WO1997049715A1

WO1997049715A1 - Glycosidic perfluoroaliphatic surface-active agents, their preparation and use

Info

Publication number: WO1997049715A1
Application number: PCT/GB1997/001761
Authority: WO
Inventors: Aime Cambon; Carl Martin Edwards; Ralf-Peter Franke; Kenneth Charles Lowe; Peter Reuter; Wolfgang Roehlke; Heidi Trabelsi; Giampaolo Gambaretto; Massimo Napoli; Lino Conte
Original assignee: F2 Chemicals Limited
Priority date: 1996-06-24
Filing date: 1997-06-24
Publication date: 1997-12-31
Also published as: AU3351797A; MC2447A1

Abstract

The present invention is concerned with the synthesis of new carbamates derived from monosaccharides or disaccharides and their precursors. These compounds may be used as surface-active agents or co-surface-active agents of yolk phospholipids or Pluronic F-68 in preparing emulsions of fluorocarbons and other compounds. The compounds in accordance with the invention can be represented by the general formula: RFC(O)(CH2)nNHC(O)-SUGAR in which the sugar residue is connected at position C-6 and can be, for example, a glycosyl, α-methylglucopyranosyl, β-methylglucopyranosyl, galactosyl, α-methylgalactopyranosyl, β-methylgalactopyranosyl, mannosyl, lactosyl or gentiobiosyl group. The symbol RF represents a linear or branched perfluoroaliphatic chain, preferably with 1 to 10 carbon atoms, and n is preferably equal to 4 or 5.

Description

GLYCOSIDIC PERFLUOROALIPHATIC SURFACE-ACTTVΕ AGENTS, THEIR PREPARATION AND USE

The present invention is concerned with the synthesis of new carbamates derived from monosaccharides or disaccharides and their precursors. These compounds may be used as surface-active agents or co-surface-active agents of yolk phosphohpids or Pluronic F-68 in preparing emulsions of fluorocarbons and other compounds.

Fluorocarbons are chemically inert, they are capable of dissolving gases, in this case, oxygen and carbon dioxide, and are not metabolised in the human body. This is why many research projects throughout the world have, for many years, been devoted to possible therapeutic applications of these compounds in all their forms (emulsions, gels, liposomes or synthetic vesicles and other organised systems), for example, as injectable oxygen carriers, ie so-called blood substitutes. A blood substitute is 5 simply a synthetic preparation which allows the blood to be replaced temporarily during a surgical operation and thus makes it possible to limit the use of blood transfusions. These compounds have been used as respiratory liquids in the treatment of respiratory distress syndrome, as additives in radiology and cancer chemotherapy, haemodilution during operations, antithrombotic agents, treatment of 0 burns victims, diagnosis, preservation of tissues and organs, etc...

In addition, it is a known fact that the properties of emulsions (size and particle size distribution, surface charge, viscosity, etc..) and their long-term stability are determined by the surface-active agent which is used. Despite the great many 5 surface-active compounds which are used in the formulation of injectable emulsions, there is, to our knowledge, no surface-active agent which is capable of combining all the desired qualities at the same time: in other words, which is biocompatible and is optimally adapted to fluorocarbon emulsification.

0 The following are examples of the surface-active agents which may be used: Pluronic F-68, a sequenced copolymer of polyoxyethylene and poly disperse polyoxypropylene, which is acknowledged as being responsible for transient anaphylactic reactions in certain patients [lnt.Anesth.Clin. 23 (1985) 47], hydrolysable, oxidizable yolk phosphohpids (lecithins), which have certain oxidation products which can cause undesirable physiological reactions [Lipid Peroxides in Biology and Medicine, Academic Press, New York, (1982)], perfluoroalkyl amphiphiles such as derivatives of carnitine which can be hydrolysed when hot and which cannot withstand sterilisation of the emulsions, betaines, N-oxides, ethers, saccharides or disaccharides which have in their structures an ester, ether, amide or carbamide substituent, sulphonic compounds, polyoxyethyl compounds, etc.... [Carbohydrates as Organic Raw Materials, Verlagsgesellschaft, (Ed), Weinheim, (1993) 209-259]. However, as a whole, emulsions prepared from these compounds are not very stable and are only slightly more stable than those obtained with Pluronic F-68, or have an inadequate level of in vivo biocompatibility or do not have the same haemolysis properties (Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, R. Filler et al (Eds), Elsevier, (1993) 339-380].

There are few known natural sugars which contain an oxycarbamoyl group, and this type of substituent is also fundamental with regard to the biological activity of glycosidic antibiotics such as novobiocin [J.Am.Chem.Soc. 79 (1957) 3789] and venturicidin [Helv.Chim.Acta 51 (1968) 1293]. In recent times we described the preparation of perfluoroalkyl monocarbamates derived from monosaccharides which are particularly likely to be used in the field of microbiology for the purpose of extracting membranous proteins without causing their denaturation, or, in other words, by respecting, or even glorifying, their enzymatic activity [Bull.Soc.Chim.Fr. 131 (1994) 173].

The aim of the present invention is thus to synthesise new surface-active compounds or co-surface-active compounds of, in particular, phosphohpids, especially of yolk, or a copolymer of polyoxyethylene and polydisperse polyoxypropylene for the purpose of preparing or stabilising emulsions of fluorocarbons and other compounds. In one aspect, the present invention provides glycosidic perfluoroalkyl carbamates of the following general formula:

R_FC(O)(CH₂)„NHC(O) - SUGAR

We have found that the invention enables the provision of compounds which display a fairly good level of biological tolerance and do not cause haemolysis of red blood corpuscles. They may be obtained by adding unprotected sugar to perfluoroalkyl oxoisocyanates in accordance with the following reaction sequence:

R_F-C-(CH₂)_nC0₂R R_rC-(CH₂)_nC0₂H R_F-C-(CH₂)_nC0₂Cl

II in

R_F-CKCH^NCO + sugar R_rC-(CH₂)_nNHC(0) - SUGAR

IV

The oxoesters of the general formula (I) are prepared using a process which we have already reported in literature on this subject [Synthesis (1992) 315]. The oxoacids of the general formula (II), in which Rp represents a linear or branched perfiuoro- aliphatic (e.g. perfluoroalkyl) chain, preferably with 1 to 10 carbon atoms, and where n is from 1 to 10 and preferably is 4 or 5, may be obtained by formolysis of the corresponding oxoesters, working in the presence of a catalytic quantity of sulphuric acid (suitably about 0.08 moles of concentrated sulphuric acid per mole of oxoester used). Most of the prepared oxoacids are solids with the exception of compounds in which R_F = CF₃, which is a liquid. The acid chlorides of general formula (III), in which R_F and n are as defined above, may be obtained by the action of phosphorus pentachloride on the corresponding oxoacids. The oxoisocyanates of general formula (IV), in which R_F and n are as defined above, may be obtained by a Curtius rearrangement by the action of the acid chlorides on azidotrimethlysilane.

The sugar may be a glycosyl, α-methylglucopyranosyl, β-methylglucopyranosyl, galactosyl, α-methylgalactopyranosyl, β-methylgalactopyranosyl, mannosyl, lactosyl or gentiobiosyl group, for example. Compounds in which the sugar is β-methyl¬ galactopyranosyl and/or R_F contains 1, 3, 4, 5, 6, 7, 8 or 10 carbon atoms are particularly suitable as antithrombotic agents.

The following Examples illustrate the present invention but are by no means limitative.

Example 1 : Preparation of oxoacids by formolysis of oxoesters.

A. 10^"2 mole of formic acid with a concentration of 95-97% and 0.08 mole of concentrated sulphuric acid per mole of oxoester used are added to 2.10^'2 mole of oxoester. The mixture is heated in an oil bath to a temperature of 60°C, agitating constantly, until all of the oxoester has been used up (approximately 12 hours of reaction time). The formate thus formed and the excess of formic acid are driven off at a reduced pressure. 30 ml of toluene RP and half a spatula of ground charcoal are added to the residue. The mixture is then brought up to boiling point, agitating constantly, for 30 minutes, and then filtered whilst hot. The ground charcoal is washed twice with 10 ml of hot toluene, then the solution is concentrated down to a third by solvent evaporation. After cooling, the oxoacids are recovered in the form of transparent crystals.

We give the yields and properties of a number of compounds by way of example:

N°l. CF₃C(O)CH₂CH₂CH₂CH.COOH Yield = 85 %, bp°C / mmHg = 87 / 0,25 I.R (v ,) : 1762, 1714, 1300 - 1100 Proton NMR (CDC1₃ / TMS) : 1,71 [m, 4H,-(CH₂ )₂-];2,40(t, 2H, CH,, J = 6,86 Hz); 2,75 (t^CH^J = 6,70 Hz); 10,44(ls,OH). Fluorine NMR (CDC1₃ / CC1₃F) : -79,8

N°2. C_sF_nC(0)CH₂CH₂CH₂CH₂COOH Yield = 80 % mp°C = 57 I.R (v .) : 1751, 1704, 1300 - 1100

Proton NMR (CDC1₃ / TMS) : 1,71 [m,4H,-(CH₂)₂-];2,40 (t, 2H, CH₂, J = 6,86 Hz); 2,75 (t, 2H, CH₂, J = 6,70 Hz); 9,44 (Is, OH).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3(3F, CF₃); -120,8(2F, 1-CF₂); -122,8(4F, 2, 3- CF₂); -126,7 (2F, 4-CF₂).

N°3. C₆F₁₃C(0)CH₂CH₂CH₂CH₂COOH Yield = 79 % , mp°C = 71 I.R (v ,) : 1751, 1704, 1300 - 1100

Proton NMR (CDC1₃ / TMS) : 1,71 [m,4H,-(CH₂)₂-]; 2,40 (t, 2H, CH₂, J = 6,86 Hz); 2,75 (t, 2H, CH₂, J = 6,70 Hz); 9,44 (Is, OH).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF₂); -122,7 (2F, 3-CF ₂); -123,3 (2F, 4-CF₂); -126,6(2F, 5-CF₂).

N°4. C₇F₁₅C(0)CH₂CH₂CH₂CH₂COOH Yield = 80 % , mp°C = 84 I.R (v ,) : 1751, 1704, 1300 - 1100

Proton NMR (CDC1₃/ TMS) : 1,71 [m, 4H, -(CH ₂)₂-]; 2,40 (t, 2H, CH₂, J = 6.86 Hz); 2,75 (t, 2H, CH₂, J = 6,70 Hz); 9,44 (Is, OH).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF₂); -122,6 (4F, 3, 4-CF₂); -123,1 (2F, 5-CF₂); -126,7 (2F, 6-CF.).

N°5. C_gF_l7C(0)CH₂CH₂CH₂CH₂COOH Yield = 84 %, mp°C = 96

I.R (v .) : 1751, 1704, 1300 - 1100

Proton NMR (CDC1₃/ TMS) : 1,71 [m, 4H, -(CH ₂)₂-]; 2,40 (t, 2H, CH₂, J = 6,86 Hz);

2,75 (t, 2H, CH₂, J = 6,70 Hz); 9,44 (ls,OH). Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2-

CF₂); -122,7 (6F, 3, 4, 5-CF .); -123 (2F, 6-CF₂); -126,7 (2F, 7-CF₂).

N°6. C₅F_nC(O)CH₂CH₂CH₂CH₂CH₂COOH Yield = 80 %, mp°C = 45 I.R (v_{cm l}) : 1753, 1694, 1300 - 1100

Proton NMR (CDC1, / TMS) : 1,40 (m, 2H, CH ₂); 1,71 [m, 4H, -(CH,),-]; 2,38 (t, 2H, CH₂, J = 7,20 Hz); 2,81 (t,2H, CH₂, J = 7 Hz); 8,8(ls, OH). Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,8 (2F, 1-CF ₂); -122.8 (4F, 2, 3-CF₂); -126,7 (2F, 4-CF₂).

N°7. C₇F_|5C(O)CH₂CH₂CH₂CH₂CH₂COOH Yield = 82 % mp°C = 66 I.R ( ^vv cm- .1) ^/ : 1753, ' 1694, ⁷ 1300 - 1100

Proton NMR (CDC1₃ / TMS) : 1,40 (m, 2H, CH ₂); 1,71 (m, 4H, CH₂)_; 2,38 (t, 2H, CH,, J = 7,20 Hz); 2,81 (t, 2H, CH₂, J = 7 Hz); 8,8 (Is, OH).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122(2F, 2- CF₂); -122,7 (4F, 3, 4-CF ₂); -123,3 (2F, 5-CF₂); -126,6 (2F, 6-CF₂).

N°8. C₈F_I7C(O)CH₂CH₂CH₂CH₂CH₂COOH Yield = 88 % mp°C = 75 I.R ( ^vv cm- , 1) ' : 1753, * 1694, ⁷ 1300 - 1100

Proton NMR (CDC1₃/ TMS) : 1,40 (m, 2H, CH₂); 1,71 [m, 4H, -(CH₂)₂-]_; 2,38 (t, 2H, CH₂, J = 7,20 Hz); 2,8 l(t, 2H, CH,, J = 7 Hz); 8,8 (Is, OH).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF₂); -122,7 (6F, 3, 4, 5-CF ₂); -123 (2F,6-CF₂); -126,7 (2F, 7-CF₂).

Example 2: Preparation of acid chlorides.

1.5 . 10^"2 mole of phosphorus pentachloride are added to 10^"2 mole of oxoacid. A heating process takes place. The mixture, protected by a silica gel guard tube, is agitated at ambient temperature for half an hour, then heated gradually to 120°C for one hour. It is left at this temperature for 20 minutes and then allowed to cool down again (to around 35°C). The different constituents of the mixture are then separated by vacuum distillation. The first fraction consists of phosphorus oxychloride and the excess of phosphorus pentachloride, which sublimes. The acid chloride is recovered afterwards.

We give the yields and properties of a number of compounds by way of example: N°l. CF₃C(O)CH₂CH₂CH₂CH₂COCl Yield % = 85, bp°C/mmHg = 60/0,8 I.R (v ,) : 1799, 1765. 1300 - 1100.

N°2. C₅F„C(0)CH₂CH₂CH₂CH₂COCl Yield % = 90, bp°C/mmHg = 69/0,15 I.R (v ,) : 1799, 1757, 1300 - 1100.

N°3. C₆F_|3C(O)CH₂CH₂CH₂CH₂COCl Yield % = 88, bp°C/mmHg = 75/0,12 I.R (v ,) : 1799, 1759, 1300 - 1100.

N°4. C₇F₁₅C(0)CH₂CH₂CH₂CH₂COCl Yield % = 90, bp°C/mmHg = 90/0,1 I.R (v ,) : 1799, 1768, 1300 - 1100.

N°5. C₈F_]7C(O)CH₂CH₂CH₂CH₂COCl Yield % = 86, bp°C/mmHg = 130/0, 1 I.R (v ,) : 1799, 1768, 1300 - 1100.

N°6. C_SF, ,C(O)CH₂CH₂CH₂CH₂CH₂COC Yield % = 88, bp°C/mmHg = 87/1 I.R (v ,) : 1799, 1757, 1300 - 1100.

N°7. C₇F₎₅C(O)CH₂CH₂CH₂CH₂CH₂COCl Yield % = 85, bp⁰C/mmHg = 89/1 I.R ( ^vv cm- ,κ) : 1799, 1757, 1300 - 1100.

N°8. C_gF₁₇C(O)CH₂CH₂CH₂CH₂CH₂COCl Yield % = 86, bp°C/mmHg = 121/1 I.R ( ^vv cm-l ,)^/ : 1799, ⁷ 1757, 1300 - 1100.

Example 3 : Preparation of oxoisocyanates .

0.01 mole of oxoacid chloride, as obtained previously, is placed in a 50 ml flask which is equipped with a cooling apparatus, a dropping funnel and a magnetic agitation system, in a dry nitrogen atmosphere. 0.012 mole of trimethylsilane nitride is added to excess, drop by drop, monitoring the heating process throughout. After one hour of agitation, the trimethylsilane chloride formed is driven off, at ambient temperature and with reduced pressure. The oily residue, which is protected by a guard tube filled with dry CaCl₂ is heated to 80°C for one hour. When the reaction has finished (CPV inspection), the isocyanate obtained is then purified by vacuum distillation.

We give the yields and properties of a number of compounds by way of example:

N°l . CF₃C(O)CH₂CH₂CH₂CH₂NCO Yield % = 76, bp°C/mmHg = 43/0,2 I.R ( ^vv cm- ,ι)^/ : 2273, 1765, 1300 - 1100

Proton NMR (CDC1₃ / TMS) : 1,71 [m, 4H, -(CH ₂)₂-]; 2,78 (t, 2H, CH₂, J = 6,34 Hz); 3,37 (t, 2H, CFL,, J = 6,38 Hz)

(CDC1₃ / CC1₃F): -79,8.

N°2. C₅F_πC(O)CH₂CH₂CH₂CH₂NCO Yield % = 86, bp°C/mmHg = 74/7,5 10^"2 I.R (v .) : 2273, 1761, 1300 - 1100 Proton NMR (CDC1₃/ TMS) : 1,75 [m, 4H, -(CH ₂)₂-]; 2,81 (t, 2H, CH₂, J = 6.53 Hz); 3,38 (t, 2H, CH₂, J = 6,38 Hz).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,8 (2F, 1-CF₂); -122,8 (4F, 2, 3-CF₂); -126,7 (2F, 4-CF₂).

N°3. C₆F₁₃C(O)CH₂CH₂CH₂CH₂NCO Yield % = 92, bp°C/mmHg = 92/7,5 10^"2

I.R (v ,) : 2273, 1759, 1300 - 1100

Proton NMR (CDC1₃/ TMS) : 1,75 [m, 4H, -(CH ₂)₂-]; 2,82 (t, 2H, CH₂, J = 6,79 Hz);

3,37 (t, 2H, CH,, J = 6,38 Hz).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF ₂); -122 (2F, 2- CF₂); -122,7 (2F, 3-CF ₂); -123,3 (2F, 4-CF ₂); -126,6 (2F, 5-CF₂).

N°4. C₇F₁₅C(0)CH₂CH₂CH₂CH₂NCO Yield % = 90, bp°C/mmHg = 78/7 10^"2 I.R (v ,) : 2270, 1759, 1300 - 1100

Proton NMR (CDC1₃/ TMS) : 1,75 [m, 4H, -(CH ₂)_-]; 2,82 (t, 2H, CH₂, J = 6.79 Hz); 3,37 (t, 2H, CH₂. J = 6,38 Hz).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF,); -122,7 (4F, 3, 4-CF₂); -123,3 (2F, 5-CF₂); -126,7 (2F, 6-CF₂). N°5. C_gF₁₇C(O)CH₂CH₂CH₂CH₂NCO Yield % = 85, bp°C/mmHg = 92 / 6.5 10° I.R (v ,) : 2273, 1761, 1300 - 1100

Proton NMR (CDC1₃ / TMS): 1,75 [m,4H,-(CH ₂)₂-];2,82(t, 2H. CH,, J = 6.79 Hz): 3,37 (t, 2H, CH₂, J = 6,38 Hz). Fluorine NMR (CDC1₃ / CC1₃F): -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF,); -122,7 (6F, 3, 4, 5-CF ₂); -123 (2F, 6-CF,); -126,7 (2F, 7-CF₂).

N°6. C₅F„C(O)CH₂CH₂CH₂CH₂CH₂NCO Yield % = 87, bp°C/mmHg = 65 / 7.5 10^"2 I.R (v_cm ,) : 2290, 1759, 1300 - 1100 Proton NMR (CDC1₃ / TMS) : 1,43 (m, 2H, CH₂); 1,75 [m, 4H, -(CH₂),-]; 2,79 (t, 2H. CH₂, J = 6,93 Hz); 3,34 (t, 2H, CH₂, J = 6,38 Hz).

Fluorine NMR (CDC1, / CC1₃F) : -81,3 (3F, CF₃); -120,8 (2F, 1-CF.); -122.8 (4F, 2, 3-CF,); -126,7 (2F, 4-CF₂).

N°7. C₇F_]5C(O)CH₂CH₂CH₂CH₂CH₂NCO Yield % = 89, bp°C/mmHg = 78/7,5 10 ^"2

I.R (v ,) : 2290, 1759, 1300 - 1100

Proton NMR (CDC1₃ / TMS) : 1,43 (m, 2H, CH ₂); 1,75 [m, 4H, -(CH ₂)₂-]; 2,79(t,

2H. CH₂, J = 6,93 Hz); 3,34 (t, 2H, CH₂, J = 6,38 Hz).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF,): -122,7

(4F, 3, 4-CF ₂); -123,3 (2F, 5-CF₂); -126,6 (2F, 6-CF₂).

N°8. C₈F_I7C(O)CH₂CH₂CH₂CH₂CH₂NCO Yield % = 82, bp°C/mmHg = 80/6.5.10 ^"2 I.R (v ,) : 2290, 1759, 1300 - 1100 Proton NMR (CDC1₃ / TMS) : 1 ,43 (m, 2H, CH₂); 1 ,75 [m, 4H, -(CH₂)₂-]; 2,79 (t, 2H, CH,, J = 6,93 Hz); 3,34 (t,2H, CH₂, J = 6,38 Hz).

Fluorine NMR (CDC1₃ / CC1₃F) : -81,3 (3F, CF₃); -120,7 (2F, 1-CF₂); -122 (2F, 2- CF,); -122,7 (6F, 3, 4, 5-CF ₂); -123 (2F, 6-CF₂); -126,7 (2F, 7-CF₂).

Example 4: Preparation of glycosidic carbamates:

15 mmoles (1.5 eq) of sugar in solution in anhydrous pyridine (20 ml) is placed in a flask with a standard taper-ground joint, which is equipped with a cooling apparatus, a dropping funnel and a magnetic agitation system. Oxoisocyanate (10 mmoles. 1 eq) is added, drop by drop, using the dropping funnel at a temperature of between 5 and 10°C. After returning to ambient temperature, agitation is maintained for 20 hours. The solvent is evaporated and water (30 ml) and ethyl acetate (150 ml) are added to the residue obtained. After decanting, the organic phase is then evaporated until dry and the residue obtained is purified using a silica column (eluant e_thyl acetate / methanol: 9/1).

We give the yields and properties of a number of compounds by way of example:

N°l. 2-O-methyl-6-0-[(5-F pentyl-5-oxopentyl)carbamoyl]-α-D-glucoside (α anomer):

Yield % = 65, mp°C = 135

I.R (v ,) : 3394, 2940, 1757, 1701, 1300 - 1100.

Proton NMR (DMSO-D6 / TMS), δ ppm: 1,60 (m, 4H, -CH₂CH₂-); 2,90 - 3.08 (m, 4H, -CH₂COC₅F_π and NHCH₂- ); 3,34 (s, 3H, OMe); 3,30 to 3,80 (m, 4H CH²-OH,

CH³-OH, CH₂0- ); 4,1 (dd, 1H, CH⁵-OH); 4,3 (d,lH,C H⁴-OH); 4,60 (d, 1H. H¹- _β,

J,., = 3,13 Hz); 4,77, 4,90, 5,13 (3d,3H, OH', ,OH'₃ , OH'₄ ); 7,25 (t, 1H, NH); enol

(21%) : 9,44 (s, OH); 7,37 (t, NH ).

Fluorine NMR (DMSO-D6 / CC1₃F), δ ppm : -81,4 (3F, CF₃); -120,9 (2F, 1-CF,); - 122,8(4F, 2, 3-CF₂); -126,8 (2F, 4-CF₂). Carbon 13 NMR (CDC1₃ / TMS), δ ppm : 193,8 (t, COC₅F„, J = 26.4 Hz ): 157 (NHCO); 99,6 (C,); 73,9 (C₃); 72 (C,); 70 (C₄); 70 (C_s); 63,8 (C₆); 55,3 (OMe); 40,6 (NHCH₂); 37,4, 28,9, 19,6 (other groups ). Surface Tension: γ_s (Nm/m) / [C] (mol / L) = 16,2 / 4,24.10^"\

N°2. 2-O-methyl-6-0-[(5-F hexyl-5-oxopentyl)carbamoyl]-α -D-glucoside (α anomer ):

Yield % = 60, mp°C = 166

I.R ( vv cm- ,l)^/ : 3370, , 2940,, 1756,⁷ 1700,⁷ 1300 - 1100.

Proton NMR (DMSO-D6 / TMS), δ ppm : 1,60 (m, 4H, -CH,CH₂-); 2,90 - 3.08 (m, 4H, -CH₂COC₆F_]3 and NHCH₂- );3,34 (s,3H, OMe); 3,30 to 3,80 (m, 4H, CH²-OH, CH³-OH, CH₂O- );4,1 (dd,lH,CH⁵-OH); 4,3 (d,lH,CH⁴-OH), 4,60 (d,lH, H¹- b, J,., = 3,13 Hz); 4,77,4,90, 5,13 (3d,3H, OH'₂,OH'₃ , OH₄ ); 7,25 (t, NH); enol (21%) : 9,44

(s, OH); 7,37 (t, NH ).

Fluorine NMR (DMSO-D6 / CC1₃F), δ ppm: -81,3(3F,CF₃); -120,7(2F,1-CF₂);-

122,7(4F,2,3-CF₂); -123,3(2F,4-CF₂); -126,7(2F,5-CF₂).

Carbon 13 NMR (CD₃OD / TMS), δ ppm : 193,5 (t, COC₆F₁₃, J = 26,4 Hz ); 157,4

(NHCO); 99,5 (C ,); 73,4 (C₃); 71,8 (C₂); 70,1 (C₄); 69,8 (C,); 63,5 (C₆); 53,9

(OMe); 39,5 (NHCH₂); 36,8, 28,2, 19 (other groups ).

Surface Tension: γ (Nm/m) / [C] (mol / L) = 15,2 /1,97.10^"3. N°3. 2-O-methyl-6-O-[(5-F heptyl-5-oxopentyl)carbamoyl]-α-D-glucoside (a anomer) :

Yield % = 65, mp°C = 181

I.R ( ^v cm- ,κ) : 3373, 2940, 1756, 1700, 1300 - 1100.

Proton NMR (DMSO-D6 / TMS), δ ppm : 1,60 (m, -CH_;CH_:-); 2,90 - 3,08 (m, - CH₂COC₇F_]5 and NHCH_;- );3,34 (s, OMe); 3,30 to 3,80 (m, C H²-OH, CH³-OH,

CH₂O- );4,1 (dd,lH,CH⁵-OH);

4,3 (d,lH,C H⁴-OH), 4,60 (d, H¹- β, J, ₂ = 3,13 Hz); 4,77,4,90, 5,13 (3d, OH', ,OH'₃ ,

OH'₄ ); 7,25 (t, NH); enol (21%) : 9,44 (s, OH); 7,37 (t, NH ).

Fluorine NMR (DMSO-D6 / CC1₃F), δ ppm: -81,3(3F,CF₃); -120,7(2F,1-CF₂);- 122(2F,2-CF₂); -122,6(4F,3,4-CF₂); -123,1(2F,5-CF₂); -126,7 (2F,6-CF₂).

Carbon 13 NMR (CDC1₃ / TMS), δ ppm : 193,8 (t, COC₇F₁₅, J = 26,4 Hz ), 157

(NHCO), 99,6 C, 73,9 (C₃), 72 (C₂), 70 (C₄), 70, (C₅), 63,8 (C₆), 55,3 (OMe), 40,6

(NHCH₂),37,4, 28,9, 19,6 (other groups ).

Surface Tension: γ (Nm/m) / [C] (mol / L) = 14,8 /4,06.10^"3.

N°4. 2-O-methyl-6-O-[(6-F pentyl-6-oxohexyl)carbamoyl]-α-D-glucoside (α anomer) : O O

OCNH(CH₂)_sCCsF_|

Yield %=68, mp^v 165

I.R( ^vv cm-, 1⁷) : 3373, 2940, 1756, 1700, 1300- 1100.

Proton NMR (DMSO-D6 / TMS), δ ppm : 1,30 - 1,60 (m,6H, -CH,CH₂CH.-): 2,90 - 3,08 (m,4H, -CH₂COC₅F_n and NHCH₂- );3,34 (s, 3H, OMe); 3,30 to 3,80 (m,4H CH²-OH, CH³-OH, CH₂O- ); 4,1 (dd,lH,C H⁵-OH); 4,3 (d,lH,CH⁴-OH), 4,60 (d, H¹- β, J,.₂= 3,13 Hz); 4,77,4,90, 5,13 (3d,3H, OH'₂ ,OH'₃ , OH'₄ ); 7,25 (t, NH).

Fluorine NMR (DMSO-D6 / CC1₃F), δ ppm : -81,3(3F,CF₃); -120,9(2F,1-CF₂);-

122,7(4F,2,3-CF,); -126,7(2F,4-CF₂).

Carbon 13 NMR (CDC1₃ / TMS), δ ppm : 193,3 (t, COC₅F_n, J = 26,4 Hz ); 156,9

(NHCO); 99,5 (C ,); 73,7 (C₃); 71,9 (C₂); 70 (C₄); 69,8 (C₅); 63,5 (C₆); 55,2 (OMe); 40,7 (NHCH₂); 37,6, 29,5, 25,2, 22 (other groups ).

Surface Tension: γ (Nm/m) / [C] (mol / L) = 15,8 /1,65.10^'\

N°5. 2-O-methyl-6-O-[(5-F heptyl-5-oxopentyl)carbamoyl]-β-D-glucoside(β anomer)

Yield % = 63, mp°C = 156

I-R ^.,) : 3373, 2940, 1756, 1700, 1300 - 1100.

Proton NMR (DMSO-D6 / TMS), δ ppm : 1,50 (m, 4H, -CH₂CH₂-); 2,89, 2,99 (m, 4H, -CH₂COC₇F₁₅ and NHCH₂- );3,37 (s,3H, OMe); 3,55, 4,03, 4,80, 4,99 (CH²-OH, CH³-OH, CH₂O-CH⁵-OH, CH⁴-OH, OH'₂ ,OH'₃ , OH'₄ ); 4,60 (d,lH, H'- α, J,_., = 4,44

Hz); enol (17%) : 6,70 (s, OH); 7,27 (t, NH). Fluorine NMR (DMSO-D6 / CC1₃F), δ ppm : -81,3(3F,CF₃); -120,7 (2F,1-CF₂); -

122(2F, 2-CF₂); -122,6 (4F, 3, 4-CF₂); -123,1(2F, 5-CF₂); -126,6 (2F, 6-CF₂).

Carbon 13 NMR (CD₃OD / TMS) δ ppm : 193,8 (t, COC₇ F_]5, J = 26,4 Hz ); 157,4

(NHCO); 104,3 (C,); 73,2 (C₃); 72,7 (C,); 70,8 (C₄); 68,6 (C₅); 63,3 (C₆); 55,6

(OMe); 40,6 (NHCH ₂); 37,4, 28,2, 19,6 (other groups ). Surface Tension: γ_s(Nm/m) / [C] (mol / L) = 15,1 / 3,63.10^'3.

Further aspects of the invention as well as preferred embodiments thereof are set forth in the following claims.

Claims

1. A glycosidic perfluoroaliphatic surface-active compound of the general formula:

R_FC(O)(CH₂)_nNHC(O) - SUGAR

in which the sugar residue is connected at position C-6 and R_F represents a linear or branched perfluoroaliphatic chain and n is from 1 to 10.

2. A perfluoroaliphatic compound of Claim 1 in which R_F contains from 1 to 10 carbon atoms and/or n is 4 or 5.

3. A perfluoroaliphatic compound of Claim 1 or Claim 2 in which the sugar residue is a glycosyl, α-methylglucopyranosyl, β-methylglucopyranosyl, galactosyl, α-methylgalactopyranosyl, β-methylgalactopyranosyl, mannosyl, lactosyl or gentiobiosyl group.

4. A perfluoroaliphatic compound of Claim 3 in which the sugar residue is a β- methylgalactopyranosyl group.

5. A perfluoroaliphatic compound of Claim 3 in which the sugar residue is an α- methylglucopyranosyl group.

6. A perfluoroaliphatic compound of any of Claims 1 to 5 in which R_F is a linear perfluoroaliphatic group containing 1, 3, 4, 5, 6, 7, 8 or 10 carbon atoms.

7. A perfluoroaliphatic compound of any of Claims 1 to 6 in which R_F is a perfluoroalkyl group.

8. A process for preparing an oxoacid of formula (II):

in which R_F and n are as defined in any of claims 1, 2, 6 or 7, characterised in that formic acid is reacted with a corresponding perfluoroaliphatic oxoester in the presence of a catalytic quantity of sulphuric acid.

9. A process for preparing an acid chloride of formula (III):

R_F-C-(CH₂)_nCO₂Cl (III)

O

in which R_F and n are as defined in any of claims 1, 2, 6 or 7, characterised in that phosphorus pentachloride is reacted with the corresponding perfluoroaliphatic oxoacid.

10. A process for preparing an oxoisocyanate of formula (IV);

in which R_F and n are as defined in any of claims 1, 2, 6 or 7, characterised in that it is obtained by thermal decomposition of the corresponding perfluoroaliphatic nitride, the latter optionally having been prepared by the reaction of a perfluoroaliphatic acid chloride with azidomethylsilane.

11. A process for preparing a glycosidic carbamate of the general formula (V): R_F-C-(CH₂)_nNHC(O) - SUGAR (V)

O

in which the sugar residue is as defined in any of Claims 1 to 5, and R_F and n are as defined in any of claims 1 , 2, 6 or 7, characterised in that a perfluoroaliphatic oxoisocyanate is reacted with an unprotected or partially protected sugar.

12. A compound of formula (II), (III), (IV) or (V) as defined, respectively, in Claims 7 to 11.

13. The use of a compound of any of Claims 1 to 7 as a surface-active agent or a co-surface-active agent of yolk phosphohpids or of a copolymer of polyoxyethylene and polydisperse polyoxypropylene in preparing emulsions or microemulsions.

14. The use of Claim 13, wherein the emulsion or microemulsion is of one or more fluorocarbons.

15. A perfluoroaliphatic compound of any of Claims 1, 2, 4 or 6 for use as an antithrombotic agent.

16. A fluorocarbon emulsion which contains a compound of any of Claims 1 to 7.

17. A fluorocarbon emulsion of Claim 16 which is for use as a blood substitute.

16. A method of infusing a patient with a blood substitute, comprising infusing said patient with a fluorocarbon emulsion which contains a compound of any of Claims 1 to 7.