg / ml) is administered for 2 minutes with a second Monaghan ultrasound sprayer (Model 670) and through a similar glass chamber. The decrease in compliance in the third minute after LTD _{4 administration is} read. The average of three animals is compared with the average of three control animals and the percentage inhibition of compliance is achieved according to the following formula:

(100 - compliance preparation) · 100 % inhibition 100 -

(100 - compliance control)

When different drug concentrations are assayed, the percent inhibition is plotted for each concentration, and the log concentration on the abscissa is plotted against the percent inhibition on the ordinate. The IC ₅₀ is then determined by linear regression analysis.

In vitro test for the determination of the inhibition of phospholipase A ₂ from human leukocytes

Neutrophils polymorphic human leukocytes are isolated and deep-frozen by multistage fractional sedimentation from "buffy coats." The phospholipase A ₂ is extracted from the cell suspension by homogenization with the addition of ice-cold 0.36N H ₂ SO ₄ in 2N NaCl and added after centrifugation 10000 g of supernatant dialyzed against sodium acetate buffer pH4.5

For the determination of enzyme activity, enzyme (10-30, Ug protein) in 0.1 M Tris / HCl buffer pH 7 with the addition of 1 mM CaCl ₂ and substrate, consisting of biosynthetic mji; ¹⁴ C-oleic acid radiolabelled phospholipids (2μ, Μ) of Escherichia coli incubated at 37 ⁰ C for 1 hour. The reaction is stopped by addition of Dole's reagent (isopropanol / heptane / 1 NH ₂ SO ₄ 40: 10: 1, v / v) and the ¹⁴ C-oleic acid selectively liberated by phospholipase A _{2 is} extracted. Also co-extracted substrate is completely removed by filtration of the extract through a column of silica gel. The determination of ¹⁴ C-oleic acid

in the eluate is done by radiometry.

To determine an inhibitory effect of test substances on the phospholipase A ₂ , these are added to the Incubationsumsatz as solutions in water, dimethyl sulfoxide (final concentration in the batch to 5%, v / v) or ethanol (final concentration in the batch to 2 ^ 5% v / v). The potency of the test substances is expressed by the IC ₆₀ , ie the concentration which causes an inhibition of 50% of the control activity. The IC ₅₀ is plotted by plotting the percent inhibition on the ordinate against the log of the concentration (μ.Μ) on the abscissa.

Under the experimental conditions described, mepacrine inhibits phospholipase A ₂ with an IC ₅₀ of 1 600 / xM.

In vitro test to determine the inhibition of phospholipase C from human platelets

Human platelets are obtained from "buffy coats" by fractional centrifugation and then deep frozen.The phospholipase C is released by sonication of the cell suspension and is found after ultracentrifugation (150000 χ g for 1 hour) in soluble form in the supernatant.

For the determination of the enzyme activity enzyme (20-10O ₁ Ug protein) in O, O25MTris / maleate buffer pH 6 with the addition of 0.2mM CaCl ₂ and 0.02 mM radioactively labeled substrate, phosphatidyl [ ¹⁴ C] inositol , incubated at 37 ° C for 5 minutes. The reaction is stopped by shaking with CHCl 3 / CH 3 OH 2: 1 (v / v). This unconsumed substrate is extracted into the organic phase, while the reaction product ¹⁴ C-Inositphophat remains in the aqueous phase and can be measured by radiometry of an aliquot.

To determine an inhibitory effect of test substances on the phospholipase C these are added as solutions in water, dimethyl sulfoxide (final concentration in the batch to 5%, v / v) or ethanol (final concentration in the batch to 2.5%, v / v) the incubation. The potency of the test substances is expressed by the IC ₅₀ , ie the concentration which causes an inhibition of 50% of the control activity. The IC ₅₀ is plotted by plotting the percentage inhibition on the ordinate versus the log of the concentration (/ zM) on the abscissa.

Under the experimental conditions described, mepacrine inhibits phospholipase C with an IC ₅₀ of 20μ.Μ.

Claims (1)

Invention claim: 1. A process for the preparation of a compound of the formula E ² -CH = CH-CC- (CH ") ₉ -R ¹ έ li ⁽ " H
CH ₂ -X-CO-R ³