WO2015030504A1 - Pharmaceutical composition for prevention or treatment of toxoplasmosis, comprising anti-non-small cell lung cancer agent as active ingredient - Google Patents

Pharmaceutical composition for prevention or treatment of toxoplasmosis, comprising anti-non-small cell lung cancer agent as active ingredient Download PDF

Info

Publication number
WO2015030504A1
WO2015030504A1 PCT/KR2014/008031 KR2014008031W WO2015030504A1 WO 2015030504 A1 WO2015030504 A1 WO 2015030504A1 KR 2014008031 W KR2014008031 W KR 2014008031W WO 2015030504 A1 WO2015030504 A1 WO 2015030504A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
toxoplasma
lung cancer
small cell
cell lung
Prior art date
Application number
PCT/KR2014/008031
Other languages
French (fr)
Korean (ko)
Inventor
남호우
Original Assignee
가톨릭대학교 산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR20130104884A external-priority patent/KR101508611B1/en
Priority claimed from KR1020130104885A external-priority patent/KR101538385B1/en
Priority claimed from KR1020130104886A external-priority patent/KR101540739B1/en
Priority claimed from KR1020130104883A external-priority patent/KR101508610B1/en
Application filed by 가톨릭대학교 산학협력단 filed Critical 가톨릭대학교 산학협력단
Publication of WO2015030504A1 publication Critical patent/WO2015030504A1/en

Links

Images

Classifications

    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • the present invention relates to a pharmaceutical composition, a veterinary composition, an adjuvant for adjuvant, and a method for preventing or treating toxoplasma infection, comprising the non-small cell lung cancer treatment agent as an active ingredient.
  • Toxoplasma gondii is an opportunistic protozoan parasite that invades macrophages and infects the central nervous system.
  • Toxoplasma worms are infected with oocyst from feces of cats, which are infected by drinking contaminated water directly or by ingesting them on vegetables, or as a cyst to meats such as pigs, sheep and cows, which are intermediate hosts. It is infected by feeding on toxoplasma worms present, and can be infected by various warm-blooded animals including humans. About one third of the world's population is infected with toxoplasma spp., And in Korea, it is reported that the infection rate is 2 to 25% depending on the group.
  • the treatment for toxoplasma worm infection includes the administration of spiramycin or pyrimethamine alone, or a combination of pyrimethamine and sulfa, which have been developed as an antimalarial drug.
  • the treatment method is used for 2-3 weeks, and especially when combined administration is showing a good effect.
  • Stevens-Johnson syndrome which is the main symptom of skin and mucous membrane detachment, may be a side effect of the co-administration. Therefore, it is urgent to develop a safer therapeutic agent.
  • composition comprising an oleuropine compound isolated from ash tree (Domestic Patent Registration No. 10-0834444), 1- [4- (4-nitro-phenoxy-phenyl -Propan-1-one compound (Domestic Patent Registration No. 10-1148098), 1,5-diphenyl-8-methyl-6,7-dioxa-bicyclo [3.2.2] nonanebeta body compound (Domestic Patent Registration No. 10-0946466), 7-ethoxycoumarin (Domestic Patent Registration No. 10-0903287), and the like have been proposed, but the effect has not been fully verified yet.
  • dacomitinib is a target anticancer agent used in patients with advanced non-small cell lung cancer, and acts as an inhibitor of tyrosine kinase, thereby signaling epidermal growth factor receptor (EGFR). By preventing the treatment effect.
  • Dacomitinib refers to compound PF-00299804, developed by Pfizer, which is commercially available.
  • afatinib is an oral lung cancer drug used in patients with metastatic non-small cell lung cancer, and acts as an inhibitor of tyrosine kinase, thereby signaling epidermal growth factor receptor (EGFR). By preventing the treatment effect.
  • Afatinib refers to compound BIBW2992, developed by Boehringer Ingelheim, and is commercially available under the trade name Geotrip.
  • crizotinib is a lung cancer target anticancer agent used in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, and acts as an inhibitor of c-MET / ALK (hepatocyte growth factor receptor). It has a therapeutic effect by preventing the epidermal growth factor receptor (EGFR) signaling.
  • Crizotinib refers to compound PF-02341066, developed by Pfizer, which is commercially available.
  • pelitinib is a target anticancer agent used in patients with non-small cell lung cancer, and selectively inhibits tyrosine kinase activity of epidermal growth factor receptor (EGFR) of tumor cells. It has a therapeutic effect by blocking signals involved in cell growth.
  • EGFR epidermal growth factor receptor
  • Pellitinib refers to compound EKB-569, which is commercially available from Selleck Chemicals.
  • the inventors of the present invention have shown that dacomitinib, afatinib, crizotinib, or pelitinib, which are known as only anticancer drugs, are surprisingly excellent in inhibiting the division and proliferation of toxoplasma worms.
  • the present invention was completed by confirming that it is possible.
  • One object of the present invention to provide a pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising a non-small cell lung cancer treatment agent dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof will be.
  • One object of the present invention to provide a veterinary composition for the prevention or treatment of toxoplasma gonitis infection, including non-small cell lung cancer treatment agent dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof It is.
  • One object of the present invention to provide an adjuvant for the prevention or treatment of toxoplasma gonitis infection, including dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof, which is a non-small cell lung cancer treatment agent. It is.
  • Another object of the present invention comprises administering to a subject an effective amount of a composition comprising dacomitinib, afatinib, crizotinib, or pelitinib, or a pharmaceutically acceptable salt thereof, for treating non-small cell lung cancer
  • a composition comprising dacomitinib, afatinib, crizotinib, or pelitinib, or a pharmaceutically acceptable salt thereof, for treating non-small cell lung cancer
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising a non-small cell lung cancer therapeutic agent as an active ingredient.
  • the non-small cell lung cancer therapeutic agent may be a compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof:
  • Formula 1 may be purchased as a commercially available "dacomitinib" (dacomitinib), the chemical name '(E) -N- (4- (3-chloro-4-fluorophenylamino) -7- Methoxyquinazolin-6-yl) -4- (piperidin-1-yl) -2-butynamide '.
  • dacomitinib is used herein to include all of dacomitinib and its racemates, enantiomers, homologues, hydrates, and solvates.
  • Formula 2 may be purchased as a commercially available "afatinib", the chemical name is' N- [4-[(3-chloro-4-fluorophenyl) amino] -7-[[ (3S) -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4- (dimethylamino) -2-butynamide '.
  • afatinib is used herein to include all of afatinib and its racemates, enantiomers, homologues, hydrates, and solvates.
  • Formula 3 may be purchased commercially available as "crizotinib", the chemical name is' 3-[(1R) -1- (2,6-dichloro-3-fluorophenyl) ethoxy ] -5- (1-piperidin-4-ylpyrazol-4-yl) pyridin-2-amine '.
  • crizotinib is used to mean all of crizotinib and its racemates, enantiomers, homologues, hydrates, and solvates thereof.
  • Formula 4 may be purchased as a commercially available "pelitinib", the chemical name is' N- [4- (3-chloro-4-fluorophenylamino) -3-cyano-7- Ethoxyquinolin-5-yl] -4- (dimethylamino) -2 (E) -butynamide '.
  • Pellitinib is commercially available and can be synthesized through known synthetic methods. The synthesis method is disclosed in "Strategies for Organic Drug Synthesis and Design by Daniel Lednicer” as follows.
  • pelitinib is used herein to include both pelitinib and its racemates, enantiomers, homologues, hydrates, and solvates.
  • the present invention relates to a pharmaceutical composition for the prevention or treatment of toxoplasma nephritis, comprising a non-small cell lung cancer therapeutic agent, such as dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof.
  • a non-small cell lung cancer therapeutic agent such as dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof.
  • the toxoplasma worm infection may be an infection caused by Toxoplama gondii .
  • the toxoplasma worm infection may be one or more selected from the group consisting of retinitis, choroiditis and retinal choroiditis.
  • the pharmaceutical composition may comprise 0.1 to 50% by weight of dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides a method of treating a non-small cell lung cancer, preferably an effective amount of a composition comprising dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It relates to a method for preventing or treating Toxoplasma worm infection comprising the step of administering).
  • the present invention is for the prevention or treatment of toxoplasmosis infection comprising a non-small cell lung cancer treatment agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof It relates to a veterinary composition.
  • the veterinary composition may be a composition that is applied to an animal subject to toxoplasma worm infection is mammalian or poultry.
  • the present invention is for the prevention or treatment of toxoplasmosis infection comprising a non-small cell lung cancer treatment agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof An antigen supplement adjuvant.
  • toxoplasma worm infection refers to a disease caused by an infection of toxoplasma worm , more preferably, Toxoplama gondii , which is a kind of protozoa, including abortion and infertility when a woman is infected during pregnancy. It is a type of common infectious disease that can cause abnormalities in the fetus. Toxoplasma worm infection can also be expressed as "toxoplasmosis".
  • Toxoplasma worm infections in the present invention include all diseases and symptoms that can be caused by the infection of toxoplasma worms.
  • Toxoplasma worms can live in various parts of the body, such as the lymph glands, brain, lungs, myocardium, spleen, bone marrow, kidneys, adrenal glands, and nervous system. Rapid tachyzoite is active in reticulum and circulatory endothelial cells. Division and proliferation can necrotic tissue.
  • various diseases and symptoms may be caused according to the infected area, for example, lymphadenitis, retinal choroiditis, meningitis, encephalomyelitis, hepatitis, myositis, myocarditis, pneumonia, and tubule diseases.
  • the toxoplasma infection in the present invention may be an infectious disease appearing in the retina or choroid, and may exemplify retinitis, choroiditis, and retinal choroiditis. Since the retina is in contact with the choroid, if the retina is inflamed, the choroid may also change. In contrast, the choroid may cause changes in the retina. Therefore, retinitis and choroiditis often appear together, and this is called retinal choroiditis or chorioretinitis.
  • Toxoplasma worms make pockets in the brain, eyes, and liver when they enter the body, and then become active again when the immune system is weakened. Toxoplasma worms can cause retinitis, choroiditis, and retinal choroiditis if they invade the eye and cause inflammation. have.
  • the treatment of retinal epithelial cells with dacomitinib inhibits the proliferation of toxoplasma worms, whereby dacomitinib exhibits a therapeutic effect comparable to that of pyramidamine, a conventional toxoplasma treatment. It was confirmed.
  • crizotinib in another embodiment of the present invention, by treating the retinal epithelial cells with crizotinib to inhibit the proliferation of toxoplasma worms, crizotinib exhibits a therapeutic effect comparable to that of the conventional toxoplasma worm pyrimethamine. It was confirmed.
  • pelinib by treating the retinal epithelial cells with pelinib, inhibiting the proliferation of toxoplasma worms, it was confirmed that pelinib exhibits a therapeutic effect comparable to that of pyrimethamine, which is a conventional toxoplasma cure It was.
  • the present invention is directed to an adjuvant for preventing or treating Toxoplasma gondii infections, including a non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It is about.
  • a non-small cell lung cancer therapeutic agent preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It is about.
  • the term "antigen supplement” refers to a medicament that can be used with the main antiprotozoal agent.
  • the present invention provides a method of administering to a subject an effective amount of a composition comprising a non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It provides a method for preventing or treating Toxoplasma worm infection comprising the step.
  • prevention refers to any action that inhibits or delays the onset of toxoplasmosis infection by administration of a composition according to the invention.
  • treatment refers to any action by which administration of a composition according to the present invention improves or advantageously alters the symptoms of toxoplasmosis infection.
  • the present invention provides an active ingredient for the prevention or treatment of Toxoplasma worm infection, and provides a non-small cell lung cancer therapeutic agent such as dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically or veterinary acceptable salt thereof. It is characterized by.
  • the present invention may also include a non-small cell lung cancer treatment agent, preferably a pharmaceutically acceptable salt of dacomitinib, afatinib, crizotinib, or pelitinib as an active ingredient.
  • a pharmaceutically acceptable salt of dacomitinib, afatinib, crizotinib, or pelitinib as an active ingredient.
  • pharmaceutically acceptable salts includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases.
  • veterinary acceptable salt includes salts derived from veterinary acceptable inorganic, organic, or bases.
  • acids examples include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like.
  • Acid addition salts can be prepared by conventional methods, for example by dissolving a compound in an excess of an aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It is also possible to prepare equimolar amounts of the compound and acid or alcohol in water and then evaporate the mixture to dryness or to precipitate filtered salts by suction filtration.
  • a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile.
  • Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, and ammonium and the like.
  • An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate.
  • the metal salt it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
  • Combination treatment of pyrimethamine and sulfa which is currently used as a treatment for toxoplasmosis, continues to increase its resistance and has little effect on toxoplasmosis at the Bradyzoite stage. Stevens Johnson syndrome can cause side effects.
  • non-small cell lung cancer therapeutic agents such as dacomitinib, afatinib, crizotinib or pelitinib
  • dacomitinib afatinib
  • crizotinib afatinib
  • the content of the non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progression of symptoms, the condition of the patient, For example, it is preferably 0.0001 to 99.9% by weight, preferably 0.001 to 50% by weight based on the total weight of the composition, but is not limited thereto.
  • the content ratio is a value based on the drying amount from which the solvent is removed.
  • composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical and veterinary compositions, and powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols according to conventional methods Oral formulations, external preparations, suppositories, or sterile injectable solutions and the like.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions can be prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient and / or lubricants, and the like.
  • Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups.
  • various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
  • Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • the term “therapeutically effective amount” or “effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to toxoplasmosis treatment, with the effective dose level being an individual type, condition and severity, age, sex. According to the type of infected bacteria, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, the factors including the drug used concurrently and other factors well known in the medical arts, Can be selected. For a more preferable effect, the dosage of the composition of the present invention is preferably 0.1 mg / kg to 100 mg / kg per day based on the active ingredient, but is not limited thereto.
  • compositions of the present invention can be administered by various routes to an animal, preferably a mammal, including a human. All modes of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous injection or the like.
  • compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
  • compositions of the present invention include, but are not limited to, humans, mammals such as pigs, cows and goats, poultry such as pheasants, chickens, ducks, and turkeys.
  • Toxoplasma gonitis infectious agent provided by the present invention, safe to humans and animals without toxicity or side effects, and excellent killing effect on toxoplasma spores, can be widely used in the pharmaceutical and veterinary fields.
  • Figure 1 compares the growth inhibitory effect of toxoplasma spp. Of various protein kinase inhibitors (sunitinib, dacomitinib), a positive control pyrimethamine, and an untreated control.
  • Figure 2 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with dacomitinib.
  • Figure 3 compares the inhibitory effect of toxoplasmosis growth of various protein kinase inhibitors (sunitinib, afatinib), a positive control pyrimethamine, and an untreated control.
  • Figure 4 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with afatinib.
  • Figure 5 compares the inhibitory effect of toxoplasmosis growth of various protein kinase inhibitors (sunitinib, crizotinib), a positive control pyrimethamine, and an untreated control.
  • Figure 6 shows the cleavage of Toxoplasma gondii in the protozoan-containing membrane in retinal cells according to incubation time after treatment with crizotinib.
  • FIG. 7 compares the growth inhibitory effects of toxoplasma spp. Of various protein kinase inhibitors (sunitinib, pelitinib), a positive control pyrimethamine, and an untreated control group.
  • Figure 8 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with pelitinib.
  • the host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used.
  • Protein kinase inhibitors include sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 ⁇ M, pyrimethamine (purchased from Sigma Chem Co.) 5.0 ⁇ M, and dacomitinib (obtained from Selleck Chemicals) 5.0 ⁇ M Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
  • sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes produced in retinal cells, whereas dacomitinib showed an effect at 5.0 ⁇ M or more.
  • Inhibition of fission growth equivalent to pyrimethamine (5.0 ⁇ M) used as a control drug was not treated with the toxoplasma schizophrenic growth, but in the Dacomitinib treated group toxoplasma worms did not multiply and maintained the first infiltrated form.
  • Host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used.
  • Protein kinase inhibitors include Sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 ⁇ M, pyrimethamine (purchased from Sigma Chem Co.) 5.0 ⁇ M, and afatinib (afatinib; purchased from Selleck Chemicals) 5.0 ⁇ M Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
  • sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes generated in retinal cells, whereas afatinib showed an effect at 5.0 ⁇ M or more.
  • Inhibition of fission growth equivalent to pyrimethamine (5.0 ⁇ M) used as a control drug was not treated with toxoplasma spp., But in the afatinib treated group, the toxoplasma spp. Almost did not proliferate and maintained the first infiltrated form.
  • the host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used.
  • Protein kinase inhibitors include sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 ⁇ M, pyrimethamine (purchased from Sigma Chem Co.) 5.0 ⁇ M, and crizotinib (obtained from Sigma Chem Co.) 5.0 ⁇ M was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours, the number of toxoplasma spp. Per protozoan membrane was counted and its effect was confirmed.
  • sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes produced in retinal cells, whereas crizotinib showed an effect at 5.0 ⁇ M or more.
  • Inhibition of fission growth equivalent to pyrimethamine (5.0 ⁇ M) used as a control drug was not treated with the toxoplasma spp., But in the cryostinib-treated group, the toxoplasma spp. Almost did not proliferate and maintained the first infiltrated form.
  • the host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used.
  • Protein kinase inhibitors include Sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 ⁇ M, pyrimethamine (purchased from Sigma Chem Co.) 5.0 ⁇ M, and pelitinib (from Selleck Chemicals) 5.0 ⁇ M Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
  • sunitinib used as a negative control agent did not show an effect on toxoplasma pluripotency that proliferates in protozoan-containing membranes produced in retinal cells, whereas pelitinib showed an effect at 5.0 ⁇ M or more.
  • Inhibition of fission growth equivalent to pyrimethamine (5.0 ⁇ M) used as a control drug was observed in the control group not treated with the medicament, but in the pelicinib treatment group, toxosporosis almost did not proliferate and maintained the first infiltrating state.
  • Toxoplasma gonitis infectious agent provided by the present invention, safe to humans and animals without toxic or side effects, and excellent killing effect for toxoplasma worms, can be used as a treatment for toxoplasma worm infection.

Landscapes

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

Abstract

The present invention relates to a pharmaceutical composition, a veterinary composition, and an antiprotozoal adjuvant agent for prevention or treatment of toxoplasmosis, the pharmaceutical composition, the veterinary composition, and the antiprotozoal adjuvant agent each comprising an anti-non-small cell lung cancer agent as an active ingredient. The present invention also relates to a method for preventing or treating toxoplasmosis.

Description

비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충감염증의 예방 또는 치료용 약학 조성물Pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising non-small cell lung cancer treatment agent as an active ingredient
본 발명은 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충감염증의 예방 또는 치료용 약학 조성물, 수의학적 조성물, 항원충보조제, 및 톡소포자충감염증 예방 또는 치료 방법에 관한 것이다. The present invention relates to a pharmaceutical composition, a veterinary composition, an adjuvant for adjuvant, and a method for preventing or treating toxoplasma infection, comprising the non-small cell lung cancer treatment agent as an active ingredient.
톡소포자충(Toxoplasma gondii)은 대식세포에 침투하여 중추신경계를 감염시키는 기회감염성 원충기생충이다. 톡소포자충은 종숙주인 고양이의 분변에 나온 우씨스트(oocyst)로 오염된 물을 직접 마시거나 야채 등에 묻은 것을 섭취함으로써 감염되거나, 중간숙주인 돼지, 양, 소 등의 육류에 씨스트(cyst)로 존재하는 톡소포자충을 섭식함으로써 감염되며, 사람을 비롯한 각종 온혈 동물에게 감염될 수 있다. 전세계 인구의 약 1/3이 톡소포자충에 감염되어 있으며, 국내에서도 그룹에 따라 2 내지 25%의 감염율을 보이고 있는 것으로 보고되어 있다. Toxoplasma gondii is an opportunistic protozoan parasite that invades macrophages and infects the central nervous system. Toxoplasma worms are infected with oocyst from feces of cats, which are infected by drinking contaminated water directly or by ingesting them on vegetables, or as a cyst to meats such as pigs, sheep and cows, which are intermediate hosts. It is infected by feeding on toxoplasma worms present, and can be infected by various warm-blooded animals including humans. About one third of the world's population is infected with toxoplasma spp., And in Korea, it is reported that the infection rate is 2 to 25% depending on the group.
산모가 톡소포자충에 감염된 경우 이의 영양형(trophozoite)이 태반을 거쳐 태아에게 감염된다. 이에 따라 초기 태아는 유사산이 일어나며, 중후기 태아의 경우에는 정상적 분만이 이루어지더라도 이후 시력손상, 수두증, 정신박약 등의 증상이 나타난다. 건강한 사람에서도 가축 혹은 야생 육류를 덜 익혀 먹어 감염됨으로써 면역계 세포, 망상내피계 세포 등을 침범하여 세포를 파괴하면서 증식하여, 림프선염, 망막맥락막염, 뇌척수염 등을 일으키며, 특히 여러 상황에서 일어나는 숙주의 면역부전시 뇌에 존재하던 씨스트의 재활성화로 뇌수막염이나 망막맥락막염이 나타난다.When a mother is infected with Toxoplasma worm, its trophozoite passes through the placenta and infects the fetus. As a result, early fetuses develop pseudoacids, and in the case of midterm fetuses, symptoms such as visual impairment, hydrocephalus, and mental weakness appear even after normal delivery. In healthy people, less-cooked livestock or wild meat eats and infects immune cells, retinal endothelial cells, and so on, destroying the cells and proliferating, causing lymphadenitis, retinal choroiditis, and encephalomyelitis. Reactivation of cysts present in the brain during immunodeficiency results in meningitis or retinal choroiditis.
현재까지 톡소포자충 감염에 대한 치료법으로는, 스피라마이신(spiramycin)또는 피리메타민(pyrimethamine)를 단독으로 투여하거나, 말라리아의 예방약으로 개발된 피리메타민(pyrimethamine)과 설파제(sulfa)를 병용 투여하여 2-3주간 치료하는 방법이 사용되고 있으며, 특히 병용 투여 시에 좋은 효과를 보이고 있다. 그러나, 병용 투여시 표피와 점막의 박리를 주요 증상으로 하는 스티븐스 존슨 증후군(Stevens-Johnson syndrome)이 부작용으로 나타날 수 있는 문제가 있어, 보다 안전한 치료제의 개발이 시급한 실정이다.Up to now, the treatment for toxoplasma worm infection includes the administration of spiramycin or pyrimethamine alone, or a combination of pyrimethamine and sulfa, which have been developed as an antimalarial drug. The treatment method is used for 2-3 weeks, and especially when combined administration is showing a good effect. However, there is a problem that Stevens-Johnson syndrome, which is the main symptom of skin and mucous membrane detachment, may be a side effect of the co-administration. Therefore, it is urgent to develop a safer therapeutic agent.
또한, 톡소포자충 감염에 대한 다른 치료제로서 물푸레나무로부터 분리된 올레우로페인 화합물을 유효성분으로 하는 조성물(국내특허등록 제10-0834444호), 1-［4-（4-니트로-페녹시-페닐-프로판-1-온 화합물(국내특허등록 제10-1148098호), 1,5-디페닐-8-메틸-6,7-디옥사-바이시클로[3.2.2]노난베타체 화합물(국내특허등록 제10-0946466호), 7-에톡시쿠마린(국내특허등록 제10-0903287호) 등이 제안되어 있으나, 그 효과가 아직 완전히 검증되지 않았다.In addition, as another therapeutic agent for toxoplasma infection, a composition comprising an oleuropine compound isolated from ash tree (Domestic Patent Registration No. 10-0834444), 1- [4- (4-nitro-phenoxy-phenyl -Propan-1-one compound (Domestic Patent Registration No. 10-1148098), 1,5-diphenyl-8-methyl-6,7-dioxa-bicyclo [3.2.2] nonanebeta body compound (Domestic Patent Registration No. 10-0946466), 7-ethoxycoumarin (Domestic Patent Registration No. 10-0903287), and the like have been proposed, but the effect has not been fully verified yet.
한편, 다코미티닙(dacomitinib)은 진행성 비소세포폐암 환자에서 사용하는 표적치료용 항암제로, 티로신 키나아제(tyrosine kinase)의 억제제로 작용하여, 표피성장인자 수용체(Epidermal growth factor receptor, EGFR)의 신호전달을 막음으로써 치료효과를 나타낸다. 다코미티닙은 화이자(Pfizer)에 의해 개발된 화합물 PF-00299804를 말하며, 시중에서 구입이 가능하다.Meanwhile, dacomitinib is a target anticancer agent used in patients with advanced non-small cell lung cancer, and acts as an inhibitor of tyrosine kinase, thereby signaling epidermal growth factor receptor (EGFR). By preventing the treatment effect. Dacomitinib refers to compound PF-00299804, developed by Pfizer, which is commercially available.
또한, 아파티닙(afatinib)은 전이성 비소세포폐암 환자에서 사용하는 경구용 폐암 치료제로, 티로신 키나아제(tyrosine kinase)의 억제제로 작용하여, 표피성장 인자 수용체(Epidermal growth factor receptor, EGFR)의 신호전달을 막음으로써 치료효과를 나타낸다. 아파티닙은 베링거인겔하임에 의해 개발된 화합물 BIBW2992를 말하며, 상표명 지오트립으로 시중에서 구입이 가능하다.In addition, afatinib is an oral lung cancer drug used in patients with metastatic non-small cell lung cancer, and acts as an inhibitor of tyrosine kinase, thereby signaling epidermal growth factor receptor (EGFR). By preventing the treatment effect. Afatinib refers to compound BIBW2992, developed by Boehringer Ingelheim, and is commercially available under the trade name Geotrip.
또한, 크리조티닙(crizotinib)은 역형성 림프종 키나아제(anaplastic lymphoma kinase, ALK) 양성 비소세포폐암 환자에서 사용하는 폐암 표적 항암제로, c-MET/ALK(hepatocyte growth factor receptor)의 억제제로 작용하여, 표피성장인 자 수용체(Epidermal growth factor receptor, EGFR)의 신호전달을 막음으로써 치료효과를 나타낸다. 크리조티닙은 화이자(Pfizer)에 의해 개발된 화합물 PF-02341066을 말하며, 시중에서 구입이 가능하다.In addition, crizotinib is a lung cancer target anticancer agent used in patients with anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer, and acts as an inhibitor of c-MET / ALK (hepatocyte growth factor receptor). It has a therapeutic effect by preventing the epidermal growth factor receptor (EGFR) signaling. Crizotinib refers to compound PF-02341066, developed by Pfizer, which is commercially available.
아울러, 펠리티닙(pelitinib)은 비소세포폐암 환자에서 사용하는 표적치료용 항암제로, 종양세포의 표피성장인자 수용체(Epidermal growth factor receptor, EGFR)의 티로신 키나아제(tyrosine kinase) 활성을 선택적으로 억제하여 종양 세포의 성장에 관여하는 신호를 차단함으로써 치료효과를 나타낸다. 펠리티닙은 화합물 EKB-569를 말하며, Selleck Chemicals를 통해 시중에서 구입이 가능하다.In addition, pelitinib is a target anticancer agent used in patients with non-small cell lung cancer, and selectively inhibits tyrosine kinase activity of epidermal growth factor receptor (EGFR) of tumor cells. It has a therapeutic effect by blocking signals involved in cell growth. Pellitinib refers to compound EKB-569, which is commercially available from Selleck Chemicals.
본 발명자들은 항암제로만 알려져 있던 비소세포폐암 치료제인 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙이 놀랍게도 톡소포자충의 분열 증식을 억제하는 효과가 우수하여 톡소포자충 감염에 대한 치료제로도 사용이 가능하다는 것을 확인하여 본 발명을 완성하게 되었다.The inventors of the present invention have shown that dacomitinib, afatinib, crizotinib, or pelitinib, which are known as only anticancer drugs, are surprisingly excellent in inhibiting the division and proliferation of toxoplasma worms. The present invention was completed by confirming that it is possible.
본 발명의 하나의 목적은 비소세포폐암 치료제인 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 약학 조성물을 제공하는 것이다.One object of the present invention to provide a pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising a non-small cell lung cancer treatment agent dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof will be.
본 발명의 하나의 목적은 비소세포폐암 치료제인 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 수의학적 조성물을 제공하는 것이다.One object of the present invention to provide a veterinary composition for the prevention or treatment of toxoplasma gonitis infection, including non-small cell lung cancer treatment agent dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof It is.
본 발명의 하나의 목적은 비소세포폐암 치료제인 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 항원충보조제를 제공하는 것이다.One object of the present invention to provide an adjuvant for the prevention or treatment of toxoplasma gonitis infection, including dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof, which is a non-small cell lung cancer treatment agent. It is.
본 발명의 또 하나의 목적은 비소세포폐암 치료제인 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 조성물의 유효량을 개체에 투여하는 단계를 포함하는 톡소포자충 감염증의 치료방법을 제공하는 것이다.Another object of the present invention comprises administering to a subject an effective amount of a composition comprising dacomitinib, afatinib, crizotinib, or pelitinib, or a pharmaceutically acceptable salt thereof, for treating non-small cell lung cancer To provide a method for the treatment of toxoplasma worm infection.
상기 목적을 달성하기 위한 하나의 양태로서, 본 발명은 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충감염증의 예방 또는 치료용 약학 조성물에 관한 것이다. As one aspect for achieving the above object, the present invention relates to a pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising a non-small cell lung cancer therapeutic agent as an active ingredient.
바람직한 양태로서, 상기 비소세포폐암 치료제는 하기 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염일 수 있다:In a preferred embodiment, the non-small cell lung cancer therapeutic agent may be a compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2014008031-appb-I000001
Figure PCTKR2014008031-appb-I000001
상기 화학식 1은 "다코미티닙(dacomitinib)"으로 시중에 시판되는 것을 구입할 수 있고, 화학적 명칭이 '(E)-N-(4-(3-클로로-4-플로오로페닐아미노)-7-메톡시퀴나졸린-6-일)-4-(피페리딘-1-일)-2-부틴아마이드' 이다.Formula 1 may be purchased as a commercially available "dacomitinib" (dacomitinib), the chemical name '(E) -N- (4- (3-chloro-4-fluorophenylamino) -7- Methoxyquinazolin-6-yl) -4- (piperidin-1-yl) -2-butynamide '.
또한 본 명세서 내에서 다코미티닙이란 다코미티닙 및 이의 라세미체, 에난티오머, 동질이상체, 수화물, 용매화물을 모두 포함하는 의미로 사용된다.In addition, dacomitinib is used herein to include all of dacomitinib and its racemates, enantiomers, homologues, hydrates, and solvates.
[화학식 2][Formula 2]
Figure PCTKR2014008031-appb-I000002
Figure PCTKR2014008031-appb-I000002
상기 화학식 2는 "아파티닙(afatinib)"으로 시중에 시판되는 것을 구입할 수 있고, 화학적 명칭이 'N-[4-[(3-클로로-4-플로오로페닐)아미노]-7-[[(3S)-테트라히드로-3-푸라닐]옥시]-6-퀴나졸리닐]-4-(디메틸아미노)-2-부틴아마이드' 이다.Formula 2 may be purchased as a commercially available "afatinib", the chemical name is' N- [4-[(3-chloro-4-fluorophenyl) amino] -7-[[ (3S) -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4- (dimethylamino) -2-butynamide '.
또한 본 명세서 내에서 아파티닙이란 아파티닙 및 이의 라세미체, 에난티오머, 동질이상체, 수화물, 용매화물을 모두 포함하는 의미로 사용된다.In addition, afatinib is used herein to include all of afatinib and its racemates, enantiomers, homologues, hydrates, and solvates.
[화학식 3][Formula 3]
Figure PCTKR2014008031-appb-I000003
Figure PCTKR2014008031-appb-I000003
상기 화학식 3은 "크리조티닙(crizotinib)"으로 시중에 시판되는 것을 구입할 수 있으며, 화학적 명칭이 '3-[(1R)-1-(2,6-디클로로-3-플루오로페닐)에톡시]-5-(1-피페리딘-4-일피라졸-4-일)피리딘-2-아민'이다.Formula 3 may be purchased commercially available as "crizotinib", the chemical name is' 3-[(1R) -1- (2,6-dichloro-3-fluorophenyl) ethoxy ] -5- (1-piperidin-4-ylpyrazol-4-yl) pyridin-2-amine '.
또한 본 명세서 내에서 크리조티닙이란 크리조티닙 및 이의 라세미체, 에난티오머, 동질이상체, 수화물, 용매화물을 모두 포함하는 의미로 사용된다.In addition, in the present specification, crizotinib is used to mean all of crizotinib and its racemates, enantiomers, homologues, hydrates, and solvates thereof.
[화학식 4][Formula 4]
Figure PCTKR2014008031-appb-I000004
Figure PCTKR2014008031-appb-I000004
상기 화학식 4는 "펠리티닙(pelitinib)"으로 시중에 시판되는 것을 구입할 수 있으며, 화학적 명칭이 'N-[4-(3-클로로-4-플루오로페닐아미노)-3-시아노-7-에톡시퀴놀린-5-일]-4-(디메틸아미노)-2(E)-부틴아마이드'이다.Formula 4 may be purchased as a commercially available "pelitinib", the chemical name is' N- [4- (3-chloro-4-fluorophenylamino) -3-cyano-7- Ethoxyquinolin-5-yl] -4- (dimethylamino) -2 (E) -butynamide '.
펠리티닙은 시중에서 구입할 수 있으며, 공지의 합성방법을 통해 합성할 수 있다. "Strategies for Organic Drug Synthesis and Design (Daniel Lednicer 저)" 내에 아래와 같이 합성방법이 개시되어 있다.Pellitinib is commercially available and can be synthesized through known synthetic methods. The synthesis method is disclosed in "Strategies for Organic Drug Synthesis and Design by Daniel Lednicer" as follows.
Figure PCTKR2014008031-appb-I000005
Figure PCTKR2014008031-appb-I000005
또한 본 명세서 내에서 펠리티닙이란 펠리티닙 및 이의 라세미체, 에난티오머, 동질이상체, 수화물, 용매화물을 모두 포함하는 의미로 사용된다.In addition, the term pelitinib is used herein to include both pelitinib and its racemates, enantiomers, homologues, hydrates, and solvates.
바람직한 양태로서, 본 발명은 비소세포폐암 치료제, 예컨대 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 약학 조성물에 관한 것이다.In a preferred embodiment, the present invention relates to a pharmaceutical composition for the prevention or treatment of toxoplasma nephritis, comprising a non-small cell lung cancer therapeutic agent, such as dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. will be.
바람직한 양태로서, 상기 톡소포자충 감염증은 톡소플라즈마 곤디(Toxoplama gondii)에 의한 감염증일 수 있다. In a preferred embodiment, the toxoplasma worm infection may be an infection caused by Toxoplama gondii .
바람직한 양태로서, 상기 톡소포자충 감염증은 망막염, 맥락막염 및 망막맥락막염으로 이루어진 군에서 선택되는 1종 이상인 것일 수 있다.In a preferred embodiment, the toxoplasma worm infection may be one or more selected from the group consisting of retinitis, choroiditis and retinal choroiditis.
바람직한 양태로서, 상기 약학 조성물은 조성물 총 중량에 대하여 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 0.1 내지 50 중량%로 포함하는 것일 수 있다.In a preferred embodiment, the pharmaceutical composition may comprise 0.1 to 50% by weight of dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition.
바람직한 양태로서, 상기 약학 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것일 수 있다.In a preferred embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent.
또 하나의 양태로서, 본 발명은 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 조성물의 유효량을 개체(subject)에 투여하는 단계를 포함하는 톡소포자충 감염증의 예방 또는 치료 방법에 관한 것이다.In another embodiment, the present invention provides a method of treating a non-small cell lung cancer, preferably an effective amount of a composition comprising dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It relates to a method for preventing or treating Toxoplasma worm infection comprising the step of administering).
또 하나의 양태로서, 본 발명은 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 수의학적 조성물에 관한 것이다.As another aspect, the present invention is for the prevention or treatment of toxoplasmosis infection comprising a non-small cell lung cancer treatment agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof It relates to a veterinary composition.
바람직한 양태로서, 상기 수의학적 조성물은 톡소포자충 감염 대상 동물이 포유동물 또는 가금류인 것에 대하여 적용되는 조성물일 수 있다.In a preferred embodiment, the veterinary composition may be a composition that is applied to an animal subject to toxoplasma worm infection is mammalian or poultry.
또 하나의 양태로서, 본 발명은 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 항원충보조제에 관한 것이다. As another aspect, the present invention is for the prevention or treatment of toxoplasmosis infection comprising a non-small cell lung cancer treatment agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof An antigen supplement adjuvant.
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서 용어, "톡소포자충 감염증"은 원충의 일종인 톡소포자충, 보다 바람직하게는 톡소플라즈마 곤디(Toxoplama gondii)의 감염에 의해 일어나는 질환으로, 여성이 임신 중에 감염될 경우 유산과 불임을 포함하여 태아에 이상을 유발할 수 있는 인수공통 전염병의 한 종류를 말한다. 톡소포자충 감염증을 "톡소플라즈마증"으로 표현할 수도 있다.As used herein, the term "toxoplasma worm infection" refers to a disease caused by an infection of toxoplasma worm , more preferably, Toxoplama gondii , which is a kind of protozoa, including abortion and infertility when a woman is infected during pregnancy. It is a type of common infectious disease that can cause abnormalities in the fetus. Toxoplasma worm infection can also be expressed as "toxoplasmosis".
본 발명에서 톡소포자충 감염증은 톡소포자충의 감염에 의해 일어날 수 있는 모든 질환 및 증상을 포함한다. 톡소포자충은 체내 다양한 부위, 예를 들어 림프선, 뇌, 폐, 심근, 비장, 골수, 신장, 부신, 신경계 등에 기생할 수 있으며, 빠른 분열소체(tachyzoite)는 망상내피계와 순환계 내피세포 속에서 활발히 분열 및 증식하여 조직을 괴사시킬 수 있다. 또한, 감염부위에 따라 다양한 질병 및 증상을 일으킬 수 있는데, 예를 들어 림프선염, 망막맥락막염, 뇌수막염, 뇌척수염, 간염, 근육염, 심근염, 폐렴, 세뇨관 질환 등을 일으킬 수 있다.Toxoplasma worm infections in the present invention include all diseases and symptoms that can be caused by the infection of toxoplasma worms. Toxoplasma worms can live in various parts of the body, such as the lymph glands, brain, lungs, myocardium, spleen, bone marrow, kidneys, adrenal glands, and nervous system. Rapid tachyzoite is active in reticulum and circulatory endothelial cells. Division and proliferation can necrotic tissue. In addition, various diseases and symptoms may be caused according to the infected area, for example, lymphadenitis, retinal choroiditis, meningitis, encephalomyelitis, hepatitis, myositis, myocarditis, pneumonia, and tubule diseases.
바람직하게, 본 발명에서 톡소플라즈마 감염증은 망막 또는 맥락막에 나타나는 감염성 질환일 수 있으며, 망막염, 맥락막염 및 망막맥락막염 등을 예시할 수있다. 망막은 맥락막과 접해 있기 때문에 망막에 염증이 있을 경우에는 맥락막에도 변화가 생기고, 반대로 맥락막의 염증으로 인해 망막에 변화가 일어날 수도 있다. 따라서 망막염과 맥락염은 함께 나타나는 경우가 많고, 이를 망막맥락막염 또는 맥락망막염이라 한다.Preferably, the toxoplasma infection in the present invention may be an infectious disease appearing in the retina or choroid, and may exemplify retinitis, choroiditis, and retinal choroiditis. Since the retina is in contact with the choroid, if the retina is inflamed, the choroid may also change. In contrast, the choroid may cause changes in the retina. Therefore, retinitis and choroiditis often appear together, and this is called retinal choroiditis or chorioretinitis.
톡소포자충은 인체에 들어가면 뇌, 눈, 간 등에 주머니를 만들어 숨어있다가 면역력이 약해지면 다시 활동을 하는데, 톡소포자충이 눈에 침범하여 염증을 일으킨 경우, 망막염, 맥락막염 및 망막맥락막염을 일으킬 수 있다. Toxoplasma worms make pockets in the brain, eyes, and liver when they enter the body, and then become active again when the immune system is weakened. Toxoplasma worms can cause retinitis, choroiditis, and retinal choroiditis if they invade the eye and cause inflammation. have.
본 발명의 한 구현예에서는 망막 상피세포에 다코미티닙을 처리하여, 톡소포자충의 분열증식을 억제하는 것을 관찰함으로써, 다코미티닙이 기존의 톡소포자충 치료제인 피리메타민에 못지않은 치료 효과를 나타내는 것을 확인하였다. 본 발명의 다른 구현예에서는 망막 상피세포에 아파티닙을 처리하여, 톡소포자충의 분열증식을 억제하는 것을 관찰함으로써, 아파티닙이 기존의 톡소포자충 치료제인 피리메타민에 못지 않은 치료 효과를 나타내는 것을 확인하였다. 본 발명의 다른 구현예에서는 망막 상피세포에 크리조티닙을 처리하여, 톡소포자충의 분열증식을 억제하는 것을 관찰함으로써, 크리조티닙이 기존의 톡소포자충 치료제인 피리메타민에 못지 않은 치료 효과를 나타내는 것을 확인하였다. 본 발명의 다른 구현예에서는 망막 상피세포에 펠리티닙을 처리하여, 톡소포자충의 분열증식을 억제하는 것을 관찰함으로써, 펠리티닙이 기존의 톡소포자충 치료제인 피리메타민에 못지 않은 치료 효과를 나타내는 것을 확인하였다.In one embodiment of the present invention, the treatment of retinal epithelial cells with dacomitinib inhibits the proliferation of toxoplasma worms, whereby dacomitinib exhibits a therapeutic effect comparable to that of pyramidamine, a conventional toxoplasma treatment. It was confirmed. In another embodiment of the present invention, by treating apatinib with retinal epithelial cells to inhibit toxoplasmosis proliferation, afatinib exhibits a therapeutic effect comparable to that of pyrimethamine, a conventional toxoplasma treatment It was confirmed. In another embodiment of the present invention, by treating the retinal epithelial cells with crizotinib to inhibit the proliferation of toxoplasma worms, crizotinib exhibits a therapeutic effect comparable to that of the conventional toxoplasma worm pyrimethamine. It was confirmed. In another embodiment of the present invention, by treating the retinal epithelial cells with pelinib, inhibiting the proliferation of toxoplasma worms, it was confirmed that pelinib exhibits a therapeutic effect comparable to that of pyrimethamine, which is a conventional toxoplasma cure It was.
또한, 본 발명은 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 톡소포자충 감염증 예방 또는 치료용 항원충보조제에 관한 것이다. 본 발명에서 용어, "항원충보조제"는 주가 되는 항원충제와 함께 사용될 수 있는 약제를 의미한다. In addition, the present invention is directed to an adjuvant for preventing or treating Toxoplasma gondii infections, including a non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It is about. As used herein, the term "antigen supplement" refers to a medicament that can be used with the main antiprotozoal agent.
또한, 본 발명은 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적으로 허용되는 염을 포함하는 조성물의 유효량을 개체(subject)에 투여하는 단계를 포함하는 톡소포자충 감염증의 예방 또는 치료 방법을 제공한다.In addition, the present invention provides a method of administering to a subject an effective amount of a composition comprising a non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically acceptable salt thereof. It provides a method for preventing or treating Toxoplasma worm infection comprising the step.
본 발명에서 사용되는 용어, "예방"은 본 발명에 따른 조성물의 투여로 톡소포자충 감염증의 발병을 억제 또는 지연시키는 모든 행위를 말한다.As used herein, the term "prevention" refers to any action that inhibits or delays the onset of toxoplasmosis infection by administration of a composition according to the invention.
본 발명에서 사용되는 용어, "치료"는 본 발명에 따른 조성물의 투여로 톡소포자충 감염증의 증세가 호전되거나 이롭게 변경되는 모든 행위를 말한다.As used herein, the term "treatment" refers to any action by which administration of a composition according to the present invention improves or advantageously alters the symptoms of toxoplasmosis infection.
본 발명은 톡소포자충 감염증의 예방 또는 치료를 위한 유효성분으로, 비소세포폐암 치료제, 예컨대 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙, 또는 이의 약학적, 수의학적으로 허용되는 염을 제공함을 특징으로 한다.The present invention provides an active ingredient for the prevention or treatment of Toxoplasma worm infection, and provides a non-small cell lung cancer therapeutic agent such as dacomitinib, afatinib, crizotinib or pelitinib, or a pharmaceutically or veterinary acceptable salt thereof. It is characterized by.
본 발명은 또한, 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙의 약학적으로 허용가능한 염을 유효성분으로 포함할 수 있다. 본 발명에서 용어, "약학적으로 허용 가능한 염"이란 약학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다. 본 발명에서 용어, "수의학적으로 허용 가능한 염"이란 수의학적으로 허용되는 무기산, 유기산, 또는 염기로부터 유도된 염을 포함한다.The present invention may also include a non-small cell lung cancer treatment agent, preferably a pharmaceutically acceptable salt of dacomitinib, afatinib, crizotinib, or pelitinib as an active ingredient. As used herein, the term "pharmaceutically acceptable salts" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. As used herein, the term "veterinary acceptable salt" includes salts derived from veterinary acceptable inorganic, organic, or bases.
적합한 산의 예로는 염산, 브롬산, 황산, 질산, 과염소산, 푸마르산, 말레산, 인산, 글리콜산, 락트산, 살리실산, 숙신산, 톨루엔-p-설폰산, 타르타르산, 아세트산, 시트르산, 메탄설폰산, 포름산, 벤조산, 말론산, 나프탈렌-2-설폰산, 벤젠설폰산 등을 들 수 있다. 산부가염은 통상의 방법, 예를 들면 화합물을 과량의 산수용액에 용해시키고, 이 염을 메탄올, 에탄올, 아세톤 또는 아세토니트릴과 같은 수혼화성 유기 용매를 사용하여 침전시켜서 제조할 수 있다. 또한, 동몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. Acid addition salts can be prepared by conventional methods, for example by dissolving a compound in an excess of an aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It is also possible to prepare equimolar amounts of the compound and acid or alcohol in water and then evaporate the mixture to dryness or to precipitate filtered salts by suction filtration.
적합한 염기로부터 유도된 염은 나트륨, 칼륨 등의 알칼리 금속, 마그네슘 등의 알칼리 토금속, 및 암모늄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다. 알칼리 금속 또는 알칼리 토금속염은, 예를 들면 화합물을 과량의 알칼리 금속수산화물 또는 알칼리토 금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻을 수 있다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium, potassium, alkaline earth metals such as magnesium, and ammonium and the like. An alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).
현재 톡소포자충 치료제로 사용되고 있는 피리메타민과 설파제의 병용 치료는, 그 내성이 계속 증가하고 있고, 감염형원충(bradyzoite) 단계의 톡소포자충에대한 효과는 별로 없으며, 표피와 점막의 박리를 주요 증상으로 하는 스티븐스 존슨 증후군이 부작용으로 나타날 수 있는 문제가 있다.Combination treatment of pyrimethamine and sulfa, which is currently used as a treatment for toxoplasmosis, continues to increase its resistance and has little effect on toxoplasmosis at the Bradyzoite stage. Stevens Johnson syndrome can cause side effects.
본 발명에서 제공하는 비소세포폐암 치료제, 예컨대 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙의 경우, 항암제로서 이미 수많은 임상실험을 거친 결과 사람과 동물에게 독성이나 부작용이 없이 안전한 것으로 검증된 화합물이며, 본 발명자들에 의하여 톡소포자충에 대한 분열 증식 억제 효과가 우수하다는 것이 입증되었다.In the case of non-small cell lung cancer therapeutic agents provided by the present invention, such as dacomitinib, afatinib, crizotinib or pelitinib, as a result of many clinical trials as anticancer agents, it has been proved to be safe for humans and animals without toxicity or side effects. It is a compound, and the inventors have demonstrated that the effect of inhibiting fission proliferation against toxoplasma worms is excellent.
본 발명의 조성물 내의 상기 비소세포폐암 치료제, 바람직하게는 다코미티닙, 아파티닙, 크리조티닙 또는 펠리티닙의 함량은 질환의 증상, 증상의 진행 정도, 환자의 상태 등에 따라서 적절히 조절 가능하며, 예컨대, 전체 조성물 중량을 기준으로 0.0001 내지 99.9중량%, 바람직하게는 0.001 내지 50중량%인 것이 바람직하나, 이에 한정되는 것은 아니다. 상기 함량비는 용매를 제거한 건조량을 기준으로 한 값이다.The content of the non-small cell lung cancer therapeutic agent, preferably dacomitinib, afatinib, crizotinib or pelitinib in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progression of symptoms, the condition of the patient, For example, it is preferably 0.0001 to 99.9% by weight, preferably 0.001 to 50% by weight based on the total weight of the composition, but is not limited thereto. The content ratio is a value based on the drying amount from which the solvent is removed.
상기 조성물은 약학적 및 수의학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있으며, 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액 등의 형태로 제형화하여 사용될 수 있다.The composition may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical and veterinary compositions, and powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols according to conventional methods Oral formulations, external preparations, suppositories, or sterile injectable solutions and the like.
본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
상기 조성물을 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제할 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 적어도 한 가지 이상의 부형제 및/또는 윤활제 등을 포함할 수 있다.　경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함될 수 있다.When formulating the composition can be prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient and / or lubricants, and the like. Liquid preparations for oral administration include suspensions, liquid solutions, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
본원에서 용어 "치료학적 유효량" 또는 "유효량"은 톡소포자충 치료에 적용가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 개체 종류, 상태 및 중증도, 연령, 성별, 감염된 세균의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라, 당업자에 의해 적절하게 선택될 수 있다. 보다 바람직한 효과를 위해서, 본 발명의 조성물의 투여량은 유효성분을 기준으로 1일 0.1 mg/kg 내지 100 mg/kg으로 하는 것이 좋으나 이에 제한되는 것은 아니다.　투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 본 발명의 조성물은 동물, 바람직하게는 인간을 포함하는 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 정맥, 근육, 피하주사 등에 의해 투여될 수 있다.As used herein, the term “therapeutically effective amount” or “effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to toxoplasmosis treatment, with the effective dose level being an individual type, condition and severity, age, sex. According to the type of infected bacteria, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, the factors including the drug used concurrently and other factors well known in the medical arts, Can be selected. For a more preferable effect, the dosage of the composition of the present invention is preferably 0.1 mg / kg to 100 mg / kg per day based on the active ingredient, but is not limited thereto. Administration may be administered once a day or may be divided several times. The compositions of the present invention can be administered by various routes to an animal, preferably a mammal, including a human. All modes of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous injection or the like.
본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다.The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. And single or multiple administrations. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, and can be easily determined by those skilled in the art.
본 발명의 조성물로 치료할 수 있는 개체로는 인간을 비롯하여 돼지, 소 및 염소 등의 포유류, 꿩, 닭, 오리 및 칠면조 등의 가금류를 포함하나, 이에 제한되지 않는다.Individuals that can be treated with the composition of the present invention include, but are not limited to, humans, mammals such as pigs, cows and goats, poultry such as pheasants, chickens, ducks, and turkeys.
본 발명에서 제공하는 톡소포자충 감염증 치료제는, 사람과 동물에게 독성이나 부작용이 없이 안전하며, 톡소포자충에 대한 살상 효과가 우수하므로, 약학 및 수의학 분야에 널리 사용될 수 있다.Toxoplasma gonitis infectious agent provided by the present invention, safe to humans and animals without toxicity or side effects, and excellent killing effect on toxoplasma spores, can be widely used in the pharmaceutical and veterinary fields.
도 1은 다양한 단백질 카이네이즈 억제제(수니티닙, 다코미티닙), 양성대조약제인 피리메타민 및 무처리 대조군의 톡소포자충 성장 억제 효과를 비교한 것이다.Figure 1 compares the growth inhibitory effect of toxoplasma spp. Of various protein kinase inhibitors (sunitinib, dacomitinib), a positive control pyrimethamine, and an untreated control.
도 2는 다코미티닙을 처리한 후 배양시간에 따른 망막세포내 원충함유막에서 톡소포자충의 분열증식 양상을 나타낸 것이다.Figure 2 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with dacomitinib.
도 3은 다양한 단백질 카이네이즈 억제제(수니티닙, 아파티닙), 양성대조약제인 피리메타민 및 무처리 대조군의 톡소포자충 성장 억제 효과를 비교한 것이다.Figure 3 compares the inhibitory effect of toxoplasmosis growth of various protein kinase inhibitors (sunitinib, afatinib), a positive control pyrimethamine, and an untreated control.
도 4는 아파티닙을 처리한 후 배양시간에 따른 망막세포내 원충함유막에서 톡소포자충의 분열증식 양상을 나타낸 것이다.Figure 4 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with afatinib.
도 5는 다양한 단백질 카이네이즈 억제제(수니티닙, 크리조티닙), 양성대조약제인 피리메타민 및 무처리 대조군의 톡소포자충 성장 억제 효과를 비교한 것이다.Figure 5 compares the inhibitory effect of toxoplasmosis growth of various protein kinase inhibitors (sunitinib, crizotinib), a positive control pyrimethamine, and an untreated control.
도 6은 크리조티닙을 처리한 후 배양시간에 따른 망막세포내 원충함유막에서 톡소포자충의 분열증식 양상을 나타낸 것이다.Figure 6 shows the cleavage of Toxoplasma gondii in the protozoan-containing membrane in retinal cells according to incubation time after treatment with crizotinib.
도 7은 다양한 단백질 카이네이즈 억제제(수니티닙, 펠리티닙), 양성대조약제인 피리메타민 및 무처리 대조군의 톡소포자충 성장 억제 효과를 비교한 것이다.FIG. 7 compares the growth inhibitory effects of toxoplasma spp. Of various protein kinase inhibitors (sunitinib, pelitinib), a positive control pyrimethamine, and an untreated control group.
도 8은 펠리티닙을 처리한 후 배양시간에 따른 망막세포내 원충함유막에서 톡소포자충의 분열증식 양상을 나타낸 것이다.Figure 8 shows the proliferation of Toxoplasma gondii in protozoan-containing membranes in retinal cells according to incubation time after treatment with pelitinib.
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of examples. However, the following examples are merely to illustrate the invention, the present invention is not limited by the following examples.
실시예 1. 다코미티닙의 톡소포자충 살상 효과Example 1. Toxoplasma killing effect of dacomitinib
숙주세포는 사람 망막의 상피세포인 ARPE-19 세포(ATCC, CRL 2302)를 10% 우혈청 (fetal bovine serum)을 첨가한 DMEM과 F12의 1:1 혼합배지에서 유지하였으며, 톡소포자충은 마우스 복강 내에서 계대하는 RH주 (수의과학검역원으로부터 분양받아 계대배양)를 사용하였다. 단백질 카이네이즈 억제제로는 수니티닙(Sunitinib; Sigma Chem Co.로부터 구입) 10μM, 피리메타민(pyrimethamine; Sigma Chem Co.로부터 구입) 5.0μM, 및 다코미티닙(dacomitinib; Selleck Chemicals 로부터 구입) 5.0μM 을 톡소포자충을 감염시킨 숙주세포에 처리하였으며, 72시간 동안 12시간 마다 김자(Giemsa)액으로 염색하여 원충함유막당 톡소포자충의 개체수를 세어 그 효과를 확인하였다.The host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used. Protein kinase inhibitors include sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 μM, pyrimethamine (purchased from Sigma Chem Co.) 5.0 μM, and dacomitinib (obtained from Selleck Chemicals) 5.0 μM Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
그 결과, 도 1에서와 같이 음성대조약제로 사용한 수니티닙은 망막세포 내에 생성한 원충함유막내에서 분열증식하는 톡소포자충에 효과를 보이지 않은 반면, 다코미티닙은 5.0μM 이상에서 효과를 보여 양성대조약제로 사용한 피리메타민(5.0μM)과 동등한 분열증식 억제 효과를 보였다. 또한, 세포 염색 결과에서도 도 2에서와 같이 약제를 처리하지 않은 대조군에서는 톡소포자충의 분열증식이 나타났으나, 다코미티닙 처리군에서는 톡소포자충이 거의 분열증식하지 못하여 처음 침투한 모양 그대로를 유지하였다.As a result, as shown in FIG. 1, sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes produced in retinal cells, whereas dacomitinib showed an effect at 5.0 μM or more. Inhibition of fission growth equivalent to pyrimethamine (5.0 μM) used as a control drug. In addition, in the cell staining results, as shown in Figure 2, the control group was not treated with the toxoplasma schizophrenic growth, but in the Dacomitinib treated group toxoplasma worms did not multiply and maintained the first infiltrated form.
실시예 2. 아파티닙의 톡소포자충 살상 효과Example 2 Toxiform Spores Killing Effect of Afatinib
숙주세포는 사람 망막의 상피세포인 ARPE-19 세포(ATCC, CRL 2302)를 10% 우혈청(fetal bovine serum)을 첨가한 DMEM과 F12의 1:1 혼합배지에서 유지하였으며, 톡소포자충은 마우스 복강 내에서 계대하는 RH주 (수의과학검역원으로부터 분양받아 계대배양)를 사용하였다. 단백질 카이네이즈 억제제로는 수니티닙(Sunitinib; Sigma Chem Co.로부터 구입) 10μM, 피리메타민(pyrimethamine; Sigma Chem Co.로부터 구입) 5.0μM, 및 아파티닙 (afatinib; Selleck Chemicals로부터 구입) 5.0μM 을 톡소포자충을 감염시킨 숙주세포에 처리하였으며, 72시간 동안 12시간 마다 김자(Giemsa)액으로 염색하여 원충함유막당 톡소포자충의 개체수를 세어 그 효과를 확인하였다.Host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used. Protein kinase inhibitors include Sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 μM, pyrimethamine (purchased from Sigma Chem Co.) 5.0 μM, and afatinib (afatinib; purchased from Selleck Chemicals) 5.0 μM Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
그 결과, 도 3에서와 같이 음성대조약제로 사용한 수니티닙은 망막세포 내에 생성한 원충함유막내에서 분열증식하는 톡소포자충에 효과를 보이지 않은 반면, 아파티닙은 5.0μM 이상에서 효과를 보여 양성대조약제로 사용한 피리메타민(5.0μM)과 동등한 분열증식 억제 효과를 보였다. 또한, 세포 염색 결과에서도 도 4에서와 같이 약제를 처리하지 않은 대조군에서는 톡소포자충의 분열증식이 나타났으나, 아파티닙 처리군에서는 톡소포자충이 거의 분열증식하지 못하여 처음 침투한 모양 그대로를 유지하였다.As a result, as shown in FIG. 3, sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes generated in retinal cells, whereas afatinib showed an effect at 5.0 μM or more. Inhibition of fission growth equivalent to pyrimethamine (5.0 μM) used as a control drug. In addition, in the cell staining results, as shown in Fig. 4, the control group was not treated with toxoplasma spp., But in the afatinib treated group, the toxoplasma spp. Almost did not proliferate and maintained the first infiltrated form.
실시예 3. 크리조티닙의 톡소포자충 살상 효과Example 3. Toxoplasma killing effect of crizotinib
숙주세포는 사람 망막의 상피세포인 ARPE-19 세포(ATCC, CRL 2302)를 10% 우혈청 (fetal bovine serum)을 첨가한 DMEM과 F12의 1:1 혼합배지에서 유지하였으며, 톡소포자충은 마우스 복강 내에서 계대하는 RH주 (수의과학검역원으로부터 분양받아 계대배양)를 사용하였다. 단백질 카이네이즈 억제제로는 수니티닙(Sunitinib; Sigma Chem Co.로부터 구입) 10μM, 피리메타민(pyrimethamine; Sigma Chem Co.로부터 구입) 5.0μM, 및 크리조티닙(crizotinib; Sigma Chem Co.로부터 구입) 5.0μM을 톡소포자충을 감염시킨 숙주세포에 처리하였으며, 72시간 동안 12시간 마다 김자(Giemsa)액으로 염색하여 원충함유막당 톡소포자충의 개체수를 세어 그 효과를 확인하였다.The host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used. Protein kinase inhibitors include sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 μM, pyrimethamine (purchased from Sigma Chem Co.) 5.0 μM, and crizotinib (obtained from Sigma Chem Co.) 5.0 μM was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours, the number of toxoplasma spp. Per protozoan membrane was counted and its effect was confirmed.
그 결과, 도 5에서와 같이 음성대조약제로 사용한 수니티닙은 망막세포 내에 생성한 원충함유막내에서 분열증식하는 톡소포자충에 효과를 보이지 않은 반면, 크리조티닙은 5.0μM 이상에서 효과를 보여 양성대조약제로 사용한 피리메타민(5.0μM)과 동등한 분열증식 억제 효과를 보였다. 또한, 세포 염색 결과에서도 도 6에서와 같이 약제를 처리하지 않은 대조군에서는 톡소포자충의 분열증식이 나타났으나, 크리조티닙 처리군에서는 톡소포자충이 거의 분열증식하지 못하여 처음 침투한 모양 그대로를 유지하였다.As a result, as shown in Fig. 5, sunitinib used as a negative control agent did not show an effect on toxoplasmosis proliferating in protozoan-containing membranes produced in retinal cells, whereas crizotinib showed an effect at 5.0 μM or more. Inhibition of fission growth equivalent to pyrimethamine (5.0 μM) used as a control drug. In addition, in the cell staining results, as shown in Fig. 6, the control group was not treated with the toxoplasma spp., But in the cryostinib-treated group, the toxoplasma spp. Almost did not proliferate and maintained the first infiltrated form.
실시예 4. 펠리티닙의 톡소포자충 살상 효과Example 4. Toxoplasma killing effect of pelitinib
숙주세포는 사람 망막의 상피세포인 ARPE-19 세포(ATCC, CRL 2302)를 10% 우혈청 (fetal bovine serum)을 첨가한 DMEM과 F12의 1:1 혼합배지에서 유지하였으며, 톡소포자충은 마우스 복강 내에서 계대하는 RH주 (수의과학검역원으로부터 분양받아 계대배양)를 사용하였다. 단백질 카이네이즈 억제제로는 수니티닙(Sunitinib; Sigma Chem Co.로부터 구입) 10μM, 피리메타민(pyrimethamine; Sigma Chem Co.로부터 구입) 5.0μM, 및 펠리티닙(pelitinib; Selleck Chemicals로 부터 구입) 5.0μM 을 톡소포자충을 감염시킨 숙주세포에 처리하였으며, 72시간 동안 12시간 마다 김자(Giemsa)액으로 염색하여 원충함유막당 톡소포자충의 개체수를 세어 그 효과를 확인하였다.The host cells were maintained in human retinal epithelial cells, ARPE-19 cells (ATCC, CRL 2302) in a 1: 1 mixed medium of DMEM and F12 added with 10% fetal bovine serum. RH strains (passages received from veterinary quarantine) were used. Protein kinase inhibitors include Sunitinib (Sunitinib; purchased from Sigma Chem Co.) 10 μM, pyrimethamine (purchased from Sigma Chem Co.) 5.0 μM, and pelitinib (from Selleck Chemicals) 5.0 μM Was treated to the host cells infected with Toxoplasma spp., And stained with Giemsa solution every 12 hours for 72 hours to determine the effect of the number of toxoplasma spp. Per protozoal membrane.
그 결과, 도 7에서와 같이 음성대조약제로 사용한 수니티닙은 망막세포 내에 생성한 원충함유막 내에서 분열증식하는 톡소포자충에 효과를 보이지 않은 반면, 펠리티닙은 5.0μM 이상에서 효과를 보여 양성대조약제로 사용한 피리메타민(5.0μM)과 동등한 분열증식 억제 효과를 보였다. 또한, 세포 염색 결과에서도 도 8에서와 같이 약제를 처리하지 않은 대조군에서는 톡소포자충의 분열증식이 나타났으나, 펠리티닙 처리군에서는 톡소포자충이 거의 분열증식하지 못하여 처음 침투한 모양 그대로를 유지하였다.As a result, as shown in Figure 7, sunitinib used as a negative control agent did not show an effect on toxoplasma pluripotency that proliferates in protozoan-containing membranes produced in retinal cells, whereas pelitinib showed an effect at 5.0 μM or more. Inhibition of fission growth equivalent to pyrimethamine (5.0 μM) used as a control drug. In addition, in the cell staining results, as shown in FIG. 8, toxoplasma schizophrenic growth was observed in the control group not treated with the medicament, but in the pelicinib treatment group, toxosporosis almost did not proliferate and maintained the first infiltrating state.
본 발명에서 제공하는 톡소포자충 감염증 치료제는, 사람과 동물에게 독성이나 부작용이 없이 안전하며, 톡소포자충에 대한 살상 효과가 우수하므로, 톡소포자충 감염에 대한 치료제로 사용될 수 있다.Toxoplasma gonitis infectious agent provided by the present invention, safe to humans and animals without toxic or side effects, and excellent killing effect for toxoplasma worms, can be used as a treatment for toxoplasma worm infection.

Claims (13)

  1. 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충감염증의 예방 또는 치료용 약학 조성물.Pharmaceutical composition for the prevention or treatment of toxoplasma gonitis infection comprising non-small cell lung cancer treatment agent as an active ingredient.
  2. 청구항 1에 있어서, The method according to claim 1,
    상기 비소세포폐암 치료제는 하기 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염인 약학 조성물:The non-small cell lung cancer therapeutic agent is a compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2014008031-appb-I000006
    ,
    Figure PCTKR2014008031-appb-I000006
    ,
    [화학식 2][Formula 2]
    Figure PCTKR2014008031-appb-I000007
    ,
    Figure PCTKR2014008031-appb-I000007
    ,
    [화학식 3] [Formula 3]
    Figure PCTKR2014008031-appb-I000008
    및
    Figure PCTKR2014008031-appb-I000008
    And
    [화학식 4][Formula 4]
    Figure PCTKR2014008031-appb-I000009
    .
    Figure PCTKR2014008031-appb-I000009
    .
  3. 청구항 1에 있어서, The method according to claim 1,
    상기 톡소포자충 감염증은 톡소플라즈마 곤디(Toxoplama gondii)에 의한 감염증인 약학 조성물.The toxoplasma worm infection is an infectious disease caused by Toxoplama gondii .
  4. 청구항 1에 있어서, The method according to claim 1,
    상기 톡소포자충 감염증은 망막염, 맥락막염 또는 망막맥락막염인 것인 약학 조성물.The toxoplasma worm infection is retinitis, choroiditis or retinitis choroiditis pharmaceutical composition.
  5. 청구항 2에 있어서, The method according to claim 2,
    상기 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염은 조성물 총 중량에 대하여 0.1 내지 50 중량%로 포함하는 것인 약학 조성물.The compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof is 0.1 to 50% by weight based on the total weight of the composition.
  6. 청구항 1에 있어서, The method according to claim 1,
    약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것인 약학 조성물.A pharmaceutical composition further comprising a pharmaceutically acceptable carrier, excipient or diluent.
  7. 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충 감염증 예방 또는 치료용 수의학적 조성물.A veterinary composition for preventing or treating toxoplasma worm infection, comprising a non-small cell lung cancer therapeutic agent as an active ingredient.
  8. 청구항 7에 있어서, The method according to claim 7,
    상기 비소세포폐암 치료제는 하기 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염인 수의학적 조성물:The veterinary composition for treating non-small cell lung cancer is a compound selected from the group consisting of the following Chemical Formulas 1 to 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2014008031-appb-I000010
    ,
    Figure PCTKR2014008031-appb-I000010
    ,
    [화학식 2][Formula 2]
    Figure PCTKR2014008031-appb-I000011
    ,
    Figure PCTKR2014008031-appb-I000011
    ,
    [화학식 3] [Formula 3]
    Figure PCTKR2014008031-appb-I000012
    및
    Figure PCTKR2014008031-appb-I000012
    And
    [화학식 4][Formula 4]
    Figure PCTKR2014008031-appb-I000013
    .
    Figure PCTKR2014008031-appb-I000013
    .
  9. 청구항 7에 있어서, The method according to claim 7,
    톡소포자충 감염 대상 동물로 포유동물 또는 가금류에 적용되는 수의학적 조성물.A veterinary composition applied to a mammal or poultry as an animal toxoplasma worm infection.
  10. 비소세포폐암 치료제를 유효성분으로 포함하는 톡소포자충 감염증 예방 또는 치료용 항원충보조제.Antigen supplement for the prevention or treatment of toxoplasma worm infection comprising non-small cell lung cancer treatment agent as an active ingredient.
  11. 청구항 10에 있어서, The method according to claim 10,
    상기 비소세포폐암 치료제는 하기 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염인 항원충보조제:The non-small cell lung cancer therapeutic agent is a compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2014008031-appb-I000014
    ,
    Figure PCTKR2014008031-appb-I000014
    ,
    [화학식 2][Formula 2]
    Figure PCTKR2014008031-appb-I000015
    ,
    Figure PCTKR2014008031-appb-I000015
    ,
    [화학식 3] [Formula 3]
    Figure PCTKR2014008031-appb-I000016
    및
    Figure PCTKR2014008031-appb-I000016
    And
    [화학식 4][Formula 4]
    Figure PCTKR2014008031-appb-I000017
    .
    Figure PCTKR2014008031-appb-I000017
    .
  12. 비소세포폐암 치료제의 유효량을 개체(subject)에 투여하는 단계를 포함하는 톡소포자충 감염증 예방 또는 치료 방법.A method for preventing or treating Toxoplasma worm infection, comprising administering to a subject an effective amount of a non-small cell lung cancer therapeutic agent.
  13. 청구항 12에 있어서, The method according to claim 12,
    상기 비소세포폐암 치료제는 화학식 1 내지 화학식 4로 이루어진 군으로부터 선택되는 화합물 또는 이의 약학적으로 허용되는 염인 방법:The non-small cell lung cancer therapeutic agent is a compound selected from the group consisting of Formula 1 to Formula 4 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2014008031-appb-I000018
    ,
    Figure PCTKR2014008031-appb-I000018
    ,
    [화학식 2][Formula 2]
    , ,
    [화학식 3] [Formula 3]
    Figure PCTKR2014008031-appb-I000020
    및
    Figure PCTKR2014008031-appb-I000020
    And
    [화학식 4][Formula 4]
    Figure PCTKR2014008031-appb-I000021
    .
    Figure PCTKR2014008031-appb-I000021
    .
PCT/KR2014/008031 2013-09-02 2014-08-28 Pharmaceutical composition for prevention or treatment of toxoplasmosis, comprising anti-non-small cell lung cancer agent as active ingredient WO2015030504A1 (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
KR20130104884A KR101508611B1 (en) 2013-09-02 2013-09-02 Composition for preventing and treating Toxoplasma gondii infection comprising afatinib
KR10-2013-0104883 2013-09-02
KR1020130104885A KR101538385B1 (en) 2013-09-02 2013-09-02 Composition for preventing and treating Toxoplasma gondii infection comprising crizotinib
KR1020130104886A KR101540739B1 (en) 2013-09-02 2013-09-02 Composition for preventing and treating Toxoplasma gondii infection comprising pelitinib
KR10-2013-0104884 2013-09-02
KR1020130104883A KR101508610B1 (en) 2013-09-02 2013-09-02 Composition for preventing and treating Toxoplasma gondii infection comprising dacomitinib
KR10-2013-0104885 2013-09-02
KR10-2013-0104886 2013-09-02

Publications (1)

Publication Number Publication Date
WO2015030504A1 true WO2015030504A1 (en) 2015-03-05

Family

ID=52586962

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2014/008031 WO2015030504A1 (en) 2013-09-02 2014-08-28 Pharmaceutical composition for prevention or treatment of toxoplasmosis, comprising anti-non-small cell lung cancer agent as active ingredient

Country Status (1)

Country Link
WO (1) WO2015030504A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210103674A (en) * 2020-02-14 2021-08-24 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising VEGFR2 inhibitor as active ingredient for preventing or treating toxoplasma gondii infection
KR20210103673A (en) * 2020-02-14 2021-08-24 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising c-Met kinase inhibitor as active ingredient for preventing or treating toxoplasma gondii infection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07196607A (en) * 1993-02-15 1995-08-01 Ajinomoto Co Inc Anisomycin derivative and anticancer agent, antifungal agent and antiprotozoal agent containing the same
WO2008066755A2 (en) * 2006-11-22 2008-06-05 University Of Georgia Research Foundation, Inc. Tyrosine kinase inhibitors as anti-kinetolastid and anti-apicomplexan agents
WO2012158699A1 (en) * 2011-05-16 2012-11-22 Romark Laboratories, L.C. Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07196607A (en) * 1993-02-15 1995-08-01 Ajinomoto Co Inc Anisomycin derivative and anticancer agent, antifungal agent and antiprotozoal agent containing the same
WO2008066755A2 (en) * 2006-11-22 2008-06-05 University Of Georgia Research Foundation, Inc. Tyrosine kinase inhibitors as anti-kinetolastid and anti-apicomplexan agents
WO2012158699A1 (en) * 2011-05-16 2012-11-22 Romark Laboratories, L.C. Use of thiazolide compounds for the prevention and treatment of viral diseases, cancer and diseases caused by intracellular infections

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JIANG MEIHUA: "Anti-Toxoplasma gondii effects of Zingiber officinale", MASTER'S THESIS, August 2009 (2009-08-01) *
KO, WON GYU, J. KOREAN MED ASSOC, vol. 55, no. 1, January 2012 (2012-01-01), pages 49 - 55 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210103674A (en) * 2020-02-14 2021-08-24 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising VEGFR2 inhibitor as active ingredient for preventing or treating toxoplasma gondii infection
KR20210103673A (en) * 2020-02-14 2021-08-24 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising c-Met kinase inhibitor as active ingredient for preventing or treating toxoplasma gondii infection
KR102301217B1 (en) 2020-02-14 2021-09-10 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising VEGFR2 inhibitor as active ingredient for preventing or treating toxoplasma gondii infection
KR102304573B1 (en) 2020-02-14 2021-09-27 가톨릭대학교 산학협력단 Pharmaceutical Composition comprising c-Met kinase inhibitor as active ingredient for preventing or treating toxoplasma gondii infection

Similar Documents

Publication Publication Date Title
Brun et al. Drug sensitivity of Chinese Trypanosoma evansi and Trypanosoma equiperdum isolates
WO2017010835A1 (en) Use of radotinib for prevention or treatment of viral respiratory disease
EP3308786A1 (en) Fgfr regulaton for the treatment of viral infections
CN101163470A (en) Association between ferroquine and an artemisinine derivative for treating malaria
CN1181009A (en) A Pharmaceutical composition N-chlorophenylcarbamates, N-chlorophenylthiocarbamates and N-phosphonoglycine derwatives for inhibiting the growth of cancers and viruses in mammals
WO2015030504A1 (en) Pharmaceutical composition for prevention or treatment of toxoplasmosis, comprising anti-non-small cell lung cancer agent as active ingredient
WO2022055285A1 (en) Pharmaceutical composition for killing cancer progenitor cells
JPS63310819A (en) Antiretroviral sugar protein treatment inhibitor
KR20140070765A (en) Composition for preventing and treating Toxoplasma gondii infection comprising gefitinib
WO2018155921A1 (en) Pharmaceutical composition for preventing and treating pancreatic cancer, containing gossypol and phenformin as active ingredients
WO2018111008A1 (en) Use of carbamate compounds for prevention, alleviation or treatment of bipolar disorder
WO2023224303A1 (en) Pharmaceutical composition for treating or preventing severe fever with thrombocytopenia syndrome, and medical use thereof
JPH11500130A (en) Antiviral triaza compounds
KR101540739B1 (en) Composition for preventing and treating Toxoplasma gondii infection comprising pelitinib
JPH0347251B2 (en)
WO2022114881A1 (en) Pharmaceutical composition for preventing or treating wound or scar, comprising benzbromarone
GB1570063A (en) Compositions containing 5'-amino-5'-deoxythymidine and pharmaceutically acceptable salts thereof
KR101538385B1 (en) Composition for preventing and treating Toxoplasma gondii infection comprising crizotinib
KR101508610B1 (en) Composition for preventing and treating Toxoplasma gondii infection comprising dacomitinib
KR102304573B1 (en) Pharmaceutical Composition comprising c-Met kinase inhibitor as active ingredient for preventing or treating toxoplasma gondii infection
WO2015167246A1 (en) Pharmaceutical composition and method for treating stroke on basis of ampk suppression function
KR101508611B1 (en) Composition for preventing and treating Toxoplasma gondii infection comprising afatinib
WO2016126073A2 (en) Pharmaceutical composition for inhibiting growth of cancer stem cells, containing aldehyde inhibitor and biguanide-based compound
WO2020060252A1 (en) Use of carbamate compound for prevention, alleviation, or treatment of concurrent seizures
WO2023219360A1 (en) Pharmaceutical composition for preventing or treating hepatitis b

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14841210

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14841210

Country of ref document: EP

Kind code of ref document: A1