WO2001058888A1 - Compose sesquiterpenoique et formulations pharmaceutiques contenant ce compose - Google Patents

Compose sesquiterpenoique et formulations pharmaceutiques contenant ce compose Download PDF

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WO2001058888A1
WO2001058888A1 PCT/JP2001/000962 JP0100962W WO0158888A1 WO 2001058888 A1 WO2001058888 A1 WO 2001058888A1 JP 0100962 W JP0100962 W JP 0100962W WO 0158888 A1 WO0158888 A1 WO 0158888A1
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Prior art keywords
methyl
compound
represent
bond
single bond
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PCT/JP2001/000962
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English (en)
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Motoyoshi Satake
Hiroyuki Fuchino
Tatsuo Koide
Marii Takahashi
Setsuko Sekita
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Motoyoshi Satake
Hiroyuki Fuchino
Tatsuo Koide
Marii Takahashi
Setsuko Sekita
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Application filed by Motoyoshi Satake, Hiroyuki Fuchino, Tatsuo Koide, Marii Takahashi, Setsuko Sekita filed Critical Motoyoshi Satake
Publication of WO2001058888A1 publication Critical patent/WO2001058888A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered

Definitions

  • a sesquiterpenoic compound and pharmaceutical formulations comprising the same
  • the present invention relates to a germacranolide-type or guaianolide-type sesquiterpenoic compound and pharmaceutical formulations, particularly antiprotozoal agents, comprising the same.
  • chemotherapeutic agents against infectious diseases caused by protozoans As chemotherapeutic agents against infectious diseases caused by protozoans, a large number of agents, including quinine used against malaria, have been developed. However, every time a protozoan develops resistance to an agent, a new specific agent is required. Especially, in respect of malaria, the achievement of agent resistance by a protozoan causes a serious problem.
  • Leishmaniasis is a parasitic disease, which is caused by a protozoan, leishmania and appears specifically in tropical regions including South America, and it is one of the Six tropical diseases designated by WHO.
  • WHO The total number of patients in Africa, Middle East, Central and South America and Asia is approximately twelve million, and four hundred thousand people become newly infected with this disease every year.
  • the infection route of this disease is a blood sucking insect, sandfly (Phlebotomus). When a sandfly sucks blood from the body, leishmania parasitizing in the sandfly infests into a human body, thereby establishing an infection.
  • Leishmania is comprised of 4 complexes: Leishmania donovani, L. tropica, L.
  • L. tropicana The old-world type cutaneous leishmaniasis is developed by L. tropicana, whereas the new-world type cutaneous leishmaniasis is developed by L. mexicana. Both types are developed by the parasite of a protozoan to a macrophage in skin and subsequently form a cutaneous ulcer. L. braziliensis usually develops mucosal-cutaneous leishmaniasis creating a lesion in mucous membrane and skin, but some of them may develop cutaneous leishmaniasis.
  • a protozoan, leishmania has a variety of species. Further, from the viewpoint of immunology, even though the morbidity is similar, their antigenicities are different depending on regions. This makes the development of vaccine difficult, and chemotherapy is highly required.
  • pentavalent antimony agents are used as the agents of first choice.
  • Pentostam the trade name: Pentostam, Glucantime
  • Pentamidine the trade name: Pentamidine
  • Amphotericin B the trade name: Pentamidine
  • Amphotericin B the trade name: Pentamidine
  • Amphotericin B the trade name: Pentamidine
  • Amphotericin B the trade name: Pentamidine
  • Amphotericin B are used instead, but these agents have lower efficacy than antimony agents do.
  • the antimony agents may have strong side effect after the administration, a medical doctor's care is needed for their use.
  • the high price of antimony agents causes another problem.
  • some kinds of protozoans have already developed resistance to the antimony agents, and so a novel, low-priced and safe therapeutical agent with fewer side effects is desirable.
  • the object of the present invention is to provide a pharmaceutically useful compound which is effective against drug resistant protozoans, particularly to leishmania.
  • sesquiterpenoic compounds shown in formulas I to IV set forth later or derivatives thereof are useful as pharmaceuticals, particularly as antiprotozoal agents.
  • the present inventors have found the use of the sesquiterpenoic compounds shown in formulas I to IV or derivatives thereof as antiprotozoal agents, that is to say, they have found the use of antiprotozoal agents comprising the above sesquiterpenoic compounds or derivatives thereof; the use of the above sesquiterpenoic compounds or derivatives thereof for the production of antiprotozoal agents; or the use of the above sesquiterpenoic compounds or derivatives thereof for the treatment of protozoal infections.
  • the present inventors have found the sesquiterpenoic compounds shown in formulas 5, 6, 7, 9, 10, 14 and 17 or derivatives thereof, and their utility as a pharmaceutical formulations.
  • the present inventors have found the use of the sesquiterpenoic compounds shown in formulas 1 to 7, 9, 10, and 13 to 18 or derivatives thereof as antiprotozoal agents, that is to say, they have found the use of antiprotozoal agents comprising the above sesquiterpenoic compounds or derivatives thereof; the use of the above sesquiterpenoic compounds or derivatives thereof for the production of antiprotozoal agents; or the use of the above sesquiterpenoic compounds or derivatives thereof for the treatment of protozoal infections. Furthermore, the present inventors have found that a composition comprising, as active ingredients, the compounds of formulas I to IV obtained by extracting from composite plants, is useful as a pharmaceutical formulation, particularly as an antiprotozoal agent.
  • an antiprotozoal agent particularly an anti-leishmanial agent could be obtained, not only where the agent comprises any one of the structures of compounds 1 to 7, but also where it comprises a germacran-type or guaian-type sesquiterpenoic compound having specific substituents shown in the following formulas I, II and III:
  • the present inventors claiming the right of priority regarding this Japanese patent application, file the present application with some further examples providing support for this conception. Furthermore, the present application comprises a new finding, that compounds shown in the following formulas Ila (the part comprised in formula ⁇ is excluded) and IV are also useful as antiprotozoal agents, particularly anti-leishmanial agents, which was not disclosed in Japanese Patent Application No. 2000-33232. That is to say, the present invention relates to a sesquiterpenoic compound shown in the following formula I, Ila, nib or IV, or a derivative thereof:
  • -X-, -Y- and -A- represent a single bond or a double bond
  • R 2 is methyl or methylene
  • R 4 is methyl or methylene
  • R 5 is methyl
  • R 3 and R 4 may together form -O-CO-; with the exception that the following compounds (1) to (4) are excluded from the compounds shown in the above formula I or derivatives thereof:
  • -X-, -Y-, -Z- and -A- represent a single bond or a double bond
  • R 6 does not exist or represents OH
  • R 7 is methyl or methylene
  • R 9 and R 10 do not exist or represent methyl, methylene or OH
  • R n represents methyl
  • Rj 2 is methyl or methylene
  • R 14 and R 15 respectively represent methyl or OH, and alkoxyl.
  • the present invention relates to a pharmaceutical formulation comprising a sesquiterpenoic compound shown in the following formula I, Ila, Hie or
  • R 2 is methyl or methylene
  • R 4 is methyl or methylene
  • R 5 is methyl
  • R 3 and R 4 may together form -O-CO-; with the exception that the following compounds (1) to (3) are excluded from the compounds shown in the above formula I or derivatives thereof:
  • -X-, -Y-, -Z- and -A- represent a single bond or a double bond
  • R 6 does not exist or represents OH
  • R 7 is methyl or methylene
  • R 9 and R 10 do not exist or represent methyl, methylene or OH
  • R ⁇ represents methyl
  • -A- represents a single bond or a double bond
  • R 12 is methyl or methylene
  • R 13 is methyl
  • R 14 and R 15 respectively represent methyl or OH, and alkoxyl.
  • the present invention relates to the use of a sesquiterpenoic compound shown in formula I, Ha, Hie or IV or a derivative thereof, as an antiprotozoal agent, that is to say, the use of antiprotozoal agents comprising the above sesquiterpenoic compound or a derivative thereof; the use of the above sesquiterpenoic compound or a derivative thereof for the production of antiprotozoal agents; or the use of the above sesquiterpenoic compound or a derivative thereof for the treatment of protozoal infections.
  • the present invention relates to a pharmaceutical formulation comprising the compound shown in the above formula 5, 6 or 7, or the following formula 9, 10, 14 or 17, or a derivative thereof:
  • the present invention relates to the use of a sesquiterpenoic compound shown in the above formula 1 to 7, 9, 10, 14 or 17, or in the following formula 13, 15, 16 or 18, or a derivative thereof, as an antiprotozoal agent, that is to say, the use of antiprotozoal agents comprising the above sesquiterpenoic compound or a derivative thereof; the use of the above sesquiterpenoic compound or a derivative thereof for the production of antiprotozoal agents; or the use of the above sesquiterpenoic compound or a derivative thereof for the treatment of protozoal infections.
  • the present invention relates to a pharmaceutical formulation which consists of a composition comprising, as active ingredient, the compound of the above formula I, Ila, Hie or IV obtained by extraction from composite plants.
  • the present invention relates to the use of the compound of the above formula I, Ha, Die or IV obtained by extraction from composite plants, as an antiprotozoal agent, that is to say, the use of antiprotozoal agent comprising the above composition or a derivative thereof; the use of the above composition or a derivative thereof for the production of antiprotozoal agents; or the use of the above composition or a derivative thereof for the treatment of protozoal infections.
  • the derivatives of the sesquiterpenoic compound of the present invention include those of hydroxyl and carbonyl.
  • the derivatives of the compound shown in formula 1 include those of hydroxyl and carbonyl, and the derivatives of the compounds shown in formulas 2 and 3 include acetal derivatives of carbonyl in a lactone ring.
  • the derivatives of the compound shown in formula 5 include those of hydroxyl
  • the derivatives of the compound shown in formula 6 include those of carbonyl at position 2
  • the derivatives of the compound shown in formula 7 include those of hydroxyl and carbonyl at position 2
  • the derivatives of the compounds shown in formulas 9 and 10 include those of hydroxyl.
  • the preferable derivatives of hydroxyl include alkoxyl, acyloxy, silyloxyl, etc.
  • examples of alkoxyl include methoxyl, ethoxyl, propyloxyl, butyloxyl, etc.
  • examples of acyloxy include acetyloxy, propionyloxy, butyryloxy, alkylcarbonyloxy such as valeryloxy, and arylcarbonyloxy such as benzoyloxy.
  • examples of silyloxyl include trimethylsilyloxyl.
  • the derivatives of carbonyl include acetal, hydrazone or oxime.
  • the sesquiterpenoic compound of the present invention characteristically has a common basic skeleton shown in the following formula A:
  • Elephontopus mollis H. B. K. (which is called “lingua de vaca” locally) is a composite plant distributed in Central and South America, and locally is used as a decoction to make the body analeptic or to treat dyshidrosis, coughing, bronchitis and nephrolithiasis. It is also used as a strapping for dermatosis or elephantiasis. It has also been reported that the compounds shown in formulas 1 and 2 have antitumoral activity (S. Kupchan et al, J .Am. Chem. Soc, vol.
  • the compounds shown in formulas 9 and 10 are novel ones obtained by purifying and isolating from Elephantopus mollis H.B.K. of Brazilian origin by the present inventors.
  • the compounds of formulas 13 and 15 are known (Lee KH, Furukawa H, Kozuka M, Chemical Communication, J. Chem. Soc, p.476-477 (1973); Lee KH, Ibuka T, Furukawa H, Kozuka M, Wu RY, Hall IH, Huang HC, J. Pharm. Sci., vol.68, p.1050-1056 (1980)), and each of two compounds have been obtained by derivation from the compound of formula 1.
  • the compound shown in formula 14 is novel.
  • the compounds shown in formulas 16 to 18 have been obtained from the compound of formula 1 according to a known production method (Lee KH, Ibuka T, Furukawa H, Kozuka M, Wu RY, Hall IH, Huang IC, J. Pharm. Sci., vol.68, p.1050- 1056 (1980).
  • the compounds of formulas 16 and 18 are known, but the compound of formula 17 is novel.
  • the specific compounds having the antiprotozoal activity of the present invention include the compounds shown in the following formulas 8, 8-1, 11, 11-1 and the above formulas 13 to 18, as well as the compounds shown in the above formulas 1 to 7, 9 and 10:
  • the sesquiterpenoic compounds shown in formulas I-IV or the derivatives of the present invention can be obtained by purifying and separating from plants e.g. composite plants, or production from compounds which are extracted from plants.
  • the sesquiterpenoic compounds shown in formulas 1 to 4 or formula 8 are publicly known.
  • the production method of the compounds of formulas 1 to 7, as stated above, has already been reported by the present inventors (Hiroyuki Fuchino et al, the 46 th Annual Meeting of the Japanese Society of Pharmacognosy Abstract Papers, p.150 (1999) and Hiroyuki Fuchino et al., 22 nd IUPAC International Symposium on the Chemistry of Natural Products Abstract Papers, PPA-035 (2000)).
  • the production method of the compounds of formulas 13 to 18 has also been reported (Hiroyuki Fuchino et al., the Pharmaceutical Society of Japan the 120 th Annual Meeting Abstract Papers, vol.2, p.125 (2000).
  • the plants from which the sesquiterpenoic compounds are extracted include Elephantopus or Helianthus, Calea, and Vanillosmopsis.
  • the extraction and purification from plants can be carried out according to the following publicly known method.
  • the entire or the terrestrial part of plants used as a material is collected at appropriate period, is subjected to air-drying and the like, and then is extracted to obtain the extract.
  • the juice squeezed out of plants can also be used as an extract material.
  • Sesquiterpenoic compounds can be extracted from the above dried plant body according to known procedures.
  • the extract can be obtained from natural extract materials, or crushed or macerated ones, using a solvent. This process can be carried out according to a batch system or continuous system extraction.
  • organic solvents such as dichloromethane, chloroform, hexane, etc. can be used. Generally, this extraction procedure is carried out at room temperature.
  • sesquiterpenoid is purified and separated.
  • insoluble residue can be removed from the crude extract by filtration, centrifugation and so on.
  • a more concentrated extract is obtained by removing solvent from the extract, and then the concentrated extract is purified and separated.
  • known methods including silica gel or activated carbon column chromatography, gel filtration chromatography and liquid chromatography can be used singly or in combination.
  • Alkoxyl derivatives can be produced by alkylating with known alkylating agents such as alkyl halide.
  • methoxyl derivatives can be produced using iodomethane according to the method described in N. Finch, J. Fitt, LH.S.Hsu, J. Org. Chem., vol.40, p.206 (1975) or an equivalent method.
  • Acyloxy derivatives can be produced by acylating with known acylating agents such as acid anhydride or acid chloride.
  • Acetoxyl derivatives can be produced using acetic anhydride according to the method described in H. Weber, H.G. Khorana, J. Mol. Biol., vol.72, p.219 (1972) or an equivalent method.
  • Silyloxyl derivatives can be produced by silylating with known silylating agents such as trialkylsilylchloride.
  • Triethylsilyloxyl derivatives can be produced using triethylsilylchloride according to the method described in E. J. Corey, H. Cho, C. Rucker, D.H. Hua, Tetrahedron Lett., vol.22, p.3455 (1981) or an equivalent method.
  • Acetal derivatives can be produced using ethylene glycol according to the method described in C. H. Heasthcock, R. Ratcliffe, J. Am. Chem. Soc, vol.93, p.1746 (1971) or an equivalent method. Hydrazone derivatives can be produced according to the method described in G. R. Newkome, D. L. Fishel, Org. Synth., vol.50, p.102 (1970) or an equivalent method.
  • Oxime derivatives can be produced according to the method described in R. V. Stevens, F. C. A. Gaeta, D. S. Lawrence, J. Am. Chem. Soc, vol. 105, p.7713 (1983) or an equivalent method.
  • the sesquiterpenoic compounds shown in formulas 1 to 7, 9 and 10 can be obtained by extraction from a Peruvian composite plant, Elephantopus mollis H. B. K. (which is locally called "lingua de vaca"), and then purifying the extract to separate.
  • a method of purifying and separating the sesquiterpenoic compound silica gel column chromatography, gel filtration chromatography, high performance liquid chromatography and the like can be used.
  • the sesquiterpenoic compound shown in formula IHc (or nib) or the derivatives can be produced by the following process:
  • the compound of formula 8 can be produced by iodinating hydroxymethyl at position C-5 of the compound of formula 8-2, and then deriving it to methyl using metallic reagent such as tributyltin hydride.
  • the compound of formula 8-1 can be produced by reducing a double bond at position 4 of the compound of formula 8-2 by catalytic hydrogenation.
  • Iodination can be carried out according to the method described in P. J. Garegg, B. Samuelsson, J. Chem. Soc. Chem. Commun., p.978 (1979) or an equivalent method.
  • the conversion of methyl iodide into methyl can be carried out, for example, according to the methods described in S. J. Cristol, R. M. Sequeira, C. H. DePuy, J. Am. Chem. Soc, vol. 87, p.4007 (1965) and G. Cardillo, M. Orena, S. Sandri, C. Tomasini, J. Org. Chem., vol. 49, p.3951 (1984) or an equivalent method.
  • the compound of formula 8 can be derived to the compound of formula 8-1, for example, according to the method described in W.F. Bruce, J. O. Rails, Org. Synth., Coll. vol. ⁇ , p.191 (1943) or an equivalent method.
  • the compound of formula 8-2 used as a material can be extracted from composite plants according to the methods described in W. Vichnewski, S. J. Sarti, B. Gilbert, W. Herz, Phytochemistry, vol.15, p.191 (1966) and W. Herz, G. Hogenauer, J. Org. Chem., vol. 27, p.905 (1962) or an equivalent method.
  • the compound of formula 13 can be produced according to the method described in Lee KH, Furukawa H, Kozuka M, Chemical Communication, J. Chem. Soc, p.476-477 (1973) and Lee KH, Ibuka T, Furukawa H, Kozuka M, Wu Ry, Hall IH, Huang HC, J. Pharm. Sci., vol.68, p.1050-1056 (1980), or an equivalent method.
  • the compound formula 14 can be produced according the method described later or an equivalent method.
  • the compound of formula 15 can be produced according to the method described in Lee KH, Ibuka T, Furukawa H, Kozuka M, Wu Ry, Hall IH, Huang HC, J. Pharm. Sci., vol.68, p.1050-1056 (1980), or an equivalent method.
  • the compounds of formula 16, 17 and 18 can be produced according to the method described in Lee KH, Ibuka T, Furukawa H, Kozuka M, Wu Ry, Hall IH, Huang HC, J. Pharm. Sci., vol.68, p.1050-1056 (1980), or an equivalent method.
  • the sesquiterpenoic compounds of the present invention or these derivatives have antiprotozoal activity, particularly anti-leishmanial activity. So, these compounds can be used as antiprotozoal agents. As described later, when an acute toxicity test was carried out using the methanol extract obtained from Elephantopus mollis H.B.K. containing large amounts of sesquiterpenoid of the present invention, there was found no toxicity. Therefore, it is considered that the sesquiterpenoic compounds of the present invention or these derivatives do not have any serious toxicity problems.
  • the pharmaceutical formulation of the present invention can be administered both orally and parenterally, and the formulation can be processed into dosage forms suitable for each case.
  • this can be applied as a tablet, pill, capsule, powder, granule, emulsion, solution, syrup and elixir. It is also preferable to be applied as an extract containing the above compound, which is an extract composition from plants.
  • the present pharmaceutical formulation when applied as a tablet, pill, capsule, powder or granule, it may contain additive agents such as an excipient, lubricant, bonding agent, disintegrating agent, stabilizer, solubilizer and the like.
  • the present pharmaceutical formulation When the present pharmaceutical formulation is applied as an emulsion, solution, syrup or elixir, it can contain other additive agents such as an antiseptic as an adjuvant. Where the present pharmaceutical formulation is administered parenterally, this can be applied as an injection, ointment, plaster, poultice, liniment, lotion, suppository and the like.
  • the present pharmaceutical formulation When the present pharmaceutical formulation is applied as an injection, it may contain some additive agents such as a stabilizer, solubilizer, suspending agent, emulsifier, buffer agent, preservative, or other appropriate additive agents. Diluents may be added to the preparation to be dissolved before use.
  • it When it is applied as an aqueous injection, it may contain, e.g. distilled water for injection, physiological salt solution and Ringer's solution, as solvents.
  • it When it is applied as a nonaqueous injection, it may contain e.g. vegetable oil.
  • an appropriate base When the present pharmaceutical formulation is applied as an ointment, plaster and suppository, an appropriate base may be used.
  • an appropriate base When it is applied as a poultice, liniment, lotion, it may contain a preservative or an aromatic.
  • the liniment may contain water, ethanol, fatty oil, glycerin, soap, emulsifier, suspending agent or other appropriate additive agents.
  • the lotion may contain the mixture of aqueous liquid and an appropriate solvent, emulsifier, suspending agent or the like.
  • the poultice may contain appropriate essential oil ingredients.
  • the applied dosage of the present pharmaceutical formulation depends on morbidity, age, body weight and administration route, but when it is administered orally, in general, lmg to l,000mg per adult is administered one or several times per day. However, this applied dosage depends on patients' body condition, and the amount is not limited to the above range.
  • Artemisia rothrockii can be obtained from Artemisia rothrockii, according to the method described in M. A. Irwin, T. A. Geissman, Phytochemistry, vol.10, p.637-645 (1971) or an equivalent method. That is to say, 0.78kg of crushed Artemisia rothrockii is extracted with 2.5L of chloroform 3 times, then the obtained extract is concentrated. 2L of methanol water (3:1) is added to the concentrated extract, which is then suspended and extracted with IL of hexane. The obtained water layer is concentrated to 0.3L under reduced pressure, and extracted with 0.5L of chloroform 4 times. The residue obtained by concentrating such obtained extract is purified with silica gel column chromatography.
  • the inner diameter of the used column is 8cm, and the height is 37cm.
  • elution solvents first a mixed solvent of chloroform and benzene is used, then the polarity of the solvent is gradually increased by adding acetone. 0.5L per fraction is separated, and a total of 30 fractions are separated. The 6 th to 10 th fractions are together concentrated to obtain 0.26g of Rothin-A.
  • the obtained Rothin-A is induced to the compound of formula 11-1 according to the following method: in a 20mL of reaction vessel, lOOmg (0.4mM) of Rothin-A is dissolved into lmL of dried pyridine, and while the solution is stirred with multi-shaft stirring blades, it is cooled down to 10°C Then, 50.1mg (0.19mM) of metacryloyl chloride is slowly added to the solution, followed by stirring for 1 to 3 hours. After completing the reaction, 20mL of water is added to the reaction solution and extracted with low polar organic solvent, chloroform. The organic layer is washed and dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the compound of interest shown in formula 11-1.
  • triphenyl phosphine and 2 mol of triiodoimidazole are used for 1 mol of the compound of formula 8-2.
  • the compound of formula 8-2, triphenyl phosphine and triiodoimidazole are put into a reaction vessel and dissolved into toluene.
  • the reaction solution is stirred with multi-shaft stirring blades. Then, the reaction solution was heated up to 120° C This reaction is completed within 30 minutes to 30 hours. After completing the reaction, the reaction solution is washed and the solvent is removed under reduced pressure, to obtain the crude crystal of the compound of interest.
  • 0.5g of Adam's platinum oxide catalyst is used for 1 mol of the compound of formula 8.
  • the compound of formula 8 is put into a reaction vessel and dissolved into ethanol.
  • Adam's platinum oxide is added thereto and shaken strongly under hydrogen ambient at room temperature.
  • the reaction time is 0.5 to 5 hours.
  • the catalyst is filtrated and the solvent is removed from the filtrate under reduced pressure.
  • the obtained residue is purified with silica gel column chromatography, using the mixed solvent of n-hexane and ethyl acetate as a developing solvent, to obtain the compound of formula 8-1.
  • acetic anhydride 1.5 mol of acetic anhydride is used for 1 mol of the compound of formula 1.
  • Pyridine is used as a reaction solvent.
  • the mixture of the above-stated compositions put into the reaction vessel is stirred with multi-shaft stirring blades.
  • the reaction time is approx. 1 to 3 hours.
  • water is added thereto and left for 30 minutes.
  • the reaction solution is extracted with a lower polar organic solvent and chloroform. Then, the organic layer is washed. The solvent of the organic layer is removed to obtain the acetoxyl derivative of interest.
  • reaction solvents dimethylformamide anhydride and 2.5 mol of imidazole are used.
  • dimethylformamide is added to a reaction vessel, and then the compound of formula 9 is dissolved thereto.
  • the solution is cooled down to 0°C, and triethylsilyl chloride and imidazole are slowly added thereto.
  • the mixture of the above-stated compositions is stirred with multi-shaft stirring blades.
  • the reaction time is approx. 0.5 to 3 hours.
  • the reaction solution is directly purified with silica gel column chromatography.
  • an elution solvent a mixed solvent of chloroform and ethyl acetate is used. According to this process, triethylsilyloxyl derivative of the compound of formula 1 of interest is obtained.
  • N,N-dimethylhydrazine 2 mol of N,N-dimethylhydrazine is used for 1. mol of the compound of formula 1.
  • a reaction solvent a mixture of ethanol and acetic acid is used. The reaction mixture is heated under reflux in a reaction flask in which a reflux condenser is installed. The reaction time depends on conditions, but it is approx. 10 to 20 hours. After completing the reaction, the reaction solution is cooled down, and water and a low polar organic solvent, chloroform are added thereto. Then, the reaction solution is washed with 3% hydrochloric acid solution, then with water. The solvent of the organic layer is removed to obtain the N,N-dimethylhydrazine compound of interest.
  • 1.2 mol of acetic anhydride is used for 1 mol of the compound of formula 1.
  • the compound of formula 1 is put into a reaction vessel and dissolved into pyridine. After adding thereto acetic anhydride, the solution is stirred at room temperature. The reaction time is approx. 1 to 24 hours. After the reaction, the reaction solution is put into ice water and then the eluted crystal is filtrated, thereby the compound of formula 13 of interest is obtained.
  • the compound of formula 1 is put into a reaction vessel and dissolved in acetone. While stirring the reaction solution at room temperature, Jones reagent is dribbled thereinto drop by drop. The dropping is finished when the reaction solution keeps red color.
  • the reaction solution is poured to ice water, and extracted with dichloromethane. The solvent is removed under reduced pressure, and the obtained residue is purified with silica gel column chromatography. The mixed solvent of ethyl acetate and hexane is used as an elution solvent. According to the above process, the compound of formula 15 of interest is obtained.
  • Example 14 Production of the compounds of formulas 16, 17 and 18
  • Anti-leishmanial activity was tested according to the following method: Test Method
  • Leishmania major was cultured on Medium 199 in a tissue culture flask (25cm 2 size) placed in a CO 2 incubator, wherein the conditions were kept at 26.5 °C and 5% CO 2 . It was subcultured by diluting to 50 to 100 times at intervals of one or two days. Protozoans used for assay were counted on a blood cell counting chamber just before the use, and then these were diluted with Medium 199 to 1 X lOVml.
  • the sample dissolved in DMSO was diluted to 50 times on Medium 199, and then the sample solution was sterilized with a membrane filter (0.2 ⁇ ). 9 types of sample solution, the concentration of each of which was different, was prepared by doubling dilution. Both 50 ⁇ 1 of each sample solution each having a different concentration and 50 ⁇ L of leishmania whose concentration was controlled were put onto a microtiter plate to prepare total 100 ⁇ 1 of culmre liquid. After the incubation at 26.5° C at 5% CO 2 for 24 hours, the number of protozoans in each well was counted on a blood cell counting chamber.
  • any of the compounds of the present invention has activity equivalent to or greater than previously known antiprotozoal agents.
  • mice An acute toxicity test using mice was carried out for the extract that was obtained by extracting with methanol, Elephantopus mollis H.B.K. containing the compounds of formulas 1 to 7, 9 and 10 of the present invention. That is to say, the extract was suspended in corn oil, and then 280mg/kg, 240mg/kg, 200mg/kg, 160mg/kg, 120mg/kg, 80mg/kg and 40mg/kg of the extract was intraperitonealy administered to each mouse. All of these mice were survived after 7 days of observation. 50% lethal dose of a control agent, amphotericin B is 88mg/kg.
  • the compound shown in formula 1 was mixed with lactose, corn starch and carboxy methylcellulose calcium. Then, according to standard techniques, kneaded liquid prepared with methylcellulose and purified water was kneaded in. After that, the mixture was dried to obtain granules. Magnesium stearate was further added to the granules and mixed, and then tablets were produced by compression molding.
  • the compound of formula 1 was dissolved in physiological salt solution containing 30% (w/v) polyethylene glycol 400 to prepare 0.05% solution of the compound. Then, according to standard techniques, the solution was sterilized and filtrated, and 50 ml of the solution was independently poured into each vial, so that lOmg of the compound could be contained in each vial. Thus, intravenous agents were obtained.
  • the present invention provides a pharmaceutically useful sesquiterpenoic compound that has antiprotozoal activity, particularly anti-leishmanial activity, and pharmaceutical formulations comprising the same, particularly an antiprotozoal agent.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

L'invention concerne un composé pharmaceutiquement utile ayant une action efficace contre des protozoaires résistant aux médicaments, en particulier contre des protozoaires du genre Leishmania. Cet objectif est atteint grâce à l'utilisation d'un composé sesquiterpénoïque correspondant à la formule (I), ou d'un dérivé de celui-ci.
PCT/JP2001/000962 2000-02-10 2001-02-09 Compose sesquiterpenoique et formulations pharmaceutiques contenant ce compose WO2001058888A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP1792599A1 (fr) * 2004-09-24 2007-06-06 Shiseido Company, Limited Agent de blanchiment
CN102811992A (zh) * 2010-10-19 2012-12-05 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药
CN104945361A (zh) * 2015-06-19 2015-09-30 中国医学科学院药用植物研究所 吉玛烷型倍半萜衍生物及其制备方法与应用
WO2022231520A1 (fr) * 2021-04-29 2022-11-03 Nanyang Technological University Dérivés de molephantin utiles dans le traitement du cancer

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Publication number Priority date Publication date Assignee Title
EP2488176B1 (fr) 2009-10-13 2016-12-07 Hoshi University Dérivé de rhodacyanine et composition pharmaceutique pour le traitement de la leishmaniose
CN114933602B (zh) * 2022-06-10 2023-10-13 沈阳药科大学 白花地胆草中高度氧化的吉玛烷型倍半萜内酯类化合物及其制备方法和应用

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1792599A1 (fr) * 2004-09-24 2007-06-06 Shiseido Company, Limited Agent de blanchiment
EP1792599A4 (fr) * 2004-09-24 2012-07-11 Shiseido Co Ltd Agent de blanchiment
CN102811992A (zh) * 2010-10-19 2012-12-05 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药
CN102811992B (zh) * 2010-10-19 2015-06-17 学校法人青山学院 抗利什曼原虫化合物以及抗利什曼原虫药
CN104945361A (zh) * 2015-06-19 2015-09-30 中国医学科学院药用植物研究所 吉玛烷型倍半萜衍生物及其制备方法与应用
CN104945361B (zh) * 2015-06-19 2017-06-13 中国医学科学院药用植物研究所 吉玛烷型倍半萜衍生物及其制备方法与应用
WO2022231520A1 (fr) * 2021-04-29 2022-11-03 Nanyang Technological University Dérivés de molephantin utiles dans le traitement du cancer

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