Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-08-31
2003-01-14
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S076000, C560S008000
Reexamination Certificate
active
06506928
ABSTRACT:
The invention relates to dendrimeric fullerene derivatives, that is fullerene derivatives which are substituted by one or more dendrons. Fullerenes are carbon compounds of the formula C
2
(10+m), where m is a natural number. They contain twelve five-membered and any desired number, i.e. m, but at least two, six-membered rings of carbon atoms.
The outwardly vaulted surface of fullerenes and the alignment of the &pgr; electrons produced thereby cause a great reactivity to free radicals /1/ (The literature references are listed at the end of the description). Thus, it is known for C
60
Buckminsterfullerene that it very easily adds radicals. The absorption of up to 34 methyl radicals is described and the name “radical sponge” has been proposed therefor /1/.
It is known that hydroxyl and hydroperoxide radicals in biological systems preferably attack polyunsaturated fatty acids. This attack brings about crosslinking and polymerization of the fatty acid structures. Free radicals thus also bring about damage to biomembranes, in particular the membranes of nerve cells, which are distinguished by a particularly high proportion of unsaturated fatty acids in their lipids. As a result of the change in the lipid structure of such biomembranes, a change in the membrane permeabilities, a change in their transport functions, a change in their barrier mechanisms and changes in their receptor activities can occur and this can lead to the death of the nerve cells. Overstimulation of glutamate receptors likewise led to the formation of free oxygen radicals and nitric oxide radicals /2-6/ and as a result to damage to nerve cells and to the occurrence of specific syndromes /7-10/.
Radical scavengers provide for the removal of harmful free radicals, act as antioxidants and suppress the damage to the nerve cells and the loss of function of neuromembranes. Therefore, especially fullerenes with their excellent radical-scavenging properties should act as neuroprotectants and should be able to be employed for the protection of biological membranes against oxidative changes. C
60
fullerene, however, is only soluble in very few organic solvents, such as benzene and toluene, and thus cannot also be administered to biological membranes. The addition of suitable functional groups on C
60
, however, should improve the water solubility and thus also make possible use as antioxidants in biological systems. The first positive results were achieved using polyhydroxylated C
60
/11/, and trisubstituted synthetic malonic acid derivatives C
60
[C(COOH)
2
]
3
, which had both in vitro and in vivo neuroprotective activities, afforded better results /12/. The preparation of the two isomers having C
3
or D
3
symmetry described in /12/ was carried out by the method of Hirsch /13/ by triple cyclopropanylation of C
60
with diethyl malonate, hydrolysis and subsequent chromatographic purification. The two test compounds exhibited strong affinity for free radicals, as it was possible to show by EPR spectroscopy, and inhibited the excitotoxic death of cell cultures of cortical neurons which were induced by N-methyl-D-aspartate (NMDA) exposure, by &agr;-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) exposure or by oxygen/glucose withdrawal. The C
3
-symmetrical derivative moreover reduced apoptotic neural death which was induced either by serum withdrawal or exposure of A
&bgr;
1-42 protein. In all cases, the C
3
regioisomer exhibited greater efficacy than the D
3
isomer, which can be attributed to the greater polarity and thus improved ability of lipid membrane penetration /12/.
Relative to the polyhydroxy-substituted fullerenes, the malonic acid derivatives exhibited better activity as radical scavengers as it [lacuna] with the lower degree of addition and resulting from this an improved provision of a relatively large reactive surface with, at the same time, accompanying improved water solubility.
Furthermore, fullerenes are known from /17/ which are linked to poly(benzyl ether) dendrons. These fullerene derivatives, however, are insoluble in water. In /19/, dendrimeric fullerenes are likewise disclosed which are insoluble in water.
In relation to this prior art, the invention was based on the object of further improving the water solubility of fullerenes or fullerene derivatives without at the same time, as in the cases known to date, making smaller or screening off the reactive C
60
surface and thus reducing the radical-scavenging properties.
This object is achieved according to the invention by dendrimeric fullerene derivatives in which the fullerene is linked to at least one dendron, wherein the or each dendron has at least one protic group which imparts water solubility.
Another object of the invention further relates to an agent comprising the inventive fullerene for thereapeutic purposes. The invention additionally relates to an agent comprising the inventive fullerene as neuroprotectant. The inventive fullerene derivates can be used in the production of pharmaceuticals for the treatment of diseases in which free radicals have a harmful effect on the organism to be treated.
Suitable protic groups are the hydrophilic groups known to the person skilled in the art, preferably —OH, —COOH, —NH
2
, —SO
3
H, —PO
3
H, NR
4
+
, —NHOH, or —SO
2
NH
2
, where the four radicals R independently of one another can in each case identically or differently be —H, alkyl or aryl. —OH, —COOH and —NH
2
are particularly preferred. The group —COH can also be employed.
The water solubility of the fullerene derivatives according to the invention can be greater than 1 mg/ml at 25° C. and pH 7, preferably greater than 5 mg/ml, particularly preferably greater than 10 g/l and very particularly preferably greater than 20 mg/ml. At 25° C. and pH 10 it can be greater than 10 mg/ml, preferably greater than 50 mg/ml, particularly preferably greater than 100 g/l and very particularly preferably greater than 200 mg/ml.
A dendron within the meaning of the invention is an addendum of the C
60
nucleus unit which has a branching at the end as a structural unit. Again, in each case the same or another subunit, at whose other end a branching is likewise located in turn, can be linked to this. Depending on the degree of branching, the number of the nearest branchings and thus also the number of functional (and water-soluble) end groups is thus doubled, tripled or multiplied. Each radially symmetrical “shell” formed by repeated linkage of dendrons is designated as the next generation. In order to make available more reactive surface for radicals, it appears sensible to keep the dendrons necessary for the water solubility at as far a distance as possible from the C
60
core in order to prevent its “covering”. This is possible by binding of the dendrons of the first generation via a so-called “spacer”, i.e. a carbon chain of length C
1
up to about C
100
, preferably C
2
-C
10
, which serves the 1
st
generation as a “separator”.
Suitable branchings are especially trivalent or polyvalent elements such as, for example, N-, C-, P-, Si, or polyvalent molecular segments such as aryl-, heteroaryl. The degree of branching is preferably between two and three and the number of generations can be between 1 and 10 inclusive.
Preferred solutions to the object according to the invention follow from the subclaims. Individual features or a number of the features disclosed in the subclaims can also in each case represent solutions to the underlying object per se or in combination and the individual features can also be combined in any desired manner within the claim categories.
In relation to the examples mentioned further above, monoadducts of fullerenes should be an improvement if their water solubility is adequately high. The lower the degree of addition of the fullerenes, the greater their free reactive surface will be, which appears responsible for the radical-scavenging properties. Such monoadducts, however, should have a lower water solubility in relation to polyadducts, as the number of hydrophilic groups decreases corresponding
Connolly Bove & Lodge & Hutz LLP
Killos Paul J.
Reyes Hector M
Siemens Axiva GmbH & Co. KG
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