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

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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
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prodrug
inhibitor
formula
intercalating
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Bernd Clement
Christiane Reeh
Helen HUNGELING
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Dritte Patentportfolio Beteiligungs GmbH and Co KG
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Priority to US14/581,384 priority patent/US9662308B2/en
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    • 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.

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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)

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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

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2550963A1 (de) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Pentamidin-Amidoximsäureesters als Prodrugs und ihre Verwendung als Arzneimittel
EP2550966A1 (de) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Dabigatran-Amidoximsäureesters als Prodrugs und ihre Verwendung als Arzneimittel
ES2416004A1 (es) * 2012-01-24 2013-07-29 Investigaciones Farmaceuticas Y Veterinarias, S.L. Composición farmacéutica que comprende cloruro de isometamidium en solución para el tratamiento de la tripanosomiasis en animales.
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 (de) * 2009-01-09 2010-07-15 Christian-Albrechts-Universität Zu Kiel Verfahren zur verbesserten Bioaktivierung von Arzneistoffen
CN103420994B (zh) * 2012-05-24 2016-04-06 天津药物研究院 作为前药的达比加群酯衍生物及其制备方法和用途
KR20150126595A (ko) 2012-12-21 2015-11-12 벌릭스 파마 인코포레이티드 간 질환 또는 증상의 치료를 위한 용도 및 방법
CN106831611B (zh) * 2017-01-23 2019-06-21 北京化工大学 一种偕胺肟类化合物及其在制备抑制癌细胞增殖药的应用

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 (ja) * 1999-07-14 2001-02-06 Sunstar Inc 動脈硬化症及び動脈硬化症に起因する疾患の予防又は治療組成物
AU7130101A (en) 2000-06-14 2001-12-24 Corixa Corp Enzyme-cleavable prodrug compounds
MXPA04003169A (es) 2001-10-03 2004-07-08 Pharmacia Corp Profarmacos de compuestos policiclicos sustituidos utiles para inhibicion selectiva de la cascada de coagulacion.
EP1767526B1 (en) * 2004-06-30 2012-10-24 Toyama Chemical Co., Ltd. Arylamidine derivative, salt thereof and antifungal containing these
DE102008007381A1 (de) 2008-02-01 2009-08-13 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co.Kg Amidine und Guanidine und deren Derivate zur Behandlung von Krankheiten

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 *

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* Cited by examiner, † Cited by third party
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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
WO2013013946A1 (de) * 2011-07-25 2013-01-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Dabigatran-amidoximsäureesters als prodrugs und ihre verwendung als arzneimittel
EP2550963A1 (de) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Pentamidin-Amidoximsäureesters als Prodrugs und ihre Verwendung als Arzneimittel
WO2013014059A1 (de) * 2011-07-25 2013-01-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Pentamidin-amidoximsäureesters als prodrugs und ihre verwendung als arzneimittel
US20130085180A1 (en) * 2011-07-25 2013-04-04 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Oral bioavailable pentamidin prodrugs for treatment of diseases
CN103874491A (zh) * 2011-07-25 2014-06-18 第三专利投资有限两合公司 喷他脒-偕胺肟酸酯作为前药以及其作为药物的用途
US8853245B2 (en) * 2011-07-25 2014-10-07 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Orally bioavailable dabigatran 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
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 (ru) * 2011-07-25 2017-01-18 Дритте Патентпортфолио Бетайлигунгсгезельшафт Мбх Унд Ко.Кг Сложные эфиры пентамидин-амидоксим кислот как пролекарства и их применение в качестве лекарственных средств
EP2550966A1 (de) * 2011-07-25 2013-01-30 Dritte Patentportfolio Beteiligungsgesellschaft mbH & Co. KG Dabigatran-Amidoximsäureesters als Prodrugs und ihre Verwendung als Arzneimittel
ES2416004A1 (es) * 2012-01-24 2013-07-29 Investigaciones Farmaceuticas Y Veterinarias, S.L. Composición farmacéutica que comprende cloruro de isometamidium en solución para el tratamiento de la tripanosomiasis en animales.

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US20140350293A1 (en) 2014-11-27
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BRPI0906569A2 (pt) 2015-07-07
KR20100110875A (ko) 2010-10-13
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SI2249821T1 (sl) 2015-12-31
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