EP2242488A2 - Dérivés d'acides aminés utilisés comme substances pharmaceutiques - Google Patents

Dérivés d'acides aminés utilisés comme substances pharmaceutiques

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Publication number
EP2242488A2
EP2242488A2 EP09706232A EP09706232A EP2242488A2 EP 2242488 A2 EP2242488 A2 EP 2242488A2 EP 09706232 A EP09706232 A EP 09706232A EP 09706232 A EP09706232 A EP 09706232A EP 2242488 A2 EP2242488 A2 EP 2242488A2
Authority
EP
European Patent Office
Prior art keywords
inhibitor
blood
amino acid
use according
amidoxime
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.)
Ceased
Application number
EP09706232A
Other languages
German (de)
English (en)
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
Priority to EP14195400.8A priority Critical patent/EP2848249A3/fr
Publication of EP2242488A2 publication Critical patent/EP2242488A2/fr
Ceased legal-status Critical Current

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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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • 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
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
    • C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
    • 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 the use of an amidoximainic acid ester in a method for improving bioavailability and permitting blood-brain barrier access of drugs comprising at least one or more amidine, guanidine, N-hydroxyamidine (amidoxime) and N-hydroxyguanidine, respectively.
  • drugs comprising at least one or more amidine, guanidine, N-hydroxyamidine (amidoxime) and N-hydroxyguanidine, respectively.
  • N-hydroxyamidines (amidoximes) and N-hydroxyguanidines provide well-known prodrug principles for increasing the oral bioavailability of amidines [Clement, B. Methods for the treatment and prophylaxis of Pneumocystis carinii pneumonia (PCP) and others Diseases, as well as compounds and formulations for use in said methods. P 432444.4, 1993] and guanidines.
  • compositions which contain an active substance with one or more amidine or guanidine mills show almost no pharmacological action when administered orally.
  • the prerequisite for a therapeutic effect of an active substance after oral administration is its uptake from the gastrointestinal tract.
  • the most important mechanism of such an effect is the passive diffusion, the degree of absorption on the way of passive diffusion depends on the lipophilicity and thus dependent on the acidity and the Basizitä 't of the active ingredient.
  • the blood-brain barrier provides an effective barrier to the absorption of substances into the brain. It ensures selective uptake and prevents the ingress of substances.
  • the blood-brain barrier functions not only as a physical, but also as an enzymatic barrier.
  • Various processes are involved in the penetration of substances into the brain.
  • there are only a few drugs on the market that have an effect in the central nervous system (CNS). The majority of these pass through diffusion into the CNS. In this way, diseases such as epilepsy, chronic pain or depression are treated.
  • sustance In order to overcome the blood-brain barrier by passive diffusion, sustance must be lipophilic, lower in molecular weight than 400-500 Da and uncharged.
  • various transporter systems such as nucleoside transporters, influx and efflux transporters for organic anions, glucose transporters, peptide transporters, and amino acid transporters are expressed at the blood-brain barrier [TAMAI, L; TSUJI, A, J Pharm.
  • Diamidines are used as antiparasitic agents against malaria, against Pneumocystis jiroveci (formerly carinii) pneumonia, against trypanosomiasis (African sleeping sickness) and against leishmaniasis [WERBOVETZ, K. Curr Opin Investig Drugs 2006, 7, 147-157]. Especially in developing countries, these diseases are a serious problem with high mortality rates.
  • Pentamidine has been used in the early stages of African sleeping sickness for 60 years. In the second stage of African sleeping sickness, the meningoenzephalitischem stage is no longer effective because the blood-brain barrier can not be successfully passed. It must therefore be given highly toxic arsenic compounds. There is a lack of drugs that act in the second stage of African sleeping sickness.
  • Pentamidine and diminazene are diamidines and are not absorbed after oral administration. Therefore, they were converted into amidoxime prodrugs. (DE 10 2006 034 256.9).
  • pentamidine shows that the conversion into the pentoxime ester is accompanied by a reduction in solubility. This is probably also the reason for the not one hundred percent bioavailability of pentamidine after oral administration of pentoxime ester [Clement B .; Bürenheide A .; Rieckert W .; Black J. ChemMedChem 2006, 1, 1260-7].
  • amidoxime amino acid ester (I) is amidoxime amino acid ester (I)
  • R 1 is hydrogen, an alkyl radical, an aryl radical, one of the groups listed below
  • N-hydroxyamidine as a substitute for one or more amidine, N-hydroxyamidine (amidoxime), guanidine or N-hydroxyguanidine functions of a drug in medicaments to improve solubility, bioavailability and allow blood-brain barrier mobility of the drug use.
  • N-hydroxyarnidines (amidoximes) and N-hydroxyguanidines are successful prodrug principles for increasing the oral bioavailability of the amidines (DE 10 2006 034 256.9)
  • the erfgenndungsgeniäß proposed esterification of amidoximes or N-hydroxyguanidines with amino acids improves the solubility > in particular the solubility in aqueous media and the bioavailability compared to the known prodrugs considerably.
  • the particular advantage of the water-soluble amino acid esters according to the invention is their improved absorption from the gastrointestinal tract by specific amino acid and peptide transporters.
  • Another advantage lies in the fact that the esterification of amidoximes or N-hydroxyguanidines with amino acids also injectable dosage forms are possible because, as in Amidineii water solubility is restored, by the novel prodrug principles of the invention is the possibility overcoming the blood-brain barrier. This would be a decisive step forward in the treatment of African sleeping sickness, as it can effectively treat the second phase of the disease.
  • the substitution of at least one or more amidine, IV-hydroxyamidine (amidoxime), guanidine or N-hydroxyguanidine functional groups by the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect of increasing the solubility of the drug in question .
  • the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect of increasing the solubility of the drug in question .
  • the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect of increasing the solubility of the drug in question .
  • the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect of increasing the solubility of the drug in question .
  • the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect of increasing the solubility of the drug in question .
  • the amidoxime amino acid ester and the N-hydroxyguanidine amino acid ester achieves the effect
  • the active ingredient at least one or more effective amidine, N-hydroxy amidin- (Arnidoxün), guanidine or JV-Hydroxyguanidin functions in the proposed form contains.
  • the active ingredient may contain, for example, several amidoxime functions (eg two as in the case of the pentoxime ester) or N-hydroxyguanidine functions, in which case at least one of these groups is modified in the manner described above.
  • it is also possible to use mixtures of active ingredients if at least one active substance has one or more amidine, N-hydroxyamidine (amidoxime), guanidine or N-hydroxyguanidiiv functions.
  • the oral dosage form can be presented as a liquid, semisolid or solid preparation, in particular as a tablet, dragee, pellet or microcapsule.
  • the active substance or the active ingredient mixture is in a suitable, non-toxic solvent ,
  • a suitable, non-toxic solvent for example, water, monohydric alcohols, in particular ethanols, polyhydric alcohols, in particular glycerol and / or propanediol, polyglycols, in particular polyethylene glycols and / or miglyol, glycerol formal, dimethylisosorbitol, natural or sj'nthetician oils included.
  • the usual Grundmassert such as bentonite, veegum, guar gum and / or cellulose derivatives, in particular methylcellulose and / or carboxymethylcellulose, and polymers of vinyl alcohols and / or vinylpyrrolidones, alginates, pectins, polyacrylates, solid and / or liquid polyethylene glycols, paraffins, fatty alcohols, Vaseline and / or waxes, fatty acids and / or fatty acid esters for use.
  • Grundmassert such as bentonite, veegum, guar gum and / or cellulose derivatives, in particular methylcellulose and / or carboxymethylcellulose, and polymers of vinyl alcohols and / or vinylpyrrolidones, alginates, pectins, polyacrylates, solid and / or liquid polyethylene glycols, paraffins, fatty alcohols, Vaseline and / or waxes, fatty acids and / or fatty acid esters for use.
  • Strecl ⁇ r ⁇ ttel such as colloidal silica, talc, lactose, starch powder, sugar, gelatin, metal oxides and / or metal salts may be contained in solid preparations.
  • Other additives include stabilizers, emulsifiers, dispersants and preservatives.
  • the drugs modified according to the use according to the invention have an excellent absorbability and thus bioavailability when administered orally, as a result of which the pharmacological action of amidine or guanidine is markedly increased.
  • an optimal dosage form for the oral administration of amidines can now be provided, Particular importance is given to the use according to the invention in that the functional groups amidine and guanidine are essential constituents of various important active compounds for various fields of application.
  • protease inhibitors such as melagatran, inhibitors of factor Xa, factor VII or all proteases of the coagulation cascade, matriptase inhibitors
  • anticoagulants such as melagatran, inhibitors of factor Xa, factor VII or all proteases of the coagulation cascade, matriptase inhibitors
  • anticoagulants such as melagatran, inhibitors of factor Xa, factor VII or all proteases of the coagulation cascade, matriptase inhibitors
  • anticoagulants such as melagatran, inhibitors of factor Xa, factor VII or all proteases of the coagulation cascade, matriptase inhibitors
  • anticoagulants such as melagatran, inhibitors of factor Xa, factor VII or all proteases of the coagulation cascade, matriptase inhibitors
  • anticoagulants such as pentamidine , Diminazene, isometamidium
  • Active ingredients which contain an effective a ⁇ din-function or guanidine-function may i.a. for the inhibition of blood coagulation, for the prophylaxis and therapy of visceral and cutaneous leishmaniasis, trypanosomiasis, pneumocystis carinii pneumonia (PCP), growth inhibition of malignant tumors, hypertension, neuroprotection, as well as for the control of viral infections such as influenza and used by HTV infections.
  • the invention basically comprises all active ingredients which have at least one amidine function or guanidine function, which has been converted according to the invention into an improved prodrug.
  • the method according to the invention is thus applicable to a very broad range of classes of active ingredient and indications and can significantly increase the bioavailability of many drugs whose active form contains an amidine or a guanidine.
  • Examples of compounds modified by the process according to the invention are those which are called valbenzamidoxime, the pentamidine valine ester, and the diminazene valine ester.
  • valbenzamidoxime is orally administered to three rats.
  • the metabolism of the ester to benzamidine proceeds in vivo as follows:
  • the anesthesia is done by xylazine and ketamine. Both were injected in.
  • the silicone catheters are implanted in the jugular vein and the carotid artery. They have locally antithrombotic and anti-inflammatory properties, but do not work systemically.
  • the eyes were during the operation by means of a corneaprotektiven ointment (Oculotect; protected as well as 3-4 ml Ringer's lactate solution sc for improving the post-operative power applied to animals are anti-inflammatory (Finadyne ®, 1 mg / kg body weight) and an antibiotic (amoxicillin ®.
  • the animals receive Nutri plus ® , an energy paste (soybean oil, molasses, cod liver oil, meat extract, mineral pre-mix vitamin pre-mix).
  • the experimental animals are male Wistar rats with an average weight of 200 g.
  • the animals are kept individually in cages. Every two days they receive concentrated feed. Water and dried food were available ad libitum.
  • the animals are weighed in the evening before the substance application.
  • the orally administered substances are administered via a gavage.
  • the valbenzamidoxime are dissolved in 100 mM phosphate buffer pH 6.5.
  • the intravenous benzamidine is dissolved in 0.9% NaCl solution to prevent hemolysis. After the injection, 0.9% is rinsed again with at least 0.5 ml of NaCl solution.
  • the substance application takes place in the morning.
  • the prodrugs are applied to three rats.
  • Benzamidine is administered intravenously to two rats.
  • the oral doses of valbenzamide oxime are 50 mg / kg body weight.
  • Benzamidine was administered at a concentration of 10 mg / kg body weight.
  • the trial period for a condition lasts one day.
  • the blood samples are collected over a period of eight hours after oral administration and six hours after intravenous administration. After oral administration, the samples are taken after 30, 60, 90, 120, 240 and 480 minutes, after intravenous administration after 5, 10, 20, 40, 80 and 360 minutes.
  • the catheter is emptied by briefly aspirating until the appearance of blood. Blood collection (300 ⁇ l) is carried out using multivets (Multivetten ® 600, Sahrstedt, Nümbrecht). To keep the catheter free, about 0.3 ml of a mixture of heparin and NaCl are subsequently injected.
  • the plasma samples are processed by means of solid phase extraction. After conditioning the column with 1000 .mu.l of methanol and equilibrating with 1000 .mu.l of bidistilled water. the sample is applied (600 ⁇ l). The sorbent is washed after the sample application with 600 .mu.l of bidistilled water. The elution of the substances is carried out by means of double-distilled water pH 3 / methanol (6/4, WV). The eluate is then concentrated to dryness and redistilled with 100 ⁇ l of water. / Methanol (9/1, v / v) and fed to the HPLC.
  • 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
  • Benzamidine 26.5 ⁇ 0.5 min
  • the eluent was filtered with a Satorius membrane filter (0.45 ⁇ m) and degassed in an ultrasonic bath for 15 minutes.
  • HPLC Pump Waters 600 Detector: Waters 2417 Tunable Absorban.ce Detector Autosampler. Waters 717 Plus Autosampler Integrator: EZChrom Elite Client / Server Version 2.8.3 Build 2249 Recording and Evaluation Software
  • Detector sensitivity Absorbance units fullscale: 2,000 Retention times: Benzamidine: 7.5 ⁇ 0.3 min
  • FIG. 1 The results of the experiments are shown in FIG. 1, in which the plasma level curves of benzamidine after oral administration of valbenzamidoxime are shown.
  • Fig. 2 The metabolism of the dirninaceirvalin ester is shown in Fig. 2 and the metabolism of the pentamidine valine ester is shown in Fig. 3,
  • benzamidine has a bioavailability of 88% after oral administration of valbenzamidoxime. This shows that the prodrug was completely absorbed after oral administration and metabolized in the blood to the active form of benzamidine.
  • R 1 is selected from the group consisting of hydrogen, an alkyl radical, an aryl radical and one of the groups depicted below
  • the drug is selected from the group of protease inhibitors, the DNA and RNA intercalating compounds, the inhibitors of viral enzymes and the N-methyl-D-aspartate receptor antagonists.
  • the protease inhibitor is a tririn inhibitor, an inhibitor of factor Xa, factor VII or all proteases of the coagulation cascade or a Matriptasehemmstoff.
  • the medicament substance for the prophylaxis and therapy of visceral and / or cutaneous leishmaniasis, trypanosomiasis, the second phase of trypanosomiasis or caused by Pneumocystis carinii pneumonia, for growth inhibition of malignant tumors is designed for anticoagulation, lowering blood pressure, for neuroprotection or for controlling viral infections, including influenza and HIV infections,

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

Abstract

L'invention concerne un procédé pour améliorer la biodisponibilité de substances pharmaceutiques et pour permettre à ces dernières de franchir la barrière hémato-encéphalique, lesdites substances pharmaceutiques présentant au moins une ou plusieurs fonctions amidine, guanidine, N-hydroxyamidine (amidoxime) ou N-hydroxyguanidine. L'invention concerne également des médicaments contenant des substances pharmaceutiques modifiées de manière correspondante.
EP09706232A 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques Ceased EP2242488A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP14195400.8A EP2848249A3 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008007440A DE102008007440A1 (de) 2008-02-01 2008-02-01 Aminosäurederivate als Arzneistoffe
PCT/EP2009/051162 WO2009095503A2 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP14195400.8A Division EP2848249A3 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques

Publications (1)

Publication Number Publication Date
EP2242488A2 true EP2242488A2 (fr) 2010-10-27

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Family Applications (2)

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EP14195400.8A Withdrawn EP2848249A3 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques
EP09706232A Ceased EP2242488A2 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques

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EP14195400.8A Withdrawn EP2848249A3 (fr) 2008-02-01 2009-02-02 Dérivés d'acides aminés utilisés comme substances pharmaceutiques

Country Status (13)

Country Link
US (2) US8658826B2 (fr)
EP (2) EP2848249A3 (fr)
JP (1) JP5631218B2 (fr)
KR (2) KR20160080116A (fr)
CN (1) CN101969941B (fr)
AU (1) AU2009209564B2 (fr)
BR (1) BRPI0906733A2 (fr)
CA (1) CA2713780C (fr)
DE (1) DE102008007440A1 (fr)
HK (1) HK1209022A1 (fr)
IL (1) IL207287A0 (fr)
WO (1) WO2009095503A2 (fr)
ZA (1) ZA201004864B (fr)

Families Citing this family (3)

* 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
JP5429488B2 (ja) * 2010-03-31 2014-02-26 セイコーエプソン株式会社 液体噴射装置
PL2550966T3 (pl) * 2011-07-25 2017-03-31 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Estry kwasu amidooksymokarboksylowego dabigatranu jako proleki i ich zastosowanie jako lek

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009264A1 (fr) * 2006-07-21 2008-01-24 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Amélioration de la biodisponibilité de principes actifs à fonction amidine dans des médicaments

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4321444A1 (de) * 1993-06-28 1995-01-05 Bernd Prof Dr Clement Pharmazeutische Zubereitung
AR013084A1 (es) * 1997-06-19 2000-12-13 Astrazeneca Ab Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados
WO2001097794A2 (fr) * 2000-06-21 2001-12-27 Georgetown University Decouverte a l'aide d'une structure d'inhibiteurs de matriptase destines au traitement du cancer et d'autres pathologies
DE10323898A1 (de) * 2003-05-26 2004-12-23 Wilex Ag Hydroxyamidin- und Hydroxyguanidin-Verbindungen als Urokinase-Hemmstoffe
JP4885722B2 (ja) * 2004-06-30 2012-02-29 富山化学工業株式会社 新規なアリールアミジン誘導体およびその塩ならびにそれらを含有する抗真菌剤
WO2006011499A1 (fr) * 2004-07-28 2006-02-02 Toyama Chemical Co., Ltd. Nouveau dérivé d’arylamidine, sel de celui-ci et antifongique contenant celui-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008009264A1 (fr) * 2006-07-21 2008-01-24 Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co. Kg Amélioration de la biodisponibilité de principes actifs à fonction amidine dans des médicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CLEMENT B. ET AL: "Isolation and characterization of the protein components of the liver microsomal O2-insensitive NADH-benzamidoxime reductase", THE JOURNAL OPF BIOLOGICAL CHEMISTRY, vol. 272, no. 31, 1 August 1997 (1997-08-01), pages 19615 - 19620, XP002993713

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KR20160080116A (ko) 2016-07-07
EP2848249A2 (fr) 2015-03-18
DE102008007440A1 (de) 2009-08-13
AU2009209564B2 (en) 2015-07-02
US8658826B2 (en) 2014-02-25
EP2848249A3 (fr) 2015-07-22
US20110021835A1 (en) 2011-01-27
HK1209022A1 (en) 2016-03-24
CN101969941B (zh) 2014-11-26
WO2009095503A2 (fr) 2009-08-06
ZA201004864B (en) 2011-03-30
CA2713780A1 (fr) 2009-08-06
WO2009095503A3 (fr) 2009-12-03
CN101969941A (zh) 2011-02-09
JP2012516830A (ja) 2012-07-26
JP5631218B2 (ja) 2014-11-26
AU2009209564A1 (en) 2009-08-06
US20140066648A1 (en) 2014-03-06
KR20100106588A (ko) 2010-10-01
BRPI0906733A2 (pt) 2015-07-14
CA2713780C (fr) 2016-09-20

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