EP4045056A1 - Préparations combinées de dérivés d'acide 3-n-formylhydroxylaminopropyl phosphonique ou de dérivés d'acide 3-n-acétylhydroxylaminopropyl phosphonique avec de la clindamycine et l'artésunate - Google Patents

Préparations combinées de dérivés d'acide 3-n-formylhydroxylaminopropyl phosphonique ou de dérivés d'acide 3-n-acétylhydroxylaminopropyl phosphonique avec de la clindamycine et l'artésunate

Info

Publication number
EP4045056A1
EP4045056A1 EP20806935.1A EP20806935A EP4045056A1 EP 4045056 A1 EP4045056 A1 EP 4045056A1 EP 20806935 A EP20806935 A EP 20806935A EP 4045056 A1 EP4045056 A1 EP 4045056A1
Authority
EP
European Patent Office
Prior art keywords
treatment
substituted
cerebral malaria
unsubstituted
artesunate
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.)
Pending
Application number
EP20806935.1A
Other languages
German (de)
English (en)
Inventor
David Hutchinson
Björn Friedrich LINDEMANN
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.)
Dmg Deutsche Malaria GmbH
Original Assignee
Dmg Deutsche Malaria GmbH
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 Dmg Deutsche Malaria GmbH filed Critical Dmg Deutsche Malaria GmbH
Publication of EP4045056A1 publication Critical patent/EP4045056A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61P33/06—Antimalarials
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • 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 pharmaceutical preparations containing 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-
  • W02002000208A2 describes pharmaceutical preparations that contain 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-
  • the present invention has therefore set itself the task of increasing the effect of these pharmaceutical agents by means of further therapeutic instructions.
  • the aim is to enlarge the therapeutic range of application of these pharmaceutical agents, in particular for the treatment of problematic groups such.
  • the antiparasitic effect is to be increased so that these pharmaceutical agents can be administered in suitable and optimized doses and thus a faster therapeutic success in cerebral malaria is achieved.
  • Cerebral malaria is understood to mean a form or complication of a malaria infection affecting the brain, whereby the patient can become unconscious or even coma and in particular those patients can have comatose phases that usually last longer than half an hour persist and are often accompanied by convulsive jerks. Further symptoms can be abnormal movements of the eyes, cramp-like closed mouth with simultaneous rubbing of the rows of teeth against each other or pouty lips, slight stiffness of the neck, as well as a whole range of movement disorders.
  • Clindamycin or methyl -6-amino-7-chloro-6, 7, 8-trideoxy-N - [(2S, 4R) -l-methyl-4-propylprolyl] -l-thio- ⁇ -L-threo-D -galactooctopyranoside has the formula (a):
  • 3-N-formyl-hydroxylamino-propylphosphonic acid derivatives and 3-N-acetyl-hydroxylamino-propylphosphonic acid derivatives are compounds of the formula (I) according to the invention in which Ri is selected from the group consisting of hydrogen and methyl, and in which R2 and R 3 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted silyl, substituted or unsubstituted heterocyclic radical, or together form a substituted or unsubstituted Ci -alkyl chain, the Alkyl groups can be saturated or contain one or more double bonds or triple bonds.
  • this combination preparation also includes and includes the respective salts or any stereoisomers.
  • Ri, R2 and R3 are hydrogen or the formula I is fosmidomycin, including salts and stereoisomers thereof.
  • the combination preparation according to the invention can bring about 100% clearance of the malaria pathogen Plasmodium falciparum in a patient group within 3 days and, in particular, a decrease in malaria-related fever to normal temperature within 48 hours, especially in the case of simultaneous administration. Such an imposing effect could not have been foreseen.
  • clindamycin and formula I prevent a delay in the effect of fully or partially artesunate-resistant malaria pathogens (Plasmodium falciparum), so that patients who have been infected with artesunate-resistant Plasmodium falciparum can also be treated.
  • the invention therefore relates to a combination preparation according to the invention as well as a medicament for use in the treatment of cerebral malaria.
  • the combination preparation according to the invention allows treatment even in the presence of other bacterial infections which, for example, are also introduced via the malaria pathogen or are not warded off as a result of the malaria disease, since clindamycin and formula I, preferably fosmidomycin, have a broad anti-bacterial effect
  • the patient is selected from the group of children 0-14 years, in particular 0-10 years.
  • the dose for use in the treatment of cerebral malaria is three times the amount (weight in mg) of an active ingredient of the formula I, in particular fosmidomycin versus clindamycin and / or 7.5 times - to fifteen times the amount (weight in mg) of an active ingredient of the formula I, in particular fosmidomycin against artesunate.
  • the dose for use in the treatment of cerebral malaria is 1-6 mg artesunate, 5-15 mg clindamycin and 10-40 mg according to formula I, in particular fosmidomycin per kg body weight of a patient, preferably a dose of 2- 4 mg artesunate, 10 mg clindamycin and 30 mg according to formula I, in particular fosmidomycin per kg body weight of a patient.
  • a dose for a child weighing 25 kg is 25-150 mg artesunate, 125-375 mg clindamycin and 250-1,000 mg according to formula I, in particular fosmidomycin per kg body weight of a patient, preferably a dose of 50-100 mg artesunate, 250 mg clindamycin and 750 mg according to formula I, in particular fosmidomycin
  • these doses according to the invention are used in acute therapy for the treatment of cerebral malaria.
  • these doses are administered within 12 hours.
  • these doses are administered continuously every 12 hours within 3-5 days.
  • Acyl is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioacid or imidic acid corresponding to each of the above acids, or from an organic sulfonic acid, where these acids each include aliphatic, aromatic and / or heterocyclic groups in the molecule and also carbamoyl or carbamimidoyl.
  • Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
  • Alkanoyl e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isoval eryl, pivaloyl, etc.
  • Alkenoyl e.g. acryloyl, methacryloyl, crotonoyl, etc.
  • alkylthioalkanoyl e.g. methylthioacetyl, ethylthioacetyl etc.
  • Alkanesulfonyl e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.
  • Alkoxycarbonyl e.g.
  • alkylcarbamoyl e.g. methylcarbamoyl, etc.
  • (N-alkyl) thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
  • Alkylcarbamimidoyl e.g., methylcarbamimidoyl, etc.
  • Oxalo Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
  • the aliphatic hydrocarbon moiety in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (e.g. fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, Alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g.
  • acyl radicals with such substituents are, for example, alkanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
  • Aromatic acyl radicals are those acyl radicals which originate from an acid with a substituted or unsubstituted aryl group, it being possible for the aryl group to include phenyl, toluyl, xylyl, naphthyl and the like; suitable examples are given below: aroyl (eg benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); Aralkanoyl (e.g. phenylacetyl etc.); Aralkenoyl (e.g. cinnamoyl etc.); Aryloxyalkanoyl (e.g.
  • phenoxyacetyl etc. Arylthioalkanoyl (e.g. phenylthioacetyl etc.); Arylaminoalkanoyl (e.g., N-phenylglycyl, etc.); Arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl etc.); Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl etc.); Aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.); Arylcarbamoyl (e.g.
  • aromatic hydrocarbon moiety and / or the aliphatic hydrocarbon moiety can optionally have one or more suitable substituents, such as those already specified as suitable substituents for the alkyl group or the alkane radical.
  • aromatic acyl radicals with particular substituents are aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino, as well as arylthiocarbamoyl (eg phenylthiocarbamoyl etc.); Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
  • a heterocyclic acyl radical is understood to mean an acyl radical which originates from an acid with a heterocyclic group, such as the following:
  • Heterocyclic carbonyl in which the heterocyclic radical is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, furoyl, pyrrole carbonyl, nicotinoyl etc.);
  • Heterocycle-alkanoyl in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group nitrogen, oxygen and sulfur (e.g. thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
  • nitrogen, oxygen and sulfur e.g. thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2-amino-4- thiazolyl) -2-methoxyiminoacetyl etc.
  • heterocyclic acyl radicals the heterocycle and / or the aliphatic hydrocarbon moiety can optionally have one or more suitable substituents, such as those indicated as being suitable for alkyl and alkane groups.
  • alkyl group "or” alkyl is a straight or branched chain alkyl radical with up to 26 carbon atoms, but preferably C1-C6 with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, Hexyl and structural isomers thereof. It can be substituted, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), oxo radicals and alkoxy radicals, such as methoxy, ethoxy radicals.
  • halogen for example fluorine, bromine, chlorine
  • Cycloalkyl is preferably an optionally substituted C3 - 8 cycloalkyl; possible substituents include alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine,
  • Aryl is an aromatic hydrocarbon radical such as phenyl, naphthyl etc., which may have one or more suitable substituents such as alkyl, alkoxy (e.g. methoxy, ethoxy etc.), trifluoromethylene, halogen (e.g. fluorine, chlorine, bromine etc.) ), Nitro and the like.
  • Alkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part can optionally have one or more suitable substituents such as alkoxy (eg methoxy, ethoxy etc.), halogen (eg Fluorine, chlorine, bromine etc.), nitro and the like.
  • the combination preparation according to the invention is effective against bacteria and single- and multicellular parasites, in particular in the treatment and prevention of malaria pathogens (Plasmodium).
  • the pharmaceutically active agents can be prepared in the form of pharmaceutical preparations in dosage units. This means that the preparation is in the form of individual parts, for example tablets, coated tablets, capsules, pills, suppositories and ampoules, the active ingredient content of which corresponds to a fraction or a multiple of an individual dose.
  • the dosage units can contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose.
  • a single dose preferably contains the amount Active ingredient which is administered in one application and which usually corresponds to a full, half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as meaning solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all types.
  • Tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as a) fillers and extenders, e.g. starches, lactose, cane sugar, glucose, mannitol and silicic acid, b) binders, e.g. carboxymethyl cellulose, alginates, gelatin , Polyvinylpyrrolidone, c) humectants, e.g.
  • glycerol d) disintegrants, e.g. agar-agar, calcium carbonate and sodium carbonate, e) dissolution retarders, e.g. paraffin and f) absorption accelerators, e.g. quaternary ammonium compounds, g) wetting agents, e.g. cetyl alcohol, glycerol monostearate, h) adsorbents , for example kaolin and bentonite and i) lubricants, for example talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under a) to i).
  • disintegrants e.g. agar-agar, calcium carbonate and sodium carbonate
  • dissolution retarders e.g. paraffin
  • absorption accelerators e.g. quaternary ammonium compounds
  • g) wetting agents e.g. cetyl alcohol, glycerol monostearate
  • adsorbents for
  • the tablets, dragees, capsules, pills and granules can be provided with the usual coatings and shells, optionally containing opacifying agents, and can also be composed so that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, with as Embedding materials such as polymer substances and waxes can be used.
  • the active ingredient (s) can, if appropriate, also be in microencapsulated form with one or more of the abovementioned carriers.
  • suppositories can contain the usual water-soluble or water-insoluble carrier substances, e.g. polyethylene glycols, fats, e.g. cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these substances.
  • water-soluble or water-insoluble carrier substances e.g. polyethylene glycols, fats, e.g. cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these substances.
  • Ointments, pastes, creams and gels can contain the usual carrier substances in addition to the active ingredient (s), for example animal and vegetable fats, waxes, paraffins, starch, tragacanth cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
  • powders and sprays can contain the usual carrier substances, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. water, physiological saline solution (0.9%), ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- Contain butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents e.g. water, physiological saline solution (0.9%)
  • ethyl alcohol isopropyl alcohol
  • ethyl carbonate ethyl acetate
  • benzyl alcohol benzyl benzoate
  • suspensions can contain the usual carriers such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances contain.
  • liquid diluents for example water, ethyl alcohol, propylene glycol
  • suspending agents for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metal hydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances contain.
  • the formulation forms mentioned can also contain colorants, preservatives and additives to improve smell and taste, e.g. peppermint oil and eucalyptus oil, and sweeteners, e.g. saccharin.
  • the combination preparation according to the invention can be administered parenterally or orally.
  • it can be administered intravenously (i.v.).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des préparations pharmaceutiques contenant en tant que principes actifs des dérivés d'acide 3-N-formylhydroxylaminopropyl phosphonique ou des dérivés d'acide 3-N-acétylhydroxylaminopropyl phosphonique en combinaison avec de la clindamycine et de l'artésunate pour le traitement du paludisme, en particulier pour une thérapie aiguë dans le paludisme cérébral, ainsi qu'un dosage associé, en particulier pour le groupe de patients enfants.
EP20806935.1A 2019-10-19 2020-10-19 Préparations combinées de dérivés d'acide 3-n-formylhydroxylaminopropyl phosphonique ou de dérivés d'acide 3-n-acétylhydroxylaminopropyl phosphonique avec de la clindamycine et l'artésunate Pending EP4045056A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP19204213 2019-10-19
PCT/EP2020/079401 WO2021074452A1 (fr) 2019-10-19 2020-10-19 Préparations combinées de dérivés d'acide 3-n-formylhydroxylaminopropyl phosphonique ou de dérivés d'acide 3-n-acétylhydroxylaminopropyl phosphonique avec de la clindamycine et l'artésunate

Publications (1)

Publication Number Publication Date
EP4045056A1 true EP4045056A1 (fr) 2022-08-24

Family

ID=68296186

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20806935.1A Pending EP4045056A1 (fr) 2019-10-19 2020-10-19 Préparations combinées de dérivés d'acide 3-n-formylhydroxylaminopropyl phosphonique ou de dérivés d'acide 3-n-acétylhydroxylaminopropyl phosphonique avec de la clindamycine et l'artésunate

Country Status (3)

Country Link
US (1) US20220401462A1 (fr)
EP (1) EP4045056A1 (fr)
WO (1) WO2021074452A1 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1580899A (en) 1976-07-27 1980-12-10 Fujisawa Pharmaceutical Co Hydroxyaminohydrocarbonphosphonic acid derivatives and production and use thereof
DE19825585A1 (de) 1998-04-14 1999-10-21 Hassan Jomaa Verwendung von Aminohydrocarbylphosphonsäurederivaten zur therapeutischen und prophylaktischen Behandlung von Infektionen, die durch Parasiten, Pilze oder Viren hervorgerufen werden
DE10030781A1 (de) 2000-06-29 2002-01-17 Hassan Jomaa Kombinationspräparate von 3-N-Formylhydroxylaminopropylphosphonsäurederivaten oder 3-N-Acetylhydroxylaminopropylphosphonsäurederivaten mit spezielen pharmazeutischen Wirkstoffen

Also Published As

Publication number Publication date
WO2021074452A1 (fr) 2021-04-22
US20220401462A1 (en) 2022-12-22

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