Saccharide conjugates

Details Saccharide conjugates Saccharide conjugates

1998-04-20

2002-12-03

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S053000, C514S054000, C514S885000, C514S904000

Reexamination Certificate

active

06489302

ABSTRACT:

The present invention relates to saccharide conjugates and their use.
In general, many agents, particularly those serving for cancer treatment and those which shall reach certain organs and the cells thereof, e.g. brain, neurons, gliacytes, astrogliacytes and non-neuronal cells, are accompanied by the problem that they are poorly transported to their site of action and thus have considerable side-effects.
Therefore, it is the object of the present invention to provide a product by which agents of the most varying kinds can be transported in well-calculated fashion to their site of action, so that their side-effects can be reduced.
According to the invention this is achieved by the subject matters defined in the claims.
Thus, the subject matter of the present invention relates to a conjugate, comprising a saccharide and one or more agents.
The present invention is based upon the applicant's finding that &bgr;-D-glucose isophosphoramide has good anti-tumor properties and extremely low side-effects as compared to cyclophosphoramide and isophosphoramide. Furthermore, he has found that &bgr;-D-glucose isophosphoramide reaches the tumor cells by means of site-directed transport. For this transport, a glucose transporter has proved to be essential.
On the basis of the above findings, conjugates were developed which have one or more agents bonded to a saccharide, particularly a monosaccharide, disaccharide or oligosaccharide. Particularly glucose, more particularly D-glucose, galactose, mannose, arabinose, xylose, fucose, rhamnose, 2-amino-2-deoxyglucose, 2-fluoro-2-deoxyglucose, N-acetyl-2-amino-2-deoxyglucose, N-acetyl-2-amino-2-deoxy-galactose, digitoxose and 2-amino-2-deoxygalactose have to be mentioned as monosaccharide. Suitable disaccharides are particularly maltose, lactose or gentiobiose, either 1,4-linked or 1,6-linked. Particularly a linear and branched, e.g. di-, tri-, especially N,N′-di-2-chloroethyl-(3,6-di-O-(&bgr;-D-glucopyranosyl)-&bgr;-D-glucopyranosyl)-phosphoric ester diamide, and tetraantennary oligosaccharide have to be mentioned as oligosaccharide.
Every therapeutically and/or diagnostically usable substances are in consideration as agents. These are particularly:
antioxidants, e.g. cysteine, N-acetylcysteine, &agr;-tocopherol (vitamin E), probucol, &agr;-lipoic acid, limonene (perillic acid), xanthines, carotenoids and nitrons, antirheumatics antiallergics, antianemic agents, antibiotics, e.g. sulfonamides, antidiabetics, antiemetics, antihistaminics, antiepileptics, &bgr;-receptor blockers, calcium antagonists, ACE inhibitors, bronchodilating agents, antiasthmatics, cholinergics, corticoids, dermatics, diuretics, enzyme inhibitors, remedies for gout, remedies for influenza, sedative agents, immunotherapeutic agents, hepato-therapeutic agents, antilipemics, remedies for migraine, muscle relaxants, anesthetics, neuropathy preparations, antihyperkinetic agents, psychoactive drugs, thyreo-therapeutic agents, sex hormones and their inhibitors, antispasmodic agents, vitamins, wound treating agents, analgesics, e.g. indomethacin, paracetamol, ibuprofen and acetylsalicylic acid, cimetidine, oncotherapeutic agents, e.g. cyclophosphoramide, isophosphoramide, cisplatin complexes, antimetabolites, such as methotrexate and 5-fluorouracil deoxyribonucleoside, and topoisomerase inhibitors such as mitoxanthrone, tumor diagnostic agents, radiosensitizers, e.g. misonidazole, inhibitors of DNA repair, e.g. O
6
-benzyldeoxyguanosine, &agr;-sympathicomimetics, e.g. L-dopa and dopamine, nucleic acids, e.g. oligonucleotides, and anti-AIDS agents, such as azidothymidine, dideoxyinositol and dideoxycytidine.
The linkage between the saccharide and the agent or agents may be present as usual. It is favorable when there is at least a linkage via the 1-position of the saccharide. This includes the advantage that at the site of action, i.e. in the cell, the agent linked via the 1-position of the saccharide is cleaved enzymatically and released.
In a preferred embodiment of the conjugate according to the invention, the saccharide is linked at least with one agent via a common linker. Suitable linkers are particularly diols, more particularly short-chain diols from 1,2-diol, e.g. ethylene glycol, to 1,6-hexanediol.
Conjugates according to the invention accumulate in cells, organs and tissues which have glucose transporters and/or related transporters thereof. The conjugates accumulate particularly in the liver, kidney, heart, thymus, thyroid gland, intestines, and brain as well as in all kinds of tumors.
Therefore, conjugates according to the invention are especially suitable for treating neurologic diseases, such as Alzheimer's disease, apoplexy, Parkinson's disease and other dementia diseases. For this purpose, it is favorable when the conjugates contain antioxidants as agent. These agents prevent that in aerobic cells an incomplete reaction of oxygen takes place in the mitochondrial electron-transport chain and thus superoxide radicals, hydroxyl peroxides or hydroxyl radicals being released into the cytosol, which may cause apoptosis. In the case of apoplexy and other arteriosclerotic diseases, especially the oxidation of LDL particles into lipid peroxides, which represent a critical occurrence with the formation of arteriosclerotic plaques, is inhibited by the administration of andioxidants. When Parkinson's disease is treated, the use of L-dopa or dopamine as agent has also proved its value.
Conjugates according to the invention, which contain antioxidants as agents, are also suitable for treating cardiovascular diseases, diabetes, inflammations, particularly rheumatic arthritis, inflammatory intestinal diseases and pancreatitis, high-blood pressure and pulmonary diseases, e.g. idiopathic pulmonary fibrosis and cystic fibrosis, AIDS-caused apoptosis of CD4-T cells, arteriosclerosis, osteoporosis, ischemia, cataract as well as multiple sclerosis. Furthermore, such conjugates are also suited for the prevention of the above-mentioned diseases, particularly arteriosclerotic diseases and Alzheimer's disease.
In addition, when they contain corresponding agents, conjugates according to the invention can be used successfully for treating and/or diagnosing tumors. Examples of therapeutically usable agents are cyclo-phosphoramide and isophosphoramide. Furthermore, particularly radiosensitizers such as misonidazole have to be mentioned which result in a tumor-specific enhancement of a radiotherapy and/or photodynamic treatment. Moreover, particularly inhibitors of DNA repair such as O
6
benzyl deoxyguanosine have to be mentioned. These agents contribute to the tumor-specific reduction of the DNA repair capacity and thus to the improvement of a treatment by alkylating tumor-chemotherapeutic agents. Conjugates containing antioxidants are also suitable for tumor treatment and the prevention of tumor diseases. As explained above, these agents serve for stopping the formation of free radicals which are known to result in cellular injury and promote degeneration of cells. Thus, conjugates having antioxidants may also be used for protecting healthy cells in the case of chemotherapies and radiation therapies. In addition, the most recent applicant's results refer to the fact that when inventive conjugates containing oncotherapeutic agents are administered, much less resistance is developed than upon administration of oncotherapeutic agents alone.
Moreover, conjugates according to the invention, which contain nucleic acids, e.g. oligonucleotides, as agents, are suitable for diagnosis and/or treatment of genetic defects, particularly those which are organ-specific.
Besides, conjugates according to the invention can also be used for controlling pathogens of any kind, which have a glucose transporter or a transporter related thereto. Such pathogens are especially viruses, bacteria and protozoan organisms. Thus, conjugates according to the invention are also suited for treating diseases caused by such pathogens, e.g. viral infections, particularly AIDS.


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