| PATENT ASSIGNEE'S COUNTRY | France |
| UPDATE | 03.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 21.03.00 |
| PATENT TITLE |
Fluorinated organic compounds, ophthalmological applications thereof and method for making same |
| PATENT ABSTRACT |
The invention relates to novel fluorinated organic compounds having the following molecular structure: ##STR1## where R.sub.F is a fluorinated carbon chain, R.sub.1H is hydrogen or a saturated hydrogenated carbon chain, R.sub.2H is hydrogen or a saturated hydrogenated carbon chain, R.sub.1H and R.sub.2H being not simultaneously hydrogen, the group ##STR2## comprising a principal chain and at least one linear or cyclic branch. These compounds may be prepared by reacting a phosphine with a halide under heating, and then hot reacting in a solvent the resulting phosphonium salt with a branched aldehyde or a ketone. These compounds have an excellent stability, a good biocompatibility and a high capacity to solubilize gases and particularly oxygen, such properties allowing their use in applications of the ophthalmological type or as an organ preservation medium. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 26.02.98 |
| PATENT CT FILE DATE | 29.08.95 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | 06.03.97 |
| PATENT REFERENCES CITED |
by C. Cecutti et al., "Potential Blood Substitutes Synthesis and Microemulsification of mixed Hydrogenated and Fluorinated Oils", J. Dispersion Science and Technology, vol. 7, No. 3, 1986, pp. 307-318. by C. Cecutti et al., "New Formulation of Blood Substitutes; Optimization of Novel Fluorinated Microemulsions", Eur. J. Med. Chem., vol. 24, 1989, pp. 485-492. by C. Cecutti et al., "A New Formulation for Blood Substitutes", J. Dispersion Science and Technology, vol. 11, No. 2, 1990, pp. 115-123. by A. Novelli, "Microemulsification et Biocompatibilite d'un Radioprotecteur Hydrophile et d'un Transporteur d'Oxygene Hydrophobe", Le Titre De Docteur De L'Institut National Polytechnique De Toulouse, May 1990, pp. 9-10; 13-31 and 217-218. |
| PATENT CLAIMS | CpF2p+1-CH2-CH=CH-(CH2)n-Me; p = 2-12; n > 0 |
| PATENT DESCRIPTION |
DESCRIPTION 1. Technical Field of the Invention The present invention relates to novel fluorinated organic compounds having a fluorinated chain and a hydrogenated chain; the invention aims at applications of these novel compounds, particularly ophthalmological applications or as cell preservation medium, and relates to the method of making said compounds. 2. Background Art Fluorinated compounds are known to have specific properties such as good stability, biocompatibility, and capacity to solubilize gases and specially oxygen, these properties being decisive in numerous applications. Amoung these fluorinated compounds, specific compounds having a hydrogenated chain with a double bond: R.sub.F --CH.sub.2 --CH.dbd.CH--R.sub.H where R.sub.F is a fluorinated carbon chain and R.sub.H a saturated hydrogenated linear chain were recently prepared. Reference may be made to the following publications relating to this type of linear compounds and the applications thereof as blood substitutes or replacement of the vitrous humor in the eye: C. Cecutti et al., POTENTIAL BLOOD SUBSTITUTES SYNTHESIS AND MICROEMULSIFICATION OF MIXED HYDROGENATED AND FLUORINATED OILS, J. DISPERSION SCIENCE AND TECHNOLOGY, 7(3), 307-318 (1986); C. Cecutti et al., NEW FORMULTAION OF BLOOD SUBSTITUTES: OPTIMIZATION OF NOVEL FLUORINATED MICROEMULSIONS, Eur. J. Med. Chem. 24 (1989) 485-492 ; C. Cecutti et al., A NEW FORMULATION FOR BLOOD SUBSTITUTES, J. DISPERSION SCIENCE AND TECHNOLOGY, 11(2), 115-123 (1990). Anne NOVELLI, Thesis MICROEMULSIFICATION ET BIOCOMPATIBILITE D'UN RADIOPROTECTEUR HYDROPHILE ET D'UN TRANSPORTEUR D'OXYGENE HYDROPHOBE, I.N.P.T., presentation of May 18, 1990. This family of linear fluorinated compounds has specific stability, density and oxygen solubilization properties which, in various applications, make the use thereof advantageous as compared to the other fluorinated compounds. Such properties result one the one hand from the central double bond and on the other hand from the hydrogenated chain located opposite to the fluorinated chain. The double bond reduces the volatility of the compound for a same number of carbons and increases their oxygen solubilization capacity. The presence of the hydrogenated chain leads to a density which is a function of the chain length, and which is lower than in the case of non hydrogenated fluorinated compounds having the same fluorinated chain. Accordingly, the combined choice of the fluorinated R.sub.F and hydrogenated R.sub.H chains allows to some extent to obtain liquid compounds with the desired density and number of fluorine atoms, i.e. a given oxygen solubilization capacity. These linear fluorinated compounds are currently prepared by means of a method using the Wittig's reaction. However, the yield of this synthesis is low; for example, the average synthesis yields for fluorinated chains with eight carbon atoms are of the order of 50% (overall yield). Since the starting materials used in the Wittig's reaction are costly, the cost of the resulting linear fluorinated compounds is very high, which limits the possibility of their application considerably. To the knowledge of the inventors, these linear compounds were only synthesized in the laboratory for research purposes, and are not being used. Moreover, these linear compounds have good oxygen solubilization properties, provided that their fluorinated chain has a comparatively high number of carbon atoms, which is associated with high density compounds. For numerous applications, the density/oxygen solubilization compromise would therefore not be easy to obtain with such type of compounds. DISCLOSURE OF THE INVENTION The present invention aims at providing novel fluorinated organic compounds the properties thereof are at least as attractive as the above-mentioned linear fluorinated compounds, but with the benefit of higher synthesis yields, allowing a reduction in the preparation costs thereof in marked proportions, whereby the possibilities of application would be widened. A further object of the invention is to provide fluorinated compounds having an increased oxygen solubilization capacity as compared to the above-mentioned linear compounds having the same fluorinated chain. Yet a further object of the invention is to facilitate the adjustment of the physicochemical properties of the compound in each application, according to the specifications of the application. In view of these objects, the novel compounds according to the invention have the following molecular structure: ##STR3## where R.sub.F is a fluorinated carbon chain, R.sub.1H is hydrogen or a saturated hydrogenated carbon chain, R.sub.2H is hydrogen or a saturated hydrogenated carbon chain, R.sub.1H and R.sub.2H being not simultaneously hydrogen, the group ##STR4## comprising a principal chain and at least one linear or cyclic branch. The organic compounds according to the invention are thus characterized by the following, in combination: the presence of a non reactive central double bond in the molecule, the presence, on the respective sides of the double bond of a fluorinated and a hydrogenated chain, the branched character of the hydrogenated chain. These compounds are liquid at ambient temperature, perfectly biocompatible, the density, oxygen solubilization capacity and refractive index thereof varying as a function of the fluorinated and hydrogenated chains thereof. The oxygen solubilization capacity thereof appears to be markedly increased as compared to the similar (same fluorinated chain, similar total number of carbon atoms) linear compounds, and the preparation costs thereof are lower. In a subfamily, the moiety R.sub.1H may be constituted of a hydrogen, the molecular structure of the compound being the following: ##STR5## where the groups R', R" and R'", identical or not, have each the following formula: (CH.sub.2).sub.m --C.sub.x H.sub.y, with: n.gtoreq.0 m.gtoreq.0 y=2x or 2x+1 with x.gtoreq.0 at least two of the groups R', R" and R'" are not hydrogen atoms, the total number of carbon atoms of the groups R', R" and R'" being lower than 25-n. The group C.sub.x H.sub.y may particularly consist of one or more methyl, ethyl or propyl groups, so as to lead to compounds which, as will be more apparent hereinafter, have very advantageous properties in ophthalmological applications, particularly the three compounds with the following structure: ##STR6## where k=1, 2, or 3. The following compound in the above-mentioned subfamily has a high refractive index of approx. 1.37, which makes it very attractive in ophthalmological applications because of the difference between such index and that of physiological serum (1, 33), which facilitates the use thereof (improved injection and removal due to a perfect visualization of the product): ##STR7## In a further subfamily, neither R.sub.1H and R.sub.2H moieties are hydrogen, the compounds having the following molecular structure: ##STR8## where y=2x+1, with x.gtoreq.1, y'=2x'+1, with x'.gtoreq.1. In this subfamily, the groups C.sub.x H.sub.y and C.sub.x' H.sub.y' may also be methyl, ethyl or propyl groups. The fluorinated chain R.sub.F may be a perfluorinated or non perfluorinated chain, and may possibly comprise a heteroatom. The presence of a perfluorinated chain with a formula C.sub.p F.sub.2p+1 with p in the range between 2 and 12 is preferred in various applications, due to its improved stability. The branched compounds having such chain have a density which is in the range between 1.1 and 2.2 and increases as a function of p (and which decreases to a lesser extent as a function of the number of carbon atoms in the branched hydrogenated chain). The refractive index of such branched compounds with a perfluorinated chain is comprised between 1.2 and 1.7, as a function of p and the number of carbon atoms in the R.sub.1H and R.sub.2H moieties. The solubility in silicone oil of such compounds is greater than 10 wt %. The novel branched fluorinated compounds according to the invention may be prepared using a Wittig's reaction: it was unexpectedly observed that the overall synthesis yields are higher than with known linear compounds having the same fluorinated chain. This result currently remains hardly explained, but one may suppose it derives from a lower volatility of the branched compounds. For example, in a case where the R.sub.F chain consists of the perfluorinated chain with eight carbon atoms C.sub.8 F.sub.17, the overall synthesis yield is about 70% (namely a relative increase of 40% as related to the synthesis yield of similar linear compounds); furthermore, an improved reproducibility of the results is observed, the synthesis of linear compounds depending tightly of the conditions under which the reaction is carried out. Moreover, it was evidenced that with an equivalent number of carbon atoms, the oxygen solubilization capacity is significantly higher for the branched compounds according to the invention (as compared to linear compounds with a same number of carbon atoms). This may be explained by the fact that, in the case of the compounds according to the invention, this oxygen solubilization capacity results not only from the fluorinated chain but also from the branched portions of the molecules, by a sterical hindrance effect. DESCRIPTION OF A PREFERRED EMBODIMENT In the general embodiment thereof, the method for preparing the branched fluorinated compounds according to the invention comprises the following steps: a phosphine Z.sub.3 P is reacted with a halogenide of the formula XCH.sub.2 CH.sub.2 R.sub.F in order to obtain a phosphonium salt Z.sub.3 P.sup.+ X.sup.- CH.sub.2 CH.sub.2 R.sub.F, and said phosphonium salt is reacted in a solvent with a branched aldehyde or ketone ##STR9## in the presence of a weak base. For preparing a compound of the subfamily (2), the phosphonium salt is reacted under heating with a branched aldehyde of the following structure: ##STR10## In the case of the three above-mentioned compounds (3), a triphenylphosphine (C.sub.6 C.sub.5).sub.3 P may be selected as the phosphine and a fluoroalkyl iodide I(CH.sub.2).sub.2 R.sub.F as the halogenide. The resultant phosphonium salt is then reacted with the following branched aldehyde: ##STR11## where k=1, 2, or 3. Dioxane is preferably used as a solvent, in the presence of potassium carbonate and water acting as a catalyst. The reaction temperature is then adjusted to the reflux temperature of the dioxane. The potassium carbonate may subsequently be removed by filtration, and the resultant triphenylphosphine oxide is removed by precipitation followed by filtration, the branched fluorinated compound being collected by means of distillation steps. For preparing a compound of the subfamily (5), the phosphonium salt is reacted under heating with a ketone of the following formula: ##STR12## The branched fluorinated compounds according to the invention may be used for preparing an artificial composition of vitrous or aqueous humor for an eye, particularly compounds (2) where the group C.sub.x H.sub.y consists of one or more of methyl, ethyl and/or ethyl groups. The following compounds: ##STR13## where k=1, 2, or 3, are particularly adapted for preparing an artificial composition for the temporary replacement of the vitrous humor in the eye in view of a re-adhesion of the retina. The density of such compounds is comprised in the range between 1.48 and 1.54 and the refractive index between 1.33 and 1.35. In ophthalmological applications and more generally in applications where a high purity is prescribed, the synthesis method is complemented with the final purification steps of: combined extraction in organic and aqueous phases, adapted for removing the remaining traces of the solvent and phosphine oxide, removal of the aqueous phase by means of decantation, evaporation of the organic phase, flash distillation under vacuum and cooling of the resultant product with nitrogen, and subjecting the resultant product to filtration and neutralization steps in order to remove the last residues. It was besides observed that the branched fluorinated compounds according to the invention have a good solubility in silicone and fluorosilicone oils. This property allows, when needed, their use in the form of a solution or suspension in this oil so that products having the properties of silicone or fluorosilicone oils and an adjustable density greater or equal to 1 are obtained. Oils having a viscosity in the range between 100 cSt and 10,000 cSt are advantageously used for this purpose. For example, in the field of ophthalmology, the above-mentioned compounds (2) or (7) may be used as a solution in a silicone or fluorosilicone oil, for the preparation of an artificial composition to replace the vitrous or aqueous humor in the eye in order to provide an internal buffer effect in the eye. This provides a further means for decreasing the density and adjusting same to the desired value, particularly for products intended to remain in the eye for long periods. Moreover, in some ophthalmological applications, this allows also to combine the properties of the silicone oils with the properties (viscosity, density, refractive index) of the compounds according to the invention. It should be noted that the high solubility of the compounds according to the invention in silicone oils avoids any risk of formation of an emulsion or interface in the mass. The branched fluorinated compounds according to the invention may also be used in all applications where the oxygen solubilization capacity is desired, particularly for preparing a medium for the preservation of biological organs, tissues or cells, particularly a medium for the preservation of ocular tissues such as corneae. The following examples are intended to illustrate the invention. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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