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WO2016169908A1 - Dérivés d'uracile pour le traitement de la malaria - Google Patents

Dérivés d'uracile pour le traitement de la malaria Download PDF

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Publication number
WO2016169908A1
WO2016169908A1 PCT/EP2016/058604 EP2016058604W WO2016169908A1 WO 2016169908 A1 WO2016169908 A1 WO 2016169908A1 EP 2016058604 W EP2016058604 W EP 2016058604W WO 2016169908 A1 WO2016169908 A1 WO 2016169908A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
methyl
mmol
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PCT/EP2016/058604
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Inventor
Jose Maria Bueno Calderon
Mariola GORDO-LOPEZ
Esther Pilar Fernandez Velando
Jorge Fernandez-Molina
Maria Luisa Leon-Diaz
Jose Ignacio Martin Hernando
David Matthew Wilson
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GlaxoSmithKline Intellectual Property Development Ltd
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GlaxoSmithKline Intellectual Property Development Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • 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 novel dione compounds having pharmacological activity, processes for their preparation, pharmaceutical compositions and their use in the treatment of certain parasitic protozoal infections such as malaria, in particular infection by Plasmodium falciparum.
  • Parasitic protozoal infections are responsible for a wide variety of diseases of medical and veterinary importance, including malaria in man and various coccidioses in birds, fish and mammals. Many of the diseases are life-threatening to the host and cause considerable economic loss in animal husbandry, such as diseases caused by infection by species of Eimeria, Theileria, Babesia, Cryptosporidium, Toxoplasma (such as Toxoplasma brucei, African sleeping sickness and Toxoplasma cruzi, Chagas disease) and Plasmodium (such as Plasmodium falciparum), and the Mastigophora such as species of Leishmania (such as Leishmania donovani).
  • Another parasitic organism of increasing concern is Pneumocytis carinii, which can cause an often fatal pneumonia in immunodeficient or immunocompromised hosts, including those infected with HIV.
  • Malaria is a mosquito-borne disease that, in humans, can be caused by five species of Plasmodium parasite, of which Plasmodium falciparum is the most virulent.
  • Plasmodium parasite of which Plasmodium falciparum is the most virulent.
  • malarial disease was responsible for an estimated 584,000 deaths (90% of them in sub-saharian Africa), young children and pregnant women being the most affected groups.
  • the present invention is directed to novel dione compounds for use in the chemotherapy of certain parasitic infections such as malaria, and in particular infection by Plasmodium falciparum, processes for their preparation and pharmaceutical compositions comprising such a compound.
  • the present invention provides compounds of Formula (I):
  • R-i is morpholinyl or pyridyl
  • R 2 is fluoro or hydrogen when R-i is morpholinyl
  • R 2 is hydrogen when R-i is pyridyl
  • pharmaceutically acceptable salts are also included in the present invention.
  • pharmaceutically acceptable salts of compounds of Formula (I) may be preferred over the respective free base because such salts impart greater stability or solubility to the molecule thereby facilitating formulation into a dosage form. Therefore, the present invention also covers the pharmaceutically acceptable salts of compounds of Formula (I).
  • pharmaceutically acceptable salt refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesired toxicological effects.
  • suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1 -19.
  • pharmaceutically acceptable salt includes any pharmaceutically acceptable acid or basic addition salts.
  • These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free base form with a suitable acid or base, respectively.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the invention provides a pharmaceutically acceptable salt of compounds of Formula (I) thereof.
  • the compounds of Formula (I) contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • a pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of Formula (I) with a suitable strong inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, perchloric, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g.
  • 2- naphthalenesulfonic optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • Pharmaceutically acceptable acid addition salts include a hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, nitrate, phosphate, perchlorate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, hemi-edisylate naphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt.
  • a pharmaceutically acceptable acid addition salt of a compound of Formula (I) is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.
  • a strong acid for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.
  • Suitable pharmaceutically acceptable salts of compounds of Formula (I) include mono- or di- basic salts with the appropriate base.
  • a pharmaceutically acceptable basic addition salt may be formed by reaction of a compound of Formula (I) with a suitable inorganic or organic base.
  • Pharmaceutically acceptable basic addition salt include sodium, potassium, calcium, magnesium, ammonium, N-methylglucamine, ammonium and choline salts
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of compounds of Formula (I).
  • Compounds of Formula (I) or a pharmaceutically acceptable salt thereof may exist as solids or liquids, both of which are included in the invention. In the solid state, compounds of Formula (I) or pharmaceutically acceptable salts thereof, may exist as either amorphous material or in crystalline form, or as a mixture thereof. Compounds of Formula (I) or a pharmaceutically acceptable salt thereof, may exist in solvated or unsolvated forms and may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallisation.
  • Solvates may involve non-aqueous solvents such as ethanol, isopropanol, dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Salts of a compound of Formula (I) may be prepared by contacting appropriate stoichiometric amounts of the free base/acid with the appropriate acid/base in a suitable solvent. The free base/acid of a compound of Formula (I) may for example be in solution with the appropriate acid/base added as a solid or both the free base/acid of a compound of Formula (I) and the appropriate acid/base may independently be in solution.
  • DMSO dimethylsulfoxide
  • Suitable solvents for solubilising a compound of Formula (I) free base include for example alcohols such as isopropanol; ketones such as acetone; acetonitrile or toluene. If the base is to be added as a solution in a solvent, the solvent used may include acetone, methanol or water.
  • the salts of a compound of Formula (I) may be isolated in solid form by conventional means from a solution thereof obtained as above.
  • a non-crystalline salt may be prepared by precipitation from solution, spray drying or freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.
  • the salts of a compound of Formula (I) may be prepared by directly crystallising from a solvent in which the salt has limited solubility, or by triturating or otherwise crystallising a noncrystalline salt.
  • salts and solvates of a compound of Formula (I) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of a compound of Formula (I) or their pharmaceutically acceptable salts.
  • prodrugs for compounds of Formula (I) or salts or solvates thereof include : amides, carbamates, azo-compounds, phosphamides, glycosides.
  • compounds of Formula (I) may be in the form of their free base or a pharmaceutically acceptable salt, solvate, or prodrug of compounds of Formula (I), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of Formula (I), or an active metabolite or residue thereof.
  • Such pharmaceutically acceptable salts, solvates, and prodrugs are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • some of the crystalline forms of compounds of Formula (I) or salts thereof may exist in one or more polymorphic form, which are included in the present invention.
  • Compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be useful in the treatment of certain parasitic infections such as parasitic protozoal infections by the malarial parasite Plasmodium falciparum, species of Eimeria, Pneumocytis carinii, Trypanosoma cruzi, Trypanosoma brucei or Leishmania donovani.
  • compounds of Formula (I) or pharmaceutically acceptable salts thereof can be useful for treatment of infection by Plasmodium falciparum. Accordingly, the invention is directed to methods of treating such infections. Therefore, there is provided compounds of Formula (I) or pharmaceutically acceptable salts thereof, for use in therapy.
  • compounds of Formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of a parasitic protozoal infection In another aspect of the invention there is provided compounds of Formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of malaria.
  • a method for the treatment of a human or animal subject suffering from a parasitic protozoal infection comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a human or animal subject suffering from malaria comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for the treatment of a human or animal subject suffering from a parasitic protozoal infection by Plasmodium falciparum comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula (I), and a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • treatment means: (1 ) the amelioration or prevention of the condition being treated or one or more of the biological manifestations of the condition being treated, (2) the interference with (a) one or more points in the biological cascade that leads to or is responsible for the condition being treated or (b) one or more of the biological manifestations of the condition being treated, or (3) the alleviation of one or more of the symptoms or effects associated with the condition being treated.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • an "effective amount” or a “safe and effective amount” means an amount of the compound sufficient to significantly induce a positive modification in the condition to be treated but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will vary with the particular compound chosen (e.g.
  • the route of administration chosen depends on the potency, efficacy, and half-life of the compound); the route of administration chosen; the nature of the infection and/or condition being treated; the severity of the infection and/or condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other animal subject.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered once only, or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. The dosage will also vary according to the nature of the intended treatment, wherein "treatment” is as herein defined, for example a greater dose of compound may be given for amelioration as compared with prevention of a condition being treated.
  • Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered depend on the route of administration of the compound, on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of any concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • the dosing regimen of the compound of the invention may also vary according to the nature and amount of the one or more additional active therapeutic agents as necessary.
  • Typical dosages of a compound of Formula (I) may vary depending upon the particular route of administration chosen. Typical dosages for oral administration are predicted to be in a range from about 25 to about 1000mg. Typically a compound of Formula (I) may be administered once a day, once every two days or even up to once weekly.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may also be used in combination with other active therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof together with a further active therapeutic agent.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second active therapeutic agent which is active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be used alone or in combination with one or more additional active therapeutic agents, such as other antiparasitic drugs, for example antimalarial drugs.
  • Such other active therapeutic agents include antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quinine, artemisinin, halofantrine, doxycycline, amodiaquine, atovaquone, tafenoquinedapsone, proguanil, sulfadoxine, cycloguanil) and fansidar.
  • antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quinine, artemisinin, halofantrine, doxycycline, amodiaquine, atovaquone, tafenoquinedapsone, proguanil, sulfadoxine, cycloguanil) and fansidar.
  • antimalarial drugs such as (e.g. chloroquine, mefloquine, primaquine, pyrimethamine, quin
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier and/or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or the one or more additional active therapeutic agent(s) may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the one or more additional active therapeutic agent(s) must be stable and compatible with each other and the other components of the formulation.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the one or more additional active therapeutic agent(s) may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient.
  • the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a pharmaceutical composition comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable carriers.
  • the invention provides a pharmaceutical composition comprising (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.
  • the carrier and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from about 0.1 to 1000mg, in another aspect 0.1 mg to about 500 mg of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain one compound of Formula (I) or a pharmaceutically acceptable salt thereof. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the invention contain two compounds of Formula (I).
  • the pharmaceutical compositions of the invention may optionally further comprise one or more additional active therapeutic compounds.
  • the pharmaceutical compositions of the invention typically contain more than one pharmaceutically acceptable excipient.
  • the pharmaceutical compositions of the invention contain one pharmaceutically acceptable excipient.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; and (5) inhalation such as aerosols and solutions.
  • Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carriage or transport of compounds of Formula (I) or pharmaceutically acceptable salts thereof from one organ, or portion of the body, to another organ, or portion of the body, once administered to the patient.
  • Certain pharmaceutically acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically acceptable excipients include the following types of excipients: binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid or liquid oral dosage form such as a liquid, tablet, lozenge or a capsule, comprising a safe and effective amount of a compound of the invention and a carrier.
  • the carrier may be in the form of a diluent or filler.
  • Suitable diluents and fillers in general include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • a liquid dosage form will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • a liquid carrier for example, ethanol, olive oil, glycerine, glucose (syrup) or water (e.g. with an added flavouring, suspending, or colouring agent).
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc,
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums or oils, and may be incorporated in a soft capsule shell.
  • An oral solid dosage form may further comprise an excipient in the form of a binder.
  • Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose).
  • the oral solid dosage form may further comprise an excipient in the form of a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise an excipient in the form of a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.
  • a process of preparing a pharmaceutical composition which process comprises mixing compounds of Formula (I) or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier and/or excipient.
  • Preparations for oral administration may be suitably formulated to give controlled/extended release of the active compound.
  • the compounds of formula (I) may be synthesised by asymmetric or non-asymmetric routes.
  • a non-asymmetric synthesis of compounds of Formula (I) is shown in Scheme 1 .
  • the reaction mixture was partially evaporated under reduced pressure to remove volatiles then the residue was partitioned between half-saturated sodium bicarbonate solution (100 mL) and EtOAc (100 mL).[NB it was necessary to filter the aqueous/organic mixture to help avoid emulsion formation].
  • the aqueous phase was further extracted with EtOAc (3 x 50 mL).
  • the combined organic phases were washed with brine (50 mL), dried over Na 2 S0 4 and evaporated under reduced pressure.
  • the residue was chromatographed on NH-modified silica gel (SNAP 28) eluting with a gradient of 50-100% EtOAc in cyclohexane but many product containing fractions were mixed.
  • Phenyl chloroformate (ALDRICH, 10.53 mL, 84 mmol) was added at 0 °C to a solution of ethyl 3-amino-2-(morpholin-4-yl)but-2-enoate (intermediate 9, 15 g, 70 mmol) and pyridine (ALDRICH, 1 1.32 mL, 140 mmol) in chloroform (73 mL). The resulting mixture was allowed to reach room temperature and stirred overnight. The reaction was diluted with EtOAc and it was washed with 0.5 M HCI, saturated aqueous sodium bicarbonate and brine.
  • reaction mixture was allowed to warm slowly to room temperature and stir for 4 hours.
  • the reaction mixture was diluted with EtOAc (100 mL), washed with 1 M HCI solution (50 mL), sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulphate and evaporated under reduced pressure.
  • Chiral separation was carried out by semi-preparative chiral HPLC (Column Chiralpack IC 20X250mm, isocratic gradient Hexane:Ethanol 85:15; wavelenght 254 nm, flow 14 mL/min) to obtain, eluting the second compound.
  • a compound of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • the assays are described below.
  • the sensitivity of P. falciparum infected erythrocytes to the compound is determined in triplicate using the [3H]hypoxanthine incorporation method with an inoculum of 0.5% parasitemia (ring stage) and 2% hematocrit.
  • the parasites were grown in RPMI 1640, 25 mM HEPES and supplemented with 5% Albumax. Plates are incubated at 37°C, 5% C02, 5% 02, 90% N2. After 24h of incubation, [3H]hypoxanthine is added and plates are incubated for another 24 h. After that period, plates are harvested on a glass fiber filter using a TOMTEC Cell harvester 96.
  • Antimalarial in vivo efficacy was determined using the P.falciparum mouse model following the procedure described in: Jimenez-Diaz, M.B., Mulet, T., Viera, S., Gomez, V., Garuti, H., Ibafiez, J., Alvarez-Doval, A., Shlutz, D.L., Martinez, A., Improved Murine Model Of Malaria Using Plasmodium falciparum (Competent Strains and Non-Myelodepleted NOD-sc/c/ ⁇ L2R_nu ⁇

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

Abstract

La présente invention concerne un composé de formule (I) ayant une activité pharmacologique, des procédés pour sa préparation, des compositions pharmaceutiques et leur utilisation dans le traitement de certaines infections causées par des protozoaires parasites telles que la malaria, en particulier une infection par Plasmodium falciparum. R1 est un groupe morpholinyle ou pyridyle; R2 est fluoro ou hydrogène lorsque R1 est un groupe morpholinyle; et R2 est un atome d'hydrogène lorsque R1 est pyridyle ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/EP2016/058604 2015-04-21 2016-04-19 Dérivés d'uracile pour le traitement de la malaria Ceased WO2016169908A1 (fr)

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CN112300081A (zh) * 2019-07-31 2021-02-02 上海度德医药科技有限公司 噁拉戈利的中间体及其制备方法和应用

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WO2007138048A1 (fr) * 2006-05-31 2007-12-06 Glaxo Group Limited Nouveaux composés hétérocycliques
WO2014067985A1 (fr) * 2012-10-31 2014-05-08 Irbm Science Park S.P.A. Composés destinés à être utilisés dans le traitement de maladies parasitaires

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ADELE M. LEHANE ET AL: "Diverse chemotypes disrupt ion homeostasis in the malaria parasite", MOLECULAR MICROBIOLOGY., vol. 94, no. 2, 15 October 2014 (2014-10-15), GB, pages 327 - 339, XP055270931, ISSN: 0950-382X, DOI: 10.1111/mmi.12765 *
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300081A (zh) * 2019-07-31 2021-02-02 上海度德医药科技有限公司 噁拉戈利的中间体及其制备方法和应用

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