Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• the invention relates to proline derivatives, in particular cis-hydroxy-proline derivatives (CHP derivatives) and their salts, pharmaceutical compositions comprising them and the use of these compositions for the treatment of tumors.
• the invention further relates to processes for the preparation of the compounds mentioned and pharmaceutical compositions.
• tumor or cancer describes a complex clinical picture in which the growth and differentiation of the cells has gotten out of control. If cancer is not treated, it usually leads to death. Around 7 million new cases of cancer occur worldwide every year, and the number is rising. For the year 2000, the disease was the number one cause of death in the industrialized countries. '
• One of the amino acids used was proline and hydroxyproline.
• follow-up studies showed that such results from mice were not transferable to human cancer diseases (DE 35 38 619).
• WO 97/33578 describes a medicament comprising the combination of cis-hydroxyproline and N-methyl-cis-hydroxyproline for use as a therapeutic agent, in particular for cancer therapy. According to WO 97/33578, an anti-tumor effect based on a significant inhibition of cell proliferation has been demonstrated in cell cultures of tumor cells.
• the agents disclosed must be used in high doses to achieve an effect. It was also very difficult to reproduce the results described.
• the object of the invention was therefore to provide means which can be used simply, safely and effectively in order to inhibit or prevent the proliferation, infiltration, invasion, angiogenesis and / or metastasis of cancer cells.
• the invention solves this problem by providing a compound of the general formula (I)
• i is a hydroxy, an aryl or an amino acid group
• R 2 represents a hydrogen, an alkyl (C - C 4 ) -, a substituted alkyl (C x - C 4 ) - group, a dialkyl (Ci - C 4 ) -, a cyclohexyl, a phenyl or diphenyl group
• R 3 is an alkyl (C 2 - C 5 ) group, and / or their salts, with the proviso that when R x is a hydroxy group, R 2 is different from a methyl group.
• CHP hydroxyproline
• the agents according to the invention can be administered intravenously, for example in a range from 5 to 15 g and orally in a range from for example 50 to 150 g per day. While the known proline derivatives are particularly suitable for carcinomas, that is to say for tumors of epithelial origin can be used, it is possible to use the agents according to the invention in numerous diseases which are essentially determined by cell proliferation or by metastasis.
• the compounds according to the invention can be used with particular advantage as hybrid molecules or in combination agents.
• the hybrid molecules can be, for example, structures which comprise the compounds according to the invention bound to oxoplatin or to oxoplatin and 5-fluorouracil (5-FU).
• the hybrid molecules can be provided according to the galenical methods known to the person skilled in the art so that they can be used as a prodrug.
• prodrug concept which is well known to the person skilled in the art.
• a prodrug contains its active ingredient in the form of an inactive precursor metabolite.
• partially multi-part carrier prodrug systems and biotransformation systems.
• the latter contain the active ingredient in a form that requires chemical or biological metabolism.
• prodrug systems are known to the person skilled in the art.
• Carrier-prodrug systems contain the active substance as such, bound to a masking group, which can be split off by a mechanism that is as simple as possible to control.
• the function according to the invention of masking groups in the compounds according to the invention is the neutralization of the charge for improved cell uptake. If the connections according to the invention are combined with a masking group used, this can also influence other pharmacological parameters, such as oral bioavailability, tissue distribution, pharmacokinetics and stability to non-specific phosphatases.
• the delayed release of the active ingredient can also have a depot effect. Modified metabolism can also occur, resulting in higher drug efficiency or organic specificity.
• the masking group or a linker group which binds the masking group to the active ingredient are selected such that the prodrug has sufficient hydrophilicity to be dissolved in the blood serum, and has sufficient chemical and enzymatic stability to the site of action to arrive and has such a hydrophilicity that it is suitable for a diffusion-controlled membrane transport. Furthermore, it should enable a chemically or enzymatically induced release of the active ingredient within a reasonable period of time and, of course, the auxiliary components released should have no toxicity. According to the invention, however, the connection can also be understood as a prodrug without a mask or a linker and a mask, which must first be provided in the cell from the compound taken up by enzymatic and biochemical processes.
• the amino acids are preferably natural or artificial amino acids, such as those used in biochemistry; Berg, Tymoczko, Stryer (2003) or other standard works of biology.
• R x is a hydroxy, a phenylamino or an amino acid group
• R 2 is a hydrogen, a methyl, a dimethyl, a cyclohexyl or a diphenylmethyl group
• R 3 is an ethyl, an isobutyl and / or a hydrogen group.
• the phenylamino group of the compounds comprises modified amino groups, in particular phenylamino-carbonyloxy groups. It is particularly preferred if the compound is selected from the group comprising 4-hydroxyproline ethyl ester, 4-hydroxy-l, 1-dimethyl-prolinethyl ester iodide, 4-hydroxyproline isobutyl ester, 4-hydroxy-l, 1- dimethyl-prolin-isobutyl ester iodide, 4-hydroxy-1-cyclohexylproline-isobutyl ester, 4-hydroxy-1-diphenylmethyl-prolin-isobutyl ester hydrobromide, 4-hydroxy-1-methyl-proline, 4-hydroxy-1- methyl-prolin-ethyl ester, 4-hydroxy-1-methyl-proline-isobutyl ester, 1-methyl-4-phenylamino-carbonyl-oxy-proline and / or 1-methyl-4-phenylamino-carbonyloxy-proline
• the invention also relates to a pharmaceutical composition which comprises a compound according to the invention, optionally together with customary auxiliaries, preferably pharmaceutically acceptable carriers, adjuvants and / or vehicles.
• the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Included among such salts are, for example, the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, hemisate phosphate, hemisate phosphate Hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate,.
• the salts of the compounds are particularly preferably iodides, bromides and / or chlorides.
• a pharmaceutical agent in the sense of the invention is any agent in the field of medicine which can be used in the prophylaxis, diagnosis, therapy, follow-up or follow-up treatment of patients who have come into contact with tumor cells or carcinogens in such a way that at least temporarily established a pathogenic modification of the overall condition or the condition of individual parts of the organism.
• the pharmaceutical agent in the sense of the invention can be a vaccine, an immunotherapeutic or an immunoprophylactic.
• the pharmaceutical agent in the sense of the invention can comprise the compound according to the invention or the compound according to the invention and / or an acceptable salt or components thereof. These can be, for example, salts of inorganic acids, such as phosphoric acid, or salts of organic acids.
• the salts are free of carboxyl groups and have been derived from inorganic bases, such as, for example, sodium, potassium, ammonium, calcium or iron hydroxides or from organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol , Histidine and others.
• inorganic bases such as, for example, sodium, potassium, ammonium, calcium or iron hydroxides or from organic bases such as isopropylamine, trimethylamine, 2-ethylaminoethanol , Histidine and others.
• liquid carriers are sterile aqueous solutions which do not comprise any further materials or active ingredients, such as water or those which comprise a buffer such as sodium phosphate with a physiological pH or a physiological saline solution or both, such as phosphate-buffered Sodium chloride solution. More liquid carriers can do more than just a buffer salt such as sodium and potassium chloride, dextrose, propylene glycol, polyethylene glycol or others.
• Liquid compositions of the pharmaceutical compositions can additionally comprise a liquid phase, also with the exclusion of water.
• additional liquid phases are glycerol, vegetable oils, organic esters or water-oil emulsions.
• the pharmaceutical composition or the pharmaceutical composition typically contains at least 0.1% by weight of the compounds according to the invention, based on the total pharmaceutical composition.
• the respective dose or the dose range for the administration of the pharmaceutical agent according to the invention is large enough to achieve the desired prophylactic or therapeutic antiviral effect.
• the dose should not be chosen so that undesirable side effects dominate.
• the dose will vary with the age, constitution, gender of the patient and, of course, also with regard to the severity of the; Illness.
• the individual dose can be set in relation to the primary disease as well as in relation to the occurrence of additional complications.
• the exact dose can be determined by a person skilled in the art using known means and methods, for example by determining the size of the tumor, the number of leukocytes or the like as a function of the dose or as a function of the vaccination schedule or the pharmaceutical carriers and the like.
• the dose can be selected individually depending on the patient.
• a dose of the pharmaceutical agent that is still tolerated by the patient can be one whose range in the plasma or in individual organs is locally in the range from 0.1 to 100000 ⁇ M, preferably between 1 and 1000 ⁇ M.
• the dose can also be calculated in relation to the patient's body weight.
• a typical dose of the pharmaceutical agent would have to be set in a range of more than 0.1 g per kg of body weight, preferably between 0.1 and 5000 g / kg.
• a biopolymer introduced into the respective patient, near certain organs by means of an operation.
• biopolymers are known to those skilled in the art that can release molecules in a desired manner.
• Such a gel can, for example, 1 to 1000 g of the compounds of the invention or the pharmaceutical agent per ml
• Contain gel composition preferably between 5 to 500 g / ml and particularly preferably between 10 and 100 g / ml.
• the therapeutic agent is administered as a solid, gel-like or liquid composition.
• the compounds can also be used in a total amount of 0.05 to 500 g / kg body weight per 24 hours, preferably from 1 to 10 g / kg Body weight. This is advantageously a therapeutic amount that is used to prevent or improve the symptoms of a disorder or responsive, pathologically physiological condition.
• the amount administered is sufficient to prevent or inhibit the growth, metastasis, invasion, infiltration and / or angiogenesis of the tumor.
• the effect of the compound according to the invention on the tumors with regard to their prophylactic or therapeutic potential is shown, for example, as an inhibition of growth or otherwise.
• the therapeutic effect can also consist, for example, in that certain anti-tumor drugs act better as a desired side effect through the application of the compounds according to the invention, or the number of side effects of these drugs is reduced by reducing the dose.
• the therapeutic effect also includes a direct impact on the tumor.
• the activity of the compounds according to the invention is not limited to the elimination of the tumors, but rather encompasses the entire spectrum of advantageous effects in prophylaxis and therapy.
• the dose will depend on the age, the health and the weight of the recipient, the degree of the disease, the type of simultaneous treatment required, the frequency of treatment and the type of effects desired and the side effects.
• the daily dose of 0.05 to 500 g / kg body weight can be used once or several times to achieve the desired results.
• the dose levels per Tag can be used in the prevention and treatment of a tumor.
• pharmaceutical agents are used in particular for administration approximately 1 to 15 times per day or alternatively or additionally as a continuous infusion. Such administrations can be used as chronic or acute therapy.
• the amounts of active ingredient that are combined with the carrier materials to produce a single dosage form can of course vary depending on the host to be treated and the particular mode of administration.
• the target dose over 2 to 5 applications, 1 to 2 tablets with an active ingredient content of 0.05 to 5 g / kg body weight being administered for each application.
• an active ingredient content of 0.05 to 5 g / kg body weight being administered for each application.
• a higher active substance content for example up to a concentration of 500 g / kg.
• tablets can also be delayed, which increases the number of. Applications per day reduced to 1 to 3.
• the active substance content of the prolonged-release tablets can be 3 to 300 g. If the active ingredient
• the person skilled in the art can easily determine the optimum dosages required in each case and the type of application of the active compounds on the basis of his specialist knowledge.
• the compounds according to the invention or the pharmaceutical compositions are used in a single dose of from 1 to 80, in particular from 1 to 30, g / kg of body weight. Like the total amount per day, the amount of the single dose per application can be varied by the person skilled in the art on the basis of his specialist knowledge.
• the compounds used according to the invention can also be given in the individual concentrations and preparations mentioned together with the feed or with feed preparations or with the drinking water in veterinary medicine.
• a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, half a daily dose or a third or a quarter of a daily dose.
• the dosage units can accordingly preferably contain 1, 2, 3 or 4 or more single doses or 0.5, 0.3 or 0.25 of a single dose.
• the daily dose of the compounds according to the invention is preferably divided into 2 to 10 applications, preferably to 2 to 7, particularly preferably to 3 to 5 applications. A permanent infusion of the agents according to the invention is of course also possible.
• 1 to 2 tablets are given for each oral application of the compounds according to the invention.
• the tablets according to the invention can be provided with coatings and casings known to the person skilled in the art and can also be composed in such a way that they release the active ingredient (s) only in a certain part of the host, if preferred.
• the compounds according to the invention can be used with at least one other known pharmaceutical agent. This means that the compounds according to the invention can be used in a prophylactic or therapeutic combination in conjunction with the known medicaments.
• These combinations can be administered together, for example in a uniform pharmaceutical formulation, or separately, for example in the form of a combination of tablets, injection or other medications, which are administered at the same or at different times, with the aim of achieving the desired one to achieve prophylactic or therapeutic effects.
• These known agents can be agents which increase the activity of the compounds according to the invention.
• This includes antibacterial or antiviral agents such as benzylpyrimidines, pyrimidines, sulphoamides, rifampicin, tobramycin, fusidic acid, clindamycin, chloramphenicol and erythromycin.
• an additional embodiment of the invention relates to a combination in which the second agent is at least one of the aforementioned antiviral or antibacterial agents or classes of agents. It should also be pointed out that the compounds and combinations according to the invention can also be used in conjunction with immunomodulatory treatments and therapies.
• an optimal ratio of the compound (s) according to the invention to one another and / or to other therapeutic or activity-increasing agents such as transport inhibitors, metabolism inhibitors, inhibitors of kidney excretion or glucuronidation, such as sample oath, acetaminophen, aspirin, lorazepan, cimetidine, ranitidine, Colifibrate, indomethacin, ketoprofen, naproxen etc.
• An optimal ratio is defined as the ratio at which the compound (s) according to the invention with another therapeutic agent or agents is such that the overall therapeutic effect is greater than the sum of the effects of the individual therapeutic agents.
• the optimal ratio is usually found when the means are in the ratio of 10: 1 to 1:10, 20: 1 to 1:20, 100: 1 to 1: 100 and 500: 1 to 1: 500. Occasionally, a negligible amount of a therapeutic agent will suffice to increase the effectiveness of one or more other agents.
• the use of the compounds according to the invention in combinations is particularly useful in order to reduce the risk of developing the resistance of the tumors.
• the compounds according to the invention can of course be used in combination with other known antitumor agents. Such means are known to the person skilled in the art.
• the compounds according to the invention can accordingly be administered with all conventional agents, in particular other drugs, which are available for use in connection with tumor drugs in particular, either as individual drugs or in a combination of drugs. They can be administered alone or in combination with them.
• the compounds according to the invention are administered with the other known pharmaceutical agents in a ratio of about 0.005 to 1. It is preferred to administer the compounds according to the invention with, in particular, tumor-inhibiting agents in a ratio of 0.05 to about 0.5 parts to about 1 part of the known agents. These can also be antibacterial agents.
• the pharmaceutical composition may be in bulk or as an aqueous solution along with others Materials such as preservatives, buffer substances, agents which are provided for adjusting the osmolarity of the solution etc.
• the invention also relates to a kit which comprises the compounds according to the invention, optionally with information for combining the contents of the kit.
• the information on combining the contents of the kit relates to the use of the kit for the prophylaxis and / or therapy of diseases, in particular tumor diseases.
• the information can also relate, for example, to a therapy scheme, that is to say to a specific injection or application scheme, to the dose to be administered or something else.
• the pharmaceutical agent can preferably further comprise one or more additional agents from the group of antiviral, fungicidal or antibacterial agents and / or immune stimulators or chemotherapeutic agents.
• the antiviral agent is preferably protease inhibitors and / or reverse transcriptase inhibitors.
• the immune stimulators are preferably
• chemotherapeutic agents are preferably alitretinoin, aldesleukin (IL-2), altretamine, all-trans-retinoic acid (tretinoin), aminoglutethimide, anagrelide, anastrozole, asparaginase ⁇ E.
• coli azathioprine
• bicalutamide bleomycin
• busulfan capecitabine
• carboplatin carmustine, chlorambucil, cisplatin, cladribine (2-CDA), cyclophosphamide, cytarabine, dacarbazine, dactinomycin-D,
• Daunorubicin (Daunomycin), Daunorubicin, liposomal,
• the compounds according to the invention can also be used together with immunomodulators or immune stimulators; preferred immunomodulators or immunostimulators are: propirimine, anti-human ⁇ -interferon antibodies, IL-2, GM-CSF, interferon ⁇ , diethyldithiocarbamate, tumor necrosis factor, naltrexone, Tuscarasol, rEPO and antibiotics such as pentamidine isethionate; but also agents that prevent or fight malignant tumors associated with viral diseases.
• preferred immunomodulators or immunostimulators are: propirimine, anti-human ⁇ -interferon antibodies, IL-2, GM-CSF, interferon ⁇ , diethyldithiocarbamate, tumor necrosis factor, naltrexone, Tuscarasol, rEPO and antibiotics such as pentamidine isethionate; but also agents that prevent or fight malignant tumors associated with viral diseases.
• Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the medicaments of this invention include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d ⁇ -tocopherol polyethylene glycol 1000 succinate, or other similar polymers Release matrices, serum proreins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acids, potassium sorbate, partial glyceride mixtures of saturated vegetable fat Acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates and polyethylene, waxes, polyethylene block, polyethylene glycol, polyethylene block, polyethylene glycol, polyethylene block Wool
• Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives, such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl- ⁇ -cyclodextrins, or other solubilized derivatives can also be used advantageously to deliver to increase the compounds of the invention.
• the compounds according to the invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration or administration by injection is preferred as the form of contacting.
• the drugs of this invention can contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle.
• the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to increase the stability of the formulated compound or its delivery form.
• parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion methods in the form of contacting.
• the carriers are selected from the group comprising fillers, extenders, binders, humectants, Disintegrants, solution retarders, absorption accelerators, wetting agents, adsorbents, and / or lubricants.
• the fillers and extenders are preferably starches, milk sugar, cane sugar, glucose, mannitol and silica, the binder, preferably carbomethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, the humectant, preferably glycerol, the disintegrant preferably agar-agar, calcium carbonate and sodium carbonate, in the solution retarder preferably paraffin and in the absorption accelerator preferably quaternary ammonium compounds, in the wetting agent preferably cetyl alcohol and glycerol monostearate, in the adsorbent preferably kaolin and bentonite and in the lubricant preferably talc, Calcium and magnesium stearate and solid polyethylene glycols or mixtures of the listed substances.
• the binder preferably carbomethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, the humectant, preferably glycerol, the disintegrant preferably agar-agar,
• the compounds according to the invention are used as pharmaceutical agents as a gel, powder, powder, tablet, slow-release tablet, premix, emulsion, infusion formulation, drops, concentrate, granules, syrup, pellet, bolus, capsule, aerosol, spray and / or inhalation prepared and / or applied in this form.
• the tablets, dragées, capsules, pills and granules can be provided with the usual coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, possibly with a delay , whereby polymer substances and waxes can be used as embedding compositions.
• the compounds or drugs of this invention may preferably be for oral administration in any oral compatible dosage form, including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
• carriers that are used frequently include lactose and corn starch.
• Lubricants such as magnesium stearate are typically added.
• diluents which may be used include lactose and dried corn starch.
• aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners and / or flavors and / or colorants can be added.
• the compounds can optionally also be in microencapsulated form with one or more of the above-mentioned carriers.
• suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C ⁇ 4 alcohol with C 16 fatty acid) or mixtures of these substances).
• water-soluble or water-insoluble carriers for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C ⁇ 4 alcohol with C 16 fatty acid) or mixtures of these substances).
• ointments, pastes, creams and gels can contain the usual excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances ,
• powders and sprays can contain the usual carriers, for example milk sugar,
• Sprays can additionally contain the usual blowing agents, for example chlorofluorocarbons.
• solutions and emulsions can include the customary carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils , in particular cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
• solvents such as solvents, solubilizers and emulsifiers
• solvents such as solvents, solubilizers and emulsifiers
• solvents such as solvents, solubilizers and emulsifiers
• solvents such as solvents, solubilizer
• suspensions can contain the customary excipients such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols,
• the medicaments can be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oily suspension.
• This suspension can also be formulated using methods known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
• the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally compatible diluent or solvent, for example as a solution in 1,3-butanediol.
• suitable vehicles and solvents used can include mannitol, water, Ringer's solution and isotonic sodium chloride solution.
• sterile, non-volatile oils are usually used as solvents or suspending media.
• Any mild, non-volatile oil including synthetic mono- or diglycerides, can be used for this purpose.
• Fatty acids such as oleic acid and its glyceride derivatives, can be used in the production of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, in particular in their polyoxyethylated forms.
• oils such as olive oil or castor oil, in particular in their polyoxyethylated forms.
• These oil solutions or suspensions can also contain a long-chain alcohol or a similar alcohol as a diluent or dispersant.
• the formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
• the active compounds of the formula (I) should preferably be present in the listed pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.
• the listed pharmaceutical preparations can also contain other active pharmaceutical ingredients.
• the pharmaceutical preparations listed above are prepared in a customary manner by known methods, for example by mixing the active ingredient (s) with the carrier (s).
• the preparations mentioned can be used in humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powder, ointment, drops) and for therapy.
• ophthalmic and dermatological formulations, silver and other salts, ear drops, eye ointments, powder or solutions can be used.
• suitable formulations can also be ingested through feed or drinking water.
• Gels, powders, powders, tablets, prolonged-release tablets, premixes, concentrates, granules, pellets, tablets, boluses, capsules, aerosols, sprays, inhalants can also be used in humans and animals.
• the compounds according to the invention can be incorporated into other carrier materials, such as, for example, plastics (plastic chains for local therapy), collagen or bone cement.
• the compounds according to the invention are incorporated in a preparation in a concentration of 0.1 to 99.5, preferably 0.5 to 95, particularly preferably 20 to 80% by weight. That is, the compounds according to the invention are present in the pharmaceutical preparations listed above, for example tablets, pills, granules and others, preferably in a concentration of 0.1 to 99.5% by weight of the total mixture.
• the amount of active ingredient i.e. the amount of a compound of the invention, which is combined with the carrier materials to produce a single dosage form, may vary depending on the host to be treated and the particular mode of administration. After the condition of a host or a patient has improved, the proportion of the active compound in the preparation can be changed so that a maintenance dose is available.
• the dose or frequency of administration or both as a function of symptoms can then be reduced to a level in which the improved condition is maintained. If the symptoms have been relieved to the desired level, treatment should stop. However, patients may need long-term interruption treatment after any recurrence of disease symptoms. Accordingly, the proportion of the compounds, that is to say their concentration, in the overall mixture of the pharmaceutical preparation as well as their composition or combination is variable and can be modified and adapted by the person skilled in the art on the basis of his specialist knowledge.
• the compounds according to the invention can be brought into contact with an organism, preferably a human or an animal, in various ways. It is also known to the person skilled in the art that in particular the pharmaceutical compositions can be administered in different dosages.
• the application should be carried out in such a way that the viral disease is combated as effectively as possible or the outbreak of such a disease is prevented by prophylactic administration.
• the concentration and the type of application can be determined by a person skilled in the art through routine tests.
• Preferred applications of the compounds according to the invention are oral application in the form of powder, tablets, juice, drops, capsules or the like, rectal application in the form of suppositories, solutions and the like, parenterally in the form of injections, infusions and solutions, inhalation of vapors, Aerosols and dusts and plasters as well as locally in the form of ointments, plasters, envelopes, rinses and the like.
• the contacting of the compounds according to the invention is preferably carried out prophylactically or therapeutically. In the case of prophylactic administration, the establishment of a tumor should be prevented. In the case of therapeutic contacting, there is already a tumor disease and those already in the body Cancer cells are said to either be killed or to be prevented from multiplying. Further preferred forms of application for this are, for example, subcutaneous, sublingual, intravenous, intramuscular, intraperitoneal and / or topical.
• the suitability of the chosen forms of application as well as the dose, the application scheme, the choice of adjuvant and the like can be determined, for example, by taking serum aliquots from the patient or imaging methods in the course of the treatment protocol.
• the condition of the liver, but also the amount of T cells or other cells of the immune system can be determined in a conventional accompanying manner in order to provide an overview of the immunological constitution of the patient and in particular the constitution of organs important for metabolism, in particular the Liver.
• the clinical condition of the patient can be observed for the desired effect, in particular the antitumor effect. Since tumor diseases can be associated with other, for example bacterial or fungicidal, infections, it is also possible to additionally follow the course of these accompanying infections clinically.
• the patient can be modified and treated further with agents according to the invention or other known medicaments, from which an improvement in the overall constitution can be expected.
• agents according to the invention or other known medicaments, from which an improvement in the overall constitution can be expected.
• injections for example intramuscularly or subcutaneously or into the blood vessels, are a further preferred route for the therapeutic are the administration of the compounds according to the invention.
• delivery via catheters or surgical tubes can also be used.
• the invention also relates to the use of the compound for diagnosis, prophylaxis, reduction, therapy, follow-up and / or post-treatment of diseases associated with cell growth, differentiation and / or division.
• the disease associated with cell growth, differentiation and / or division is a tumor.
• the tumor is particularly preferably a solid tumor and / or leukemia.
• the cancer or the tumor which is treated, prevented prophylactically or whose recurrence is prevented is selected from the group of cancers or tumor diseases of the ear, nose and throat area, the lungs, the mediastinum, the Gastrointestinal tract, the urogenital system, the gynecological system, the breast, the endocrine system, the skin, bone and soft tissue sarcomas, mesotheliomas, melanomas, neoplasms of the central nervous system, cancer or tumor diseases in the group of cancers or tumor diseases of the ear, nose and throat area, the lungs, the mediastinum, the Gastrointestinal tract, the urogenital system, the gynecological system, the breast, the endocrine system, the skin, bone and soft tissue sarcomas, mesotheliomas, melanomas, neoplasms of the central nervous system, cancer or tumor diseases in the
• lymphomas Childhood, lymphomas, leukaemias, paraneoplastic syndromes, metastases without a known primary tumor (CUP syndrome), peritoneal carcinoma disorders, immunosuppression-related malignancies and / or tumor metastases.
• CUP syndrome primary tumor
• peritoneal carcinoma disorders immunosuppression-related malignancies and / or tumor metastases.
• the tumors can be the following types of cancer: adenocarcinoma of the breast, prostate and colon; all forms of lung cancer that originate from the bronchi; Bone marrow cancer, melanoma, hepatoma, neuroblastoma; the papilloma; the apudome, the Choristom, the Branchiom; the malignant carcinoid syndrome; the carcinoid heart disease; the carcinoma (for example Walker carcinoma, basal cell carcinoma, basosquamous carcinoma, Brown-Pearce carcinoma, ductal carcinoma, Ehrlich tumor, in situ carcinoma, cancer 2 carcinoma, Merkel cell carcinoma, mucus cancer, non- small cell bronchial carcinoma, oat cell carcinoma, papillary carcinoma, scarring carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, squamous cell carcinoma and transitional cell carcinoma); histiocytic dysfunction; Leukemia (for example in connection with B-cell leukemia, mixed-cell leukemia, zero-cell leukemia, zero
• osteoma osteosarcoma; Ewing's sarcoma; synovioma; Adenofribrom; Adenolymphom; Carcinosarcoma, chordoma, craniopharyngioma, dysgerminoma, hamartoma; Mesenchymom; Mesonephroma, myosarcoma, ameloblastoma, cementoma; odontoma; teratoma; Thymoma, chorioblastoma; Adenocarcinoma, adenoma; cholangiomas; cholesteatoma; cylindroma; Cystadenocarcinoma, cystadenoma; granulosa cell tumor; Gynadroblastom; Hidradenoma; Islet cell tumor; Leydig cell tumor; papilloma; Sertoli cell tumor, theca cell tumor, leiomyoma; leiomyosarcoma; myo
• Ganglioneuroma glioma; Medulloblastoma, ⁇ meningioma; neurilemmoma; neuroblastoma; Neuroepithelioma, neurofibroma, neuroma, paraganglioma, non-chromaffin paraganglioma, angiokeratome, angiolymphoid hyperplasia with eosinophilia; sclerosing angioma; angiomatosis; Glomus Tumor; Hemangio- endothelioma; hemangioma; Hemangiopericytoma, hemangiosarcoma; Lymphangioma, lymphangiomyoma, lymphangiosarcoma; pinealoma; Cystosarcoma phyllodes; Hemangiosarkom; lymphangiosarcoma; Myxosarcoma, ovarian cancer; Sarcoma (for example, Ewing's sarcoma, experimental,
• the cancer or tumor being treated, prevented prophylactically or prevented from recurring is selected from the group of cancer diseases or tumor diseases comprising cells comprising the MUC1 in the definition according to the invention, selected from the Group: Tumors of the ear, nose and throat area including tumors of the inner nose, paranasal sinuses, nasopharynx, lips, oral cavity, oropharynx, larynx, hypopharynx, ear, salivary glands and paragangliomas, including tumors of the lungs non-small cell bronchial carcinoma, small cell bronchial carcinoma, tumors of the mediastinum, tumors of the gastrointestinal tract including tumors of the esophagus, stomach, pancreas, liver, gallbladder and biliary tract, small intestine, colon and rectal cancer , Urogenital tumors including tumors of the kidneys, ureters, the Bladder, prostate, urethra, penis and testicles, gy
• AIDS-associated Hodgkin's disease and AIDS-associated anogenital tumors transplant-related malignancies, metastatic tumors including brain metastases, lung metastases, liver metastases, bone metastases, pleural and pericardial metastases and malignant ascites.
• the cancer or the tumor which is treated, prevented prophylactically or whose recurrence is prevented is selected from the group comprising cancers or tumors of breast carcinomas, gastrointestinal tumors, including colon carcinomas, gastric carcinomas, colon cancer and small bowel cancer. pancreatic carcinoma, ovarian carcinoma, liver carcinoma, lung cancer, renal cell carcinoma and multiple myeloma.
• the compound or the pharmaceutical composition is used in a combination therapy, in particular for the treatment of tumors. It is particularly preferred here that the combination therapy comprises chemotherapy, cytostatic treatment and / or radiation therapy.
• the combination therapy is an adjuvant, biologically specified form of therapy. It is very particularly preferred that this form of therapy is an immunotherapy. Furthermore, it is particularly preferred that the combination therapy is a gene therapy.
• a gene therapy in the sense of the invention is a form of treatment using natural or recombinantly modified nucleic acid constructs, individual gene sequences or entire gene or chromosome sections or coded transcript areas, their derivatives / modifications with the aim of a biologically-based and selective inhibition or reversion of the disease symptoms and / or their causal causes, which in the special case means the inhibition of a target molecule overexpressed in the course of a disease at the nucleic acid level, in particular at the transcript level.
• a cytostatic treatment takes place within a combination therapy or, for example, irradiation of a specific tumor area, this treatment being combined with a gene therapy, the compound according to the invention being used as Anti-cancer drug is used.
• the agents according to the invention can also be used in combination with other anti-cancer agents.
• the compound can very particularly preferably be used to increase the sensitivity of tumor cells to cytostatics and / or radiation. It is further preferred that the compound is used to inhibit viability, the proliferation rate of cells and / or to induce apoptosis and cell cycle arrest
• the invention also relates to a process for the preparation of the compounds according to the invention.
• 1-methyl-4-phenylaminocarbonyl-oxy-prol'in ethyl ester is obtained by reacting 4-hydroxy-1-methyl-prolin ethyl ester and phenyl isocyanate in acetonitrile.
• the compound 1-methyl-4-phenylamino-carbonyl-oxy-proline isobutyl ester is obtained by reacting 4-hydroxy-1-methyl-proline isobutyl ester and phenyl isocyanate in acetonitrile.
• 4-Hydroxy-1-methyl-proline is obtained by reacting 4-hydroxy-proline in formalin and Pd / C in a hydrogenation apparatus.
• 4-Hydroxy-1-methyl-prolinethyl ester is obtained by the reaction of 4-hydroxy-prolinethyl ester and formalin in ethanol.
• 4-Hydroxy-1-methyl-proline isobutyl ester is obtained by the reaction of formalin, Pd / C and ethanol and 4-hydroxy-proline isobutyl ester.
• 4-Hydroxy-1-methyl-proline isobutyl ester is obtained by the reaction of formalin and 4-hydroxy-proline isobutyl ester in the presence of Pd / C in ethanol.
• cis-4-Hydroxy-L-prolinethyl ester is obtained by contacting -Hydroxy-Prolin in ethanol with HC1 (see example).
• Cis-4-hydroxy-L-proline iso-butyl ester is obtained by the reaction of 4-hydroxyproline in isobutanol, the purification being carried out analogously to 4-hydroxyproline ethyl ester.
• 4-Hydroxy-l, 1-dimethyl-prolinethyl ester iodide is obtained by dissolving hydroxyproline ethyl ester in acetonitrile and adding methyl iodide and triethylamine.
• 4-Hydroxy-1, 1-dimethyl-proline-iso-butyl ester iodide is obtained by the reaction of 4-hydroxyproline isobutyl ester and methyl iodide in triethylamine and acetonitrile.
• 4-Hydroxy-l-alkyl-prolinester bromide is obtained by suspending 4-hydroxy-prolinester in acetonitrile and bringing it into contact with the corresponding alkyl bromide.
• 4-Hydroxy-l-cyclohexyl-proline isobutyl ester is formed by dissolving hydrobromide in chloroform and then drying in ammonia gas.
• 4-Hydroxy-1-diphenylmethyl-prolin-isobutyl ester hydrobromide is obtained analogously to 4-hydroxy-1, 1-dimethylproline-iso-butyl ester iodide.
• the invention also relates to the use of the compounds for inhibiting collagen IV and / or glutathione-S-transferase (GST), the compounds being those described above for cancer therapy.
• GST inhibition or lowering and / or collagen IV inhibition or lowering in a cell culture or in an organism has numerous consequences.
• GST is able to bind GSH to itself in order to prepare it for extracellular transport.
• Due to the increased binding of GSH, it is no longer available for other cell processes, which leads to pathological changes in the cell. Binding of tumor cell fragments also results in a different processing of information within the cell and thus also in other functional processes, whereby the transformation of the cell is initiated or promoted. Apoptosis is also promoted by the above-mentioned processes.
• collagen inhibition not only leads to a reduction in metastasis and infiltration and invasions in the case of tumor diseases, but it also has a therapeutic effect in all inflammatory diseases in which normal tissue in the connective tissue is transformed, for example in pulmonary fibrosis Cirrhosis of the liver, pancreatic fibrosis and / or glomerular sclerosis.
• collagen IV inhibition has a positive influence on scleroderma / Marfan syndrome, vascular diseases, metabolic diseases, autoimmune diseases and neurological diseases in which nerve tissue is converted into connective tissue - the so-called gliosis, for example also in Alzheimer's disease.
• CHP derivatives it is possible, in addition to the inhibition of collagen IV by CHP derivatives, to give parallel medications which induce fibrosis, such as bleomycin / busulfan in the form of supportive / additive therapy.
• the invention also relates to a method for inhibiting collagen IV and / or GST in an organism and / or in a sample, the organism or the sample being brought into contact with the CHP derivatives mentioned.
• the method can be used, for example, in a combination therapy by means of which cells in an organism regenerate after chemotherapy.
• Contacting CHP with the organism or the treating sample can be done, for example, orally, subcutaneously, intravenously, intramuscularly, intraperitoneally, vaginally, rectally, topically and / or sublingually.
• the invention also relates to an anti-collagen IV and / or an anti-GST agent or a collagen IV or GST depressant, which comprise the CHP derivatives, optionally together with customary auxiliaries.
• customary auxiliaries are in particular pharmaceutically acceptable carriers, adjuvants and / or vehicles, the carriers being selected from the group comprising fillers, extenders, binders, humectants, disintegrants, solution retarders, absorption accelerators, wetting agents, adsorbents and / or lubricants .
• the collagen IV depressant or inhibitor or the GST depressant or inhibitor, which comprise CHP derivatives can be used as a gel, powder, powder, tablet, sustained release tablet, premix, emulsion, infusion formulation, drops, concentrate, infusion solutions, Granules, syrup, pellet, bolus, capsule, aerosol, spray and / or inhalate can be prepared or used.
• CHP is present in a preparation in a concentration of 0.1 to 99.5, preferably 0.5 to 95 and particularly preferably 1 to 80% by weight. It is particularly preferred if the preparation is an infusion solution in which CHP derivatives are present in the range from 1 to 2% by weight.
• CHP derivatives are used in a total amount of 0.05 to 1000 mg per kg body weight, preferably from 5 to 450 mg per kg
• CHP derivatives alone can be used so that 0.1 to 100 g are administered per day per patient. Self- Of course, it can be provided to split the daily dose and to bring the split amount into contact with the organism 2, 4, 6 or 10 times or several times.
• the inhibition of collagen IV and / or GST, preferably ⁇ GST, by CHP derivatives is preferably used for the treatment of (i) inflammation, particularly preferably of (ii) autoimmune diseases.
• Inflammation in the sense of the invention is the reaction of the organism to an external or internal inflammation stimulus carried by the connective tissue and the blood vessels with the purpose of eliminating or inactivating it and repairing the irritation-related tissue damage.
• Mechanical stimuli foreign bodies, pressure, injury
• other physical factors ionizing rays, UV light, heat, cold
• chemical substances alkalis, acids, heavy metals, bacterial toxins, allergens and immune complexes
• pathogens microorganisms, worms
• Insects or pathological metabolic products, derailed enzymes, malignant tumors.
• the process is supplemented by a disturbance in the electrolyte balance (trans-mineralization), immigration of neutrophil granulocytes and monocytes through the vessel walls (see also leukotaxis), the latter with the purpose of eliminating the inflammatory stimulus and damaged to neurotic cells (phagocytosis); Furthermore, lymphocyte effector cells migrate, which lead to the formation of specific antibodies against the inflammatory stimulus (immune reaction), as well as eosinophils (in the healing phase or - very early - in allergic-hyperergic events).
• Preferred inflammations in the sense of the invention are purulent, exudative, fibrinous, gangrenescent, granulomatous, hemorrhagic, catarrhal, necrotizing, proliferative or productive, pseudomembranous, serous, specific and / or ulcerative inflammation , (ii) are autoimmune diseases for the purposes of the invention
• organ-specific autoimmune diseases are HASHIMOTO thyroiditis, primary myxedema, thyrotoxicosis (BASEDOW disease), pernicious anemia, ADDISON disease, myasthenia gravis and / or juvenile diabetes mellitus.
• Preferred intermediate autoimmune diseases are GOODPASTURE syndrome, autoimmune hemolytic anemia, autoimmune leukopenia, idiopathic thrombocytopenia, pemphigus vulgaris, sympathetic ophthalmia, primary biliary cirrhosis, autoimmune hepatitis, ulcerative colitis and / or SJ ⁇ GREN syndrome.
• Preferred systemic autoimmune diseases are rheumatoid arthritis, rheumatic fever, systemic lupus erythematosus, dermatomyositis / polymyositis, progressive systemic sclerosis, WEGENER granulomatosis, panarteritis nodosa and / or hypersensitivity angiitis.
• Typical autoimmune diseases are thyrotoxicosis, thyroid-related myxedema, HASHIMOTO thyroiditis, generalized endocrinopathy, pernicious anemia, chronic gastritis type A, diseases of individual or all corpuscular elements of the blood (for example autoimmune hemolytic anemia, idiopathic and idiopathic thrombocytopenia; idiopath .
• the basis is an aggressive immune reaction as a result
• Dry HCl gas is passed into a suspension of 20 g (0.15 mol) of 4-hydroxy-proline in 400 ml of anhydrous ethanol with stirring and ice-cooling (about 2 hours) until the 4-hydroxy-proline has gone into solution is, with further HCl gas being introduced once a day (about 5 to 10 min.).
• 0.8 g of hydroxyproline ethyl ester are dissolved in 30 ml of acetonitrile and mixed with 0.6 g of methyl iodide and 1 ml of triethylamine. After standing overnight (at room temperature), the reaction mixture is briefly heated (the reaction product dissolves completely in the acetonitrile) and immediately filtered hot (removal of the triethylammonium iodide). The acetonitrile is removed in vacuo and the solid crystalline end product is dried in vacuo.
• the compounds according to the invention were tested using pancreatic tumor cell lines MIYPaCa2 and BxPC3 as well as on breast cancer cell lines MDA-MB-435 and BT20 and on colon cancer cell lines Colo205 and HT29.
• the cells were placed in 96-well microtiter plates in culture medium (RPMI-1640 with 10% fetal calf serum and 4 mM glutamine); 10,000 cells per well.
• the components to be tested according to the invention were diluted in accordance with the known procedure in the microtiter plates and incubated for 4 days under cell culture conditions (37 ° C., 5% CO 2 ).
• CHP has the highest activity (40 + 10.1% inhibition; mean ⁇ SEM for all 6 cell lines at 400 ⁇ g / ml, followed by AI.21 (36.5 + 11.4) and A0.21 (16.3 ⁇ 2.7) and AI.23, A2.21, A2.23 with activities less than 8% AI.21 has a spectrum which is different from CHP and has a much lower activity at the low concentration compared to CHP.
• N-methyl-cis-hydroxy-proline-ethyl ester was more effective for certain cell lines such as MDA-MB435 and BT20, both of which are breast cancer cell lines, and in other experiments substances were dissolved in water and in their effect on colon adenocarcinoma cell lines Colo205 and pancreatic adenocarcinoma cell lines BxPC3 as targets, the results obtained in IC 50 concentrations in ⁇ g / ml are shown in Table 2.
• cis-4-hydroxy-1, 1-dimethyl-prolinethyl ester iodide (A-l-01) showed a specifically higher activity against the pancreatic adenocarcinoma cell lines (BX PC3) than cis-4-hydroxy-L-proline.
• the determination of the IC 50 is a relevant parameter for measuring the pharmacological effectiveness of an active ingredient.
• the use of the substances cis-4-hydroxy-L-proline ethyl ester, cis-4-hydroxy-L-proline isobutyl ester, cis-4-hydroxy-1-diphenylmethyl-proline isobutyl ester hydrobromide and cis-hydroxy-1 , 1-dimethyl-prolinethyl ester iodide could have great therapeutic advantages over other substances such as cis-4-hydroxy-L-prolin and / or cis-4-hydroxy-l-methylproline.
• the therapeutic dosages required will be much lower, for example pharmaceutical oral formulations could be possible for once a day (low dose and once a day) instead of repeated daily dosing.
• the patient's quality of life, therapy costs and patient compliance depend on this.
• Cis-4-hydroxy-L-proline was orally repeatedly administered to rats over a period of 28 days.
• cis-4-hydroxy-L-proline was analyzed using the LC / MS technique.
• trans-4-hydroxy-L-proline or other products of the biotransformation is disadvantageous since these are often not pharmacologically active.
• the biotransformation or the conversion of cis-4-hydroxy-L-proline into trans-4-hydroxy-L- Proline, trans-4-hydroxy-D-proline, trans-3-hydroxy-D-proline or generally in D-proline can be prevented, whereby the concentration of cis - 4-hydroxy-L-proline in the organism at a high level remains .
• CHP isomerase inhibitors and / or CHP CHP epimerase inhibitors are also given at the same time or with a delay in connection with an oral or another administration of cis-4-hydroxy-L-proline or its derivatives, the dosage of cis-4-hydroxy-L-proline or its derivatives are lower, since loss through biotransformation - that is to say through isomerization and epimerization - is avoided in the organism.

Landscapes

• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Hematology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyrrole Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Applications Claiming Priority (1)

Publications (1)

Family

ID=34683207

Family Applications (1)

Country Status (10)

Families Citing this family (11)

Family Cites Families (6)

• 2003
  • 2003-12-18 CA CA002548391A patent/CA2548391A1/en not_active Abandoned
  • 2003-12-18 US US10/596,636 patent/US20080176923A1/en not_active Abandoned
  • 2003-12-18 AU AU2003298077A patent/AU2003298077A1/en not_active Abandoned
  • 2003-12-18 UA UAA200608086A patent/UA82753C2/uk unknown
  • 2003-12-18 MX MXPA06007007A patent/MXPA06007007A/es not_active Application Discontinuation
  • 2003-12-18 EP EP03795774A patent/EP1711462A1/de not_active Withdrawn
  • 2003-12-18 WO PCT/DE2003/004211 patent/WO2005058816A1/de active Application Filing
  • 2003-12-18 JP JP2005512148A patent/JP2007523829A/ja not_active Withdrawn
  • 2003-12-18 BR BRPI0318659-8A patent/BR0318659A/pt not_active IP Right Cessation
  • 2003-12-18 CN CNA200380110862XA patent/CN1942438A/zh active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events