EP4045056A1

EP4045056A1 - Combination preparations of 3-n-formylhydroxylaminopropyl phosphonic acid derivatives or 3-n-acetylhydroxylaminopropyl phosphonic acid derivatives with clindamycin and artesunate

Info

Publication number: EP4045056A1
Application number: EP20806935.1A
Authority: EP
Inventors: David Hutchinson; Björn Friedrich LINDEMANN
Original assignee: Dmg Deutsche Malaria GmbH
Current assignee: Dmg Deutsche Malaria GmbH
Priority date: 2019-10-19
Filing date: 2020-10-19
Publication date: 2022-08-24
Also published as: WO2021074452A1; US20220401462A1

Abstract

The present invention relates to pharmaceutical preparations containing as active ingredients 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-acetylhydroxylaminopropylphosphonic acid derivatives in combination with clindamycin and artesunate for the treatment of malaria, in particular for acute therapy in cerebral malaria, as well as an associated dosage, in particular for the patient group of children.

Description

Combination preparations of 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-acetylhydroxylaminopropylphosphonic acid derivatives with clindamycin and artesunate

description

The present invention relates to pharmaceutical preparations containing 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-

Acetylhydroxylaminopropylphosphonic acid derivatives in combination with clindamycin and artesunate for the treatment of malaria, especially for acute therapy in cerebral malaria, and an associated dosage, especially for the patient group of children.

The use of 3-N-formylhydroxylaminopropylphosphonic acid derivatives and 3-N-acetylhydroxylaminopropylphosphonic acid derivatives for the prophylactic and therapeutic treatment of infectious processes, in particular infections caused by unicellular parasites (also called protozoa in the context of this invention) or multicellular parasites, have already been established in DE 198 25 585 Al known. A bacterial effectiveness is already described in DE 2733 658 A1. While these compounds have shown good results in treating infections caused by parasites or bacteria, these drugs also show undesirable side effects.

W02002000208A2 describes pharmaceutical preparations that contain 3-N-formylhydroxylaminopropylphosphonic acid derivatives or 3-N-

Contain acetylhydroxylaminopropylphosphonic acid derivatives in combination with clindamycin or artesunate for the treatment of malaria,

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. B. Children with cerebral malaria. 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.

Such combination preparations, however, behave very differently in terms of stability, efficacy, pharmacology and much more, especially depending on the course of malaria disease and its symptoms (fever, etc.) as well as course forms.

It has now surprisingly been found that 3-N-formylhydroxylaminopropylphosphonic acid derivatives and / or 3-N-acetylhydroxylaminopropylphosphonic acid derivatives in combination with clindamycin and artesunate - hereinafter referred to as “combination preparation” or “composition” - are particularly suitable for the treatment of cerebral malaria.

In the context of this invention, “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.

Cerebral malaria kills around 20% of adults and 15% of children. About 10% of surviving children and 2% of adults, who mostly had other symptoms of severe malaria, suffer permanent brain damage.

Clindamycin or methyl -6-amino-7-chloro-6, 7, 8-trideoxy-N - [(2S, 4R) -l-methyl-4-propylprolyl] -l-thio-β-L-threo-D -galactooctopyranoside has the formula (a):

Artesunate or (3R, 5aS, 6R, 8aS, 9R, 10S, 12R, 12aR) -decahydro-3,6,9-trimethyl-3,12-epoxy-12H-pyrano [4,3-j] -l, 2-benzodioxepin-10-ol-hydrogen succinate has the formula (b):

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.

According to the invention, this combination preparation also includes and includes the respective salts or any stereoisomers.

It is particularly preferred that Ri, R2 and R3 are hydrogen or the formula I is fosmidomycin, including salts and stereoisomers thereof.

Surprisingly, 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.

100% parasite clearance and normal body temperature means that patients are free of parasites and symptoms.

Particularly advantageously, clindamycin and formula I, preferably fosmidomycin, 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.

In a preferred embodiment, 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.

Furthermore, it is advantageous that 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

In a further preferred embodiment, the patient is selected from the group of children 0-14 years, in particular 0-10 years. In a further preferred embodiment, 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.

In a further preferred embodiment, 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.

For example, 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

It is also preferred that these doses according to the invention are used in acute therapy for the treatment of cerebral malaria.

In a further preferred embodiment, these doses are administered within 12 hours.

It is further preferred that these doses are administered continuously every 12 hours within 3-5 days.

Special features of the above definitions for formula I and suitable examples are given below:

"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. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.); 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.).

In the above examples of aliphatic acyl groups, 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. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic 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. phenylcarbamoyl, naphthylcarbamoyl, etc.); Arylglyoxyloyl (e.g. phenylglyoxyloyl etc.). In the above examples of aromatic acyl groups, the aromatic hydrocarbon moiety and / or the aliphatic hydrocarbon moiety (in particular the alkane radical) can optionally have one or more suitable substituents, such as those already specified as suitable substituents for the alkyl group or the alkane radical. Examples of preferred 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.

In the above examples of 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.

Unless otherwise defined, 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. "Cycloalkyl" is preferably an optionally substituted C3 - ₈ cycloalkyl; possible substituents include alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine,

Bromine etc.), nitro and the like are suitable.

"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.

"Aralkyl" 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.

When using combination therapy, it is possible to use the active ingredients in a so-called fixed combination, i.e. H. to be administered in a single pharmaceutical formulation containing all three active ingredients, or to choose a so-called free combination in which the active ingredients in the form of separate pharmaceutical formulations can be applied simultaneously or simultaneously but also one after the other - staggered in time.

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).

All indicated indications including the associated symptoms are described in Pschyrembel®, de Gruyter, Berlin.

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).

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.

In addition to the active ingredient (s), 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.

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. In addition to the active ingredients, 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.

In addition to the active ingredient (s), 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.

In addition to the active ingredient (s), 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.

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. In particular, it can be administered intravenously (i.v.).

Claims

1. Medicaments for use in the treatment of cerebral malaria containing a compound of general formula I as active ingredient in which Ri is selected from the group consisting of hydrogen and methyl, and in which R2 and R3 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 C i-5 alkyl chain, where the alkyl groups can be saturated or contain one or more double bonds or triple bonds in Combination with a second and third pharmaceutical agent clindamycin and artesunate.

2. Medicament for use in the treatment of cerebral malaria according to claim 1, characterized in that Ri, R2 and R3 are each hydrogen or the formula I is fosmidomycin.

3. Medicament containing a composition according to claim 1 or claim 2 for use in the treatment of cerebral malaria, characterized in that the patient is selected from the group of children 0-14 years, in particular 0-10 years.

4. Medicament containing a composition according to one of the preceding claims for use in the treatment of cerebral malaria, characterized in that three times the amount (weight in mg) of formula I, in particular fosmidomycin versus clindamycin, is present in one dose and / or the 7, 5 to fifteen times the amount (weight in mg) of formula I, in particular fosmidomycin against artesunate, is present.

5. Medicament containing a composition according to one of the preceding claims for use in the treatment of cerebral malaria, characterized in that a dose of 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 is, in particular 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.

6. Medicament for use in the treatment of cerebral malaria according to claim 5, characterized in that the dose is administered to a patient within 12 hours.

7. Medicament for use in the treatment of cerebral malaria according to claim 5, characterized in that the dose is continuously administered to a patient every 12 hours within 3-5 days.

8. Medicament for use in the treatment of cerebral malaria according to one of the preceding claims, characterized in that the treatment is carried out for acute therapy.

9. Medicament for use in the treatment of cerebral malaria according to one of the preceding claims, characterized in that the administration or application takes place parenterally or orally, in particular intravenously.