WO2007131488A2 - Utilisation de dérivés de quinolone comme agents antiprotozoaires et dans des associations médicamenteuses - Google Patents

Utilisation de dérivés de quinolone comme agents antiprotozoaires et dans des associations médicamenteuses Download PDF

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WO2007131488A2
WO2007131488A2 PCT/DE2007/000879 DE2007000879W WO2007131488A2 WO 2007131488 A2 WO2007131488 A2 WO 2007131488A2 DE 2007000879 W DE2007000879 W DE 2007000879W WO 2007131488 A2 WO2007131488 A2 WO 2007131488A2
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use according
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protozoan
prophylaxis
treatment
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PCT/DE2007/000879
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WO2007131488A3 (fr
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Wolfgang Bohne
Uwe Gross
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Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts (Universitätsmedizin)
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • 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 certain quinolone derivatives as anti-protozoan pharmaceuticals in humans and animals. More specifically, the present concerns
  • Protozoa belonging to the Apicomplexa or Flagellata is directed to combination preparations containing the quinolone derivatives according to the invention and at least one further antiprotozoal active ingredient and their use in the prophylaxis and therapy of
  • Protozoan infections are a common cause of potentially life-threatening diseases. About one-third of the world's population lives in areas threatened by malaria. Malaria is caused, for example, by Plasmodium falciparum, the causative agent of malaria tropica. According to World Health Organization (WHO) estimates, up to 500 million people are infected with malaria each year; Of these, over one million die each year from the consequences of the disease. Although extensive efforts have been made to eradicate malaria, malaria is a serious endemic disease in many areas of Africa, Asia, Latin America and Oceania. In Africa alone, 20 to 30% of all hospitalizations are due to malaria. In fact, there is even a dramatic increase in malaria cases worldwide. Probably due to global warming, we have been experiencing an expansion of endemic areas for several years. For example, malaria cases have recently been reported from parts of Florida and northeastern Australia. This spread continues to be increasingly due to malaria becoming increasingly resistant to common malaria drugs.
  • WHO World Health Organization
  • Human malaria is caused by one of the four species of the protozoan Plasmodium: Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax and Plasmodium ovale, with Plasmodium falciparum being the most abundant and virulent.
  • Plasmodium falciparum The transmission to humans takes place via a certain mosquito species, the Anopheles mosquito. Malaria is next to HIV and the
  • Tuberculosis is the leading cause of fatalities caused by infectious diseases worldwide.
  • the malaria pathogens are increasingly developing resistance to common malaria medications.
  • chloroquine used to be used therapeutically as well as prophylactically.
  • initial chloroquine resistance developed in plasmodia.
  • resistance to other malaria medications such as Pyrimethamine, mefloquine, halofantrine and other antimalarials.
  • Chloroquine for example, has a very narrow therapeutic range, even a triple overdose is potentially lethal. Quinine therapy is often associated with fever, confusion, dyspnoea, and arrhythmias, and rapid intravenous administration may even result in potentially lethal side effects.
  • Another standard agent sulfadoxine-pyrimethamine (Fansidar) is no longer authorized in Germany since 1992 because of its photosensitizing effect and the risk of toxic epidermolysis.
  • tetracycline derivatives have harmful effects on the growth of bones and teeth and therefore can not be used especially in infants and pregnant women.
  • Mefloquine the most important malaria drug in the developed world, causes neuropsychiatric side effects; Serious side effects occur at curative doses with a probability of 1 in 250. Because of the neuropsychiatric effects, for example, a malaria prophylaxis with mefloquine in aviation pilots is not possible. Therefore, the side effects of malaria drugs are often a reason for premature discontinuation of therapy or prophylaxis. This has the consequence that the development of resistance is further promoted.
  • toxoplasmosis Another example of protozoan-induced infectious diseases is toxoplasmosis. It is caused by Toxoplasma gondii, a protozoan of the coccidia subclass. It is estimated that 25 to 30% of the world's population are chronically infected with toxoplasma. In Germany, seroprevalence correlates fairly closely with age, with approximately 50% of 50-year-olds being latently infected. Infections with toxoplasmas are usually latent and therefore unnoticed, but in particular in primary infection during pregnancy in about 50% of cases diaplazentar can pass to the child and infect the brain and / or eyes of the child.
  • toxoplasmosis occurs as an opportunistic disease, eg in AIDS patients as life-threatening cerebral toxoplasmosis.
  • Transplant recipients with therapeutically induced immunosuppression can also be critically ill with toxoplasmosis.
  • Toxoplasmosis also plays an important role in veterinary medicine. So it comes after infection during pregnancy, for example in sheep to a high rate of spontaneous abortions.
  • coccidia-related protozoa In addition to Toxoplasma gondii, other coccidia-related protozoa also play an important role as pathogens for humans and animals. Called here are the genera Eimeria, Isospora, Sarcocystis, Hammondia, Neospora and Cryptosporidium. Particularly noteworthy as animal pathogens are Eimeria (infections in poultry), Neospora (infections in dogs) and Cryptosporidium (infections in calves). Coccidoses can cause great losses, especially in poultry rearing. In order to avoid this, prophylactic coccidiosis agents are used in the working area. The cost of anti-coccidia in poultry farming is estimated at around US $ 300 million. However, as described above for malaria, resistances to the means used have developed, and thus these remedies are no longer usable after a short time.
  • protozoa plasmodia and coccidia
  • Apicomplexa a parasite group with a common developmental origin, which are characterized by a predominantly intracellular lifestyle.
  • Another important group of parasitic protozoa that frequently cause infectious diseases are the flagellates.
  • infections with Trypanosoma cruzi the causative agent of Chagas' disease
  • infections with Trypanosoma brucei the pathogen of sleeping sickness and infections with Leishmania, the causative agents of leishmaniasis.
  • the present invention has therefore set itself the task of new substances with activity against parasitic protozoa, such as Apicomplexa and To provide flagellates. These new compounds are said to be associated with little side effects, be effective against protozoa and be effective in the lowest possible doses.
  • the aim is to increase the therapeutic scope of these pharmaceutical agents, in particular to the treatment of problematic patient groups, such as children, patients with immunodeficiency, pregnant women, etc. expand.
  • Ri is a hydrogen, OH, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 6 alkenyl group, a C 1 -C 6 alkoxy group or a C 1 -C 6 alkenyloxy group, these groups may be optionally substituted;
  • R 2 is a C 4 -C 2O alkyl group, a C 4 -C 2 O alkenyl group, a C 4 -C 2O alkoxy group or a C 4 -C 2O alkenyloxy group, these groups may optionally be substituted, or 4- (4-halophenyl ) -cyclohexyl, 4-phenylcyclohexyl, which may optionally be substituted;
  • R 3 is 4- (4-halophenyl) cyclohexyl, 4-phenylcyclohexyl, which may optionally be substituted, or hydrogen or OH;
  • R 4 is each independently a C1-C1 0 alkyl, alkenyl, alkoxy, alkenyloxy, amino, or diamino group which may be optionally substituted, piperazin-1-yl, 4-methylpiperazin-i-yl, 4- (C 1 -C 4 alkyl) piperazin-1-yl, OH or halogen;
  • n is an integer from 0 to 4; or pharmacologically acceptable salts, solvates or hydrates thereof.
  • the present invention is based on the finding that an alkyl chain, an alkenyl chain, an alkoxy radical or an alkenyloxy radical at the 2-position of the quinolone derivative according to the formula I exhibits advantageous anti-protozoal properties.
  • this chain is an alkyl chain at position 2 of the quinolone derivative. It should also be emphasized that in contrast to previous quinolone derivatives at position 3 no carboxyl group is present.
  • the present invention is further directed to the use of the quinolone derivatives according to the invention according to the formula I in accordance with the invention
  • Compound with already known anti-protozoal drugs such as already known malaria drugs or toxoplasmosis preparations as combined preparations.
  • these at least two components By the combined use of these at least two components, it is possible to use dosages of these drugs, which do not achieve a therapeutic effect on single administration, so-called sub-anti-protozoan doses.
  • These second anti-protozoal agents are preferably selected from the fluoroquinolones, artemisinin, chloroquine, proguanil, mefloquine, quinine, doxycycline, halofantrine, primaquine, sulfadoxine, tetracycline and in particular
  • Active agents which interfere with the respiratory chain or folic acid metabolism e.g. Pyrimethamine, atovaquone, proguanil.
  • the present invention discloses novel pharmaceutical compositions comprising at least one quinolone derivative according to the general formula I and at least one further anti-protozoan active ingredient.
  • these two agents are for example included in sub-anti-protozoan doses, ie in doses that show no administration of the drug alone anti-protozoal effect, ie in non-therapeutic amounts in monotherapy.
  • Figures 1a, 1 b, and 1c show studies on the inhibition of Toxoplasma gondii by 1-hydroxy-2-dedecyl-4 (1 H) -quinolone (HDQ).
  • Figure 1a shows the concentration-dependent influence of HDQ on the number of parasites per parasitophorous vacuole. It can be clearly seen that the effective concentrations of HDQ are in the nanomolar range.
  • Figure 1b shows the amount of reacted substrate of the enzyme beta-galactosidase determined by photometric determination as a function of the amount of added HDQ. Again, the effect of the HDQ in the nanomolar range is clearly visible.
  • Figure 1c shows the concentration-dependent influence of HDQ on the replication of Plasmodium falciparum. Shown is the parasitemia depending on the concentration of HDQ.
  • Figure 2 depicts the inhibition of Leishmania mexicana growth by HDQ.
  • the parasite count in 0.01 ⁇ l of media is determined as a function of the HDQ concentration. Again, there is an inhibition of growth in the concentrations of HDQ used.
  • Figure 3 shows the effectiveness of various 2-alkyl-1-hydroxy-4 (1H) quinolones.
  • Figure 3a shows the time of destruction of a cell lawn by the protozoa at different concentrations of the various quinolone derivatives.
  • C5, C6, etc. denotes the length of the alkyl group at position 2 according to formula (I) which corresponds to the radical R 2 .
  • Figure 3b shows the results for the C8 derivative in Plasmodium falciparum and Figure 3c for the C12 derivative. It is clear that the IC50 value is lower for the C12 derivative than for the C8 derivative.
  • Figures 4A and 4B show the combined effect of HDQ with known antiprotozoal drugs. As a measure of effectiveness, either the destruction of the cell lawn is used as in Figure 3 (4A) or, as in Figure 1, the number of parasites per parasitophorous vacuole (FIG. 4B).
  • Figure 5 shows a comparison of the anti-parasitic effects of HDQ and moxifloxacin. Again, the complete destruction of the cell lawn is used as a measure of the effectiveness of the drugs.
  • quinolone derivatives have excellent anti-protozoal activity against a wide variety of protozoa, e.g. Show Apicomplexa and Flagellata.
  • the quinolone derivative is a quinolone derivative according to the formula I:
  • Ri is a hydrogen, OH, a CI-C ⁇ alkyl group, a C 3 -C 7 cycloalkyl group, a CrC ⁇ alkenyl group, a Ci-C ⁇ alkoxy group or a Ci-C ⁇ alkenyloxy group, these groups may be optionally substituted;
  • R 2 is a C 4 -C 20 alkyl group, a C 4 -C 20 alkenyl group, a C 4 -C 20 alkoxy group or a C 4 -C 20 alkenyloxy group, these groups may optionally be substituted, or 4- (4-halophenyl) cyclohexyl, 4 -phenylcyclohexyl, which may be optionally substituted;
  • R 3 is 4- (4-halophenyl) cyclohexyl, 4-phenylcyclohexyl, which may optionally be substituted, hydrogen or OH;
  • Each R 4 independently is a C 1 -C 10 alkyl, alkenyl, alkoxy, alkenyloxy, amino, or diamino group which may optionally be substituted, piperazin-1-yl, 4-methyl-piperazin-i-yl, 4- (C 1 -C 4 alkyl) piperazin-1-yl, OH or halogen;
  • n is an integer from 0 to 4; or pharmacologically acceptable salts or solvates or hydrates thereof for the preparation of an anti-protozoan pharmaceutical composition for the prophylaxis and / or treatment of an infection with protozoa and consequent secondary and concomitant diseases.
  • radical R 1 represents a hydrogen, an OH group or a methyl radical.
  • the radical R preferably represents a cycloalkyl group, preferably a C unsubstituted or substituted 3 -C 7 cycloalkyl group such as a cyclopropane group, possible substituents include alkyl, alkoxy, halogen, trifluoromethyl, nitro, acyl, carboxyl, Sulfonic acid residues and the like.
  • R 2 is a C 4 -C 20 alkyl group, more preferably R 2 is a C ⁇ -CU alkyl group, in particular a C-io-Cu alkyl group, such as a Cn, Ci 2 , C 13 or Cu alkyl group. Furthermore, as R 2 is a C 6 -C 4
  • Alkoxy group such as a C 10 -C 14 alkoxy group and especially a Cn
  • Ci 2 , C 13 or Cu alkoxy group may be in the substituted and / or unsubstituted state.
  • R 3 is a hydrogen, OH or CH 3 .
  • n is an integer 0, 1 or 2.
  • the radical R 4 independently of one another preferably denotes a C 1 -C 10 -alkyl group, a 4- (4-halophenyl) -cyclophenyl group or a halogen, such as fluorine, chlorine, bromine or iodine.
  • the radical R 4 is absent, ie n is 0.
  • a particularly preferred embodiment is a quinolone derivative in which R 1 is OH, R 2 is a C 6 -C 12 -alkyl group, R 3 is a hydrogen and n is 0.
  • the quinolone derivative is 1-hydroxy-2-dodecyl-4 (1) quinolone (HDQ).
  • alkyl means a straight-chain or branched-chain or cyclic alkyl radical
  • R The number of carbon atoms in the alkyl radical is called R for the respective radical
  • This alkyl radical may optionally be substituted.
  • substituents are independently one or more of inter alia -C 6 alkyl, -C 6 alkenyl group, CIC east alkoxy (eg methoxy, ethoxy, etc.), OH, halogen (eg Fluorine, chlorine, bromine, iodine), trifluoromethyl, oxo groups,
  • Amino, nitro, substituted or unsubstituted acyl radicals, substituted or unsubstituted aryl radicals, unsubstituted or substituted heteroaryl radicals, carboxyl radicals, sulfonic acid radicals and the like are suitable, these may optionally be substituted again, wherein R 3 is not substituted with a
  • Alkenyl includes straight-chain or branched-chain and cyclic alkenyl groups having the number of carbon atoms mentioned for the respective radicals; these may optionally be substituted.
  • alkoxy is understood as meaning straight-chain or branched-chain or cyclic alkoxy radicals with correspondingly stated number of carbon atoms, these alkoxy radicals being optionally substituted.
  • Alkoxy or "alkenyloxy” denotes a straight-chain or branched-chain or cyclic alkyloxy or alkenyloxy radical having an appropriately stated number of carbon atoms. These alkoxy or alkenyloxy groups may optionally be substituted.
  • the compounds according to the invention allow, for example, for double bonds or chiral groups, the occurrence of spatial isomers.
  • the use of the compounds according to the invention comprises all spatial isomers both as pure substances and in the form of their mixtures.
  • the compounds according to the invention also comprise the corresponding tautomeric forms of the compounds according to the invention, as described e.g. especially for the inventive 1-hydroxy-2-alkyl-4 (1 H) quinolone are conceivable.
  • acyl residues derived from an acid.
  • examples include: alkanoyl, alkenoyl, etc.
  • the aryl radical includes groups such as phenyl, ToIyI, XyIyI, naphthyl and the like, Aroyle, aralkanoyl, Aralkenoyl etc, which may optionally be substituted.
  • aryl or "aryl radical” as used herein, e.g. is used as a substituent, fall aromatic single-ring and multi-ring systems with a corresponding number of hydrogen atoms depending on the further substitution, spiro compounds are also covered by this expression.
  • Suitable aryl radicals are e.g. -phenyl, 1H-indene, 9H-fluorenes, naphthalenes, anthracenes and phenanthrenes.
  • heteroaryl or “heteroaryl” fall aryl ring systems in which one or more of the carbon atoms of the skeleton of the ring system have been replaced by a heteroatom, such as O, N, S.
  • Suitable heteroaryls are:
  • the quinolone derivatives of the invention have an anti-protozoal effect, i. they are for the prophylaxis and / or treatment of a disease caused by infections with protozoa, in particular flagellates such. Leishmania
  • Toxoplasma Eimeria babesia, Isospora; Theileria, Neospora, Cryptosporidia, etc. and resulting secondary and comorbidities in humans and animals, such as mammals, suitable. According to the invention can also
  • the individual active compounds can be used as free bases, or acid or as different salt forms.
  • pharmaceutically acceptable prodrugs of the individual drugs e.g. be used in the form of organic or inorganic esters.
  • the compounds may be present as hydrates or solvates of the active compounds or their salts.
  • salts refers to salts that are toxicologically-safe for human or animal administration.
  • organic or inorganic salts may be selected from a group including hydrochlorides, hydrobromides, hydroiodides, sulfates, Bisulfates, nitrates, citrates, tartrates, bitatrates, phosphates, hydrogen phosphates, dihydrogen phosphates, carbonates, bicarbonates, malates, maleates, fumarates, succinates, acetates, thermophthalates, laurates, palmitates, pamoates and pectinates.
  • sub-anti-protozoic dosage for an individual to be treated, as used herein, refers to a single dose
  • sub-antiprotozoal dosage of an active ingredient depends on the route of administration or the route of administration. Suitable sub-anti-protozoan dosages of the active ingredients can be determined by a person skilled in the art. In any case, a sub-antiprotozoal dosage is below a dosage of the active ingredient as recommended for use alone of the active ingredient as therapeutically effective.
  • compositions of the invention can be prepared in liquid or solid form for enteral or parenteral administration.
  • enteral or parenteral administration all the usual forms of administration are suitable, for example tablets, capsules, dragees, syrups, solutions, suspensions, powders or freeze-dried powders. But they can also be in the form of pastes, potions, granules, jars, medicated feed or drinking water, especially in relation to the treatment of animals.
  • Parenteral administration is e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal, intraocular) or by implants.
  • Suitable formulations are solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels, emulsions and suspensions, solid preparations such as powders, premix or concentrates, granules, pellets, Tablets, capsules; Aerosols, inhalants, active substance-containing moldings.
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additional solubilizers, acids, bases, buffer salts, antioxidants and / or preservatives.
  • the solutions are sterile filtered and bottled.
  • These other additives are common additives used in the pharmacological field.
  • injection solutions may also be reconstituted directly before use from freeze-dried powder with addition of a suitable solvent.
  • Semi-solid preparations may be administered orally or dermally.
  • the active compounds are mixed with suitable excipients, if appropriate with the addition of auxiliaries, and brought into the desired form.
  • suitable carriers are all physiologically compatible solid inert substances, such as inorganic and organic substances.
  • Carriers may further be diluents or excipients as commonly used in pharmaceutical preparations. As additional auxiliaries, preservatives, antioxidants, dyes and binders, etc. are possible.
  • the quinolone derivatives according to the invention are used together with known anti-protozoan active compounds for the preparation of a pharmaceutical composition.
  • active ingredients may also be in the form of a pharmaceutically acceptable salt as hydrates or solvates.
  • the use of a combination therapy by means of the pharmaceutical compositions of the present invention further offers the advantage of enhancing the anti-parasitic activity of the individual substances.
  • the toxicity of the individual substances can be reduced while maintaining the anti-protozoal efficacy. Also a positive effect on the avoidance of the emergence of resistances is to be expected.
  • Contain I as well as at least one other anti-protozoan agent they may be present in a single pharmaceutical formulation.
  • the active ingredients in the form of separate pharmaceutical formulations simultaneously but also be applied sequentially. If the active substances are solids, they can be processed by conventional methods into solid pharmaceutical preparations in which e.g. both active ingredients mixed together and with conventional carrier or
  • Excipients for example, compressed into tablets. But it is also possible that
  • packaging unit contains the two active ingredients in separate pharmaceutical formulations.
  • the formulations may be formulated for administration by the oral, parenteral, topical, dermal, inhalatory route, wherein one of the active ingredients may be administered by a route of administration, while the at least two different active agent may be administered via the same or a different route of administration.
  • the further anti-protozoan agent may be selected from the group consisting of fluoroquinolones, artemethers, chloroquine, proguanil, mefloquine, lumefantrine, quinine, doxycycline, halofantrine,
  • the quinolone derivatives according to the invention in long-term experiments show a stronger inhibitory effect with increasing length of the aliphatic side chain at the position 2 of the formula I, the best values have been obtained with C12 alkyl and C14 alkyl radicals.
  • known solubilizers are used according to the invention or the substituents R 1 , R 3 and / or R 4 are selected such that the solubility of the compounds is increased without significantly lowering the activity.
  • a pegylation of the compounds can be made to increase the solubility, as is generally known from the literature.
  • the quinolone derivatives of the formula I according to the invention have the advantage that, in comparison to the anti-parasitic fluoroquinolones, e.g. Ciprofloxacin or moxifloxacin allow a faster inhibition of protozoan proliferation.
  • quinolone derivatives of the formula I according to the invention and, in particular, in combination with other anti-protozoan active compounds make it possible to reduce the dosages and thus to reduce the side effects.
  • risk groups such as immunocompromised individuals, pregnant women and children can be subjected to prophylaxis and therapy.
  • the use of the quinolone derivatives according to the invention alone or in combination with other anti-protozoal agents in methods for the treatment of individuals infected with protozoa is possible. These methods involve administering the quinolone derivatives of Formula I in a therapeutically effective amount for a sufficiently long period of time.
  • the dosages may vary depending on the route of administration.
  • the administration routes for the at least two active ingredients may be the same or different.
  • the methods of treating infections with protozoa are suitable for humans and animals, in particular for humans and domestic animals, such as e.g. Dogs, cats, poultry, cloven-hoofed animals and horses.
  • the quinolone derivatives according to the invention are capable of inhibiting various apoplexy-containing protoplasts in their replication.
  • various concentrations of the active ingredients were added to infected human host cells.
  • Human foreskin fibroblasts were used as host cells for the obligate intracellular parasite Toxoplasma gondii.
  • the cell culture medium for growth of the human fibroblasts consisted of Dulbecco 's MEM (DMEM) with 10% fetal
  • Fibroblasts were cultured in 24-well dishes to which glass coverslips were previously added. Confluent cell lawns from human fibroblasts were incubated with 2x10 4
  • HDQ 1-hydroxy-2-dodecyl-4 (1H) quinolone
  • the fixed cells which were on glass coverslips, were first incubated with 1% bovine serum albumin (BSA) in PBS for 1 h at room temperature (RT) in order to block unspecific binding sites. Thereafter, the samples were incubated with an anti-Toxoplasma rabbit antiserum (diluted 1: 1000 in PBS / 1% BSA) for 1 h at RT. After washing 3 times in PBS for 2 minutes each, the samples were incubated with a Cy3-conjugated anti-rabbit IgG (1: 500 in PBS / 1% BSA) for 1 h at RT. After washing 3 times in PBS, the samples were fixed with Mowiol on slides and the samples were evaluated in a fluorescence microscope.
  • BSA bovine serum albumin
  • FIG. 1A shows the average number of T. gondii per parasitophorous vacuole at different HDQ concentrations. As can be clearly seen, the effective concentrations are in the nanomolar range and are thus therapeutically extremely interesting. In another test system, this replication rate of T. gondii was also examined under the influence of HDQ. For this purpose, a confluent cell monolayer of human fibroblasts in 24-well dishes containing 1x10 4 beta-galactosidase-expressing T. gondii infected (McFadden DC, Seeber F, Boothroyd JC.
  • Toxoplasma gondii expressing beta-galactosidase for colorimetric assessment of drug activity in vitro Antimicrob Agents Chemother 1997 Sep; 41 (9): 1849-53).
  • the cell lawn was washed 2x with DMEM to remove residual extracellular parasites.
  • the cells were incubated for the further course of the experiment in a cell culture medium that consisted of DMEM without phenol red, as well as 1% FCS, penicillin / streptomycin and the various concentrations of HDQ (1, 0.1, 0.01, and 0.001 ⁇ M).
  • this medium contained 100 ⁇ M CPRG, a substrate that is converted by the beta-galactosidase activity of the parasites.
  • CPRG a substrate that is converted by the beta-galactosidase activity of the parasites.
  • As a measure of the parasite replication was the amount of reacted substrate, which was determined by photometric determination of OD 54 O and OD 6 3o 30h after infection.
  • FCBR Rhoplasminogen activator-like protein
  • the culture medium consisted of RPM1 1640 medium containing 10% human plasma and human blood group A erythrocytes (Rhesus positive). (Trager, W., and Jensen, JB (1976) Science 193, 673-675).
  • the culture bottles were gassed with the following gas mixture: 90% nitrogen, 5% oxygen, 5% CO 2 . Synchronization of the plasmodium cultures was carried out by the sorbitol method (Lambros and Vanderberg, 1979; J Parasitol 65: 418-20).
  • the quinolone derivatives according to the invention are capable of inhibiting the replication of the flagellate-bearing protozoa Leishmania mexicana.
  • different concentrations of HDQ were added to L. mexicana cultures.
  • the promastigote stage of Leishmania mexicana was cultured in T25 cell culture flasks with 5 ml of medium (Mattei DM, Goldenberg S, and Morel C (1977); FEBS Letters 74: 264-268). For passage, every 3-4 days -1x10 6 parasites were added to 5 ml of fresh medium containing 10% FCS. For the inhibition experiments, Leishmania HDQ was added to the fresh medium immediately after passage of the indicated concentrations. The HDQ stock solution had a concentration of 2.5 mM and was dissolved in DMSO. Controls given the same amount of DMSO without HDQ were run in parallel.
  • the active substances were 1-hydroxy-2-alkyl-4 (1H) quinolones, the alkyl chain at position 2 being the following:
  • 1-Hydroxy-2-alkyl-4 (1H) quinolones with alkyl side chains of length C8 and C12 (HDQ) were compared for their growth inhibitory effect on Plasmodium falciparum.
  • the culture conditions were as described in Example 1.
  • IC50 half-maximal inhibitory concentrations
  • the initial parasitemia was 2%. Each drug concentration was tested in triplicates.
  • the IC50 was calculated as follows: The required drug concentration at which the fluorescence signal a Value which lies exactly between that of the untreated control (maximum growth) and that of the choroquine control (maximum inhibition). As can be seen in Figures 3B and 3C, the concentration at which semi-maximal inhibition (IC50) occurs is -14 nM lower for the C12 derivative than for the -70 nM C8 derivative. As with T. gondii, the antiparasitic effect correlates with the length of the side chain.
  • Example 2A the time period in which the fibroblasts survived after T. gondii infection was determined.
  • the morphology of the fibroblast cell lawn in each batch was examined once a day under the phase contrast microscope.
  • the time at which the cell lawn was completely destroyed by parasite growth is shown in Figure 4.
  • the star-marked batches still had an intact lawn of fibroblasts at the end of the experiment on day 12.
  • no medium change was carried out, the addition of the active ingredients thus took place only once at the start of the test.
  • a synergistic effect can be observed with simultaneous administration of HDQ and pyrimethamine.
  • Example 5 Cell culture conditions for this experiment were performed as described in Example 1. In this experiment, cells were treated either once with a) atovaquone, or b) HDQ, or c) a combination of atovaquone and HDQ. The concentrations of the active ingredients used were: 100 nM, 10 nM and 1 nM. In combination approach (c), each of the two individual active substances was used in the concentrations indicated. The evaluation was carried out after 36 h, wherein as described in Example 1, the average number of parasites per parasitophorous vacuole was determined. As can be seen in Figure 4B, the combination of HDQ + atovaquone acts synergistically, with the IC50 value well below 1 nM. Example 5:
  • the cell culture conditions for this experiment were carried out as described in Example 1, except that the strain "NTE" was used instead of the T. gondii strain RH in this experiment In this experiment, the cells were treated either once with a) HDQ or b
  • the final concentrations of the drugs used were for HDQ: 250 nM, 62 nM, 16 nM, 4 nM and 1 nM and for moxifloxacin: 4 ⁇ M, 1 ⁇ M, 250 nM, 62 nM, 16 nM.
  • Flurochinolones e.g. Ciprofloxacin or moxifloxacin show an inhibitory effect on the replication of Toxoplasma gondii only after a time delay (Fichera et al 1997, Nature 390: 407-409). This delayed effect could be confirmed in the experiment described above.
  • a morphological examination in the phase contrast microscope 24 hours after infection showed a limited parasite division even in the highest concentration of 4 .mu.M moxifloxacin.
  • the inhibitory effect of e.g. 100 nM HDQ immediately on, i. the parasites are already prevented from their first cell division.

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Abstract

La présente invention concerne l'utilisation de certains dérivés de quinolone comme agents pharmaceutiques antiprotozoaires sur les êtres humains et les animaux. Cette invention concerne plus précisément l'utilisation de ces dérivés de quinolone dans la prophylaxie et/ou le traitement d'une maladie causée, en particulier, par des protozoaires appartenant à la famille des apicomplexes ou des flagellés. Ladite invention se rapporte enfin à des associations médicamenteuses contenant les dérivés de quinolone selon l'invention et au moins un autre principe actif antiprotozoaire ainsi que leur utilisation dans la prophylaxie et le traitement d'infections à protozoaires.
PCT/DE2007/000879 2006-05-15 2007-05-15 Utilisation de dérivés de quinolone comme agents antiprotozoaires et dans des associations médicamenteuses WO2007131488A2 (fr)

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DE102006022908A DE102006022908A1 (de) 2006-05-15 2006-05-15 Verwendung von Chinolonderivaten als antiprotozoäre Mittel und in Kombinationspräparaten
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Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BIAGINI GIANCARLO A ET AL: "Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria" ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Bd. 50, Nr. 5, Mai 2006 (2006-05), Seiten 1841-1851, XP002458398 ISSN: 0066-4804 *
BIAVATTI, MAIQUE W. ET AL: "Biological activity of quinoline alkaloids from Raulinoa echinata and X-ray structure of flindersiamine" JOURNAL OF THE BRAZILIAN CHEMICAL SOCIETY , 13(1), 66-70 CODEN: JOCSET; ISSN: 0103-5053, 2002, XP002458397 *
CASEY A C: "4(1H) quinolones. 2. Antimalarial effect of some 2 methyl 3 (1' alkenyl) or 3 alkyl 4(1H) quinolones" JOURNAL OF MEDICINAL CHEMISTRY 1974, Bd. 17, Nr. 2, 1974, Seiten 255-256, XP002458400 ISSN: 0022-2623 *
ESCHEMANN ANDREA ET AL: "HDQ (1-hydroxy-2-dodecyl-4(1H)quinolone), a high affinity inhibitor for mitochondrial alternative NADH dehydrogenase" JOURNAL OF BIOLOGICAL CHEMISTRY, Bd. 280, Nr. 5, 4. Februar 2005 (2005-02-04), Seiten 3138-3142, XP002458399 ISSN: 0021-9258 *
MUNSON H R ET AL: "ANTIMALARIALS.10.SUBSTITUTED 3-HALO- AND 3-METHOXY-2-ARYL-4- QUINOLINE (DI-N-BUTYLAMINOMETHYL)METHANOLS" JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, Bd. 18, Nr. 12, 1. Dezember 1975 (1975-12-01), Seiten 1232-1236, XP000645380 ISSN: 0022-2623 *
SALEH AHMAD ET AL: "Growth inhibition of Toxoplasma gondii and Plasmodium falciparum by nanomolar concentrations of 1-hydroxy-2-dodecyl-4(1H)quinolone, a high-affinity inhibitor of alternative (type II) NADH dehydrogenases" ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Bd. 51, Nr. 4, April 2007 (2007-04), Seiten 1217-1222, XP002458401 ISSN: 0066-4804 *

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