WO2014076965A1 - Dérivé 1-indane ayant une activité anti-protozoaire - Google Patents

Dérivé 1-indane ayant une activité anti-protozoaire Download PDF

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WO2014076965A1
WO2014076965A1 PCT/JP2013/006722 JP2013006722W WO2014076965A1 WO 2014076965 A1 WO2014076965 A1 WO 2014076965A1 JP 2013006722 W JP2013006722 W JP 2013006722W WO 2014076965 A1 WO2014076965 A1 WO 2014076965A1
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group
optionally substituted
protozoa
trypanosoma
malaria
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PCT/JP2013/006722
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English (en)
Japanese (ja)
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大村　智
一彦 乙黒
正人 岩月
亜紀 石山
義博 大滝
聖至 柴原
近藤　信一
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学校法人北里研究所
株式会社 バイオフロンティア パートナーズ
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Priority to JP2014546882A priority Critical patent/JPWO2014076965A1/ja
Publication of WO2014076965A1 publication Critical patent/WO2014076965A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • 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 belongs to the field of growth inhibition of malaria parasites and trypanosoma protozoa. Specifically, the present invention relates to a compound having an activity of inhibiting the growth of malaria parasites and trypanosoma parasites, 1-indane derivatives, and uses thereof, which are effective as animal drugs and pharmaceuticals.
  • Malaria parasites that parasitize humans are Plasmodium falciparum, P. vivax, P. malariae, and oval malaria protozoa (P. ovale). Classified into types. Among these, the most troublesome is P. falciparum, which accounts for 80% of those infected with malaria. In severe cases, cerebral malaria develops and results in death.
  • chloroquine and funcidal which are known as classic drugs and are mainly synthesized in the 1930s and 1960s, are known as antimalarial agents against these malaria parasites.
  • Artemisinin which is an active ingredient of herbal medicine Aoi, which was called a new drug and was developed after 1980, has been used.
  • drug-resistant malaria parasites against chloroquine and fancidar are now widely spread in malaria-endemic areas, and multidrug-resistant strains that are resistant to both drugs have emerged.
  • Usefulness of these drugs as antimalarial agents Is significantly reduced.
  • artemisinin acts quickly, it is prescribed as a temporary treatment, but there is a problem that it is not completely cured and is likely to recur.
  • trypanosomiasis includes African sleeping sickness (human African trypanosomiasis) that is prevalent in Africa and Chagas disease that is prevalent in South America. African sleeping sickness is a re-emerging protozoal infection, and the risk of infection is estimated to be 70 million, and the annual death toll is about 50,000.
  • Trypanosoma protozoa parasitizing humans are classified into two types: Gambia Trypanosoma protozoa (Trypanosoma brucei gambiense) and Rhodesia Trypanosoma protozoa (T. b. Rhodesiens), the latter causing acute sleep disease.
  • Trypanosoma protozoa move to the central nervous system, and more than 80% of Trypanosoma protozoa suffer from coma, leading to death. These Trypanosoma protozoa are mediated by tsetse flies that only inhabit Africa.
  • T. is a protozoan of the subgenus Trypanosoma Brucei brucei (against protozoan), a protozoan of the subgenus Duttonella Vivax vivax (Zuma disease-causing protozoa), etc., and when these protozoa are infected, a fatal infection course is followed depending on the animal species.
  • T. is a protozoan of the subgenus Trypanosoma Brucei brucei (against protozoan), a protozoan of the subgenus Duttonella Vivax vivax (Zuma disease-causing protozoa), etc., and when these protozoa are infected, a fatal infection course is followed depending on the animal species.
  • T. is a protozoan of the subgenus Trypanosoma. Evansi (Sura disease-causing protozoa), T. Eg, equiperdum (protozoan caused by pesticidal disease).
  • Surah disease is particularly prevalent in Africa, Central and South America, Southeast Asia, China, the Middle East, India and other countries. In recent years, the epidemic has been increasing, and it is animal trypanosomiasis that should be most wary of entering Japan.
  • the arsenic agent Meralsoprol is effective at the end stage of infection of Gambia trypanosomiasis and Rhodesia trypanosomiasis (central neurosis) by passing through the blood-brain barrier, but it has strong side effects on the central nervous system and may cause encephalopathy It was a problem.
  • the emergence of protozoan strains resistant to meralsoprol is also a problem.
  • Ephronitin is effective at the end of infection with resistant Gambia trypanosomiasis to which melansoprol does not work by passing through the blood-brain barrier, but is ineffective against rhodesia trypanosoma protozoa.
  • diminazen, suramin, isometadium, and mutagenic substance fomidium have been used to treat animal trypanosomiasis. Since these drugs have been used in large quantities for a long time, drug-resistant protozoa are now appearing in various places. The usefulness of these antitrypanosome protozoan agents has been significantly reduced, which is a major problem.
  • An object of the present invention is to provide a novel antimalarial drug and antitrypanosoma drug in order to solve the above-mentioned problems of the prior art.
  • Malaria and / or trypanosomiasis is caused by the proliferation of plasmodium and / or trypanosomiasis in the host, respectively. Therefore, the present invention provides a novel antimalarial drug that suppresses the development of malaria and / or trypanosomiasis or alleviates symptoms by finding a novel substance that inhibits the growth of Plasmodium and / or Trypanosoma protozoa, and / or It aims to provide antitrypanosoma drugs.
  • the present inventors measured the proliferation inhibitory activity of malaria parasites and trypanosoma protozoa for a large number of compounds, and further evaluated the cytotoxicity against mammalian cells as an indicator of side effects. And / or a substance with high selective toxicity against Trypanosoma protozoa was selected. As a result, it has been found that the compound represented by the following general formula (I) has the activity of inhibiting the growth of malaria parasites and trypanosoma protozoa, and has completed the present invention.
  • a growth inhibitor of malaria parasites and / or trypanosoma protozoa comprising as an active ingredient a compound represented by the following general formula (I) and / or a pharmacologically acceptable salt thereof: [Wherein R 1 to R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C1-8 alkyl group, an optionally substituted C2-8 alkenyl group, or an optionally substituted group.
  • R 5 and R 6 are the same or different and each represents a hydroxyl group or a —SO 3 Na group, or R 5 and R 6 together represent an oxo group or a ⁇ N—R 7 group. Show.
  • R 7 represents an optionally substituted amino group, a hydroxyl group, or an optionally substituted C1-8 alkoxy group.
  • R 5 and R 6 are the same or different and each represents a hydroxyl group or a —SO 3 Na group, or R 5 and R 6 together represent a ⁇ N—R 7 group.
  • R 7 represents an optionally substituted amino group (excluding an amino group substituted by a 2,4-dinitrophenyl group), a hydroxyl group, or an optionally substituted C1-8 alkoxy group.
  • a compound represented by any of the following structural formulas, or a pharmacologically acceptable salt thereof A growth inhibitor of malaria parasites and / or trypanosoma protozoa comprising the compound according to (3) or (4) as an active ingredient; (6) Inhibition of growth of malaria parasite and / or trypanosoma protozoa according to (1), (2) or (5), which is a pharmaceutical composition for preventing or treating infections caused by malaria parasites and / or trypanosoma parasites Agent; (7) A malaria parasite and / or comprising administering an effective amount of the growth inhibitor of the malaria parasite and / or trypanosoma protozoa described in (1), (2) or (5) to a subject in need thereof (8) Malaria according to (1), (2) or (5) for use in the treatment or prevention of infections caused by Trypanosoma protozoa; and (8) malaria parasites and / or Trypanosoma protozoa.
  • the present invention relates to a growth inhibitor of protozoa and
  • C1-8 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, i-propyl, n-butyl, sec-butyl, t-butyl, isobutyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, cyclohexyl, pentyl, octyl, etc.
  • a C1-5 alkyl group more preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a t-butyl group, An isobutyl group, a pentyl group, an isopentyl group, or a 2,3-dimethylpropyl group. More preferred is a C1-3 alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, and an i-propyl group, and most preferred is a methyl group or an ethyl group.
  • examples of such a substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a hydroxyl group; C1-8 An alkoxy group; an amino group; an oxycarbonyl group; and a carboxy group.
  • the “alkoxy group” means a group (alkyl group —O— group) bonded to the alkyl group through an oxygen atom, and the alkyl group portion is branched or branched. It may be a shape.
  • the C1-8 alkoxy group means that the alkyl group moiety has 1 to 8 carbon atoms. Examples of the alkoxy group include a methoxy group, an ethoxy group, a 1-propyloxy group, a 2-propyloxy group, a 2-methyl-1-propyloxy group, a 2-methyl-2-propyloxy group, and 2,2-dimethyl.
  • -1-propyloxy group 1-butyloxy group, 2-butyloxy group, 2-methyl-1-butyloxy group, 3-methyl-1-butyloxy group, 2-methyl-2-butyloxy group, 3-methyl-2-butyloxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-pentyloxy group, 3-methyl-1-pentyloxy group, 2-methyl-2-pentyloxy group 3-methyl-2-pentyloxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group and the like.
  • the C1-8 alkoxy group is preferably a C1-5 alkoxy group, more preferably a methoxy group, ethoxy group, n-propyloxy group, i-propyloxy group, n-butyloxy group, sec-butyloxy group, t -Butyloxy group, isobutyloxy group, pentyloxy group, isopentyloxy group, and 2,3-dimethylpropyloxy group, more preferably a C1-3 alkoxy group (methoxy group, ethoxy group, and propyloxy group) And more preferably a methoxy group or an ethoxy group.
  • examples of such substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; hydroxyl group; C1-8 An alkoxy group; an amino group; an oxycarbonyl group; and a carboxy group.
  • alkylthio group means a group (alkyl group—S— group) bonded to the alkyl group via a sulfur atom, and the alkyl group portion may be linear or branched. It may be a shape.
  • the C1-8 alkylthio group means that the alkyl group moiety has 1 to 8 carbon atoms.
  • Examples of the C1-8 alkylthio group include a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, a sec-butylthio group, a t-butylthio group, an isobutylthio group, a pentylthio group, and an isopentyl group.
  • examples of such substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; hydroxyl group; C1-8 An alkoxy group; an amino group; an oxycarbonyl group; and a carboxy group.
  • the C2-8 alkenyl group is a monovalent group obtained by removing one hydrogen atom from any carbon atom of an unsaturated hydrocarbon represented by a linear or branched chemical formula C n H 2n.
  • the C2-8 alkenyl group means having 2 to 8 carbon atoms.
  • Preferred examples of the C2-8 alkenyl group include vinyl group, allyl group, butenyl group and octenyl group.
  • examples of such a substituent include a fluorine atom and a chlorine atom.
  • the C6-10 aryl group means a monovalent group obtained by removing one hydrogen atom from an arbitrary carbon atom of an aromatic hydrocarbon, and the C6-10 aryl group has 6 to 10 carbon atoms. It means that there is.
  • Preferable examples of the C6-10 aryl group include a phenyl group and a naphthyl group.
  • C6-10 aryl group when the C6-10 aryl group may be “substituted”, such a substituent includes a fluorine atom, chlorine atom, methyl group, ethyl group, propyl group, hydroxyl group, alkoxy group, amino group, and the like. Group and carboxy group.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom, more preferably a fluorine atom, Or it is a chlorine atom.
  • the “pharmacologically acceptable salt” is a salt formed by combining the compound of the present invention with an inorganic or organic base or acid, and is a salt that can be administered to the body as a medicine. That is.
  • Such salts are described, for example, by Berge et al. Pharm. Sci. 66: 1-19 (1977) and the like.
  • the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, and the like when an acidic group such as a carboxylic acid group is present.
  • amines such as dicyclohexylamine, tris (hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine, etc. Salts; or salts with basic amino acids such as lysine, ⁇ -hydroxylysine, arginine can be formed.
  • salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
  • the hydrate or solvate of the compound represented by the general formula (I) and the hydrate or solvate of the pharmacologically acceptable salt of the compound represented by the general formula (I) are also included in the present invention. Included in the compound.
  • the “compound represented by the general formula (I)” means the pharmacology of the compound represented by the general formula (I) even when it is not explicitly specified unless it is clearly not suitable. Also included are pharmaceutically acceptable salts, hydrates and solvates, as well as hydrates or solvates of pharmacologically acceptable salts of the compounds of general formula (I).
  • R 1 to R 4 for example, the following groups are preferable: (A1) R 1 to R 4 are the same or different and each is a hydrogen atom, an optionally substituted C1-8 alkyl group, an optionally substituted C3-8 alkenyl group, or optionally substituted.
  • R 1 to R 4 are the same or different and each is a hydrogen atom, an optionally substituted C1-5 alkyl group, an optionally substituted C3-5 alkenyl group, or optionally substituted.
  • R 1 to R 4 are the same or different and each represents a hydrogen atom, an optionally substituted C1-3 alkyl group, an optionally substituted C1-3 alkoxy group, or a hydroxyl group;
  • R 1 to R 4 are the same or different and each represents a hydrogen atom or an optionally substituted C1-3 alkoxy group;
  • R 5 and R 4 are a hydrogen atom, and R 2 and R 3 are the same or different and each is a hydrogen atom, an optionally substituted C1-3 alkyl group, or optionally substituted.
  • R 1 and R 4 are hydrogen atoms
  • R 5 and R 6 for example, the following groups are preferable: (B1) R 5 represents a hydroxyl group and R 6 represents a —SO 3 Na group; (B2) R 5 and R 6 together represent an oxo group; (B3) R 5 and R 6 together represent a ⁇ N—R 7 group.
  • R 7 represents an amino group, a hydroxyl group, or a C1-8 alkoxy group which may be substituted with a carbamoyl group, a carbamimidoyl group, or an aminothioxomethyl group.
  • R 7 represents a carbamoyl group or an amino group which may be substituted with a carbamimidoyl group.
  • a combination of any one of the above (a1) to (a6) and any one of (b1) to (b4) is preferable.
  • the compound represented by the general formula (I) in the present specification is more preferably a compound in which R 1 to R 7 are groups represented by the following.
  • a compound represented by the following structural formula or a pharmacologically acceptable salt thereof is preferable.
  • the present invention includes these novel compounds.
  • the compound represented by the general formula (I) of the present invention has an asymmetric carbon, an optical stereoisomer exists, and the present invention includes each of these optical stereoisomers and a mixture ( For example, a racemate).
  • R 5 and R 6 represent different groups
  • the following optical stereoisomers exist, and such optical stereoisomers are also included in the present invention.
  • R 5 is a SO 3 Na group and R 6 is an OH group
  • the compounds represented by the general formulas (Ic) and (Ie) are R isomers
  • the general formula (Id) ) And (If) are S-isomers.
  • R 5 and R 6 together represent a ⁇ N—R 7 group, and R 7 represents an amino group substituted with a carbamimidoyl group
  • donepezil used as a therapeutic agent for Alzheimer-type dementia is a mixture (1: 1) of optical stereoisomers at the 2-position of the indanone skeleton.
  • the compound represented by the general formula (I) in the present invention may be a mixture of such optical stereoisomers at the 2-position of the indanone skeleton.
  • the 1-indane derivatives represented by Compound 6 and Compound 11 also have isomers represented by the following structural formulas. Therefore, the compounds represented by the general formula (I) of the present invention are those Each of the isomers and / or a mixture thereof may be used.
  • the compound represented by the general formula (I) of the present invention has a strong growth inhibitory action against malaria parasites and / or trypanosoma protozoa, and therefore can be used as a growth inhibitor of malaria parasites and / or trypanosoma protozoa.
  • the compound represented by the general formula (I) does not necessarily require the inhibition of the growth of both malaria parasites and trypanosoma protozoa, but only malaria parasites or trypanosoma protozoa It may be a substance that inhibits the growth of.
  • the present invention is a compound represented by the above general formula (I), which inhibits the growth of both Plasmodium and Trypanosoma.
  • this invention includes the growth inhibitor of the malaria parasite and / or trypanosoma protozoa which contains the compound represented with the said general formula (I), or its pharmacologically acceptable salt as an active ingredient. More preferably, the present invention relates to the prevention or treatment of infectious diseases caused by malaria parasites and / or trypanosoma protozoa, comprising the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to a pharmaceutical composition.
  • infectious diseases caused by Plasmodium and / or Trypanosoma protozoa mean diseases caused by infection with Plasmodium and / or Trypanosoma protozoa.
  • the pharmaceutical composition of the present invention contains a compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient for preventing or treating malaria parasite infection.
  • a composition, or a pharmaceutical composition for preventing or treating an infection caused by Trypanosoma protozoa comprising as an active ingredient the compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof. Also good.
  • this invention relates to the compound or its pharmacologically acceptable salt represented by the said general formula (I) used for the prevention or treatment of the infection by the malaria parasite and Trypanosoma parasite in another aspect.
  • malaria parasite is a protozoan belonging to the order of the apicomplexa spore genus Coccidia.
  • the malaria parasite is preferably a human infectious malaria parasite, such as P. falciparum, P. vivax, P. malariae, P. malariae, oval malaria Including protozoa (P. ovale) and simian malaria (P. knowlesi).
  • protopanosoma protozoa refers to trypanosoma cruzi, trypanosoma brucei, and trypanosol T. gossos brucei, trypanosol brucei, and trypanosol brucei. , Trypanosoma Vivacs (T. vivax), Trypanosoma Evansi (T. evansi), Trypanosoma tyreli (T. equiperdum).
  • diseases derived from infection with Trypanosoma protozoa include diseases generally known as Trypanosomiasis, such as Nagana disease and African Trypanosomiasis.
  • the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof of the present invention can strongly inhibit the growth of plasmodium and / or trypanosoma protozoa, a novel antimalarial drug and It can be used as an antitrypanosoma drug.
  • the compound represented by the general formula (I) of the present invention is derived from 1-indanone derivatives such as commercially available donepezil (related compounds CAS registration numbers 120011-70-3, 120014-06-4 and 888740-09-4). It can be obtained by appropriately guiding.
  • the compound represented by the general formula (I) of the present invention can be synthesized by utilizing a general chemical reaction for a carbonyl group.
  • a general chemical reaction for a carbonyl group For example, in the compound represented by the general formula (I), as shown by the following reaction formula, an aqueous solution of sodium hydrogen sulfite or a hydrazine or hydroxylamine represented by R 7 —NH 2 is used as a corresponding precursor.
  • alkoxylamines can be obtained by utilizing a general chemical reaction for a carbonyl group under appropriate conditions.
  • the compound represented by the general formula (I) prepared using donepezil as a starting material is an optical stereoisomer at the 2-position of the indanone skeleton. It is a mixture of bodies.
  • the target optical stereoisomer can be isolated and purified by using fractional recrystallization (salt resolution) that recrystallizes with an appropriate salt, column chromatography, or the like.
  • the present invention provides a treatment for diseases caused by infection with malaria parasites and / or trypanosoma protozoa, comprising administering an effective amount of the compound represented by the above general formula (I) to a patient in need thereof. Including methods or prophylactic methods.
  • the pharmaceutical composition of the present invention can be formulated by a conventional method using a normal pharmaceutically acceptable carrier.
  • a solid preparation for oral administration add excipients to the active ingredient and, if necessary, binders, disintegrants, lubricants, etc., and then add solvents, granules, powders, capsules, etc. by conventional methods.
  • a pH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. may be added to the main drug as necessary to obtain a subcutaneous or intravenous injection by a conventional method.
  • the antimalarial and trypanosoma protozoan infection treatment and prevention agents of the present invention can be used in oral dosage forms or parenteral dosage forms such as injections and drops.
  • this compound When this compound is administered to mammals or the like, it may be administered orally as tablets, powders, granules, syrups, etc., or may be administered parenterally as injections or drops.
  • the dosage can be appropriately set depending on the degree of symptoms, age, weight, sex, administration route, dosage form, reactivity to drugs, disease type, etc. For example, it is usually 50 to 500 mg per day per day for an adult. Administer in several divided doses.
  • Example 1 Synthesis of Compound 6 In 1 ml of ethanol, 50 mg of donepezil hydrochloride monohydrate (manufactured by Sigma, USA), 16.3 mg of aminoguanidine carbonate, and then 0.12 ml of ethanolic 1M hydrochloric acid were stirred at room temperature. In addition, several drops of ethanolic 1M hydrochloric acid were added to adjust the pH to 2.0. This solution was heated and stirred at 80 ° C. for 4 hours.
  • Donepezil as raw material is a mixture (1: 1) of optical stereoisomers at the 2-position of the indanone skeleton.
  • compound 6 derived from donepezil contains an optical stereoisomer at the 2-position of the indanone skeleton and a geometric isomer related to hydrazone, as represented by the following structural formula.
  • Example 2 Synthesis of Compound 1 1 ml of an aqueous solution in which 576 mg of sodium bisulfite was dissolved was dropped into 1 ml of methanol in which 200 mg of donepezil hydrochloride monohydrate was dissolved at room temperature. The slightly purple-colored solution was stirred overnight at room temperature, and the resulting colorless crystal-like solid was filtered, washed with 0.5 ml of cold isopropanol, and dried under reduced pressure to obtain 130 mg (yield 60%) of Compound 1. It was.
  • Example 3 Synthesis of Compound 11 A solution in which 200 mg of donepezil hydrochloride monohydrate and 53.5 mg of semicarbazide hydrochloride were suspended in 1 ml of methanol while stirring at room temperature and stirred for a whole day and night, then gradually turned yellow. Was concentrated to dryness. The residue was stirred and washed with 5 ml of ice-cold isopropanol to obtain 198 mg (yield 85%) of Compound 11.
  • Donepezil (CAS registration numbers 120011-70-3, 120014-06-4 and 888740-07-4 of related compounds) is a mixture (1: 1) of optical stereoisomers at the 2-position of the indanone skeleton
  • Compound 11 derived from donepezil contains an optical stereoisomer at the 2-position of the indanone skeleton and a geometric isomer related to hydrazone, as represented by the following structural formula.
  • Example 4 Synthesis of Partial Structures of Compounds 6 and 11
  • compounds 25 (donepezil), compounds 1, 6 and 11 as Plasmodium falciparum and Trypanosoma protozoa (causal protozoa of Nagana disease). Since it was first found to be effective for Trypanosoma brucei brucei), partial structures of compounds 1, 6 and 11 were prepared in order to find a pharmacophore essential for the expression of the action.
  • Candidates for partial structures of compounds 1, 6 and 11 include 1-indane skeleton represented by the following general formula (II), N-benzylpiperidine-4-carboxa represented by the general formula (III) Assuming a aldehyde skeleton and an N-debenzyldonepezyl skeleton represented by the general formula (IV), each of which is a partial structure in which various basic functional groups are introduced from a compound in which X is an oxygen atom. 1 to 6 were prepared and their antimalarial activity was evaluated.
  • Partial structure 1 (5,6-dimethoxyindanone (compound in which general formula (II) X is an oxygen atom)) was heated with aminoguanidine in acetic acid water (80 ° C., 3 hours) to form partial structure 2 (Guanidylimino derivative (compound in which X is ⁇ N—NH—C (—NH 2 ) ⁇ NH in the general formula (II))) was obtained.
  • Partial structure 2 was prepared according to a known method for preparing related compounds (Synthesis of new piperidylindylene derivatives as anti-duty, A Ru, Ah, H .; Shamsher Alam, M .; Ahmed, Sharieque: Medicinal Chemistry Research (2012), 21 (6), 726-733.).
  • partial structure 3 N-benzylpiperidine-4-carboxaldehyde (compound in which X is an oxygen atom in the general formula (III)) is treated with aminoguanidine in acetic acid water (80 ° C., 3 hours).
  • partial structure 4 (guanidinymino derivative (compound in which X is ⁇ N—NH—C (—NH 2 ) ⁇ NH in the general formula (III))) was obtained (yield 85%).
  • partial structure 5 N-debenzyldonepezil (compound in which general formula (IV), X is an oxygen atom)
  • aminoguanidine in acetic acid water (80 ° C., 3 hours)
  • aminoguanidine in acetic acid water (80 ° C., 3 hours)
  • the physicochemical properties of the partial structure 6 were as follows. mp 213.3-215.2 ° C, IR v (KBr, cm ⁇ 1 ): 3423, 2927, 2854, 1745, 1672, 1618, 1597, 1504, 1456; UV-vis (MeOH): ⁇ (nm) (log ⁇ / L mol ⁇ 1 cm ⁇ 1 ): 249.0 (4.07), 278.5 (3.99), 294.5 (4.00), 320.0 (4.09), 331.5 (4.05); 1 H NMR (400 MHz, MeOH-d 4 ) ⁇ (ppm) 1.32 (1H, m), 1.50 (1H, m), 1.68 (1H, m), 1.77 (1H, m ), 1.88 (2H, m), 2.09 (1H, d), 2.85 (1H, d), 2.99 (2H, m), 3.20 (1H, dd), 3.35 (1H, m), 3, 42 (1H, m), 3.50 (1H, m), 3.86 (6H,
  • Example 5 In vitro malaria parasite growth inhibitory activity of 1-indane derivatives and partial structures Drug resistance of Plasmodium falciparum distributed by Professor Kitayoshi of the graduate School of Medicine, University of Tokyo Using the strain K1 and the drug-sensitive strain FCR3, in vitro compounds 1, 6, 11, and 25 and the antimalarial activity of partial structures 1 to 6 against these malaria parasites Otoguro et al. [Otoguro, K. et al. , Kohana, A .; Manab, C.I.
  • Test protozoa include the method of Trager and Jensen [Trager, W and Jensen, J. et al. : Human malaria parasites in continuous culture, Science, 193: 673-677, (1976)], which were maintained and passaged. That is, protozoa-infected erythrocytes subcultured using RPMI 1640 medium supplemented with 10% human plasma and fresh human erythrocytes in a culture dish were diluted (hematocrit value: 2-5%, protozoa-infected erythrocyte rate: 0.25 Incubate in a mixed gas of 3% O 2 -4% CO 2 -93% N 2 at 37 ° C, and change the medium and add fresh erythrocytes every 2-3 days for continuous culture. went.
  • the drug sensitivity test was performed by the method of Desjardins et al. E. , Canfield, C.I. J. Haynes, D .; E. And Chulay, J.H. D. : Quantitative assessment of antimalial activity in vitro by a semi-automated microdilution technique. Antimicrob. Agents Chemother. , 16: 710-718 (1979)].
  • test compounds compounds 6, 1 and 11 prepared by the above-mentioned method, partial structures 1 to 6, and chloroquine (manufactured by Sigma, USA) which is a known antimalarial agent against cultured Plasmodium falciparum were used. .
  • protozoan suspension precultured in each well of a 96-well plate (hematocrit value: 2%, protozoa-infected erythrocyte rate: 0.5 or 1%) and a final concentration of 100 to 0.0001 ⁇ g / mL 10 ⁇ l of a test compound solution (50% ethanol solution) serially diluted at such a concentration was added, mixed, and cultured for 72 hours under the aforementioned mixed gas.
  • the 96-well plate was directly frozen at ⁇ 20 ° C. for 18 hours and then thawed at 37 ° C. to hemolyze protozoa-infected erythrocytes and destroy the protozoa, thereby preparing a crude enzyme solution.
  • the blue formazan product produced by the reaction is measured for absorbance at a measurement wavelength of 655 nm using a microplate reader (manufactured by Labosystems, Finland), and the presence or absence of protozoa is colorimetrically determined. Quantified. The 50% protozoan growth inhibitory concentration (IC 50 value) of the compound was determined from the compound concentration action curve.
  • IC 50 value 50% protozoan growth inhibitory concentration
  • compounds 25 and 11 have the same activity against drug-resistant K1 strain and drug-sensitive FCR3 strain, they have antimalarial activity different from the action mechanism of chloroquine in drug-resistant malaria parasites in the K1 strain and FCR3. It shows that it acts on both strains.
  • compound 6 since compound 6 has about 8 times the antimalarial activity of drug-resistant FCR3 strain as compared to drug-resistant K1 strain, resistance is caused by a mechanism similar to the chloroquine resistance mechanism in drug-resistant malaria parasites. It is estimated to be.
  • Example 6 In Vitro Trypanosoma protozoa Growth Inhibitory Activity of 1-Indane Derivatives and Partial Structures Growth of Trypanosoma protozoa in vitro of Compounds 1, 6, 11 and 25 of the present invention and Partial Structures 1-6
  • the activity of inhibiting was investigated as follows.
  • protozoan growth was measured by adding 10 ⁇ L of Alamar Blue reagent (Sigma-Aldrich, USA) to each well of a 96-well plate, mixing, and mixing at 37 ° C. under 5% CO 2 -95% air. After culturing for 6 hours, the redox potential of the protozoa is measured with a fluorescence microplate reader (Bio-Tek, USA) by measuring the fluorescence intensity at an excitation wavelength of 528/20 nm and a fluorescence wavelength of 590/35 nm. The presence or absence of proliferation was colorimetrically determined. The 50% protozoan growth inhibitory concentration (IC 50 value) of this compound was determined from the compound concentration action curve of KC-4 (manufactured by Bio-Tek, USA) with software attached to a fluorescent microplate reader.
  • IC 50 value 50% protozoan growth inhibitory concentration
  • suramin and ephronitin were used as known anti-trypanosoma protozoan agents whose effects on cultured Trypanosoma protozoa were measured.
  • Table 3 below shows the anti-trypanosoma protozoan activity of donepezil and compounds 6, 1 and 11 of the present invention and partial structures 1 to 6 and known anti-trypanosoma protozoa against cultured trypanosoma protozoa.
  • Example 7 Cytotoxicity Test of 1-Indan Derivatives and Partial Structures The cytotoxicity tests of the 1-indan derivatives 1, 6 and 11 of the present invention and the partial structures 1 to 6 were carried out by the method of Otoguro et al. K, Kohana A, Manabe C, Ishiyama A, Ui H, Shiomi K, Yamada H, Omura S. et al. Potential axial activities of polymer antibiotic, X-206. J. et al. Antibiotics, 54: 658-663, (2001)]. That is, human fetal lung-derived normal fibroblast MRC-5 cells [Dr. L. Maes (available from Tibotec NV, Mechelen, Belgium)] was maintained and subcultured in MEM medium supplemented with 10% fetal calf serum (FCS) and antibiotics.
  • FCS fetal calf serum
  • the 50% cell growth inhibitory concentration (IC 50 value) of this compound was determined from the compound concentration action curve. Further, the selectivity index (Selectivity Index: SI) was calculated by (cytotoxic IC 50 value) / (antimalarial or antitrypanosome protozoan activity IC 50 value).
  • the cytotoxicity (IC 50 values) of compounds 25, 6, 1, and 11 on human fetal lung-derived normal fibroblast MRC-5 cells were 24.33, 15.92, 19.45, and 0.81 ⁇ g / 0.8, respectively.
  • the selective toxicity ratio (SI) with antimalarial protozoal activity was 2.8, 5.6, ⁇ 1.6 and 0.8, respectively.
  • the selective toxicity ratio (SI) with antitrypanosome protozoan activity was 5.4, 23.1, 3.7 and 5.1, respectively.
  • Example 8 In Vivo Malaria Parasite Growth Inhibitory Activity of 1-Indan Derivatives berghei N strain (drug-sensitive strain) [Dr. W. Peters (available from Northwick Park Institute for Medical Research, Medlexex, UK)]
  • Otoguro et al. Otoguro, K. et al. , Kohana, A .; Manab, C.I. , Ishiyama, A .; Ui, H .; Shiomi, K .; Yamada, H .; and Omura, S .; : Potential axial activity of polymer antibiotic, X-206. J. et al.
  • test animals males of ICR mice (Charles River Japan Co., Ltd.), 5 mice with a body weight of 18 to 20 g, were used, and 2 ⁇ 10 6 parasite-infected erythrocytes were maintained and passaged by in vivo passage. Infected by tail vein inoculation.
  • the treatment experiment was conducted in a 4 days suppressive test. Assuming that the day of infection is day 0, a compound solution (10% dimethyl sulfoxide solution-Tween 80) is administered intraperitoneally (ip) 2 hours after the infection, and thereafter administered once a day for 3 consecutive days.
  • a blood smear was prepared from the tail vein at (days 1 to 3) and day 4, and the protozoa-infected red blood cell rate (parasitaemia) was observed, and the therapeutic effect (inhibition%) was determined from the infection rate of the non-administered group.
  • the murine malaria parasite P. berghei N strain infection experimental model has a suppression of protozoa-infected erythrocyte rate of 24.1 to 24.6% compared with the control group with no drug at a low dose of 5 to 10 mg / kg. It was.
  • the compound represented by the general formula (I) of the present invention exhibits an antiprotozoal activity in vitro and in vivo against human infectious P. falciparum, so that it is clinically used as an antimalarial agent. It is expected to be applicable. Moreover, since the compound represented by the general formula (I) of the present invention also exhibits antiprotozoal activity in vitro against trypanosoma protozoa, clinical application as various protozoal remedies and preventive agents is expected.

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Abstract

La présente invention concerne : un inhibiteur de la prolifération d'un protozoaire responsable de la malaria infectant l'homme et de celle d'un protozoaire infectant l'homme du genre trypanosome ; et un agent thérapeutique et un agent prophylactique. Plus particulièrement, l'invention concerne une composition pharmaceutique ayant un effet prophylactique ou thérapeutique sur des infections provoquées par un protozoaire responsable de la malaria et un protozoaire du genre trypanosome, ladite composition pharmaceutique comprenant un composé représenté par la formule générale (I) et son sel pharmacologiquement acceptable utilisés comme principes actifs. [Dans la formule, les R1 à R4 représentent indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C8, un groupe alcényle en C2 à C8, un groupe aryle en C6 à C10, un groupe alcoxy en C1 à C8, un groupe alkylthio en C1 à C8, un groupe hydroxy, un atome d'halogène ou un groupe amino (hormi le cas où chacun des R1 à R4 représente un groupe hydroxy) ; et R5 et R6 représentent indépendamment un groupe hydroxy ou un groupe -SO3Na, ou R5 et R6 forment ensemble un groupe oxo ou un groupe =N-R7.]
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4895841A (en) * 1987-06-22 1990-01-23 Eisai Co., Ltd. Cyclic amine compounds with activity against acetylcholinesterase
WO2010019560A1 (fr) * 2008-08-12 2010-02-18 Concert Pharmaceuticals Inc. Dérivés deutérés de donépézil

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4895841A (en) * 1987-06-22 1990-01-23 Eisai Co., Ltd. Cyclic amine compounds with activity against acetylcholinesterase
WO2010019560A1 (fr) * 2008-08-12 2010-02-18 Concert Pharmaceuticals Inc. Dérivés deutérés de donépézil

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DEVKOTA, K. P. ET AL.: "Cholinesterase inhibiting and antiplasmodial steroidal alkaloids from Sarcococca hookeriana", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 59, no. 9, 2007, pages 1397 - 1401 *
LENTA, B. N. ET AL.: "Anti-plasmodial and cholinesterase inhibiting activities of some constituents of Psorospermum glaberrimum", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 56, no. 2, 2008, pages 222 - 226 *
LIM, L. Y. ET AL.: "The anticholinesterase activity of mefloquine", CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, vol. 12, no. 5, 1985, pages 527 - 531, XP000900059 *
MCARDLE, J. J. ET AL.: "Mefloquine inhibits cholinesterases at the mouse neuromuscular junction", NEUROPHARMACOLOGY, vol. 49, no. 8, 2005, pages 1132 - 1139, XP005160054, DOI: doi:10.1016/j.neuropharm.2005.06.011 *

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