Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Halogenated hydrocarbon doai
Reexamination Certificate
1998-09-30
2001-07-17
Killos, Paul J. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Halogenated hydrocarbon doai
C570S134000, C514S912000, C606S004000
Reexamination Certificate
active
06262126
ABSTRACT:
BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to semifluorinated alkanes of the general formulas
R
F
R
H
or R
F
R
F
R
H
R
F
wherein R
F
is a linear or branched perfluoralkyl group and R
H
is a linear or branched, saturated (hydrocarbon)-alkyl group.
The unbranched semifluorinated alkanes have the formulas:
F(CF
2
)
n
(CH
2
)
m
H or F (CF
2
)
n
(CH
2
)
m
(CF
2
)
n
F
wherein n=1-20 and m=3-20.
The branched semifluorinated alkanes can also contain within the perfluoralkyl groups FCX units
wherein X=C
2
F
5
, C
3
F
7
or C
4
F
9
as well as —HCY— units within the alkyl groups
wherein Y=C
2
H
5
, C
3
H
7
or C
4
H
9
.
A —CX
2
— group can be contained within a perfluoralkyl chain, and a —CY
2
— group within an alkyl chain.
Instead of the perfluoralkyl group F
3
C—, an FCX
2
— or F
2
CX— group, with X=C
2
F
5
, C
3
F
7
or C
4
F
9
, can be bound in the terminal position in the molecule, and likewise an HCY
2
— or H
2
CY— group wherein Y=C
2
H
5
, C
3
H
7
, or C
4
H
9
can be found in the terminal position in the molecule instead of the alkyl group H
3
C—.
But in the case of all of the named isomers, that is to say linear or branched semifluorinated alkanes, the total number of the carbon atoms in the perfluoralkyl part remains, as stated, within the limits of n=1-20, and also in the alkyl part the number of the carbon atoms remains in the stated limits of m=3-20.
The invention furthermore relates to the use of these semifluorinated alkanes in medicine, pharmacy, biology and technology.
These semifluorinated alkanes, also called diblock compounds R
F
R
H
and triblock compounds R
F
R
H
R
F
, or also “modified perfluorocarbons,” can be linear or branched both in the perfluoralkyl groups and in the alkyl groups, while in the case of the isomers the total number of the carbon atoms in the perfluoralkyl part remains in the stated limits of n=1 to 20 and in the alkyl part the total number of carbon atoms remains in the stated limits of m=3 to 20.
These semifluorinated alkanes can be used as medicinal adjuvants, drugs for ophthalmology, as a vitreous humor substitute, as a dermal treatment for supporting oxygen transport in the skin, for instillation and fluid artificial respiration in surgical interventions and in emergency medical treatment, to facilitate breathing in divers, and as friction-reducing additives in lubricants and waxes.
These types of compounds proposed as patent-worthy are similar to the perfluorocarbons (compounds which consist only of carbon-fluorine bonds) are chemically, physically and physiologically inert and thus nontoxic.
In comparison with the perfluorocarbons, the semifluorinated diblock or triblock alkanes are of an entirely different structure. They consist of closed hydrocarbon-alkane groups, —(CH
2
)
n
— and —(CHR
H
)
n
— and —(CH
2
)
n
H, which are bound directly to perfluoralkyl groups, —(CF
2
)
m
— and —(CFR
F
)— and —(CF
2
)F, respectively. The perfluoralkyl part can also begin with a (CR
F
R
F
F)— grouping and terminate in a (CR
H
R
H
H) grouping. Within a perfluoralkyl chain an —R
F
CR
F
— group can be bound, and within an alkyl chain an —R
H
CR
H
— group can be bound.
In these types of compounds no intramolecular HF cleavage with the formation of fluorolefinic double bonds can take place. On the contrary, the closed hydrocarbon-alkane grouping has a bond strengthening effect on the sometimes very strong C-F bonds in the perfluoralkyl part of the compound in question.
The semifluorinated diblock or triblock alkanes are colorless liquids or solids. They are not attacked by strong acids or lyes or oxidants or nucleophiles, much less liable to metabolic or catabolic attack.
Physically, the semifluorinated alkanes behave like modified perfluorocarbons, and the boiling points and melting points increase with increasing molecular mass (see FIGS.
1
and
2
). Semifluorinated alkanes, like the pure perfluorocarbons, have a high solubility for gases, including O
2
and CO
2
(about 40-50 and 130-150 vol. %, respectively).
Like the perfluorocarbons and the hydrocarbons, the semifluorinated alkanes are scarcely or not at all soluble.
However, they can be converted in a manner similar to H. Meinert, A. Knoblich, Biomat. Art. Cells & Immob. Biotech., 21 (1993) 583 by means of effective tensides (fluorotensides, compounds with a fluorophilic head and a hydrophilic tail, ethylene oxide-propylene oxide block polymers, Pluronics® or phospholipids such as egg lecithin or soya lecithin, etc.) or ionic tensides, with the aid of physical emulsification methods (ultrasound or Gaulin homogenizers), to particle-stable emulsions with particle sizes of about 100-300 nm.
In contradistinction to the perfluorocarbons, the semifluorinated alkanes, regardless of their R
F
or R
H
content, are soluble both in perfluorocarbons and derivatives of perfluorocarbons (perfluorinated ethers of higher molecular weight, Hostinert®, Fomblin®, etc.) [see H. Meinert, A. Knoblich, Biomat. Art. Cells & Immob. Biotech., 21 (1993) 583; H. Meinert, Fluorine in Medicine in the 21
st
Century, Manchester (1994), paper 23; R. J. Twieg et al., Macromolecules 18 (1985) 1361; and J. Höpken et al., Macromol. Chem. 189 (1988) 911] and in hydrocarbons and their derivatives and compounds with higher alkyl group contents (e.g., liquid paraffins, silicone oils, fatty acid esters, etc.). As the perfluoralkyl content increases the solubility in the fluorocarbon systems increases, while with increasing alkyl content the solubility in hydrocarbon systems increases, and vice-versa. In solutions of semifluorinated alkanes, especially semifluorinated linear alkanes, in hydrocarbon substances, laminar double layers may be present, while under certain circumstances, e.g. depending on the concentration ratio or upon cooling, the previously homogeneous, optically clear solutions turn into opaque gels. Upon subsequent cooling the homogeneous solutions are recovered. The formation of the gel is due to the fact that the solvent hydrocarbons are absorbed by the diblock double layers of the R
F
R
H
[R. J. Twieg et al., Macromolecules 18 (1985) 1361; J. Höpken et al., Macromol. Chem. 189 (1988) 911].
In contrast to the perfluorocarbons (densities 1.8-2.0 g/cm
3
) the densities of the semifluorinated alkanes with densities between 1.1 and 1.7 g/cm
3
are substantially lower due to the fact that these molecules have a high content of hydrocarbon groupings.
On the other hand, the proposed compounds have the preferred properties of the perfluorocarbons in regard to their boundary surface tension against water (R
F
R
H
50-58 nN/m at 20° C.) and the extraordinarily low surface tension (R
F
R
H
25-22 mN/m at 20° C., due to the fact that perfluoralkyl groups are bonded to the end of the molecule.
If separation occurs in long-standing solutions of the above-mentioned hydrocarbons and their derivatives with semifluorinated diblock or triblock alkanes due to relatively great differences in density (which occurs when semifluorinated alkanes with a high perfluoralkyl content are used), the homogeneous, optically clear solution can be restored by simple shaking.
The semifluorinated diblock or triblock alkanes are obtained by the reaction of perfluoralkyl iodides with alkenes or &agr;, &ohgr;— dienes, after HI elimination followed by hydrogenation by means of a platinum catalyst Organikum, Autorenkollektiv, Dtsch. Verlag der Wissenschaften, Berlin (1977) 363 or by means of tributyltin hydride [J. Höpken et al., Macromol. Chem. 189 (1988) 911] (see the Examples of syntheses of semifluorinated diblock and triblock alkanes below).
The products thereby obtained for the proposed fields of application can, in a preferred embodiment, also be highly purified. For that purpose the semifluorinated alkanes are first treated with acid permanganate solution in a manner similar to DE 42 05 341 (WO 93/16974), then they are refluxed or autoclaved for about 72 hours at 150-180° C. with a mixture of strong aqueous caustic soda solution (4-8
Crowell & Moring , L.L.P.
Killos Paul J.
Parsa J.
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