Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
  • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

• the present invention relates to a novel glycosphingolipid having a high antitumor activity, a bone marrow cell growth-promoting activity and an immunostimulatory activity, and a use thereof. More specifically, the present invention relates to a novel glycosphingolipid, which can be used as an antitumor agent, a bone marrow cell proliferation promoter and an immunostimulant in the field of pharmaceuticals. Glycosphingolipids having improved solubility upon dissolution, and pharmaceutical compositions containing the glycosphingolipids as well as antitumor agents, bone marrow cell growth promoters and the like. And immunostimulants.
• Glycosphingolipids having antitumor activity are disclosed in
• glycosphingolipids described in WO93Z055555 are compounds having remarkable antitumor activity and immunostimulatory activity.
• Each of these is a cell mouth opening side in which one monosaccharide is bonded to the ceramide part, and has extremely low solubility in water.
• these compounds can be used as injections.
• it is necessary to suspend or dissolve in water using a pharmaceutically acceptable surfactant.
• a surfactant for example, polysorbate
• polyethylene glycol which is known as another solubilizing agent
• side effects of polyethylene glycol include lactic acidosis, hemolysis, arrhythmia, etc. Speth PA J., et al .. Therapeutic Drug Monitoring, vol.9. 255-258 (1987)), dimethylol onorem amide, and dimethinoreacetamide cause liver damage.
• solubilizers This is an example of a side effect, but other solubilizers have also been known to have side effects.
• the present invention provides a novel compound having improved solubility in water, which is useful as an antitumor, a bone marrow cell growth promoter and an immunostimulant. It is intended to provide
• glycosphingolipids having a specific chemical structure have antitumor activity, bone marrow cell growth promoting activity and immunostimulation. It has been found that these compounds have an active activity and that these compounds have a water solubility that is superior to that of conventionally known Sereb mouth side.
• the present inventors have further synthesized these analogs and found that those analogs also have the same activity, and based on these findings, completed the present invention.
• novel glycosphingolipid according to the present invention is a compound represented by the following formula (I).
• R is H or
• R and R 6 are each H or OH
• R 4 is H or OH
• R r is ⁇ or
• X is an integer from 19 to 23;
• the present invention also relates to the use of the above compound represented by the formula (I). Specifically, a pharmaceutical composition, an antitumor agent, and a bone marrow cell proliferation. It relates to enhancers and immunostimulants.
• the pharmaceutical composition according to the present invention contains the glycosphingolipid represented by the above formula (I) as an active ingredient.
• the tumor agent, bone marrow cell proliferation promoter and immunostimulator according to the present invention contain the glycosphingolipid represented by the above formula (I) as an active ingredient. It is a thing.
• the present invention relates to a therapeutic method characterized by administering an effective amount of the above compound to a patient in need of tumor suppression, bone marrow cell proliferation or immunostimulation. is there .
• FIG. 1 (& to c) is a structural formula showing the chemical structure of a preferred specific compound of the glycosphingolipid of the present invention.
• Fig. 2 (a and b) shows a preferred example of a reaction route when a compound represented by the formula (I) is synthesized using a saccharide (lyxose) as a starting material.
• glycosphingolipid according to the present invention is represented by the formula (I) as described above, and the binding mode of the sugar moiety of the preferred compound is as follows.
• the structure can be classified as shown in the following formulas (1) and (5).
• a preferred embodiment of the compound of the present invention is a glycosphingolipid represented by the following formula (II) and (IE).
• R 2 is 0 H
• X is an integer of 19 forces, any of 23 to 23;
• Y is an integer of either 1 1 or 1 3.
• X is an integer from 19 to 23, or any of 23;
• Y is an integer between 11 and 13.
• a more preferred embodiment of the compound of the present invention is represented by the formula (I):
• Preferred specific examples of the glycosphingolipids of the present invention represented by the formula (I), which is a compound of any of the groups (a) to (c), include the following compounds 1 to 17 and compounds 3 13 3 and 35, with compounds 31 3 3 and 35 being more preferred. (The structural formulas of each compound are shown in FIGS. 1 (a) to (c)).
• Compound 15 one jS—D—galactofuranosyl (1 ⁇ 3) —one D—galactopyranosyl) one (1 ⁇ 1)-(2S, 3S, AR) one 2-amino— [iR) — 2—Hide Mouth xytetracosanoyl] -1 16-Methyl-1,3,4-heptanecanetriol
• Compound 16 1 S-D-Galactofuranosyl (1 ⁇ 3) —Cou a—D-Galactobilanosyl) 1 (1 ⁇ 1) ⁇ (2 S, 3 S, 4 R —2-Amino- [(—2—Hyd mouth xytetracosanoyl) —1,3,4-Octadecanetriol
• the compound according to the present invention that is, the glycosphingolipid represented by the above formula (I) can be induced by chemical modification of an analogous compound, and can be derived from sphinfoid.
• Total synthesis by chemical synthesis means combining various common chemical reactions required to synthesize glycoglycolipids, or by extraction from sponges. It is also possible to obtain.
• glycosphingolipids of the present invention by means of chemical synthesis, the ability to use any desired method, for example, ⁇ Agicaltural and Biological ⁇ And ⁇ Bay mouth ⁇ Chemistry
• a synthesis method include a method of a reaction route described in Japanese Patent Application Laid-Open No. HEI 5-9-193, or WO 93Z055055.
• the synthetic route method described in FIGS. 1 to 4 of Japanese Patent Application Laid-Open Publication (PCT / JP92 / ⁇ 0561 specification) mutatis mutandis, the swath represented by the above formula (I) is applied.
• Glycosphingolipids can be synthesized.
• the glycosphingolipids of the present invention can be specifically synthesized, for example, according to the reaction route method shown in Fig. 2 (a and b). And are possible.
• specific compounds of the present invention (compounds 31, 33 and 35)
• other compounds represented by the formula (I) can be synthesized according to this method.
• This method uses saccharides as a starting material.
• Saccharides For example, Liebig-Anaren-Len-Dee
• the method shown in this reaction scheme uses a sugar (D-lyxose) as a starting material, and after protecting it, removes carbon from the long-chain portion of sphingosine.
• a small number of 5 hydrocarbon compounds are combined (compound 2 ⁇ ) and, after appropriate protection, undergo azide, reduction, and amidation to form the carboxylic acid portion of the ceramide.
• To form a ceramide moiety (compound 29), which is then bound to the corresponding sugar by a dalycosylation reaction to deprotect it.
• the objective glycosphingolipids of the present invention (compounds 31, 33, 35) can be obtained.
• D-galactose can be used in addition to D-lyxose.
• amino acids such as L-serine.
• reactions such as protection of hydroxyl groups, binding of hydrocarbon compounds to sugar compounds, azidation, amidation, and glycosylation are carried out in a usual manner. It can be implemented according to the following.
• benzyl group and a triphenylmethylene group are used as protecting groups for the hydroxyl group, but the purpose of the benzyl group is You can also use whatever is appropriate.
• the reaction with phenolic acid is a condensation reaction in the presence of a suitable condensing agent.
• suitable condensing agent examples include: hexanox canebodiesimide (DCC), 2-ethoxy-1 ethoxycarbonyl -1, 2-Dihydroquinoline (EEDQ), 1-Ethyl-3-(3-Dimethylaminopropyl)-Force ), Chlorocarbonates, and sodium salts are appropriate.
• DCC hexanox canebodiesimide
• EEDQ 2-ethoxy-1 ethoxycarbonyl -1
• 2-Dihydroquinoline EEDQ
• 1-Ethyl-3-(3-Dimethylaminopropyl)-Force 1-Ethyl-3-(3-Dimethylaminopropyl)-Force
• Chlorocarbonates 2-ethyl-3-(3-Dimethylaminopropyl)-Force
• Chlorocarbonates 2-ethyl-3-
• the reaction with acid chloride is generally carried out in the presence of a solvent. It goes well.
• the reaction is usually carried out using an appropriate solvent, but when the reaction rate is low, the reaction can be carried out promptly by carrying out the reaction without solvent. Any solvent may be used as long as it is an inert solvent that does not participate in the reaction. If the reaction rate is low, triethylenamine, pyridin, N-methylenolamine, dimethynolelinine or 4-dimenine By adding an organic base such as thiaminopyridine, it is possible to increase the speed and speed by adding an organic base.
• an organic base such as thiaminopyridine
• the reaction with the acid anhydride is preferably carried out in the presence of a suitable base.
• the base used here is tritinoreamine, pyridin and the like, and these are usually used also as a solvent.
• oligosaccharides can be obtained by a conventional method for obtaining oligosaccharides from commercially available or mono- or polysaccharides. You just have to use one.
• the method of obtaining from a sponge basically consists of a collection step, an extraction step and a purification step of the sponge.
• a preferred example of sponges in the collection process is S. litsa flavelli fonoremis (S ⁇ 1i ssa fu 1 abe 11 if orni is).
• S. litsa flavelli fonoremis S ⁇ 1i ssa fu 1 abe 11 if orni is.
• Agel as ax i sera for example, from the sea in Miyakojima, Okinawa or Amami-Oshima in Kagoshima, Japan. can do .
• the method usually used for the extraction of glycosphingolipids is used, preferably an organic solvent (for example, methanol, preferably Extraction using a mixture of methanol and dichloromethan) can be used for the purification process.
• an organic solvent for example, methanol, preferably Extraction using a mixture of methanol and dichloromethan
• the methods commonly used for the purification of glycosphingolipids are used, for example, various fractionation methods (fractionation methods using differences in solubility, differences in partition ratio). And other chromatographic graphs (adsorption chromatograph, distribution chromatograph, etc.) as appropriate. You can use it.
• Japanese Patent Application Laid-Open No. Hei 5 (1993) -A1 describes a specific preferred example of these.
• the compound of the present invention represented by the formula (I) is useful in that it has the following physiological activities, ie, antitumor activity, bone marrow cell growth promoting activity and immunostimulatory activity.
• lentinan an antitumor polysaccharide extracted from the fruiting body of shiitake mushroom, for example, an anticancer drug that acts on the immune system known in the past. (Hereinafter, simply referred to as “lentinan”), schizophyllan, a polysaccharide extracted from the mycelium of S.
• hirotake mushroom This is called “Shizophyllan”.
• Streptococcus ⁇ Piogenes Group A, type 3
• Pin which is a freeze-dried powder treated with Su strain penicillin Compared to vanilla (Chugai Pharmaceutical Co., Ltd.) (hereinafter simply referred to as “Pishibanil”), it is useful in that their physiological activities are sufficiently strong.
• the compound of the present invention was administered to P388 mouse leukemia cells and B16 mouse melanoma cells subcutaneously implanted in mice as shown in Experimental Example 4 below. It showed antitumor activity.
• the compound of the present invention exhibited a mouse bone marrow cell growth promoting effect in vitro.
• the compound of the present invention promotes the mouse spleen lymphocyte proliferation in vitro and the activity against the mouse lymphocyte mixed culture reaction (MLR) in vitro. It had a chemical effect.
• the compound of the present invention showed a life-prolonging effect on a lethal radiation-irradiated mouse. Such an effect indirectly expresses the above-mentioned bone marrow cell proliferation promoting activity.
• the compound of the present invention has a higher water content than a compound having the same ceramide moiety and a monosaccharide sugar moiety. It has become possible to reduce the amount of surfactant required for dissolving in water to less than 100.
• polysonorlate 2 2 inhibits mouse spleen lymphocyte proliferation and suppresses the immunostimulatory activity of the compound of the present invention. It was shown that the immunostimulatory activity was restored by reducing the amount of 2% of the resource base.
• I-D Garotopyrano-synole
• I 2 Hexaco-sano-ino-amino-3,4-octadecanediol (hereinafter referred to as compound b) was used as a comparative compound.
• the compounds of the present invention exhibit excellent antitumor activity, bone marrow cell growth promoting activity and immunostimulatory activity. Therefore, the compound of the present invention is an antitumor agent (Merano For the treatment of solid tumors such as mammary tumors and blood cancers such as leukemias), bone marrow cell growth promoters (cytopenia due to immune abnormalities, or side effects such as cancer chemotherapy or radiation therapy). For the treatment of cytopenia, etc.) and immunostimulants (for the treatment of various cancers, various infectious diseases, and acquired immunodeficiency syndrome, etc.).
• an antitumor agent Malo For the treatment of solid tumors such as mammary tumors and blood cancers such as leukemias
• bone marrow cell growth promoters cytopenia due to immune abnormalities, or side effects such as cancer chemotherapy or radiation therapy.
• immunostimulants for the treatment of various cancers, various infectious diseases, and acquired immunodeficiency syndrome, etc.
• the compound of the present invention as an antitumor agent, a bone marrow cell proliferation promoter and an immunostimulant can be administered in any desired administration route and in a dosage form determined by the adopted administration route.
• Can be administered at The drug is usually in the form diluted with a pharmaceutically acceptable carrier or diluent.
• the compound of the present invention when used as an antitumor agent, a bone marrow cell growth promoter and an immunostimulant, it can be orally or parenterally administered to a human or mammal. And can be done.
• the compound of the present invention is dissolved or suspended in a suitable injection solvent (for example, distilled water for injection) and then injected by intravenous injection, intramuscular injection, or subcutaneous injection. Can be administered.
• a suitable injection solvent for example, distilled water for injection
• a suitable carrier or diluent e.g., starch, sucrose, lactose, calcium carbonate, or any other normally used for this purpose
• Compounds e.g., starch, sucrose, lactose, calcium carbonate, or any other normally used for this purpose
• lubricants for example, stearic acid, sodium benzoate, boric acid, silica, polyethylene glycol, etc.
• the dose of the compound of the present invention should be such that the total dose does not exceed a certain amount when administered continuously or intermittently, in consideration of the results of animal tests and individual circumstances. It is determined.
• the specific dosage depends on the method of administration, the condition of the patient, or the animal to be treated, e.g., age, weight, sex, susceptibility, diet, time of administration, concomitant medication, patient, or disease. It goes without saying that the appropriate amount and the number of doses under certain conditions are determined by the specialist based on the above guidelines. Must be determined by The compound of the present invention represented by the formula (I) has an antitumor effect, a bone marrow cell proliferation promoting effect and an immunostimulating effect, and is therefore classified as a BRM (Biological Response Modifiers). (Oldham. RK Natl. Cancer Inst., 7_0. 789-796 (1983)).
• the dose of the compound of the present invention to humans is based on this. Predictions were made. First, the doses of lentinan and schizophyllan to mice and humans are shown in the following table from the literature review.
• mice Dose for humans Lentinan 1-2 mg / kg 1 ⁇ l-2 rag / body )
• the compound of the present invention shows significant antitumor activity by intravenous administration of 0.1 mg Z kg to mice as shown in Experimental Example 4 below.
• a dose of about 0.1 mg / body can be estimated. It is very difficult to determine the dose of BRM to humans, and it is very difficult to start a trial from a very low dose until the MTD (maximum tolerated dose) is reached. Oldham (Oldham R.K..J.Biol.Response Mod., Vol.4, 117-128 (1985)). Therefore, the actual dosage should be determined at the discretion of a specialist.
• the compound of the present invention (1) was repeatedly separated and separated as a colorless powder at 100 X 250 mm (Shiseido Co., Ltd.), 7% methanol, 5 m 1 / mi ⁇ ]. (14.3 mg), (2) (1.0 mg). (3 (25.0 mg), (4) (73.1 mg)> (5 (26.5 mg (6) (25.7 mg), (7 (1.0 mg), (8) (11.6 mg) ((6.8 mg))
• a sponge animal, A gelasaxisera, collected in the sea of Miyakojima, Oki Prefecture Lyophilization was performed (951 g). This was used as an extraction solvent, and then extracted with chloroform / methanol (1: 1) and 2 liters for 24 hours.
• a kiss was obtained (232 g), which was distributed between 2 liters of water and 2 liters of ethyl acetate, and the ethyl acetate layer was dried to obtain a brown residue. (65.0 s), and 27.8 g of an intermediate layer were obtained.
• the residue is distributed between 2 liters of 90% methanol and 2 liters of n-hexane, and the 90% layer of methanol is dried to remove brown residue.
• the obtained intermediate layer (53.7 g) and the 90% methanol layer were composed of silica gel chromatographic chromatographs (co-gel C120, 50). 0 g), and changing the ratio of chlorophorone: methanol / water: water to 9: 1: 0.1, and 8: 2: 0.2 as the elution solvent. did. Active Fraction
• the synthesis method and the physicochemical properties of the compound of the present invention are as follows (for the synthesis method, refer to the reaction scheme in FIG. 2).
• the total amount of the compound 18 obtained in the above reaction was dissolved in 168 ml of methylene chloride, and 100.1 g of pyridin and 39.0 g of tritinol chloride were added. In addition, the mixture was stirred at 32 ° C for 4 hours. After adding 7.8 ml of ethanol and stirring, the mixture was washed with a saturated aqueous solution of ammonium chloride. Further, the resultant was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order.
• the obtained total hexane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and then dried under reduced pressure using a vacuum pump to roughly purify the syrupy compound 21. I got something. It was used for the next reaction without further purification.
• the primary crystal was obtained in an amount of 41. ⁇ g, and the secondary crystal was obtained in an amount of 9.40 g. Total yield in three stages: 70.0%.
• IR cm- 1 , film 30 62, 30 31, 29 25, 28 85 4 , 20 96, 14 92, 1 46 55.
• Ethanol acetate was added to the concentrated residue, and the residue was washed twice with a saturated aqueous solution of NaHCO 3.
• the aqueous layer was re-extracted with ethyl acetate, combined with the ethyl acetate layer, and washed with saturated saline.
• the solution was concentrated under reduced pressure and azeotroped with toluene. Next, the mixture was sufficiently evacuated with a vacuum pump and used for the next reaction without purification.
• reaction solution was washed with a 0.5N-hydrochloric acid aqueous solution, a saturated saline solution, a saturated sodium bicarbonate aqueous solution, and a saturated saline solution in this order. After drying over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, and then sufficiently dried by a vacuum pump, and used for the next reaction without purification.
• mice purchased from Nippon Eelsells Co., Ltd., each group consisting of 5 mice.
• 1 ⁇ 10 6 P 3 S8 mouse leukemia cells were transplanted subcutaneously subcutaneously on the back of the mouse (transplantation day is day 0), and the medium (10 cells) was transplanted to day 1, 5, and 9 after transplantation.
• ml / kg) or each compound (0.1 mg / kg) dissolved in the vehicle was intravenously administered, and the number of surviving days was observed.
• Nao Lentinan and Picibanil are administered intravenously on days 1, 3, 5, 5, 7, and 9, and schizophyllan is administered subcutaneously on days 19 through 19. I did.
• a significance test was performed by the Mann-Whiteney test.
• the experiment was conducted using 6-week-old BDF i mice purchased from Nippon SLC Co., Ltd., each group consisting of 6 mice.
• Each mouse was transplanted subcutaneously to the back of the mouse (transplantation day was day O), and after transplantation, 0.1 mg / kg of each sample was administered into the tail vein at day 1, 5, and 9.
• the subcutaneous tumor volume [(major axis x minor axis x height) Z 2] was measured on day 8> 12, 16, and 20 and the tumor growth inhibition rate (TGIR) of each sample was determined. I asked.
• TGIR is When the tumor volume of the control group was c and the tumor volume of the sample administration group was exactly, the following formula was used.
• the amount of 3 H-TdR was measured by a liquid scintillation counter.
• the ratio (%) of 3 H—T dR incorporation of the sample-added group to the vehicle-added group was determined and defined as the in vitro mouse bone marrow medullary cell proliferation promoting activation rate.
• TdR 0.5 1 / well was added. 6 hours after the cells of the Ha over Beth theft was carried out S Ri write or was taken in the nucleus H - T d R amount was measured Ri by the liquid Thin Chi-les-over sheet Yo down mosquito window te one . The ratio (%) of ⁇ — TdR incorporation of the sample- added group to the vehicle-added group was determined and defined as the in vitro mouse spleen lymphocyte proliferation promoting evolution rate. The results are shown in Table 3.

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