Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-09-12
2004-09-07
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S047000, C514S051000, C514S024000, C514S081000, C514S086000, C536S026300, C544S243000, C544S264000
Reexamination Certificate
active
06787525
ABSTRACT:
The present invention relates to the novel, where appropriate amphiphilic, glyceryl nucleotides, to their preparation and to compositions for treating cancer diseases and infectious diseases.
Nucleoside analogs which exhibit defined structural features have proved to be valuable drugs in the chemotherapy of cancer diseases and infectious diseases caused by viruses (Advanced Drug Delivery Review (1996) 19, 287). However, the therapeutic effect of the nucleoside analogs is only seen when the nucleoside analogs, which are themselves inactive, are taken up by the cell, as prodrugs, and then anabolized into the actual active compounds, i.e. the 5′-triphosphate derivatives of the nucleoside analog. These nucleotides stop DNA replication and/or block the reverse transcriptase. Nucleoside analogs, such as 1-&bgr;-D-arabinofuranosylcytosine (araC) and 5-fluoro-2′-deoxyuridine (5FdU), which prevent DNA replication, are effective against malignant diseases of the hematopoietic cells and against solid tumors. Dideoxynucleoside analogs, such as 3′-azido-2′,3′-dideoxythymidine (AZT), 2′,3′-dideoxycytidine (ddC), 2′,3′-dideoxyinosine (ddl), 3′-thia-2′,3′-dideoxycytidine (3TC) and 2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), are particularly suitable for the therapy of infection with HIV.
A nonnucleosidic antiviral active compound, such as the trisodium salt of phosphonoformic acid (Foscarnet) blocks the pyrophosphate-binding site of the viral polymerase. This prevents viruses such as herpes simplex virus, HIV virus and human cytomegalovirus from replicating. Amphiphilic glyceryl derivatives of Foscamet, which are better able to traverse the membrane, contribute to optimizing the virus therapy (Antivir. Chem. & Chemother. (1998) 9, 33).
Because of the development of resistance during the course of chemotherapy, which occurs particularly rapidly in the case of HIV treatment, the progression of the disease can only be retarded in the long term by using a combination therapy. In such a therapy, several antiviral active compounds are administered jointly (Schweiz. Med. Wochenschr. (1997) 127, 436). Because the therapy regime which has to be imposed on the patients in the case of combination therapy is strict, patient compliance is low. The therapeutic success which is achieved is therefore well below the possible success which could be achieved with the high potential which the available drugs possess. (AIDS 1998 Diagnostik und Therapie (Diagnosis and Therapy, Steinhauser publishing company).
At best, administration of a form in which, for example, the two nucleosidic prodrugs (AZT and 3TC) are present as a mixture, as is the case with Combivir, only makes combination therapy more practicable for patients. However, it is scarcely possible to achieve an improved effect with such mixtures since the uptake of the prodrugs by the cell is not increased and nor is there any optimization of their anabolism to give the active compound.
On the other hand, it is possible to optimize combination therapy decisively using amphiphilic combination preparations in which two antiviral nucleoside analogs are coupled by way of a phosphodiester bond (EP 0 642 527 B 1). A certain disadvantage of these ampiphilic dinucleoside phosphate analogs is that, when a desired enzymic cleavage of the phosphodiester bond takes place, only one monomer unit is in each case released as an active nucleotide analog whereas the second monomer unit of the combination preparation inevitably remains as a nucleoside analog which is in itself inactive. If the cell does not anabolize this nucleoside analog to give the active nucleotide analog, up to 50% of the administered dimer can then not be used therapeutically and is consequently inactive. An additional disadvantage of these amphiphilic combination preparations is that at least one of the two coupled nucleoside analogs has to possess a lipophilic radical so as to ensure that the resulting dimer is amphiphilic. Consequently, two nucleoside analogs which are suitable for combination therapy, but neither of which can be lipophilized, cannot be converted into amphiphilic dimers and used as a combination preparation in therapy.
The object of this invention is to make available novel combination preparations which can be used to combat cancer diseases and infections even more effectively. This object is achieved by means of novel glyceryl nucleotides which, on being metabolized, are in each case able to liberate two active compounds simultaneously such that the advantages of the abovementioned combination of two active compounds are fully exploited. In order to prepare the novel glyceryl nucleotides, preference is given to covalently bonding either two therapeutically active nucleoside derivatives to each other, or a nucleoside derivative to phosphonoformic acid or its salt form (Foscarnet), by way of a glycerol lipid backbone.
The invention firstly relates to glyceryl nucleotides of the formula la
in which
a) one of the radicals A
1
, A
2
and A
3
is a hydrogen atom, or a radical which is selected from hydroxyl, mercapto, alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio and arylthio, where the alkyl, alkenyl and acyl are optionally substituted by 1 to 3 aryl radicals; and
b1) two of the remaining radicals A
1
, A
2
and A
3
are two nucleoside groups which differ from each other, each of which nucleoside groups is linked to the carbon atom of the glyceryl chain by way of a physiologically cleavable phosphorus-containing bridging group; or
b2) one of the remaining radicals A
1
, A
2
and A
3
is a nucleoside group and the other of the remaining radicals is a hydroxycarbonyl group, each of which is linked to the carbon atom of the glyceryl chain by way of a physiologically cleavable phosphorus-containing bridging group;
where at least one of the nucleoside groups is not a naturally occurring nucleoside group, which nucleoside group is optionally substituted, in its base moiety, on one or more ring atoms and/or on one or more side groups, such as amino side groups, by one or more radicals which are selected from hydroxyl, amino, halogen, alkyl, alkenyl, polyoxyalkenyl, aryl, acyl, alkyloxy, alkenyloxy, polyoxyalkenyloxy, acyloxy, aryloxy, alkylthio, alkenylthio, acylthio and arylthio, where the alkyl, alkenyl and acyl radicals are optionally substituted by 1 to 3 aryl radicals or halogen atoms; and which nucleoside group is optionally substituted, once or more than once, in its carbohydrate moiety, by substituents which are selected from hydrogen, halogen, such as F, Cl, Br and I, hydroxyl, ethynyl and azido, optionally possesses a heteroatom, which is selected from S, N and O, in place of a carbon atom, and optionally contains one or two non-adjacent C═C double bonds;
in racemic or enantiomerically pure form, and to the pharmaceutically tolerated salts of these compounds.
The nucleoside groups which do not occur naturally and which are present in the compounds according to the invention are derived from nucleosides (nucleoside derivatives) which comprise a heterocyclic radical (base moiety) which is linked N-glycosidically or O-glycosidically to a sugar radical (carbohydrate moiety). They differ from the naturally occurring nucleosides, adenosine, guanosine, cytidine, uridine and thymidine and the corresponding deoxynucleosides in the carbohydrate moiety and/or in the base moiety.
The sugar radical of the nucleoside or nucleoside derivative which does not occur naturally is derived from a hexose or heptose, preferably from a pentose, such as deoxyribose or ribose. Where appropriate, single or several protons or hydroxyl groups can be substituted or eliminated in the sugar radical. In this connection, suitable substituents are selected from the abovementioned substituents hydrogen, halogen, such as F, Cl, Br and I, hydroxyl, ethynyl and azido. Where appropriate, a heteroatom, selected from S, N and O, can
Ludwig Peter Stephan
Schott Herbert
Bacon & Thomas
Crane Lawrence E.
Wilson James O.
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