Physiologically acceptable emulsion containing hydrides perfluorocarbon ether, and methods of their use

 

(57) Abstract:

The invention relates to the field of pharmaceutical industry and relates to a physiologically compatible emulsions containing hydrides perftoruglerodnykh esters. The invention consists in that the emulsions have different medical applications. In particular, they are useful as a contrast medium for such methods of biomedical research, as a means of nuclear and19F-magnetic resonance, ultrasound and x-ray methods, method of computer tomography, as carriers of oxygen or "artificial" blood in the treatment of heart diseases and vascular diseases, as adjuvants to coronary angioplasty and in radiation and cancer chemotherapy. The invention provides the desired level of oxygen transfer, rather stable in liquid or frozen state, is rapidly excreted from the body in order to avoid toxicitiy. 13 C.p. f-crystals, 1 table.

The present invention relates to aqueous physiologically acceptable emulsion of a perfluorocarbon hydrides ether having 8 to 12 carbon atoms. Consider emulsions have different medical applications. Medical t is Avani, such as nuclear magnetic resonance,19F-magnetic resonance, ultrasound, x-ray, computed tomography, as a carrier of oxygen or blood substitute - "artificial blood" in the treatment of heart failure, heart attacks and other vascular diseases, as adjuvants to coronary angioplasty and in radiation and cancer chemotherapy.

It is well known that highly fluorinated organic compounds and in particular fluorinated carbon compounds are stable and chemically inert. In the last 25 years, special attention was paid to the use of such compounds in biological systems due to their ability to dissolve and transport large quantities of oxygen. These properties determine the prospects of using such compounds as contrast medium, agents for the transport of oxygen or "artificial blood" in the treatment of heart attacks, stroke and other vascular diseases, as adjuvants to coronary angioplasty and in radiation and cancer chemotherapy.

Highly fluorinated organic compounds, which, as noted above, useful in such applications are Targetelement, performimplemented, PERFLUORO-2,2,4,4-tetramethylpentane; C9-C12performin, such as performapply, performability, PERFLUORO-1 - estrellitas amines; promptrelease compounds, such as performancebased and perforative; And-4 - metalictastelipitor and perforator, including chlorinated politiceskie esters. Such compounds are described, for example, in U.S. patent No. 3, 962, 439; N 3, 493, 581; N 4, 110, 474; N 4, 186, 253; N 4, 187, 252; N 4, 252, 827; N 4, 423, 077; N 4, 443, 480; N 4, 534, 978; N 4. 686, 024; N 4, 865, 836; N 4, 866, 096; N 4, 868,318, in European application N 80710 and N 158, 996, in the description of the patent of great Britain No. 1, 549, 038 and in the description of the posted application Germany N 2, 650, 586.

In the publication EP-A-307-087 are emulsions, including perfluorocarbons, emulsifier, preferably lecithin, and water. The publication describes the use of various perfluorocarbons in the emulsion, including F[CF(CF3CF2O]2CHFCF3. In publications FR-A-2620445 and W092/02560 provides information about the use for the transport of gases of various highly fluorinated compounds, including F[CF(CF3CF2O]2CHFCF3and F[CF(CF3CF2O]3CHFCF3. In the publication W0 93/01798 describes emulsion containing PV which the fluorocarbon is selected from various compounds, F[CF(CF3CF2O]2CHFCF3.

For intravenous use vysokopetrovsky organic compounds must be pre-dispersed as an emulsion. See, for example, L. C. Clark, Jr. et al, "Emulsion Of Perfluorinated Solvents For Intravascular Gas Transport", Ped.Proc., 34(6), pp. 1468-77 (1975); K. Yokoyama et al. "A Perfluorochemical Emulsion As An Oxygen Carrier," Artif. Organs (Cleve). 8(1), pp. 34-40 (1984); and United States patents 4,110,474 and 4,177,252. Briefly note that vysokopetrovsky organic compounds are not mixed in the blood.

In U.S. patent No. 3, 991, 138 reported use as an artificial blood perfluorocarbon emulsions containing fluorocarbons, which can be derived from the body of the animal within a clinically acceptable period of time. In U.S. patent No. 3, 991, 138, for example, it was described that perversonality removed from the body of the animal faster than the PFC. In contrast, it was found that when a living organism was introduced perfluorocarbon ethers, they remained in the liver and spleen for a long time. As recently as synthetic blood emulsion was tested hydrophilanthropy simple ether F[CF(CF3CF2O]4CHFCF3but he found the trend of the change in a living organism perfluorocarbon ethers unsuitable for use as carriers of oxygen for medical purposes.

As a result, for emulsions containing perfluorocarbons, continue research on the effectiveness of their use as carriers of oxygen and ways of their elimination from the body within a clinically acceptable period of time. Such emulsions should not only contain a high enough concentration vysokoorientirovannogo organic compounds in order to provide the desired level of oxygen transfer, but also to be sensitive to sterilization, mainly heat, must be sufficiently stable in liquid or frozen state, must be chemically stable in the blood stream over a long enough period of time to deliver the necessary amount of oxygen, and should quickly excreted from the body in order to avoid toxicitiy and retention in organs and body parts.

The present invention relates to aqueous physiologically acceptable aqueous emulsion of a perfluorocarbon hydrides ether, in particular to hydroinformatics simple esters or simple esters, substituted performlicensechecks group ("hydrides PFC ether"). It was found that these hydrides PFC ether very EPA in the body. In fact, it was found that these hydrides PFC ether are chemically stable in the blood stream for a time sufficient to transfer the necessary amount of oxygen, and rapidly excreted from the body, so there is no trace in the vital organs was not observed even in the few days after their introduction. These hydrides PFC ether are excellent candidates for use in blood substitutes and emulsions used for oxygen transport.

Emulsions in accordance with the present invention can be used in various medical purposes, for example as a contrast agent in various methods of biological research, including the method of nuclear magnetic resonance,19F-magnetic resonance, ultrasound, x-ray methods, the method of computer tomography, as carriers of oxygen or blood substitutes in the treatment of heart failure, seizures and other vascular diseases, as adjuvants to coronary angioplasty and in cancer radiation and chemotherapy.

Physiologically acceptable emulsion in accordance with the present invention contain a C8-C12perforations group, or a mixture of the two esters. Aliphatic simple ester is a straight or branched chain of carbon atoms. Other components of the emulsion includes water and a surfactant, and the quantitative content of these components in emulsions meets acceptable physiological reception.

Especially preferred are emulsions containing hydrides C9-C11PFC ether, which were found, are derived from vital organs such as the liver, within an exceptionally short time. Hydrides PFC ether present a new flexible changes in the formulation of physiologically acceptable emulsions. These hydrides PFC ether can easily be prepared and have a lower density and boiling point, which makes them very convenient for cooking, transport of oxygen and excretion from the body of the animal. These hydrides PFC ether not have any adverse effects on the lungs when cleaning the body. In addition, volatility, molecular weight, solubility and ozone characteristics determine their preference in medical applications. The essence of the present invention, its advantages and opportunities datasim description, the term "PERFLUORO", as well as the terms "perforations", "perforazione", "perforaciones" or "performanceheavy" means that, except as specifically indicated by the prefix "hydro", there are no associated carbon atoms of the hydrogen replaced by fluorine, there is no unsaturation. Thus, the term "hydroinformatics ether" means that there is at least one hydrogen atom bound to carbon, and the remaining carbon atoms in the aliphatic group of this compound is associated with fluorine or oxygen. Such a connection may also be called "hydride perforations ether". The prefixes "dihydro" and "trihydro" means that the compound are, respectively, two or three hydrogen atoms associated with carbon. For simplicity, the phrase "hydride PFC ether" will sometimes mean that considers all forms of compounds in accordance with the present invention, which contains one to three atoms of hydrogen, one or more atoms of oxygen in ordinary air or carbon group is aliphatic, alicyclic or electricequipment aliphatic or straight or branched chain. "1ohydrogen or 2ohydrogen" further means that the atom is administered water emulsion in accordance with the present invention contain hydrides WITH8-C12PFC ether, water and surfactant, and these components are contained in the emulsion in amounts corresponding acceptable physiological reception. Hydride PFC ether is selected from the group busy WITH8-C12hydroinformatics ether, hydroinformatics ether, substituted saturated performlicensechecks group and hydrophilicities ether and mixtures of such ethers. These aliphatic ethers have straight or branched chains of carbon atoms. The term "saturated" means that these compounds do not have a single double bond or are not saturated in the molecule.

Preferably the emulsions contain hydrides WITH9-C11PFC ether, as such compounds, has been found to most effectively perform in emulsions feature vectors of oxygen and at the same time only briefly delayed in the body. As a class hydrides PFC ether have a boiling point of about 120oC, which makes them non-toxic with a satisfactory ability excretion from the body.

A preferred class of hydrides PFC ether may be represented by the formula I X-Rf-O(R'f)nRf-H, d ether;

X is a fluorine atom, a primary hydrogen atom or 2othe hydrogen atom on the carbon atom adjacent to the oxygen atom in a simple ether;

n is an integer from 0 to 4;

Rf, R'f, Rfis independently selected from unbranched or branched group consisting of performanceline, peritonsillitis or perversonality containing one or more atoms of oxygen in ordinary air. Compounds according to formula 1, in which the hydrogen atoms are either primary or secondary and are attached to the carbon atom adjacent to the oxygen atom in a simple ether, are preferred because they are easy to prepare and are more stable against heat, oxidation and alkaline attack. Therefore, they are more suitable to withstand heat sterilization, and at the same time are not biologically active and is not prone to metabolism.

A first preferred group of hydrides PFC ether according to formula 1 consists of C9-C10dihydrotestosterone esters, in which the hydrogen atoms may be 1oor 2oon the carbon atom adjacent to the oxygen atom in a simple ether. They can be represented is Otago time. It is followed by " cyclo-C6F11or cyclo-C6F10"that represent perftorirovannogo group or perforcerepository respectively.

N-C3F6OC4F8OC3F6-H; H-C2F4OCF2C(CF3)2CF2OC2F2-H; HC2F4-O-(CF2)5-O-C2F4-H; H-C2F4-O-(CF2)6-O-C2F4-H; H-CF2O-(C2F4O)3CF2-H; H-CF2O-(C2F4O)4CF2-H; H-C2F4-O-cyclo-C6F10-O-C2F4-H

The second group preferred hydrides PFC ether according to formula 1 consists of hydrides C9-C11perferctly or perversionelizabeth performanceheavy esters represented by the following compounds, which leave the body within a few days.

cyclo-C6F11-CF2OC2F4H; cyclo-C6F11-OC4F8H; cyclo-C6F11-C2F4OCF2-H;

p-CF3O-cyclo-C6F10-C2F4-H;

< / BR>
< / BR>
The third class of hydrides PFC ether preferably will include a C9-C10hydromeliorative ether is an ode to simple ester, or associated with the end carbon atom or an intermediate carbon atom adjacent to a simple ether; as shown in the following compounds: C4F9OCF(CF3CF2O-CFH-CF3; CF3(CF2)6O-CF2CF2-H; C8F17OCF2H; CF3(CF2)5- O-(CF2)2-O-CF2-H; C6F13-O - C4F8-H; C5F11-O-C5F10-H;

C4F9-O-C2F4-O-C3F6-H;

< / BR>
CF3O-C8F16-CF2H; C9F19-O-CF2-H.

Hydrides PFC ether in accordance with the present invention typically contain from one to five atoms of oxygen in ordinary air. Mostly one or two oxygen atoms in a simple ether are monohydride and five atoms of oxygen are dihydride. Although the hydrogen atom can be located at any carbon atom in the compound, we believe it is preferable when there is more than one hydrogen atom, so they are on different carbon atoms (i.e., no coupling). In one of the most preferred forms hydrides PFC esters in accordance with the present invention the hydrogen atom is located on protivopul.

It should be emphasized that, in accordance with the present invention any hydrides PFC esters can be mixed together with other well-known vysokovostrebovannye organic compounds and used in the emulsions according to the application. When intravenous use of such emulsion may contain from 10% to 75% of the hydride PFC ether. In accordance with the present invention emulsions preferably contain from 10% to 50% (by volume) hydride PFC ether, and the most preferred content is about 40% (by volume).

If such emulsions are used as artificial blood substitutes for red blood cells, PFCs are present in them in the highest permissible concentration, for example, is often preferred is 40% by volume, since this concentration corresponds to the approximate content of oxygen throughout the body.

Emulsions in accordance with the present invention are prepared in a common manner and include components that are common to well-known emulsions vysokotirazhnyh organic compounds. Surfactants used successfully in the emulsions in accordance with the present invention, t is positive are non-ionic surfactants, such as alkalemia and arrowie compounds, hydrophilic part which consists of polyoxyethylene chains of sugar molecules, polisportiva derivatives or other hydrophilic groups, for example, any of the formulations BASF Wyandotte oxides of polyoxyethylene and polyoxypropylene sold under the trademark "Pluronic", such as Pluronic F-68 or F-108 or empinia surfactants. The emulsions in accordance with the present invention can be used fluorinated surfactants, for example ATSURRF-31 (ICI, Wilmington, DE). See, for example, Riess et al. , "Design, Synthesis And Evaluation Of Fluorocarbons And Surfactans For In Vivo Applications, New Perfluoroalkylated Polyhydrohylated Surfactans", Artif. Cells Artif. Organs. 16, pp.421-30 (1988). Combinations of these surfactants can, of course, be used in the emulsions in accordance with the present invention. In addition, a mixture of compounds, one or more of which are not surface-active substances, but joint compounds which act as surfactants, can also be used as surface-active component in the emulsions in accordance with the present invention.

Although these compositions can in General be considered as an emulsion, and vesicular suspensions or mixtures of all of these physical States. Accordingly, when used herein, the term "emulsion" includes all of these States and surfactant or solvent agent is used in order to increase the stability of mixtures of these States and to increase the sustainability of their water and oil phases.

Surfactants used in the emulsion in accordance with the present invention are physiologically acceptable, such as are preferably used one or more of the following substances: egg or soy phosphatides, lecithin, alkalemia salt of oleic acid, such as sodium oleate. Most preferred is lecithin. Although the number of specific surfactants used in the emulsion in accordance with the present invention depends on the number and nature of other components of the emulsion, usually we use from 0.5 to 10% surfactant (by weight of the total emulsion). We mainly use about 1 to 4% (by weight).

Emulsions in accordance with the present invention may also contain oil, which has no significant surface activity and RA is oil, hydrocarbons, paraffins, such as complex monetary fatty acids and monohydroxy alcohol, ethers, long chain, di - and triglycerides, silicone oils and NITRILES. Most useful in these classes oils are dalmatinova the oleate, octillery, dodecanethiol, soybean oil, safflower oil, mineral oil, hexadecane, di - and triglycerides, with C12-C18the carbon chain. Of course, there can be used any mixture of triglycerides and/or oils such as triglycerides in the compositions of fatty acids. These oils can be used in emulsions and methods in accordance with the present invention both independently and in various combinations. In those cases, when our emulsion should be used for medical purposes, such oil or a combination of them must be, of course, biologically acceptable liquid fatty oils, such as soybean and safflower oils.

The amount of oil or oils, if they are present in the emulsions in accordance with the present invention may vary within a wide range depending on the concentration and properties of the other components of the emulsion, and essentially it is determined by the characteristics of the emulsion of imponente, it is easy to determine in accordance with the present invention, using a fairly simple technique for the preparation of emulsions with different concentrations of oil. In accordance with our recommendations, we usually use from 0.5 to 20% by volume of the oil or mixture of oils. Mostly, we use 1 to 5% by volume.

In addition hydrides PFC esters, oils, surfactants and water emulsion in accordance with the present invention may also contain other components commonly used in artificial blood or blood substitutes, in carriers of oxygen or in contrasting environments. For example, emulsions in accordance with this invention usually contain isotonic agent, as a rule, sugars such as glucose, mannose and fructose, glycerin or other polyhydride alcohols to regulate the osmotic pressure of the emulsion to approximately the level of osmotic pressure in the blood. Osmotic pressure can also be adjusted after sterilization with buffers, such as sodium chloride, sodium bicarbonate, magnesium chloride and the like, in order to reduce the likelihood of damage to red blood cells. For example, we usually use about 1% to 2.5% (e pressure controlling agents, for example Tyrode solution. In addition, these emulsions can be mixed with 0.9% sodium chloride solution, a solution of lactate ringer's serum or products that do not have adverse effects on the particle size of the emulsion and its stability. Emulsions in accordance with the present invention may also include other components, such as osmotic agents, such as dextran or hydroxyethyloxy starch (HES), and antioxidants.

The emulsions in accordance with the present invention is most preferably used hydride C9-C10- ether, and egg yolk lecithin as surfactant and safflower oil, if oil is included in the emulsion. To regulate isotonicity in the emulsion add the glycerin. Most preferably the emulsions in accordance with the present invention hydrides PFC ether constitute about 40% by volume, lecithin - about 2% by weight or volume and safflower oil, if present in the emulsion is about 2% by volume of the emulsion.

As already noted, the emulsions in accordance with the present invention can successfully be used as contrast agents in various biological visa the first resonance, ultrasonic and x-ray methods, the method of computer tomography. In addition, as contrast agents emulsion useful for direct visualization in19F-magnetic resonance. When used as a contrast medium of the emulsion in accordance with the present invention can be in the form of pills, orally, subcutaneously, intraperitoneally, through the synovial sheath of the tendon or other medical permissible methods of taking, for example by means of a catheter, if only the emulsion provided enough to clearly identify the desired part or parts of the body.

Emulsions in accordance with the present invention can be used as artificial blood, and fed intravenously to the animals or the person with anemia or with a lack of oxygen in the blood. In addition, these emulsions can be used in preservatives to preserve the internal organs outside the body transplant. Efficiency vysokotirazhnyh organic compounds containing emulsion, for the preservation of organs outside the body of a person or animal is demonstrated in publications Kawamura et al., "A New Simple Two Lauer (Euro-Collins' Solution/Perfluorochemical) Cold Storage Method For Pancreas Preservation", Transplantation Proc., pp. 1376-77 (1989); Se Flusol-43 Or Erithrocyte Media", Am J Physol. 252, pp. H349-59 (1987); Segal and Rending, "Isolated Working Rat Heart Perfusion With Perfluorochemical Fluosol-43", Am j Physol 242, pp. H485-89 (1982). Emulsions in accordance with the present invention is similar in its properties mentioned in these publications.

The ability of hydrides PFC esters dispersed as emulsion, to carry oxygen make them useful in radiation and chemotherapy for cancer, coronary angioplasty, in the treatment of heart attack, brain stroke and other vascular diseases. Publications demonstrating the usefulness of such emulsions in radiation and cancer chemotherapy include work Teicher and Rose, "Oxyden-Carrying Perfluorochamical Emulsion As An Adjuvant To Radiation Therapy In Mice", Cancer Res. 44, pp. 4285-88 (1984); Teicher and Rose, "Effects Of Dose And Scheduling On Growth Delay Of The Lewis Lung Carcinoma Produced By The Perfluorochemical Emulsion, Fluodol-DA", Int. J. Radiation Oncology Biol. Phys. 12, pp. 1311-13 (1986); Rockwell et al., "Reactions Of Tumors And Normal Tissues In Mice To Irradiation In The Presence And Absence Of A Perfluoerochemical Emulsion", Int. J. Radiation Oncology Biol Phys. 12, pp. 1315-18 (1986); Teicher and Rose, "Perfluorochemical Emulsions Can Increase Tumor Radiosensivity", Science, 223, pp. 934-36 (1984); Teicher et al., "Effect Of Various Oxygenation Conditions And Fluosol-DA on Cytotoxicity And Antitumor Activity Of Bleomycin In Mice", J. Nail. Cancer Inst. 80, pp. 599-603 (1988). Emulsions in accordance with the present invention is similar in its properties referred to in these publications. The efficiency of the use of emulsions containing Wysocki demonstrated in the publications "Virmani et al., "Myocardial Protection By Perfluorochamical Infusion During Transient Ischemia Produced By Balloon Coronary Occlusion", Am. Heart J. 116, pp. 421-31 (1988); Jaffe et al., "Preservation Of Left Ventricular Ejection Fraction During Percutanious Coronary Angioplasty By Distal Transcatheter Coronary Perfusion Of Oxygenated Fluosol DA 20%", Am. Heart J., 115, pp. 1156-64 (1988); Cleman et al., "Prevention Of Inchemia During Percutaneous Transluminal Coronary Angioplasty By Transcatheter Infusion Of Oxygenated Fluosol DA 20%", Circulation. 74, pp. 555-62 (1986); Anderson et al. "Distal Coronary Artery Perfusion During Percutaneous Transluminal Coronary Angioplasty", Am. Heart J., 110, pp. 720-26 (1984). Emulsions in accordance with the present invention is applicable for similar purposes.

The efficiency of the use of emulsions containing vysokopetrovsky organic compounds in the treatment of heart attack, brain stroke and vascular disease is demonstrated in publications Peerless et al. "Modification Of Cerebral Ischemia With Fluosol", Stroke, 16, pp. 38-43 (1985); Osterholm et al. "Severe Perfusion With An Oxygenated Fluorocarbon Emulsion", Neurosura, 13, pp. 381-87 (1983); Rose et al. "Protective Effect Of Fluosol-DA In Acute Cerebral Ischemia", Stroke. 12, pp. 558-63 (1981); Forman et al. "Reduction Of Infarct Dementia Size With Intracoronary Perfluorochemical In A Canine Preparation Of Reperfusion", Circulation. 71, pp. 1060-68 (1985). Emulsions in accordance with the present invention are also useful for such purposes.

Emulsions in accordance with the present invention can be prepared by conventional mixing fluorinated components hydrides perforacion ether is accordance with the present invention can be prepared by mixing the aqueous phase with any surface-active substance and, by choice, osmotic agents, buffer agents, electrolytes, if you want other emulsifiers, additional antioxidants and other components that are similar to them, in aqueous dispersion. Hydrides perforacion esters can then be mixed with the aqueous dispersion to obtain an emulsion in accordance with the present invention.

Emulsions in accordance with the present invention can be obtained by pre-mixing the aqueous dispersion with any suitable surface - active substance (substances) and with known artificial blood components, such as osmotic agents, and the like. The oil, if present, can also be entered in a quantity in the above-described aqueous dispersion. Then, this aqueous dispersion to obtain an emulsion in accordance with the present invention can be introduced hydrides perforacion ethers,

The prepared emulsion is sterilized mainly at temperatures above 115oC, more preferably at 121oC, and sent for further storage and use.

Mixing, pre-mixing, if desired, and emulsification of the components is t to be used in mixers and dispersers firm Fisher and homogenizers company Gaulin. In the preparation of emulsions in accordance with the present invention we prefer to use an inert atmosphere, for example, N2to prevent the collapse of surfactants and fatty oils, if any, supporting the temperature within 45o-55oC.

The invention is illustrated further by the following examples, but the particular materials and their number, as well as the specific conditions and details shown in these examples should not restrict the present invention.

1. PREPARATION OF HYDRIDES PFC ESTERS

Example 1. Preparation of C8F17-O-C2F4H of C8F12-O-C2F4CO2CH3< / BR>
The original organic material, C8H17-O-C2H4CO2CH3was prepared by alkaline catalytic method of Michel addition of n-octanol to Acrylonitrile, followed by acid-catalytic methanolysis. The methyl ester was directly fluorinated F2obtaining fluorinated ether complex C8F17-O-C2F4CO2CH3. This fluorination was carried out in 2-liter reaction vessel made of metal MonelTMjacketed, agitator with m the Oia. Line feed gas was a tube with a diameter of 0.3 cm, which was located beneath the impeller stirrers. Supply line of the reagent was made in the form of a tube with a diameter of 0.15 cm, connected to the injection pump. The partial condenser hot irrigation consisted of two 6-metre spiral concentric pipes, the inner diameter of the tube was 1.27 cm, the diameter of the outer tube 2.54 see Gases from the reactor were cooled in the inner pipe of refrigerant, the water containing the glycol flowing between the two pipes. The reactor was filled with approximately 1.8 liters of chlorofluorocarbon FreonTM113 and purified stream of nitrogen at a speed of 650 ml/min for 20 minutes. The gas flow was then replaced by a stream of a mixture of 310 ml/min fluorine and 1100 ml/min of nitrogen. After 12 minutes 100 g C8H17-O-C2H4CO2CH3diluted up to 260 ml chlorofluorocarbon FreonTM113, filed in the reactor at the rate of 13 ml/h (5 g/h). In the process of fluorination in the reactor was maintained at about 16-18oC. condensing Temperature was about -22oC. Submission of fluorine continued for 10 min after the filing of the organic reagent. Then the reactor was purged with nitrogen for one hour. A solution of crude Persiani within 24 hours. The mixture was washed with water, dried MgSO4and distilled (boiling point 40oC and a pressure of 0.2 Torr. (2.2 mm RT. Art.)) to obtain C8F17-O-C2F4CO2CH3(47% yield). For decarboxylation 39 g of 85% KOH was dissolved in about 300 ml of ethylene glycol and this solution was added at room temperature dropwise with stirring to the above fluorinated methyl ester. After the reaction mixture had a pH of 8 to 9. The mixture was slowly heated with stirring and the product of decarboxylation, C8F17-O-C2F4H, distilled with methanol to prevent saponification of its methyl ether, water from a CON and a small amount of ethylene glycol. When the temperature of the reaction mixture reached 170oC, heating was stopped. Lower fluorinated phase of the distillate was separated, washed with water, dried and distilled to Snyder column, equipped with three plates. The main fraction boiling at 146-150oC, gave a yield 122 g of the final product. Gas chromatography and mass spectrometry of a sample of the product showed that the purity of the product is 94% and it corresponds to the structural formula C8F17-O-C2F4H.

Example 2. Preparation, The B>-O-C2-H4CO2CH3was prepared by alkaline catalytic method of Michel addition of n-octanol to Acrylonitrile, followed by acid-catalytic methanolysis. Ester carboxylic acids directly ferromoly essentially the same as described in example 1 method to get during the hydrolysis of the corresponding simple acid ester, C8F17-O-C2F4COOH.

A solution of 116 g of 85% KOH in 800 ml of ethylene glycol was obtained in a 3 l flask with a round bottom. 1000 g C8F17-O-C2F4CO2H was added dropwise to a solution of KOH. After this was added an additional 10 g of KOH and the mixture was heated. Fluorinated product of decarboxylation was distilled together with a small amount of water to prevent neutralization of the acid. Lower fluorinated fraction of the distillate was separated, washed with salted water, dried with Na2SO4and distilled as in example 1 to obtain 817 g C8F17-O-C2F4H.

Example 3. Getting C7F15-C2F4H of C7F15-O-C2F4CO2CH3< / BR>
C7H15-O-C2H4CO2CH3was prepared by alkaline koceski the methanolysis. 550 g of the corresponding methyl ester, C7F15-O-C2F4COOCH3obtained analogously to example 1, was added dropwise in a solution containing 166.5 g of KOH and 880 ml of ethylene glycol. Fluorinated product (output 440 g) was obtained similarly, distilled at the Snyder column with six plates and the fraction with a boiling point of from 130 to 131oC was selected. This fraction was mixed with 8.5 g of MnO4and with approximately 350 g of acetone and heated. After 4 hours was added an additional 5 g of MnO4and the resulting mixture was heated for 3 hours. Then the mixture was filtered, the precipitate washed with acetone and the filtrate was added to water to form a more low fluorinated phase, which is then washed with water, concentrated H2SO4again with water and then filtered through silica. Research methods 1H and19F-nuclear magnetic resonance confirmed that the reaction product has the proper structure, C7F15-O-C2F2H. gas-Liquid chromatography of the sample showed that it has a purity of 98.7%.

Example 4. Getting C6F13-O-C2F4-O-CF2H of C6F13-O-C2F4-OCF2CO2CH3< / BR>
Source material, C is ethoxyethanol with acetylchloride. The acetate is then turned into C6F13-O-C2F4-OCF2CO2CH3using essentially the same fluorination processes and methanolysis as in example 1. Then 548 g of this fluorinated compounds mixed with 144.2 g of KOH and 600 g of ethylene glycol. The resulting mixture was heated, drove and got the finished product, C6F13-O-C2F4-OCF2H, as in example 1. The total yield of the product is 433, Then the product is again distilled (boiling point 131oC) 12" (30.5 cm) column at atmospheric pressure. Studies with1H and19F-NMR showed that the product has a structure corresponding to the formula C6F13-O-C2F4-OCF2H. GC/MS studies showed that the sample has a purity of 99.6%.

Example 5. Preparation of C8F17-O-CF2H of C8F17-O-CF2-CO2CH3< / BR>
C8-H17-O-C2H4-O-(CO)CF3received via acetylation of octinoxate triperoxonane anhydride. 100 g of triptoreline directly ferromoly under essentially the same fluorination procedure as in example 1, and the obtained product was cooled solution BF3in methanol to obtain C8H17-T. Art.

58 g sample of methyl last of ester decarboxylase using 10.8 g of KOH in ethylene glycol, and receive the product, C8F17-O-CF2H. the Structure of this product is confirmed 19F-NMR. Gas-liquid chromatography showed that the product has a purity of 99.6%, boiling point 134-136oC.

Example 6. Preparation of C4F9-O-(CF2)5H of C4F9-O(CF2)5-CO2H

118.2 g (1.0 mol) of hexane-1,6-diol, 4.4 g of AdogenTM464 salt of Quaternary ammonium, 80.0 g (2.0 mol) of NaOH and 250 ml of tetrahydrofuran was mixed with irrigation. To improve the mixing was added 80 ml of water. After 20 min for 0.5 hours was added 137 g (1 mol) of butylbromide and the mixture was stirred over night. The reaction mixture is cooled in 1 liter of H2O, the upper layer was combined with the extract of a simple ester of the lower layer was dried with MgSO4and mixed on a rotary evaporator. Processing of the received layer in 100 ml of CHCl3with the addition of one drop of 150 ml acetylchloride, the subsequent 4-hour heated under irrigation and removal of solvent gave 225.4 g of liquid product. Distillation of the liquid gave 176.0 g of distillate (boiling point 100-104oC/0.9 mm RT. Art. ). Gasoil what oxohexanoyl amounted to 56% of the received product. 100 g of this mixture was ferromoly in accordance essentially with the fluorination procedure of example 1. As a result of processing the obtained fluorinated product 30 ml of 10 wt.% solution H2SO4in H2Oh, shake for 2 hours at room temperature, filtration of the solid fluorinated adipic acid, separation layer F-113, drying with MnSO4and distillation received a major fraction of 73.4 g C4F9-O-(CF2)5COOH 96% purity (boiling point 116oC/20 mm RT. Art.). The last was added in a solution consisting of 10.0 g (0.25 mol) of NaOH and 100 ml of ethylene glycol, and the mixture was heated to 120oC together with a by-product of the process of fluorination C4F9-O(CF2)6-O-C4F9going in the Dean-Stark trap. With further heating started the gas and the liquid fraction, C4H9-O(CF)5-H (44.6 g), which was collected in the trap was completely evaporated at 170oC. the resulting liquid was dried with silica gel and drove in 4-inch (10.2 cm) Vigreux column to obtain 38.8 g of product with a boiling point of 131oC.19F-NMR confirmed that the resulting product has the structure of a C4F9-O-(CF2)5H.

Example 7. Prigotovleniya alkylated n-interbraided, product azetilirovanie, and the crude acetate5H11-O- (CH2)6OS(O)CH3surpassed (boiling point 125oC/3 mm RT. Art.) and the distillate was ferromoly in accordance with the same procedure in example 1. Fluorinated ester hydrolyzed to the corresponding salt. Decarboxylation of fluorinated acid, C5F11O(CF2)5COOH, an alkali NaOH gave 829 g of the product. This product was washed with water, dried with MgSO4and it was brought before receiving 555 g C5F11-O-(CF2)5H (boiling point 145-149oC).

Example 8. Preparation of C4F9-O-CF2C(CF3)2CF2H with C4F9-O-CF2C(CF3)2CF2Cl

Alkylation of 2,2-dimethyl-1,3-propane diol n-butylbromide performed analogously to example 8, gives crude monoalkylamines product, which was processed SOCl2and received WITH4H9-O-CH2C(CH3)2CH2Cl, boiling point 80-90oC/20-30 mm RT. Art. This compound was then ferromoly analogously to example 1 to obtain a4F9-O-CF2C(CF3)2CF2Cl. 20 g of the last chloride was mixed with 5.3 g soaked in water Raney Ni and 50 ml of NH3-saturated methanol. Aadom pressure of hydrogen in the first day of 21 kPa (3 psig). The product in the amount of 7.9 g with some mechanical losses obtained by filtering and cooling water.19F-NMR method confirmed that the product has the structure of a4F9-O-CF2C(CF3)2CF2H.

Example 9. Preparation H(CF2)4-O-(CF2)4H with Cl(CF2)4-O-(CF2)4Cl

To obtain CI(CF2)4-O-(CF2)4Cl was filtered Cl(CH2)4-O-(CH2)4Cl. A mixture of 30.3 g CI(CF2)4-O-(CF2)4Cl, 11.3 g soaked in fresh water Raney Ni and 200 ml of methanol was purged for several minutes, NH3and was treated with hydrogen at a pressure of 310 kPa on the Parr hydrogenation apparatus at a temperature of approximately 25oC. After 17 hours, the pressure was lowered to 255 kPa, and the mixture was acidic with visible etching glass. Added ammonium again and continued reduction of pressure drop of 62 kPa. The reaction product was filtered and cooled with water to obtain 15.4 g much lower phase. Gas-liquid chromatography showed that 68% of the pure product is H(CF2)4-O-(CF2)4H. After distillation, boiling point 121-124oC, obtain 27.0 g of the product of a purity of 87%.

Example 10. Preparation H(CF4CI

A mixture of 50.0 g CI(CF2)4-O-(CF2)4CI and 30 r Zn in butanol was stirred at 110oC for 2 days. Gas-liquid chromatography of a sample of the final reaction product showed partial mixing. Added additional 21 g Zn, and the mixture was heated for another day. After filtration and cooling of the final product in water has received 27,0 colorless liquid. This product consisted of 35% H(CF2)4-O-(CF2)4H, 42% of monohydride and 16% unrestored dichloride.

Example 11. Preparation of C6F13-O-CF2CF2H from C6F13-O-C2F4CO2H

Source material, C6F13-O-C2H4-CO2CH3got way Michael addition of hexanol to Acrylonitrile and subsequent acid-catalyzed esterification with methanol. After fluorination and formed by hydrolysis of ester obtained C6F13-O-C2F4CO2H.

500 r acid, C6F13-O-C2F4CO2H, was slowly added to a solution of 68.7 g of KOH in 700 g of ethylene glycol. At the end of this procedure in the homogeneous solution were further added 5 g of KOH to obtain a pH of 9. After dicarboxyl the product was treated with potassium permanganate is similar in essence to example 3. Gas chromatography, mass spectrometry19F-NMR,1H-NMR and infrared spectroscopy showed that the product had a structure WITH6F13-O-CF2-CF2N.

Example 13. Cooking WITH4F9-O-(CF2)4-O-(CF2)3H of C4F9-O-C4F8-O-(CF2)3CO2CH3< / BR>
To obtain C4F9-O-C4F8-O-(CF2)3CO2CH3source material, C4H9-O-C4H8-O-(CH2)3CH2OCOCH3directly was ferromoly and metapolitical similarly to the corresponding procedures of example 1. 56 g of the obtained product was quickly added to a solution of 5.6 g of KOH in 250 ml of ethylene glycol. Performed decarboxylation and after phase separation, washing with brine and distillation received the product (boiling point 155-158oC) 100% purity by gas-liquid chromatography. Gas chromatography, ACC spectrometry1H and 19F-NMR studies showed that the resulting product is C4F9-O-C4F8-O-(CF2)3H. Example 13. Preparation of C6F11CF2-O-C2F4H of cyclo-C6F11CF2-O-C2F4C(O)OCH3< / BR>
And what of ethanol with Acrylonitrile and subsequent acid-catalyzed esterification with methanol, then it was ferromoly and metapolitical BF3in methanol in accordance with essentially similar to the procedures of example 1 and received 65% yield cyclo-C6F11CF2OC2F4CO2CH3.

224 g last fluorinated ether complex was added to a solution of 28.8 g of 85% KOH and 466 g of ethylene glycol at 60oC. the resulting mixture was then heated to 100oC and its pH was brought to pH 7 by adding 5 g of 45 wt.% water CON. Decarboxylation was performed using a distillation of the resulting mixture. Lower fluorinated phase of the distillate was separated, washed in an equal volume of water and drove at 123-126oC to obtain 155 g of product purity 99.7%. This product was treated with KMnO4in acetone and received cycly-C6F11CF2-O-C2F4N.

Example 14. Cooking WITH4F9-O-C2F4-O-C3F6H from C4F9-O-C2F4-O-C3F6C(O)OCH3< / BR>
C4H9-O-C2H4-O-C4H8OCOCH3was fluorinated and metapolitical in accordance with essentially similar to the procedures of example 1. The resulting product4F9-O-C2F4-O-C3F6C(O)OCH3in kolichestvennoi temperature of vessel 190oC. during this heating the methanol from the saponification of ester, water and C4F9-O-C2F4-O-C3F6H drove from the reaction mixture. The distillate was added water, singled and drove in a lower fluorinated phase (355 g) to obtain 308 g4F9-O-C2F4-OS3F6H (yield 82%).

Example 15. Cooking WITH6F13-O-C4F8-H of C6F13-O-C4F8-CO2CH3< / BR>
The source material, WITH6F13-O-C5H10-OC(O)CH3got monoalkylammonium 1,5-pentadione with Vekselbergom with subsequent acetylation with acetylchloride. This compound was ferromoly and metapolitical essentially in accordance with the same procedures of example 1 for6F13-O-C4F8-CO2CH3, boiling point 100oC/13 mm RT. Art. This ester was decarboxylative by heating a solution of 200 grams of the ester in 250 ml of ethylene glycol with 30 g of KOH until then, until you drove a hybrid. This liquid was washed with water, dried with MgSO4and got 128 g C6F13-O-C4F8-H 82% purity. Then the product is purified by distillation using dvenadtsatimilnuju glass is Example 16. Cooking WITH6F13-O-C3F6-H from C6F13-O-C3F6-CO2K

The source material, WITH6F13-O-C4H8-OC(O)CH3got monoalkylammonium 1,4-butanediol with Vekselbergom with subsequent acetylation with acetic anhydride. This compound was ferromoly and metapolitical according essentially to the same procedures of example 1 for6F13-O-C3F6-CO2CH3. Complex ethyl ester, milili using an excess of KOH, and then dried in a vacuum oven to obtain the potassium salt. 575 g of this salt was heated with stirring in 250 ml of ethylene glycol and of the distillate obtained hydride product, boiling point 129oC. Its structure was confirmed using19F-NMR.

Example 17. Cooking WITH5F11-O-C4F8H of C4F11-O-C4F8-CO2-Na

The source material, WITH5H11-O-C5H10-O-C(O)CH3got monoalkylammonium 1,5-pentadione with Vekselbergom with subsequent acetylation with acetylchloride. This compound was ferromoly and metapolitical essentially in accordance with the same procedures of example 1 for p is Itok NaOH, was decarboxylative and drove essentially as in example 16. Distillation through dvenadtsatimilnuju glass column gave a pure C5F11-O-C4F8-H, boiling point 125oC. Its structure was confirmed using19F-NMR.

Example 18. Cooking WITH8F17OCF2OC3F6H of C8F17OCF2OC3F6CO2CH3< / BR>
Source material, C8H17OCH2OC4H8OH, got monoalkylammonium butanediol with octylimidazolium ether. This material was first azetilirovanie with acetylchloride in methylene chloride containing triethylamine and then ferromoly.

Part of the crude perforated products have metapolitical essentially as in example 1 to obtain C8F17OCF2OC3F6CO2CH3having a boiling point 124-130oC at 25 mm RT. Art. the Last methyl ester was then decarboxylative using the procedure of example 1, to obtain C8F17OCF2OC3F6H, having a boiling point 178-183oC; structure of the hydride and the intermediate fluorinated ether complex were confirmed19F-NMR.

Example 1 the example 1, to obtain, after hydrolysis, PERFLUORO-2-(3,4-dimethoxycinnamoyl)acetic acid. Then the product was decarboxylative as described in example 1, the perfluorinated everykid.

Example 20. Preparation of

< / BR>
Starting material, methyl 3-(4-ethoxyphenyl)-TRANS - 2-propenoate, obtained by condensation of 4-ethoxybenzaldehyde and malonic acid followed by esterification. This methyl ester was ferromoly, metapolitical and decarboxylative essentially as in example 1, to obtain a perforated everykid.

Example 21. Preparation of

< / BR>
The source material was obtained by condensation of 2,2-diethylpropane with dimethyl 3-oxoglutarate. This dimethyl ester was ferromoly, metapolitical in an ester of dibasic acid and decarboxylative as in example 1 to obtain perfluorinated everykid.

Example 22. Preparation of

< / BR>
The source material was obtained by reaction of 2,6-dimethylphenol with ethylene carbonate resulting and subsequent acetylation with acetylchloride. This acetate was ferromoly, metapolitical and decarboxylative as in example 1 to obtain perfluorinated everykid, boiling point 132oC.

When is analgorithm. It was ferromoly as in example 1, with the subsequent recovery of Raney Ni chloride as described in example S, to obtain perfluorinated everykid, which surpassed at 145-150oC.

Example 24. Preparation of

< / BR>
Source material obtained by adding-naphthol to ethylene carbonate resulting from the subsequent acetylation with acetylchloride. This acetate was ferromoly, metapolitical and decarboxylative as in example 1 to obtain perfluorinated everykid, boiling point 171oC.

Example 25. Cooking WITH7F15OCHFCF3from C7H15OCH(CH3)CO2CH3< / BR>
The source material was obtained by adding 2-chloropropionic acid to n-heptanol and aqueous solution of sodium hydride followed by esterification in methyl ester. This ester was ferromoly and dicarbonitrile as in example 1 to obtain perfluorinated everykid, boiling point 130oC.

Example 26. Preparation of C4F9OCHFC4F9from (C4H9O)2CHCO2C4H9< / BR>
The source material was obtained by adding dichloracetic acid to piperonyl sodium in n-butanol and subsequent oxidation in butanol. This complex everdred.

Example 27. Preparation of C7F15OCHFC2F5from C8H15OCH(C2H5)CO2CH3< / BR>
The source material was obtained by adding 2-bromo-butorowy acid to n-heptanol and sodium hydroxide with subsequent esterification with methanolic HCl. This ester was ferromoly, metapolitical and decarboxylative as in example 1 to obtain perfluorinated everykid.

Example 28. Cooking WITH5F11OCF2C(CF3)2CF2H from C5H11OCH2C(CH3)2CH2Cl

The source material received in accordance with the description U. S. 08/246962, registration 5/20/94 (SM). Everhard was ferromoly as in example 1, with subsequent restoration of chloride using Raney Ni as described in example 8, to obtain perfluorinated everykid, boiling point 148oC.

Example 29. Preparation (C4F9O)2CFCF2H from (C4H2O)2CHCH2Cl

The source material was obtained by adding n-butanol to 2-Chloroacetic the aldehyde and ferromoly as in example 1, with subsequent restoration of chloride using Raney Ni as described in example 8, to obtain perfluorinated everykid.

Example 30. what monoalkylammonium 1,10-decandiol using dimethylsulfate with subsequent acetylation with acetylchloride. This acetate was ferromoly, hydrolysable and decarboxylative as in example 1 to obtain perfluorinated everykid.

Example 31. Preparation of C9F19OCF2H of C9H19OC2H4OAc

The source material received by monoalkylammonium of ethylene glycol with n-nonyl bromide and subsequent acetylation with acetylchloride. This acetate was ferromoly, hydrolysable and decarboxylative as in example 1 to obtain perfluorinated everykid, distilleries at 153 to 155oC.

Example 32. Preparation of (iso-C3F7)2CFOC2F4H from (ico-C3H7)2CHOC2H4CO2CH3< / BR>
Source material obtained by adding by way Michael 2,4-dimethyl-3-pentanol in Acrylonitrile followed by methanolysis in the methyl ester. This broadcast was ferromoly, hydrolysable and decarboxylative as in example 1 to obtain perfluorinated everykid.

Example 33. Preparation of C7F15OCHFCF3from C7H15OCH(CH3)CO2CH3< / BR>
The source material was obtained by adding 2-chloropropionic acid in n-heptanol and sodium hydroxide with subsequent esterification with CF(CF3)CO2F loss COF2. This floramite was decarboxylative as in example 1, by adding a KOH in ethylene glycol and subsequent heating. The product was formed at a temperature of 126oC and selected by distillation at a boiling point of 130oC.

Example 34. Preparation of

< / BR>
The source material received alkylating 4-ethylphenol with methylchlorosilanes. This ester was ferromoly, hydrolysable and decarboxylative as in example 1, to obtain a perforated everykid, boiling point 131oC.

Example 35. Preparation of

< / BR>
Source material obtained by adding glycerol 4-methylcyclohexanone with subsequent acetylation with acetylchloride. This acetate was ferromoly, hydrolysable and decarboxylative as in example 1 to obtain perfluorinated everykid, boiling point 138oC.

II. THE PREPARATION OF EMULSIONS AND THEIR PROPERTIES

Emulsion receive, using the above-mentioned hydrides PFC esters (GPFU). In accordance with the General procedure, the crude emulsion consisting of 2 weight. or about. % of egg yolk lecithin, 2% vol. safflower oil, 40% vol. GPFU and water, get mixing these components in an inert atmosphere (N2at large skoroy using the apparatus of homogenization MICROFLOUIDIZERTMModel No. 110. Then within 15 minutes this crude emulsion is subjected to a cyclic process through the homogenizer at a pressure of approximately 562 kg/cm2and at a speed of 350 ml/min using an air pressure of 4.2 kg/cm2to start piston pump. The temperature of the support below the 50oC and pH control from 7.5 to 8.5. After preparation, each emulsion containing 2 weight. or% vol. lecithin egg yolk, 2% vol. safflower oil, 40% vol. GPFM, placed in a nitrogen atmosphere in a 100 ml glass flask, the flask sealed with membranes of the butyl rubber of the series TeflonTMand aluminum tubes. Placed in a flask emulsion is sterilized in a rotary sterilizer heating in moist heat flux to approximately 121oC for 15 minutes.

To compare the physiological characteristics of the compounds prepared in the form of emulsions, evaluate the consequences of removal contained in GPFU of the organs of rats during a period of seventy days or more. As noted above, physiologically useful emulsion should be maintained in the blood stream for quite a long time in order to ensure transfer of the necessary amount of oxygen. On the other hand, forcedjamie due the knosti. Excretion of GPFM contained in various emulsions of the organs examined in the following way. Sprague-Dawley rats administered dose of each emulsion (10 cm3/kg of body weight). Then kill rats and examined at discrete points in the study period. The number of persuadere in the organs examined, extragere it using carbon tetrachloride, containing 0.1-1% n-octane or n-heptane as internal standards from crushed in a TissuemizerTMtissue and analyzing the extract body using gas chromatography. The obtained data are given in the table as a percentage of the dose present in the liver, during the period of several days, for example, the entry "2-16-30" in the column "time(days)" means the percentage of the dose present in the liver in two days, 16 days and 30 days after injection of the emulsion. The percentage of doses equal to the percentage of the total number of PFLOAG entered the rat.

From the table it follows that C9-C10-damagerecoverygrid diesters as a group possess exceptional properties in cleaning the vital organs such as the liver, very quickly, within a few days. For example, in compounds 1 and 2 WITH9-damagerecoverygrid fluids were derived from the liver immediately or within two dablice connection 17, two days later it was discovered 30.4% of the dose, and 16 days in the liver was found only trace of him. The dose in the liver10-damagerecoverygrid diapir, as shown by compound 3 in the table, within 30 days decreased from 45.1% to about 5.6%.

The exceptional properties of cyclo-C9-C10afiliados are shown in the table of compounds 4-7. For example, WITH10perversonality monophyletic, compound 7 in the table, completely leaves the liver in the course of 16 days. It is remarkable that in the case of9-performcallback of monoethylene or perversionelizabeth performcallback of monoethylene, compounds 4-6 in the table, in the liver do not detect any traces of PFCs everykid. Thus, in accordance with the principles of the present invention these compounds as a class are great examples of physiologically acceptable emulsions.

Activity9-C10monohydroperoxide mono - or diapiric compounds presented in the table other compounds, for example compounds 8-16. In the case of9monohydroperoxide of monoether, the connection 9 in the table, in the liver after 16 days only 10.5% of the dose PFC efingerd is a tendency toward linger in the liver over a long period of time, than9PFC everykid. On the basis of limited experimental data, it was found that WITH8monohydroperoxide monoether presented in table connection 13 is toxic. However, with reference to the mixture of compounds 16 table8Iomega-hydrophility tetraethyl even in combination with10volgagidrostroy pentaform provides 100% survival of the animal and its excretion from the liver occurs as quickly as other iomegaware PFC esters. Thus, currently excluded from the broader class of compounds of specific hydride PFC ether may be acceptable in mixtures with other compounds. The mixture PFC esters, which are included in the scope of the present invention, referred to as "physiologically acceptable" in order to exclude unsuitable connection.

As described above, a hydrogen atom hydride PFC ether can be connected at the end or on the omega carbon atom of the carbon chain or at an intermediate atom, as in the case of compound 14 in the table in which the hydrogen atom bound to a secondary carbon atom adjacent to the ether group. In the case of compound 14 bringing this TO9monohydroperoxide of monoether andwere described various embodiments of the invention, it should be obvious that within the scope of the invention, there are also other examples of its implementation. Therefore, it should be understood that the scope of the present invention should be defined by the claims, and do not represent specific embodiments of the invention that have been described above as the examples.

1. Physiologically acceptable aqueous emulsion containing perfluorocarbon compound, surfactant and water, characterized in that as perfluorocarbon compounds it contains the hydride saturated WITH9-C10perfluorocarbon ether selected from the group consisting of hydroinformatics ether, hydroinformatics ether, substituted performlicensechecks group, and hydrophilicities ether and mixtures thereof, and specified aliphatic ester is a straight or branched chain of carbon atoms, and the number of these components in the emulsion meets acceptable physiological reception.

2. The emulsion under item 1, characterized in that the specified simple ether has a boiling point of at least about 120oC.

3. The emulsion under item 1 or 2, characterized in that the primary or secondary hydrogen atom on the carbon atom, adjacent to the oxygen atom in a simple ether;

X is a fluorine atom, or a primary hydrogen atom, or a secondary hydrogen atom on the carbon atom adjacent to the oxygen atom in a simple ether;

n = 0 - 4, integer;

Rf, R'fand Rfis independently selected from unbranched or branched group consisting of performanceline, peritonsillitis and perversonality containing one or more atoms of oxygen in ordinary air, this group can be replaced by oxygen atom in a simple ether.

4. Emulsion according to any one of the preceding paragraphs, characterized in that the specified simple ether selected from C9-C10dihydrophosphate ether hydride WITH9-C10performcallback ether or hydride WITH9-C10perversionelizabeth performancelevel ether and9-C10hydropericardium esters, in which the hydrogen atom is a primary or secondary hydrogen atom connected to carbon atom adjacent to the oxygen atom in a simple ester or associated with the destination or an intermediate carbon atom adjacent to a simple ether.

5. The emulsion under item 4, characterized in that the specified simple ether selected from H->F4-H; H-C2F4-O-(CF2)5-O-C2F4-H; H-C2F4-O-(CF2)6-O-C2F4-H; H-CF2O-(C2F4O)4CF2-H; H-C2F4-O-cyclo-C6F10-O-C2F4-H; cyclo-C6F11-CF2OC2F4H; cyclo-C6F11-OC4F8H; cyclo-C6F11-C2F4OCF2-H; p-CF3O-cyclo-C6F10-C2F4-H;

< / BR>
C4F9OCF(CF3CF2O-CFH-CF3; CF3(CF2)6-O-CF2CF2-H; C8F17OCF2H;

CF3(CF2)5-O-(CF2)2-O-CF2-H; C6F13-O-C4F8-H; C5F11-O-C5F10-H;

C4F9-O-C2F4-O-C3F6-H;

< / BR>
< / BR>
CF3O-C8F16-CF2H; C9F19-O-CF2-H, and mixtures thereof.

6. Emulsion according to any one of the preceding paragraphs, characterized in that the surfactant is taken in the amount of approximately 0.5 to 10.0% by weight of the emulsion.

7. The emulsion under item 6, characterized in that the surfactant is taken in the amount of approximately 1 to 4% by weight of the emulsion.

8. Emulsion according to any one of prepulse under item 8, characterized in that the specified simple ether taken in an amount of at least 40% by volume of the emulsion.

10. Emulsion according to any one of the preceding paragraphs, characterized in that as surface-active substances it contains lecithin.

11. Emulsion according to any one of the preceding paragraphs, characterized in that it further comprises a physiologically acceptable oil, which is not essentially surface-active and does not dissolve much in water.

12. The emulsion under item 11, wherein the oil is selected from safflower and soybean oil.

13. Emulsion according to any one of the preceding paragraphs, characterized in that it further contains at least one compound selected from isotonic agents, agents, controlling osmotic pressure, agents, pulling serum, and antioxidants.

14. Emulsion according to any one of the preceding paragraphs, characterized in that it is an artificial blood composition to reduce the undesirable consequences for coronary angioplasty, a contrast agent for biological imaging, which is clinically effective for the visualization methods in nuclear magnetic REOI tomography, the composition to increase the effectiveness of radiation and chemotherapy for cancer, a composition for preservation of organs containing effective for the purposes of conservation, the amount of the emulsion or composition for the treatment of heart attack, brain stroke and vascular diseases.

Priority points and features:

17.05.95 on PP.1, 2, 4, 6 - 13;

20.05.94 on PP.3 and 5;

20.05.94 on p. 14 with a sign of "artificial blood";

17.05.95 on p. 14 with the other signs.

 

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