GB2186877A

GB2186877A - Phospholipids

Info

Publication number: GB2186877A
Application number: GB08703625A
Authority: GB
Inventors: Julian Marian Charles Golec; Charles John Robert Hedgecock; Peter David Kennewell
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1986-02-18
Filing date: 1987-02-17
Publication date: 1987-08-26
Anticipated expiration: 2007-02-17
Also published as: GB2186877B; FR2595703B1; FR2595703A1; GB8604000D0; GB8703625D0

Abstract

Compounds of general formula (I): <IMAGE> wherein R1 represents an aliphatic hydrocarbyl group containing from 1 to 22 carbon atoms, or a <IMAGE> radical wherein n represents an integer from 1 to 22; either Z represents a hydrogen atom and R2 represents a <IMAGE> radical (wherein R' represents a hydrogen atom, an aliphatic hydrocarbyl group containing from 2 to 22 carbon atoms or a -(CH2)n-C6H5 radical where n' is an integer from 1 to 8) or R2 represents a <IMAGE> a (RO)2-CH-CH2- radical (where R represents an alkyl radical containing from 1 to 8 carbon atoms), a <IMAGE> radical where P is as defined above; or R<2> and Z together with the carbon atom to which they are attached represent a <IMAGE> radical or a <IMAGE> radical; R3, R4 and R5 each represents a straight or branched C1-8 alkyl radical or a C3-6 cycloalkyl radical or R3, R4 and R5 together with the nitrogen atom to which they are attached represent an N-methylpiperidinium group exhibit anti-inflammatory properties. Processes for the preparation of the compounds and pharmaceutical compositions containing them are described.

Description

SPECIFICATION Chemical compounds The invention relates to new phospholipids, to processes for their preparation and to pharmaceutical compositions containing them.

According to one feature of the present invention there are provided compounds of general formula (I):

wherein R1 represents a straight or branched, saturated or unsaturated, aliphatic hydrocarbyl group containing from 1 to 22 carbon atoms, or a

radical wherein n represents an integer from 1 to 22; either Z represents a hydrogen atom and R2 represents a

radical (wherein R' represents a hydrogen atom, a straight or branched, saturated or unsaturated, aliphatic hydrocarbyl group containing from 2 to 22 carbon atoms or a -(CH2)n-C6Hs radical where n' is an integer from 1 to 8) or R2 represents a

G)-CH2- group, a (RO)2-CH-CH2- radical (where R represents an alkyl radical containing from 1 to 8 carbon atoms),

d | )-CH2-radical - C) or a

radical where R is a defined above; or R2 and Z together with the carbon atom to which they are attached represent a

radical or a

radical; and either R3, R4 and R5 (which may be the same or different) each represents a straight or branched Cn, H2n,+, alkyl radical where n' is as defined above or a cycloalkyl radical containing from 3 to 6 carbon atoms, or R3, R4 and R5 together with the nitrogen atom to which they are attached represent an N-methylpiperidinium group.

When R1 represents a straight or branched, saturated or unsaturated, aliphatic hydrocarbyl group this may be a straight or branched alkyl, alkenyl or alkynyl group.

Where R1 represents an alkyl radical this may, for example, be a methyl or an ethyl group or a straight or branched propyl, butyl, pentyl, hexyl, heptyi, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl or docosyl group.

Where R1 represents an alkenyl radical containing 2 to 22 carbon atoms this may, for example, be a vinyl group; a straight or branched propenyl, butenyl, pentenyl, hexenyl, octenyl, decenyl, undecenyl, pentadecenyl, octadecenyl, eicosenyl, heneicosenyl or docosenyl group; or a 1,3-butadienyl, 1,3 pentadienyl, 1.4-pentadienyl, 1,3-decadienyl, 1 ,4-decadienyl, 1 .5-decadienyl, 1 ,6-decadienyl, 1,8-decadienyl, 1.3,6-decatrienyl, 1,5,7-decatrienyl or 1 ,3,6,9-decatetraenyl group.

Where R1 represents an alkynyl radical containing 2 to 22 carbon atoms this may, for example, be an ethynyl, 1-propynyl, 2-propynyl, straight or branched butynyl, 1,3-butadiynyl, straight or branched pentynyl, 1,3-pentadiynyl, 1 ,4-pentadiynyl, straight or branched hexynyl, straight or branched octynyl, straight or branched decynyl, 1,3-decadiynyi, 1,4-decadiynyl, 1,5-decadiynyl, 1,6-decadiynyl, 1,8-deca diynyl, 1,3,6-decatriynyl, 1,5,7-decatriynyl or 1 3,6,9-decatetraynyl group or a straight or branched undecynyl, pentadecynyl, octadecynyl, eicosynyl, heneicosynyl or docosynyl group.

Where R, R3, R4 or R5 represents an alkyl radical containing from 1 to 8 carbon atoms this may, for example, be a methyl or ethyl group or a straight or branched propyl, butyl, pentyl, hexyl, heptyl or octyl group.

Where R3, R4 or R5 represents a cycloalkyl radical this may be a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The compounds of the present invention possess interesting pharmacological properties and in particular an antiphospholipase activity and an anti-inflammatory action in the carrageenin paw oedema in rat, properties which can be used for treating inflammatory states. Preferred compounds according to the invention include those of formula (I) wherein R1 represents a straight or branched CnH2n+' alkyl radical where n represents an integer from 1 to 22 or R1 represents a

radical or a

radical where n is as defined above.

In particular there may be mentioned compounds of formula (I) wherein R3, R4 and R5 each represents a methyl group or together with the nitrogen atom to which they are attached represent an N-methyl piperidinium group.

Most particularly of interest are compounds of formula (I) wherein R2 represents a

radical in which R' represents a hydrogen atom, a straight chain CVH2n+1 alkyl radical (where n is as defined above) or a -(CH2)3-C6H5 radical, or R2 represents a

group, a (C2H50)2-CH-CH2 radical, a

radical or a

radical; and compounds of formula (I) wherein R2 and Z together with the carbon atom to which they are attached represent a

radical or a

radical.

Particularly preferred compounds according to the invention include: -3-(octadecyloxymethyl)-4-(phosphorylcholinyl)butanal, -1-(1,3-dioxolan-2-yl)-2-(hexadecyloxymethyl)-3-(phosphorylcholinyl)-propane, -3-(hexyloxymethyl)-4-(phosphorylcholinyl)butanal, 5-(octadecyloxymethyl)-5-(phosphorylcholinylmethyl)-2(3H)-dihydrofuranone, -5-phosphorylcholinoxymethyl-5-stearoyloxymethyl- 1 ,3-dioxane, methyl 3-(hexadecyloxymethyl)-4-(phosphorylcholinyl)butanoate.

The compounds of general formula (I) wherein R1, R3, R4 and R5 are as defined above and R2 is other than a radical

may, for example, be prepared by a process which comprises reacting a compound of general formula (ill):

(wherein R1 and Z are as defined above and R'2 is as defined above for R2 other than the radical R'-C-CH2) 0 with 2-chloro-2-oxo-1,3,2-dioxaphospholane of formula

followed by reaction of the product initially obtained with an amine of formula (Ill)

(wherein R3, R4 and R5 are as defined above) to obtain a compound of formula (IA)

wherein R1, R'2, R3, R4, R5 and Z are as defined above.

The reaction of the compound of formula (II) with the 2-chloro-2-oxo-1,3,2-dioxaphospholane is conveniently effected in an organic solvent such as benzene, in the presence of an amine such as pyridine or dimethylaminopyridine.

The compounds of general formula (I) wherein R1, R3, R4 and R5 are as defined above and R2 represents a

radical in which R' is as defined above may, for example, be prepared by a process which comprises submitting a compound of formula (IV):

(where Y is 2 or 3 and R1, R', R3, R4 and R5 are as defined above) to the action of chloramine T to obtain the required compound of formula (IB)

wherein R1, R', R3, R4 and R5 are as defined above.

The reaction of the compound of formula (IV) with chloramine T is conveniently effected in an organic solvent such as methanol-THF-water or acetone-water.

The compounds of general formula I wherein R1, R2, R4 and R5 are as hereinbefore defined and R2 represents a group of formula

may, for example, be prepared by a process which comprises submitting a compound of formula (IVA):

(wherein R, R1, R3, R4, R5 and Y are as hereinbefore defined) to the action of p-toluenesulfonic acid to obtain the required compound of formula (IC):

wherein R1, R3, R4 and R5 are as hereinbefore defined.

The reaction of the compound of formula (IVA) or (IVB) with p-toluenesulfonic acid is conveniently effected in an organic solvent such as methanol-THF-water or acetone-water.

The compound of formula (IV) may be obtained by reacting a compound of formula (ill'):

(wherein Y is 2 or 3 and R1 and R' are as defined above) with 2-chloro-2-oxo-1,3,2-dioxaphospholane of formula:

and then reacting the product initially obtained with an amine of formula (III):

wherein R3, R4 and R5 are as defined above.

The reaction of the compound of formula (II') with 2-chloro-2-oxo-1 2,2-dioxaphospholane is conveniently effected in an organic solvent such as benzene, in the presence of an amine such as pyridine or dimethylaminopyridine.

The above processes constitute further features of the present invention.

As mentioned above the compounds of general formula (I) possess interesting pharmacological properties.

Those compounds which we have tested exhibit a remarkable anti-phospholipase activity and an anti-inflammatory action in the carrageenin paw oedema in rat, properties which can be used for treating inflammatory states.

According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising at least one compound of formula (I) and one or more pharmaceutical carriers and/or excipients.

For pharmaceutical administration the compounds of general formula I may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal, parenteral or topical administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, granules, ampoules, suppositories and solutions e.g. for injection.

The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 200 to 10 mg of the compound of formula (I) preferably from 10 to 50 mg of the compound of formula (I).

The oral daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 20 to 100 mg.

According to a still further feature of the present invention there are provided compounds of formula (I) as defined above for use in the treatment of inflammatory disorders.

Compounds of formula (II) wherein R'2 represents a

radical may for example be prepared by a process which comprises reacting diethyl malonate with 2 bromomethyl-1 ,3-dioxolane, to obtain a compound of formula (V):

submitting said compound to the action of a reducing agent such as LiAIH4 to obtain a compound of formula (Vl):

and reacting said compound with sodium hydride and methanesulfonic ester of formula R1-03-S-CH3 or with CnH2n, 1-N=C=O or with Cl-CO-CnH2n! 1 to obtain a compound of formula:

/ \ ĭ;:1 (=11) with 1 X /CH2 OH (=II) with H'2 = t > H2 wherein R1 is as defined above.

Compounds of formula (II) wherein R'2 and Z together with the carbon atom to which they are attached represent a

radical may for example be prepared by a process which comprises reacting a compound of formula (Vll):

with sodium hydride and methanesulfonic ester of formula R,-03SCH3 or with CnH2n+1-N=C=O or with Cl-CO-CnH2n+ to obtain a compound of formula (II"):

go N OR1 (II"'){ II with R'2 Z * (:?,.1 (1I...)( 11 with R2 w the atta'ted wherein R1 is as above mentioned.

radical may for example be prepared by a process which comprises reacting a compound of general formula (114):

(wherein R1 is as defined above) with a peracid such as metachloroperbenzoic acid to obtain a compound of general formula (X)

submitting said compound of formula (X) to the action of tert.-butyldimethylsilyl chloride to obtain a compound of general formula (XI):

reacting said compound with n-butyllithium, N-isopropylcyclohexylamine, acetic acid and DME to obtain a compound of general formula (XII):

and finally submitting said compound to the action of a strong acid to obtain the desired compound of formula (115)::

II with R'2 and Z ro R1 (I}5)/ IT with R'2 the ogether with the H attached carbon atom= j s wherein R1 is as defined above.

Compounds of formula (114) may be prepared by a process which comprises reacting a compound of formula (Vlli):

with sodium hydride, R,-OH or CnH2n+1 N=C=O or Cl-CO-CnH2n+, to obtain a compound of general formula (IX): O-R1 CH2= C~O2-C2H5 (IX) and submitting the said compound to the action of a reducing agent such as dissobutylaluminium hydride, to obtain compounds of general formula (114)

#=II with Z and R'2=CH2=# wherein R1 is as defined above.

Compounds of formula (II) wherein R'2 represent a

radical (wherein R represents a methyl radical) may for example be prepared by a process which comprises reacting a compound of formula (XIII):

wherein R and R1 are as defined above, with tosic acid, to obtain a compound of general formula (XIV):

wherein R and R1 are as defined above, submitting said compound to the action of boron trifluoride etherate and metachloroperbenzoic acid to obtain a compound of general formula:

wherein R1 is as defined above and then reacting said compound with methanol in the presence of concentrated sulfuric acid to obtain the desired compound of formula (116):

wherein R1 is as defined above.

Compounds of formula (ill'):

(wherein Y is 2 or 3 and R1 and R' are as defined above with the exception of hydrogen) may for example be prepared by a process which comprises reacting a compound of formula (XVI):

with a reducing agent such as lithium aluminium hydride to obtain a compound of formula (XVII):

reacting said compound of formula (XVII) with sodium hydride, then with a methanesulfonic ester of formula: R103-S-CH3 or with an isocyanate of formula CnH2n+1-N=C=O or with Cl-CO-CnH2n+1, to obtain a compound of general formula (XVIII):

reacting the compound of formula (XVIII) with acetic anhydride in the presence of pyridine to obtain a compound of formula (XIX]::

submitting the compound of general formula (XIX) to the action of a dithiol of formula (XX): H-S-(CH2)y-S-H (XX) in which Y is as defined above, in the presence of boron trifluoride etherate to obtain a compound of formula (XXI):

in which Y is as defined above, reacting said compound with potassium carbonate to obtain a compound of general formula (XXII):

submitting said compound to the action of tert. butyldimethyl chlorosilane, to obtain a compound of general formula (XXIII):

reacting said compound of formula (XXIII) with n-butyllithium, then with a compound of formula: R'-X' (XXIV) (where R' is as above defined with the exception of hydrogen and X' represents an halogen atom) to obtain a compound of general formula::

(where R', Y and R1 are as above defined) and finally, submitting said compound to the action of a strong acid to obtain the desired compound of formula:

in which R', Y and R1 are as above defined.

According to this process, a) the reaction of the compound of formula (XVII) with sodium hydride and then with a methanesulfonic ester of formula R103SCH3 is conveniently effected in an organic solvent such as tetrahydrofuran; b) the reaction of the compound of formula (XIX) with a dithiol of formula (XX) in the presence of boron trifluoride etherate is conveniently effected in methylene chloride; c) the reaction of compound (XXI) with potassium carbonate is conveniently effected in a mixture of methanol and water; d) the reaction of compound (XXII) with tert. butyldimethyl chlorosilane is conveniently effected in a mixture of tert-butyl dimethylsilyl ether and dimethylformamide in the presence of a suitable base such as, for example, imidazole;; e) the reaction of compound (XXIII) with n-butyllithium and then with a compound of formula R'-X' is conveniently effected in a mixture of tetrahydrofuran and hexane; f) the hydrolysis of compound (XXV) by a strong acid is conveniently effected by a solution of hydrochloric acid in acetone.

In a further aspect the invention provides as novel industrial products useful as intermediates in the preparation of compounds of formula (I), the compounds of formula (II), (II') and (IV) as hereinbefore defined.

Example 1: + 2-(Octadecyloxymethyl)- 1-(phosphorylcholinyl)dodecan-4-one

a) Preparation of Diethyl 2-(2,2-diethoxyethyl)- 1,3-propanedloate Intermediate (I)

Sodium hydride (1009, 80% oil disperson) was carefully added in portions to dry ethanol (1.671), followed by diethyl malonate (5679, 3.54mol). The solution was stirred for 30 mins then bromoacetaldehyde diethylacetal (567g, 2.88mol) was added dropwise over 30 mins. The solution was refluxed gently for 48 hrs. The precipitated sodium bromide was filtered off and washed with ethanol. The combined ethanolic solutions were reduced to an oil in vacuo, washed with water and brine and dried over Mg SO4.

The red/brown oil recovered after filtration (7509) was distilled 112-122 C/0.4mmHg to give 4379 of colourless oil (55% yield).

NMR (CDCl3) '54.54 (t O-CH-O); 4.20 (d.q, 2xCOOCH2); 3.35-3.73 (complex, 2xCH3CH20, CH(COOEt); 2.23 (d.d, CHCH2CH-); 1.26 (t,2xCOOCH2CH3); 1.19 (t, 2xOCH2CH3).

IR (film) 2930, 2890, 1730, 1370, 1060cm-1 b) Preparation of 2-(2,2-Diethoxyethyl)-1,3-propanediol Intermediate (2)

Intermediate (I) (1409, 0.5mol) in dry ether (400ml) was added dropwise to LiAIH4 (28.59, 0.75mol) suspended in dry ether (400ml) at a sufficient rate to maintain gentle reflux, (approx 2 hrs). After stirring for a further 2 hrs saturated sodium sulphate solution was added dropwise until all reaction had ceased. The white granular precipitate was filtered off and the solution concentrated in vacuo to leave a very pale yellow oil (949, yield 98%) (b.p. 130-133 C/0.8mmHg), which was of sufficient purity to be used directly in the next step.

NMR (CDCl3) '54.59 (t, (EtOì2CH); 3.27-3.87 (complex, 10H, 2xCH2OH, 2xCH3CH2O); 1.47-2.09 (broad, -CH-); 1.69 (q, CH2); 1.19 (t, 6H CH2CH20).

IR (film) 3485, 2970, 2925, 2875, 1440, 1375, 1340, 1115, 1050, 995cm-1.

c) Preparation of 4,4-Diethoxy-2-(octadecyloxymethyl)butan- 1-ol Intermediate (3)

The monosodium salt of Intermediate (2) (249, 0.13 mol) was formed in dry THF (200ml) using sodium hydride. Octadecyl methanesulfonate (43.59, 0.13 mol) in dry THF (200ml) was added dropwise to the refluxing solution over 3.5 hrs with the exclusion of moisture. After a total of 5 hrs at reflux the solvent was evaporated, the product taken in ether and washed with water several times. The solution was dried over magnesium sulphate and the solvent distilled off under vacuum.

The product was purified by column chromatography on silica gel to give 46.59 of octadecyl ether (3) (84% of theoretical).

NMR (CDCl3) '54.58 (t, (EtO)2CH); 3.18-3.82 (complex, 6H, -0CH2-C-CH2OCH2-) 2.89 (m, 1H, -CH-); 1.62 (d.d, -CHCH2CH-); 1.24 (s, (CH2)16); 1.19 (t, 6H, CH3CH2O); 0.87 (t, 3H, Me).

IR (film) 3450 (br), 2925, 2850, 1465, 1370, 1115, 1060cma d) Preparation of 4,4-Diethoxy-2-(octadecyloxymethyl)but- 1-yl Acetate Intermediate (4)

Intermediate (3) (46.59) in dry pyridine (200ml) was treated with acetic anhydride (50ml) for 18 hrs at R.T.

The solution was poured into ice/water and stirred for 1 hr. The oily product (4) was separated, taken in ether and washed with water, dilute hydrochloric acid, water, sodium bicarbonate solution and saturated sodium chloride then dried over magnesium sulphate.

NMR (CDCl3) '54.58 (t, (EtO)2CH); 4.05 (d, CH2OAc); 3.13-3.82 (m, 6H, 2 x CH3CH20, CH20CH2-); 1.99 (s, CH3CO); 1.06 (t, 2xCH3CH2O); 0.87 (t, CH2).

IR (film) 2920, 2850, 1748, 1370, 1240, 1120cm-'.

m/e 441 (M±EtO); 381, 308, 281, 103.

C29Hs805 Requires C, 71.56%; H, 12.01%.

Found C, 71.83%; H, 11.83%.

e) Preparation of Intermediate (6)

The oil (4) recovered was dissolved in methylene chloride (250ml) and treated with 1,3propanedithiol (12.5ml, 0.12 mol) and borontrifluoroetherate (1 ml). After lhr the solvent was removed by distillation then methanol (800ml), water (50ml) and potassium carbonate (309) were added.

The solution was stirred and maintained at a gentle boil for 45 mins until complete cleavage of the acetate was indicated by t.l.c.

After copling and removing the methanol, diethyl ether was added and the solution washed with water twice and dried over magnesium sulphate. Evaporation of solvent gave an oily wax which was used directly in the next step.

f) Preparation of Intermediate (7)

The oil/wax (6) isolated was converted to the t-butyldimethylsilyl ether in DMF (150ml) containing imidazole (14.59, 0.12 mol) and t-butyldimethyl chlorosilane (16.89, 0.11 mol). After stirring for 2 hrs the DMF was diluted with ether, washed with water and dried over magnesium sulphate. Removing solvent and purifying the product over silica gel gave 559 (95.8mmol) of intermediate (7).

(91.5% of theoretical from the octadecyl ether (3)).

NMR (CDCl3) 84.13 (t, S-CH-S); 3.60 (d, CH2OTBDMS); 3.30-3.45 m, CH2OCH2); 2.83 (m, 4H, SCH2); 2.09 (m, 2H, SCHCH2); 1.85 (m, -CH); 1.78 (m, SCH2CH2CH2S); 1.53 (m, OCH2CH2-); 1.25 (s, 30H); 0.89 (s, t-Bu); 0.85 (t, Me).

IR (film) 2920, 2850, 1468, 1255, 1115, 1100, 835, 770cm - ' .

m/e 574 (my), 559, 545, 517, 489, 441, 353, 305, 247.

g) Example preparation of Intermediate (9)

a) Intermediate (7) (6.09, 10.4mmol) in dry THF (25ml) at -20" under argon was treated with butyl lithium in hexane (1.6M, 7.8ml). After stirring for 1.5 hrs at 200 the solution was cooled to 780 and 1-bromooctane (2.15ml) added. The solution was warmed to -15" over 15 mins and kept at this temperature for 18 hrs. Solvent was removed and an ethereal solution of the residue washed with water and dried (MgS04). Purification over silica gel gave 5.89 of intermediate (8) as a colourless oil (80.5% of theoretical).

b) The TBDMS group was removed by gentle reflux in acetone (100ml) containing hydrochloric acid (2M, 10ml). After 30 mins the solvent was evaporated, the residue dissolved in ether, washed with aqueous sodium bicarbonate and then water and dried (MgS04). Purification over silica gel gave 3.89 of intermediate (9) as a waxy solid (83.5% of theoretical).

Examples of intermediates (8) and (9) are listed in Table 1.

h) Preparation of 2-(Octadecyloxvmethyl)- l-(phosphorylcholinyl)dodecan-4-one

a) The 2-octyl 1,3-dithiane (9) (3.09, 5.3mmol) in dry benzene (30ml) containing triethylamine (1.5ml) and 4-dimethylaminopyridine (50mg) was treated at 0 C with 2-chloro-2-oxo-1 ,3,2-dioxa- phospholane (1.25M, 4.25ml) in benzene. After stirring for 1.5 hrs at ambient temperature the solution was filtered to remove triethylamine hydrochloride, solvent removed in vacuo and the solid recovered dissolved in dry acetonitrile (100 ml) and maintained at 60 C for 18 hrs in the presence of trimethylamine (4ml) in a Parr pressure vessel.

Solvent was then removed in vacuo and the product purified over silica gel eluting in 30-45% methanol in chloroform (1% water) to give 3.369 of phosphorylcholine product (10) (87% of theoretical).

b) 2.419 (3.27mmol) of this material was stirred at ambient temperature in methanol/ THF/water 9:3:1 (130ml) with chloramine T (2.02g, 7.19mmol). Conversion of the dithiane to a ketone was complete after 30 mins. The solvent mixture was evaporated and the product purified over silica gel to give 1.569 of (#) 2-(Octadecyloxymethyl)-1-(phosphorylcholinyl)-dodecan-4-one as a colourless wax. (73.7% of theoretical).

NMR (CD3OD) 4.25 (br, POCH2); 3.83 (d.t, CH2OP; J=5 5, + + 2.5H3); 3.64 (m, CH2N);3.26-3.51 (m,CH2OCH2);3.24(S, NME3); 2.40-1.59 (d+t+m, CH2C0CH2CH); 1.53 (br, OCH2CH2); 0.90 (t, 2xMe).

IR (film) 3390, 2910, 2840, 1705, 1465, 1235, 1085, 965 cm-1 m/e 464 (m±183), 435, 421, 379, 309, 195, 181.

C36H74NO6P 2H2OrequiresC, 63.21; H, 11.50; N, 2.05.

found C, 62.96; H, 10.97; N, 2.12.

TABLE I - Intermediates

R R6 YIELD THEORY/FOUND IR m.p. MS FORMULA M.Wt. C H from R'=H H TBDMS - 2929,2850 oil 574(M.+) C32H66O2S2Si 1575.11 66.83 11.57 (7) 1468 69.70 17.70 2920,2850 (9) C4H9 H 76,8% C30H60O2S2 516.94 1465 (9) C8H17 H 67.2% 3450,2925 oil 572(M.+) C34H68O2S2 573.05 71.26 11.96 2845,1465 71.49 12.01 (8) C18H37 TBDMS 82.2% 2920,2850 46-47 C 826(M.+) C50H102O2S2Si 827.59 72.57 12.42 1472 72.78 12.46 (9) Ph(CH2)3 H 54% 3450,2920 oil 578(M.+) C35H62O2S2 579.01 72.60 10.79 2845,1605 72.76 10.82 (8) Cl(CH2)4 TBDMS 87.2% 2950,2850 oil 664(M.+) C36H73ClO2S2Si 665.96 64.96 11.05 1470 65.33 11.13 TBDMS 68.6% 2920,2845 oil 630(M.+) C36H75O2S2Si 632.22 68.39 11.96 (8) (CH3)2CHCH2 1470 90.6% 3440,2920 4.88(M.+) 68.79 11.55 (9) C2H5 H oil C28H52O2S2 488,89 2840,1465,1375 68.39 11.23 Example 2: Compound (10) with R,=C18H37 R2=H, Rs=R4=R5=Me.

Intermediate (6) (3g, 6.52mmol) in dry benzene (25ml) containing dry triethylamine (1.5ml) and 4 (dimethylamino)pyridine (50mg) at 0 C was treated with 2-chloro-2-oxo-1,3,2-dioxaphospholane (4.1ml, 2M in benzene). After stirring for 70 mins the solution was filtered, the solvent removed in vacuo and dry acetonitrile (100ml) and trimethylamine (4ml) added. The reaction was kept at 60 C/40psi in a bomb for 20 hours. The solvent was removed in vacuo and the product purified by flash chromatography. Crystallisation from hot acetonitrile gave 3.329 of white crystals (m.p.

94-96"0). Yield 81.5%.

NMR (CD30D) '54.28 (m, POCH2); 4.24 (t, SCHS); 3.89 (m,CH2OP); 3.64 (m, CH2N); 3.33-3.55 (m, CH2OCH2); 3.24 (s. NMe3); 2.96-3.03 (m, SCH2CCH2S); 2.01-2.83 (m, CH2); 1.70-1.93 (m, 3H, SCCH2CS±CH) 1.56 (OCH2CH2); 0.89 (t, Me).

IR (KBr) 3320, 2910, 2840, 1470, 1240, 1210, 1090, 1035, 960cm-1.

m/e 460, 442 (m±183), 369, 335, 283, 253, 189.

C31H64NO5PS2 + 1.5H2O requires C 57.02%; H, 10.34%; N, 2.15 found C 57.10%; H, 9.90%; N, 2.09%.

Example 3: compound (10) with F?1 R,=C,8H3, R2=H, Rs=Me, R4+R5=

Intermediate (6) (59, 10.9mmol) in dry benzene (30ml) was treated with dry triethylamine (3ml) and 4-dimethylamino pyridine (50mg). 2-Chloro-2-oxo 1.3,2-dioxaphospholane (13ml, 1M in benzene) was added at 000. After 40 mins the solution was filtered, the solvent removed in vacuo and dry acetonitrile (120cm3) and N-methylpiperidine (4ml, 33mmol) added. The solution was refluxed for 4 hrs and a further (4ml) N-methylpiperidine was added. After a further 4 hrs reflux, solvent was removed in vacuo and the product purified by flash chromatography eluting in 25.30% methanol in chloroform (1% H20). The product was crystallised from methylene chloride/acetone (2.349) (m.p.

66-69 C) (Yield 32%).

NMR (CD30D) #4.01-4.39 (2H, POCH2); 4.21 (t, SCHS); 3.86 (m, CH2OP); 3.22-3.72 (complex, 10H; CH20CH2, N(CH2)3); 3.17 (s, NMe); 2.68-3.00 (m, 2xSCH2); 0.87 (t, Me).

IR (KBr) 3340, 2920, 2850. 1665. 1635, 1465, 1225, 1100, 1080. 1065, 950, 835, 755 cm '.

C34H68NOsPS2 3.5 H20 requires C, 56.01; H, 10.39; N, 1.92.

found C. 55.81; H, 10.13; N, 1.90.

Example 4: compound of formula:

Intermediate (2) (1.9g, 10mmol) in dry benzene (30ml) containing triethylamine (2.8ml) was treated with n-octadecyl isocyanate (2.959, lOmmol). After stirring at ambient temperature for 24 hrs 4dimethylaminopyridine (25mg) was added followed by 2-chloro-2-oxo-1,3,2-dioxaphospholane (12ml, 1M benzene solution). After 2 hrs the reaction appeared complete by t.l.c. The solution was filtered, solvent removed in vacuo and the remaining oil dissolved in acetonitrile (100ml).

Trimethylamine (5ml) was added to the solution and heated at 60 C/40psi; in a bomb for 20 hrs.

The solvent was removed and the residue purified by two flash columns eluting in 35-45% methanol in chloroform (1% water) to give a colourless wax (2.459, yield 38%).

NMR (CDsOD) 4.63 (t, OCHO); 4.22 (br, POCH2); 3.44-4.16 (complex, 10H, CH20C, CH20P, CH2N, (CH20)2C); 3.20 (s, NMe3); 3.04 (t, OCNCH2); 1.15 (t, 6H, OCH2Me); 0.86 (t, 3H, Me).

IR (film) 3340 br, 1705, 1695, 1465, 1280, 1090, 1060cm-1.

C33H69N2O8P 1.5 H2OrequiresC, 58.30; H, 10.67%; N, 4.12%.

found C, 58.22; H, 10.36%; N, 4.08.

Examples 5, 6, 7 and 8: compounds l4a, 14b, 15a, 15b.

a) R=C,6H33 a) R=C16H33 b) R=C6H13 b) R=C6H13 a) Diethyl 2-(1,3-dioxolan-2-ylmethyl)-1,3-propanedioate (11) -Diethyl malonate (10g, 62.4mmol) was added dropwise to a stirred suspension of 80% sodium hydride (2.06g, 68.64mmol) in dry DMF (50ml) under nitrogen. The reaction mixture was kept stirring until the sodium hydride had reacted, then 2-bromomethyl-1,3-dioxolane (6.66ml, 62.4mmol) was added. The reaction mixture was stirred at 100 C for 36 hrs. The mixture was diluted with water (200ml) and extracted with ether (2 x200ml). The combined extracts were washed with water and dried (MgSO4). The solvent was removed under reduced pressure to give an oil.The oil was distilled under reduced pressure to give the diester as an oil (6.079, 40%), 6.p. (0.4mm) 108 ; VmaX (film) 1730 (C=O ester; # (200MH2; CDCl3) 2.34 (2H, q, 1-H), 3.57 (1H, t, 1-H), 3.87 (4h, m, ethylene, 5.0 (1H, t, 3-H).

b) (1,3-Dioxolan-2-ylmethyl)- 1,3-propanediol (12)-A solution of the diester (11) (10g, 40.6mmol) in dry ether (25ml) was added dropwise at 5 C to a stirred suspension of LiAIH4 (3.089, 81.16mmol) in dry ether (100mol) under nitrogen. The mixture was kept stirring overnight at room temperature, then quenched with saturated sodium sulphate solution. The resulting mixture was heated under reflux for 30 mins, cooled then filtered. The solids were washed well with ethanol. The solvents were removed from the combined filtrate under reduced pressure.

The crude product was purified by flash chromatography (10% methanol in chloroform as eluent). The product was isolated as an unstable colourless oil (4.619, 70%); v max (film) 3380 (OH), 2880 (CH)cm '; #[CDCl3] 1.725 (2H dd, CH2(CH)2), 1.95 (1H, m, CH(CH2OH)2ì, 3.275 (2H, br, OH),) (lost in D2O), 3.7 (4H, m, CH2OH), 3.925 (4H, m, OCH2CH2O), 4.95 (1H, t, CHO2), unstable for C, H, N.

c) 3-(1,3-Dioxolan-2-yl)-2-(hexadecyloxymethyl)propan-1-ol(13a)-80% sodium hydride (0.20g, 6.17mmol) was added to a stirred solution of the diol (2) (1g, 6.17mmol) in dry THF (20ml) under nitrogen. The mixture was boiled under reflux for 15 mins, then cooled to room temperature. A solution of hexadecylmethanesulphonate (2.079, 6.48mmol) in dry THF (30mmol) was added dropwise, then the mixture was heated under reflux for 24 hrs. The mixture was quenched with water, then extracted with ether (2x 20ml). The combined extracts were washed twice with brine then dried (MgSO4). The solvent was removed under reduced pressure, then the residue was purified by flash chromatography (10 to 40% ethylacetate and 40-60 light petroleum as eluent) to give a colourless waxy solid. (1.719, 72%); m.p. 47-48 C; v max (film) 3400 (OH), 2920, 2850 (CH)cm-1; (CDCI3) 0.9 (3H, t, CH3, 1.275 (26H, s, C,3H26ì, 1.325 (2H, m, OCH2CH2C,3), 1.725 (2H, m, 3-CH2), 2.1 (1H, m, 2-CH), 3.375-3.5 (6H, m, CH20C,6, 1-CH2, OCH2CH2C16), 3.7 (1H, br, OH, lost in D20), 3.85-4.05 (4H, m, OCH2CH2O), 4.95 (1H, t, CHO2): C23H4604 requires C, 71.45; H, 11.99%: Found C, 71.52: H, 11.89%.

c') 3-(1,3-Dioxolan-2-yl)-2-(hexyloxymethyl)propan- 1-ol(13b) -As for 13a. Gave a pale yellow liquid (47%). v max (film) 3440 (OH), 2930, 2860 (CH), 1120, 1035 (C=O)cm-'; #[CDCl3] 0.9 (3H, t, Me), 1.3 (6H, s, (CH2)3), 1.57 (2H, m, OCH2CH2H6), 1.72 (2H, t, 3-CH2), 2.10 (1H, m, 2 CH), 3.0 (1H, t, OH, lost in D20), 3.37-3.60 (4H, m, CH2OCH2OH2), 3.70 (2H, m, 1-CH2), 4.05-3.82 (4H, m, OCH2CH2O), 4.96 (1H, t, CHO2). No C, H, N.

d) 1-(1,3-Dioxolan-2-yl)-2-(hexadecyloxymethyl)-3-(phosphorycholinyl)propane (14a)-A solution (1M in benzene) of 2-chloro-2-oxo-1,3,2-dioxaphospholane (9.33ml, 9.33mmol) was added to a stirred mixture of the alcohol (13a) (39, 7.77mmol), dimethylaminopyridine (0.39), triethylamine (2.17ml, 15.54mmol), and benzene (100ml) under nitrogen at 0O. The mixture was stirred at room temperature for 2 hrs then filtered. The solvent was removed under reduced pressure. The residue was heated in a bomb at 60 C for 17 hrs, with acetonitrile (30ml) and trimethylamine (15ml).The solvent was removed from the mixture, then the residue was purified by flash column using CHCl3-MeOH-H2O (65:25:4) as eluent, to give the phospholipid as a colourless waxy solid (1.119, 26%), m.p. indistinct, v max (film) 2920, 2850 (CH), 1240, 1090, 1050, 965cm-'; S [d6-MeOH] 1.75 (2H, m, 1-CH2), 2.125 (1H, m, 2-CH), 3.25 (9H, s, NMe3), 3.3-3.55 (4H, m, CH2OCH2), 3.65 (2H, m, CH2NMe3), 3.8-4.0 (6H, m, OCH2CH2O, 3-CH2), 4.3 (2H, m, POCH2CH2), 4.975 (1H, t, CHO2). No C, H, N.

d') 1-(1,3-Dioxolan-2-yl)-2-(hexyloxymethyl)-3-(phosphorylcholinyl)propane ( Prepared as above, as a colourless liquid, v max 2930, 2860 (CH), 1240, 1090, 1040cm-'; ; # #[d6-MeOH] 1.725 (2H, m, 1-CH2), 2.125 (1H, m, 2-CH), 3.225 (9H, s. NMe3), 3.3-3.5 (4H, m, OH2OCK2), 3.625 (2H, m, OH2NMe3), 3.75-4.0 (6H. m, OCH2CH20, 3-CH2), 4.25 (2H, m, POCH2CH2), 4.95 (1H, t, CHO2). No C, H, N.

e) 3-(Hexadecyloxymethyl)-4-(phosphorylcholinyl)butanal (15a)-a stirred mixture of the dioxolane (14a) (1.229, 2.41 mmol), acetone (40ml). water (8ml), and tosic acid (80mg) was boiled under reflux for 17 hrs. The mixture was cooled then neutralised with sodium carbonate solution. The solvent was removed under reduced-pressure then the residue was purified by flash column using CHCI3-MeOH H20) (65:25:4) as eluent, to give the product as a waxy solid, (0.879, 77%); m.p. indistinct; v max (film), 2920, 2850 (CH), 1720 (C=O), 1050cm 1; (5 [d-6 MeOH] 1.65 (2H, m, 2-CH2), 2.07 (1H, m, 3 CH), 3.225 (9H, s, NMe3), 3.3-3.5 (m, CH20CH2), 3.625 (2H, m, CH2NMe3) 3.9 (2H, m, 4-CH2), 4.25 (2H, m, POCH2CH2), 9.725 (1H, unresolved. 1-H).No C, H. N.

e' 3-Hexyloxymethyl)-4-(phosphorylcholinyl)butanal (15b)-was prepared by the same method as (15a), giving a colourless liquid, v max, 2930, 2860 (CH), 1720 (C=O), 1050cm '; '5[d-6 MeOH], 1.65 (2H, m, 2-CH2), 2.075 (1H, m, 3-CH), 3.3-3.5 (m, CH20CH2), 3.65 (2H, m, CH2N), 3.9 (2H, m, 4-CH2), 4.25 (2H, m, POCH2CH2), 9.725 (1H, t, 1-CH). No C, H, N.

Example 9: compound (23)

Ethyl α-(bromomethyl)acrylate(16)-was prepared by the method of J. Villieras and M. Rambaud, Synthesis, 1982, 924.

a) Ethyl 2-(octadecyíoxymethyl)propenoate(17)A stirred mixture of 80% sodium hydride (0.879, 28.5mmol), octadecanol (7.09, 25.9mmol), 15-crown-5 (5 drops), and dry THF (100ml) was boiled under reflux for 30 mins under nitrogen. The mixture was cooled to room temperature, then ethyl a-(bromomethyl)acrylate (16) (59, 25.9mmol) was added dropwise, followed by sodium iodide (0.59). The mixture was kept stirring for 4 hrs, then glacial acetic acid (25ml) followed by water (50ml) were added. The resulting mixture was extracted by ether (2 X 50 ml).

The extracts were washed with water (3 x 50 ml), dried (MgSO4), then evaporated under reduced pressure. The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (1:9) as eluent, to give the product as a colourless solid, m.p. 36-37"C; v max (film) 2920, 2850 (CH), 1720 (C=O ester); '5 [CDCI3] 0.875 (3H, t, C,5H30CH3), 1.25 (15H, s, C15H30), 1.6 (2H, m, CHC15H30), 3.5 (2H, t, OCH2CH2), 4.175 (2H, m, CH20C,8H37), 5.875 and 6.3 (2x 1H, 2xq, 3-CH2). (Found: C, 75.40 H, 12.09%; C24H4603 requires C, 75.34; H, 12.12%).

b) 2-(Octadecyloxymethyl)-2-propen-1-ol(18)-1M Diisobutylaluminium hydride in toluene (58ml, 58mmol) was added via a syringe to a stirred solution of the ester (17) (109, 26.2mmol) in toluene (100ml) under nitrogen. The mixture was kept for 2 hrs, then quenched with saturated sodium sulphate solution. Ethanol (100ml) was added then the mixture was boiled under reflux for 1 hr, cooled then filtered. The filtrate was evaporated under reduced pressure. The residue was dissolved in ether. The ethereal solution was dried (MgSO4) then evaporated under reduced pressure.The dry residue was purified by flash chromatography using EtOAc-40-60 light petroleum (5:95) as eluent, to give the product as a colourless waxy solid, m.p. 43-44O; v max (film). 3350 (OH), 2920, 2840 (CH), 1465cm 1; '5 [CDCI3] 4.0 (2H, s, OH2O) 4.15 (2H, m, 1-CH2), 5.10 (2H, br, 3-H2) (Found: C, 77.72; H, 13.03%; C22H4402 requires c, 77.58; H, 13.02%).

c) 2,3-Epoxy-2-(octadecyloxymethyl)propan- 1-ol(19)-A solution of m-chloroperbenzoic acid (4.879, 28.2mmol) in dry methylene chloride (50ml) was added dropwise to a stirred solution of the alkene (18) (3.79, 18.8mmol) in dry methylene chloride (25ml), under nitrogen at room temperature. The mixture was kept overnight, then a 10% solution of Na2SO3 was added until the mixture gave a negative starch iodide test. The mixture was washed with 5% NaHOO3 (2x50ml), then saturated brine (20ml). The mixture was dried (MgSO4) then the solvent was removed under vacuum. The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (10 to 30%) as eluent, to give the product as a colourless solid. (3.349; 86%) m.p. 42-43"0; v max (film) 3420 (OH), 2920, 2850 (CH), 1470. 1115, 720cm-1; #[CDCl3] 2.15 (1H, abq, OH, lost D20), 2.85 (2H, abq, 3-CH2), 3.475 (2H, t, OCH2C,7H35), 3.625 (2H, abq, CH20C,8H37), 3.825 (2H, dabq, 1-CH2); C22H4403 requires: C, 74.10; H, 12.44%; Found: C, 74.27; H, 12.40%.

d) 1-(t-Butyldimethylsilyloxymethyl)-2,3-epoxy-2-(octadecyloxymethyl)propane(20)-A solution of tert butyldimethylsilylchloride (0.159, 3.37mmol) in dry DMF (10ml) was added to a stirred mixture of the alcohol (19) (19, 2.81mmol), imidazole (0.489, 7.03mmol), and dry DMF (30) under nitrogen at 000. The mixture was stirred at room temperature for 2 hrs, then ether (100ml) followed by water (100ml) was added. The ethereal layer was separated, washed with water (50ml), dried (MgSO4), then concentrated under vacuum.The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (5:95) to give the product as a colourless oil. (0.949, 71%); v max (film) 2910, 2860 (CH), 1460 1105, 840, 780cm-1; #[CDCl3] 0.1 (6H, s, SiMe2), 0.92 (12H, m, SiBu, C15H30CH3), 2.75 (2H, abq, 3-CH2), 3.45 (2H, t, OCH2CH2C15), 3.6 (2H, abq, 1-CH2), 3.8 (2H, abq, CH2OO18H37); Q8HO3S: requires C, 71.42; H, 12.42%; Found: C, 71.14; H, 12.25%.

e) 5-(t-Butyldimethylsilyloxymethyl)-5-(octadecyloxymethyl)-2(3H)-dihydrofuranone(21)-(see S. Danishefsky, P.F. Schuda, T. Kitahara, and S.J. Etheredge, J. Am. Chem. Soc., 1977, 99, 6066). A 1.6m solution of n-butyl lithium in hexane (197ml, 315.2mmol) was added dropwise to a stirred mixture of N-isopropyl-cyclohexylamine (40.329, 285.39mmol) and dry DME (360ml) under nitrogen while maintaining the temperature at -40 C. The mixture was kept at -40 C for 15 mins, then dry acetic acid (8.19ml, 113.1mmol) was added while the temperature was maintained. The mixture was heated at 45-50 C for 90 mins to provide a 15 fold excess of acetic acid dianion.

A solution of the epoxide (20) (4.59, 9.57mmol) in DME (90ml) was added to the mixture at room temperature. The mixture was heated at -60 C for 17 hrs, then cooled. Water (180ml) was added while maintaining the temperature at 0 C, then the mixture was neutralised with 10% H2SO4 and extracted with ethyl acetate (3 x 300ml). The extracts were washed with water then dried (MgSO4).

The solvent was removed under reduced pressure. The residue was boiled under reflux for 30 mins with benzene (200ml) and tosic acid (40mg) under Dean and Stark conditions. The benzene was removed under reduced pressure. then the residue was purified by flash chromatography using EtOAc -40-60 C light petroleum as eluent (2.5 to 5% EtOAc) to give the product as a colourless oil (3.689, 75%), v max (film) 2920, 2860 (CH), 1780 (C=O iactone)cm 1; # [CDCI3] 2.05-2.3 (2H, m, 4 CH2), 2.55-2.65 (2H, m, 3-CH2) 3.475 (2H, t, OCHC17H35), 3.5 (2H, s, OH2OSi), 3.7 (2H, abq, CH2OC18H37).

f) 5-Hydroxymethyl-5-(octadecyloxymethyl)-2(3H)-dinydrofuranone(22)-A mixture of the lactone (21) (3.279, 6.38mmol). acetone (120ml), and 10% HCí (10ml) was kept at room temperature overnight.

The mixture was evaporated under reduced pressure to half voiume then water (100ml) was added.

The mixture was extracted with ethylacetate (2 x 100ml), then the extracts were washed with water (4x 100ml) and dried (MgSO4). The solvent was removed under reduced pressure, then the residue was purified by flash chromatography using EtOAc-40-60 light petroleum (30-40% EtOAc), to give the product as a colourless solid. (2.29g, 90%), m.p. indistinct; # max (film melted on), 3440 (OH), 2920, 2860 (CH), 1770 (C=O lactone) #[CDCl3] 2.125-2.225 (2H, complex, 4-CH2), 2.5-2.8 (2H, complex, 3-CH2), 3.475 (2H, t, OCH2C17H35), 3.55 (2H, abq, OH2OH). 3.7 (2H, abq, CH20Cl8H37).

9) 5-(Octadecyloxymethyl)-5-(phosphorylcholinylmethyl)-2(3H)-dshydrofuranone(23)This was prepared from the alcohol (22) as for (14a) in 44% yield, to give a colourless wax. v max (film) 2910, 2850 (CH), 1770 (C=O lactone); #[d4-MeOH] 2.2 (2H, m, 4-CH2), 2.65 (2H, m, 3-CH2), 3.25 (15H, s, NMe3), 3.5 (2H, m, OCH2C17H35), 3.6 (2H, s, CH20Cl8H37), 3.65 (2H, M, CH2NMe3), 4.0 (2H. m, CH2OP), 4.3 (2H, m, CH2CH2N).

Example 10: compound 25

a) 3-( 1,3-Dioxolan-2-yl)-2-(stearoyloxymethyl)propan- 1 -ol(24)-A solution of stearoylchloride (3.499, 11.56mmol) in dry methylene chloride (25ml) was added dropwise to a stirred mixture of the diol (12) (1.569, 9.63mmol), triethylamine (1.959, 19.26mmol), and methylene chloride (25ml) under nitrogen at room temperature. The mixture was kept overnight, then washed with water and dried (MgSO4).

The solvent was removed under reduced pressure then the residue was purified by flash chromatography using MeOH-CHCI3 (O to 5% MeOH) as eluent, to given slightly impure brownish crystals (2.085, 50%) m.p. r.t.; v max (film) 3480 (OH), 2920, 2850 (CH), 1735 (ester C=O); a [CDCI3j 0.875 (3H, t, CH3), 1.25 (28H, s, C,4H28), 1.625 (2H, m, OCH2CH2) 1.8 (2H, m, 3-CH2), 2.1 (1H, m, 2-CH2), 2.325 (2H, t, OCOCH2), 2.575 (1H, t, OH, lost in D20) 3.625 (2H, m-D in D20, 1-CH2), 3.75-4.25 (6H, m, CK2OOO, OCH2CH2O), 4.975 (1H, t, CHO2).

b) 1-(1,3-Dioxolan-2-yl)-3-(phosphorylcholinyl)-2-stearoyloxymethyl)propane(25)-This was prepared as for (14a) from (24), to give the product as a colourless wax (57%). v max (film) 2960, 2920, 2850 (CH), 1730 (C=O ester; #[MeOH] 1.8 (2H, m, 1-CH2), 2.25 (1H, m, 2-CH), 2.35 (2H, t, OCOCH2), 3.25 (9H, s, NME3), 3.65 (2H, m, CH2NMe3), 3.8-4.0 (6H, m, CH20CO, OCH2CH20), 4.15 (2H, m, 3-CH2), 4.3 (2H, m, 3-CH2), 4.975 (1H, t, 2-CH).

Example 11: compound 27

a) 5-Hydroxymethyl-5-(octadecyloxymethyl)-1,3-dioxane (26Hwas prepared from octadecanylmethane sulphonate and 5,5-dihydroxymethyl-1,3-dioxane by the method used for (13a and b). The product was obtained as a colourless solid, (79%) m.p. 51-52"0; y max 3450 (OH), 2920, 2850 (CH); #[CDCl3] 0.875 (3H, t, CH3), 1.25 (30H, s, C15H30), 1.575 (2H, m, OCH2CH2C,5H30), 2.65 (1H, br, OK-D20 lost), 3.45 (2H, t, OCH2CH2C,5H30), 3.6 (2H, s, CH2OK), 3.675 (2H, s, CH20C18H37), 3.75 (4H, abq, 4, 6CH2), 4.825 (2H, abq, 2-CH2). C24H4804 requires C, 71.95; H, 12.08%. Found C, 72.27; H, 12.02%.

b) 5-(Octadecyloxymethyl)-5-(phosphorylcholinylmethyl)-1,3-dioxane(27)-was prepared from (26) as for (14a), to give the product as a wax (87%). v max (film) 2920, 2850 (CH), 1050cm-1; # [d4-MeOH] 3.25 (15H, s, MNe3) 3.325 (4h, m, CH2OCH2C17H35), 3.65 (2H, m, CH2NMe3), 3.8 (4H, abq, 4, 6-CH2) 3.95 (2H, d. CH20P), 4.3 (2H, m, CH2CH2N), 4.8 (2H, abq, 2-CH2).

Example 12: compound 29

a) 5-Hydroxymethyl-5-(stearoyloxymethyl)- 1,3-dioxane(28)-This was prepared from 5, 5-dihydroxy methyí-1,3-dioxane and stearoylchloride by the method used for (24), to give a colourless solid (39%).

m.p. 53-54"0; # max (film) 3460 (OH), 2960, 2920, 2860 (CH), 1740 (C-O ester); #[CDCl3] 0.875 (3H, t, Me), 1.3 (28H, s, C,4H28), 1.65 (2H, m, CO.CH2CH2), 2.625 (2H, t, CO.CH2CH2), 3.5 (2H, s, CH2OH), 3.8 (4H, abq, 4, 6-CH2), 4.3 (2H, s, CH2OOO), 4.85 (2H, abq, 2-CH2). C24H46O5 requires; C, 69.52; H, 11.18%; Found: c, 69.49; H, 11.04%.

b) 5-(Phosphorylcholinylmethyl)-5-(stearoyloxymethyl)-1,3-dioxane(29)-was prepared from (28) in 25% yield as for (14a), to give a colourless wax. # max (film) 2920, 2850 (CH), 1730 (ester C=O), 1040cm ', b [d4-MeOH] 3.2 (9H, s, NMe3). 3.625 (2H, m, CH2N), 3.775 (4H, abq, 4, 6-CH2). 4.0 (2H, d, OH2OP), 4.075 (2H, s, CH20CO), 4.55 (2H, m, POCH2CH2N), 4.8 (2H, abq, 2-CH2). C29H58NO8P.

4K2O requires c, 53.44; H, 10.20; N, 2.15; P, 4.75%. Found: C, 53.41; H, 9.39; N, 2.14; P, 4.66%.

Example 13: compound (31)

a) 5-Hydroxymethyl-5-(octadecylcarbamoyloxymethyl)-1,3-dioxane(30)-A solution of octadecylisocyanate (16.959, 37mmol) in dry ether (100ml) was added to a stirred mixture of 5,5-dihydroxymethyl1,3-dioxane (59, 33.7mmol) triethylamine (3.759, 37mmol), dimethylaminopyridine (0.059), and diethyl ether (200ml) during 1 hr. The mixture was heated under reflux for 1.5 hrs, then the solvent was removed under vacuum.The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (10 to 30% EtOAc) followed by recrystallisation from 40-60 C light petroleum to give colourless crystals (10.319, 69%), m.p. 64-65 C; v max (nujol), 3460, 3320, 3250 (NH, OH), 1680 (C=O); #[CDCl3] 0.875 (3H, t, C15H30CH3), 1.25 (30H, s, C,5H30), 1.5 (2H, m, NHCH2CH2), 3.2 (2H, m, NHCH2), 3.4 (3H, br, becomes 2H, s in D2Q, CH2OK), 3.725 (4H, abq, 4,6-CH2), 4.3 (2H, s, CH20CO), 4.8 (3H, abq+broad peak lost in D20; 2-CH2, NH); C25H49NO5 requires C, 67.68; H, 11.13; N, 3.16%. Found: C, 67.67; H, 11.02; N, 3.23%.

b) 5-(Octadecylcarbamoyloxymethyl)-5(phosphorylcholinylmethyl)-1,3-dioxane (31)-was prepared from (30) as for (14a), to give the product as a colourless powder (21%) m.p. indistinct v max (nujol), 1700 (C=O), 1050cm-1; # [d4-MeOH] 3.225 (9H, s, NMe3), 3.65 (2H, m, CH2N), 3.8 (4H, abq, 4, 6 CH2). 3.95 (2H, d, OH2OP), 4.05 (2H, s, CH20CO), 4.275 (2H, m, CH2CH2N), 4.8 (2H, abq, 2-CH2), C30H6,N208P. 2.75 H20 requires c, 54.73; H, 10.18; N, 4.25; P, 4.70%: Found: C, 54.77; H, 9.90; N, 4.20; P, 4.77%.

Example 14: compound (33)

a) 4,4-Diethoxy-2-(stearoyloxymethyl)butan-1-ol (32)-A solution of stearoylchloride (9.479, 31.2mmol) in dry ether (100ml) was added dropwise to a stirred mixture of (2) (59, 26mmol), ether (100ml), triethylamine (81 ml, 57.2mmol) and DMAP (0.05g) at room temperature. The mixture was kept for 1 hr, then filtered. The filtrate was evaporated to dryness under vacuum.The residue was purified by flash chromatography using EtOAc-40-60 light petroleum as eluent (20 to 30% EtOAc) to give a yellow oil, (5.149, 43%); V max (film) 3460 (OH), 2920, 2860 (CH), 1730 (C=O)cm '; # [CDCl3] 0.875 (3H, t, C,4H28CH3), 1.2 (6H, m, (OCH2CH3)2), 1.25 (28H, s, C14H28), 1.625 (2H, m, COaCH2CH2), 2.3 (2H, t, CO.CH2CH2), 1.625-2.85 (3H, complex, 2-CH, 3-CH2). 3.5-4.25 (8H, complex, 1-CH2, CH20CO, (OCH2CH3)2), 5.15 (1H, dt, 4-CH). C27H54O5 requires C, 70.69; H, 11.86%.

Found: C, 70.92; H, 11.79%.

b) 1,1-Diethoxy-4-(phosphorylcholinyl)-3-(stearoyloxymethyl)butane (33)-was prepared as a colourless wax in 12% yield as for (14a), from (32). # max (film) 2920, 2850 (CH), 1727 (C=O), 1050cm '; a [d4-MeOH] 1.5-1.75 (4H, complex, CO.CH2CH2, 2-CH), 2.125 (1H, m, 3-CH), 2.35 (2H, t, CO.CH2), 3.225 (9H, s, NMe3), 3.55 (4H, q. (OEt)2), 3.65 (2H, m, CH2NMe3), 3.9 (2H, m, 4-CH2), 4.15 (2H, m, CH20CO). 4.3 (2H, m, POCH2CH2N), 4.675 (1H, t, 1-CH).

Example 15: compound (38)

a) 4.4-Diethoxy-2-(hexadecyloxymethyl)butan- 1-ol (34)-was prepared as a yellow oil (74%) from (2) by the method used for the preparation of (13), with Nal catalysis. # max (film) 3450 (OH), 2920, 2860 (OH), 1465, 1370, 1120, 1050, 760 cm '; #[CDCl3] 0.9 (3H, t, C,3H26CH3), 1.225, 6H, t, (OEt)2), 1.25 [0D06] (26H, s, C13H26), 1.55 (2H, m, CH2C,3H26), 1.65 (2H, t, 3-CH2), 2.0 (1H, m, 2 CH), 3.05 (1H, t, OH--lost in D20), 3.35-3.8 (10H, complex CH20CH2), (OEt)2, 1-CH2 4.6 (1H, t, 4 CH). C25H52O4 requires C, 72.13; H, 12.58%. Found: C, 72.38; H, 12.51%.

+ b) 2-Ethoxy-4-(hexadecyloxymethyl)tetrahydrofuran (35)-A mixture of the alcohol (34) (5g, 12 mmol), tosic acid (0.059) and acetone (50ml) was stirred at room temperature for 0.5 hrs. The mixture was evaporated to half volume under vacuum, then ether (100ml) was added. The mixture was washed with NaHCO3 solution followed by brine. The organic phase was dried (MgSO4) then evaporated to dryness under vacuum. The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (2-5% EtOAc) as eluent, to give the product as an oil (4.399).

The product was a mixture of isomers making the n.m.r. complex v max (film) 2920, 2860 (CH)cm-1. C23H4603 requires C, 74.54; H, 12.51%. Found: C, 74.72; H, 12.46%.

c) 4-(Hexadecyloxymethyl)-2(3H)-dihydrofuranone (36)-(method of 0. Hoppe and A. Bronneke, Tet Letts., 1983, 24, 1687). Boron trifluoride etherate (0.066ml), 5.4mmol) was added to a stirred mixture of the lactol ether (35) (1g, 2.7mmol), mCPBA (0.569, 3.24mmol), and dry methylenechloride under nitrogen. The mixture was kept overnight, then the excess mCPBA was destroyed with dime thyl sulphide (0.049ml, 0.675mmol) (sodium sulphite solution may be used). Ether (35ml) was added, then the mixture was neutralised by the dropwise addition of NaHCO3 solution. The organic layer was separated, washed with water and brine, then dried (MgSO4).The solvent was removed under reduced pressure then the residue was purified by flash chromatography using EtOAC-40-60 light petroleum as eluent (10 to 20% EtOAc). This gave the pure product as colourless crystals (0.879, 95%), m.p. 43-44"C, v max (nujol), 1795 (C=O), '5[ODOI3j 2.5 (2H, dabq, 3-CH2), 2.825 (1H, m, 4 CH), 3.425 (4H, m, CH20CH2), 4.3 (2H, dabq, 5-CH2), C21H4003 requires C, 74.07; H, 11.84. Found C, 74.32; H, 11.84%.

d) Methyl 3-(hexadecyloxymethyl)-4-hydroxybutanoate (37) -(see H.C. Brown and K.A. Keblys, J.

Org Chem., (1966, 31, 485). A stirred mixture of the lactone (36) (4g, 11 .7mmol), methanol (80ml) and conc. sulphuric acid (1.6ml) was kept at room temperature overnight. Ether (100ml) was added to the mixture which was then washed with NaHOO3 solution until the mixture was neutral. The aqueous layer was extracted with ether (100ml). The organic layers were combined then washed successively with NaHCO3 solution, and water. The mixture was dried (MgSO4) then the solvent was removed under reduced pressure.The residue was purified by flash chromatography using EtOAc-40-60 light petroleum (10 to 30% EtOAc) to give the product as a colourless solid, (1.249, 28% or 63% corrected for recovered starting material). m.p. 38-39 C, v max (film) 3450 (OH), 2920, 2850 (CH), 1735 (ester C=O); #[CDCl3] 2.35 (1H, m, 3-CH), 2.425 (2H, m-abq in DMSO, 2-CH2], 2.16 (1H, t, OH--lost in D20), 3.525 (2H, dabq, CH20C16H33), 3.7 (5H, m, CO2Me, 4-CH2).

e) Methyl 3-(hexadecyloxymethyl)-4-(phosphorylcholinyl)butanoate (38)-was prepared from (37) as for (14a) except that the intermediate phospholane was purified by flash chromatography. The product was obtained as a colourless wax (56%) from phospholane) v max (nujol) 1730 (ester C=O); # [,MeOH d-4] 2.3-2.55 (3H, m, 2-CH2, 3-CH), 3.255 (9H, s, NMe3), 3.25-3.55 (m, CH20CH2), 3.65 (5H, m, s, CO2Me, CH2N), 3.9 (2H, m; 4-CH2), 4.25 (2H, m, CH2CH2N). O27K56O7NP1/2H2O requires C, 59.30; H, 10.51; N, 2.56; P, 5.67%. Found C, 59.16; H, 10.37; N, 2.41; P, 5.52%.

TABLE 2

The compounds of Examples 16 to 21 below were obtained in an analogous manner to the compound of Example 1 (tablulated hereinbelow for comparison purposes)

R' YIELD IR M.p. MS FORMULA M.Wt. THEORY/FOUND Example (from dithiane) M.+ - 183 C H N 1 C8H17 73.6% 3390 - 464 C36H74NO6P.2H2O 684.00 63.21 11.50 2.05 (42.9%) 1705 62.96 10.97 2.12 16 C18H37 84% 3435 82-83 C C46H94NO6P 788.24 70.09 12.02 1.78 (47.3%) 1715 17 C4H9 69.6% 3400 - C32H66NO6P.2@H2O 591.87 60.35 11.24 2.20 (39.8%) 1718 60.47 10.71 2.36 18 H 79.5% 3350 92-94 C 355 C28H58NO6P 535.75 62.77 10.91 2.62 (68.4%) 1715 (M.++H) - 183 19 Ph(CH2)3 74.6% 3400 - C37H68NO6P 653.93 67.96 10.48 2.14 (38.7%) 1710 1650 20 (CH3)2CHCH2 53.2% 3400 592 (M++1) 559 C32H66NO6P.3H2O 591.87 59.51 11.23 2.17 75-77 C (27.1%) 1720 424,408,893 59.52 10.81 2.01 3430 60.07 11.09 2.34 21 C2H5 71.5% 1705 C30H62NO6P.2H2O 563.80 60.15 10.52 2.58 Example 22: Tablets were prepared according to the formulation: -compound of example 18 ..... ...... .. .......... 20 mg -excipient q.s. for one tablet up to . 200 mg (detail of excipient: lactose, starch, talc, magnesium, stearate).

Example 23: A dose aerosol was prepared delivering per dose: product of example 8.... 10 mg -emulsifier.... . . .. 0.15 mg -propellant.... 50 mg.

Example 24: A syrup was prepared according to the formulation: -product of example 13. . ..... . .. 5 mg -odoring and sweetening excipient q.s.p.... 100 ml.

Pharmacological activity I Anti-phospholipase A2 Activity Rat peritoneal neutrophils were incubated with ['4C] arachidonic acid. After washing, the cells were subjected to freeze/thaw disruption and the resulting preparations were incubated in the presence of calcium with or without test compound. This resulted in redistribution of the [14C] label from both the phospholipid and neutral lipid to free [14C] arachidonic acid as assessed by radiochromatography. The results in table 3 are the micromolar concentrations of test compound required to inhibit hydrolysis of phospholipid by 50% compared to control (íCsO M).

II. Antiedematous properties The antiedematous properties of the compounds were preliminarily assessed by modification of the carrageenin induced oedema procedure (Proc. Soc. Exp. Biol. Med., 1962, 11, 544) following oral administration to male Wistar rats. The results in table 3 are the percentage inhibitions by weight compared to control after a dose of 100mg/kg i.p.

Table 3

1 I Example R1 z R3 Mti-Pla2 Activity POR (81 ~ - IrM) 100po Soip 1 C18H37 CH20OO811L7 H -N+(cH3)3 0 ~ .~ .

2 C18H37 CN2 .. (cH3)3 14 66 . ~ ~ . ~ 3 1 " a 15 63 4 aSL8H37(INI=18CLI ILl(aC2)5)2 .. on (CH3) 3 6.7 16 76 5 C16H33 CH24) n 41 6 C6H13 I S 200 7 C16H33 CH2CR) . 7.8 14 8 c6El13 200 22 6 13 200 22 C18H37 S 6.6 17 10 OCO17H35 H H ! 27 0 11 C18H37 1 11 36 41 12 a C17R35 " ! 32 8 17 35 1 3 CCNglQH37 6.8 30

Example R1 R2 Z R3 Anti-Pla2 Activity POR (%) (IC50 - #M) 100po 50ip 14 COC17H35 CH2CH(OC2H5)2 H #N(CH3)3 52.9 28 15 C16H33 CH2CO2Me " " 7.4 34 16 C18H37 CH2COC18H37 ' " 5 17 " CH2COC4H9 ' " 39 70 18 " CH2CHO " 3.3 37 67 19 " CH2CO(CH2)3Ph " " 13 72 20 " CH2COCH2CHMe2 " " 0 37 21 " CH2COC2H5 " " 21 86

Claims

1. Compounds of general formula (I):

~S)-tH2' group, a (RO)2-CH-CH2- radical (where R represents an alkyl radical containing from 1 to 8 carbon atoms),

a " )-CH2-radical -o or a

radical where R is as defined above; or R2 and Z together with the carbon atom to which they are attached represent a

radical or a

radical; and either R3, R4 and R5 (which may be the same or different) each represents a straight or branched CnH2n+, alkyl radical where n' is as defined above or a cycloalkyl radical containing from 3 to 6 carbon atoms, or R3, R4 and R6 together with the nitrogen atom to which they are attached represent an N-methylpiperidinium group.

2. Compounds of formula (I) as claimed in claim 1 wherein R, represents a straight or branched CnH2n+1 alkyl radical where n represents an integer from 1 to 22 or R, represents a

radical or a

radical where n is an integer from 1 to 22.

3. Compounds of formula (I) as claimed in claim 1 or claim 2 wherein R3, R4 and R5 each represents a methyl group or together with the nitrogen atom to which they are attached represent an N-methyl piperidinium group.

4. Compounds of formula (I) as claimed in any one of the preceding claims wherein R2 represents a

radical in which R' represents a hydrogen atom, a straight chain CnH2nF1 alkyl radical (where n is an integer from 1 to 22) or a -(CH2)3-C6H5 radical, or R2 represents a

group, a (C2H50)2-CH-CH2 radical, a

radical or a

radical.

5. A compound selected from 3-(octadecyloxymethyl)-4-(phosphorylcholinyl) butanal, 1 -(1 ,3-dioxolan-2-yI)-2-(hexadecyloxymethyl)-3-(phosphorylcholinyl)-propane, 3-(hexyloxymethyl)-4-(phosphorylcholinyl)butanal, 5-(octadecyloxymethyl)-5-(phosphorylcholinylmethyl)-2(3H)-dihydrofuranone, 5-phosphorylcholinoxymethyl-5-stearoyloxymethyl- 1 ,3-dioxane, and methyl 3-(hexadecyloxymethyl)-4-(phosphorylcholinyl)butanoate.

6. Compounds as claimed in claim 1 as herein specifically disclosed in any one of Examples 1 to 21.

7. A process for the preparation of a compound of general formula (I) as defined in claim 1 wherein R2 is other than the radical

which comprises reacting a compound of general formula (Il)

(wherein R, and Z are as defined in claim 1 and R'2 is as defined in claim 1 for R2 other than the radical

with 2-chloro-2-oxo-1.3,2-dioxaphospholane of formula

and subsequently reacting the product initially obtained with an amine of formula (III)

wherein R3, R4 and R5 are as defined in claim 1, whereby the desired compound of formula (I) is obtained.

8. A process as claimed in claim 7 wherein the reaction of the compound of formula (II) with the 2-chloro-2-oxo-1,3,2-dioxaphospholane is effected in benzene as solvent.

9. A process as claimed in claim 7 or claim 8 wherein the reaction of the compound of formula (II) with the 2-chloro-2-oxo-1 3,2-dioxaphospholane is effected in the presence of an amine.

10. A process as claimed in claim 9 wherein the amine is pyridine or dimethylaminopyridine.

11. A process for the preparation of a compound of general formula (I) as defined in claim 1 wherein R2 represents a

radical, wherein R' is as defined in claim 1, which comprises submitting a compound of formula (IV):

(where Y is 2 or 3 and R1, R', R3, R4 and R5 are as defined in claim 1) to the action of chloramine T whereby the desired compound of formula (I) is obtained.

12. A process as claimed in claim 11 wherein the reaction of the compound of formula (IV) with chloramine T is effected in methanol-THF-water or acetone-water as solvent.

13. A process for the preparation of a compound of general formula (I) as defined in claim 1 wherein R2 represents a group of formula

which comprises submitting a compound of formula (IVA):

wherein R, R1, R3, R4 and R5 are as defined in claim 1 and Y is 2 or 3, to the action of ptoluenesulfonic acid whereby the desired compound of formula (I) is obtained.

14. A process as claimed in claim 13 wherein the reaction of the compound of formula (IVA) or (IVB) with p-toluene-sulfonic acid is effected in methanol-THF-water or acetone-water as solvent.

15. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

16. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 21.

17. Compounds of formula (I) as claimed in claim 1 whenever prepared by a process as defined in any one of claims 7 to 16.

18. Compounds as claimed in any one of claims 1 to 6 for use in therapy.

19. The use of a compound as claimed in any one of claims 1 to 6 for the manufacture of an anti-inflammatory medicament.

20. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) as defined in claim 1 in association with a pharmaceutical carrier and/or excipient.

21. Compositions as claimed in claim 20 wherein the active ingredient comprises a compound as claimed in claim 6.

22. Compositions as claimed in claim 20 or claim 21 in the form of dosage units.

23. Compositions as claimed in claim 22 wherein each dosage unit contains from 10 to 200 mg of the compound of formula (I).

24. Compositions as claimed in claim 23 wherein each dosage unit contains from 10 to 50 mg of the compound of formula (I).

25. Pharmaceutical compositions as claimed in claim 20 substantially as herein described.

26. Pharmaceutical compositions substantially as herein described in any one of Examples 22 to 24.

27. Compounds of formula (IV) as defined in claim 11.

28. A process for the preparation of the compounds of formula (IV) which comprises reacting a compound of formula (II')

(wherein Y is 2 or 3 and R1 and R' are as defined in claim 1) with 2-chloro-2-oxo-l ,3,2-dioxaphos- pholane of formula:

wherein R3, R4 and R5 are as defined in claim 1.

29. A process as claimed in claim 28 wherein the reaction of the compound of formula (II') with 2 chloro-2-oxo-1,3,2-dioxaphospholane is effected in benzene as solvent.

30. A process as claimed in claim 28 or claim 29 wherein the reaction of the compound of formula (II') with 2-chloro-2-oxo-1,3,2-dioxaphospholane is effected in the presence of an amine.

31. A process as claimed in claim 30 wherein the amine is pyridine or dimethylaminopyridine.

32. Compounds of formula (II) as defined in claim 7.

33. A process for the preparation of compounds of formula (II) as defined in claim 7 wherein R2, represents a

radical which comprises reacting diethyl malonate with 2-bromomethyl-1 ,3-dioxolane, to obtain a compound of formula (V):

and reacting said compound with sodium hydride and methanesulfonic ester of formula R1-03-S-CH3 or with C4H2n+1-N=C=O or with Cl-CO-CnH2n,1, whereby the desired compound of formula (II) is obtained.

34. A process for the preparation of compounds of formula (II) as defined in claim 7 wherein R'2 and Z together with the carbon atom to which they are attached represent a

radical which comprises reacting a compound of formula (VII):

with sodium hydride and methanesulfonic ester of formula R1-03S-CH3 or with CnH2n+1-N=C=O or with Cl-CO-CnH2n+1 whereby the desired compound of formula (II) is obtained.

35. A process for the preparation of compounds of formula (II) wherein R'2 and Z together with the carbon atom to which they are attached represent a

radical which comprises reacting a compound of formula (VIII):

with sodium hydride, R1-OH or CnH2n+l N=C=O or Cl-CO-CnH2n+l to obtain a compound of general formula (IX):

wherein R1 is as defined in claim 1, and submitting the said compound to the action of a reducing agent to obtain compounds of general formula (114)

wherein R1 is as defined in claim 1, reacting said compound of formula (114) with a peracid to obtain a compound of general formula (X)

wherein R1 is as defined in claim 1, submitting said compound of formula (X) to the action of tert.

butyldimethylsilyl chloride to obtain a compound of general formula (Xl):

wherein R1 is as defined in claim 1, reacting said compound with n-butyllithium, N-isopropylcyclohexylamine, acetic acid and DME to obtain a compound of general formula (XII):

(wherein R1 is as defined in claim 1) and finally submitting said compound to the action of a strong acid whereby the desired compound of formula (II) is obtained.

36. A process for the preparation of compounds of formula (II) as defined in claim 7 wherein R'2 represents a

radical (wherein R represents a methyl radical) which comprises reacting a compound of formula (XIII):

wherein R represents a methyl radical and R1 is as defined in claim 1, with tosic acid, to obtain a compound of general formula (XIV):

wherein R represents a methyl radical and R1 is as defined in claim 1, submitting said compound to the action of boron trifluoride etherate and metachloroperbenzoic acid to obtain a compound of general formula:

wherein R1 is as defined in claim 1 and then reacting said compound with methanol in the presence of concentrated sulfuric acid whereby the desired compound of formula (II) is obtained.

37. Compounds of formula (II') as defined in claim 28.

38. A process for the preparation of a compound of formula (II') as defined in claim 28 which comprises reacting a compound of formula (XVI):

reacting said compound of formula (XVII) with sodium hydride, then with a methanesulfonic ester of formula: R103-S-OH3 wherein R, is as defined in claim 1, or with an isocyanate of formula CnH2n,1-N=C=O or with Cl-CO-CnH2nFr, to obtain a compound of general formula (XVIII):

wherein Rl is as defined in claim 1, reacting the compound of formula (XVIII) with acetic anhydride in the presence of pyridine to obtain a compound of formula (XIX)::

wherein R1 is as defined in claim 1, submitting the compound of general formula (XIX) to the action of a dithiol of formula (XX): H-S-(CH2)y-S-H (XX) in which Y is 2 or 3, in the presence of boron trifluoride etherate to obtain a compound of formula (XXXI):

in which Y is 2 or 3 and R1 is as defined in claim 1, reacting said compound with potassium carbonate to obtain a compound of general formula (XXII):

wherein Y is 2 or 3 and R1 is as defined in claim 1, reacting said compound of formula (XXIII) with nbutyllithium, then with a compound of formula: : R'-X' (XXIV) (where R' is as defined in claim 1 with the exception of hydrogen and X' represents an halogen atom) to obtain a compound of general formula:

where R' is as defined in claim 1 with the exception of hydrogen, R1 is as defined in claim 1 and Y is 2 or 3, and finally, submitting said compound to the action of a strong acid whereby the desired compound of formula (II') is obtained.

39. Processes for the preparation of compounds of formulae (II), (II'), and (IV) substantially as herein described.