Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Boron containing doai
Reexamination Certificate
2000-12-15
2003-02-18
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Boron containing doai
C568S004000, C568S005000
Reexamination Certificate
active
06521604
ABSTRACT:
The invention relates to compounds containing boron, their production and the use thereof for the energy-filtering transmission electron microscopy and for the boron neutron-capture therapy.
It is known to detect boron-containing compounds by the energy-filtering transmission electron microscopy (EFTEM).
For example, Qualmann B. et al.,
Angew. Chem.,
1996 180, pages 970 to 973, describes the synthesis of boron-containing lysine dendrimers for protein labeling in electron microscopy. The boron-containing compound described in this publication and serving for labeling proteins is unsuitable for labeling small biological molecules, e.g. oligonucleotides, because of its large expansion, since the material properties of such small biological molecules are modified excessively. Furthermore, because of the large expansion of the compound and the arrangement of the 1,2-dicarbadodecaborane fragments (carboranes) in the outermost sphere of the molecule the boron density is very low. Therefore, a specification of this compound by means of EFTEM is not possible to a satisfactory extent. In addition, the described compound has a peptide base structure with L-lysine as building blocks, so that it is susceptible to enzymatic degradation.
The publication by Newkome G. R. et al., in
Angew. Chem.,
1994, 106, pages 701 to 703, describes unimolecular micelles, which contain 4 or 12 carboranes in the micelle interior and hydrophilic groups on the surface of the micelles. These unimolecular micelles are also too big. Furthermore, no binding site exists for the linkage of a spacer for attachment to biomolecules, such as oligonucleotides and proteins.
Therefore, it was formerly not possible to label for detection by EFTEM small biologically active substances, such as oligonucleotides, by a boron-containing compound to be bonded covalently.
It is also known to use boron-containing compounds in the boron neutron-capture therapy. However, it was not yet possible to selectively introduce sufficiently high boron concentrations into the tumor tissue.
Thus, the object of this invention is to provide a compound which does not show the drawbacks of the prior art.
According to the invention this is achieved by the subject matters defined in the claims.
The subject matter of the present invention relates to a boron-containing compound which has the following general formula (1)
in which
Cb stands for a carborane,
R
2
and R
3
are independently a hydrogen atom or an organic residue, and
R and R
1
are independently a hydrogen atom or an organic residue with the carbon atom to which they are bound.
The expression “carborane” comprises compounds of any kind, which include the summation formula B
10
C
2
H
12
. The carboranes may form three isomers: 1,2-dicarba-closo-dodecaborane, 1,7-dicarba-closo-dodecaborane, and 1,12-dicarba-closo-dodecaborane, which are also referred to as ortho-, meta-, and para-carborane. Of these isomers the 1,2-dicarba-closo-dodecaborane is preferred, which is symbolized as follows:
Because of the two carbon atoms the carboranes have two possible binding sites with other compounds. Due to the linkage of the four carboranes with the hydrocarbon skeleton indicated in formula (1) one binding site of the carborane is occupied. The second binding site can now be used for binding spacers and/or solubility-modulating compounds.
The expression “spacer” comprises compounds of any kind, which can be used for linkage, in particular for covalent linkage, of the boron-containing compound according to the invention with other molecules, e.g. with biological molecules. Such compounds are known to a person skilled in the art. They are preferably compounds derived from C2 to C10 alkanes, in particular C6 alkanes, which are preferably linear and optionally have ether bridges or may be bound via such a bridge to the carborane. The expression “biological molecules” refers to the fact that any kind of molecule relevant for biological processes is concerned. Examples are proteins, nucleotides, such as mono-, oligo-, and polynucleotides, nucleosides, nucleoside diphosphates and nucleoside triphosphates. Of the proteins those are preferred which accumulate in tumors, such as albumin.
The “solubility-modulating compounds” are compounds of any kind, which raise or lower the solubility of the compound according to the invention in a solvent, in particular water or an aqueous solvent. To raise the water solubility, the solubility-modulating compounds may have at least one polar group, such as a hydroxyl group. Examples thereof are —CH
2
OH and polyhydroxy compounds, such as inositol or saccharides, in particular monosaccharides, preferably glucose. Because of the high degree of lipophilia of the carboranes and the hydrocarbon skeleton the bonding of solubility-modulating compounds is favorable for raising the water solubility of the boron-containing compound.
By the use of carbohydrates, in particular glucose, galactose, xylose, fucose or also gentiobiose the tumor selectivity of the boron-containing compound according to the invention can also be increased.
Examples of compounds in which glucose is bound to the carboranes are the compounds shown in formulae (2) and (3).
This serves for obtaining small lipophilic molecule cores in which the entire boron amount is concentrated and a hydrophilic molecule shell which increases the water solubility of the boron-containing compound and optionally the tumor selectivity. All in all, a unimolecular micelle is thus obtained.
In the boron-containing compound according to the invention, the substituents R
2
and R
3
are independently a hydrogen atom or an organic residue. The expression “organic residue” covers organic compounds of any kind, which comprise carbon, hydrogen and optionally oxygen, sulfur, phosphorus and boron. Examples thereof are the groups —NO
2
, —(C═O)—, —C≡N—, phenyl and —COOR
4
, wherein R
4
represents e.g. an alkyl residue such as ethyl. R
2
and R
3
can also be linked with each other, i.e. the residues denoting R
2
and R
3
are chosen such that they form a ring, preferably a 6-membered ring, with the carbon atoms to which they are directly bound and with the carbon atom including the residues R and R
1
. Further carboranes can be bound to the ring, so that the total number of carboranes in the compound according to the invention is increased, e.g. to 6. Examples of R
2
and R
3
for forming a 6-membered ring are:
In the boron-containing compound according to the invention, the substituents R and R
1
are independently a hydrogen atom, an organic group or R and R
1
form a carbonyl group together with the carbon atom to which they are bound. The organic group can be every compound containing carbon, hydrogen and optionally oxygen, sulfur, phosphorus and boron. For example, the group is a C2 to C10, in particular C6, alkyl group bound via an ether bridge. A phosphate group (PO
4
3−
) can be bound to the alkyl group, in particular to the end thereof. The phosphate group can be bound to a biological molecule, such as a poly-, oligo- or mononucleotide, preferably at the 51 ends thereof. An example of such an organic group standing for R and R
1
, respectively, is shown in above formula (3).
Another subject matter of the present invention relates to a method of producing the boron-containing compounds according to the invention, in which a decaborane is reacted with an alkyne of formula (4).
A decaborane is a compound with the summation formula B
10
H
14
, which differs from the above described carboranes in that inter alia the two carbon atoms are not present. They are introduced by the two carbon atoms of the alkyne bond.
It was found surprisingly that this reaction will also be possible if at least four carboranes are bound to a very small hydrocarbon base structure in spite of the steric impediment. It was also found that surprisingly high yields will be obtained if a carbonyl group is disposed in the &bgr;-position relative to the alkyne group. If necessary, the carbonyl group can be protected as usual and then be deprotected
Raddatz Stefan
Spiess Eberhard
Trendelenburg Michael
Tröster Helmut
Wiessler Manfred
Deutches Krebsforschungszentrum
Halluin Albert P.
Howrey Simon Arnold & White , LLP
Kung Viola T.
Vollano Jean F.
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