EP1198467A1 - Derives de 5-nitrofurfural - Google Patents

Derives de 5-nitrofurfural

Info

Publication number
EP1198467A1
EP1198467A1 EP00946560A EP00946560A EP1198467A1 EP 1198467 A1 EP1198467 A1 EP 1198467A1 EP 00946560 A EP00946560 A EP 00946560A EP 00946560 A EP00946560 A EP 00946560A EP 1198467 A1 EP1198467 A1 EP 1198467A1
Authority
EP
European Patent Office
Prior art keywords
nitrofurfurylidene
glucopyranose
deoxy
amino
galactopyranose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00946560A
Other languages
German (de)
English (en)
Inventor
Bernt Borretzen
Vidar Moen
Rolf Olaf Larsen
Erik Olai Pettersen
Camilla Bruno Dunsaed
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Norsk Hydro ASA
Original Assignee
Norsk Hydro ASA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Norsk Hydro ASA filed Critical Norsk Hydro ASA
Publication of EP1198467A1 publication Critical patent/EP1198467A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • the present invention relates to derivatives of 5-nitrofurfural which are useful as anticancer agents, antiviral agents, immunopotentiators and/or as agents which may be used for combating illnesses which arise due to an elevated cell proliferation and/or for combating auto immune diseases.
  • Most of the compounds of this invention are novel er se.
  • anticancer agents are cytotoxic in their action. Although these agents have shown good results in treatment of some cancers like lymphoma, leukaemia and testicular cancer, they often produce severe and unacceptable side-effects limiting the possibility for an effective treatment. Furthermore, in several types of cancer like in solid tumours (carcinoma), chemotherapy has so far proven to be of limited value since established cytostatic drug seldom improves the prognosis for the patient. The ability of cancer cells to develop resistance against cytotoxic products is also a main reason for the failure in their use in the treatment of solid tumours. There is thus a great need for new anticancer agents having fewer side effects and having a more selective action on malignant cells.
  • 5-nitrofurfurylidene diacetate is disclosed. This compound exerts a stronger effect on NT JK 3025 cells than the 3- and 4-nitrobenzylidene analogues.
  • aldehydes react with a range of O, S or N nucleofilic entities like hydroxy groups, sulfhydryl groups and amino groups to form carbonyl condensation products like acetals, mercaptals, aminals, etc.
  • the reaction normally take the form of Schiffs base (imine) adduct formation.
  • Schiffs bases are known to take place readily also in physiological conditions, and many carbonyl condensation reactions are well known in vivo (E. Schauenstein et. al., Aldehydes in biological systems. London, Pion Ltd. 1977).
  • the Schiffs base tend to be a reactive species itself and is prone to further reaction resulting in the addition of nucleofilic agents to the double bond.
  • the initially formed Schiffs base can undergo reversible internal cyclization in which the sulfhydryl group adds to the imine to form thiazolidine carboxylate (M. Friedman, The chemistry and biochemistry of the sulfhydryl group in amino acids, peptides and proteins, Oxford, Pergamon Press, 1973).
  • Aromatic- and heteroaromatic aldehydes readily form Schiffs base imines with membrane amino groups, and high equilibrium constants have been measured for benzaldehyde reacting with amines (J. J. Pesek and J. H. Frost, Org. Magnet. Res. 8 (1976), 173 - 176; J. N. Williams Jr. and R. M. Jacobs Biochim Biophys Acta. 154, (1968) 323 - 331). Substituents possessing electron withdrawing properties in the aromatic ring will make the carbonyl carbon more electrofilic and thus more prone to addition reactions with amino nucleofiles.
  • aldehydes bind to amines and other nucleofilic entities on the cell membrane to form Schiffs bases and other condensation products
  • stimulation of cell growth is mediated by a cascade of events acting from outside the cell membrane.
  • the derivatives in the present patent application may act by forming adducts with ligands on the cell membrane, triggering impulses inside the cell with significance on cell growth parameters like protein synthesis and mitosis, and on the expression of tumour suppressor genes and immune responses. Since the condensation reactions are reversible, cellular effects can be modulated as a result of a shift in equilibrium involving ligating species. The presence of dynamic equlibria at a chemical level is consistent with the reversible action observed with the aldehyde derivatives.
  • FIG. 5A shows that compounds 2 and 3 are more effective as protein synthesis inhibitors than the formerly known compound, 5-nitrofurfurylidene diacetate by a factor of about an order of magnitude for low drug doses.
  • N-(5-Nitrofurfuryliden)-l-aminohydantoin is a chemotherapeutic agent still in use to cure urinary tract infections (US 2 610 181, US 2 779 786, US 2 898 335 and US 2 927 110).
  • the hydantoin ring is further derivatised with a methylmorpholine entity.
  • bis(5-nitrofurfurylidene)acetone guanylhydrazone (Nitrovin) is widely in use as a feed additive.
  • the compound 5-nitrofurfurylidene-D-glucosamine and its inhibitory effects upon bacteria as well as pathogenic fungi is disclosed in US 3 122 535.
  • Dermatologic abnormalities such as psoriasis are often characterised by rapid turnover of epidermis. While normal skin produces about 1250 new cells/day/cm 2 of skin consisting of about 27,000 cells, psoriatic skin produces 35,000 new cells/day/cm 2 from 52,000 cells The cells involved in these diseases are however "normal” cells reproducing rapidly and repeatedly by cell division While the renewal of normal skin cells takes approximately 311 hours, this process is elevated to take about 10 to 36 hours for psoriatic skin
  • ratio effect/side effect (therapeutic index) for this class of products may be dependent of the degree of this reversibility, and to optimize the therapeutic benefit of the products, these properties must be taken into consideration
  • the immune system In order to provide a specific response to the huge range of biotic variation represented by the invaders, the immune system has to be highly diversified. However, over-stimulation of this finely tuned system can lead to various allergic- and inflammatoric reactions and cause auto-immune diseases. The rejection of beneficial transplants is also difficult to overcome. It is therefore a big therapeutic challenge to modulate the immune system, either by up-regulating or down-regulating a specific response.
  • a fragment of a foreign protein is confined in the groove of the class II MHC protein on the surface of an antigen presenting cell (APC). Attached to this MHC-antibody complex is also the receptor of a T helper cell.
  • the primary signal is mediated by the antigen itself, via the class II MHC complex and augmented by CD4 co-receptors.
  • the second signal can be provided by a specific plasma-membrane bound signalling molecule on the surface of the APC.
  • a matching co-receptor protein is located on the surface of the T-helper cell. Both signals are needed for the T-cells to be activated. When activated, they will stimulate their own proliferation by secreting interleukin growth factors and synthesising matching cell-surface receptors. The binding of interleukins to these receptors then directly stimulates the T-cells to proliferate.
  • APC-donor/T-cell receptor interaction site responsible for the second co-stimulatory signal, and that these take form of carbonyl-amino condensations (Schiffs base formation). Moreover, these interactions can be mimiced by synthetic chemical entities.
  • glycoproteins bound to the cell plasma membrane have the ability to associate with sugar molecules dissolved in the extracellular fluid. Affinity to such receptors will contribute to enrich and anchor sugar/aldehyde derivatives to the cell surface. Reactive aldehyde is released through hydrolysis and become available for in situ Schiffs base formation with amino groups protruding from the cell surface.
  • 5-nitrofurfural is derivatised with biologic acceptable carbohydrates like glucose, glucosamine, galactosamine and other sugars, deoxysugars and aminosugars by either an acetal- or an imine linkage. The sugar moiety will also contribute by improving stability and enhancing bioavailability of the aldehyde function to the target cells.
  • the immune stimulating effect of the invented compounds may also be used in the treatment of certain virus diseases in combination with other anti-viral therapy like anti-viral drugs or vaccines.
  • Many virus types after the first infection, incorporate with the cell nucleus and are inactive for a long period of time. Oncogenic viruses like hepatitis B and C, certain retro virus and certain papilloma virus may cause development of cancer. In these latent period it is very difficult to cure the virus infection. These viruses can often be triggered by immune responses to cause viremia, and in this stage make it possible to get rid of the virus infection.
  • the ability of the aldehyde derivatives to trigger the immune response may be used in combination with antivirals or vaccines to develop a treatment for these diseases.
  • a second object of the invention is to provide new compounds being able to potentiate immune responses giving a possibility to combat infectious diseases caused by virus, bacteria, fungus and other micro organisms.
  • a third object of the invention is to provide compounds for prophylaxis or treatment of cancer and diseases related to immune disorders not giving toxic side-effects.
  • a fourth object of the invention is to provide compounds for effective and favourable prophylaxis and/or treatment of cancer in tissues and cells having receptors with affinity to corresponding sugar moieties.
  • a fifth object of the invention is to provide compounds for treatment of diseases related to the immune system like psoriasis, bowel inflammations, arthritis, SLE, PSS etc.
  • the compounds of the present invention have the general formula (I):
  • R t and R 2 are H or D or are linked together to form a 6-membered acetal ring comprising the substructure (II):
  • X is selected from the atoms or groups comprising H, D, OH, OR4, NH 2 , NHR,, NR4R5, NHC(O)R4 or NC(O)R4R5 wherein R4 and R 5 are alkyl with 1-6 carbon atoms or cycloalkyl with 3-6 carbon atoms and can be the same or different.
  • X can optionally comprise the substructure (III):
  • Ri, R 2 and X are interrelated such that if R, and R 2 are H or D, then X is (III). If R, and R 2 are linked together to form the substructure (II), then X is H, D, OH, OR*, NH 2 , NHRt, N Jls, NHC(O)R4 or NC(O)R4R 5 wherein R, and R 5 are defined as above.
  • R 3 is H, D, alkyl with 1-20 carbon atoms, cycloalkyl with 3-6 carbon atoms, fluoroalkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-6 carbon atoms, or a pharmaceutical acceptable salt thereof.
  • the compounds of formula (I) wherein L is deuterium may be prepared as described above, but starting with 5-nitrofurfural which is deuterated in the formyl position.
  • the preparation of the deuterated aldehyde may be performed according to one of the examples given in EP 0 552 880 Al, of which the umpolung strategy is the most prefered method
  • the aldehyde is protected as its 1,3-dithioacetal, BuLi is added to generate the lithium salt which is subsequently quenched with D 2 O and the protecting group removed.
  • the thus formed 5-nitrofurfural-d ⁇ is used as a starting material in analogy with the undeuterated counterpart
  • the acetalisation reactions may be carried out in a dipolar, aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethoxy ethane or the like
  • a dipolar, aprotic solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethoxy ethane or the like
  • an azeotrope forming solvent such as chloroform, dichloromethane or ethylacetate
  • the catalyst may be a mineral acid, e g sulphuric acid, an organic acid, e g /? ⁇ ra-toluene sulfonic acid, an acidic ion exchanger resin, e g Amberlyst 15, a Lewis acid mineral clay, e g Montmorillonite K- 10 or a resin supported super acid, e g Nafion NR 50
  • 1,2,3-tri-O-acetyl-D-galactopyranose is confirmed by NMR analysis
  • This intermediate (0 0517 mol) is dissolved in ethylacetate under N 2 A stoichiometric excess of 10% Pd on active carbon is added and H 2 bubbled through at ambient temp over night The reaction mixture is filtered and evaporated The raw product is repeatedly diluted and evaporated with CHCb and CH 2 C1 2 to remove traces of ethylacetate
  • the structure of the formed 1,2,3-tri O-acetyl-4,6-O-(5-nitrofurfurylidene)-D-galactopyranose is confirmed by NMR analysis
  • the 4,6-O-deprotected tri-O-acetyl sugar (max 0 0517 mol) and 5-nitrofurfural (0 052 mol) are dissolved in CH 2 C1 2 together with a catalytic amount of r ⁇ -toluene sulphonic acid The reaction mixture is boiled over night
  • 5-nitrofurfural- 1,3 -propane dithioacetal-di HgCl 2 (2.2 eqv.) and HgO (1.1 eqv.) are dissolved in a 9: 1 mixture of acetonitril and water and boiled at reflux for approx. 2 h. After cooling, insoluble mercury salts are filtered off and the filtrate washed with 5 % ammonium acetate solution. 5-nitrofurfural-d ⁇ is formed as a precipitate, which is filtered off and recrystallised from an appropriate solvent. The identity is confirmed by NMR spectroscopy.
  • 1,2,3-tri-O-Acetyl-D-glucopyranose is prepared as described in the preparation of compound 1.
  • 5-Nitrofurfural-d ⁇ is prepared as described above and is condensed with glucosamine hydrochloride according to the procedure given in example 2
  • Figure 1 Cell survival as measured by colony-forming ability for human cervix carcinoma cells, NHIK 3025, after treatment for 4 or 20h with compound 1.
  • Cells were treated in open plastic Petri dishes incubated in CO 2 -incubators at 37°C.
  • the plotted survival values represent mean values from 5 simultaneously and similarly treated dishes. Standard errors are indicated by vertical barrs in all cases where they exceed the symbols. From the data cell survival is down to 20 % following 4h treatment with 1 mM of compound 1. For comparison, the same survival of 20 % is obtained with only 0.3mM of compound 1 when treatment time is increased to 20h. On a drug-dose basis the effect thus, is about 3 times stronger when treatment is extended to 20 as compared to 4h.
  • Figure 2 Cell survival as measured by colony-forming ability for human cervix carcinoma cells, NHIK 3025, after treatment for 20h with compounds 2 or 3. The technique and statistics are as described in figure 1. The effect of these two compounds are similar. The effect is stronger than the effect of compound 1.
  • a direct comparison between figures 1 and 2 shows that 10% survival following 20h treatment is obtained with 500 ⁇ M of compound 1 and with only 10 ⁇ M of compounds 2 and 3. Thus, on a concentration basis the latter two compounds are 50 times more effective than the former one.
  • Figure 3 Cell survival as measured by colony-forming ability for human cervix carcinoma cells, NFflK 3025, after treatment for 20h with compound 3 and tucaresol. The technique and statistics are as described in figure 1. The data indicate that cell survival is about 30 % following treatment with 1000 ⁇ M tucaresol as compared with 7 ⁇ M of compound 3. Thus compound 3 induces a stronger effect than tucaresol by a factor of about 140 on a drug dose basis.
  • Figure 4 Rate of protein synthesis of human cervix carcinoma cells, NHIK 3025, as measured by amount of incorporated [ 3 H]-valine during a pulse period of lh starting either immediately following addition of test compound (in this case compound 1) or starting 3h later, with test compound present during the pulse.
  • Cells were pre-labelled with [ 14 C]-valine for at least 4 days in order to have all cellular protein labelled to saturation.
  • Incorporated amount of [ 3 H] was related to inco ⁇ orated amount of [ 14 C] so that protein synthesis was calculated as per cent of total amount of protein. Rate of protein synthesis is given as per cent of that in an untreated control.
  • the plotted values for protein synthesis represent mean values from 4 simultaneously and similarly treated wells.
  • Figure 5 Rate of protein synthesis as measured by amount of incorporated [ 3 H]-valine during a pulse period of lh starting immediately following addition of test compounds (in this case compounds 2 and 3 together with similar data for 5-nitrofurfurylidene diacetate).
  • Cell treatment, calculation of protein synthesis and statistics were as described under the heading of figure 4.
  • Data for compounds 2 and 3 represent two different experiments, one in panel A and one in panel B. Note that panels A and B differs with respect to scaling on the abscissa. The data indicate that both compounds 2 and 3 are efficient inhibitors of protein synthesis. Both compounds reduce protein synthesis to a low level of approximately 35% of the control level for a drug concentration as low as about 25 ⁇ M.
  • Figure 6 Rate of protein synthesis as measured by amount of incorporated [ 3 H]-valine during a pulse period of lh starting at different times following addition of 25 ⁇ M of test compounds (in this case compounds 2 and 3).
  • Cell treatment, calculation of protein synthesis and statistics were as in figure 4.
  • the control value of 100% is plotted at time 0, since this is the level of the rate of protein synthesis just before the drugs are added to the cells.
  • the next point is plotted at time l/2h, i.e. in the midst of the 0-lh pulse. After 4h treatment drugs were removed and fresh, drug-free medium was added to the cells.
  • Each experimental point represent the mean values of tumor volumes from 6 animals, each tumour volume taken relative to the volume of the same tumour at day 1. Standard errors are given as vertical barrs, but represent, in this case, biological variation in tumor growth rate between individual animals in addition to uncertainty in measurement. Both groups given compound 1 shows a slightly reduced rate of tumor growth as compared with the placebo-treated animals. The effect is somewhat more pronounced with 1 than with 7.5 mg/kg drug, indicating that the anti-tumor effect may be optimal at a certain dose region with reduced effect for lower as well as higher drug doses.
  • Human cells NHTK 3025, originating form a cervical carcinoma in situ (Nordbye, K , and Oftebro, R. Exp Cell Res , 58 458, 1969, Oftebro R., and Nordbye K , Exp Cell Res., 58: 15 459-460, 1969) were cultivated in Eagel's Minimal Essential Medium (MEM) supplemented with 15%) foetal calf serum (Gibco BRL Ltd). The cells are routinely grown as monolayers at 37°C in tissue culture flasks. In order to maintain cells in continuous exponential growth, the cells were trypsinised and recultured three times a week
  • the rate of protein synthesis was calculated as described previously (Ronmng, O W et al , J Cell Physiol , 107 47-57, 1981) Briefly, cellular protein was labelled to saturation during a minimum 4 day preincubation with [ 14 C]valine of constant specific radioactivity (0 5 Ci/mol) In order to keep the specific radioactivity at a constant level, a high concentration of valine (1 0 mM) was used in the medium At this concentration of valine, the dilution of [ l4 C]valine by intracellular valine and proteolytically generated valine will be negligible (Ronmng, O W , et al , Exp Cell Res 123 63-72, 1979) The rate of protein synthesis was calculated from the incorporation of [ 3 H]valine related to the total [ l4 C]rad ⁇ oact ⁇ vity in protein at the beginning of the respective measurement periods and expressed as percentage per hour (Ronning, O W et al , J Cell Physiol , 107
  • Compound 1 induces an inhibition of protein synthesis which increases linearly with increasing dose up to 4 mM, the highest dose tested (figure 4) Whether pulsing with [ 3 H]-valin was done the first or the third hour after start of treatment the effect was the same Thus, compound 1 induces an inhibition of protein synthesis which is constant as long as the compound is present in the cell culture
  • both of the compounds 2 and 3 are seen to induce increasing protein synthesis inhibition with increasing treatment time. Both drugs are seen to be reversible to some extent since the rate of protein synthesis increases immediately after removal of drugs. However, protein synthesis is not completely restored during the first hour after treatment, the increase is only up to a level of 50% of that of control cells. It is possible that a fraction of the cells are irreveribly inactivated with respect to protein synthesis, but without beeing lysed during the first 3 hours of treatment. These cells would then contribute to the amount of [ 1 C], but not to that of [ 3 H] in the final sample, and thereby mask the possible reversibility of inhibition of protein synthesis of cells surviving the 3h treatment.
  • Drugs were tested in the treatment of three human cancer xenografts implanted into female, athymic mice.
  • the cell lines used are SK-OV-3 ovarian carcinoma, A-549 lung carcinoma and Caco-2 colorectal carcinoma. They were purchased from the American Type Culture Collection and cultivated shortly in vitro before being implanted into nude mice.
  • the tumour lines were passaged as s.c. implants in nude mice. Mice which should be used in experiments were 8-9 weeks of age at the time of tumour implantation. Small tumour pieces were implanted s.c. on the left flank of the animals. Animals with growing tumours (tumour volumes 25-110 mm 3 ) were randomly assigned to drug-treated or control groups, with the average tumour size among the groups being approximately equal.
  • RV relative tumour volume
  • tumour volume doubling time was determined from the fitted curve (loge2/&, where k is the estimated rate constant for the process.) Histological evaluation was based on macroscopic examination of the tumour and light microscopic examination of small tumour sections (6-8 mm thick) embedded in paraffin and stained with hematoxylin and eosin.
  • Figure 7 shows that compound 1 induces a growth-inhibitory effect on SKOV-3 ovarian carcinoma grown as xenografts in nude mice. These data indicate that inhibition of tumour volume growth is stronger with 1 mg/kg than with 7.5 mg/kg daily dose in these animals.
  • the products of this invention react with active groups on the cell surface, e.g. amino-, hydroxy- or sulfhydryl groups in a substantial more efficient way than products previously known, to form carbonyl condensation products like Schif s bases, acetals, mercaptals, thiazolidenes, aminals etc. on the cell surface.
  • active groups on the cell surface e.g. amino-, hydroxy- or sulfhydryl groups in a substantial more efficient way than products previously known, to form carbonyl condensation products like Schif s bases, acetals, mercaptals, thiazolidenes, aminals etc.
  • This can influence on the signal machinery of cells and can be used in the treatment of diseases like cancer, immunological disorders, microbial infections etc.
  • the aldehyde derivatives of this invention react with certain groups on the cell surface, e.g. with free amino groups to form Schiffs bases. As many cell processes, like protein synthesis, cell-cycle progression, immune response etc. are controlled by signals from the cell-surface, these bindings will alter the behaviour of the cell. We have also shown that the aldehyde complex of the cell surface change the adhesion characteristics of the cell. We have shown that the compounds of this invention can be useful in new therapies to combat cancer, auto immune diseases, viral infections and also infections of other microorganisms.
  • compositions according to the present invention may be administered in anti-cancer treatment, anti-viral treatment or in treatment of diseases which arise due to abnormally elevated cell proliferation and/or for combating auto immune diseases. These pharmaceutical compositions may also be administered as immunopotentiators.
  • the compounds of formula (I) may be formulated in any suitable manner for administration to a patient, either alone or in admixture with suitable pharmaceutical carriers or adjuvants.
  • formulations for systemic therapy are especially preferred to prepare the formulations for systemic therapy either as oral preparations or parenteral formulations.
  • Suitable enteral preparations will be tablets, capsules, e.g. soft or hard gelatine capsules, granules, grains or powders, syrups, suspensions, solutions or suppositories. Such will be prepared as known in the art by mixing one or more of the compounds of formula (I) with non-toxic, inert, solid or liquid carriers.
  • Suitable parental preparations of the compounds of formula (I) are injection or infusion solutions.
  • the compounds of formula (I) When administered topically the compounds of formula (I) may be formulated as a lotion, salve, cream, gel, tincture, spray or the like containing the compounds of formula (I) in admixture with non-toxic, inert, solid or liquid carriers which are usual in topical preparations. It is especially suitable to use a formulation which protects the active ingredient against air, water and the like.
  • the preparations can contain inert or pharmacodynamically active additives. Tablets or granulates e.g. can contain a series of binding agents, filler materials, carrier substances and/or diluents. Liquid preparations may be present, for example, in the form of a sterile solution.
  • Capsules can contain a filler material or thickening agent in addition to the active ingredient. Furthermore, flavour-improving additives as well as the substances usually used as preserving, stabilising, moisture-retaining and emulsifying agents, salts for varying the osmotic pressure, buffers and other additives may also be present.
  • a daily dosage for a systemic therapy for an adult average patient will be about 0.01 -500mg/kg body weight once or twice a day, preferably 0.1-100 mg/kg body weight once or twice a day, and most preferred 1-20 mg/kg weight once or twice a day.
  • the pharmaceutical preparation of the compound of formula (I) can contain an antioxidant, e.g. tocopherol, N-methyl-tocopheramine, butylated hydroxyanisole, ascorbic acid or butylated hydroxytoluene.
  • an antioxidant e.g. tocopherol, N-methyl-tocopheramine, butylated hydroxyanisole, ascorbic acid or butylated hydroxytoluene.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention concerne des dérivés de 5-nitrofurfural qui sont utiles comme agents anticancéreux, agents antiviraux, immunopotentialisateurs et/ou comme agents pouvant être utilisés contre des maladies dues à une prolifération cellulaire importante et/ou contre des maladies auto-immunes.
EP00946560A 1999-07-05 2000-06-28 Derives de 5-nitrofurfural Withdrawn EP1198467A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NO993313A NO309815B1 (no) 1999-07-05 1999-07-05 Derivater av 5-nitrofurfural
NO993313 1999-07-05
PCT/NO2000/000226 WO2001002412A1 (fr) 1999-07-05 2000-06-28 Derives de 5-nitrofurfural

Publications (1)

Publication Number Publication Date
EP1198467A1 true EP1198467A1 (fr) 2002-04-24

Family

ID=19903539

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00946560A Withdrawn EP1198467A1 (fr) 1999-07-05 2000-06-28 Derives de 5-nitrofurfural

Country Status (4)

Country Link
EP (1) EP1198467A1 (fr)
AU (1) AU6030000A (fr)
NO (1) NO309815B1 (fr)
WO (1) WO2001002412A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2007203244B2 (en) * 2006-07-13 2010-08-12 Aristocrat Technologies Australia Pty Limited An electronic gaming machine

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE515245A (fr) * 1950-05-29
US3122535A (en) * 1961-06-02 1964-02-25 Benckiser Gmbh Joh A 5-nitro furfurylidene-d-glucosamine, and process of making same
US4402965A (en) * 1982-08-05 1983-09-06 John R. A. Simoons Treatment of rheumatoid arthritis and related diseases
JPS6256423A (ja) * 1985-09-06 1987-03-12 Kaken Pharmaceut Co Ltd 悪液質治療改善剤
GB9026080D0 (en) * 1990-11-30 1991-01-16 Norsk Hydro As Pharmaceutical compositions
GB9400047D0 (en) * 1994-01-04 1994-03-02 Norsk Hydro As Pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0102412A1 *

Also Published As

Publication number Publication date
NO309815B1 (no) 2001-04-02
AU6030000A (en) 2001-01-22
WO2001002412A1 (fr) 2001-01-11
NO993313L (no) 2001-01-08
NO993313D0 (no) 1999-07-05

Similar Documents

Publication Publication Date Title
US5149820A (en) Deuterated compounds
US4728641A (en) Ganglioside derivatives
JPH03504122A (ja) 抗ウイルス・抗腫瘍・抗転移・免疫系増強ヌクレオシド類およびヌクレオチド類
CA2362306A1 (fr) Composes chimiques
US4874780A (en) Anticancer compounds
Citarella et al. Activity of a Novel Anthracenyl Bishydrazone, 9, 10-Anthracenedicarboxaldehyde Bis [(4, 5-dihydro-1 H-imidazol-2-yl) hydrazone] Dihydrochloride, against Experimental Tumors in Mice
US5441932A (en) Sugar compounds for inhibition of the biosynthesis of sugar chains containing sialic acid
EP0792148B1 (fr) Preparations therapeutiques a base de quassino des presentant une activite antineoplasique, antivirale et herbistatique
US5534531A (en) Compounds
WO2001002412A1 (fr) Derives de 5-nitrofurfural
US7737123B2 (en) Multidrug resistant anticancer anthracyclines
US4302449A (en) Carminomycin analogue
RU2144540C1 (ru) Антрациклиновые дисахариды, способ их получения и содержащие их фармацевтические композиции
US20090298784A1 (en) Isolation and structure of turbostatins 1-4
JPH09124489A (ja) インターロイキン−６生産抑制剤
CN113321692A (zh) 一种阿霉素前药及其制备方法和应用
FR2970969A1 (fr) Oligosaccharides 3-o-alkyles activateurs des recepteurs des fgfs, leur preparation et leur application en therapeutique
JPS6341885B2 (fr)
KR100398289B1 (ko) 신규 안트라사이클린 유도체 및 그 제조방법
Preobrazhenskaya et al. Synthesis and cytostatic properties of daunorubicin derivatives, containing N-phenylthiourea or N-ethylthiourea moieties in the 3'-position
KR20010108231A (ko) 화합물
JPS6310713B2 (fr)
MXPA01009025A (es) L-arabino-disacaridos de antraciclinas, proceso para su preparacion, y composiciones farmaceuticas que los contienen..
NZ237941A (en) Mitomycin derivatives and pharmaceutical compositions thereof.
JPS59231023A (ja) 抗腫瘍剤

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20020122

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

17Q First examination report despatched

Effective date: 20020626

GRAG Despatch of communication of intention to grant

Free format text: ORIGINAL CODE: EPIDOS AGRA

GRAH Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOS IGRA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20030111