WO1993021211A1

WO1993021211A1 - Amides having inhibiting activity on phospholipase a2, a process for the preparation thereof and pharmaceutical compositions containing them

Info

Publication number: WO1993021211A1
Application number: PCT/EP1993/000866
Authority: WO
Inventors: Germano Carganico; David Mauleon Casellas; Maria Luisa Garcia Perez
Original assignee: Laboratorios Menarini S.A.
Priority date: 1992-04-14
Filing date: 1993-04-07
Publication date: 1993-10-28
Also published as: ES2044781B1; AU3952593A; ES2044781A1

Abstract

The present invention relates to amides of general formula (I), a process for the preparation thereof and pharmaceutical compositions containing them. In formula (I), X is oxygen or sulphur; R1 is alkyl; R2 is hydrogen, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl or the corresponding arylalkyl groups; R3 is hydrogen, carboxyl, alkoxycarbonyl or aryloxycarbonyl; and R4 hydrogen, alkyl, arylalkyl, heteroarylalkyl, hydroxyalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, carboxyalkyl, carbamoyl, guanidinoalkyl or sulfoalkyl. Said compounds inhibit phospholipase A¿2?, therefore they can be used as antiinflammatory, antiallergic, antithrombotic, antiasthmatic agents and in the prevention of anaphylactic shock. Said amides can be obtained by reacting a compound (II), wherein R?6¿ is the same as R2 or a suitable protecting group, with a suitable amine H¿2?NCHR?3R4¿, in the presence of a proton-binding base and a carboxy-activating agent.

Description

AMIDES HAVING INHIBITING ACTIVITY ON PHOSPHOLIPASE A₂, A PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

FIELD OF THE INVENTION

The present invention relates to novel amides, a process for the preparation thereof, the pharmaceutically acceptable salts thereof and pharmaceutical compositions containing them.

Said amides have inhibiting action on phospholipase A₂. TECHNOLOGICAL BACKGROUND

It is well established that the major part of eicosanoids, prostaglandins and related compounds derive from a C₂₀ fatty acid, having 4 in saturations, which is named arachidonic acid (AA), which is mainly obtained esterifying the hydroxy group at the 2-position of glycerophospholipids contained in cell membranes. AA is released from the phospholipid containing it by the action of a lipase, i.e. phospholipase A₂ (PLA₂) ("CRC Handbook of Eicosanoids and Related Lipids", vol. (II), Ed. A. L. Willis, CRS Press, Inc. Florida (1989)). After the release, AA is metabolized in mammals through different pathways or enzyme systems. Through cyclooxygenase, AA gives rise to prostaglandins and thromboxanes, the most significant being PGE, and TxA₂, which participate directly in inflammation (Higgs et al. Annals of Clinical Research, 16, 287-299 (1984)). Through lipooxygenase, AA produces leukotrienes, the most important being LTB₄, LTC₄ and LTD₄, which also participate in inflammatory reactions, showing chemotactic activities, stimulate segregation of lysosomal enzymes and act as important factors in the immediate hypersensitivity reactions (Bailey and Casey, Ann. Rep. Med. Chem. , 17, 203-217 (1982)).

By the action of PLA₂, besides the release of fatty acids, the corresponding lysophospholipids are obtained, which either can then be re-esterified or be converted into PAF (platelet activating factor) by acetylation at 2-position, if they have phosphocholine at the 3-position, an ether bond at the 1-position and are in a cell system having acetyl-transferase activity. PAF is also a pro-inflammatory agent, that has been ascribed to play an important role in various pathological processes, such as asthma, anaphylaxis, inflammation and ischemia (Braquet et al., Pharmacol. Rev., 39 (2), 97 (1987)).

PLA₂, besides being related to the inflammatory processes, can also be involved, either directly or indirectly, in degenerative thrombotic and cancerous pathologies.

From what stated above, it is evident that PLA₂ is of great importance in controlling the production of the mediators involved in the pathologies indicated above. As a consequence, compounds inhibiting PLA₂ provide a new rational approach for the prevention, elimination or improvement of different allergic, anaphylactic, asthmatic, inflammatory and thrombotic conditions.

Various compounds have been described to be in vitro inhibitors of PLA₂ (Wilkerson, Drugs of the Future, 15, 141 (1990)), however nowadays there are no specific PLA₂ inhibitors for the clinical use.

The compounds of general formula (I) are not structurally related to any PLA₂ inhibitor described in literature. Some compounds that could be considered structurally related to the compounds of the present invention are not included in formula (I) and show very different activities, for example some of them are receptor inhibitors of LTC₄, (Sala et al., Eicosanoids, 3, 105 (1990)), or of glutathione S-transferase (Adang et al., J. Biol. Chem., 266, 830 (1991)), or they enhance the immune activity (JP 55085553); or they are S-butylglutathione-like metabolites (James et al., Bio-chem. J. 109, 727 (1968)).

Up to now, corticosteroids are the only medicaments considered likely to exert an inhibitory mechanism on PLA₂, even though in an indirect way. However, said compounds have a series of adverse systemic side-effects which restrict the use thereof, particularly in chronic pathologies. PLA₂ selective inhibitors, such as the compounds of the present invention, advantageously have the same effectiveness as corticosteroids, without the side-effects thereof.

DISCLOSURE

The compounds of the present invention have the following general formula (I)

wherein:

- X is an oxygen or sulphur atom; - R¹ is a C₄-C₂₀ straight or branched alkyl group ;

- R² is hydrogen or a R⁵-CO-, R⁵-O-CO- or R⁵-SO₂-group, in which R⁵ is a C₁-C₂₀ straight or branched alkyl group, phenyl or an arylalkyl group of less than 20 carbon atoms totally;

- R³ is hydrogen, a carboxy group, an alkoxycarbonyl, aryloxycarbonyl or arylalkoxycarbonyl group of less than 10 carbon atoms in the last three cases;

- R⁴ is hydrogen, a C₁-C₆ straight or branched alkyl group, an arylalkyl group of less than 10 carbon atoms, an heteroarylalkyl group of less than 10 carbon atoms, an hydroxyalkyl group of less than 4 carbon atoms, a thioalkyl or alkylthioalkyl group of less than 4 carbon atoms, an aminoalkyl group of less than 6 carbon atoms, the amino group being in the free or derivatized form, as an alkyl amide of less than 4 carbon atoms, a C₂-C₅ carboxyalkyl group, the carboxy group being in the free or derivatized form as an alkyl or aralkyl ester of less than 8 carbon atoms, a carbamoylalkyl group of less than 4 carbon atoms, a guanidinoalkyl group of less than 5 carbon atoms, or a sulfoalkyl group of less than 4 carbon atoms; with the proviso that R⁴ cannot be hydrogen when R³ is hydrogen or when R¹ is C₄ alkyl and R² is hydrogen or acetyl.

When R² is hydrogen, the compounds of formula (I) can be obtained in form of salts, as represented by formula (la)

wherein X- is a pharmaceutically acceptable anion of an inorganic acid (e.g. hydrochloric or sulfuric) or organic carboxylic acid (e.g. acetic, trifluoroacetic, lactic or tartaric), or organic sulfonic acid (e.g. methanesulfonic, ethanesulfonic or toluenesulfonic).

When R³ is a carboxy group, the compounds of formula (I) can also be obtained in form of salts, as represented by formula (lb)

wherein M⁺ is an alkali metal cation (e.g. Na⁺, K⁺), or the equivalent of an alkaline-earth metal cation (e.g. 1/2 Ca²+, 1/2 Mg²⁺).

When the compounds of formula (I) have more than one basic nitrogen, the double acid addition salts can also be obtained (e.g. dihydrochlorides or dihydrobromides). Similarly, when the compounds of formula (I) have more than one carboxylic or sulfonic acid group, the double base addition salts can also be obtained (e.g. sodium, potassium, calcium or magnesium salts).

The compounds of general formula (I) have one or more asymmetric carbons in their structure. The present invention includes all the possible stereoisomers as well as the mixtures thereof.

In the compounds of general formula (I), R¹ can be for example butyl, hexyl, decyl, tetradecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or icosyl; when R² is a R⁵-CO-, R⁵-O-CO- or R -SO₂-, in which R⁵ is an alkyl or arylalkyl group, this can be methyl, ethyl, propyl, butyl, decyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, benzyl or 11-phenylundecyl; when R³ is an alkoxycarbonyl, aryloxycarbonyl or arylalkoxycarbonyl group, they can be methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, phenoxycarbonyl or benzyloxycarbonyl; when R⁴ is an alkyl group, this can be methyl, isopropyl, butyl, isobutyl or sec-butyl; when R⁴ is an arylalkyl group, this can be benzyl or p-hydroxybenzyl; when R⁴ is an heteroarylalkyl group, this can be 4-imidazolylmethyl or 3-indolylmethyl; when R ⁴ is an hydroxyalkyl group, this can be hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl; when R⁴ is a thioalkyl or alkylthioalkyl group, this can be mercaptomethyl or 2-methylthioethyl; when R⁴ is an aminoalkyl group, this can be 4-aminobutyl, 3-aminopropyl or 4-acetylaminobutyl; when R⁴ is a carboxyalkyl group, this can be carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, methoxycarbonylmethyl or 2-methoxycarbonylethyl; when R⁴ is a carbamoylalkyl group, this can be carbamoylmethyl or 2-carbamoylethyl; when R⁴ is a guanidinoalkyl group, this can be 2-guanidinoethyl or 3-guanidinopropylj when R⁴ is a sulfoalkyl group, this can be sulfomethyl, 2-sulfoethyl or 3-sulfopropyl.

Preferred compounds of the present invention are those in which:

- X and R¹ are the groups defined above;

- R² is hydrogen, a C₁-C₂₁ alkoxycarbonyl group atoms, preferably groups acetyl, hexanoyl, dodecanoyl or hexadecanoyl; - R³ is hydrogen, a carboxy group or an alkoxycarbonyl group of less than 10 carbon atoms, preferably methoxycarbonyl or ethoxycarbonyl;

- R⁴ is hydrogen, a C₁-C₆ straight or branched alkyl group, preferably methyl or isobutyl, an hydroxyalkyl group of less than 4 carbon atoms, preferably hydroxymethyl or 2-hydroxyethyl, an aminoalkyl or alkylcarbonylaminoalkyl group of less than 7 carbon atoms totally, preferably 4-aminobutyl or 4-acetylaminobutyl, a C₂-C₅ carboxyalkyl group, preferably carboxymethyl or

2-carboxyethyl, or a sulfoalkyl of less than 4 carbon atoms, preferably sulfomethyl.

Particularly preferred compounds of the present invention are the following:

N-Hexanoyl-O-octadecyl-D-serinyl-L-valine.

N-Hexadecanoyl-O-decyl-D-serinylglycine.

N-Acetyl-O-oσtadecyl-D-serinyl-L-glutamic acid.

N-Acetyl-O-oσtadecyl-D,L-serinyl-L-glutamic acid.

N-Acetyl-O-octadecyl-D-serinyl-D-glutamic acid.

N-Acetyl-O-octadecyl-D,L-serinyl-L-leucine.

N-Acetyl-O-octadecyl-D,L-serinyl-D,L-leucine.

N-Acetyl-O-octadecyl-D-serinyl-L-leucine.

N-Hexadecanoyl-S-decyl-D-cysteinyl-L-lysine.

N-Acetyl-S-octadecyl-D-cysteinyl-L-lysine.

S-Octadecyl-D-cysteinylglycine (hydrobromide).

S-Octadecyl-D-cysteinyl-L-lysine (hydrobromide).

S-Octadecyl-L-cysteinyl-L-lysine (hydrobromide).

S-Octadecyl-D-cysteinyl-D-lysine (hydrobromide).

S-Octadecyl-L-cysteinyl-D-lysine (hydrobromide).

S-butyl-D-cysteinyl-L-glutamic acid (hydrobromide).

S-Butyl-D-cysteinyl-L-leucine (hydrobromide). S-Butyl-D-cysteinyl-L-lysine (hydrobromide).

N-Acetyl-S-octadecyl-D-cysteinyl-L-leucine.

N-Acetyl-S-octadecyl-D,L-cysteinyl-D,L-leucine.

N-Acetyl-S-octadecyl-D-cysteinylglycine.

Methyl N-acetyl-S-octadecyl-D-cysteinyl-L-glutamate.

N-Acetyl-S-octadecyl-D-cysteinyl-L-glutamic acid.

N-Acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-L-lysine.

N-Acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-L-lysine.

N-Acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-D-lysine. N-Acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-D-lysine.

N-Acetyl-S-octadecyl-D-cysteinyl-L-serine.

N-Acetyl-S-octadecyl-D-cysteinyl-L-homoserine.

N-Dodecanoyl-S-butyl-D-cysteinyl-L-glutamic acid.

N-Dodecanoyl-S-butyl-D-cysteinyl-L-leucine.

N-Acetyl-S-butyl-D-cysteinyl-trN-acetyl-L-lysine.

N-Acetyl-S-octadecyl-D,L-cysteinyltaurine (sodium salt).

N-Acetyl-S-decyl-D ,L-cysteinyltaurine ( sodium salt ) .

N-Acetyl-S-octadecyl-D-cysteinyltaurine ( sodium salt) . N-Acetyl-S-octadecyl-D-serinyltaurine (sodium salt ) .

According to the present invention , the compounds of general formula ( I ) can be prepared by reacting a compound of formula ( II) , of suitable stereochemistry at the carbon at the 2-position

wherein X and R¹ are the groups defined above and R⁶ can be equivalent to the group R² above or, if R² in formula (I) is hydrogen, then R⁶ is a suitable aminoprotecting group, for example benzyloxycarbonyl or tert-butyloxycarbonyl, with:

a) When in (I) R³ is one of the groups defined above, except for hydrogen, and R⁴ is one of the groups defined above, except for a sulfoalkyl group, a reactive of formula (III), of suitable stereochemistry,

wherein R ⁷ can be equivalent to R³ in formula (I), except for hydrogen, and, when in (I) R is a carboxy group, then R⁷ is a suitably protected carboxy group, for example in form of the benzyl or tert-butyl ester, and R 8 can be the same as R⁴, except when in formula (I) R⁴ contains a functional group in the free form, in which case in R⁸ such a group is suitably protected, for example when R⁴ in formula (I) contains an amino group, R⁸ in formula (III) can contain a benzyloxycarbonylamino or tert-butyloxycarbonylamino group; when R⁴ in (I) contains a carboxy group, this is for example in form of the benzyl or tert-butyl ester in (III); the reaction between (II) and (III) is carried out in the presence of a proton-binding base, such as triethylamine or pyridine and a carboxy-activating agent, such as dicyclohexylcarbodiimide or pivaloyl chloride, in suitable aprotic solvents such as chloroform, methylene chloride or N,N-dimethylformamide, at a temperature from 0° to 40°C for a time from 3 to 24 hours, to obtain an intermediate of formula (IV)

fi 8

wherein X, R¹, R⁶, R⁷ and R⁸ are the groups described above . This compound of formula ( IV) is converted into ( I ) by removing any protecting groups present in R⁶ , R⁷ g and R⁸, according to conventional methods; when R⁶ and R⁷ are benzyloxycarbonyl groups and a benzyloxycarbonylamino or a benzyloxycarbonyl group can be present in R⁸, the benzyl groups can be removed by catalytic hydrogenation with Pd-C or with Pd(OH)₂, in solvents such as methanol, water or acetic acid, under hydrogen pressures from atmospheric pressure to 50 psi, at a tempe rature from 20° to 50°C for a time from 3 to 20 hours; or in an acid medium, for example with hydrobromic or trifluoroacetic acid, in a suitable solvent such as acetic acid or chloroform, at a temperature from 0º to

40°C for a time from 15 minutes to 6 hours; when R⁶ and R⁷ are tert-butyloxycarbonyl groups and a tert-butyloxycarbonylamino or tert-butyloxycarbonyl group can be present in R⁸, the tert-butyl groups can be removed under the same acid conditions as mentioned above . If R⁶ in formula ( IV) is an amino-protecting group , such as benzyloxycarbonyl or tert-butyloxycarbonyl , this is deprotected to obtain compounds of formula ( I) wherein R² is hydrogen , which can in their turn be converted into the compounds (I. with R² different from hydrogen by an acylation or sulfonylation reaction with suitable acid halides or anhydrides (R⁵ COX, R⁵ OCOX or R⁵SO₂X).

b) When in (I) R³ is hydrogen and R⁴ is a sulfoalkyl group of less than 4 carbon atoms, a compound of formula (II) is reacted with a carboxy-activating agent such as N-hydroxy-5-norbornen-2,3-dicarboxymide acid or

N-hydroxy succinimide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, in a suitable solvent such as dioxane, tetrahydrofuran or N,N-dimethylformamide, at a temperature from 0º to 40°C for a time from 5 to 24 hours. Subsequently, it is reacted with a reactive (V)

NH₂-CH₂-R⁴ V

wherein R⁴ is a sulfoalkyl group of less than 4 carbon atoms, in the presence of a base such as sodium bicarbonate or aqueous sodium hydroxide, in a suitable organic solvent such as dioxane or tetrahydrofuran at a temperature from 0ºC to the solvent's reflux, for a time from 5 to 24 hours, to obtain a compound of formula (VI)

wherein X, R¹, R⁴ and R⁶ are group described above.

When R⁶ is the same as R², this compound (VI) coincides with compound (I) wherein R³ is hydrogen and with the proviso that R² is hydrogen. When R⁶ is an amino-protecting group, this compound can be transformed into compound (I. wherein R² is hydrogen, by means of con- ventional deprotection methods, or optionally it can be converted into the remaining compounds (I), as indicated above.

Finally, if a salt of (I) is desired, a treatment with a suitable acid, base or ion exchanger is carried out, according to conventional methods.

A starting compound (II) wherein X is sulphur can be prepared, for example, following the synthetic sequence shown in Scheme 1.

Scheme 1

A compound of formula (VIII) wherein R⁶ is one of the groups defined above can be obtained (step a) starting from cysteine ((VII)) of suitable stereochemistry, this product being commercially available in both the chiral D or L forms and the racemic one, by reaction with a suitable acyl or sulfonyl halide R⁶Y, wherein R⁶ is the group described above and Y can be iodide, chloride or bromide, in the presence of a base such as trie thy lamine, sodium acetate or sodium bicarbonate, in a suitable solvent such as water or N,N-dimethylformamide, at a temperature from 0ºC to the solvent's reflux, for a time from 1 to 12 hours.

A compound of formula (II) can be obtained (step b) by reacting the compound (VIII) with a compound ZR , wherein R¹ is the group described above and Z is a suitable leaving group, such as for example bromide, iodide, mesylate or tosylate in the presence of a base such as potassium hydroxide or sodium carbonate, in a suitable organic solvent such as ethanol or N,N-dimethylformamide, at a temperature from 0° to 50°C, for a time from 5 to 24 hours.

A starting compound (II) wherein X is oxygen can be prepared, for example, following the synthetic sequence shown in Scheme 2.

Scheme 2

A compound of formula (X) can be prepared, for example, starting from compound (IX), the preparation of which is well described in literature (Hajdu et al.

J. Org. Chem. 48, 1197 (1983)), by means of a process already described in Spanish Patent application N°

9101610.

A compound of formula (XI), wherein R¹ and R⁶ are the groups defined above, can be obtained (step d), by means of reaction with a suitable acyl or sulfonyl halide as described above.

A compound of formula (II) wherein X is oxygen can be prepared, for example, by subjecting a compound (XI) to the action of an oxidizing agent such as the system formed by RuCl₃.3H₂O/NaIO₄, in mixtures of suitable solvents such as carbon tetrachloride:acetonitrile:water (3:3:2) or carbon tetrachloride:ethyl acetate:water (3:3:2), at a temperature from -20° to 30ºC, for a time from 15 min to 18 hours.

The compounds of the present invention show a marked activity as inhibitors of PLA₂ activity, and accordingly they have antiinflammatory and antiallergic properties which make them useful for the treatment of diseases in which this enzyme is involved. For this purpose, said compounds can be used in human therapy for the prevention and treatment of allergic rhinitis, bronchial asthma, hypersensitivity reactions such as allergic conjunctivitis, various inflammatory conditions such as those present in rheumatoid arthritis, osteoarthritis, tendinitis, bursitis, psoriasis and other related inflammations.

For the therapeutical uses, the compounds of the present invention are formulated in the appropriate pharmaceutical form, according to conventional techniques and excipients, such as those described in Remington's Pharmaceutical Science Handbook, Mack Pub. Co., N.Y., USA. Examples of said forms include capsules, tablets, syrups and the like, containing from 1 to 1000 mg per unitary dose.

The following examples illustrate the preparation and the pharmacological activity of the compounds of the present invention.

EXAMPLE 1

N-Benzyloxycarbonyl-D-cysteine ((VIII), R⁶=COOCH₂C₆H₅).

A solution of D-cysteine (1.50 g, 8.54 mmol) in water (5 ml) is added, at 0°C, with 1M NaHCO₃ (25.62 ml) and 1.32 ml (9.41 mmol) of benzyl chloroformate. The mixture is stirred at 0°C for 4 h. After that, it is left at room temperature and the benzyl chloroformate excess is removed by means of extraction with ethyl ether. The resulting aqueous phase is acidified with concentrated hydrochloric acid to pH=3, extracted with ethyl acetate, dried and solvent is removed, to obtain the title compound in an 87% yield.

T.L.C.: eluent chloroform :methanol: acetic acid,

65:25:3, R_f=58

N.M.R. ¹Η (300 MHz, CDCl₃) δ ppm: 3.01 (m, 2H); 4.68 (m, 1H); 5.08 (s, 2H); 7.35 (broad s, 5H).

EXAMPLE 2

N-Benzyloxycarbonyl-L-cysteine ((VIII), R⁶=COOCH₂C₆H₅).

Following the process described in example 1, starting from L-cysteine, the title compound was prepared in a 93 % yield.

T.L.C.: eluent chloroform:methanol: acetic acid, 65:25:3, R_f=0.58

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 3.01 (m, 2H); 4.68 (m, 1H); 5.08 (s, 2H); 7.35 (broad s, 5H).

EXAMPLE 3

N-Benzyloxycarbonyl-S-octadecyl-D-cysteine

((II), X=S, R¹=(CH₂)₁₇CH₃, R⁶=COOCH₂C₆H₅).

A solution of N-benzyloxycarbonyl-D-cysteine (1.67 g, 6.51 mmol) in ethanol (13.4 ml) is added with 0.36 g (6.51 mmol) of KOH dissolved in ethanol (13.4 ml) under inert atmosphere. The mixture is cooled to 5°C and 1-bromooctadecane (2.17 g, 6.51 mmol) and 0.36 g more of KOH in ethanol are added. The mixture is stirred at room temperature for 24 h. Subsequently, water (100 ml) is added to the mixture, which is acidified with concentrated hydrochloric acid to pH=3-4, extracted with ethyl acetate, dried and solvent is removed, to obtain a crude product which is purified by flash chromatography on silica gel column. Eluting with chloroform:methanol, 20:1, 2.44 g of the title compound are obtained as a white solid melting at 79-81°C (74% yield).

[α]_D ²⁰ = -7.5° (c=1.164, CHCl₃).

T.L.C.: eluent chloroform:methanol:water,65:25:4, R_f=

0.76

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.25

(m, 30H); 1.51 (m, 2H); 2.49 (t, 2H); 2.98 (d, 2H); 4.58 (m, 1H); 5.10 (s, 2H); 7.30 (m, 5H).

EXAMPLE 4

N-Benzyloxycarbonyl-S-octadecyl-L-cysteine

((II), X=S, R¹=(CH₂)₁₇CH₃, R⁶=COOCH₂C₆H₅).

Following the process described in example 3, starting from N-benzyloxycarbonyl-L-cysteine and 1-bromooctadecane the title compound was prepared, 78-81°C (87% yield).

[α] = +7.6° (c=1.163, CHCl₃)

T.L.C.: eluent chloroform:methanol:water, 65:25:4, R_f= 0.76

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.25 (m, 30H) ; 1.51 (m, 2H) ; 2 .49 (t , 2H ) ; 2 . 98 ( d, 2H) ; 4 . 58 ( m, 1H) ; 5. 10 ( s , 2H ) ; 7 .30 (m, 5H ) .

EXAMPLE 5

N-Benzyloxycarbonyl-S-butyl-D-cysteine

((II), X=S, R¹=(CH₂)₃CH₃, R⁶=COOCH₂C₆H₅).

Following the process described in example 3, starting from N-benzyloxycarbonyl-D-cysteine and 1-bromobutane, the title compound was prepared in a 73 % yield.

T.L.C.: eluent chloroform:methanol:water, 65:25:4, R_f=0.44

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.32 (m, 2H); 1.50 (m, 2H); 2.49 (t, 2H); 2.98 (d, 2H); 4.58 (m, 1H); 5.10 (s, 2H); 7.30 (m, 5H).

EXAMPLE 6

Benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ɤ- benzyl-L-glutamate ((IV), X=S, R¹=(CH₂) ₁₇CH₃, R⁶ and R⁷=COOCH₂C₆H₅ , R⁸=CH₂CH₂COOCH₂C₆H₅) .

A mixture of N-benzyloxycarbonyl-S-octadecyl-D-cysteine (0.250 g, 0.49 mmol), L-glutamic acid dibenzyl ester (p-toluenesulfonate) (0.244 g, 0.49 mmol) and methylene chloride (15 ml) is added, at 0°C, with triethylamine (0.068 ml, 0.49 mmol) and dicyclohexylcarbodiimide (0.109 mg, 0.53 mmol). The mixture is stirred at room temperature for 3 h. Thereafter it is added with some drops of glacial acetic acid, stirred for 30 min and the formed dicyclohexylurea is filtered off. The filtrate is washed with water, dried and the volatiles are evaporated off, to obtain a crude product which is purified by flash chromatography on a silica gel column. Eluting with petroleum ether : chloroform, 1:1, 0.323 g of the title compound are recovered in form of a colourless oil (82% yield).

T.L.C. : ethyl ether, 2:1, R_f = 0.68

N.M.R. ¹H (300 MHz, CDCl₃ ) δ ppm: 0.80 (t, 3H); 1.23 (m. 30H); 1.47 (m, 2H); 2.00 (m, 1H); 2.16 (m, 1H)

2.31 (m, 2H); 2.45 (m, 2H); 2.75 (m, 2H); 4.24 (m, 1H)

4.57 (m, 1H); 5.01 (s, 2H); 5.04 (s, 2H); 5.08 (d, 2H)

7.26 (m, 15H).

EXAMPLE 7

Benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-L-leucinate ((IV), X=S, R¹=(CH₂) ₁₇CH₃, R⁶ and

R⁷=COOCH₂C₆H₅ , R⁸=CH₂CH (CH₃ )₂).

According to the procedure described in example 6 starting from N-benzyloxycarbonyl-S-octadecyl-D-cysteine and benzyl L-leucinate (hydrochloride), the title compound was prepared as a colourless oil (88% yield).

T.L.C: eluent ethyl ether, R_f = 0.77

N.M.R. ¹H (300 MHz, CDCl₃ ) δ ppm: 0.85 (t, 9H); 1.24 (m, 30H); 1.56 (m, 5H); 2.50 (m, 2H); 2.79 (dd, 1H);

2.92 (dd, 1H); 4.31 (m, 1H); 4.60 (m, 1H); 5.10 (m,

4H); 7.30 (m, 10H).

EXAMPLE 8

Benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinylglycinate ((IV), X=S, R¹=(CH₂) ₁₇CH₃, R⁶ and R⁷=COOCH₂C₆H₅,

R⁸=H).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-octadecyl-D-cysteine and benzyl glycinate (hydrochloride), the title compound was prepared as a colourless oil (76% yield).

T.L.C: eluent ethyl ether, R_f = 0.66 N.M.R. ¹H (300 MHz, CDCl₃ ) ε ppm: 0.90 (t, 3H); 1.21

(m, 30H); 1.56 (m, 2H); 2.50 (m, 2H); 2.82 (dd, 1H);

2.96 (dd, 1H); 4.06 (m, 2H); 4.36 (m, 1H); 5.11 (s,

2H); 5.16 (s, 2H); 7.32 (m, 10H).

EXAMPLE 9

Benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ε-Nbenzyloxycarbonyl-L-lysinate ((IV), X=S, R₁=(CH₂)₁₇CH ,

R⁶ and R⁷=COOCH₂C₆H₅, R⁸=(CH₂) ₄NHCOOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-octadecyl-D-cysteine and benzyl ε-N-benzyloxycarbonyl-L-lysinate

(hydrochloride), the title compound was prepared as a colourless oil (77% yield).

T.L.C: eluent ethyl ether, R_f = 0.67

N.M.R. ¹Έ (300 MHz, CDCl₃) δ ppm: 0.86 (t, 3H); 1.25

(m, 30H); 1.40-1.90 (complex signal, 8H); 2.48 (m, 2H);

2.84 (m, 2H); 3.05 (m, 2H); 4.30 (m, 1H); 4.58 (m, 1H);

5.10 (m, 6H); 7.30 (m, 15H).

EXAMPLE 10

Benzyl N-benzyloxycarbonyl-S-octadecyl-L-cysteinyl-ε-N-benzyloxycarbonyl-L-lysinate ((IV), X=S, R =(CH₂)₁₇CH₃,

R⁶ and R⁷=COOCH₂C₆H₅, R⁸=(CH₂)₄NHCOOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-octadecyl-L-cysteine and benzyl δ-N-benzyloxycarbonyl-L-lysinate

(hydrochloride), the title compound was prepared as a colourless oil (80% yield).

T.L.C: eluent ethyl ether, R_f = 0.67

N.M.R. ¹H (300 MHz, CDCl₃) S ppm: 0.86 (t, 3H); 1.25 (m, 30H); 1.40-1.90 (complex signal, 8H); 2.48 (m, 2H);

2.84 (m, 2H); 3.05 (m. 2H); 4.30 (m, 1H); 4.58 (m, 1H); 5.10 (m, 6H) ; 7 .30 (m, 15H) .

EXAMPLE 11

Benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ε-N-benzyloxycarbonyl-D-lysinate ((IV), X=S, R¹=(CH₂)₁₇CH₃, R⁶ and R⁷=COOCH₂C₆H₅, R⁸=(CH₂)₄NHCOOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-octadecyl-D-cysteine and benzyl ε-N-benzyloxycarbonyl-D-lysinate (hydrochloride), the title compound was prepared as a colourless oil (84% yield).

T.L.C: eluent ethyl ether, R_f = 0.67

N.M.R. ¹H (300 MHz, CDCl₃ ) δ ppm: 0.86 (t, 3H); 1.25 (m, 30H); 1.40-1.90 (complex signal, 8H); 2.48 (m, 2H); 2.84 (m, 2H); 3.05 (m, 2H); 4.30 (m, 1H); 4.58 (m, 1H); 5.10 (m, 6H); 7.30 (m, 15H).

EXAMPLE 12

Benzyl N-benzyloxycarbonyl-S-octadecyl-L-cysteinyl-ε-N-benzyloxycarbonyl-D-lysinate ((IV), X=S, R¹=(CH₂)₁₇CH₃, R⁶ and R⁷=COOCH₂C₆H₅, R⁸=(CH₂)₄NHCOOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-octadecyl-L-cysteine and benzyl ε-N-benzyloxycarbonyl-D-lysinate (hydrochloride), the title compound was prepared as a colourless oil (79% yield).

T.L.C: eluent ethyl ether, R_f = 0.67

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.86 (t, 3H); 1.25 (m, 30H); 1.40-1.90 (complex signal, 8H); 2.48 (m, 2H); 2.84 (m, 2H); 3.05 (m, 2H); 4.30 (m, 1H); 4.58 (m, 1H); 5.10 (m, 6H); 7.30 (m, 15H). EXAMPLE 13

Benzyl N-benzyloxycarbonyl-S-butyl-D-cysteinyl-ɤ-benzyl-L-glutamate ((IV), X=S, R¹= (CH₂)₃CH₃, R⁶ and R⁷=COOCH₂C₆H₅ , R⁸=CH₂CH₂COOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-butyl-D-cysteine and L-glutamic acid dibenzyl ester (p-toluenesulfonate), the title compound was prepared as a colourless oil (92 % yield).

T.L.C: eluent ethyl ether, R_f=0.57

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.88 (t, 3H); 1.35 (m, 2H); 1.50 (m, 2H); 2.02 (m, 1H); 2.24 (m, 1H); 2.40 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 4.39 (m, 1H); 4.69 (m, 1H); 5.10 (m, 6H); 7.26 (m, 15H).

EXAMPLE 14

Benzyl N-benzyloxycarbonyl-S-butyl-D-cysteinyl-L-leucinate ((IV), X=S, R¹=(CH₂)₃CH₃, R⁶ and R⁷=COOCH₂C₆ H₅, R⁸-=CH₂CH(CH₃)₂).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-butyl-D-cysteine and benzyl L-leucinate (hydrochloride), the title compound was prepared as a colourless oil (96 % yield).

T.L.C: eluent ethyl ether, R_f=0.57

N.M.R. ¹H (300 MHz, CDCl₃ ) δ ppm: 0.87 (m, 9H); 1.34 (m, 2H); 1.58 (m, 5H); 2.50 (m, 2H); 2.86 (m, 2H); 4.37

(m, 1H); 4.64 (m, 1H); 5.08 (m, 4H); 7.28 (m, 10H).

EXAMPLE 15

Benzyl N-benzyloxycarbonyl-S-butyl-D-cysteinyl-ε-N-benzyloxyσarbonyl-L-lysinate ((IV), X=S, R¹=(CH₂)₃CH₃, R⁶ and R⁷=COOCH₂C₆H₅, R⁸=(CH₂)₄NHCOOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-benzyloxycarbonyl-S-butyl-D-cysteine and benzyl ε-N-benzyloxycarbonyl-L-lysinate (hydrochloride), the title compound was prepared as a colourless oil (85 % yield).

T.L.C: eluent ethyl ether, R_f=0.38

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.20-1.90 (complex signal, 10H); 2.48 (t, 2H); 2.70 (dd, 1H); 2.88 (dd, 1H); 3.08 (m, 2H); 4.30 (m, 1H); 4.59 (m, 1H); 5.10 (m, 6H); 7.30 (m, 15H).

EXAMPLE 16

Benzyl S-octadecyl-D-cysteinyl-L-glutamate (hydrobromide) ((I), X=S, R¹=(CH₂)₁₇CH₃, R₂=H, R³=COOCH₂C₆H₅, R⁴=CH₂CH₂COOH).

A mixture of benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ɤ-benzyl-L-glutamate (0.328 g, 0.40 mmol) and hydrobromic acid in 33% glacial acetic acid

(4 ml) is stirred at room temperature for 30 min. After that, the mixture is evaporated to dryness to obtain the title compound as a colourless oil (100% yield). T.L.C: eluent chloroform imethanol: water, 65:25:4,

R_f =0.10

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.89 (t, 3H); 1.29 (m, 30H); 1.60 (m, 2H); 2.02 (m, 1H); 2.22 (m, 1H); 2.43 (m, 2H); 2.62 (m, 2H); 3.00 (m, 2H); 4.10 (m, 1H); 4.54 (m, 1H); 5.19 (m, 2H); 7.34 (m, 5H).

EXAMPLE 17

Benzyl S-octadecyl-D-cysteinyl-L-leucinate (hydrobromide) ((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=COOCH₂C₆H₅, R⁴=CH₂CH(CH₃)₂).

According to the procedure described in example

16, starting from benzyl N-benzyloxycarbonyl-S-octa- decyl-D-cysteinyl-L-leucinate, the title compound was prepared as a colourless oil (95 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.47

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (m, 6H); 1.20 (m, 30H); 1.56 (m, 5H); 2.58 (m, 2H); 3.15 (m, 2H); 3.74 (m, 1H); 4.50 (m, 1H); 5.28 (q, 2H); 7.30 (m, 5H) .

EXAMPLE 18

S-Octadecyl-D-cysteinylglycine (hydrobromide)

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=C00H, R⁴=H).

According to the procedure described in example 16, starting from benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinylglycinate and after 4 h stirring at room temperature, the title compound was prepared (90 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.12

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.92 (t, 3H); 1.29

(m, 30H); 1.72 (m, 2H); 2.63 (t, 2H); 2.88 (dd, 1H); 3.12 (dd, 1H); 4.00 (s, 2H); 4.06 (m, 1H).

EXAMPLE 19

S-Octadecyl-D-cysteinyl-L-lysine (hydrobromide)

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=COOH, R⁴= (CH₂)₄NH₂).

According to the procedure described in example 18, starting from benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ε-N-benzyloxycarbonyl-L-lysinate, the title compound was prepared as a white solid which decomposes at 158ºC (99 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

Rf,=0, 17

N.M.R. ¹H (300 MHZ, CD₃OD) δ ppm: 0.90 (t, 3H); 1.30 (m, 30H); 1.49-2.02 (complex signal, 8H); 2.65 (t, 2H);

2.89 (dd, 1H); 2.84 (t, 2H); 3.18 (dd, 1H); 4.16 (m,

1H); 4.44 (m, 1H).

EXAMPLE 20

S-Octadecyl-L-cysteinyl-L-lysine (hydrobromide)

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=COOH, R⁴=(CH₂)₄NH₂).

According to the procedure described in example

18, starting from benzyl N-benzyloxycarbonyl-S-octadecyl-L-cysteinyl-ε-N-benzyloxycarbonyl-L-lysinate, the title compound was prepared (95 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.17

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.90 (t, 3H); 1.30

(m, 30H); 1.49-2.02 (complex signal, 8H); 2.65 (t, 2H); 2.89 (dd, 1H); 2.84 (t, 2H); 3.18 (dd, 1H); 4.16 (m,

1H); 4.44 (m, 1H).

EXAMPLE 21

S-Octadecyl-D-cysteinyl-D-lysine (hydrobromide)

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=COOH, R⁴=(CH₂)₄NH2).

According to the procedure described in example

18, starting from benzyl N-benzyloxycarbonyl-S-octadecyl-D-cysteinyl-ε-N-benzy loxycarbonyl-D-lysinate, the title compound was prepared (88 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.17

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.84 (t, 3H); 1.30

(m, 30H); 1.49-2.02 (complex signal, 8H); 2.65 (t, 2H);

2.89 (dd, 1H); 2.84 (t, 2H); 3.18 (dd, 1H); 4.16 (m,

1H); 4.44 (m, 1H).

EXAMPLE 22

S-Octadecyl-L-cysteinyl-D-lysine (hydrobromide) ((I), X=S, R¹=(CH₂)₁₇CH₃, R²=H, R³=COOH, R⁴= (CH₂)₄NH2). According to the procedure described in example

18, starting from benzyl N-benzyloxycarbonyl-S-octadecyl-L-cysteinyl-ε-N-benzyloxycarbonyl-D-lysinate, the title compound was prepared as a colourless oil (97 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.17

2.89 (dd, 1H); 2.84 (t, 2H); 3.18 (dd, 1H); 4.16 (m,

1H); 4.44 (m, 1H).

EXAMPLE 23

S-Butyl-D-cysteinyl-L-glutamic acid (hydrobromide)

((I), X=S, R¹=(CH₂)₃CH₃, R²=H, R³=COOH, R⁴=CH₂CH₂COOH).

According to the procedure described in example

18, starting from benzyl N-benzyloxycarbonyl-S-buty--.-Dcysteinyl-ɤ-benzyl-L-glutamate, the title compound was prepared (92 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.18

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H); 1.30

(m, 2H); 1.51 (m, 2H); 1.98 (m, 1H); 2.21 (m, 1H); 2.49

(t, 2H); 2.58 (t, 2H); 3.02 (m, 2H); 4.20 (t, 2H); 4.45 (m, 1H).

EXAMPLE 24

S-Butyl-D-cysteinyl-L-leucine (hydrobromide)

((I), X=S, R¹=(CH₂)₃CH₃, R²=H, R³=COOH,

R⁴=CH₂CH(CH₃)₂).

According to the procedure described in example

18, starting from benzyl N-benzyloxycarbonyl-S-butyl-D- cysteinyl-L-leucinate, the title compound was prepared

(98 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.38

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.80 (m, 9H); 1.28

(m, 2H); 1.68 (m, 3H); 2.54 (m, 2H); 3.03 (m, 2H); 4.31

(m, 2H).

EXAMPLE 25

S-Butyl-D-cysteinyl-L-lysine (hydrobromide)

((I), X=S, R¹=(CH₂)₃CH₃, R²=H, R³=CO0H, R⁴=(CH₂)₄NH₂)

According to the procedure described in example 18, starting from benzyl N-benzyloxycarbonyl-S-butyl-D-cysteinyl-6-N-benzyloxycarbonyl-L-lysinate, the title compound was prepared (91 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.24

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.94 (t, 3H); 1.39-2.00 (complex signal, 10H); 2.67 (t, 2H); 2.96 (m, 3H); 3.14 (dd, 1H); 4.19 (t, 1H); 4.43 (m, 1H).

EXAMPLE 26

N-Acetyl-S-octadecyl-D-cysteinyl-L-glutamic acid

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH,

R⁴=CH₂CH₂COOH) .

A mixture of benzyl S-octadecyl-D-cysteinyl-L-glutamate (hydrobromide) (0.270 g, 0.40 mmol), acetic anhydride (0.038 ml, 0.40 mmol), triethylamine (0.067 ml, 0.48 mmol) and dry benzene (8 ml) is stirred at room temperature for 4 h. After that, the mixture is evaporated to dryness, diluted with chloroform (25 ml), washed with 0.2 M hydrochloric acid, dried and solvent is removed, to obtain a crude product, which is redis- solved in a solution of hydrobromic acid in 33% acetic acid. The mixture is left under stirring at room temperature for 4 h. After that the mixture is evaporated to dryness, to obtain a crude product which is purified by flash chromatography on a functionalized silica gel column (SDS RP-18, 200-400 mesh). Eluting with water (0.045% trifluoroacetic acid) :acetonitrile (0.035% trifluoroacetic acid), 2:3, 0.187 g of the title compound are recovered as a white solid melting at 118-120ºC (86% yield).

[α]_D ²⁰ = +11.4° (c=0.440, methanol).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.15

N.M.R. ¹H (300 MHz, CD₃OD) δ Ppm: 0.92 (t, 3H); 1.29 (m, 30H); 1.58 (m, 2H); 1.97 (m, 1H); 2.00 (s, 3H);

2.19 (m, 1H); 2.43 (t, 2H); 2.56 (t, 2H); 2.73 (dd, 1H); 2.92 (dd, 1H); 4.44 (m, 1H); 4.55 (m, 1H).

EXAMPLE 27

N-Acetyl-S-octadecyl-D-cysteinyl-L-leucine

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃ , R³=COOH,

R⁴=CH₂CH(CH₃)₂).

According to the procedure described in example 26, starting from benzyl S-octadecyl-D-cysteinyl-L-leucinate, the title compound was prepared as a white solid melting at 95-97°C (73 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.54

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.81 (t, 6H); 1.20

(m, 30H); 1.52 (m, 5H); 1.92 (s, 3H); 2.46 (t, 2H); 2.74 (m, 2H); 4.43 (m, 2H). EXAMPLE 28

N-Acetyl-S-octadecyl-D-cysteinylglycine

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH, R⁴=H).

A mixture of S-octadecyl-D-cyεteinylglycine (hydrobromide) (0.102 g, 0.24 mmol), acetic anhydride

(0.030 ml, 0.31 mmol), triethyl amine (0.084 ml, 0.60 mmol) and dry benzene (10 ml) is stirred at room temperature for 4 h. After that the mixture is evaporated to dryness, diluted with chloroform (25 ml), washed with 0.2 M hydrochloric acid, dried and solvent is removed, to obtain a crude product which is purified by flash chromatography on a functionalized silica gel column (SDS RP-18, 200-400 mesh). Eluting with water (0.045% tr if luoro acetic acid) : acetonitrile (0.035% trifluoroacetic acid), 1:1, 0.092 g of the title compound are recovered as a semisolid oil (81% yield).

T.L.C: eluent chloroform: methanol: water, 65:25:4, R_f=0.42

N.M.R. ¹Η (300 MHz, CD₃OD) δ ppm: 0.89 (t, 3H); 1.33 (m, 30H); 1.54 (m, 2H); 2.01 (s, 3H); 2.55 (t, 2H);

2.73 (dd, 1H); 3.00 (dd, 1H); 3.90 (s, 2H); 4.55 (m, 1H).

EXAMPLE 29

N-Acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-L-lysine ((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃ , R³=COOH,

R⁴= (CH₂)₄NHCOCH₃).

According to the procedure described in example 28, starting from S-octadecyl-D-cysteinyl-L-lysine (hydrobromide), the title compound was prepared as a semisolid oil (67 % yield).

[α]_D ²⁰ = +4.5° (c=0.964, methanol) . T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.21

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.90 (t, 3H); 1.29 (m, 30H); 1.34-1.64 (complex signal, 6H); 1.73 (m, 1H); 1.89 (m, 1H); 1.92 (s, 3H); 2.02 (s, 3H); 2.56 (t, 2H);

2.74 (dd, 1H); 2.92 (dd, 1H); 3.14 (t, 2H); 4.39 (m, 1H); 4.58 (t, 1H).

EXAMPLE 30

N-Acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-L-lysine ((I), X=S, R¹=(CH₂)17CH₃, R²=COCH₃, R³=COOH,

R⁴=(CH₂)₄NHCOCH₃).

According to the procedure described in example 28, starting from S-octadecyl-L-cysteinyl-L-lysine (hydrobromide), the title compound was prepared as a solid melting at 120-122°C (72 % yield).

[α]_D ²⁰ = -5.9° (c=0.720, chloroform:methanol, 3:2).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.21

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.90 (t, 3H); 1.29 (m, 30H); 1.34-1.64 (complex signal, 6H); 1.73 (m, 1H);

1.89 (m, 1H); 1.92 (s, 3H); 1.84 (s, 3H); 2.56 (t, 2H);

2.71 (dd, 1H); 2.95 (dd, 1H); 3.15 (m, 2H); 4.38 (m, 1H); 4.52 (m, 1H).

EXAMPLE 31

N-Acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-D-lysine

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH,

R⁴=(CH₂)₄NHCOCH₃).

According to the procedure described in example

28, starting from S-octadecyl-D-cysteinyl-D-lysine (hydrobromide), the title compound was prepared as a white solid melting at 122-125°C (76 % yield). [α]_D ²⁰ = +6.9° (c=0.865, chloroform:methanol, 3:2).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.21

1.89 (m, 1H); 1.92 (s, 3H); 2.00 (s, 3H); 2.56 (t, 2H);

2.71 (dd, 1H); 2.95 (dd, 1H); 3.15 (m, 2H); 4.38 (m, 1H); 4.52 (m, 1H).

EXAMPLE 32

N-Acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-D-lysine

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH,

R⁴=(CH₂)₄NHCOCH₃).

According to the procedure described in example

28, starting from S-octadecyl-L-cysteinyl-D-lysine (hydrobromide), the title compound was prepared as a white solid melting at 82-85°C (70 % yield).

[α]_D ²⁰ = -6.7° (c=0.72, methanol).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.21

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.90 (t, 3H); 1.29

(m, 30H); 1.34-1.64 (complex signal, 6H) ; 1.73 (m, 1H);

1.89 (m, 1H); 1.92 (s, 3H); 2.02 (s, 3H) ; 2.56 (t, 2H);

2.74 (dd, 1H); 2.92 (dd, 1H); 3.14 (t, 2H) ; 4.39 (m, 1H); 4.58 (t, 1H).

EXAMPLE 33

N-Dodecanoyl-S-butyl-D-cysteinyl-L-glutamic acid

((I), X=S, R¹=(CH₂)₃CH₃, R²=CO(CH₂)₁₀CH3, R³=COOH,

R⁴=CH₂CH₂COOH) .

A mixture of S-butyl-D-cysteinyl-L-glutamic acid (hydrobromide) (0.419 g, 1.08 mmol), dodecaneic anhydride (0.425 mg, 1.11 mmol), triethylamine (0.563 ml, 4.04 mmol) and dry chloroform (30 ml) is stirred at room temperature for 4 h. After that it is diluted with chloroform (50 ml), washed with 0.2 M hydrochloric acid, dried and solvent is removed, to obtain a crude product, which is purified by flash chromatography on a silica gel column. Eluting with chloroform: methanol, 4:1, 0.449 g of the title compound are recovered as a semisolid oil (85 % yield).

[α]_D ²⁰ = +22.7° (c=3.33, methanol).

T.L.C: eluent chloroform:methanol:water, 65:25:4,

R_f=0.24

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.90 (m, 6H); 1.22- 1.46 (complex signal, 18H); 1.56 (m, 4H); 1.96 (m, 1H); 2.18 (m, 1H); 2.25 (t, 2H); 2.40 (q, 2H); 2.55 (t, 2H); 2.73 (m, 1H); 2.93 (m, 1H); 4.44 (m, 1H); 4.56 (m, 1H).

EXAMPLE 34

N-Dodecanoyl-S-butyl-D-cysteinyl-L-leucine

((I), X=S, R¹=(CH₂)₃CH₃, R²-CO(CH₂)₁₀CH₃, R³=COOH, R⁴=CH₂CH(CH₃)₂).

Following the process described in example 33, starting from S-octadecyl-L-cysteinyl-D-leucine (hydrobromide), the title compound was prepared as a semisolid oil (97 % yield).

[α]_D ²⁰ - +2.0° (c=5.40, methanol).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.69

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.92 (m, 12H); 1.22-1.84 (complex signal, 25H); 2.34 (t, 2H); 2.59 (t, 2H); 2.78 (dd, 1H); 2.89 (dd, 1H); 4.38 (m, 1H); 4.53 (m, 1H). EXAMPLE 35

N-Acetyl-S-butyl-D-cysteinyl-ε-N-acetyl-L-lysine

((I), X=S, R¹=(CH₂)₃CH₃, R²=COCH₃, R³=COOH, R⁴=(CH₂) ₄NHCOCH₃).

According to the procedure described in example 28, starting from S-butyl-D-cysteinyl-L-lysine (hydrobromide), the title compound was prepared as a semisolid oil (88 % yield).

[α]_D ²⁰ = +30.5° (c=1.23, methanol).

T.L.C: eluent chlofoform:methanol:water, 65:25:4, R_f=0.29

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.92 (t, 3H); 1.39-1.64 (complex signal, 8H); 1.74 (m, 1H); 1.86 (m, 1H); 1.91 (s, 3H); 1.99 (s, 3H); 2.56 (t, 2H); 2.72 (dd, 1H); 2.92 (dd, 1H); 3.14 (t, 2H); 4.38 (m, 1H); 4.56 (t, 1H).

EXAMPLE 36

S-Octadecyl-D,L-cysteine (hydrobromide)

((II), X=S, R¹=(CH₂)₁₇CH₃, R⁶=H).

Following the process described in example 18, starting from N-benzyloxycarbonyl-S-octadecyi-D,L-cysteine, the title compound was prepared as a white solid which decomposes at 230ºC (95% yield).

T.L.C: eluent chloroformimethanol:water, 65:25:4, R_f=0.05

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.92 (t, 3H); 1.34 (m, 30H); 1.65 (m, 2H); 2.65 (t, 2H); 3.04 (dd, 1H); 3.18 (dd, 1H); 4.22 (dd, 1H).

EXAMPLE 37

N-Acetyl-S-octadecyl-D,L-cysteine

((II), X=S, R¹=(CH₂)₁₇CH₃, R⁶=COCH₃). Following the process described in example 28, starting from S-Octadecyl-D,L-cysteine (hydrobromide), the title compound was prepared as a white solid melting at 96-99ºC (87% yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f-=0.53

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.25 (m, 30H); 1.55 (m, 2H); 2.06 (s, 3H); 2.50 (t, 2H); 2.99 (m, 2H); 4.72 (m, 1H).

EXAMPLE 38

N-Acetyl-S-octadecyl-D,L-cysteinyltaurine (sodium salt).

((I), X=S, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=H, R⁴=CH₂SO₃Na).

A solution of N-acetyl-S-octadecyl-D,L-cysteine (0.231 g, 0.55 mmol) and N-hydroxy-5-norbornen-2,3-dicarboxymide acid (0.109 g, 0.61 mmol) in tetrahydrofuran:dioxane, 1:1 (6 ml), is added at 0ºC with dicyclohexylcarbodiimide (0.127 g, 0.61 mmol). The mixture is stirred for 2 h a 0ºC and for 20 h at room temperature. After that, the formed dicyclohexylurea is filtered off and the filtrate is evaporated to dryness. The resulting residue is redissolved in dioxane (2.5 ml) and added with a solution of taurine (0.078 g, 0.62 mmol) in a 0.42 M sodium bicarbonate solution (1.5 ml). The mixture is stirred for 20 h at room temperature, evaporated to dryness and the resulting crude product is digested with ethyl acetate. The insoluble residue is dissolved in chloroform (300 ml), washed with 2 M hydrochloric acid and dried and solvent is removed, to obtain a crude product which is purified by flash chromatography on a functionalized silica gel column (SDS RP-18, 200-400 mesh). Eluting with water (0.045% trifluoroacetic acid) : acetonitrile (0.035% trifluoroacetic acid), 3:2, 0.234 g of the title compound are recovered as a white solid which decomposes at 168°C (78% yield). T.L.C: eluent chloroform : methanol: water, 65:25:4,

R_f=0.24

N.M.R. ¹H (300 MHz, CD₃0D) δ ppm: 0.89 (t, 3H); 1.29 (m, 30H); 1.58 (m, 2H); 1.92 (s, 3H); 2.55 (t, 2H); 2.71 (m, 1H); 2.96 (m, 3H); 3.59 (m, 2H); 4.44 (m, 1H).

EXAMPLE 39

l-O-Octadecyl-2-acetylamino-3-deoxyglycerol.

((XI), R¹=(CH₂)₁₇CH₃, R⁶=COCH₃).

Following the process described in example 28, starting from l-O-octadecyl-2-amino-3-deoxyglycerol the title compound was prepared as a white solid melting at

71-72ºC (90% yield).

T.L.C: eluent chloroform :methanol, 9:1, R_f=0.43

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.24 (m, 30H); 1.55 (m, 2H); 2.00 (s, 3H); 3.40 (t, 2H); 3.50-3.68 (complex signal, 3H); 3.80 (dd, 1H); 4.03 (m,

1H).

EXAMPLE 40

N-Acetyl-O-octadecyl-D,L-serine. ((II), X=O,

R¹= (CH₂)₁₇CH₃, R⁶=COCH₃).

A solution of l-O-octadecyl-2-acetylamino-3-deoxyglycerol (0.398 g, 1.03 mmol) in carbon tetrachloride: acetonitrile: water, 1:1:1.4 (37 ml) is added with NaIO₄ (0.909 g, 4.24 mmol) and RuCl₃.3H₂O (8.2 mg, 0.031 mmol). The mixture is stirred for 1.5 h at room temperature. After that, water (7 ml) and methylene chloride (7 ml) are added, the two formed phases are separated and the aqueous one is extracted with methylene chloride. The combined organic phases are dried and solvent is removed, to obtain a crude product which is purified by flash chromatography on silica gel column. Eluting with chloroform :methanol, 97.5:2.5, 0.346 g of the title compound are recovered as a white solid melting at 86-89°C (82% yield).

T.L.C: eluent chloroform:methanol:water, 64:25:4, R_f=0.35

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.25

(m, 30H); 1.52 (m, 2H); 2.02 (s, 3H); 3.42 (t, 2H); 3.62 (dd, 1H); 3.86 (dd, 1H); 4.68 (m, 1H).

EXAMPLE 41

N-Acetyl-O-octadecyl-D,L-serinyl-ɤ-benzyl-L-glutamate. ((IV), X=O, R¹=(CH₂)₁₇CH₃, R⁶=COCH₃ , R⁷=COOCH₂C₆H₅, R⁸=CH₂CH₂COOCH₂C₆H₅).

According to the procedure described in example 6, starting from N-acetyl-O-octadecyl-D,L-serine and L-glutamic acid dibenzyl ester (p-toluenesulfonate), the title compound was prepared as a colourless oil (83% yield).

T.L.C: eluent chloroform:methanol, 9:1, R_f = 0.54

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.25 (m, 30H); 1.50 (m, 2H); 1.99(m, 1H); 2.00 (s, 3H); 2.21 (m, 1H); 2.38 (m,2H); 3.39 (m, 3H); 3.76 (dd, 1H); 4.51 (m, 1H); 4.63 (m, 1H); 5.08 (s, 2H); 5.12 (s, 2H); 7.32 (m, 10H).

EXAMPLE 42

N-Acetyl-O-octadecyl-D,L-serinyl-L-leucinate ((IV), X=O, R¹=(CH₂)₁₇CH₃, R⁶=COCH₃, R⁷=COOCH₂C₆H₅ ,

R⁸=CH₂CH(CH₃)₂). According to the procedure described in example 6, starting from N-acetyl-O-octadecyl-D,L-serine and benzyl L-leucinate (hydrochloride), the title compound was prepared as a colourless oil (92 % yield).

T.L.C: eluent chloroformrmethanol:water, 64:25:4, R_f=0.50

N.M.R. ¹H (300 MHz, CDCl₃) δ ppm: 0.87 (m, 9H); 1.21 (m, 30H); 1.61 (m, 5H); 1.98 (s, 3H); 3.42 (m, 3H); 3.78 (m, 1H); 4.50 (m, 1H); 4.62 (m, 1H); 5.12 (s, 2H); 7.32 (m, 5H).

EXAMPLE 43

N-Acetyl-O-octadecyl-D,L-serinyl-L-glutamic acid

((I), X=O, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH, R⁴=CH₂CH₂COOH).

A solution of benzyl N-acetyl-O-octadecyl-D,L-serinyl-ɤ-benzyl-L-glutamate (0.100 g, 0.14 mmol) in glacial acetic acid (10 ml) is added with 0.015 g of 10% palladium-on-carbon and the mixture is stirred for 18 h at room temperature, under hydrogen atmosphere, then it is filtered and evaporated to dryness, to obtain a crude product which is purified by flash chromatography on a functionalized silica gel column (SDS RP-18, 200-400 mesh). Eluting with water (0.045% trifluoroacetic acid):acetonitrile (0.035% trifluoroacetic acid), 2:3, 0.056 g of the title compound are recovered as a semi-solid oil (73 % yield).

T.L.C: eluent chloroform:methanol:water, 65:25:4, R_f=0.14

N.M.R. (300 MHz, CD₃OD) δ ppm: 0.90 (t, 3H); 1.28 (m, 30H); 1.56 (m, 2H); 1.95 (m, 1H); 2.02 (s, 3H); 2.20 (m, 1H); 2.41 (m,2H); 3.46 (m, 2H); 3.65 (m, 2H); 4.46 (m, 1H); 4.58 (m, 1H).

EXAMPLE 44

N-Acetyl-O-octadecyl-D,L-serinyl-L-leucine

((I),X=O, R¹=(CH₂)₁₇CH₃, R²=COCH₃, R³=COOH, R⁴=CH₂CH(CH₃)₂).

According to the procedure described in example 43, starting from benzyl N-acetyl-O-octadecyl-D,L-serinyl-L-leucinate, the title compound was prepared as a semisolid oil (93 % yield).

T.L.C: eluent chloroform:methanol:water, 64:25:4, R_f=0.65

N.M.R. ¹H (300 MHz, CD₃OD) δ ppm: 0.92 (m, 9H); 1.29 (m, 30H); 1.49-1.74 (complex signal, 5H); 2.00 (s, 3H); 3.46 (m, 2H); 3.65 (m, 2H); 4.45 (m, 1H); 4.58 (m, 1H).

EXAMPLE 45

Determination of the inhibition on phospholipase A₂.

The PLA₂ activity is determined by radioactive evaluation of the labelled fatty acid which esterifies the sn-2 position of the phospholipid substrate and which is released by the enzyme action. E. coli phospholipid membranes, to which labelled oleic acid (1-14_C) has previously been incorporated, are used as the substrate. The used enzyme is purified PLA₂ from human synovial liquid.

The reaction mixture contains 25 mM Hepes buffer (pH 7.0), 5.0 mM Ca²⁺ and 1.4×106 E. coli autoclaved (corresponding to 10000 dpm and 10.0 nmol of phospholipid). The reaction is started by addition of 80 ng of purified enzyme, keeping stirring for 5 minutes at 37ºC The reaction is stopped by adding 3.0 ml of CHCl₃:CH₃OH (1:2 v/v), the lipids are extracted by the Bligh and Dyer procedure and the reaction products are separated by thin layer chromatography and dpm are quantified by liquid scintillation.

The study of the inhibiting effect on PLA₂ on the compounds of the present invention is carried out dissolving them in dimethylsulfoxide or ethanol and adding them to the above described reaction mixture until the required proportion. The hydrolysis percentage is calculated by means of the following equation:

free fatty acid (dpm)

% Hydrolysis = - - - - - - - - - - - - - - - - - - - - - - - - - - - - non hydrolyzed phospholipid+free fatty acid (dpm)

The compounds of the present invention were tested according to this procedure. The inhibiting action of the different compounds is expressed as the product concentration inhibiting the activity of the enzyme by 50% compared with the control in the absence of inhibitor (IC₅₀). Some examples of the obtained results are reported in the following Table.

Inhibiting effect on PLA₂ from human synovial liquid

Compound of IC₅₀

Example № (μM)

26 20

27 30

29 15

28 15

34 25

38 15

43 20

44 20

Claims

1. Compounds of general formula ( I )

wherein:

- X is an oxygen or sulphur atom;

- R¹ is a C₄-C₂₀ straight or branched alkyl group;

- R ² is hydrogen or a R⁵-CO-, R⁵-O-CO- or R⁵-SO₂-group, in which R⁵ is a C₁-C₂₀ straight or branched alkyl group, phenyl or an arylalkyl group of less than

20 carbon atoms totally;

- R⁴ is hydrogen, a C₁-C₆ straight or branched alkyl group, an arylalkyl group of less than 10 carbon atoms, an heteroarylalkyl group of less than 10 carbon atoms, an hydroxyalkyl group of less than 4 carbon atoms, a thioalkyl or alkylthioalkyl group of less than 4 carbon atoms, an aminoalkyl group of less than 6 carbon atoms, the amino group being in the free or derivatized form, as an alkyl amide of less than 4 carbon atoms, a C₂-C₅ carboxyalkyl group, the carboxy group being in the free or derivatized form as an alkyl or aralkyl ester of less than 8 carbon atoms, a carbamoylalkyl group of less than 4 carbon atoms, a guanidinoalkyl group of less than 5 carbon atoms, or a sulfoalkyl group of less than 4 carbon atoms; with the proviso that R⁴ cannot be hydrogen when R³ is hydrogen or when R¹ is C₄ alkyl and R² is hydrogen or acetyl;

and the pharmaceutically acceptable salts thereof.

2. Compounds according to claim 1 characterized in tthhaatt R³ iiss hydrogen or a carboxy group, R⁴ is a sulfomethyl group, or the group

in formula (I) is an amino acid selected from glycine, lysine with the ε-amino in the free or alkylcarbonylamino form of less than 4 carbon atoms, leucine or glutamic acid with the Y-carboxyl in the free or alkoxycarbonyl or arylalkoxycarbonyl form of less than 8 carbon atoms.

3. Compounds according to claim 2 characterized in that R ² is hydrogen or a R⁵CO- group, wherein R⁵ is a C₁-C₂₀ straight, alkyl group.

4. Compounds according to claim 3 characterized in that the group

in formula (I) is an amino acid selected from glycine, lysine with the δ-amino in the free or alkylcarbonylamino form of less than 4 carbon atoms, leucine or glutamic acid with the ɤ-carboxyl in the free or alkoxycarbonyl or arylalkoxycarbonyl form of less than 8 carbon atoms.

5. Compounds according to claim 3 characterized in that R³ is hydrogen and R⁴ is a sulfomethyl group .

6. As compounds according to claim 1:

N-acetyl-O-octadecyl-D ,L-serinyl-L-glutamic acid;

N-acetyl-O-octadecyl-D ,L-serinyl-L-leucine ;

S-octadecyl-D-cysteinylglycine (hydrobromide ) ;

S-octadecyl-D-cysteinyl-L-lysine (hydrobromide ) ;

S-octadecyl-L-cysteinyl-L-lysine (hydrobromide ) ;

S-octadecyl-D-cysteinyl-D-lysine (hydrobromide ) ;

S-octadecyl-L-cysteinyl-D-lysine (hydrobromide) ;

S-butyl-D-cysteinyl-L-glutamic acid (hydrobromide ) ;

S-butyl-D-cysteinyl-L-leucine (hydrobromide ) ;

S-butyl-D-cysteinyl-L-lysine (hydrobromide ) ;

N-acetyl-S-octadecyl-D-cysteinyl-L-leucine ;

N-acetyl-S-octadecyl-D-cysteinylglycine ;

N-acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-L-lysine ;

N-acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-L-lysine ;

N-acetyl-S-octadecyl-D-cysteinyl-ε-N-acetyl-D-lysine ;

N-acetyl-S-octadecyl-L-cysteinyl-ε-N-acetyl-D-lysine ;

N-dodecanoyl-S-butyl-D-cysteinyl-L-glutamic acid;

N-dodecanoyl-S-butyl-D-cysteinyl-L-leucine;

N-acetyl-S-butyl-D-σysteinyl-ε-N-acetyl-L-lysine;

N-acetyl-S-octadecyl-D ,L-cysteinyltaurine ( sodium salt ) .

7. A process for the preparation of compounds of general formula (I) wherein R₄ is different from a sulfoalkyl group, comprising the reaction of a compound of formula (II) of suitable stereochemistry at the 2-carbon

wherein X and R¹ have the same meanings as in claim 1 and R₆, has the same meanings as R₂ or, if R₂ is hydrogen, R₆ is a suitable amino-protecting group; with a compound of formula (III):

wherein R ₇ and R₈ are the same as R₃ and R₄ as defined in claim 1 , respectively, or they are groups which can be converted into R₃ and R₄, to give a compound of formula ( IV) :

which is converted into compounds ( I ) by removing the optional protective groups in R₆, R₇ and R₈ groups .

8. A process for the preparation of compounds of general formula ( I) wherein R₄ is a sulfoalkyl group and R₃ is hydrogen , comprising the reaction of a compound ( II ) as defined in claim 7 with a carboxy-activating agent in the presence of a dehydrating agent , followed by reaction with a compound (V)

NH₂-CH₂-R⁴ V

wherein R₄ is a sulfoalkyl group of less than 4 carbon atoms, to give a compound of formula (VI)

wherein X, R¹, R⁴ and R⁶ are as defined in the previous claims, which compound (VI) is then converted to compounds (I) by removing the optionally present protecting groups.

9. The use of the compounds of claims 1 to 6 for the preparation of a medicament for the therapeutical treatment of inflammatory and allergic diseases, rheumatoid arthritis, tendinitis, bursitis, psoriasis, bronchial asthma and the like.