WO1993001196A1

WO1993001196A1 - Ketoalkylglycerophospholipids having antitumor and anti-platelet aggregation activities, processes for the preparation thereof and pharmaceutical compositions therefrom

Info

Publication number: WO1993001196A1
Application number: PCT/EP1992/001502
Authority: WO
Inventors: Germano Carganico; David Mauleon Casellas; Maria De Los Desemparados Fos Torro
Original assignee: Laboratorios Menarini S.A.
Priority date: 1991-07-10
Filing date: 1992-07-03
Publication date: 1993-01-21
Also published as: ES2034885B1; ES2034885A1; AU2229292A

Abstract

Compounds of general formula (I) wherein R1 is a C¿1?-C16 straight or branched alkyl group, a phenyl group or a phenyl-C6-C16alkyl group; n is an integer from 3 to 18, inclusive; R?2¿ is a C¿1?-C12 straight or branched alkyl group; R?3¿ is hydrogen, a carboxy, alkoxycarbonyl, arylalkoxycarbonyl or aryloxycarbonyl group of less than 12 carbon atoms in the last three cases; R?4, R5 and R6¿, which can be the same or different, are hydrogen, a C¿1?-C6 alkyl group or N?+R4R5R6¿ is a cyclic ammonium group, which can be aromatic or non-aromatic, wherein two of the R?4, R5 or R6¿ groups form a ring together with the nitrogen atom, and the other group is hydrogen or C¿1?-C6 alkyl, have antitumor and anti-platelet aggregating activities.

Description

KETOALKYLGLYCEROPHOSPHOLIPIDS HAVING ANTITUMOR AND ANTI-PLATELET AGGREGATION ACTIVITIES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS THEREFROM

The present invention relates to novel glycerophospholipids having antitumor and anti-platelet aggregating activities, a process for the preparation thereof and pharmaceutical compositions containing them.

TECHNOLOGICAL BACKGROUND

Platelet activating factor (PAF), or 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, of formula A

is a potent cell mediator of phospholipid nature, which is ascribed to play a paramount role in various pathological processes, such as asthma, anaphylaxis, inflammation and ischemia [P. Braguet et al., Pharmacol. Rev., 39(2), 97 (1987)]. As a consequence, a great number of searches have been carried out in order to find PAF-antagonist analogues, which can block PAF action on PAF receptors at the level of the cell membrane [K. Cooper and M.J. Parry, Ann. Rep. Med. Chem., 24, 81 (1989)].

Therefore, specific PAF-antagonists can be interesting in therapy for the treatment of those pathological processes in which PAF is involved.

Another class of synthetic phospholipids is represented by those named alkyl-lyso-phospholipids (ALPs), which are structurally related to lyso- phosphatidylcholine and PAF, from which compound they differ mainly in that they contain a second ether function, which is difficult to metabolize, at the 2- position of glycerol. An example of phospholipids of this kind is ET-18-OCH₃, of formula B

Said compounds show an antitumor activity in various pharmacological models [W.E. Berdel and P.G. Munder in "PAF and related lipid mediators", Ed. F. Snyder, Plenum Press, New York, 1987, p. 449] and no interactions with cell DNA. Undoubtedly, ET-18-OCH₃ and other analogues show some of PAF actions, such as serotonine release, bronchoconstriction, platelet aggregation and hypotension. Said actions are contra-indicated in case of antitumor treatment and they can cause remarkable circulatory disorders.

As a consequence, a compound having the cytostatic action of ET-18-OCH₃ (formula B) and lacking the PAF-like action and capable of blocking the PAF action on the specific cell receptors thereof, could advantageously be used in human therapy as an antitumor agent, without suffering from the drawbacks of compound B.

The compounds of the present invention (formula I), containing a keto group in the chain 1, show an antitumor action which can be compared to that of ET- 18-OCH₃, without having PAF-agonist action. Moreover, said compounds cause no hemolysis and have a PAF-antagonist activity.

DISCLOSURE OF THE INVENTION

The present invention relates to compounds of general formula (I)

wherein R¹ is a C₁-C₁₆ straight or branched alkyl group, a phenyl group or a phenyl-C₁-C₁₆alkyl group ; n is an integer from 3 to 18, inclusive;

R² is a C₁-C₁₂ straight or branched alkyl group;

R³ is hydrogen, a carboxy, alkoxycarbonyl, arylalkoxycarbonyl or aryloxycarbonyl group of less than 12 carbon atoms in the last three cases;

R⁴, R⁵ and R⁶, which can be the same or different, are hydrogen, a C₁-C₆ alkyl group or N⁺R⁴R⁵R⁶ is a cyclic ammonium group, which can be aromatic or non-aromatic, wherein two of the R⁴, R⁵ or R⁶ groups form a ring together with the nitrogen atom, and the other group is hydrogen or C₁-C₆ alkyl.

The compounds of general formula (I) can be obtained in the form of salts, which can be represented either by formula (la)

wherein X-is a pharmaceutically acceptable anion, such as chloride, bromide or iodide anions, and the other symbols have the above mentioned meanings,

or by formula (Ib)

wherein M⁺ is an alkali metal cation, (for example Na⁺,

K⁺), or the equivalent of an alkaline-earth metal (for example 1/2 Ca⁺⁺, 1/2 Mg⁺⁺) and the other symbols have the above mentioned meanings. When R³ is a carboxy group, the compounds of general formula (I) can also be obtained in form of salts, which can be represented by formula (Ic)

wherein all the symbols have the above mentioned meanings.

Since the compounds of the present invention have one or more asymmetric carbon atoms, the present invention also relates to all the possible stereoisomers of compounds (I) and the mixtures thereof.

In compounds of general formula I, when R² is an alkyl group, this can be methyl, ethyl, propyl, butyl, pentyl or hexyl; when R³ is an alkoxycarbonyl or arylalkoxycarbonyl group, this can be methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, pentoxycarbonyl or benzyloxycarbonyl; when R³ is an aryloxycarbonyl group, this can be phenoxycarbonyl; when R⁴ , R⁵ and R⁶ are an alkyl group, this can be methyl, ethyl or propyl; when N⁺R⁴R-R⁶ is a cyclic ammonium group, this can be an aromatic group, such as 1-pyridinium, 1-quinolinium, 1-imidazolium, 1-pyrazolium, 3-thiazolium, 3-oxazolium, 1-benzimidazolium, 3-benzothiazolium or 3-benzoxazolium, or it can be non aromatic, in which case two of R⁴, R⁵ and R⁶ form, together with the nitrogen atom they are linked to, a 1-pyrrolidino, 1-piperidino, 4-morpholino or 1-piperazino ring, and the remaining group is hydrogen or a C₁-C₆ alkyl group.

Preferred compounds of the invention are those in which R¹ and R³ have the above mentioned meanings, R² is a C₁-C₃ alkyl group, n is an integer form 3 to 18, R⁴, R⁵ and R⁶ are hydrogen, methyl or ethyl, or N⁺R⁴R⁵R⁶ is preferably 1-pyridinium, 1-imidazolium, 3- thiazolium, 1-pyrrolidinium, 1-piperidinium or 4- morpholinium.

Particularly preferred compounds of the invention are the following ones:

1-O-(4-oxooctadecyl)-2-O-methylglycero-3-phosphocholine 1-O-(4-oxooctadecyl)-2-O-methylglycero-3-phosphoserine

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphocholine 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphoserine 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphoserine methyl ester

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho(N,N,N-trimethyl)serine

2-O-methyl-3-O-(7-oxooctadecyl)-sn-glycero-1-phosphocholine

2-O-methyl-1-O-(7-oxooctadecyl)-sn-glycero-3-phospho- choline

1-O-(7-oxooctadecyl)-2-O-ethylglycero-3-phosphocholine 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(3-thiazolium)ethyl]

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(1-imidazolium)ethyl]

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(N-methylpiperidinium)ethyl] 1-O-(12-oxooctadecyl)-2-O-methylglycero-3-phosphocholine

1-O-(12-oxooctadecyl)-2-O-methylglycero-3-phosphoserine

1-O-(11-phenyl-11-oxoundecyl)-2-O-methylglycero-3-phosphocholine

1-O-(14-phenyl-11-oxotetradecyl)-2-O-methylglycero-3-phosphocholine

1-O-(14-phenyl-11-oxotetradecyl)-2-O-methylglycero-3-phosphoserine.

The present invention also relates to pharmaceutical compositions containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a suitable carrier or excipient, as well as the use of compounds (I) for the preparation of a medicament.

According to the present invention, compounds (I) can be prepared starting from a racemic or enantiomerically pure compound of formula (XI)

wherein n, R¹ and R² have the above mentioned meanings, and Z is oxygen or a keto-protecting group (such as ethylenedioxy or dimethyl acetal).

According to the process of the invention:

a) A compound of formula (XI) wherein Z is oxygen and n, R¹ and R² have the above mentioned meanings, is reacted with a compound of formula (XII)

wherein X and Y, which can be the same or different, are halogens (such as Cl, Br, I), in the presence of an amine such as triethylamine or pyridine, in an inert organic solvent, such as ethyl ether, tetrahydrofuran (THF) or chloroform, at a temperature from 0° to 40 ºC, to give a compound of formula (XIII)

wherein n, R ¹, R³, X and Y have the above mentioned meanings. After that, aqueous hydrolysis in a saline solution, such as a sodium chloride solution at a temperature from 0° to 50 ºC, gives the compound of formula (XIV) ^

wherein R¹, R² and Y have the above mentioned meanings. Compound (XIV) is reacted with a compound of formula (XV)

wherein R⁴, R⁵ and R⁶ have the above mentioned meanings, in a suitable organic solvent, such as chloroform, acetonitrile, dimethylformamide (DMF) or toluene, at a temperature from 40°C to the solvent's reflux temperature, to give a compound of formula (I), wherein n, R¹, R², R⁴, R⁵ and R⁶ have the above mentioned meanings and R³ is hydrogen.

b) Alternatively, compound (XI), wherein Z is oxygen and n, R¹ and R² have the above mentioned meanings, is reacted with a compound of formula (XVI)

wherein X is halogen (such as Cl, Br, I) in a suitable organic solvent, such as ethyl ether or benzene, in the presence of an amine such as triethylamine or pyridine, at a temperature from 0° to 40 °C, to give a compound of formula (XVII)

wherein R¹ and R² have the above mentioned meanings. Subsequently, compound (XVII) is treated with a compound of formula (XV), in suitable organic solvents, such as dichloromethane, acetonitrile or benzene, at a temperature from 40ºC to the solvent's reflux temperature, to give a compound of formula (I) wherein n , R¹ , R² , R⁴ R⁵ and R⁶ have the above mentioned meanings and R³ is hydrogen .

c ) Alternatively , a compound of formula ( XI ) wherein Z is oxygen or a suitable keto-protecting group , and n ,

R¹ and R² have the above mentioned meanings, is reacted with PCI₃ in the presence of a slightly nucleophilic base, such as imidazol, and an acid-binding agent, such as triethylamine or pyridine, in suitable organic solvents, such as acetonitrile or toluene, at a temperature from 0º to 40°C, to give a compound of formula (XVIII)

wherein R¹ and R² have the above mentioned meanings and A can be hydrogen or a trialkylammonium group. Compound (XVIII) is reacted with a compound of formula (XIX)

wherein R⁷ is an amino-protecting group, such as benzyloxycarbonyl or t-butoxycarbonyl, and R³ can be an alkoxycarbonyl group having less than 12 carbon atoms, or it can be a carboxy group protected in form of the benzyl or t-butyl esters, in the presence of a base such as pyridine and of a condensing agent, such aspivaloyl chloride or 5,5-dimethyl-2-oxo-2-chloro-1,3,2-dioxophospholane, at a temperature from 0° to 40 °C, to give a compound of formula (XX)

wherein n, Z, R¹, R² , R³ and R⁷ have the above mentioned meanings, which is oxidized with an oxidizing agent, such as iodine, to give a compound of formula (XXI)

wherein n , Z , R¹ , R² R³ and R⁷ have the above mentioned meanings. This compound is transformed into a compound of formula (I) by removing the protecting groups R⁷ and Y, if necessary, when R³ is a carboxy group protected in form of a benzyl or t-butyl ester.

When R⁷ is a t-butoxycarbonyl group and R³ is a t-butyl ester, both the protecting groups, as well as Z, can be removed in an acid medium (such as HCl). When R⁷ is a benzyloxycarbonyl group and R³ is a benzyl ester, they can be deprotected simultaneously with the elimination of Z, by means of catalytic hydrogenation with 10% Pd/C or Pd(OH)₂/c in solvents such as methanol, water or mixtures thereof, in the presence of an acid, such as HCl, under pressures ranging from the atmospheric one to 50 psi.

The preparations of compounds (XI) starting from known or commercially available precursors are shown in the following schemes 1 and 2 Scheme 1

Scheme 2

A compound of formula (XI), wherein n, R¹ and R² have the above mentioned meanings and Z is oxygen, can be obtained according to step f) by reacting a compound of formula (VII) with a Grignard reactive R¹MgX, such as alkylmagnesium bromide or phenylalkylmagnesium bromide, in a suitable solvent (such as ethyl ether, THF, benzene or mixtures thereof) at a temperature from 25ºC to the solvent's reflux one, followed by hydrolysis and detritylation in an acid medium (by HCl or H₂SO₄), in the presence of a suitable solvent, such as dioxane, at a temperature from the room one to the solvent's reflux temperature.

A compound of formula (VII) can be prepared, for example, following the synthetic sequence of scheme 1, by reacting the compound of formula (II), which is commercially available, with a compound Q(CH₂)_nBr (XXII), wherein Q is halogen (for example Cl, Br) and n has the above mentioned meanings, in a suitable organic solvent, such as DMF or THF, in the presence of an alkali hydride, such as NaH, at a temperature from 0° to 50°C, to obtain a compound of formula (III). Compound (III) is subjected to a substitution reaction with NaCN or KCN in a suitable organic solvent, such as DMSO or an ethanol-water mixture, at a temperature from the room's one to 100°C, to obtain compound (IV).

A compound of formula (V) can be obtained starting from a compound of formula (IV), by means of acid hydrolysis with HCl or H₂SO₄, for example, at a temperature from room temperature to the solvent's reflux temperature, in a suitable solvent such as THF.

A compound of formula (VI) can be prepared by reacting a compound of formula (V) with trityl chloride, or in the presence of bases, such as pyridine or triethylamine, with or without DMAP, at at temperature from the room's one to 100 °C.

Step e) can be carried out by reacting a compound of formula (VI) with a compound R²X, wherein X is halogen (such as Br, Cl, I) and R² can have the above mentioned meanings, in a suitable solvent, such as DMF, THF or benzene, in the presence of sodium hydride or potassium hydride, at a temperature from the room's one to the reflux temperature of the solvent.

Alternatively, a compound of formula (XI), wherein n, Z, R¹ and R² have the above mentioned meanings, can be prepared, according to steps g) and h), by reacting an alcohol of formula (VIII), whose preparation is well disclosed in literature [M.Takatani et al., J. Med. Chem., 32, 56 (1989)], with a compound of formula (IX), in a suitable organic solvent, such as toluene, benzene, dimethylsulfoxide (DMSO) or DMF, in the presence of sodium hydride, potassium hydride or KOH, at a temperature from the room's one to the solvent's reflux temperature, then removing the benzyl group by catalytic hydrogenation under atmospheric pressure, for example with 10% Pd/C or Pd(OH)₂/c is solvents such as methanol, ethanol, water or mixtures thereof and the protecting group Z can be removed, if desired, carrying out the same catalytic hydrogenation in an acid medium, such as HCl.

A compound of formula (IX) can be prepared, for example, according to the reaction scheme 3: Scheme 3

Compounds of formula (XXII), wherein Q is a hydroxy group or a bromine atom and n has the above mentioned meanings, are commercially available.

Compounds of formula (XXIII) can be obtained, according to step i), starting from compounds of formula (XXII), by reaction with benzyl alcohol (when Q = Br) or benzyl bromide (when Q = OH) in the presence of an hydride, such as sodium hydride, in a suitable organic solvent, such as THF, at a temperature ranging from room temperature to the solvent's reflux temperature.

Compounds of formula (XXIV) can be prepared by reacting compounds of formula (XXIII) with sodium or potassium cyanides, in DMSO or in an ethanol-water mixture, at a temperature ranging from 50 °C to the solvent's reflux temperature.

Compounds of formula (XXV) can be prepared, according to step k), by reacting compounds of formula

(XXIV) with a Grignard reactive R¹MgX, for example alkylmagnesium bromide or phenylalkylmagnesium bromide, in a suitable solvent, such as ethyl ether, THF, benzene or mixtures thereof, at a temperature ranging from 20 °C to the solvent's reflux temperature, followed by acid hydrolysis, for example with HCl or H₂SO₄, in the presence of a suitable solvent, such as ethyl ether, THF or dioxane and at a temperature ranging from room temperature to the solvent's reflux temperature.

If desired, the keto function of compounds of formula (XXV) can be protected by reaction with a suitable alcohol, such as ethylene glycol or methanol in an acid medium, such as p-toluenesulfonic acid, in a suitable solvent, such as benzene or toluene, at a temperature ranging from 25 °C to the solvent's reflux temperature.

Compounds of formula (XXVII) can be prepared starting from compounds of formula (XXVI), or, when z is oxygen, starting from compounds of formula (XXV), by catalytic hydrogenation under atmospheric pressure, for example with 10% Pd/C or Pd(OH)₂/C, in solvents such as methanol, ethanol, water or mixtures thereof.

Compounds of formula (IX), wherein n, Z and R¹ have the above mentioned meanings, can be prepared by reacting compounds of formula (XXVII), for example, with methanesulfonyl chloride, in a suitable solvent, such as dichloromethane or chloroform, at a temperature ranging from -5ºC to room temperature .

The compounds of the present invention can be used in human therapy as antitumor, antiasthmatic, antithrombotic, anti-inflammatory, anti-allergic agents as well as in the prophylaxis of anaphylactic shock. Moreover, they can be used as hypotensive or antianginal agents.

For this purpose, the compounds of the invention can be formulated according to conventional techniques and excipients, such as those described in "Remington's Pharmaceutical Science Handbook", Mack Pub. Co., New York, U.S.A. Examples of said forms include capsules, tablets, syrups and the like, containing 1 to 1000 mg of the active ingredient per unitary dose.

The following non limiting Examples further illustrate the invention. EXAMPLE 1

1-a 1-O-(6-bromohexyl)-2,3-O-isopropylideneσlycerol (III, n = 6)

A suspension of 0.188 g (6.2 mmoles) of 80% NaH in anhydrous DMF is added with a solution of 2.73 g (11.2 mmoles) of dibromohexane in DMF. A solution of 0.74 g (5.6 mmoles) of isopropylidene glycerol in DMF is dropped therein. The reaction mixture is left under stirring at room temperature for 18 hours, after that ethanol and water are added. The solution is extracted with ether, washed with a sodium chloride saturated solution, dried and solvent is evaporated off. The obtained crude product is purified by distillation under high vacuum, the excess 1, 6-dibromohexane distils at 42-44 °C/0.0 torr and 1-O-(6-bromohexyl)-2,3-O-isopropylideneglycerol distils at 70-72 °C/0.3 torr. The distillation residue is purified by flash chromatography on silica gel, eluting with dichloromethane. 0.680 g of 1-O-(6-bromohexyl)-2,3-O-isopropylideneglycerol are obtained (41% yield).

TLC: eluent dichloromethane:ethyl acetate (1:1); Rf =

0.45

IR (NaCl) cm^-1: 2960, 2900, 2840, 1430, 1360, 1240,

1200

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.25 (s, 3H) ; 1.30 (s, 3H); 1.30 (m, 4H) ; 1.50 (quintuplet, 2H) ; 1.75 (quintuplet, 2H) ; 3.25-3.45 (m, 6H) ; 3.63 (t, 1H) ; 3.96 (t, 1H); 4.17 (quintuplet, 1H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 25.43, 25.59, 26.94, 28.11, 29.53, 32.88, 34.03, 67.15, 72.18, 71.86, 75.06, 109.80. Following the same procedure, the following products are obtained:

2R-1-O-(6-bromohexyl)-2,3-O-isopropylideneglycerol, starting from R-isopropylideneglycerol, 35% yield;

[α]_D = - 7.1 (c 3.9, CHCl₃)

2S-1-O-(6-bromohexyl)-2,3-O-isopropylideneglycerol, starting from S-isopropylideneglycerol, 30% yield;

[α]_D = + 8.9 (c 1.0, CHCl₃)

1-O-(10-bromodecyl)-2,3-O-isopropylideneglycerol (III, n=10), starting from 1,10-dibromodecane and isopropylideneglycerol, 35% yield;

TLC: eluent, petroleum ether:ethyl ether (1:1), Rf =

0.5

IR (NaCl) cm^-1: 3000, 2950, 2850, 1460, 1350

¹H NMR (60 MHz, CDCl₃ ) δ ppm: 1.10-1.90 (m, 22H) ; 3.10- 4.20 (m, 9H)

1-b 1-O-(6-cyanohexyl)-2,3-O-isopropylideneglycerol

(IV, n = 6)

A solution of 1.19 g (24 mmoles) of sodium cyanide in 25 ml of DMSO is heated to 90°C and added with a solution of 6 g (20 mmoles) of 1-O-(6-bromohexyl)-2,3- O-isopropylideneglycerol in DMSO. The mixture is left at 90 °C for 1 hour, then water and ethyl ether are added, the two phases are separated and the organic phase is washed with a sodium chloride saturated solution, dried, and solvent is evaporated off to obtain 4.55 g of 1-O-(6-cyanohexyl)-2,3-O-isopropylideneglycerol (95% yield).

TLC: eluent, petroleum ether:ethyl ether (1:1), Rf = 0.43

IR (NaCl) cm^-1: 3000, 2950, 2875, 2260, 1465, 1425 ¹H-NMR (300 MHz, CDCl₃) δ ppm_: 1.30 (s, 3H) ; 1.37 (s,

3H); 1.30-1.47 (m, 4H); 1.50-1.70 (m, 4H); 2.30 (t,

2H); 3.24-3.50 (m, 4H); 3.67 (dd, 1H) ; 4.02 (dd, 1H);

4.22 (quintuplet, 1H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 17.26, 25.50, 25.54,

25.62, 26.99, 28.67, 29.45, 67.16, 72.27, 71.81, 75.12,

109.92, 120.34.

Following the same procedure, the following compounds are obtained:

2R-1-O-(6-cyanohexyl)-2,3-O-isopropylideneglycerol, 94% yield;

[α]_D = -5.5 (c 11.2, CHCl₃)

2S-1-O-(6-cyanohexyl)-2,3-O-isopropylideneglycerol, 95% yield;

[α]_D = + 5.7 (c 11.2, CDCl₃)

1-O-(10-cyanodecyl)-2,3-O-isopropylideneglycerol

(IV, n = 10), 79% yield;

TLC: eluent, petroleum ether: ethyl ether (1:1), Rf = 0.3

IR (NaCl) cm^-1: 2975, 2925, 2850, 2250, 1450, 1360

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.16-1.30 (m, 12H); 1.22 (s, 3H); 1.28 (s, 3H); 1.40 (m, 2H); 1.51 (quintuplet, 2H); 2.22 (t, 2H); 3.20-3.42 (m, 4H); 3.57 (dd, 1H); 3.90 (dd, 1H); 4.13 (quintuplet, 1H).

1-c 1-O-(6-cyanohexyl)glycerol (V, n = 6)

200 ml of a 2N HCl solution are added to a solution of 4 g (16.6 mmoles) of 1-O-(6-cyanohexyl)-2,3-O)isopropylideneglycerol in 500 ml of THF. The reaction mixture is kept at room temperature and under stirring for two hours, then it is neutralized with NaHCO₃, the two phases formed are separated and the aqueous phase is extracted with ethyl acetate. The two organic phases are combined, dried and concentrated, to obtain 2.78 g of 1-O-(6-cyanohexyl)glycerol as a colourless oil (83% yield).

TLC: eluent, dichloromethane: ethyl acetate (1:1), Rf = 0,09

IR (NaCl) cm^-1: 3450, 2975, 2900, 2300, 1475, 1440

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.15-1.35 (m, 4H) ; 1.35-1.55 (m, 4H); 2.20 (t, 2H) ; 3.30 (m, 4H) ; 3.38 (dd, 1H); 3.48 (dd, 1H) ; 3.67 (quintuplet, 1H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 17.26, 25.42, 25.53, 28.61, 29.43, 64.47, 70.91, 71.73, 72.77, 120.30.

Following the same procedure, the following compounds are obtained:

2S-1-O-(6-cyanohexyl)glycerol, 75% yield;

[α]_D = + 1.3 (c 1.2, CHCl₃)

2R-1-O-(6-cyanohexyl) glycerol, 86% yield;

[α]_D = -1.4 (c 1.2, CHCl₃)

1-O-(10-cyanodecyl)glycerol (V, n = 10), 88% yield.

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.25 (broad s, 10H) ; 1.35 (m, 2H); 1.47-1.65 (m, 4H) ; 2.30 (t, 2H) ; 3.40-3.50 (m, 4H); 3.60 (dd, 1H) ; 3.67 (dd, 1H) ; 3.82 (quintuplet, 1H).

1-d 1-O-(6-cyanohexyl)-3-O-tritylglycerol (VI, n = 6) 7.24 g (26 mmoles) of trityl chloride are added to a solution of 2.6 g (13 mmoles) of 1-O-(6-cyanohexyl)glycerol in 60 ml of pyridine. The solution is stirred at room temperature for 22 hours, then it is poured onto an ice-water mixture and extracted with ethyl ether. The organic phase is washed with 0.1N HCl to acid pH, 5% NaHCO₃ and a sodium chloride saturated aqueous solution, in this order. The reaction mixture is dried and solvent is evaporated off, to obtain a crude product which is purified by flash chromatography on silica gel, eluting with mixtures of petroleum ether:ethyl ether of increasing polarity, to obtain

3,98 g of 1-O-(6-cyanohexyl)-3-O-tritylglycerol (69% yield).

TLC: eluent petroleum ether:ethyl ether (1:1), Rf =

0.14

IR (NaCl) cm^-1: 3650, 3475, 3100, 3050, 3000, 2950,

2850, 2250, 1600, 1475, 1430

1H NMR (300 MHz, CDCl₃) δ ppm: 1.25-1.70 (m, 8H) ; 2.27

(t, 2H); 2.40 (broad s, 1H) ; 3.15 (m, 2H) ; 3.36-3.55

(m, 4H); 3.93 (quintuplet, 1H) ; 7.15-7.45 (m, 15H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 17.28, 25.49, 25.58,

28.69, 29.54, 64.94, 70.24, 71.58, 72.50, 87.07,

120.35, 127.66, 128.43, 129.25, 144.48.

Following the same procedure, the following compounds are obtained:

2R-1-O-(6-cyanohexyl)-3-O-tritylglycerol, 66% yield;

[OC]_D = + 2.9 (c 0.3, CHCl₃)

2S-1-O-(6-cyanohexyl)-3-O-tritylglycerol, 60% yield;

[α]_D = -3.3 (c 0.9, CHCl₃)

1-O-(10-cyanodecyl)-3-O-tritylglycerol (VI, n = 10), 66% yield;

IR (NaCl) cm^-1: 3500, 3100, 3060, 3040, 2950, 2850, 2250, 1590, 1385

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.22 (broad s, 10H); 1.40 (m, 2H); 1.50 (m, 2H); 1.62 (quintuplet, 2H) ; 2.27 (t, 2H); 2.42 (broad s, 1H) ; 3.15 (m, 2H) ; 3.35-3.54 (m, 4H); 3.92 (quintuplet, 1H); 7.15-7.45 (m, 15H). 1-e 1-O- ( 6-cvanohexvl ) -2-O-methyl-3-O-tritylglycerol

(VII, n = 6, R² = methyl)

A solution of 3.3 g (7.45 mmoles) of 1-O-(6-cyanohexyl)-3-O-tritylglycerol in 10 ml of benzene is added to a suspension of 1.78 g (8.94 mmoles) of 20% KH in anhydrous benzene. The reaction mixture is stirred for 30 minutes at room temperature, then it is added with 4.22 g (29 mmoles) of methyl iodide in 10 ml of benzene. The reaction mixture is stirred at room temperature for 3 hours, then a few methanol, water and ethyl ether are added. The two formed phases are separated and the aqueous phase is extracted with ethyl ether. The two ether phases are combined, dried and solvent is evaporated off, to obtain a crude product which is purified by silica gel chromatography, eluting with mixtures of petroleum ether :ethyl ether of increasing polarity, to obtain 2.83 g of 1-O-(6-cyanohexyl)-2-O-methyl-3-O-tritylglycerol (83% yield). TLC: eluent petroleum ether:ethyl ether (1:1), Rf = 0.3

IR (NaCl) cm^-1:3030, 3020, 3010, 2900, 2850, 2250, 1600, 1475

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.25-1.65 (m, 8H) ; 2.27 (t, 2H); 3.17 (m, 2H) ; 3.38 (s, 3H) ; 3.35-3.60 (m, 5H) ; 7.15-7.47 (m, 15H) ;.

¹³C NMR (75 MHz, CDCl₃) δ ppm: 17.26, 25.52, 25.56, 28.70, 29.54, 58.5, 63.16, 71.33, 71.66, 80.26, 87.04, 120.38, 127.57, 128.38, 128.53, 128.60, 129.32, 144.7. Following the same procedure, the following compounds are obtained:

2R-1-O-(6-cyanohexyl)-2-O-methyl-3-O-tritylglycerol, 84% yield;

[α]_D = +7.9 (c 4.8, CHCl₃)

2S-1-O-(6-cyanohexyl)-2-O-methyl-3-O-tritylglycerol, 40% yield;

[α]_D = -5 . 2 ( c 9.8, CHCl₃)

1-O-(10-cyanodecyl)-2-O-methyl-3-O-tritylglycerol

(VII, n = 10, R² = methyl), 91% yield;

IR (NaCl) cm^-1: 3075, 3050, 2950, 2870, 2250, 1600

¹H-NMR (300 MHz, CDCl₃ ) δ ppm: 1.24 (broad s, 10H) ; 1.40 (quintuplet, 2H) ; 1.50 (quintuplet, 2H) ; 1.60 (m, 2H); 2.30 (t, 2H) ; 3.15 (m, 2H); 3.38 (s, 3H) ; 3.35- 3.60 (m, 5H); 7.15-7.50 (m, 15H).

1-f 1-O-(7-oxooctadecyl)-2-O-methylqlycerol (XI, n = 6,

Z = oxygen, R ¹ = undecyl, R² = methyl)

0.260 g of Mg and a crystal of I₂ in anhydrous ethyl ether are placed into a 3-necked flask, then a solution of 2.060 g (8.75 mmoles) of 1-bromoundecane in ethyl ether is dropped therein. The reaction mixture is refluxed for 1 hour, after that ethyl ether is evaporated off and 10 ml of anhydrous benzene are added. A solution of 2.0 g (4.38 mmoles) of 1-O-(6-cyanohexyl)-2-O-methyl-3-O-tritylglycerol in anhydrous benzene is added. The mixture is refluxed for 6 hours and left for 3 days at room temperature, after that solvent is evaporated off and 100 ml of dioxane and 30 ml of HCl IN are added thereto. The reaction mixture is refluxed for two hours, neutralized with 5% NaHCO₃ and extracted with ethyl ether. After drying and evaporating the solvent, a crude product is obtained which is purified by flash chromatography on silica gel. By eluting with mixtures of petroleum ether:ethyl ether of increasing polarity, 0.575 g of 1-O-(7-oxooctadecyl)-2-O-methylglycerol are obtained (35% yield).

IR (NaCl) cm^-1: 3450, 2945, 1714, 1468, 1406, 1384, 1131

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H) ; 1.20 (m,

20H); 1.50 (m, 6H) ; 2.30 (t, 4H) ; 3.40 (s, 3H) ; 2.38

(broad s, 1H) ; 3.32-3.42 (m, 3H); 3.47 (m, 2H) ; 3.55

(dd, 1H); 3.69 (dd, 1H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 14.12, 22.72-31.99,

42.72, 42.88, 57.90, 62.35, 70.59, 71.81, 80.63,

212.36.

Following the same procedure, the following compounds are obtained:

2S-1-O-(7-oxooctadecyl)-2-O-methylglycerol, 35% yield; [α]_D = -7.3 (c 1.3, CHCl₃)

2R-1-O-(7-oxaoctadecyl)-2-O-methylglycerol, 8.5% yield; [α]_D = +7.5 (c 1.3, CDCl₃)

1-O-(11-phenyl-11-oxoundecyl)-2-O-methylglycerol (XI, n = 10, Z = oxygen, R¹ = phenyl, R² = methyl), 35.5% yield;

IR (NaCl) cm^-1: 3450, 3050, 2925, 2850, 1660, 1585

¹H-NMR (300 MHz, CDCl₃) δ ppm: 1.22 (m, 12H) ; 1.50 (m,

2H); 1.65 (quintuplet, 2H); 2.65 (broad s, 1H) ; 2.90 (t, 2H); 3.39 (s, 3H) ; 3.32-3.42 (m, 3H); 3.46 (m, 2H) ;

3.55 (dd, 1H); 3.68 (dd, 1H) ; 7.32-7.50 (m, 3H); 7.90

(d, 2H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 24.52-29.75, 38.82,

58.07, 62.80, 70.83, 72.19, 80.43, 128.60, 129.10, 133.47, 201.51.

1-g 1-O-(7-oxooctadecyl)-2-O-methylglycerol-3-phospho choline (I, n = 6, R¹ = undecyl, R² = methyl, R³ = hydrogen, R⁴, R⁵ and R⁶ = methyl)

0.125 g (0.3 mmoles) of 1-O-(7-oxooctadecyl)-2-O- methylglycerol dissolved in ethyl ether is added to a suspension of 0.134 g (0.55 mmoles) of 2- bromoethyldichlorophosphate and 0.15 ml (1.098 mmoles) of Et₃N in anhydrous ethyl ether, at 0ºC. The reaction mixture is stirred at room temperature for 24 hours, after that 0.54 ml of a 0.1M KCl solution are added and stirring is continued at room temperature for 1.15 hours. The reaction mixture is extracted with ethyl ether, dried and solvent is evaporated off to obtain 0.150 g of 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-(2-bromoethyl)phosphate (quantitative yield).

1H NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H) ; 1.20 (m, 20H) ; 1.50 (m, 6H) ; 2.35 (broad, 4H) ; 3.41 (s, 3H) ; 3.35-3.57 (m, 7H) ; 4.00-4.40 (m, 4H).

0.135 g (0.24 mmoles) of the above bromoethyl phosphate are dissolved in 5 ml of anhydrous CDCl₃. in a closed reactor. The reaction mixture is cooled with outer bath of dry ice-acetone and 1 ml of trimethylamine is added, the reactor is closed and heated to 65 ºC for 18 hours. The solution is evaporated to dryness, to obtain a crude product which is purified by silica gel chromatography. Eluting with a chloroform:methanol 65:25 mixture and subsequently with a chloroform:methanol:water 65:25:4 mixture, 0.730 g of 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphocholine are obtained (45% yield).

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H) ; 1.20 (broad s, 20H) ; 1.50 (quintuplet, 6H); 2.34 (broad, 4H); 3.31 (s, 9H); 3.37 (s, 3H); 3.30-3.50 (m, 5H);

3.75 (m, 2H); 3.77-3.92 (m, 2H); 4.25 (m, 2H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 14.27, 22.84-32.09,

42.89, 43.12, 54.59, 58.04, 59.50, 65.02, 66.60, 70.60, 71.86, 80.06, 212.54.

Elementary analysis: Calculated for C ₂₇H₆₆NO₁₂P: C,

51.66; H, 10.59; N, 2.23. Found: C, 51.64; H, 10.38; N,

2.41.

Following the same procedure, the following compounds are obtained:

2-O-methyl-1-O-(7-oxooctadecyl)-sn-glycero-3-phosphocholine, 36% yield;

[α]_D = +1.1 (c 2.4, CHCl₃)

2-O-methyl-3-O-(7-oxooctadecyl)-sn-glycero-1-phosphocholine, 56% yield;

[α]_D = 0.9 (c 0.3, CHCl₃)

1-O-(11-phenyl-11-oxoundecyl)-2-O-methylglycero-3-phosphocholine (I, n = 10, R¹ = phenyl, R² = methyl, R³ = hydrogen, R⁴, R⁵ and R⁶ = methyl), 5% yield;

1H NMR (300 MHz, CDCl₃) δ ppm: 1.20 (m, 12H); 1.50 (m,

2H); 1.67 (m, 2H); 2.90 (t, 2H); 3.25 (s, 9H); 3.38 (s,

3H); 3.30-3.50 (m, 5H); 3.67 (m, 2H); 3.72-3.92 (m,

2H); 4.23 (m, 2H); 7.35-7.55 (m, 3H); 7.90 (d, 2H).

¹³C NMR (75 MHz, CDCl₃) δ ppm : 25.79-30.95, 39.72, 54.99, 58.55, 60.68, 66.50, 67.82, 71.40, 73.06, 81.25,

129.40, 130.00, 134.40, 203.00.

Elementary analysis: Calculated for C₂₆H₅₂NO₁₀P : C,

54.77; H, 9.20; N, 2.45. Found: C, 54.18; H, 9.04; N,

2.59.

EXAMPLE 2

2-a 1-Benzyloxy-6-bromohexane (XXIII, n = 6 A solution of 25 g (100 mmoles) of 1,6- dibromohexane in THF is added to a 80% NaH suspension in anhydrous THF. The reaction mixture is refluxed and 4.32 g (40 mmoles) of benzyl alcohol dissolved in THF are dropped therein. At the end of the addition, reflux is continued for 1 hour, after that the solution is poured into an ice-water mixture and extracted with ethyl ether. The ether phase is washed with a sodium chloride saturated solution, dried and concentrated. The resulting crude product is purified by distillation under high vacuum, 1-benzyloxy-6-bromohexane distilling at 86°C/l torr, to obtain 4.5 g (35% yield).

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.42 (m, 4H) ; 1.62 (quintuplet, 2H) ; 1.85 (quintuplet, 2H) ; 3.37 (t, 2H) ; 3.45 (t, 2H) ; 4.50 (s, 2H) ; 7.35 (m, 5H).

2-b 1-Benzyloxy-3-bromopropane (XXIII, n = 3)

A solution of 4.78 g (28 mmoles) of benzyl bromide in THF and a tip of tetrabutylammonium iodide is added to a suspension of 0.474 g (15.4 mmoles) of 80% NaH in anhydrous THF. Temperature is kept at 30°C and 2 g (14 mmoles) of 3-bromopropanol are added. At the end of the addition, temperature is kept at 30 ºC for 4 hours, after that a few methanol and water are added and the reaction mixture is extracted with ethyl ether, dried and solvent is evaporated off. The resulting crude product is purified by distillation under high vacuum: 1-benzyloxy-3-bromopropane distils at 80°C/1, to obtain 1.34 g (42% yield).

¹H NMR (300 MHz, CDCl₃) δ ppm: 2.10 (m, 2H) ; 3.47 and 3.55 (2 m, 4H); 4.50 (s, 2H) ; 7.30 (m, 5H). Following the same procedure, the following compound is obtained:

1-benzyloxy-11-bromoundecane (XXIII, n = 11), 40% yield.

2-c 7-Benzyloxyheptanonitrile (XXIV, n = 6)

A solution of 0.576 g (11.7 mmoles) of sodium cyanide in DMSO is heated to 90°C and added with a solution of 3 g (11.7 mmoles) of 1-benzyloxy-6-bromohexane in DMSO. The reaction mixture is left at 90°C for 16 hours, then water and ethyl ether are added, the two phases are separated and the organic phase is washed with a NaCl saturated solution, dried and solvent is evaporated off to obtain 2.053 g of 7-benzyloxyheptanonitrile (87% yield).

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.40 (m, 4H) ; 1.57 (m,

4H); 2.20 (t, 2H) ; 3.40 (t, 2H) ; 4.45 (s, 2H) ; 7.30 (m,

5H).

Following the same procedure, the following compounds are obtained:

4-benzyloxybutanonitrile (XXIV, n = 3), 66% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.91 (quintuplet, 2H) ;

2.46 (t, 2H); 3.55 (t, 2H) ; 4.49 (s, 2H); 7.20-7.35 (m,

5H).

12-benzyloxydodecanonitrile (XXIV, n = 11), 70% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 1.20-1.40 (m, 14H ) ; 1.57

(m, 4H); 2.25 (t, 2H) ; 3.42 (t, 2H) ; 4.45 (s, 2H) ;

7.20-7.35 (m, 5H).

2-d 1-Benzyloxy-7-octadecanone (XXV, n = 6, R¹ = undecyl)

0.320 g (13.3 mmoles) of Mg and a iodine crystal in anhydrous ethyl ether are placed into a flask. A solution of 2.7 g (11.5 mmoles) of bromoundecane in ethyl ether is dropped therein. The mixture is refluxed for 1 hour, after that a hot solution of 1 g (4.6 mmoles) of 7-benzyloxyheptanonitrile in anhydrous benzene is added. The reaction mixture is refluxed for 6 hours, after that a 10% H₂SO₄ cold solution is added, keeping reflux for 1 hour. The two phases are separated and the organic phase is washed with a 5% NaHCO₃ solution, dried and solvent is evaporated off, to obtain a crude product which is purified by silica gel flash chromatography. Eluting with mixtures of petroleum ether: ethyl ether of increasing polarity, 0.716 g of 1-benzyloxy-7-octadecanone are obtained (41.5% yield).

IR (NaCl) cm^-1: 3000, 2900, 1707, 1460, 1410, 1260

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H) ; 1.20 (m,

20H); 1.50 (m, 6H); 2.25 (t, 4H); 3.37 (t, 2H) ; 4.40 (s, 2H); 7.20 (m, 5H).

Following the same procedure, the following compounds are obtained:

1-benzyloxy-4-octadecanone (XXV, n = 3, R¹ tetradecyl), 24% yield;

Melting point: 36-37°C

IR (NaCl) cm^-1: 3000, 2950, 2850, 1714, 1450, 1360

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.84 (t, 3H) ; 1.20

(broad s, 22H); 1.50 (quintuplet, 2H) ; 1.85

(quintuplet, 1H) ; 2.35 (t, 2H) ; 2.48 (t, 2H) ; 3.44 (t,

2H) ; 4.45 (s, 2H) ; 7.22-7.37 (m, 5H).

18-benzyloxy-7-octadecanone (XXV, n = 11, R¹ = hexyl), 45% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H) ; 1.30 (broad s, 20H); 1.55 (m, 6H); 2.35 (t, 4H); 3.42 (t, 2H); 4.45 (s, 2H); 7.20-7.32 (m, 5H).

2-e 1-Benzyloxy-7-ethylenedioxyoctadecane (XXVI, n = 6, Z = ethylenedioxy, R¹ = undecyl)

A mixture of 2.7 g (7.22 mmoles) of 1-benzyloxy-7-octadecanone, 15.2 g (245 mmoles) of ethylene glycol and 1.82 g (9.6 mmoles) of p-toluenesulfonic acid in 120 ml of anhydrous benzene is refluxed for 24 hours in a Dean-Stark apparatus. At the end of this time, the reaction mixture is washed first with a 10% NaOH solution, then with water, it is dried and solvent is evaporated off, to obtain 2.51 g of 1-benzyloxy-7-ethylenedioxyoctadecane in form of an oil (83% yield). -H NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.30 (m, 18H); 1.55 (m, 6H); 3.42 (t, 2H); 3.90 (s, 4H); 4.47 (s, 2H); 7.20-7.35 (m, 5H).

Following the same procedure, the following compound is obtained:

l-benzyloxy-4-ethylenedioxyoctadecane (XXVI, n = 3, Z = ethylenedioxy, R¹ = tetradecyl), 92% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.90 (t, 3H); 1.30 (broad s, 24H); 1.60 (m, 2H); 1.70 (s, 4H); 3.47 (m, 2H); 3.92 (s, 4H); 4.50 (s, 2H); 7.25-7.35 (m, 5H).

2-f 7-Ethylenedioxy-1-octadecanol (XXVII, n = 6, Z = ethylenedioxy, R¹ = undecyl)

0.81 g of 20% Pd(OH)₂/c are added to a solution of 1.25 g (3 mmoles) of 1-benzyloxy-7-ethylenedioxyoctadecane in 81 ml of a methanol:water 9:1 mixture, and the reaction mixture is left under stirring and hydrogen atmosphere at room temperature for 16 hours. The reaction mixture is filtered and evaporated to dryness, to obtain 0.950 g of 7-ethylenedioxy-1- octadecanol (97% yield).

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.75 (t, 3H) ; 1.15-1.25 (m, 24H); 1.50 (m, 6H) ; 2.52 (broad s, 1H); 3.50 (t, 2H); 3.80 (s, 4H).

Following the same procedure, the following compounds are obtained:

4-ethylenedioxy-1-octadecanol (XXVII, n = 3, Z ethylenedioxy, R¹ = tetradecyl), 86% yield;

Melting point: 39-41°C

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H) ; 1.20 (broad s, 24H) ; 1.52-1.75 (m, 6H) ; 1.87 (broad s, 1H) ; 3.60 (t, 2H); 3.91 (s, 4H).

18-hydroxy-7-octadecanone (XXVII, n = 11 , Z = oxygen, R¹ = hexyl) starting from XXV (n, 11, R¹ = hexyl), 80% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H) ; 1.25 (broad s, 20H) ; 1.55 (s, 6H) ; 2.35 (t, 4H) ; 3.60 (t, 2H).

2-g 7-Ethylenedioxyoctadecyl methanesulfonate (IX, n = 6, Z = ethylenedioxy, R¹ = undecyl)

1.45 ml (10.74 mmoles) of Et₃N are added to a solution of 1.85 g (5.37 mmoles) of 7-ethylenedioxy-1-octadecanol in anhydrous dichloromethane. The reaction mixture is cooled to 0°C and 1.23 g (10.74 mmoles) of methanesulfonyl chloride are added. At the end of the addition, the reaction mixture is maintained at 0°C for 4 hours, after that it is washed with water, dried and solvent is evaporated off. The obtained crude product is purified by silica gel chromatography. Eluting with mixtures of petroleum ether:ethyl ether of increasing polarity, 1.79 g of 7-ethylenedioxyoctadecyl methanesulfonate are obtained (79% yield).

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H) ; 1.15-1.40 (m, 24H); 1.52 (m, 4H) ; 1.72 (quintuplet, 2H) ; 2.95 (s, 3H); 3.87 (s, 4H) ; 4.18 (t, 2H) .

Following the same procedure, the following compounds are obtained:

4-ethylenedioxyoctadecyl methanesulfonate (IX, n - 3, Z - ethylenedioxy, R¹ = tetradecyl), 60% yield;

Melting point: 52-55ºC

¹H NMR (300 MHz, CDCl₃) & ppm: 0.84 (t, 3H) ; 1.20 (broad s, 24H) ; 1.55 (m, 2H) ; 1.70 (m, 2H) ; 1.80 (m, 2H); 2.95 (s, 3H) ; 3.90 (s, 4H) ; 4.22 (t, 2H).

12-oxooctadecyl methanesulfonate (IX, n = 11, Z oxygen, R¹ = hexyl) starting from XXVII (n, 11, Z = oxygen, R¹ = hexyl), 87% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H) ; 1.15-1.35 (m, 14H); 1.48 (m, 4H) ; 1.67 (quintuplet, 2H) ; 2.32 (t, 4H); 2.92 (s, 3H) ; 4.15 (t, 2H).

EXAMPLE 3

3-a 1-O-(4-ethylenedioxyoctadecyl)-2-O-methyl-3-O-benzylqlycerol (X, n = 3, Z ethylenedioxy, R¹ tetradecyl, R² = methyl)

A solution of 0.580 g (2.9 mmoles) of 3-O-benzyl-2-O-methylglycerol in toluene is added to a suspension of 0.684 g (12.2 mmoles) of powder KOH in 24 ml of anhydrous toluene. The reaction mixture is refluxed for 1 hour in a Dean-Stark apparatus. After that, 1 g (2.4 mmoles) of 4-ethylenedioxyoctadecyl methanesulfonate dissolved in 16 ml of toluene is added. Reflux in the Dean-Stark apparatus is maintained for 5 hours, then toluene is evaporated off, some water is added and the mixture is extracted with ethyl ether. The ether phase is washed with water to neutral pH. The organic phase is dried and evaporated, to obtain a crude product which is purified by silica gel chromatography. Eluting with mixtures of petroleum ether: ethyl ether of increasing polarity, 0.569 g of 1-O-(4- ethylenedioxyoctadecyl)-2-O-methyl-3-O-benzylglycerol are obtained (46% yield).

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H) ; 1.20 (broad s, 24H) ; 1.50-1.62 (m, 6H) ; 3.40 (s, 3H) ; 3.35- 3.57 (m, 7H); 3.90 (s, 4H) ; 4.52 (s, 2H) ; 7.20-7.35 (m, 5H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 14.31, 22.90-30.18, 32.16, 33.70, 37.53, 58.37, 65.28, 70.16, 70.70, 72.04, 73.81, 79.78, 112.19, 128.17, 128.22, 128.94, 138.88. Following the same procedure, the following compounds are obtained:

1-O-(7-ethylenedioxyoctadecyl)-2-O-methyl-3-O-benzylglycerol (X, n = 6, Z = ethylenedioxy, R¹ = undecyl, R² = methyl), 30% yield;

¹H NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H) ; 1.20-1.35 (m, 24H); 1.52 (m, 6H) ; 3.40 (s, 3H) ; 3.35-3.55 (m, 7H); 3.87 (s, 4H) ; 4.50 (s, 2H) ; 7.20-7.35 (m, 5H).

1-O-(12-oxooctadecyl)-2-O-methyl-3-O-benzylglycerol (X, n = 11, Z = oxygen, R¹ = hexyl, R² = methyl) starting from IX (n = 11, Z = oxygen, R¹ = hexyl), 31% yield;

1H NMR (300 MHz, CDCl₃)δ ppm: 0.85 (t, 3H) ; 1.22 (m, 20H); 1.65 (m, 6H) ; 2.35 (t, 4H) ; 3.43 (s, 3H); 3.35-3.57 (m, 7H) ; 4.50 (s, 2H) ; 7.30 (m, 5H).

¹³C NMR (75 MHz, CDCl₃) δ ppm : 14.21, 22.70-31.84, 43.08, 58.32, 70.15, 70.68, 72.09, 73.79, 79.78, 128.15, 128.22, 128.92, 138.89, 212.65.

3-b 1-O-(4-oxooctadecyl)-2-O-methylglycerol (XI, n = 3,

Z = oxygen, R¹ = tetradecyl, R² = methyl)

0.3 ml of HCl (35%) and 0.345 g of 20% Pd(OH)₂/C are added to a solution of 0.648 g (1.28 mmoles) of 1- O-(4-ethylenedioxyoctadecyl)-2-O-methyl-3-O-benzylglycerol in 34 ml of a methanol :water 9:1 mixture. The reaction mixture is left under stirring and hydrogen atmosphere at room temperature for 15 hours, then it is filtered and evaporated to dryness, to obtain 0.425 g of 1-O-(4-oxooctadecyl)-2-O-methylglycerol (89% yield). ¹H NMR (300 MHz, CDCl₃) δ ppm: 0.82 (t, 3H); 1.20 (broad s, 22H); 1.50 (quintuplet, 2H); 1.79 (quintuplet, 2H); 2.34 (t, 2H); 2.42 (t, 2H); 3.40 (s, 3H); 3.30-3.42 (m, 3H); 3.45 (m, 2H); 3.57 (dd, 1H); 3.68 (dd, 1H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 14.28, 22.88, 23.86, 24.06, 29.46-32.14, 39.38, 43.19, 58.10, 62.65, 70.60, 71.09, 80.36, 212.05.

Following the same procedure, the following product is obtained:

1-O-(7-oxooctadecyl)-2-O-methylglycerol (XI, n = 6, Z = oxygen, R¹ = undecyl, R² = methyl), 90% yield, compound which is described in example 1-f.

Following the same procedure, except for the acid medium, the following compounds are obtained:

1-O-(12-oxooctadecyl)-2-O-methylglycerol (XI, n = 11, Z = oxygen, R¹ = hexyl, R² = methyl), 85% yield;

1H-NMR (300 MHz, CDCl₃) δ _ppm: 0.80 (t, 3H); 1.15 (broad s, 20H); 1.47 (m, 6H); 2.30 (t, 4H); 2.50 (broad s, 1H); 3.35 (s, 3H) ; 3.30-3.38 (m, 3H) ; 3.44 (m, 2H) ; 3.55 (dd, 1H); 3.66 (dd, 1H).

¹³C NMR (75 MHz, CDCl₃) δ _ppm: 14.16, 22.65-31.80, 43.02, 58.04, 62.80, 70.86, 72.20, 80.36, 212.68.

1-O-(7-ethylenedioxyoctadecyl)-2-O-methylglycerol (XI, n = 6, Z = ethylenedioxy, R¹ = undecyl, R² = methyl), 85% yield;

¹H-NMR (300 MHz, CDCl₃) δ pPm: 0.82 (t, 3H) ; 1.20-1.35 (m, 24H); 1.52 (m, 6H) ; 3.42 (s, 3H) ; 3.35-3.42 (m, 3H); 3.47 (m, 2H) ; 3.59 (dd, 1H) ; 3.71 (dd, 1H) ; 3.90 (s, 4H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 14.29, 22.88-32.14, 37.30, 37.40, 58.10, 62.95, 65.23, 70.94, 72.22, 80.25, 112.36.

3-c 1-O-(4-oxooctadecyl)-2-O-methylglycero-3-phosphocholine

(I, n = 3, R¹ = tetradecyl, R² = methyl, R³ = hydrogen, R⁴, R⁵ and R⁶ = methyl)

0.382 g (1.02 mmoles) of 1-O-(4-oxooctadecyl)-2-O-methylglycerol dissolved in ethyl ether are added to a suspension of 0.457 g (1.89 mmoles) of 2-bromoethyl dichlorophosphate and 0.53 ml (3.75 mmoles) of Et₃N in anhydrous ethyl ether, at 0°C. The reaction mixture is left under stirring at room temperature for 24 hours, after that 1,84 ml of a 0.1M KCl solution are added and the mixture is left under stirring at room temperature for two hours. The reaction mixture is extracted with ethyl ether, dried and solvent is evaporated off, to obtain 0.471 g of 1-O-(4-oxooctadecyl)-2-O-methylglycero-3-(2-bromoethyl)phosphate (quantitative yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H); 1.20 (broad s. 22H); 1.45 (m, 2H); 1.75. (quintuplet, 2H); 2.31 (t, 2H); 2.39 (t, 2H); 3.40 (s, 3H); 3.30-3.52 (m, 7H); 3.95-4.12 (m, 2H); 4.20 (m, 2H); 9.60 (broad s, 1H).

0.471 g (0.84 mmole) of the above bromophosphate dissolved in 20 ml of anhydrous CDCl₃ are placed into a closed reactor, which is cooled with a dry ice-acetone outer bath. 1.1 ml of trimethylamine are added, the reactor is closed and heated to 65 °C for 24 hours. The reaction mixture is evaporated to dryness, to obtain a crude product which is purified by silica gel chromatography. Eluting with a chloroform:methanol 95:5 mixture, increasing polarity to a chloroform:methanol 65:25 mixture, then with a chloroform:methanol: water 65:25:1 mixture, increasing polarity to a chloroform:methanol:water 65:35:4 final mixture, 0.295 g of 1-O-(4-oxooctadecyl)-2-O-methylglycero-3-phosphocholine are obtained (54% yield).

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H); 1.10-1.25 (m, 22H); 1.43 (m, 2H); 1.72 (quintuplet, 2H); 2.29 (t, 2H); 2.35 (t, 2H); 3.32 (s, 9H); 3.36 (s, 3H); 3.25- 3.47 (m, 5H); 3.75 (m, 4H); 4.21 (m, 2H).

1³C NMR (75 MHz, CDCl₃) δ ppm: 14.25, 22.83-32.1, 39.34, 43.12, 54.50, 58.05, 59.55, 64.78, 66.51, 70.60, 70.92, 79.98, 211.91.

Elementary analysis: calculated for C₂₇H₆3NO_10·5P : C, 53.98; H, 10.57; N, 2.33. Found: C, 54.17; H, 10.52; N, 2.34.

Following the same procedure, the following compound is obtained: 1-O-(12-oxooctadecyl)-2-O-methylglycero-3- phosphocholine (I, n = 11, R¹ = hexyl, R² = methyl, R³ = hydrogen, R⁴, R⁵ and R⁶ = methyl), 25% yield;

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H) ; 1.17 (m, 20H); 1.47 (m, 6H) ; 2.30 (t, 4H) ; 3.34 (s, 9H) ; 3.35 (s, 3H); 3.27-3.47 (m, 5H) ; 3.70-3.90 (m, 4H) ; 4.25 (m, 2H).

¹³C NMR (75 MHz, CDCl₃) δ ppm: 14.07, 22.52-31.67, 43.06, 54.59, 57.99, 59.70, 65.52, 66.45, 70.06 72.01, 19 . 10 , 213.0.

Elementary analysis: calculated for C₂₇H₆₂NO_10·P : C, 54.82; H, 10.49; N, 2.36. Found: C, 54.63; H, 10.44; N, 2.58.

EXAMPLE 4

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphoserine (I, n = 6, R¹ = undecyl, R² = methyl, R³ = carboxyl, R⁴, R⁵ and R⁶ = hydrogen)

0.150 g (0.36 mmole) of 1-O-(7-ethylenedioxyoctadecyl)-2-O-methylglycerol dissolved in anhydrous acetonitrile is added to a suspension of 0.350 g (5.14 mmoles) of imidazole, 0.135 ml (1.54 mmoles) of PCl₃

0.756 ml (5.43 mmoles) of Et₃N and anhydrous acetonitrile, at 0°C and under inert atmosphere. The reaction mixture is stirred for 4 hours at room temperature; 4 ml of water are added and stirring is continued at room temperature for 45 minutes. The reaction mixture is evaporated to dryness and redissolved in 11 ml of a pyridine:triethylamine 4:1 mixture, evaporated to dryness, dissolved in CHCl₃ and the organic phase is washed with water, dried and solvent is evaporated off to obtain the phosphonate triethylammonium salt corresponding to the starting alcohol (quantitative yield).

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.80 (t, 3H) ; 1.20 (m, 24H); 1.30 (t, 9H); 1.50 (m, 6H) ; 3.20 (q, 6H); 3.30 (s, 3H); 3.25-3.45 (m, 5H); 3.85 (s, 4H) ; 3.75-3.90 (m, 2H); 6.63 (d, 1H).

Following the same procedure, the triethylammonium salt corresponding to 1-O-(12-oxooctadecyl)-2-O-methylglycerol phosphonate is obtained:

¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.65 (t, 3H) ; 0.95-1.15 (m, 33H); 1.35 (m, 6H) ; 2.15 (t, 4H) ; 2.85 (q. 6H) ; 3.20 (s, 3H); 3.10-3.40 (m, 5H) ; 3.75-4.00 (m, 2H) ; 6.62 (d, 1H).

0.061 ml (0.5 mmole) of pivaloyl chloride is added to a mixture of 0.120 g (0.25 mmole) of 1-O-(7-ethylenedioxyoctadecyl)-2-O-methylglycerol phosphonate, 0.132 g (0.4 mmole) of N-benzyloxycarbonylserine benzyl ester and 3.5 ml of pyridine. The reaction mixture is stirred for 1.5 hours at room temperature, 0.2 ml of water and 0.127 g (0.5 mmole) of iodine are added. The mixture is stirred at room temperature for 25 minutes; then it is added with CDCl₃, washed with sodium metabisulfite, dried and solvent is evaporated off, to obtain a crude product which is purified by flash chromatography on a silica gel column. Eluting with petroleum ether:chloroform mixtures of increasing polarity and then with chloroform:methanol mixtures of increasing polarity, 0.035 g of 1-O-(7-ethylenedioxyoctadecyl)-2-O-methylglycerol-3-phosphobenzyl(N-ca(bobenzyloxy)serine are obtained (18% yield). ¹H-NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.10-1.35 (m, 24H); 1.40-1.60 (m, 6H); 3.30 (s, 3H); 3.25-3.42 (m, 5H); 3.86 (s, 4H); 3.85-4.00 (m, 2H); 4.1-5-4.35 (m, 2H); 4.55 (m, 1H); 4.70-5.20 (m, 4H); 7.15-7.30 (m, 10H).

Following the same procedure, the following compound is obtained:

1-O-(12-oxooctadecyl)-2-O-methylglycerol-3- phosphobenzyl(N-carbobenzyloxy)serine, 1% yield;

1H-NMR (300 MHz, CDCl₃) δ ppm: 0.85 (t, 3H); 1.20 (broad s, 24H); 1.52 (m, 6H); 2.35 (t, 4H); 3.40 (s, 3H); 3.30-3.55 (m, 5H); 3.92-4.17 (m, 2H); 4.30 (m, 1H); 4.44 (m, 1H); 4.58 (m, 1H); 5.05-5.22 (m, 4H); 7.20-7.35 (m, 10H).

0.035 g (0.045 mmole) of 1-O-(7- ethylenedioxyoctadecyl)-2-O-methylglycerol-3-phosphobenzyl(N-carbobenzyloxy) serine are dissolved in 7.5 ml of a methanol :water 9:1 mixture, 0.2 ml of HCl (35%) and 0.005 g of 20% Pd(OH)₂/C are added. The reaction mixture is left under stirring and hydrogen atmosphere at room temperature for 16 hours, then it is filtered, evaporated to dryness and purified by preparative chromatography (silica gel, fluorescence developer), extracted with a chloroform:methanol 1:1 mixture. 0.005 g of 1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphoserine is obtained (20% yield). TLC: eluent chloroform:methanol:water (65:25:4), Rf = 0.09

According to the same procedure, except for the acid medium, the following product is obtained:

1-O-(12-oxooctadecyl)-2-O-methylglycerol-3-phosphose- rine

(I, n = 11, R¹ = hexyl, R² = methyl, R³ = carboxyl, R⁴, R⁵ and R⁶ = hydrogen), 57% yield;

TLC: eluent chloroform:methanol:water (65:25:4), Rf = 0.11.

EXAMPLE 5

Evaluation of cytotoxic activity

Suspensions of HL-60 line cells, obtained starting from human promyelocyte leukemia, are incubated in 6- well culture plates for 24 hours at 37°C, at a concentration of 1 × 10⁶ cells/ml, in the presence of the test products, which have previously been dissolved in the culture medium. Cytotoxicity is measured by means of the Trypan Blue exclusion technique (Practical Immunology, pp 29-32, Oxford, England : Blackwell Scientific Publications, 1976). Cytotoxic activities of the products, expressed as IC₅₀, are reported in Tables IA and IB.

EXAMPLE 6

Evaluation of the anti-platelet action

Platelets are prepared starting from blood samples obtained by means of a carotid cannula from male albino New Zealand rabbits (2-2.5 kg), subjected to anticoagulant treatment with sodium citrate dihydrate (3.2%) 1:10. Blood is centrifuged (150xg, 10 min, 22°C) to separate the platelet-rich plasma fraction (PRP) from erythrocytes. Platelets are separated from plasmatic components by serial washings and centrifugations (Blood, 1986, 62:337), thereafter they are suspended in a physiological buffer at a concentration of 5 × 10⁵/ml. A 400 μl volume of the above mentioned suspension is placed into the cuvette of a multicanal aggregometer (Aggrecoder HU) where it is kept at constant temperature and stirring. After stabilization, platelets are added with 50 μl of physiological buffer containing 100 μM acetylsalicylic acid and apirase 5 mg/ml, in order to block any non PAF-related platelet activation metabolic pathways. Subsequently the platelet suspensions are added with 50 μl of the different solutions to be tested. Changes in light transmission, due to platelet aggregation in the suspension, are recorded and expressed as percent platelet aggregation, according to the procedure by Born and Cross (J. Physiol., 1962, 162:67). Standard curve is performed with PAF within a concentration range of 0.1-1 nM.

The results from the tests in which PAF activity was measured are reported in Tables IIA, IIB.

EXAMPLE 7

Inhibition of PAF-induced platelet aggregation

Capability to inhibit PAF-induced platelet aggregation is evaluated by means of the aggregometry technique in suspensions of rabbit washed platelets, obtained by means of the same procedure as described in Example 6. For this purpose, the inhibition potency of the products under test, expressed as the corresponding IC₅₀, is evaluated on the maximum aggregation values obtained in PAF standard curve. The results obtained from the tests, in which PAF-antagonist activity was measured, are reported in Tables IIA, IIB.

Claims

1. Compounds of general formula (I)

wherein R¹ is a C₁-C₁₆ straight or branched alkyl group, a phenyl group or a phenyl-C₆-C₁₆alkyl group; n is an integer from 3 to 18, inclusive;

R² is a C₁-C₁₂ straight or branched alkyl group;

R⁴, R⁵ and R⁶, which can be the same or different, are hydrogen, a C₁-C₆ alkyl group or N⁺R⁴R⁵R⁶ is a cyclic ammonium group, which can be aromatic or non-aromatic, wherein two of the R⁴, R⁵ or R⁶ groups form a ring together with the nitrogen atom, and the other group is hydrogen or C₁-C₆ alkyl,

and the salts, enantiomers and diastereomers thereof.

2. Compounds as claimed in claim 1, wherein R² is a C₁- C₃ alkyl group.

3. Compounds as claimed in claim 1, wherein R⁴, R⁵ and

R⁶ are hydrogen, methyl or ethyl.

4. Compounds as claimed in claim 1, wherein, when R³ is hydrogen, N⁺R⁴R⁵R⁶ is a cyclic aromatic ammonium group as claimed in claim 1.

5. Compounds as claimed in claim 4, wherein the cyclic aromatic group is 1-pyridinium, 1-imidazolium or 3- thiazolium.

6. Compounds as claimed in claim 1, wherein, when R³ is hydrogen, N⁺R⁴R⁵R⁶ is a cyclic non-aromatic ammonium group as claimed in claim 1.

7. Compounds as claimed in claim 6, wherein the cyclic ammonium group is 1-pyrrolidinium, 1-piperidinium or 4- morpholinium.

8. Compounds as claimed in claim 1, wherein R³ is a carboxy, aryloxycarbonyl, alkoxycarbonyl or arylakoxycarbonyl group, the latter two groups having less than 12 carbon atoms.

9. Compounds as claimed in any one of claims 1-8, selected from:

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho(N,N,N-trimethyl)serine

2-O-methyl-3-O-(7-oxooctadecyl)-sn-glycero-1-phospho-choline

2-O-methyl-1-O-(7-oxooctadecyl)-sn-glycero-3-phospho-choline

1-O-(7-oxooctadecyl)-2-O-ethylglycero-3-phosphocholine

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(3-thiazolium)ethyl]

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(1- imidazolium)ethyl]

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phospho[2-(N-methylpiperidinium)ethyl]

1-O-(12-oxooctadecyl)-2-O-methylglycero-3-phospho-choline

1-O-(12-oxooctadecyl)-2-O-methylglycero-3-phosphoserine 1-O-(11-phenyl-11-oxoundecyl)-2-O-methylglycero-3-phosphocholine

1-O-(14-phenyl-11-oxotetradecyl)-2-O-methylglycero-3-phosphocholine

1-O-(14-phenyl-11-oxotetradecyl)-2-O-methylglycero-3-phosphoserine.

10. As a compound as claimed in claim 9,

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphocholine in form of the R(+) enantiomer.

11. As a compound as claimed in claim 9,

1-O-(7-oxooctadecyl)-2-O-methylglycero-3-phosphocholine in form of the S(-) enantiomer.

12. A process for the preparation of the compounds claimed in claim 1, in which process:

a compound of formula (XI)

wherein Z is oxygen and n, R¹ and R² have the above mentioned meanings, is reacted with a compound of formula (XII)

wherein X and Y, which can be the same or different, are halogens, in the presence of an amine, in an inert organic solvent, at a temperature from 0° to 40 °C, to give a compound of formula (XIII)

wherein n , R¹, R², X and Y have the above mentioned meanings, which is subjected to aqueous hydrolysis in a saline solution, to give the compound of formula (XIV)

wherein R¹ , R² and Y have thhee aatbove mentioned meanings, which compound (XIV) is reacted with a compound of formula (XV)

NR⁴R⁵R⁶

XV

wherein R⁴, R⁵ and R⁶ have the above mentioned meanings, in a suitable organic solvent, at a temperature from 40ºC to the reflux one, to give a compound of formula I, wherein n, R¹, R² , R⁴ , R⁵ and R⁶ have the above mentioned meanings and R³ is hydrogen.

13. A process for the preparation of the compounds claimed in claim 1, in which process:

compound (XI), wherein X is oxygen and n, R¹ and R² have the above mentioned meanings, is reacted with a compound of formula (XVI)

wherein X is halogen (such as Cl, Br, I) in a suitable organic solvent, in the presence of an amine, at a temperature from 0º to 40°C, to give a compound of formula (XVII)

wherein R¹ and R² have the above mentioneα meanings, which compound (XVII) is treated with a compound of formula (XV), in suitable organic solvents, at a temperature from 40 °C to the reflux one, to give a compound of formula (I) wherein n, R¹, R², R⁴, R⁵ and

R⁶ have the above mentioned meanings and R³ is hydrogen.

14. A process for the preparation of the compounds claimed in claim 1, in which process:

a compound of formula (XI), wherein Z is oxygen or a suitable keto-protecting group, and n, R¹ and R² have the above mentioned meanings, is reacted with PCI, in the presence of a slightly nucleophilic base, such as imidazol, and an acid-binding agent, in suitable organic solvents, at a temperature from 0° to 40 °C, to give a compound of formula (XVIII)

wherein R¹ and R² have the above mentioned meanings and A can be hydrogen or a triethylammonium group, which compound (XVIII) is reacted with a compound of formula (XIX)

wherein R⁷ is an amino-protecting group, such as benzyloxycarbonyl or t-butyloxycarbonyl, and R³ can be an alkoxycarbonyl group having less than 12 carbon atoms, or it can be a carboxy group protected in form of the benzyl or t-butyl esters, in the presence of a base such as pyridine and of a condensing agent, such as pivaloyl chloride or 5,5-dimethyl-2-oxo-2-chloro-1,3,2-dioxaphospholane, at a temperature from 0º to 40ºC, to give a compound of formula (XX)

wherein n, Z, R¹, R², R³ and R⁷ have the above mentioned meanings, which is oxidized with an oxidizing agent, such as iodine, to give a compound of formula

wherein n, Z, R¹, R², R³ and R⁷ have the above mentioned meanings, which compound is converted into a compound of formula (I) by removing the protecting groups R⁷ and Y, if necessary, when R³ is a carboxy group protected in form of a benzyl or t-butyl ester.

15. A process as claimed in claims 12-14, in which the amine or acid-binding agent is triethylamine or pyridine .

16. A process as claimed in claim 14, wherein the protecting groups are removed by catalytic hydrogenation in an acid medium.

17. Pharmaceutical compositions containing as the active principle a compound as claimed in claims 1-11 in admixture with a suitable carrier.

18. The use of the compounds as claimed in claims 1-11 for the preparation of a medicament having antitumor and anti-platelet aggregating activities.