DE2315928A1 - Flushing agent for flushing the respiratory system of mammals - Google Patents

Description

Dr. Hans-Heinrich Willrath d - β2 Wiesbaden

Dr. Dieter Weber ^ *, / ¹ ^ ^ ft ^ s «

DipUPhys. Klaus SeiflßriSÖp ^ O ^ ÖBil .--- Ä ^. (2 ^ lS? S '^ ^6e25

r <J r Telegram address: WILLPATENT

PATENT LAWYERS _oo *. - ""

June 22nd 1973

Allied Chemical Corp. 2315928

JH model
P 2 315 928.6

Allied Chemical Corporation Morristown, New Jersey 07960 United States

and

Jerome H. model
2200 NW 34th Street
Gainesville, Florida, USA

Dishwashing detergent for irrigating the mammalian respiratory system

Priority: from Jan. 23, 1973 in the USA, Serial-No. 325 972

It is known that the respiratory systems of living warm-blooded mammals can be washed or flushed to remove undesirable, remove substances that impair breathing by adding saturated solutions of gases containing molecular oxygen, as from air, in physiologically inert fluids, through the respiratory system, d. H. the lungs, bronchi, and trachea, from Mammals such as humans, monkeys, dogs, rabbits, cats, hamsters and mice. At such a circus

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Postsdietk: Frankfurt / Main 6763-602 Bank: Dresdner Bank AG. Wiesbaden, account no. 276807

culation, the mammal breathes the oxygenated media that are dissolved in the circulating liquid, and inhale carbon dioxide as a solution in the circulating liquid from what sustains his life. Such flushing of the respiratory system of warm-blooded mammals is not only useful in studying the effects of breathing oxygen-containing gases other than air, such as mixtures of molecular Oxygen and molecular nitrogen, which contain greater or lesser concentrations of oxygen than air, but rather Such a flushing can also be used, as mentioned above, from the respiratory organs which are undesirable and impair breathing Substances such as foreign, finely divided matter, such as carbonaceous dust or pathological secretions, such as pathological mucus secretions that often clog the lungs, bronchi and / or trachea of animals, wash out those suffering from cystic fibrosis and pneumonia.

Since perfluorinated organic liquids are generally biological are inert, available with viscosities close to that of water and extremely large amounts of molecular oxygen, molecular nitrogen and carbon dioxide, compared with non-fluorinated organic compounds, with blood plasma and aqueous Salt solutions, dissolving, was already the use of oxygen-containing gas solutions in such liquids for flushing of the mammalian respiratory systems as attempted by L.C. Clark, Jr., Fed. Proc, Fed. Amer. Soc, Exp. Biol. 29 (5), p 1968 (1970) and by L.C. Clark, Jr. et al. in Science, 152,

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Page 1755 (1966) describes previous attempts at use of solutions of a gas containing molecular oxygen in a perfluorinated ether for purging dogs however, serious damage to the lungs of these mammals. For example, J. E. Modell et al. in Fed. Proc., Fed. Poor. Soc. Exp. 29 (5), page 1731 (1970) that the Flushing the respiratory system of dogs using the alicyclic monoether perfluoro-2-butyl-tetrahydrofuran (im Commercially available as "FX-80" and as "FC-75") as the oxygen gas solvent leads to post-wash hypoxemia associated with difficult breathing and pulmonary bleeding. One Similar pulmonary hemorrhage showing the lung tissue damage noted above was also reported by L.C. Clark, Jr. et al. loc. cit., Page 1756, column 1, found in cats and mice that were flushed with a saturated solution of molecular oxygen in the above-mentioned perfluorinated alicyclic monoether. Pulmonary haemorrhage and damage to the Lung tissue similar to that obtained after the above-mentioned perfluorinated alicyclic monoether was used in the Flushing, have also been observed in hamsters who received flushing using perfluorotributylamine (commercially available as "FC-43") as an oxygen transport liquid, as suggested by M.M. Patel et al. in Fed. Proc. , Fed. Amer. Soc. Exp. Biol. 29 (5), p.174o (197OJ. Others possible lung lavage products were found to be unsatisfactory, as they cannot be easily removed from the lungs after treatment and leave a substantial residue.

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permit.

The object on which the invention is based is now an improved method and detergent for flushing the respiratory system of living warm-blooded mammals that minimize abnormal lung function and / or lung tissue destruction in mammals or switch them off completely and which also reduce the problem of residues in the lungs after treatment. These and other objects and advantages are achieved with the present invention as described in detail below.

The above aim is achieved and the disadvantages mentioned the known flushing methods are overcome if you according to the invention an improved method for flushing the Respiratory system of a living warm-blooded mammal with a solution of a gas containing molecular oxygen in uses a liquid detergent that is a physiologically inert, water-insoluble, perfluorinated saturated organic liquid with a boiling point between 104 and 133 ° C at 760 mm Hg.

Perfluorinated is understood to mean that with the exception of certain physiological inert heteroatoms such as nitrogen, oxygen and sulfur, as will be more specifically set out below, all Valences in the molecule that are not through carbon-carbon bonds or carbon-heteroatom bonds are saturated, are saturated by fluorine atoms.

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The use of solutions containing molecular oxygen Gases in the liquid flushing agents for flushing the respiratory systems warm-blooded mammals according to the invention does not lead to a noticeable disruption of lung function and does not Lung tissue destruction and / or pulmonary hemorrhage, and there is no noticeable residue of liquid Rinse aid in the respiratory system after treatment.

The techniques and methods for performing lung lavage are known and any person skilled in the art can easily Perform lung lavage procedures using the improved liquid irrigants described herein by he used those procedures for lung lavage described by Clark et al., Modell et al. and Patel et al. in the above references are described.

For example, irrigation in a mammal can be performed simply by placing the animal in a solution an oxygen-containing gas is immersed in a liquid flushing agent, as described here, according to the method or submerged by L.C. Clark, Jr, et al. loc. cit. and by M.M. Patel et al. a.a.O. is described, the contraction and expansion of the living being's lungs provides the force required to circulate the oxygenated liquid flushing agent through the respiratory system, deliver the living being. In practice A saturated solution of the molecular oxygen-containing gas in the ether was used to facilitate oxygen transport to maximize the respiratory system during irrigation treatment.

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For this reason, saturated is preferably used below Solutions of the molecular oxygen-containing gas in the ether scavenging agents are referred to. Instead, it can Oxygen-containing detergents can also be circulated through the lungs of the living being under gravity, such as by alternately raising and lowering the storage container with the detergent, which is connected to the respiratory system via a line of the living being is connected so that the detergent flows into and out of the respiratory system alternately, using the conventional method described by J.H. Modell et al., Supra, and by F. Gollan et al., Fed. Proc, Fed. Amer. Soc. Exp. Biol. 29 (5), p. 1728 (1970) is. Instead, a mechanically or electrically operated pump can be used to ground the oxygen To circulate detergent through the living being's lungs.

The saturated solution of gas containing molecular oxygen in the liquid detergent can be any convenient and conventional Ways to be prepared, such as by finely dispersing or bubbling in the molecular oxygen-containing Gas in the liquid scavenger, which is either a single compound of the type described above or a mixture be two or more such connections. can. To a saturated Solution of the oxygen-containing gas in the liquid flushing agent during the entire flushing process upright obtained, the oxygen-containing gas is continuously fed into the

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Dish soap that circulates to the mammal's respiratory system is, bubbled or otherwise finely distributed therein. As is common with known irrigation methods, one lung alone, including both lungs or the entire respiratory system both lungs, bronchi and trachea of the living being are subjected to lavage by opening the supply line for the flushing agent in a suitable manner in the respiratory tract concerned of the living being.

The temperature of the oxygen carrying detergent during of the present flushing method is not critical, but in accordance with It is generally within the range of conventional flushing methods from about 20 C to about body temperature of the mammal. It will be apparent to those skilled in the art that the latter temperature will be largely depends on the particular type of living being subjected to the irrigation and also on the state of health of the living being. In general, normal body temperature is around Mammals at about 37 ° C.

According to the conventional ventilation method, the molecular oxygen-containing gas that is used to produce the saturated or unsaturated solutions that are used as rinsing agents according to the present process, is molecular Oxygen or any mixture of the same with physiologically inert gases which contain at least a sufficient proportion of contain molecular oxygen to sustain life. As will be apparent to those skilled in the art, the above will vary strongly did not mention the smallest fraction of molecular oxygen

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- R -

only according to the species of mammal that underwent the purging should be, but also according to the level of physical activity of the living being during flushing. The one mentioned above However, the smallest effective amount of molecular oxygen that is effective in supporting life can easily be without extensive experiments can be determined by a person skilled in the art. Typical examples of gases containing molecular oxygen which that can be used in the present method are as follows:

with molecular oxygen up to a content of about 30% by volume molecular oxygen enriched air;

Air enriched with molecular oxygen up to a content of about 40% by volume of molecular oxygen? molecular oxygen;

a mixture of molecular oxygen and carbon dioxide with one Content of 99% by volume of molecular oxygen; a mixture of molecular oxygen and molecular nitrogen with a content of 50 vol .-% molecular oxygen; a mixture of molecular oxygen and molecular nitrogen containing 99% by volume of molecular oxygen; a mixture of molecular oxygen, molecular nitrogen and carbon dioxide with a content of 90% by volume of molecular oxygen, 5% by volume molecular nitrogen and 5% by volume carbon dioxide; a mixture of molecular oxygen and argon containing of 20% by volume of molecular oxygen; as well as a mixture of molecular oxygen and argon with a content of 99% by volume of molecular oxygen,

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In the practice of the improved scavenging method of the invention, molecular oxygen, air, is with molecular oxygen enriched air and mixtures of molecular oxygen and a physiologically inert gas made up of molecular nitrogen and / or carbon dioxide, the preferred molecular oxygen-containing gases used to produce the present oxygen-containing detergents can be used.

According to the conventional flushing method, the flow rate should the oxygen-containing liquid detergent to the mammal, that is subjected to the lavage are sufficient to fill the living being's lungs with the oxygenated agent, and the speed should also be sufficient to oxygenate _ To supply gas to the living being at about the speed required to sustain life, if the living being the oxygen-containing gas in the absence of a liquid one Inhaling detergent rocks «This depends in part on the size of the respiratory system of the mammal in question. The flow rate of the oxygenated liquid should also be fast be enough to remove carbon dioxide so that the resulting Arterial carbon dioxide levels are compatible with the maintenance of life, if so with the living being in question is not feasible, the carbon dioxide in the blood can be removed with a tris buffer, such as tris (hydroxymethyl) aminomethane, or another suitable buffer. The desired and preferred flow rate of the oxygen-containing Liquid therefore depends on the consideration of all of the factors described above and can easily be

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ge experiments to be determined by a person skilled in the art.

The duration of the rinse treatment of the invention can generally range from very short periods of time, such as about 5 minutes or less, to long periods, such as about 8 hours or longer, depending on the particular purpose for which the rinse treatment is employed . When removing a substance blocking the respiration from the respiratory system of the living being according to the present flushing method, the flushing can be interrupted in order to test the breathing of the living being with atmospheric air or with gaseous molecular oxygen , the flushing being terminated if such Breathing shows that the irrigation has cleared the obstruction from the living being's airways.,

The liquid detergents according to the invention are physiologically inert, water-insoluble, saturated perfluorinated liquids which have a boiling point between 104 and 133 ° C. at 760 mm Hg. These materials are hydrophobic in nature and freeze well below O ⁰ C.

Preferably, the liquid detergents should have a boiling point between 104 and about 121 ° C at 760 mm Hg, and higher preferably between about 108 and about 121 ° C at 76O mm Hg.

The liquid flushing agents according to the invention dissolve large volumes of gases containing molecular oxygen and carbon dioxide with the formation of saturated solutions of these gases.

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The preferred liquid detergents of the invention are either known compounds or can be prepared from known compounds by conventional methods, as follows is discussed. The preferred liquid detergents according to the invention are as follows:

a) perfluorinated, saturated aliphatic acyclic monoethers of the empirical formula CgF ₃₀ O;

b) perfluorinated, saturated, mixed-cyclic-acyclic-tertiary amines of the empirical formula CgF ₁ -N;

c) perfluorinated, saturated alkyl tertiary amines of the empirical formula C ₃ F ₁₉ K;

d) perfluorinated saturated bis-alkyl sulfides of the empirical formula C ₃ F ₁₃ S;

e) perfluoroindene;

f) perfluorinated saturated cycloalkanes of the empirical formula

g) perfluorinated saturated alkanes of the empirical formula

h) perfluorinated saturated, polycyclic ionoethers of the empirical formula ^C 9 ^F i6 ^O?

i) perfluorinated saturated, mixed cyclic-acyclic monoether of ^r Empiris-chen formula C _Q F gO;

j) perfluorinated saturated, mixed dialkyl-cycloalkyl-tertiary amines the empirical formula CgF-N;

k) perfluorinated saturated tertiary amines of the empirical formula C ₉ F ₂₁ II;

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-12-

m) Perfluorinated saturated alkyl dieters of the structural formula R ^ OR ^1. ^ 0R " _f , V7orin R _f and R" _{f are} perfluoroalkyl groups and E'i is a perfluorinated alkylene group, and the empirical formula C ₉ F ₂₀ O ₃ .

Perfluorinated saturated aliphatic acyclic monoethers of the empirical formula CqF "_O can be prepared by reacting the corresponding ether iodides of the general formula R ^ -O-R ' ^ T, where Rf is a perfluorinated alkyl group and R', a perfluorinated alkylene group, with a fluorinating agent such as antimony pentafluoride, at about 20 to 27O ° C, the terminal iodide substituents are exchanged for fluorine. The iodide starting materials are a known class of compounds which is described in USA Patent 3,514,487. The preferred members of this class have the formula CUF -0-CgF. The particularly preferred compound is perfluotisopropyl-n-hexyl ether (iso-CgF_0-n-CgF ₃ ).

Perfluorinated saturated mixed cyclic-acyclic tertiary amines the empirical formula CnF.-N can be obtained by electrochemical Fluorination of the corresponding non-fluorinated acyclic tertiary amines, such as dialkylanilines, by the method * described in US Pat. No. 2,616,927.

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Perfluorinated saturated alkyl tertiary amines of the empirical formula CgF 'fl can by electrochemical fluorination of the corresponding non-fluorinated alkyl tertiary amines prepared by the method described in U.S. Patent 2,616,927 v / earth.

Perfluorinated saturated bisalkyl sulfides of the empirical formula CgF ₁ QS can be prepared by heating perfluoroalkyl iodides with sulfur in the manner described by Hauptschein and Grosse ^ JACS 73, page 5461 (19511? Or by Haszeldine £ 3. CS 1952, page 2198 /).

Perfluoroindane (hexadecafluoroindane)

F,

can by fluorinating indene using silver difluoride as described in U.S. Patent 2,459.

The perfluorinated saturated cycloalkanes of the empirical formula C _g F _ig are, for example, perfluoroalkyl-substituted cycloalkanes. This class of compounds can be prepared by electrochemical fluorination of the corresponding non-fluorinated, alkyl-substituted cycloalkanes according to the method described in US Pat. No. 2,519,983. The preferred compound of this class is perfluoropropylcyclohexane and can also be prepared by the electrochemical fluorination of quinoline, as in US Pat

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U.S. Patent 2,519,983.

Perfluorinated saturated alkanes of the empirical formula CgF ₃₀ can be prepared by fluorinating the corresponding non-fluorinated known hydrocarbons using CoF- at elevated temperatures, as described in J. Chem. Soc. 1950, page 3617, is described.

Perfluorinated saturated polycyclic monoethers of the empirical formula C _g F, 0 are, for example, monoethers with either fused or non-fused rings. These compounds can be prepared by fluorinating the corresponding non-fluorinated ethers, such as, for example, benzopyran, using CoF- at elevated temperatures, as described in J. Chem. Soc. 1950, page 3617, is described.

Perfluorinated saturated mixed cyclic-acyclic monoethers of the empirical formula CgF. “0 can be achieved by electrochemical Fluorination of the corresponding non-fluorinated mixed cyclic-acyclic Monoethers can be prepared by the method described in U.S. Patent 2,644,823. The preferred one Compound of the class is perfluoro-n-butyltetrahydropyran and can be prepared by the electrochemical fluorination of sebacic acid as described in U.S. Patent 2,644,823 is.

Perfluorinated saturated mixed dialkyl cycloalkyl _{tertiary amines of the empirical formula C 9} F ₁₉ N can be prepared by electrochemical fluorination of the corresponding tertiary amines

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in U.S. Patent 2,616,927 V7erden. The preferred connection

can be prepared from methylethylaniline by electrochemical fluorination as described in U.S. Patent 2,616,927 is.

Perfluorinated saturated tertiary amines of the empirical formula C ₀ F ₂ -N can be prepared by electrochemical fluorination of the corresponding non-fluorinated tertiary amines according to the method described in US Pat. No. 2,616,927.

The connection

is a well known material and is commercially available.

Perfluorinated saturated alkyl dieters of the structural formula

It

^R f ^ORL f ^OR "f ^'wor i ^nr -f ^ ¹¹¹ ^ ^R f Perf luoralkylgruppen and R' _f is a perfluorinated alkylene group ^having the empirical formula ^C 9 ^F 2O ° 2 * can be prepared by electrochemical fluorination of the corresponding non-fluorinated diether such as the method described in U.S. Patent 2,500,383

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produced v / earth.

The non-fluorinated diet precursors of the empirical formula CgK ₂ 0 "can be prepared by known synthetic methods, as described, for example, in the following literature references: ·

Wagner and Zook "Synthetic Organic Chemistry", John Wiley and Sons, Inc., 1953, pp. 227, 238, 265;

L. Liston and Dehn, J. Am. Chem. Soc., 60, p. 1264 (1938);

M.H. Palomaa et al., Reports 65B, p. 1593 (1932); Chera. Abstracts 27, page 58 (1933);

R. Riemschneider et al., Monatsh *. 90, 783 (1959); Farren et al., J, Am. Chem. Soc. 47, page 2419 (1925);

R. Alquier, Bull, Soc. Chim. 10, p. 197 (1943); Chem. Abstracts 38, page 3953 (1944); and

N.B. Lorette et al., U.S. Patent 3,127,450.

In general, non-fluorinated dietary raw materials, wherein the ether oxygen atoms through a carbon chain of 2 or more carbon atoms are linked together, conveniently by reacting a saturated acyclic aliphatic Diols with 2 or more carbon atoms with metallic Sodium to form the sodium alcoholate of the diol, reaction of the resulting sodium alcoholate with a saturated alkyl halide, for example an alkyl chloride, bromide or iodide, in excess liquid diol to form the corresponding Monoalkyl ethers of the diol, implementation of the remaining free hydroxyl group of the resulting monoether with Na-

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trium with formation of the sodium alcoholate of the honey ether and Finally, the latter sodium compound reacts with a saturated alkyl halide, that of the alkyl halide used above may be the same or different, to form the desired diether starting material be, this synthesis method, for example, by R. Riemschneider et al. and L. Liston et al. is described in the references cited above.

In general, non-fluorinated dietary raw materials, wherein the ether oxygen atoms are represented by a methylene group, d. H. the group -CI ^ -, linked together, conveniently through implementation a saturated aliphatic acyclic monohydric alcohol with dry hydrogen chloride and paraformaldehyde under Formation of the chloromethyl ether of alcohol as described by Parren et al. is described in the above literature, and by Pyrioin-catalyzed conversion of the resulting Chloromethyl ™ alkyl ethers with a saturated aliphatic acyclic monohydric alcohol which is the same as that used above as a reaction perfume alcohol used or different therefrom to form the desired non-fluorinated dietary starting material according to the method of Palomaa et al. according to the above mentioned literature getting produced. In general, non-fluorinated dietary starting materials, wherein the> '. Thether oxygen atoms by a methylene group that has a single alkyl substituent contains, are linked to each other, and v / orin the alkoxy substituents are the same, preferably by reaction of acetaldehyde or a higher saturated acyclic

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~ ⁱ⁸ ~ 2315328

see aliphatic monoaldehyde with a solution of the orthoamaisic acid ester d.nes saturated aliphatic acyclic monovalent Alcohol in the alcohol using an acid catalyst according to the procedure on page 264 of the reference manufactured by Wagner and Zook. Suitable non-fluorinated diether starting materials wherein a monoalkyl substituted Methylene group connects the liter oxygen atoms and the different Having alkoxy substituents can be made from non-fluorinated Dieters in which a monoalkyl-substituted methylene group connects the ether oxygen atoms and the same alkoxy substituents have, be prepared in such a way that one molar excess of the latter diether with a saturated aliphatic acyclic monohydric alcohol in which the alkoxy group differs from that of the reactant used Diether is different in the presence of a mineral acid by the method of R. Alquier in the above-mentioned reference implements.

In general, non-fluorinated dietary raw materials, wherein the ether oxygen atoms are connected by an ethylene group substituted by two alkyl groups and wherein the alkoxy substituents are the same, can conveniently be prepared by combining an acyclic aliphatic saturated ketone with a Dissolving the orthoformic acid ester of a saturated aliphatic acyclic alcohol in the alcohol using a Acid catalyst according to the procedure on page 264 of the reference implemented by Wagner and Zook. Suitable non-fluorinated diether starting materials wherein a dialky! Substituted me-

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ethylene group connects the ethereal atoms and the different Alkoxy substituents can be selected from non-fluorinated Dieters made v / earth in which a dialkyl substituted Methylene group connects the ether oxygen atoms and the same Have alkoxy substituents by adding the latter dieter with a saturated aliphatic acyclic monohydric alcohol in which the alkoxy group differs from that of the reactant Diethers used is different, in the presence of an acid catalyst by a method which is analogous to is' which from N.E; Lorette et al. in the above cited USA patent is described.

The perfluorinated diether can also be obtained by coupling two perfluorinated monoether iodides in the presence of a suitable one Coupling agent such as metallic zinc powder in an inert solvent such as methanol and separation of the coupled Dietherproduct can be produced by fractional distillation. This coupling method is described in detail by Hycka et al. in U.S. Patent 3,435,078.

The detergents described above, chemically as well as biologically are highly inert are also valuable as gas dissolving reaction solvents or diluents for liquid phase reactions between compounds and air, molecular oxygen, molecular nitrogen, carbon dioxide or mixtures thereof. In this regard, oxygen-containing gas solutions are after of the invention, particularly saturated oxygen-containing gas solutions useful as solvents or diluents in the liquid

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Sig-phase oxidation of organic compounds with oxygen-containing gases, such as air, molecular oxygen or mixtures of molecular oxygen and molecular nitrogen. Solutions according to the invention that contain dissolved molecular nitrogen, particularly saturated solutions that contain dissolved molecular nitrogen, are useful in liquid phase reactions of molecular nitrogen with organometallic Phosphorus compounds of the type as described by M ₀ E. Vollpin et al. In Xzv. Akad. Nauck. SSSR Ser. Khim. 1966 (6), page 1083, Chem. Abstracts 65, column 13747h (1966), and in liquid phase exchange reactions of molecular nitrogen of the type as described by AK Shilova et al. in Kinat. Katal "10 (2), page 267 (1966), Chem. Abstracts 71, column 25095p X1969) is described. Solutions of the present detergents, which contain dissolved carbon dioxide, especially when they are saturated with carbon dioxide, are particularly useful as reaction solvents in the known carboxylation of organomagnesium halide compounds, ie Grignard compounds, especially in the carboxylation of a polyfluoroisoalkoxyalkylmagnesium iodide, such as in Example 6 by MH Litt et al. in U.S. Patent 3,453,333. As is obvious to those skilled in the art, reactions of the above type can be carried out using the present compositions containing dissolved gas or diluent at a temperature above the normal boiling point of these compositions, provided that the reaction according to conventional methods at a sufficient elevated pressure is carried out in order to keep these agents in the liquid phase at the reaction temperature.

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The following examples serve to further illustrate the invention. Parts and percentages are parts by weight and percentages by weight, unless otherwise expressly stated, and temperatures are given in degrees Celsius.

example 1

Preparation of perfluoroisopropyl-n-hexyl ether Over a period of about 30 minutes, 50.0 g (0.082 mol) of perfluoroisopropyl-G-iodo-dodecafluorohexyl ether were added with stirring to 127 g (0.59 mol) of antimony pentafluoride, which was heated to 70 to 80.degree was held, added. The resulting mixture was allowed to cool to 25 ° C. and then poured into about 500 ml of ice water. The lower organic layer that formed was separated, washed twice with water and dried over anhydrous calcium chloride. Fractional distillation of the resulting dried raw product at atmospheric pressure gave 28.5 g (69% yield, based on the starting iodide material) of the distilled product perfluoroisopropyl-n-hexyl ether, bp = 121 ° C. at atmospheric pressure.

Example 2

Irrigation of the respiratory system with perfluoroisopropyl nh.3xyl ether 12 beagle dogs weighing 9 (+1) kg were anesthetized intravenously with sodium pentobarbital (about 20 mg per kg). The dogs' trachea was intubated / A polyethylene catheter was inserted through the left femoral artery to the lower

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leibsaorta screwed in to take a blood sample and a pressure record to allow. The oxygen and carbon dioxide pressure of arterial blood (mm Eg) and the pH of the arterial elute were measured using direct reading electrodes measured while the dogs were ventilated with air, and then 20 minutes while the dogs were with pure Were ventilated with oxygen.

The dogs were then paralyzed by intravenous administration of succinylcholine chloride (2.5 mg) and their tracheal tubes connected to the bottom of an atmosphere-communicating plastic container containing approximately 1.2 liters of liquid parfluoroisapropyl-n-hexyl ether, prepared as in Example l _f included. The ethereal liquid was enriched with molecular oxygen at about 25 ° C and kept in equilibrium with an overlying vapor phase of liquid ether and oxygen with a total pressure of about 1 atmosphere with the help of a stream of molecular oxygen, which is continuously flowing through the ether was bubbled through a gas distribution tube at a rate of about 3 to 5 liters per minute = the lungs and the trachea of the dogs were then ventilated, that is, flushed with wave-like volumes (each about 300 ml) of the ether by the container chamber 3 to 4 times each Minute was raised and lowered in order to alternately flood and drain the respiratory system of the dogs.su, the exact speed of the raising and lowering being determined according to the time required to remove the used ether, which was essentially saturated with exhaled carbon dioxide was to go to the container

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to run back.

During the aeration, the temperature of the gas began to be transported Ether at room temperature (about 25 ° C) and gradually warmed up on the temperature of the dog (about 37 ° C).

Endotracheal pressures were recorded in a T-arm where the tracheal tube was connected to the canister chamber. The oxygen and carbon dioxide vapor pressure of arterial blood and the pH of the arterial blood, 5 _r 10, 15, 30, determined 45 and 60 minutes after the start of aeration of the liquid.

The continuous ventilation of the dogs was stopped after about 1 hour, after which time the liquid ether was removed from the The dogs respiratory system was drained under gravity. The tracheal tubes were then connected to gas canister bags with check valves and the dogs allowed to 100% inhale molecular oxygen for about 3 hours. The dogs were then extubated and placed in oxygen tents After getting them with molecular oxygen up to a volume concentration of about 30 to 40% air enriched for about 24 Allowing hours to inhale, the dogs were returned to standard dog cages under observation.

The gas tensions of the arterial blood, the vapor pressures of the arterial blood and lung function were restored 1, 3, 7, 27, 84 and 168 days after ventilation with the liquid ether.

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repeated.

About the dispersion time of the liquid ILether in the exhaled To determine gas, four other dogs were ventilated with liquid ether as described above. The exhaled gas became intermittent collected between 3 hours and 26 weeks after liquid ventilation and carried out with regard to the liquid ether Gas chromatography analyzed.

11 of the 12 dogs examined were alive during the entire experiment. The 12th dog died as a result of an experimental error when a polyethylene catheter entered the right ventricle, and perforated them.

All 11 surviving dogs maintained good arterial oxygen levels during liquid ventilation. The arterial carbon dioxide content rose and the pH fell during this time, but both values reverted to normal inerts when the liquid Ether has been drained from the dogs' lungs. The arterial oxygen vapor pressure was 3 hours after liquid ventilation much less than before the dogs were anesthetized for that Experiment while the animals were breathing air or when breathing 100% oxygen. The arterial oxygen vapor pressure rose noticeably within 24 hours, but it was mean oxygen vapor pressure during inhalation of 100% oxygen at this point is not significantly different from the pre-experimental values. The carbon dioxide vapor pressure and the arterial pH remained stable after the animals became too

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had returned to gas ventilation and none of these values was at any point in time significantly different from the pre-experimental values. 24 hours after aeration with liquid Later there was an increase in pulmonary resistance and a decrease in compliance and the dispersal capacity of individual breathing established. 48 hours later there was a clear return to normal conditions for all values, with only the expansion capacity remained significantly different from the control period. Then even this value returned normal conditions. After 6 months, the dogs' lungs were even more compliant than before the experiment.

Liquid ether levels of 148 to 268 ppm were exhaled in Gas detected 3 hours after ventilation with the liquid ether. The concentration then fell during the next 72 hours decreased significantly and continued to decrease over the next 26 weeks. These values are summarized in the following table:

Tabel

Concentration of perfluoroisopropyl-n-ethyl ether vapor in exhaled Air from dogs after ventilation with liquid perfluorinated ether in parts ie Hillion _ ^ _

Time after
the beat
mung dog
No. 13 dog
No. 14 dog
No. 15 , 2 dog
No. 16 3 hours 176.2 268.2 192 , 64 148.8 24 hours 6.05 4.37 5 , 74 68.6 72 hours 2.89 0.92 0 , 64
1 1 1 0.86 4 weeks 0.10 0.14
409 O
831 / 0.30
5

12 weeks 0.02 0.02 0.08 0.05 26 weeks 0.0015 0.002 0.0011 0.0018

There was no sign of stretching, rupture, or bleeding of the lung tissue.

Example 3

The experiment of Example 2 was carried out with a similar dog, as described above, with the exception that the animal suffered from pneumonia. His arterial acid vapor pressure was only 43.4 mm Hg while breathing at room temperature. The animal was anesthetized with sodium pentobarbital, and his trachea was intubated under direct observation. His lungs were then combined with the one mentioned above Fluorocarbon liquid was rinsed in the same manner as for the Example 2 animals. Thick, tough mucus secretions were in small lumps from the windpipe with the outflows liquid ether washed out and remained on the surface of the fluorocarbon float in the reservoir. After the flushing was finished, the mucus was drained from the respiratory system of the dog was flushed out, collected. An essentially quantitative recovery of the slime was obtained. After flushing, the dog's lung function was up and down his arterial oxygen vapor pressure is significantly improved. For example, within 72 hours the arterial oxygen vapor pressure was above 60 mm Hg and continued to improve so that after 1 month it was normal. similarly, large volumes of

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mlna of pulmonary breath fluid that is hypertonic by inhalation Glucose was caused in another dog with an improvement in arterial oxygen levels from the lungs harausgevzaschen. The amount of "dsn.iquidksit that comes from the Lung was washed out within an hour., Was about twice as large as that obtained by a drainage in one Knoll animal could run under the force of gravity. The arterial Oxygen vapor pressure of the animal was significantly higher than that of other animals after completion of the lung lavage were treated in the classic way of mechanical ventilation without flushing with positive end breath pressure.

The experiments described above demonstrate that mammals are ventilated with perfluoroisopropyl-n-hexyl ether and then used to breathe can be returned with gaseous oxygen without permanent changes in lung function and blood gas exchange appear. The perfluoroisopropyl-n-hexylether is effectively removed from the lung for a period of time without leaving any substantial residue that would cause structural lung damage would cause.

In addition to the ether of Example 1, the following are further examples Suitable liquid flushing agents listed as gas transport liquids in the respiratory system flushing of warm-blooded Mammals can be used according to the invention.

0 9 8 3 1/1115

231592

Perfluorinated saturated aliphatic acyclic monoethers of the Foirraal C ₁ ^ P _0n O ^

CP ₃ -O-Ii-C ₈ P ₁₇ ·; CF ₃ ■ CP ₃ ~ 0- (CF ₂ ) ₅ CP

CF ₃

CF

CF ₃ -O- (CP ₂ ) j, -C-CP ₂ CF ₃

f ₃

C (CF ₂ ). CF

CF 1

CF,

_? CF

t. -* 1

C-C

F F

409831/1115

5- C F

0 ι .

C F CF.

CF

, 3

) - C - CFp-CFo

'

Perfluorinated citfcigfce, mixed cyclic-acyclic tertiary amines

the Eiuoirian formula C _n F, _M

ο 1 /

> T

K.P. 110-ni ° C / 6th

4 0 9 8 3 1/1115

CFj

F ₂

F ₂

- ■ y.

'2- 5

FoC-C-CF-

^J -ο -

Perfluorinated saturated alkyl tertiary amines of the pharmaceuticals. Formula C ₃ F ₁₉ N

C ₂ T

¹ b

pN-Cf, Fq (n, iso./tert.)

"K, p.

nm

■ 2 ^! q

(n,! s

CF

3 · ■

13th

409 831/1 1 15

"Ti"

CF-

CF-t 3

C 2 ^ j-VI- C

Perfluorinated saturated bisalkyl sulfides of the empirical formula

7 ^ n min

Perfluorinated saturated cycloalkanes of the empirical formula

C _g F

IS

nn

409831/1115

Perfluorinated saturated alkanes of the empirical formula C _O F

20th

Kp

Γ · "!? ^ (HO \ " ft?

A O 9 8-3 1/1115

■ -33-

Pi; rfluorierta <fosaturated polvcvclischa Ilonoäthar of the empirical formula C ₉ F ₁₆ U * ·.

.Kp. 114-115 / 7 * 0 ϊπτπ Cost.)

Perfluorinated saturated, mixed cyclic-acyclic monoethers of the empirical formula CgF ₁ "Ο

'' V ^ F

K.p

Po

mw

F-P

^c: 5 ^V ll

409831/1115

.) ι

Perfluorinated saturated mixed dialkyl-cycloalkyl-tertiary amines of the empirical formula CgF ₁ ~ 1 $

Kjρ. 127 ° C / 75n ππ Cest ..).

F,

ι, ₂

, F ₅ C ₂ V

409831 / Ί115

^C 5 ^F 11

Perfluorinated saturated tertiary aquarines of the empirical formula

- - ' ^C ^ ⁷ CF

K.j). 130 ° C / 760 mm

C ₃ Fy

? 3 ^F 7

Perfluorinated saturated alkyl dieters of the structural formula R-OR ',. OR ", where R _f and R" ^ are perfluoro alkylene groups and R ¹ ^ is a perfluorinated alkylene group, and with the empirical formula GgF ₃ O ₂

0-C ₃ P ₇ -OIC ₃ P ₇ -OIC ₃ P ₇ Kp ll8-120 ° C / 760 nn Cost.)

409831/1115

Various c-s

-C JjP

JjP (J

-3G-

K. p. llf-in ° C / 7hl ra

409831/1 1 15

Claims (5)

received on the UfZL · - 37 - Iο Ι 59ζο patent claims That it is the first detergent for rinsing of the respiratory system of warm-blooded living mammals, characterized in that a physiologically inert, water, saturated perfluozderte organic liquid having a boiling point of 104-133 ⁰ C at 760 mm Hg. 2. Detergent according to claim 1, characterized in that it zwröhen a boiling point 104 and has about 121 ⁰ C at 760 mm Hg. 3. Rinsing agent according to claim 1 and 2, characterized in that that it has a boiling point between about 108 and about 121 C at 760 mm Hg. 4. detergent according to claim 1 to 3, characterized in that it consists of (a) perfluorinated saturated aliphatic acyclic monoethers of the empirical formula C ₉ F ₃₀ O, (b) perfluorinated saturated, mixed cyclischacyclic tertiary amines of the empirical formula C ₈ F ₁₇ N, 409831/1115 " ³⁸ " received (c) perfluorinated saturated alkyl tert-oxaramines of the empirical formula CgF ₁₉ N, (d) perfluorinated saturated bisalkyl sulfides of the empirical formula C ₀ F ₁₀ S, ο 10 (e) perfluoroindene, (f) perfluorinated saturated cycloalkanes of the empirical formula C ₉ F ₁₈ , (g) perfluorinated saturated alkanes of the empirical formula C ₉ F ₂₀ , (h) perfluorinated saturated polycyclic monoethers the emphatic formula C ρ O,
(i) perfluorinated saturated mixed cyclic-acyclic Monoethers of the empirical formula CF ₁₃ O, (j) perfluorinated saturated, mixed dialkyl cycloalkyl Tertiary amines of the empirical formula CF ₁ -N, (k) perfluorinated saturated tertiary amines of the empirical formula C ₉ F ₃₁ N, - and or (m) perfluorinated saturated Alkyldiäthern having the structural formula R _f OR _'f OR' _f, where R _f and R _"ψ PerfluoralkyIgruppen and R _f represents a perfluorinated alkylene group and ^faestellt having the empirical formula CGF ₂ O · ^ 4098 3 1/1115 "ΠΠΑΠΟΟΟΒΪΙ II ........ 5. Detergent according to claim 1 to 4, characterized in that it is a perfluorinated saturated aliphatic acyclic monoether of the formula C ^ FO-CcF ₁ -, preferably of the formula iso-C _o F_0-n-37 6 13 37 CT? τ o-f- 409831/1115