Title of Invention


Abstract Where n=l or 2; m = 2 or 3 X represnets or, at n=2 X represents are used as a basis for gas conveying emulsions. PFCTA is a group of compounds near to perfluor-N-(4- methylcyclohexyl)-piperidine with respect to the properties thereof, in particular with respect to a critical solution temperature in hexane. Said compounds are used in a mixture, thereby producing a range of compounds which exhibit gradually changing characteristics and making it possible to obtain highly uniform fluorocarhon phases of the emulsions and to increase the stability of emulsion particles which are stabilised with the aid of ethylene oxide-propylene oxide block polymers without being toxic for small and large animals. The PFCTA is produced by electrochemical fluorination of n-piperidine heptane fluor toluene in anhydrous hydrogen fluoride. The use of said PFCTA mixture instead of the individual perfluor-N-(4-methylcyclohexyl)-piperidine makes it possible to simplify, accelerate and lower the price of the production of perfluoronated organic compounds and extend the use of gas conveying emulsioins produced on the basis thereof.
Full Text Field of the Art
The present invention relates to the chemistry of fluororganic compounds and more particularly to a group of new tertiary perf luorocycloamines (TPFCA) . The invention may be used most effectively as a basis for producing gas transport media intended for the preservation of organs, blood substitution and treating pathologies associated with regional blood flow disturbances.
State of the Art
Known in the art is a tertiary perf luorocycloamine, perfluoro-N- (4-methylcyclohexyl) -piperidirie, which has the formula

(Formula Removed)
possesses lipophobic properties and is used as a basis • for gas transport media both singly and in combination with lipophilic perfluororganic compounds (PFOCs) , for instance, with perfluorodecalin (PFD) [see S.I .Vorobyev, G.R.Ivanitskij , K.N.Makarov, V.V.Moroz, V.P.Kutyshenko // Perfluorocarbon Emulsions Stabilized with Nonionogenic Block Copolymers // in: Collection of Papers "Perfluorocarbon Active Media for Medicine and Biology (New Aspects of Research}", Pushchino, 1993, pp. 33-46 (in Russian)].
In the specification to RU 2088217 published in the Bulletin "Izobreteniya. . . (Zayavki ...,)" No. 24 , 27.08.1S98 it is shown that introducing a lipophilic TPFCA perf luoro-N-(4-methylcyclohegxyl) -piperidine into the formulation of the
lipophilic fluorocarbon phase provides the elimination of toxicity in emulsions for large animals, this toxicity being typical of gas transport emulsions containing lipophilic rapidly eliminable PFOCs. However, in spite of all positive properties of emulsions prepared on the basis of lipophilic PFOCs and lipophobic perfluoro-N-(4-methylcyclohexyl)-piperidine, particles of such an emulsion are insufficiently stable. Their instability under freezing and thawing condi-tions during storage and when getting into the blood flow is caused, according to calculations and model experiments [G.R.Ivanitskij, S.I.Vorobyev, A.A.Deev // "Life" of Per-fluorocarbon Emulsion // in: Collection of Papers "Physio-logical Activity of Fluorine-Containing Compounds (Experi-ments and Clinical Tests)", Pushchino, 1995, pp. 5—32 (in Russian)], by that PFOCs sharply differing in the lipo-philicity, particularly in the temperature of critical dis-solution in hexane, form heterogeneous clustered structures in the fluorocarbon phase, that are characterized by perma-nent turbulent motion within the emulsion particles, the stability of the adsorption layer of the surface active com-ponent being thus disturbed.
Besides, the preparation of perfluoro-N-(4-methylcyclo-hexyl)-piperidine is a highly labor-consuming and therefore costly process, so that using this compound individually in-volves difficulties. These factors taken together impose es-sential limitations on the commercial preparation of this

combound an on a wide use of gas transport media for bio-medical purposes.
Essence of the Invention
It is an object of the present invention to provide new tertiary perfluorocycloamines close in their physicochenu-cal and biological properties to perfluoro-N-(4-methylcyclo-hexyl)-piperidine, non-toxic for large animals, and improv-
"ing the stability of emulsions under freezing and thawing conditions and upon getting into the blood flow,
Another object of the invention is to simplify and speed-up the technological process of preparing TPFCAs suit-able for use as a basis for the production of gas transport media and displaying an improved complex of useful proper-ties .
Said objects are accomplished by using as the basis for gas transport emulsions a group of tertiary perfluoro-cycloamines of general formula (1)
(Formula Removed)
where n=lor2, m=2or3, X is

(Formula Removed)
wherein at n = 2 X is

(Formula Removed)
Said group of compounds is prepared by the electrochemical fluorination of n-piperidinoheptaf luorotoluene . This group contains compounds having close physicochemical properties which provide their successful use in a mixture :
two isomers of perf luororaethylpropyl (methylcyclopentyl) -
cis/trans-perfluoromethylpropyl(methylcyclohexyl)amine, ☺ perf luoromethylbutyl- (4-methylcyclohexyl) amine, ☺ cis/Lidus-perfluoro-N—(4-methylcyclohexyl)-2-methylpyrro-
lidine, ☺ cis/trans-perfluoro-N—(4-methylcyclohexyl)-piperidine.
The critical parameter decisive for the possibility of using the products of the electrochemical fluorination of n-piperidinoheptafluorotoluene is the absence of underfluori-nated products: hydrogen-containing or unsaturated compounds responsible for toxicity. In terms of toxicity parameters, the individual perfluoro-N-(4-methylcyclohexyl)-piperidine and a mixture of TPFCAs practically coincide both in the form of liquids and in the formulation of emulsions (Tables 1, 2) .
All compounds of this group of TPFCAs are close in the lipophilic-lipophobic properties and in the critical tem-perature of dissolution in hexane (CTDH in the range of 34— 36°C with dissolution of 25 mol.%). In a mixture they form a number of compounds with gradually varying characteristics. Owing to this, a greater homogeneity of the fluorocarbon phase is achievable both in emulsions based on this group of compounds only and on a combination thereof with lipophilic perfluororganic compounds. Thereby it becomes possible to enhance the stability of the adsorption layer of the emul-sion particles stabilized by an ethylene oxide-propylene ox-ide block copolymer (Table 3) . The emulsions based on the TPFCA group, similarly to the emulsions containing individ-ual perfluoro-N-(4-methylcyclohexyl)-piperidine, are not toxic for large animals (Table 2) . In addition, these emul-sions display a better complex of properties manifested in a greater stability of the prepared emulsions (Table 3). All this makes these emulsions suitable for use as perfusion me-dia and blood-substituting compositions.
The electrochemical fluorination is carried out in an electrolytic cell charged with an electrolyte containing 10— 25% of the starting n-piperidinoheptafluorotoluene la anhy-drous hydrogen fluoride. The temperature is maintained in the range of 20—25°C. The current density is varied from 200 to 400 A/m2 at 5—6 V. The process is run for 10—12 hours with periodic replenishing the reaction mixture with a more con-centrated solution of the starting substance in anhydrous hydrogen fluoride. Depending on the reaction conditions, the yield of the fluorination products is from 61 to 78% of the starting product. After the removal of underfluorinated (hy-drogen-containing and unsaturated) products a number of ter-tiary perfluorocycloamines are obtained with a boiling point within 179-196°C.
All the compounds are identified by chromatographic mass spectrometry and NMR spectromentry techniques the main
compound of the group of interest is cis/trans-perfluoro-N-(4-methylcyclohexyl)-piperidine (with the yield of 60% to 70%) . Other TPFCAs are products of partial degradation and isomerization of the starting substance in the course of the electrochemical fluorination. Variations in the percentage of compounds in the TPFCA mixture upon variations of the cis/trans-perfluoro-N-(4-methylcyclohexyl)-piperidine con-tent within the range of 60% to 70% do not tell in any sub-stantial manner on the physicochemical and biological parameters of the obtained emulsions. A typical chromatogram of the prepared tertiary perfluorocycloamines is shown in Figure 1 (capillary column, squalane, 100 m).
The described process for the preparation of TPFCA is much simpler and cheaper then the preparation of individual pure perfluoro-N-(4-methylcyclohexyl)-piperidine, whatever process for the preparation of the latter is used, because the above-described process does not require carrying out such labor-consuming procedures as preparative chromatogra-
phy and rectification. The process for the preparation of individual perfluoro-N- (4-methylcyclohexyl)-piperidine is not described in the literature. Nevertheless, according to our estimates, the elimination from the process of the preparative chromatography and rectification operations, inevitable in isolating the individual products, makes the process several-fold simpler, faster and cheaper.
Said TPFCA mixture is used instread of individual perfluoro-N-(4-methylcyclohexyl)-piperidine for the preparation of gas transport emulsions. The simplified technology of the process makes it possible to contract expenses for the production of TPFCAs and thereby to reduce the production costs of gas transport media with a simultaneous enhancement of the stability and Theological properties of these media. All this opens up prospects for the commercial production and broader use of emulsions of perfluororganic compounds in research and clinical practice.
The present invention will be further illustrated by an example of preparing particular TPFCAs, this example being intended only for supporing the possibility of carrying out the invention, but not for limiting the Applicant's claims reflected in the set of claims hereinbelow.
According to the present invention there is provided a tertiary perfluorocycloamines of general formula (1)

(Formula Removed)
where n = 1 or 2, m = 2 or 3, Xis

(Formula Removed)
wherein at n = 2 Xis
as the basis for gas transport emulsions.
Brief Description of Figure 1
Figure 1 is a chromatogram of the prepared mixture of tertiary perfluorocycloamines (capillary column, squalane, 100 m), which shows the temperature shift amplitude determined with the help of a catharometric sensor vs. the substance yield time:
Peak 1. two isomers of perfluoromethylpropyl (methylcyclopentyl) -amine, Peak 2. cis/trans-perfluoromethylpropyl (methylcyclohexyl)-amine, Peak 3. perfluoromethylbutyl-(4-methylcyclohexyl) amine, Peak 4. cis/trans-perfluoro-N-(4-methylcyclohexyl)-2-methylpyrrolidine, Peak 5. cis/trans-perfluoro-N-(4-methylcyclohexyl) - piperidine.
Example 1
Preparation of tertiary perfluorocycloamines (TPFCAs) A 2-liter electrolytic cell with external circulation of the electrolyte, provided with nickel electrodes having an area of 3000 cm2, was charged with 1500 ml of an electro-lyte containing 10% of n-piperidinoheptafluorotoluene in an-hydrous hydrogen fluoride. The process of electrochemical fluorination was carried out at the temperature of 22 °C, initial current density of 200 A/m2 and voltage of 5 V. An electrolyte containing 60% solution of n-piperidinohepta-fluorotoluene in anhydrous hydrogen fluoride was added peri-odically. Dur,ing 10 hours of the fluorination the current density was increased gradually to 400 A/m2 by increasing the voltage to 6 V. The total amount of the current passed was 800 Ah, and 330 g of n-piperidino-heptaf luorotoluene were introduced into the reaction. Liquid products of the fluori-nation were separated from the electrolyte, washed with wa-ter, and with sodium bicarbonate solution to remove HF. Af-ter removing underfluorinated admixtures, the mixture of fluorination products was distilled, and 388 g (61%) of com-pletely fluorinated compounds having a boiling point within 179—196°C were obtained. According to the NMR spectroscopy and mass spectroiretry data, the obtained completely fluori-nated tertiary cycloamines comprise five kinds of compounds: 1 — isomers of perfluoromethylpropyl(methylcyclopentyl) -amine (1%), 2 — cis/trans-perfluoromethylpropyl(methylcyclo-hexyl)-amine, 3 — perfluoromethylbutyl-(4-methylcyclo-hexyl)amine (2%), 4 — cis/trans-perfluoro-N—(4-methylcyelo-hexyl)-2-methylpyrrolidine (25%), 5 — cis/trans-perfluoro-N— (4-methylcyclohexyl)-piperidine (64%) (see the chromatogram in Figure 1).
Example 2
The use of TPFCA
The completely fluorinated products obtained as de-scribed in Example 1 were used for preparing a submicron emulsion containing 10 vol . % of TPFCA, 3 wt% % of an ethylene oxide-propylene oxide block copolymer and an aqueous solu-tion of salts isotonic to blood plasma (120 mM of MaCl, 10 Mm of NaHC03/ 2 mM of KH2P04, 5 mM of KCl, 2 mM of CaCl2) , with 10 mM of glucose, 1 mM of sodium succinate, 1 mM of so-dium pyruvate, 1 mM of sodium 2-hydroxybutyrate (perfusate pH 7.40) . With the help of the produced emulsion, an iso-lated dog kidney was perfused under recirculation normother-mal conditions (I liter of the perfusate per 40 g of the kidney) . The vital activity of the organ was maintained for 24 hours, replacing the perfusion composition every 6 hours, without damage to cell membranes (without edema, without substantial growth of the capillary resistance, with the perfusate pH being preserved, and without a drop of the oxy-gen consumption rate).
Example 3
The use of TPFCA
A mixture of the TPFCAs prepared as described in Example 1 with perfluorodecalin in a 1:2 ratio was used for preparing a submicron emulsion containing 10 vol.% of a fluorocarbon phase, 4 wt.% of an ethylene oxide-propylene oxide block co-polymer, and an aqueous solution of salts isotonic to blood plasma (120 mM of NaCl, 8 mM of NaHC03, 1.2 mM of KH2PO4, 5 mM KCl), with 10 mM of glucose. The obtained emulsion was used for isovolumetric substitution of 65% of the volume of circulating blood in 10 rats under general anesthesia with premedication, with oxygen-enriched air being supplied to the animals for breathing in the course of the operation and during the first 24 hours after the blood substitution. All the animals which have undergone blood substitution, sur-vived .
Example 4
The use of TPFCA
TPFCA in a mixture with perf luorodecalin were used for the preparation of a submicron emulsion as described in Ex-ample 3. The prepared emulsion was administered intrave-nously to ten 2.5—3.5 kg bodyweight rabbits in a dosage of 20 ml per kg. The deviation of the body temperature in the rabbits after the administration of the emulsion did not ex-ceed 0.3°C. No symptoms of allergic reactions were observed. The content of leukocytes in the peripheral blood lowered by not more than 5% of the initial one, this being also indica-tive of the preparation being not reactogenic. All the rab-bits successfully survived the critical period of 80 days (the period during which all the rabbits die, if an emulsion of pure perfluorodecalin is administered to them). No patho-logical abnormalities were found in the animals throughout the follow-up period (of more than 1 year).
Table 1
Comparison of the toxicity* of individual perfluoro-N-(4-methylcyclohexyl)-piperidine (PFMCP) and of a mixture of tertiary perfluorocycloamines (TPFCAs), and of emulsions
based thereon

(Table Removed)
Toxicity of perfluororganic compounds was assessed by the inhibition of the growth of cultivated transformed lym-phoid Raji line cells.
Table 2
Comparison of the toxicity of different PFOC emulsions in terms of the half-lethal dose for mice auu of the
survival of rabbits

(Table Removed)
Table :;;
Comparison of the stability of PFD/PFMCP- and PFD/TPFCA-
based emulsion

(Table Removed)

1. Tertiary perfluorocycloamines of general formula (1)
(Formula Removed)
where n = 1 or 2, m = 2 or 3, Xis
(Formula Removed)
wherein at n = 2 Xis
(Formula Removed)
as the basis for gas transport emulsions.
2. Tertiary perfluorocycloamines as claimed in claim 1, comprising a group of compounds including two isomers of perfluoromethylpropyl - (methylcycolopentyl) amine; cis/trans - perfluoromethylpropyl (4-methylcyclohexyl) amine; perfluoromethylbutyl - (4-methylcyclohexyl) amine; cis/trans-perfluoro-N- (4-methylcyclohexyl) -2 methylpyrrolidine; cit/trans-perfluoro-N- (4-methylhexyl) -piperidine, displaying close physicochemical properties and used in a mixture.
3. A process for the preparation of tertiary perfluorocycloamines as claimed in claim 1 of general formula (1)
(Formula Removed)
where n = 1 or 2, m = 2 or 3, Xis
(Formula Removed)
wherein at n = 2 Xis
(Formula Removed)
comprising electrochemical fluorination of a starting product in anhydrous hydrogen fluoride, wherein the said starting product subjected to the electrochemical fluorination is n-piperidinoheptafluorotoluene.
4. Tertiary perfluorocycloamines, substantially as hereinbefore described with
reference to the foregoing examples and accompanying drawings.
5. A process for the preparation of tertiary perfluorocycloamines, substantially as
hereinbefore described with reference to the foregoing examples and accompanying






991-delnp-2003-description (complete).pdf










Patent Number 231546
Indian Patent Application Number 991/DELNP/2003
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 05-Mar-2009
Date of Filing 25-Jun-2003
# Inventor's Name Inventor's Address
PCT International Classification Number CO7C 211/37
PCT International Application Number PCT/RU00/00547
PCT International Filing date 2000-12-29
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/RU00/00547 2000-12-29 PCT