CA1190925A - Perfluorocycloamines - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Perfluorocycloamines represented by the general formula:

Description

This invention relates to novel perfluorocycloamines useful as oxygen-carrying components for blood substitute, oxygen-carrying transfusions or the like and to a process for producing the perfluorocycloamines.
More specifically, this invention relates to perfluoro-cycloamines represented by the general formu]a:

f ~ ~ \
~CF2) A N - Z - CF B (CF2) (I) wherein either or both of ring A and ring B may be substi-tuted with one or more lower perfluoroalkyl groups, rn and n are independently 4, 5, or 6 and Z is a perfluoroalkylene group or a chernical bond, with the proviso that n is not 5 when m is 5 and Z is a chemical bond.
In the general formula (I), either or both of ring A
and ring B may be substituted with one or more lower perfluoro-alkyl groups at one or more positions (preferably 1 to 2 positions).
Such perfluoroalkyl groups as substi-tuent are linear or branched. Examples of these groups are perfluoromethyl group, perfluoroethyl group, perfluoro-n-propyl group, perfluoro-iso-propyl group, etc., each having 1 ~o 3 and preferably 1 to 2 carbon atoms. When two or more of these substituents are present, they may be different from each other.
With respect to Z in the general formula (I), the perfluoroalkylene group is linear or branched. Examples are, for instance, linear perfluoroalkylene groups of 1 to 3 carbon ",''i ~

atoms such as perfluorome-thylene, perEluoroethylene and the like and b.ranched perfluoroalkylene groups which are the above per--fluoroalkylene groups having a substituent of a lower perfluoro-alkyl group of 1 to 2 carbon atoms such as perfluoromethyl or perfluoroethyl. The total carbon atom number of Z, when Z is a perfluoroalkylene group, is usually 1 to 3 and preferably 1 to 2.
The total carbon atom number of the compound of the general formula (I) is usually 8 to 12, preferably 9 to 11, and more preferably 10.
A preferred group of the perfluorocycloamines are represented by the formula:

a) ~ N _ _ ~

wherein either the perfluorocyclohexyl group or the perfluoro-pyrrolidine or both may be substi-tuted by a perfluoromethy] group.
The compound of the general formula (I) can be produced by :Eluorinating a corresponding perhydrocompound of the formula:

(CH ~ N - Z - CH B (CH2ln (I') -As the fluorination method, there may be mentioned, for example, known fluorination methods such as the direct fluori.nation method, the cobalt fluorination method, the e.lectro]ytic fluorination method, etc.
In the production of the compouncl (I) of this invention, the use of the electrolytic fluorination me-thod is preferable.

The method can be carried out, Eor example, by adding into an electrolytic cell anhydrous hydrofluoric acid and a perhydro-compound AS starting g2~

1 material compound, making them a solution by mixing and thereaf~er subjecting the solution to electrolysis.
Normally, the voltage used in the electrolysis is 3 to 9 V, the anode current density is 1 to 300 A/dm2 and the cell temperature is 4 to 10C.
The compound of the general formula of ~I) thus formed, is insoluble in anhydrous hydrogen fluoride, so that it precipitates at the bottom layer of the electrolytic cell.
The isolation and refining of the compound (I) from the precipitate is carried out, for example, by adding to the recovered precipitate a mixture of an equal volume of an aqueous alkali solution and an amine compound, subjecting the whole mixture to refluxing, then separating the compound (I) of the lowermost layer (at this time, partially fluorinated compounds are dissolved in the amine layer), washing the compound (I) with a~ appropriate amount of an aqueous acetone solution containing potassium iodide to remove compounds having nitrogen atoms combining with fluorine atoms, and there-after conducting a frac~ional distillation to collect the compound (I).
The compound (I) according to this invention can dissolved a large volume of oxygen and, moreover, is inactive from the standpoint of metabolis~ and is rapidly excreted out of the human body. Accordingly, for example, an aqueous emulsion contai.ning 5 to 50% (w/v~ and pre-ferably 10 to 40% (w/v) of the compound (I) can be used 1 as an oxygen-carrying compound in blood substitute, oxygen-car:rying transfusions, etc. which are applied to mammals SUC].l as humans; dog, cat, cattle, horse, rat, mouse, guinea pig, etc.
In the preparation of the above emulsion, there are used emulsifiers such as high molecular, non-ionlc surEactants, phospholipids, etc., in quantities of 1 to S~ (w/v) each alone or in combination.
In the prepaxation of the above emulsion, there is also used, as a medium, a physiologically acceptable aqueous solution. If necessary, there may be further added an isotonizing amount of an isotonizlng agent such as glycerol to isotonize the emulsion and a plasma extender such as hydroxyethylstarch or dextran to adjust the colloid osmotic pressure of the emulsion.
By homogenizing the above-mentioned ingredients into particles having sizes of 0.05 to 0.3 ~, preferably 0.2 ~ or smaller using a high-pressure jet-type homo-gen:Lzer, an aqueous emulsion containing the compound II) can be prepared.
Incidentally, the perhydrocompounds as starting material corresponding to the compound (I) is substantially known compounds.
This invention will be illustrated in more detail ~elow by the way of Examples and Reference Examples, however, the invention is not restricted by these Examples.

-- 4 ~

l Exarnple 1 There was used the following electrolytic cell:
. Made of a ~lonel metal.
. Capacity: 1.5 liters . Electrode plates: 6 anode plates and 7 cathode plates, each made of nickel of a purity of at leas-c 99.6%. Anode and cathode pla-tes are alter-nately arranged with an electrode to electrode distance of 1.7 to 2.0 mm. Effective anode area is 10.5 dm2.
. Reflux condenser: Made of copper and placed at the top of cell.

Into this electrolytic cell there was introduced 1.2 liters of anhydrous hydrofluoric acid, and trace amounts of impurities (water and sulfuric acid) were removed by pre-electrolysis. Then, 0.85 mole (130 g) of N-cyclo-hexylpyrrolidine was dissolved in the hydrofluoric acid and, while helium gas was passed throuyh the cell ~rom the bottom at a rate o~ 100 ml/min, an electrolysis of 920 Ahr was conducted with an anode current density of 0.4 to 2.0 A/dm2 and an electrolytic voltage of 5 to 9 V a~ a cell temperature of 4 to 10C. Hydro-fluoric acid was supplemented by each 350 ml per 24 hr.
The condensation and subsequent collection of the vola'cile decomposi'cion products formed during the electrolysis was not conducted. After the electrolysis, the liquid inside the cell separated into two layers, with 'che upper l layer being anhydrous hydrofluoric acid and the lower layer being fluorocarbons. The lower layer was collected from the drain of the cell and 303 g was obtained (yield: 725~).
To t:he collected lower layer which was a fluorinated procluct by electrolysls, were added 70~ aqueous KOH solu-tiOIl and diisobutylamine in equal volumes, and the whole mixture was subjected to refluxing for about 7 days. The reaction mixture was cooled in an ice bath, whereby the perfluorocompound settled as the lowermost layer. The perfluorocompound was then separated using a separation funnel and subsequently washed with water, concenlrated sulfuric acid, an aqueous sodium bicarbonate solution, an aqueous acetone solution containing!potassium iodide and water in this order to ob~ain 92 g of a transparent perfluorocompound. The perfluoroc~mpound thus obtained was subjected to fractional distillation in a fractional dist:illation apparatus with a spinning band column to obtain 32.2 g (yield: 7, 75L) Of perfluoro-N-cyclohexyl-pyrrolidine having a boiling point of 145 to 152C.
This compound was verified to be the above-mentioned objective compound also from analysis by IR spectrum/ E
NMR spectrum, mass spectrum/ etc.

Examples 2 to 58 In the same manner as in Example 1, corresponding perfluorocompounds were produced from perhydrocompound materials. Materials usecl and products obtained were summari~ed in Table 1.

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1 Reference Example 1 400 g of vitelline phospholipid was added to 8.5 Q of lactic acid added Ringer's solu-tion, and stirred by a mixer to prepare a coarse emul-sion, then 2.5 kg of perfluoro-N-cyclohexylpyrrolidine was added thereto and stirred vigorously again by the mixer to prepare a coarse emulsion. This coarse emulsion was placed in a liquid tank of a jet emulsifier (manufactured by Manton-Gaulin Co.) and circulated while maintaining the liquid temperature at 50O T 5C to effect emulsification.
The concentration of perfluoro-N-cyclohexylpyrrolidine in the obtained emulsion was 27.3% (w/v). The particle diameter as measured by the centrifugal sedimentation method was 0.05 - 0.25 ~. This emulsion was allotted into vials for injection, stoppered and thermally steriliz-ed in a rotary sterilizer, but there was no significant increase in the particle diameter observed.

Reference Example 2 An emulsion was obtained by procedures similar to those in Reference Example 1 except that perfluoro-N-cyclohexylprrolidine was replaced by perfluoro-N-(3'-methylcyclohexyl)pyrrolidine. The particle diameter of th~
thus obtained emulsion was 0.05 - 0.25 ~.

Experimental Example 1 Stability of Emulsions.
Water was added to 20 g of each perfluoro-cycloamine selected in the present invention and 4 g of ~ ~ 19 -

3)2~

1 vitelline phospholipid to make the total volume 200 ml, and emulsification was effected using a Manton-Gaulin emulsifier as used above under nitrogen stream at 200 -600 kg/cm2 while maintaining the liquid temperature at 40 - 45C. Each obtained emulsion was filtered through a 0.65 ~ membrane filter, allotted into 20 ml capacity vials, and, after replacing the atmosphere by nitrogen gas, thermally treated at 100C for 30 minutes, followed by storing at 4C of room temperature to examine the stability. The particle diameter of the emulsion was measured by the centrifugal sedimentation method by Yokoyama et al. [Chem. Pharm. Bull. 22 (12) 2966 (1974)], and from the obtained data, the average particle diameter distribution was calculated using a microcomputer.
Thus, the particle diameter distributions of each perfluorocarbon emulsion before and after heating, and after heating and storing at 4~C and room tempexature (15 - 28C) are shown in Tables 2 and 3. As is evident from the results, the emulsions accoxding to the present invention are very stable against heating and the in~luence on the average particle diameter due to heating was not observed at all. Further, when stored at 4C
after heating, ~here was no increase in the average particle diam~ter or the emulsion observed even after 5 months.

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__ _ ~ 22 -1 Experimental Example 2 Acute Toxicity Test.
The acute toxicity test on the preparations of the present invention was carried owt using the prepara-tions of the present invention shown in Table 4 which had been physiologically isotonized. The test animals used were Wister-strain male rats (weighing 100 - 120 g). The emulsoin was intravenously administered and the animals were observed for one week after the administration.
The results are such that with either emulsion containing perfluoro-N-cyclohexylprrolidine or perfluoro-N-(3'-methylcyclohexyl)pyrrolidirle, thre was na death case at 100 ml/kg-body weight and thus their toxicity are very small.
Table 4 _ . __ Composition Ratio, o:l Perfluoro Compound 30 nent lng Agent Vitelline Phospholipid 4.0 ~ ... _ ... _ ... . _ ....
NaCl 6.00 NaHCO3 2.1 ly-te MgC12.6H2O 0 336 CaC12 2H2 0.356 D-Glucose 1.802 _ .___ pH 8.0 _ __ ._ 1 ~xperimental Example 3 Distribution of Perfluoro-compound in Organs.
Using Wister-strain male rats weighing 1~0 - 130 g, the emulsion prepared in Reference Example 1 was admini-~tered into the tail vein [at 4 g/kg as perfluoro~N-cyclo-hexylpyrrolidine], and for a period of 3 months after the administration, the content of said compound in the liever, spleen and fat tissues due to uptake were measured by m~ans of gas chromatography.
The content of perfluoro-N-cyclohexylpyrrolidine uptake in each organ 1, 2 and 4 weeks and 3~months after the administration are shown in Table S. The compound was taken up in greater amounts by the reticulo-endothelial organs shortly after the administration, but soon dis-lS appeared rapidly. There was no evidence of adverse influence on the liver or spleen organ.
As a result, the half-life of perfluoro-N-hexylpyrrolidine was calculated to be 16 days.

., ~

Table 5 Time after theResidual Rate of Organ Administratlonperfluoro-compound . .__ 1 Week 21.23 2 Weeks 13.63 Liver . 4 Weeks 4.98 3 Months 0.24 _. . ~

1 Week 12.33 2 Weeks 10.49 Spleen 4 Weeks 8.52 3 Months 0.51 1 Experimental Example 4 Anatominal Remarks.
Wister-strain male ra-ts weighing 120 - 130 g were administered with 4 g/kg of the perfluorocycloamine emulsion prepared in Reference Example 1 or 2, and the s dissected organs were observed for a period of 3 months af-ter -the administration, and further the organs (liver and spleen) were weighed, to determine the weight relative to the body weight.
One, 2 and 4 weeks and 3 months after the administration of the emulsion, the important organs, i.e. the lung, liver and spleen were observed, to find no evidence of -the influence on the organs by ei-ther said compound because of their rapid elimination.

Claims (29)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of perfluorocycloamine represented by the general formula:

(I) wherein either or both of ring A and ring B may be substituted with one or more lower perfluoroalkyl groups, m and n are independently 4, 5 or 6 and Z is a perfluoroalkylene group or a chemical bond with the proviso that n is not 5 when m is 5 and Z is a chemical bond, which process comprises fluorinating a corresponding perhydro-compound of the formula:

(I')

2. A perfluorocycloamine of formula (I) as defined in claim 1, whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1, wherein in the starting material ring A is pyrrolidine.

4. A process according to claim 3, wherein in the starting material Z is a chemical bond.

5. A process according to claim 4, wherein in the starting material ring B is cyclopentyl or cyclohexyl, each of ring A and ring B is unsubstituted or mono- or di-substituted with methyl or ethyl, and the total carbon atom number is 8 to 12.

6. A process according to claim 4, wherein in the starting material ring B is cyclohexyl and each of ring A and ring B is unsubstituted or mono substituted with methyl.

7. A process according to claim 1, 3 or 4, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

8. A process according to claim 5 or 6, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

9. A process for the preparation of perfluorocycloamine represented by the formula:

(I-a) wherein either the perfluorocyclohexyl group or the perfluoro-pyrrolidine or both may be substituted by a perfluoromethyl group, which process comprises:

fluorinating a corresponding perhydro-compound of the formula:

(I'-a) wherein the cyclohexyl group or the pyrrolidine group or both may be substituted by a methyl group.

10. A process according to claim 9, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

11. A perfluorocycloamine of formula (I-a) as defined in claim 9, whenever prepared or produced by the process of claim 9 or 10 or by an obvious chemical equivalent thereof.

12. A process for the preparation of perfluoro-N-cyclo-hexylpyrrolidine, which process comprises fluorinating N-cyclo-hexylpyrrolidine.

13. A process according to claim 12, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

14. Perfluoro-N-cyclohexylpyrrolidine, whenever prepared or produced by the process of claim 12 or 13 or by an obvious chemical equivalent thereof.

15. A process for the preparation of perfluoro-N-(3'-methylcyclohexyl)pyrrolidine, which process comprises fluorinating N-(3'-methylcyclohexyl)pyrrolicline.

16. A process according to claim 15, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

17. Perfluoro-N-(3'-methylcyclohexyl)pyrrolidine, whenever prepared or produced by the process of claim 15 or 16 or by an obvious chemical equivalent thereof.

18. A process for the preparation of a perfluoro-N-cyclohexyl-2-methylpyrrolidine, which process comprises fluorinating N-cyclohexyl-2-methylpyrrolidine.

19. A process according to claim 18, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

20. Perfluoro-N-cyclohexyl-2-methylpyrrolidine, whenever prepared or produced by the process of claim 18 or 19 or by an obvious chemical equivalent thereof.

21. A process for the preparation of perfluoro-N-cyclohexyl-3-methylpyrrolidine, which process comprises fluorinating N-cyclohexyl-3-methylpyrrolidine.

22. A process according to claim 21, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

23. Perfluoro-N-cyclonexyl-3-methylpyrrolidine, whenever prepared or produced by the process of claim 21 or 22 or by an obvious chemical equivalent thereof.

24. A process for the preparation of perfluoro-N-(2'-methylcyclohexyl)pyrrolidine, which process comprises fluorinating N-(2'-methylcyclohexyl)pyrrolidine.

25. A process according to claim 24, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

26. Perfluoro-N-(2'-methylcyclohexyl)pyrrolidine, whenever prepared or produced by the process of claim 24 or 25 or by an obvious chemical equivalent thereof.

27. A process for the preparation of perfluoro-N-(4'-methylcyclohexyl)pyrrolidine, which process comprises fluorinating N-(4'-methylcyclohexyl)pyrrolidine.

28. A process according to claim 27, wherein the reaction is carried out by the electrolytic fluorination method using anhydrous hydrofluoric acid.

29. Perfluoro-N-(4'-me-thylcyclohexyl)pyrrolidine, whenever prepared or produced by the process of claim 27 or 28 or by an obvious chemical equivalent thereof.