US20110028756A1 - Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs - Google Patents

Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs Download PDF

Info

Publication number
US20110028756A1
US20110028756A1 US12/847,415 US84741510A US2011028756A1 US 20110028756 A1 US20110028756 A1 US 20110028756A1 US 84741510 A US84741510 A US 84741510A US 2011028756 A1 US2011028756 A1 US 2011028756A1
Authority
US
United States
Prior art keywords
prodrug
inhibitor
formula
intercalating
medicinal substance
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.)
Abandoned
Application number
US12/847,415
Inventor
Bernd Clement
Christiane Reeh
Helen HUNGELING
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.)
Dritte Patentportfolio Beteiligungs GmbH and Co KG
Original Assignee
Dritte Patentportfolio Beteiligungs GmbH and Co KG
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 Dritte Patentportfolio Beteiligungs GmbH and Co KG filed Critical Dritte Patentportfolio Beteiligungs GmbH and Co KG
Assigned to DRITTE PATENTPORTFOLIO BETEILIGUNGSGESELLSCHAFT MBH & CO. KG reassignment DRITTE PATENTPORTFOLIO BETEILIGUNGSGESELLSCHAFT MBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: REEH, CHRISTIANE, HUNGELING, HELEN, CLEMENT, BERND
Publication of US20110028756A1 publication Critical patent/US20110028756A1/en
Priority to US14/455,272 priority Critical patent/US9353047B2/en
Priority to US14/581,384 priority patent/US9662308B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/62—Oximes having oxygen atoms of oxyimino groups esterified
    • C07C251/64—Oximes having oxygen atoms of oxyimino groups esterified by carboxylic acids
    • C07C251/66—Oximes having oxygen atoms of oxyimino groups esterified by carboxylic acids with the esterifying carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to use of an amidoxime carboxylic acid ester in a method for improving the bioavailability and enabling the blood-brain barrier crossing of medicinal substances, which have at least one or more amidine functions, guanidine functions, N-hydroxyamidine (amidoxime) functions or N-hydroxyguanidine functions, and drugs containing correspondingly modified medicinal substances.
  • compositions containing an active agent having one or more amidine or guanidine functions exhibit almost no pharmacological effect in oral application.
  • the precondition for a therapeutical effect of an active agent after oral administration is represented by its resorption from the gastrointestinal tract.
  • the most important mechanism of such an effect is passive diffusion.
  • the degree of resorption by way of passive diffusion is dependent on the lipophilicity and thus also the acidity and basicity of the active agent.
  • the blood-brain barrier is an effective barrier with regard to the resorption of substances into the brain. It ensures the selective uptake and prevents the penetration of substances. Furthermore, the blood-brain barrier does no only act as a physical but also as an enzymatic barrier.
  • Various processes are involved in the penetration of substances into the brain. As compared to other indications, only few drugs are marketed, which develop their effect in the central nervous system (CNS). The greater part thereof reaches the CNS by diffusion. Diseases like epilepsy, chronic pain or depressions are treated this way. Other serious functional disorders such as brain tumors or amyotrophic lateral sclerosis yet cannot be treated in this way today [PARDRIDGE, W.
  • a substance is required to be lipophilic, have a lower molecular weight than 400-500 Da, and be present in an uncharged state.
  • various transporter systems such as nucleoside transporters, influx and efflux transporters for organic anions, glucose transporters, peptide transporters, and amino acid transporters are expressed on the blood-brain barrier [TAMAI, I.; TSUJI, A. J. Pharm Sci 2000, 89, 1371-1388 and DE BOER, A.; VAN DER SANDT, I. Annu Rev Pharmacol Toxicol 2003, 43, 629-656].
  • Diamidines are used as antiparasitic agents against malaria, pneumocystis jiroveci (previously carinii ) pneumonia, trypanosomiasis (African sleeping sickness), and leishmaniasis [WERBOVETZ, K. Curr Opin Investig Drugs 2006, 7, 147-157]. Particularly in developing countries, these diseases represent a serious problem involving high mortality rates.
  • Pentamidine (Pentacarinat®) has been used in the early stage of the African sleeping sickness already for 60 years. Efficiency is no longer provided in the 2 nd stage of the African sleeping sickness, the meningo-encephalitic stage, since the blood-brain barrier cannot be passed successfully. As a result, highly toxic arsenic compounds must be administered. There is a lack of medicinal substances which are efficient in the 2 nd stage of the African sleeping sickness.
  • Medicinal substances containing carboxylic acids are very widely used and can also be applied as oral dosage forms.
  • analgesics from the group of acetic acid, propionic acid and salicylic acid derivatives must be mentioned here.
  • N-hydroxylated derivatives such as amidoximes, and the N-hydroxyguanidines, due to the introduction of the oxygen atom, exhibit a lower basicity. Under physiological conditions, they are not present in a protonated form.
  • Benzamidoxime represents a model compound for many medicinal substances containing an amidoxime function [Clement, B., Drug Met Rev 2002, 34, 565-579].
  • Pentamidine and diminazene represent diamidines and are not resorbed after oral application. They were therefore transferred into amidoxime prodrugs. (DE 10 2006 034 256.9).
  • the example pentamidine demonstrates that the transfer into the pentoxime ester also entails a reduction of the solubility. This probably is also the reason for the bioavailability of pentamidine not to reach one hundred percent after oral application of the pentoxime ester [Clement, B.; Bürenheide, A.; Rieckert, W.; Schwarz, J., ChemMedChem 2006, 1, 1260-7].
  • the reduced water solubility induces the disadvantage that an administration of the medicinal substance is no longer possible by injecting aqueous solutions. This is a problem, particularly when an oral administration is out of question.
  • the present invention relates to a method comprising using a partial structure forming formula (I) or formula (II),
  • n 0, . . . , 12 and R1 is selected from the group consisting of hydrogen, an alkyl radical and aryl radical.
  • a method according to an embodiment of the present invention comprises using an amidoxime carboxylic acid ester of the formula (I) or an N-hydroxyguanidine carboxylic acid ester of the formula (II),
  • Another general aspect of the present invention relates to a prodrug comprising a partial structure having the formula (I) or (II),
  • n 0, . . . , 12, and R 1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical, the prodrug is a prodrug for a medicinal substance, the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
  • the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor.
  • the DNA-intercalating compound or RNA-intercalating compound is pentamidine, diminazene or isometamidium.
  • the inhibitor of viral enzymes is a neuraminidase inhibitor.
  • the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2 nd phase of trypanosomiasis, or pneumonia caused by pneumocystis carinii , for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, and for combating viral infections including influenza and HIV infections.
  • FIG. 1 is a graphic representation of the plasma levels of benzamidine in rats after the oral application of O-succinyl benzamidoxime;
  • FIG. 2 is a flow chart depicting the metabolism of the diminazene succinyl acid ester
  • FIG. 3 is a flow chart depicting the metabolism of the pentamidine succinyl acid ester.
  • amidoxime carboxylic acid esters (I) and the N-hydroxyguanidine carboxylic acid esters (II) of the following formulas are proposed to be used:
  • R 1 represents hydrogen, an alkyl or aryl radical, or the salts thereof as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of a medicinal substance in drugs for improving the solubility, bioavailability and enabling the medicinal substance to pass the blood-brain barrier.
  • n is selected to be greater than 12, an improvement of the solubility, bioavailability and capacity of the medicinal drug to pass the blood-brain barrier is no longer given.
  • N-hydroxyamidines (amidoximes) and N-hydroxyguanidines are successful prodrug principles for increasing the oral bioavailability of amidines (DE 10 2006 034 256.9).
  • esterification of the amidoximes or N-hydroxyguanidines with dicarboxylic acids and esters of the dicarboxylic acids which is proposed according to the invention, considerably improves the solubility, in particular the solubility in aqueous media, and the bioavailability as compared to known prodrugs.
  • the particular advantage of the compounds according to the invention is that they are present in the blood in a deprotonated form and so act as a substrate for the organic anion transporter (OAT), and thus exhibit a distinctly improved absorption from the gastrointestinal tract and therefore increased bioavailability.
  • OAT organic anion transporter
  • Such organic anion transporters can consequently be enabled to pass the blood-brain barrier. This would be a decisive progress in the therapy of the African sleeping sickness, since the 2 nd phase of the disease can thus also be treated effectively.
  • this esterification is to enable the blood-brain barrier to be passed.
  • the compound will be present in the blood in a deprotonated form so that it could constitute a substrate for the organic anion transporter (OAT) at the blood-brain barrier.
  • OAT organic anion transporter
  • Injectable dosage forms are also possible thanks to the introducing of carboxylic acids, since, just as in the case of amidines, the water solubility is restored. This applies in particular for the case, where R 1 is hydrogen.
  • the substituting of at least one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxy guanidine functions by the amidoxime dicarboxylic acid ester and N-hydroxyguanidine dicarboxylic acid ester achieves for the solubility of the medicinal substance concerned to be increased.
  • it can be firstly resorbed effectively after oral administration, and subsequently be reconverted again into the actual active form, the amidine, respectively, guanidine, by the body's own esterases and N-reductases (prodrug principle).
  • the excellent resorbability of the modified amidoxime function or N-hydroxyguanidine function in the gastrointestinal tract is obviously due to the increased solubility of the active agent molecules. Furthermore, the novel prodrug principles are capable of enabling the blood-brain barrier to be overcome.
  • the active agent it is sufficient for the active agent to contain at least one or more active amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions in the proposed form.
  • the active agent consequently may contain, e.g., a plurality of amidoxime functions (e.g. two as in the case of pentoxime ester) or N-hydroxyguanidine functions, with at least one of these groups being then modified in the manner described above.
  • Mixtures of active agents may be used just the same, provided that at least one active agent has one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions.
  • the oral dosage form may be a liquid, semisolid or solid preparation, packaged in particular as a tablet, dragee, pellet or microcapsule.
  • the active agent or active agent mixture for embodiments of the type in which liquid preparations are used is incorporated in a suitable non-toxic solvent such as water, monovalent alcohols, in particular ethanols, polyvalent alcohols, in particular glycerine and/or propanediol, polyglycols, in particular polyethylene glycols and/or miglyol, glycerol formal, dimethyl isosorbite, natural or synthetic oils.
  • the usual base materials are used such as bentonite, veegum, guar flour and/or cellulose derivatives, in particular methylcellulose and/or carboxymethyl cellulose, as well as polymers of vinyl alcohols and/or vinylpyrrolidones, alginates, pectins, polyacrylates, solid and/or liquid polyethylene glycols, paraffins, fatty alcohols, vaselines and/or waxes, fatty acids and/or fatty acid esters.
  • bentonite veegum
  • guar flour and/or cellulose derivatives in particular methylcellulose and/or carboxymethyl cellulose
  • polymers of vinyl alcohols and/or vinylpyrrolidones alginates, pectins, polyacrylates
  • solid and/or liquid polyethylene glycols paraffins
  • fatty alcohols fatty alcohols
  • vaselines and/or waxes fatty acids and/or fatty acid esters.
  • the extenders known per se such as colloidal silicic acid, talc, lactose, starch powder, sugar, gelatine, metal oxides and/or metal salts may be contained.
  • Stabilizers, emulsifiers, deflocculants and preservatives are suitable as further additives.
  • the medicinal substances modified according to the use according to the invention exhibit an excellent resorbability and thus bioavailability in oral administration, whereby the pharmacological effect of the amidine or guanidine is distinctly increased.
  • an optimum dosage form for the oral application of amidines may be provided.
  • amidine and guanidine are essential constituents of various important active agents for different fields of application.
  • they are a constituent of the following substance classes, respectively active agents: protease inhibitors (thrombin inhibitors such as melagatran, inhibitors of factor Xa, Factor VII, respectively of all of the proteases of the coagulation cascade; matriptase inhibitors), anticoagulants, thrombolytics, antifibrinolytics, DNA-intercalating and RNA-intercalating compounds (such as pentamidine, diminazene, isometamidium), N-methyl-D-aspartate receptor antagonists and inhibitors of viral enzymes (such as, e.g., neuraminidase inhibitors).
  • protease inhibitors thrombin inhibitors such as melagatran, inhibitors of factor Xa, Factor VII, respectively of all of the proteases of the coagulation cascade; matriptase inhibitors
  • anticoagulants such as melaga
  • Active agents containing an effective amidine function or guanidine function may be used inter alia for inhibiting blood coagulation, for the prophylaxis and therapy of visceral and cutaneous leishmaniasis, trypanosomiasis (African sleeping sickness), pneumonia caused by pneumocystis carinii (PCP), for inhibiting the growth of malign tumors, blood pressure reduction, neuroprotection, and for combating viral infections such as influenza and HIV infections.
  • PCP pneumocystis carinii
  • the invention basically encompasses any active agents, which have at least one amidine function or guanidine function that has been transferred into an improved prodrug according to the invention.
  • the method according to the invention is thus applicable to a very wide range of substance classes and indications and is capable of distinctly increasing the bioavailability of many medicinal substances, the active form of which contains an amidine or a guanidine.
  • O-succinyl benzamidoxime pentamidine succinic acid ester and diminazene succinic acid ester can be mentioned.
  • V 3648, 3480, 3062, 2912, 1744, 1704, 1614, 1368 cm ⁇ 1 .
  • the O-succinyl benzamidoxime is selected as model compounds for the new prodrug principles and orally administered in each case to three rats.
  • the metabolization of the ester into benzamidine in this case takes place in vivo as follows:
  • the anaesthesia was carried out using xylazine and ketamine. Both were administered by intramuscular injection.
  • the silicone catheters were implanted in the vena jugularis and the arteria carotis. They have locally antithrombotic and anti-inflammatory properties, but are not systemically active.
  • the eyes were protected with a cornea-protective ointment (Oculotect®), and 3-4 ml of Ringer lactate solution was applied subcutaneously for improving the postoperative energy supply.
  • the animals were treated antiphlogistically (Finadyne®, 1 mg/kg of body weight) and antibiotically (Amoxicillin® 15%, 10 mg/kg of body weight) and postoperatively attended and kept warm until they woke up.
  • the day after the surgery the animals got Nutri Plus®, an energy paste (soy bean oil, molasses, cod-liver oil, meat extract, mineral premixture, vitamin premixture).
  • the animals were weighed the evening before the substance application.
  • the substances (prodrugs) to be administered orally were applied via a stomach tube.
  • O-succinyl benzamidoxime was solved in 100 mM phosphate buffer, pH 8.5.
  • the intravenously administered benzamidine was solved in 0.9% NaCl solution, so as to prevent haemolysis.
  • rerinsing with at least 0.5 ml of 0.9% NaCl solution was carried out. The substance application in each case took place in the morning.
  • the prodrugs were administered to three rats. Benzamidine was applied intravenously to two rats. The orally administered doses of O-succinyl benzamidoxime were 50 mg/kg of body weight. Benzamidine was applied in a concentration of 10 mg/kg of body weight.
  • the test period for one condition is one day.
  • the blood samples were obtained over a period of eight hours after oral application, respectively six hours after intravenous application. After the oral administration, the sampling took place after 30, 60, 90, 120, 240 and 480 minutes, after intravenous application after 5, 10, 20, 40, 80 and 360 minutes.
  • the catheter Prior to the blood withdrawal, the catheter was emptied by a short aspiration until blood appeared.
  • the blood withdrawal 300 ⁇ l was carried out by means of Multivetten (Multivetten® 600, Sahrstedt, Nümbrecht). For keeping the catheter clear, about 0.3 ml of a mixture of heparin and NaCl were subsequently injected.
  • the obtained full blood was centrifuged (1500 g, 10 min, 4° C.). After the centrifugation, about 150 ⁇ l plasma was taken as a supernatant, pipetted into Eppendorf cups and frozen at ⁇ 80° C.
  • HPLC pump Waters 600 Detector: Waters 2417 Tunable Absorbance Detector Autosampler: Waters 717 plus Autosampler Integrator: EZChrom TM Elite Client/Server Version 2.8.3 Build 2249 recording and evaluation software stationary phase: Synergy Max-RP 80A; 250 * 4.6 mm with precolumn C 18 4.0 * 3.0 mm (Phenomenex, Aillesburg) Column temperature: 24° C. constant, by means of column heater Mobile phase: 10 mM of octyl sulfonate in Aqua bidest., pH 2.5 (with conc.
  • the eluant was filtered using a Satorius membrane filter (0.45 ⁇ m) and degassed in an ultrasonic bath for 15 minutes.
  • HPLC pump Waters 600 Detector: Waters 2417 Tunable Absorbance Detector Autosampler: Waters 717 plus Autosampler Integrator: EZChrom TM Elite Client/Server Version 2.8.3 Build 2249 recording and evaluation software stationary phase: Synergy Max-RP 80A; 250 * 4.6 mm with precolumn C 18 4.0 * 3.0 mm (Phenomenex, Aillesburg) Mobile phase: 100 mM phosphate buffer in Aqua bidest., pH 7.0 (with 30% KOH)/acetonitrile (92.8, V/V) Run time: 25 minutes Detection: 229 nm Flow rate: 1.0 ml/min Injection volume: 10 ⁇ l Detector sensitivity: absorbance units fullscale: 2,000 Retention times: benzamidine: 5.3 ⁇ 0.3 min O-succinyl benzamidoxime: 11.7 ⁇ 0.3 min benzamidoxime: 15.2 ⁇ 0.3 min
  • the eluant was filtered using a Sartorius membrane filter (0.45 ⁇ m) and degassed in an ultrasonic bath for 15 minutes.
  • benzamidine has a bioavailability of 32% after the oral administration of the O-succinyl benzamidoxime. This demonstrates that the prodrug was completely resorbed after oral administration and reduced to the active form.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Emergency Medicine (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • AIDS & HIV (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a method for improving the bioavailability of pharmaceutical substances and for allowing the pharmaceutical substances to permeate the blood-brain barrier, the pharmaceutical substances having at least one or more amidine, guanidine, N-hydroxyamidine (amidoxime) or N-hydroxyguanidine functions. The invention also relates to medicaments containing the correspondingly modified pharmaceutical substances.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a Continuation of International Application No. PCT/EP2009/051132, filed Feb. 2, 2009, which was published in the German language on Aug. 6, 2009, under International Publication No. WO 2009 095499 A1 and the disclosure of which is incorporated herein by reference.
    • FIELD OF THE INVENTION
  • The present invention relates to use of an amidoxime carboxylic acid ester in a method for improving the bioavailability and enabling the blood-brain barrier crossing of medicinal substances, which have at least one or more amidine functions, guanidine functions, N-hydroxyamidine (amidoxime) functions or N-hydroxyguanidine functions, and drugs containing correspondingly modified medicinal substances.
    • BACKGROUND OF THE INVENTION
  • N-hydroxyamidines (amidoximes) and N-hydroxyguanidines represent known prodrug principles for increasing the oral bioavailability of amidines [Clement, B. Methoden zur Behandlung und Prophylaxe der Pneumocystis carinii Pneumonie (PCP) und anderen Erkrankungen sowie Verbindungen und Formulierungen zum Gebrauch bei besagten Methoden, P 432-444.4, 1993] and guanidines.
  • Pharmaceutical preparations containing an active agent having one or more amidine or guanidine functions exhibit almost no pharmacological effect in oral application. The precondition for a therapeutical effect of an active agent after oral administration is represented by its resorption from the gastrointestinal tract. The most important mechanism of such an effect is passive diffusion. The degree of resorption by way of passive diffusion is dependent on the lipophilicity and thus also the acidity and basicity of the active agent.
  • Highly basic compounds such as amidines and guanidines are present in the stomach (pH 1) and small intestine (pH 6.4) in an almost completely protonated form. A resorption after oral administration, which requires the passing of lipid bilayers of the membranes of the gastrointestinal tract, therefore only occurs to a very low degree.
  • Another problem in the medication of many diseases is the necessity to cross the blood-brain barrier. The blood-brain barrier is an effective barrier with regard to the resorption of substances into the brain. It ensures the selective uptake and prevents the penetration of substances. Furthermore, the blood-brain barrier does no only act as a physical but also as an enzymatic barrier. Various processes are involved in the penetration of substances into the brain. As compared to other indications, only few drugs are marketed, which develop their effect in the central nervous system (CNS). The greater part thereof reaches the CNS by diffusion. Diseases like epilepsy, chronic pain or depressions are treated this way. Other serious functional disorders such as brain tumors or amyotrophic lateral sclerosis yet cannot be treated in this way today [PARDRIDGE, W. M. NeuroRx 2005, 2, 3-14]. For being able to cross the blood-brain barrier by way of passive diffusion, a substance is required to be lipophilic, have a lower molecular weight than 400-500 Da, and be present in an uncharged state. For resorbing specifically small molecules such as glucose or amino acids, various transporter systems such as nucleoside transporters, influx and efflux transporters for organic anions, glucose transporters, peptide transporters, and amino acid transporters are expressed on the blood-brain barrier [TAMAI, I.; TSUJI, A. J. Pharm Sci 2000, 89, 1371-1388 and DE BOER, A.; VAN DER SANDT, I. Annu Rev Pharmacol Toxicol 2003, 43, 629-656]. Larger molecules such as insulin or iron-containing transferrin are resorbed via the receptor-mediated transport. In this case, the insulin and transferrin receptors particularly play an important role [DE BOER, A.; VAN DER SANDT, I. Annu Rev Phamacol Toxicol 2003, 43, 629-656; PARDRIDGE, W. M. Mol Interv 2003, 3, 90-105]. Taking the amino acid L-dopa as an example, one has used a prodrug principle for the water-soluble catecholamine dopamine to be capable of passing the blood-brain barrier. The transport is performed by the amino acid transporter LAT1 (large neutral amino acid transporter). After the passage, the decarboxylation into dopamine takes place [PARDRIDGE, W. M. Mol Interv 2003, 3, 90-105].
  • Diamidines are used as antiparasitic agents against malaria, pneumocystis jiroveci (previously carinii) pneumonia, trypanosomiasis (African sleeping sickness), and leishmaniasis [WERBOVETZ, K. Curr Opin Investig Drugs 2006, 7, 147-157]. Particularly in developing countries, these diseases represent a serious problem involving high mortality rates.
  • Three diamidines to be applied parenterally are on the market. Pentamidine (Pentacarinat®) has been used in the early stage of the African sleeping sickness already for 60 years. Efficiency is no longer provided in the 2nd stage of the African sleeping sickness, the meningo-encephalitic stage, since the blood-brain barrier cannot be passed successfully. As a result, highly toxic arsenic compounds must be administered. There is a lack of medicinal substances which are efficient in the 2nd stage of the African sleeping sickness.
  • It is likely that all of the active agents, which have an amidine or a guanidine as a functional group, exhibit an insufficient resorption in the oral application, if they can only be resorbed by passive diffusion.
  • Medicinal substances containing carboxylic acids are very widely used and can also be applied as oral dosage forms. In particular, analgesics from the group of acetic acid, propionic acid and salicylic acid derivatives must be mentioned here.
  • The N-hydroxylated derivatives such as amidoximes, and the N-hydroxyguanidines, due to the introduction of the oxygen atom, exhibit a lower basicity. Under physiological conditions, they are not present in a protonated form. Benzamidoxime represents a model compound for many medicinal substances containing an amidoxime function [Clement, B., Drug Met Rev 2002, 34, 565-579].
  • Pentamidine and diminazene represent diamidines and are not resorbed after oral application. They were therefore transferred into amidoxime prodrugs. (DE 10 2006 034 256.9).
  • The example pentamidine demonstrates that the transfer into the pentoxime ester also entails a reduction of the solubility. This probably is also the reason for the bioavailability of pentamidine not to reach one hundred percent after oral application of the pentoxime ester [Clement, B.; Bürenheide, A.; Rieckert, W.; Schwarz, J., ChemMedChem 2006, 1, 1260-7].
  • Furthermore, the reduced water solubility induces the disadvantage that an administration of the medicinal substance is no longer possible by injecting aqueous solutions. This is a problem, particularly when an oral administration is out of question.
  • It is therefore the task of the present invention to increase the water solubility and thus also the oral bioavailability of substances, which had been transferred into amidoxime prodrugs or N-hydroxyguanidine prodrugs, and/or thus to enable the passing of the blood-brain barrier.
  • The task is solved by methods according to embodiments of the invention, such as those methods having the features of the independent claim, and those methods having the additional features of the dependent claims, which indicate advantageous arrangements of the invention.
    • BRIEF SUMMARY OF THE INVENTION
  • In one general aspect, the present invention relates to a method comprising using a partial structure forming formula (I) or formula (II),
  • Figure US20110028756A1-20110203-C00001
  • as a constituent of the overall structure of a prodrug for a medicinal substance, wherein n=0, . . . , 12 and R1 is selected from the group consisting of hydrogen, an alkyl radical and aryl radical.
  • A method according to an embodiment of the present invention comprises using an amidoxime carboxylic acid ester of the formula (I) or an N-hydroxyguanidine carboxylic acid ester of the formula (II),
  • Figure US20110028756A1-20110203-C00002
      • as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of a prodrug for a medicinal substance for improving the solubility, bioavailability and/or capacity of the medicinal substance to pass the blood-brain barrier, wherein n=0, . . . , 12, and R1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical and the salts thereof, the medicinal substance is selected from the group consisting of protease inhibitors, the DNA-intercalating and RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
  • Another general aspect of the present invention relates to a prodrug comprising a partial structure having the formula (I) or (II),
  • Figure US20110028756A1-20110203-C00003
  • wherein n=0, . . . , 12, and R1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical, the prodrug is a prodrug for a medicinal substance, the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
  • In an embodiment of the present invention, the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor.
  • In another embodiment of the present invention, the DNA-intercalating compound or RNA-intercalating compound is pentamidine, diminazene or isometamidium.
  • In yet another embodiment of the present invention, the inhibitor of viral enzymes is a neuraminidase inhibitor.
  • According to an embodiment of the present invention, the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2nd phase of trypanosomiasis, or pneumonia caused by pneumocystis carinii, for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, and for combating viral infections including influenza and HIV infections.
  • Other aspects, features and advantages of the invention will be apparent from the following disclosure, including the detailed description of the invention and its preferred embodiments and the appended claims.
    • BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
  • The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.
  • In the drawings:
  • FIG. 1 is a graphic representation of the plasma levels of benzamidine in rats after the oral application of O-succinyl benzamidoxime;
  • FIG. 2 is a flow chart depicting the metabolism of the diminazene succinyl acid ester; and
  • FIG. 3 is a flow chart depicting the metabolism of the pentamidine succinyl acid ester.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.
  • According to embodiments of the invention, amidoxime carboxylic acid esters (I) and the N-hydroxyguanidine carboxylic acid esters (II) of the following formulas are proposed to be used:
  • Figure US20110028756A1-20110203-C00004
  • wherein n=0-12, and R1 represents hydrogen, an alkyl or aryl radical, or the salts thereof as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of a medicinal substance in drugs for improving the solubility, bioavailability and enabling the medicinal substance to pass the blood-brain barrier.
  • If n is selected to be greater than 12, an improvement of the solubility, bioavailability and capacity of the medicinal drug to pass the blood-brain barrier is no longer given.
  • N-hydroxyamidines (amidoximes) and N-hydroxyguanidines are successful prodrug principles for increasing the oral bioavailability of amidines (DE 10 2006 034 256.9).
  • The esterification of the amidoximes or N-hydroxyguanidines with dicarboxylic acids and esters of the dicarboxylic acids which is proposed according to the invention, considerably improves the solubility, in particular the solubility in aqueous media, and the bioavailability as compared to known prodrugs.
  • The esterification of the amidoximes or N-hydroxyguanidines with dicarboxylic acids/dicarboxylic acid esters, due to the introduced negative charge of the deprotonated acid function, represents a pole reversal as compared to benzamidine, an increased bioavailability and solubility in aqueous media is thus induced.
  • The particular advantage of the compounds according to the invention is that they are present in the blood in a deprotonated form and so act as a substrate for the organic anion transporter (OAT), and thus exhibit a distinctly improved absorption from the gastrointestinal tract and therefore increased bioavailability. Such organic anion transporters can consequently be enabled to pass the blood-brain barrier. This would be a decisive progress in the therapy of the African sleeping sickness, since the 2nd phase of the disease can thus also be treated effectively.
  • Furthermore, this esterification is to enable the blood-brain barrier to be passed. The compound will be present in the blood in a deprotonated form so that it could constitute a substrate for the organic anion transporter (OAT) at the blood-brain barrier.
  • Injectable dosage forms are also possible thanks to the introducing of carboxylic acids, since, just as in the case of amidines, the water solubility is restored. This applies in particular for the case, where R1 is hydrogen.
  • According to the use according to the invention, the substituting of at least one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxy guanidine functions by the amidoxime dicarboxylic acid ester and N-hydroxyguanidine dicarboxylic acid ester achieves for the solubility of the medicinal substance concerned to be increased. As a result, it can be firstly resorbed effectively after oral administration, and subsequently be reconverted again into the actual active form, the amidine, respectively, guanidine, by the body's own esterases and N-reductases (prodrug principle). The excellent resorbability of the modified amidoxime function or N-hydroxyguanidine function in the gastrointestinal tract is obviously due to the increased solubility of the active agent molecules. Furthermore, the novel prodrug principles are capable of enabling the blood-brain barrier to be overcome.
  • It is sufficient for the active agent to contain at least one or more active amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions in the proposed form. The active agent consequently may contain, e.g., a plurality of amidoxime functions (e.g. two as in the case of pentoxime ester) or N-hydroxyguanidine functions, with at least one of these groups being then modified in the manner described above. Mixtures of active agents may be used just the same, provided that at least one active agent has one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions. The oral dosage form may be a liquid, semisolid or solid preparation, packaged in particular as a tablet, dragee, pellet or microcapsule. In this case, the active agent or active agent mixture for embodiments of the type in which liquid preparations are used, is incorporated in a suitable non-toxic solvent such as water, monovalent alcohols, in particular ethanols, polyvalent alcohols, in particular glycerine and/or propanediol, polyglycols, in particular polyethylene glycols and/or miglyol, glycerol formal, dimethyl isosorbite, natural or synthetic oils. For producing semisolid or solid preparations, the usual base materials are used such as bentonite, veegum, guar flour and/or cellulose derivatives, in particular methylcellulose and/or carboxymethyl cellulose, as well as polymers of vinyl alcohols and/or vinylpyrrolidones, alginates, pectins, polyacrylates, solid and/or liquid polyethylene glycols, paraffins, fatty alcohols, vaselines and/or waxes, fatty acids and/or fatty acid esters.
  • Moreover, in solid preparations, the extenders known per se, such as colloidal silicic acid, talc, lactose, starch powder, sugar, gelatine, metal oxides and/or metal salts may be contained. Stabilizers, emulsifiers, deflocculants and preservatives are suitable as further additives.
  • The medicinal substances modified according to the use according to the invention exhibit an excellent resorbability and thus bioavailability in oral administration, whereby the pharmacological effect of the amidine or guanidine is distinctly increased. As a result, an optimum dosage form for the oral application of amidines may be provided.
  • The use according to the invention gains particular importance in that the functional groups amidine and guanidine are essential constituents of various important active agents for different fields of application. Inter alia, they are a constituent of the following substance classes, respectively active agents: protease inhibitors (thrombin inhibitors such as melagatran, inhibitors of factor Xa, Factor VII, respectively of all of the proteases of the coagulation cascade; matriptase inhibitors), anticoagulants, thrombolytics, antifibrinolytics, DNA-intercalating and RNA-intercalating compounds (such as pentamidine, diminazene, isometamidium), N-methyl-D-aspartate receptor antagonists and inhibitors of viral enzymes (such as, e.g., neuraminidase inhibitors).
  • Active agents containing an effective amidine function or guanidine function may be used inter alia for inhibiting blood coagulation, for the prophylaxis and therapy of visceral and cutaneous leishmaniasis, trypanosomiasis (African sleeping sickness), pneumonia caused by pneumocystis carinii (PCP), for inhibiting the growth of malign tumors, blood pressure reduction, neuroprotection, and for combating viral infections such as influenza and HIV infections.
  • The listings above are merely exemplary, and the invention basically encompasses any active agents, which have at least one amidine function or guanidine function that has been transferred into an improved prodrug according to the invention. The method according to the invention is thus applicable to a very wide range of substance classes and indications and is capable of distinctly increasing the bioavailability of many medicinal substances, the active form of which contains an amidine or a guanidine.
  • As examples for compounds modified according to the method according to the invention, O-succinyl benzamidoxime, pentamidine succinic acid ester and diminazene succinic acid ester can be mentioned.
  • The preparation and use according to the invention is explained in more detail by means of exemplary embodiments, which are in no way intended to limit the scope of the present invention.
    • Exemplary Embodiments Material and Methods O-succinyl benzamidoxime
  • Figure US20110028756A1-20110203-C00005
  • 1.0 g of benzamidoxime was dissolved in 40 ml of anhydrous acetone. After adding 1.64 g of succinic acid anhydride, the mixture was stirred for four hours under reflux. The completeness of the reaction was checked by means of DC. After the end of the reaction, the solvent was withdrawn completely and the raw product recrystallized from toluene.
  • Yield: 82%
  • Melting point: 151° C.
  • IR (KBr):
  • V=3648, 3480, 3062, 2912, 1744, 1704, 1614, 1368 cm−1.
  • 1H-NMR (300 MHz, DMSO-d6):
  • δ/ppm (TMS)=2.55 (t, 2H, 3J=6.9 Hz, CH2), 2.69 (t, 2H, 3J=6.9 Hz, CH2), 6.75 (s, 2H, NH2), 7.44 (m, 3H, Ar—H), 7.70 (m, 2H, Ar—H), 12.20 (s, 1H, COOH).
  • 13C-NMR (75 MHz, DMSO-d6):
  • δ/ppm (TMS)=27.86 (CH2), 28.72 (CH2), 126.66 (CAr 2.6), 128.26 (CAr 3.5), 130.36 (CAr 1), 131.59 (CAr 4), 156.56 (C—NH2), 170.19 (C═O), 173.50 (COOH).
  • MS (ESI):
  • m/z (%)=495 [2M+Na+H+] (100), 259 [M+Na+H+] (20), 237 [M+H+](43), 137 [BAO+H+](35), 121 [BA+H+] (13), 119 [C4H6O4+H+] (70).
  • C11H12N2O4 (236.23):
  • Ber.C, 55.93% H, 5.12% N, 11.86%
  • Gef.C, 55.88% H, 5.19% N, 11.55%
  • For proving the resorption from the gastrointestinal tract and the subsequent reduction to benzamidine, the O-succinyl benzamidoxime is selected as model compounds for the new prodrug principles and orally administered in each case to three rats. The metabolization of the ester into benzamidine in this case takes place in vivo as follows:
  • Figure US20110028756A1-20110203-C00006
  • The metabolism of the diminazene succinic acid ester and pentamidine succinic acid ester is shown in the flowcharts in the attached FIGS. 2-3.
  • Methods Related to the Execution of the Study with Rats
  • The animal study was permitted by the Schleswig-Holstein Ministry of Agriculture, Environment and Rural Spaces on Jul. 4, 2007.
  • The anaesthesia was carried out using xylazine and ketamine. Both were administered by intramuscular injection. The silicone catheters were implanted in the vena jugularis and the arteria carotis. They have locally antithrombotic and anti-inflammatory properties, but are not systemically active. During the surgery, the eyes were protected with a cornea-protective ointment (Oculotect®), and 3-4 ml of Ringer lactate solution was applied subcutaneously for improving the postoperative energy supply. The animals were treated antiphlogistically (Finadyne®, 1 mg/kg of body weight) and antibiotically (Amoxicillin® 15%, 10 mg/kg of body weight) and postoperatively attended and kept warm until they woke up. The day after the surgery, the animals got Nutri Plus®, an energy paste (soy bean oil, molasses, cod-liver oil, meat extract, mineral premixture, vitamin premixture).
  • After the test was completed, the animals were euthanized using pentobarbital (i.v.).
  • Keeping of the Rats
  • Male Wistar rats having an average weight of 200 g served as the test animals. The animals were kept individually in cages. Every second day they got concentrated food. Water and dry food was available ad libitum.
  • Application of the Substances
  • For being able to determine the accurate dosage of the substances, the animals were weighed the evening before the substance application. The substances (prodrugs) to be administered orally were applied via a stomach tube. For this purpose, O-succinyl benzamidoxime was solved in 100 mM phosphate buffer, pH 8.5. The intravenously administered benzamidine was solved in 0.9% NaCl solution, so as to prevent haemolysis. After the injection, rerinsing with at least 0.5 ml of 0.9% NaCl solution was carried out. The substance application in each case took place in the morning.
  • The prodrugs were administered to three rats. Benzamidine was applied intravenously to two rats. The orally administered doses of O-succinyl benzamidoxime were 50 mg/kg of body weight. Benzamidine was applied in a concentration of 10 mg/kg of body weight.
  • Blood Sampling
  • Six blood samples can be taken from one rat. The test period for one condition is one day. The blood samples were obtained over a period of eight hours after oral application, respectively six hours after intravenous application. After the oral administration, the sampling took place after 30, 60, 90, 120, 240 and 480 minutes, after intravenous application after 5, 10, 20, 40, 80 and 360 minutes. Prior to the blood withdrawal, the catheter was emptied by a short aspiration until blood appeared. The blood withdrawal (300 μl) was carried out by means of Multivetten (Multivetten® 600, Sahrstedt, Nümbrecht). For keeping the catheter clear, about 0.3 ml of a mixture of heparin and NaCl were subsequently injected. The obtained full blood was centrifuged (1500 g, 10 min, 4° C.). After the centrifugation, about 150 μl plasma was taken as a supernatant, pipetted into Eppendorf cups and frozen at −80° C.
  • Reprocessing of the Blood Samples
  • After slowly defrosting, 150 μl of plasma was diluted with Aqua bidest. ad 600 μl. The plasma samples were subsequently reprocessed by means of solid phase extraction. After conditioning the column with 1000 μl of methanol and equilibrating with 1000 μl of Aqua bidest., the sample application (600 μl) was carried out. The sorbent was washed after the sample application with 600 μl of Aqua bidest. The elution of the substances was carried out by means of Aqua bidest., pH 3/methanol (6/4, V/V). Thereupon, the eluate is concentrated to dryness and absorbed with 100 μl of Aqua bidest./methanol (9/1, V/V) and transferred to the HPLC.
  • HPLC Analysis for Separating Benzamidoxime and Benzamidine
  • For separating the substances to be analyzed, the following HPLC method was used:
  •
    HPLC pump: Waters 600
    Detector: Waters 2417 Tunable Absorbance Detector
    Autosampler: Waters 717 plus Autosampler
    Integrator: EZChrom ™ Elite Client/Server Version 2.8.3
    Build 2249 recording and evaluation software
    stationary phase: Synergy Max-RP 80A; 250 * 4.6 mm with
    precolumn C 18 4.0 * 3.0 mm (Phenomenex,
    Aschaffenburg)
    Column temperature: 24° C. constant, by means of column heater
    Mobile phase: 10 mM of octyl sulfonate in Aqua bidest., pH 2.5
    (with conc. H3PO4)/acetonitrile (82.5/17.5, V/V)
    Run time: 30 minutes
    Detection: UV detector, 229 nm
    Flow rate: 1.0 ml/min
    Injection volume: 10 μl
    Detector sensitivity: absorbance units fullscale: 2,000
    Retention times: benzamidoxime: 23.5 ± 0.5 min
    benzamidine: 26.5 ± 0.5 min
  • The eluant was filtered using a Satorius membrane filter (0.45 μm) and degassed in an ultrasonic bath for 15 minutes.
  • HPLC Analysis for Analyzing the O-Succinyl Benzamidoxime, Benzamidoxime and Benzamidine
  • For separating the substances to be analyzed, the following HPLC method was used:
  •
    HPLC pump: Waters 600
    Detector: Waters 2417 Tunable Absorbance Detector
    Autosampler: Waters 717 plus Autosampler
    Integrator: EZChrom ™ Elite Client/Server Version 2.8.3
    Build 2249 recording and evaluation software
    stationary phase: Synergy Max-RP 80A; 250 * 4.6 mm with
    precolumn C 18 4.0 * 3.0 mm (Phenomenex,
    Aschaffenburg)
    Mobile phase: 100 mM phosphate buffer in Aqua bidest.,
    pH 7.0 (with 30% KOH)/acetonitrile (92.8, V/V)
    Run time: 25 minutes
    Detection: 229 nm
    Flow rate: 1.0 ml/min
    Injection volume: 10 μl
    Detector sensitivity: absorbance units fullscale: 2,000
    Retention times: benzamidine: 5.3 ± 0.3 min
    O-succinyl benzamidoxime: 11.7 ± 0.3 min
    benzamidoxime: 15.2 ± 0.3 min
  • The eluant was filtered using a Sartorius membrane filter (0.45 μm) and degassed in an ultrasonic bath for 15 minutes.
  • The oral bioavailability of the benzamidine after oral administration of the O-succinyl benzamidoxime could be determined from the obtained data (Table. 1):
  • TABLE 1
    Bioavailability of the benzamidine after oral administration of
    O-succinyl benzamidoxime
    bioavailability mean value standard deviation
    [%] [%] [%]
    Rat 4 19.9 31.6 10.2
    Rat 10 36.1
    Rat 21 38.7
  • As can be seen from the Table above, benzamidine has a bioavailability of 32% after the oral administration of the O-succinyl benzamidoxime. This demonstrates that the prodrug was completely resorbed after oral administration and reduced to the active form.
  • Particular embodiments of the invention are:
      • 1. Use of an amidoxime carboxylic acid ester of the formula (I) or an N-hydroxyguanidine carboxylic acid ester of the formula (II)
  • Figure US20110028756A1-20110203-C00007
        • wherein n=0, . . . , 12, and R1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical and the salts thereof, as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of a medicinal substance in drugs for improving the solubility, bioavailability and/or capacity of the medicinal substance to pass the blood-brain barrier.
      • 2. Use according to embodiment 1,
        • characterized in that the medicinal substance is selected from the group of protease inhibitors, DNA-intercalating and RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
      • 3. Use according to embodiment 2,
        • characterized in that the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII, or of all of the proteases of the coagulation cascade or a matriptase inhibitor.
      • 4. Use according to embodiment 2,
        • characterized in that the protease inhibitor is an urokinase inhibitor.
      • 5. Use according to embodiment 2,
        • characterized in that the DNA-intercalating or RNA-intercalating compound is pentamidine, diminazene or isometamidium.
      • 6. Use according to embodiment 2,
        • characterized in that the inhibitor of viral enzymes is a neuraminidase inhibitor.
      • 7. Use according to any one of the preceding embodiments,
        • characterized in that the medicinal substance is designed for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2nd phase of trypanosomiasis, or pneumonia caused by pneumocystis carinii, for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, and for combating viral infections including influenza and HIV infections.
  • It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims.

Claims (16)

1. A method comprising using a partial structure forming formula (I) or formula (II),
Figure US20110028756A1-20110203-C00008
as a constituent of the overall structure of a prodrug that is a prodrug for a medicinal substance, wherein n=0, . . . , 12 and R1 is selected from the group consisting of hydrogen, an alkyl radical and aryl radical.
2. The method according to claim 1, wherein the partial structure of formula (I) or (II) is used as a substitute for one or more amidine functions, N-hydroxyamidine (amidoxime) functions, guanidine functions or N-hydroxyguanidine functions of the prodrug for improving the solubility, bioavailability and/or capacity of the medicinal substance to pass the blood-brain barrier.
3. The method according to claim 1, wherein the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
4. The method according to claim 3, wherein the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor.
5. The method according to claim 3, wherein the DNA-intercalating or RNA-intercalating compound is pentamidine, diminazene or isometamidium.
6. The method according to claim 3, wherein the inhibitor of viral enzymes is a neuraminidase inhibitor.
7. The method according to claim 1, wherein the overall structure of the prodrug comprises a plurality of at least one of the partial structures of formula (I) and formula (II).
8. The method according to claim 1, wherein the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2nd phase of trypanosomiasis, or pneumonia caused by pneumocystis carinii, for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, or for combating viral infections.
9. The method according to claim 1, wherein the prodrug is pentamidine succinic acid ester.
10. A prodrug comprising a partial structure having the formula (I) or (II),
Figure US20110028756A1-20110203-C00009
wherein n=0, . . . , 12, and R1 is selected from the group consisting of hydrogen, an alkyl radical and an aryl radical, the prodrug is a prodrug for a medicinal substance, and the medicinal substance is selected from the group consisting of protease inhibitors, DNA-intercalating compounds, RNA-intercalating compounds, inhibitors of viral enzymes and N-methyl-D-aspartate receptor antagonists.
11. The prodrug according to claim 10, wherein the protease inhibitor is a thrombin inhibitor, an inhibitor of factor Xa, Factor VII or all of the proteases of the coagulation cascade, or a matriptase inhibitor.
12. The prodrug according to claim 10, wherein the DNA-intercalating or RNA-intercalating compound is pentamidine, diminazene or isometamidium.
13. The prodrug according to claim 10, wherein the inhibitor of viral enzymes is a neuraminidase inhibitor.
14. The prodrug according to claim 10, wherein the medicinal substance is configured for the prophylaxis and therapy of visceral and/or cutaneous leishmaniasis, trypanosomiasis, the 2nd phase of trypanosomiasis, or pneumonia caused by pneumocystis carinii, for inhibiting the growth of malign tumors, for inhibiting blood coagulation, for blood pressure reduction, for neuroprotection, and for combating viral infections.
15. The prodrug according to claim 10, wherein the overall structure of the prodrug comprises a plurality of at least one of the partial structures of formula (I) and formula (II).
16. The prodrug according to claim 10, wherein the prodrug is pentamidine succinic acid ester.
US12/847,415 2008-02-01 2010-07-30 Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs Abandoned US20110028756A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US14/455,272 US9353047B2 (en) 2008-02-01 2014-08-08 Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters
US14/581,384 US9662308B2 (en) 2008-02-01 2014-12-23 Orally bioavailable pentamidine prodrugs for the treatment of diseases

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102008007381.4 2008-02-01
DE102008007381A DE102008007381A1 (en) 2008-02-01 2008-02-01 Amidines and guanidines and their derivatives for the treatment of diseases
PCT/EP2009/051132 WO2009095499A1 (en) 2008-02-01 2009-02-02 Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2009/051132 Continuation WO2009095499A1 (en) 2008-02-01 2009-02-02 Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs
US14/581,384 Continuation US9662308B2 (en) 2008-02-01 2014-12-23 Orally bioavailable pentamidine prodrugs for the treatment of diseases

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/455,272 Division US9353047B2 (en) 2008-02-01 2014-08-08 Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters

Publications (1)

Publication Number Publication Date
US20110028756A1 true US20110028756A1 (en) 2011-02-03

Family

ID=40532565

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/847,415 Abandoned US20110028756A1 (en) 2008-02-01 2010-07-30 Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs
US14/455,272 Active US9353047B2 (en) 2008-02-01 2014-08-08 Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters

Family Applications After (1)

Application Number Title Priority Date Filing Date
US14/455,272 Active US9353047B2 (en) 2008-02-01 2014-08-08 Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters

Country Status (20)

Country Link
US (2) US20110028756A1 (en)
EP (3) EP2249821B1 (en)
JP (2) JP2011510956A (en)
KR (1) KR20100110875A (en)
CN (1) CN101951897B (en)
AU (1) AU2009209560B2 (en)
BR (1) BRPI0906569A2 (en)
CA (1) CA2713784C (en)
CY (1) CY1116801T1 (en)
DE (1) DE102008007381A1 (en)
DK (1) DK2249821T3 (en)
ES (1) ES2547117T3 (en)
HR (1) HRP20150961T1 (en)
HU (1) HUE026276T2 (en)
IL (1) IL207286A0 (en)
PL (1) PL2249821T3 (en)
PT (1) PT2249821E (en)
SI (1) SI2249821T1 (en)
WO (1) WO2009095499A1 (en)
ZA (1) ZA201004767B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2550966A1 (en) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Amidoxime carboxylic acid esters of dabigatran as prodrugs and their use as medicaments
EP2550963A1 (en) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Amidoxime carboxylic acid esters of pentamidine as prodrugs and their use as medicament
ES2416004A1 (en) * 2012-01-24 2013-07-29 Investigaciones Farmaceuticas Y Veterinarias, S.L. Pharmaceutical composition comprising isometamidium chloride in solution for the treatment of trypanosomiasis in animals
US9353047B2 (en) 2008-02-01 2016-05-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters
US9662308B2 (en) 2008-02-01 2017-05-30 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Orally bioavailable pentamidine prodrugs for the treatment of diseases

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009004204A1 (en) * 2009-01-09 2010-07-15 Christian-Albrechts-Universität Zu Kiel Process for improved bioactivation of drugs
CN103420994B (en) * 2012-05-24 2016-04-06 天津药物研究院 As the dabigatran ester derivative and its production and use of prodrug
AU2013362755B2 (en) 2012-12-21 2018-09-13 Verlyx Pharma Inc. Uses and methods for the treatment of liver diseases or conditions
CN106831611B (en) * 2017-01-23 2019-06-21 北京化工大学 A kind of amidoxime compound and its application in the preparation of drug for inhibiting cancer cell proliferation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786383A (en) * 1993-06-28 1998-07-28 Clement; Bernd Pharmaceutical preparation
US20090136980A1 (en) * 2001-06-11 2009-05-28 Medarex, Inc. CD10-activated prodrug compounds
US7608623B2 (en) * 2003-05-26 2009-10-27 Wilex Ag Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors
US20090270440A1 (en) * 2006-07-21 2009-10-29 Drite Patentportfolio Beteilligungsgesellschaft Mbh & Co. Kg Bioavailability of active substances having an amidine function in medicaments

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001031586A (en) * 1999-07-14 2001-02-06 Sunstar Inc Composition for prophylaxis or therapy of both arteriosclerosis and disease caused thereby
AU7130101A (en) * 2000-06-14 2001-12-24 Corixa Corp Enzyme-cleavable prodrug compounds
JP2005509606A (en) * 2001-10-03 2005-04-14 ファルマシア・コーポレーション Prodrugs of substituted polycyclic compounds useful for selectively inhibiting the coagulation cascade
CN100567267C (en) 2004-06-30 2009-12-09 富山化学工业株式会社 Aromatic amidine derivatives, salts thereof, and antifungal agents containing them
DE102008007381A1 (en) 2008-02-01 2009-08-13 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co.Kg Amidines and guanidines and their derivatives for the treatment of diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5786383A (en) * 1993-06-28 1998-07-28 Clement; Bernd Pharmaceutical preparation
US20090136980A1 (en) * 2001-06-11 2009-05-28 Medarex, Inc. CD10-activated prodrug compounds
US7608623B2 (en) * 2003-05-26 2009-10-27 Wilex Ag Hydroxyamidine and hydroxyguanidine compounds as urokinase inhibitors
US20090270440A1 (en) * 2006-07-21 2009-10-29 Drite Patentportfolio Beteilligungsgesellschaft Mbh & Co. Kg Bioavailability of active substances having an amidine function in medicaments

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Banker, G.S. et al, "Modern Pharmaceutics, 3ed.", Marcel Dekker, New York, 1996, page 596 *
Donkor et al. (J. Med. Chem., 2003, 46, 1041) *
DrugBank pentamidine description (http://www.drugbank.ca/drugs/DB00738) *
Huang et al. (J. Pharmacy and Pharmacology, 2006, 58, 1033) *
Tao et al. (Bioorg. Med. Chem. Let., 1999, 9, 1299) *
Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I", John Wiley & Sons, 1995, pages 975-977 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9353047B2 (en) 2008-02-01 2016-05-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters
US9662308B2 (en) 2008-02-01 2017-05-30 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Orally bioavailable pentamidine prodrugs for the treatment of diseases
US20130030023A1 (en) * 2011-07-25 2013-01-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Orally bioavailable dabigatran prodrugs for the treatment of diseases
EP2550966A1 (en) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Amidoxime carboxylic acid esters of dabigatran as prodrugs and their use as medicaments
WO2013013946A1 (en) * 2011-07-25 2013-01-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Dabigatran-amidoxime acid esters as prodrugs and use thereof as pharmaceuticals
US20130085180A1 (en) * 2011-07-25 2013-04-04 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Oral bioavailable pentamidin prodrugs for treatment of diseases
CN103874491A (en) * 2011-07-25 2014-06-18 第三专利投资有限两合公司 Pentamidine amidoxime acid esters as prodrugs and use thereof as drugs
US8853245B2 (en) * 2011-07-25 2014-10-07 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Orally bioavailable dabigatran prodrugs for the treatment of diseases
WO2013014059A1 (en) * 2011-07-25 2013-01-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Pentamidine amidoxime acid esters as prodrugs and use thereof as drugs
AU2012289112B2 (en) * 2011-07-25 2017-01-05 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Dabigatran-amidoxime acid esters as prodrugs and use thereof as pharmaceuticals
AU2012288968B2 (en) * 2011-07-25 2017-01-05 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Pentamidine amidoxime acid esters as prodrugs and use thereof as drugs
RU2608388C2 (en) * 2011-07-25 2017-01-18 Дритте Патентпортфолио Бетайлигунгсгезельшафт Мбх Унд Ко.Кг Esters of pentamidine-amidoxime acids as prodrugs and their application as medicinal agents
EP2550963A1 (en) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Amidoxime carboxylic acid esters of pentamidine as prodrugs and their use as medicament
ES2416004A1 (en) * 2012-01-24 2013-07-29 Investigaciones Farmaceuticas Y Veterinarias, S.L. Pharmaceutical composition comprising isometamidium chloride in solution for the treatment of trypanosomiasis in animals

Also Published As

Publication number Publication date
ES2547117T3 (en) 2015-10-01
CA2713784A1 (en) 2009-08-06
DK2249821T3 (en) 2015-10-05
KR20100110875A (en) 2010-10-13
CY1116801T1 (en) 2017-03-15
PL2249821T3 (en) 2015-12-31
EP2249821A1 (en) 2010-11-17
US9353047B2 (en) 2016-05-31
HUE026276T2 (en) 2016-06-28
CN101951897A (en) 2011-01-19
AU2009209560B2 (en) 2013-10-31
WO2009095499A1 (en) 2009-08-06
DE102008007381A1 (en) 2009-08-13
HK1153144A1 (en) 2012-03-23
CN101951897B (en) 2016-01-20
US20140350293A1 (en) 2014-11-27
SI2249821T1 (en) 2015-12-31
ZA201004767B (en) 2011-04-28
IL207286A0 (en) 2010-12-30
PT2249821E (en) 2015-10-13
AU2009209560A1 (en) 2009-08-06
JP2011510956A (en) 2011-04-07
BRPI0906569A2 (en) 2015-07-07
EP2249821B1 (en) 2015-07-29
JP2016193927A (en) 2016-11-17
EP2985021A1 (en) 2016-02-17
HRP20150961T1 (en) 2015-11-06
EP2732816A1 (en) 2014-05-21
CA2713784C (en) 2016-09-27

Similar Documents

Publication Publication Date Title
US9353047B2 (en) Method for producing prodrug from amidoxime and N-hydroxyguanidine carboxylic acid esters
DK2046732T5 (en) Improving the bioavailability of active substances with amidine function in drugs.
US8658826B2 (en) Amino acid derivatives used as pharmaceutical substances
AU2014200451B2 (en) Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs
KR20110102506A (en) How to improve bioactivity of drugs
HK1153144B (en) Use of amidoxime carboxylic acid esters and n-hydroxyguanidine carboxylic acid esters for producing prodrugs
KR20160027967A (en) Use of Amidoxime Carboxylic Acid Esters and N-Hydroxyguanidine Carboxylic Acid Esters for Producing Prodrugs

Legal Events

Date Code Title Description
AS Assignment

Owner name: DRITTE PATENTPORTFOLIO BETEILIGUNGSGESELLSCHAFT MB

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CLEMENT, BERND;REEH, CHRISTIANE;HUNGELING, HELEN;SIGNING DATES FROM 20100730 TO 20100906;REEL/FRAME:025127/0085

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION