JPS6360025B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel perfluorocyclic amine compound useful as a blood substitute, an oxygen-carrying component in an oxygen-carrying infusion, and the like. More specifically, the present invention relates to the general formula (wherein l represents 1, 2 or 3, m represents 0 or 1, and n represents 3, 4 or 5), and the total number of carbon atoms is 10 or 11. . Compound () is, for example, a perhydro compound corresponding to compound () [later, compound (-1)
and (-2)]. The fluoridation method is as follows:
For example, direct fluorination method, cobalt fluoride method,
Examples include electrolytic fluorination method. It is preferable to perform an electrolytic fluorination method to produce the compound () of the present invention, which involves, for example, mixing and dissolving anhydrous hydrogen fluoride and a perhydro compound as a raw material compound in an electrolytic bath, and then subjecting the mixture to electrolysis. The voltage in the electrolysis is usually 4 to 8 V, and the anode current density is usually 0.1 to 3.0 A/d.
cm, and the bath temperature is usually 0 to 10°C. Since the compound () thus produced is insoluble in anhydrous hydrofluoric acid, it precipitates in the lower layer of the electrolytic cell. Isolation and purification of compound () from the precipitate are as follows:
For example, it is done as follows. An equal volume of a mixture of an aqueous alkaline solution and an amine compound is added to the recovered precipitate and heated to reflux to decompose the partially fluorinated compound.
After cooling, the compound () in the bottom layer is separated and washed with an appropriate amount of potassium iodide-containing acetone aqueous solution to remove a compound in which a fluorine atom is bonded to a nitrogen atom, followed by further fractional distillation. Compound () is fractionated. The compound () according to the present invention can dissolve a large amount of oxygen, is metabolically inert, and is rapidly excreted from the body, so that, for example, 5 to 50 w/v% of the compound () , preferably 10 to 40 w/v%, to prepare blood substitutes, oxygen-carrying infusions, etc. for warm-blooded animals including humans (dogs, cats, cows, mice, rats, guinea pigs, etc.). Used as an oxygen carrier. In preparing the above emulsion, a polymeric nonionic surfactant, phospholipid, or the like is used as an emulsifier, and the amount thereof added is 1 to 5% w/v. In addition, a physiologically acceptable aqueous solution is used as the medium, and if necessary, an isotonic agent such as glycerol or an inorganic salt is used, and a plasma expander such as HES or dextran is used to adjust the colloid osmotic pressure. may be added. An emulsion is prepared by homogenizing the above-mentioned components using, for example, a high-pressure injection emulsifier so that the particle size is 0.05 to 0.3 μm, preferably 0.2 μm or less. Note that the perhydro compound corresponding to the starting material compound () is substantially a known compound,
It is usually manufactured as follows. In this method, the N-alkylation reaction of lactam is carried out as described by CS Marvel et al., JOC, 22 , 1065 (1957).
The ring-closing reaction was carried out according to the method of Isamu Murakoshi, Pharmaceutical Journal 78 , 594 (1958). Further, a compound in which m=1 [compound (-2)] can also be produced in the same manner as above. Example 1 The electrolytic cell is made of Monel metal and has a capacity of 1.5, and has electrode plates (6 anodes, 7 cathodes) made of nickel (purity of 99.6% or more) arranged alternately with an inter-electrode distance of 1.7 to 2.0 mm, A tank with an effective anode area of 10.5 dm ² and a copper reflux condenser at the top was used. Anhydrous hydrofluoric acid 1.2 was introduced into this electrolytic cell, trace amounts of impurities (water and sulfuric acid) were removed by preliminary electrolysis, and then 1-azatricyclo(5,4,0)
130 g (0.85 mol) of undecane was dissolved in anhydrous hydrofluoric acid, and while helium gas was passed from the bottom of the tank at a flow rate of 100 ml/min, the anode current density was 2.3 to 0.3 A/min.
Electrolysis was carried out for 980 Ahr at dm ² , voltage 5.8 to 60 V, and bath temperature 3 to 8°C. 250 ml of anhydrous hydrofluoric acid was added every 24 hours. No liquefaction collection of volatile fracture products produced during electrolysis was performed. After electrolysis, the inside of the electrolytic cell is separated into hydrogen fluoride in the upper layer and fluorocarbons in the lower layer, so when the lower layer was separated and collected by the drain, 314g (crude yield 74.6
%). 50% to this fluorocarbon.
Equivalent volumes of w/v% aqueous sodium hydroxide solution and diisobutylamine were added, and reflux was carried out for about 5 days. Thereafter, an equal volume of ice water was added, and the mixture was cooled in an ice bath and then filtered by suction. Fluorocarbons settle to the bottom layer, so after separating them in a separating funnel, add dilute sulfuric acid, concentrated nitric acid, saturated aqueous sodium bicarbonate solution, and 3% potassium iodide.
Wash with 90% acetone solution and then with water 198
A transparent perfluorinated compound of g was obtained. The perfluorinated substance from which impurities including protons have been removed is distilled using a rotating band type precision fractionator to obtain 35 g of a compound with a boiling point of 143 to 154°C.
(Yield: 8%). As a result of fractionating this and analyzing it by infrared absorption spectrum, ¹⁹ F-nuclear magnetic resonance spectrum, mass spectrum, etc., it was confirmed that the target compound was perfluoro-(1-azabicyclo[5,4,0]undecane). Examples 2 to 5 A series of other perfluorocyclic amines were synthesized by the same method, purified, fractionated, and collected, and analyzed by infrared absorption spectrum, ¹⁹ F-nuclear magnetic resonance spectrum, and mass spectrum. The structural formula and boiling point of each target compound thus obtained are as shown in Nos. 2 to 5 in the table. F-" indicates that it is a perfluoro compound, for example, the formula formally represents the following equation:

【table】

[Table] Experimental example 1 Add 400 g of egg yolk phospholipid and 4 g of sodium palmitate to 8.5 g of lactated Ringer's solution, stir with a mixer to prepare a rough emulsion, and add 2.5 kg of the perfluoro compound of Example 1 to this liquid. Further, the mixture was vigorously stirred with a mixer to prepare a rough emulsion. This rough emulsified liquid is sprayed into a spray emulsifier (manufactured by Manton-Gorlin).
The mixture was placed in a liquid tank and circulated, and emulsification was carried out while maintaining the liquid temperature at 50±5°C. The concentration of perfluoro compound in the obtained emulsion was 2.73 w/v%. The particle size measured by the centrifugal sedimentation method was 0.05 to 0.25μ, and even if the vial was dispensed into an injection vial, capped, and stored in a rotary sterilizer and sterilized by heat, the particle size did not significantly increase. was not accepted. Experimental Example 2 Organ Distribution of Perfluorinated Compounds Using male Wistar rats weighing 120 to 130 g, the emulsion prepared in Experimental Example 1 [4 g/Kg as perfluorinated compound] was administered through the tail vein of the rats.
The content of perfluorinated compounds taken into the liver, spleen, and adipose tissue was measured by gas chromatography over a period of 3 months after administration. Table 1 shows the perfluorinated compound content taken into each organ at 1, 2, 4 weeks, and 3 months after administration. A large amount of these compounds is taken up into the reticuloendothelial system tissue at the beginning of administration, and then disappears rapidly. Three months after administration, the total amount of perfluorinated compounds remaining in each organ is 0.66% of the administered dose, and each organ in the liver and spleen No adverse effects on organs were observed. As a result, the half-life of the C ₁₀ perfluorinated compound was calculated to be 2.0 days. Also, the half-life of _C11 perfluorinated compounds was three to four times longer.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, l is 1, 2 or 3, m is 0 or 1, and n is 3, 4 or 5.) A perfluorocyclic amine having a total number of carbon atoms of 10 or 11.