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WO1998016235A1 - Agents augmentant le nombre de cellules souches du sang peripherique et contenant des glucosides - Google Patents

Agents augmentant le nombre de cellules souches du sang peripherique et contenant des glucosides Download PDF

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Publication number
WO1998016235A1
WO1998016235A1 PCT/JP1997/003698 JP9703698W WO9816235A1 WO 1998016235 A1 WO1998016235 A1 WO 1998016235A1 JP 9703698 W JP9703698 W JP 9703698W WO 9816235 A1 WO9816235 A1 WO 9816235A1
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Prior art keywords
peripheral blood
csf
blood stem
glycoside compound
increasing
Prior art date
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PCT/JP1997/003698
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English (en)
Japanese (ja)
Inventor
Yasuhiko Koezuka
Kazuhiro Motoki
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Kirin Brewery Company, Limited
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Filing date
Publication date
Application filed by Kirin Brewery Company, Limited filed Critical Kirin Brewery Company, Limited
Priority to AU44732/97A priority Critical patent/AU4473297A/en
Publication of WO1998016235A1 publication Critical patent/WO1998016235A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/53—Colony-stimulating factor [CSF]
    • C07K14/535—Granulocyte CSF; Granulocyte-macrophage CSF

Definitions

  • the present invention relates to an agent for increasing peripheral blood stem cells and a pharmaceutical composition for increasing peripheral blood stem cells, which is useful for treating cancer such as solid cancer and leukemia, or for treating hematologic diseases such as aplastic anemia.
  • Bone marrow transplantation involves the transplantation of prepared bone marrow cells after killing cancer cells and bone marrow cells by intense chemo / radiation therapy.
  • allogeneic bone marrow transplantation normal blood stem cells collected from the bone marrow of the donor are used as the bone marrow cells, but there is a high possibility that a graft-versus-host disease reaction will occur.
  • This method is based on the finding that hematopoietic stem cells are also present in peripheral blood in a small amount compared to bone marrow, and that they are transiently increased significantly after myeloablative treatment. No need for general anesthesia. Nevertheless, hematopoietic stem cells are rarely present and generally require multiple cell harvests.
  • G-CSF granulocyte colony stimulating factor
  • SCF stem cell factor
  • the present invention provides the following formula (A):
  • R is H or 0H
  • X is? An integer of from 25 to 25;
  • R 2 is a substituent defined by any of the following (a) to (e) Where Y is an integer from 5 to 17
  • R 3 and R 4 are H, the other is H, 0 H
  • R q is H, CHCH 2 ⁇ H or
  • a peripheral blood stem cell augmentation agent in a peripheral blood stem cell transplantation therapy using G—CSF comprising at least one glycoside compound or a salt thereof represented by the following formula: .
  • the present invention also relates to G-CSF and a glycoconjugate compound as defined in formula A. It is also intended to provide a pharmaceutical composition for increasing peripheral blood stem cells, comprising at least one kind of a substance or a salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention further relates to an increase in peripheral blood stem cells comprising G-CSF and at least one glycoside compound or a salt thereof as defined in formula A. It also provides a pharmaceutical kit for medical use.
  • the invention also requires the use of G-CSF in combination with at least one glycoside compound or a salt thereof as defined in Formula A to increase peripheral blood stem cells. Methods for treating humans or other animals are provided.
  • the present invention further relates to the use of at least one glycoside compound defined by formula A or a salt thereof for the manufacture of a medicament having a peripheral blood stem cell-enhancing action. provide .
  • Figure 1 shows donors receiving KRN 7000 and G-CSF.
  • C57BL / 6 Mouse (mes) Recipient C57B L / 6 with whole body radiation of mouse (mes) peripheral blood. It shows the effect of extending the survival time of the recipient mouse when transferred to the mouse (mes).
  • Figure 2 shows a donor BALB / c mouse treated with KRN 7000 and G-CSF (mess).
  • a recipient BALB / c mouse irradiated with whole body radiation of peripheral blood.
  • the recipe at the time Demonstrates the effect of prolonging the survival of the event mouse
  • FIG. 3 shows a donor BA receiving KRN 7000 and G—CSF.
  • Figure 4 is an electrophoretogram showing the engraftment and proliferation of hematopoietic progenitor cells when donor mouse peripheral blood was transferred to a recipient mouse.
  • R i is H or ⁇ H
  • R 2 is a substituent defined by any of the following (a) to (e), wherein Y is an integer of 5 to 17; (a) — CH 2 (CH 2 ) CH
  • R 3 and R 4 is H, and the other is H or OH
  • R 7 and R 8 are H and the other is 0 H
  • R q is H, CHCH 20 H or
  • a peripheral blood stem cell enriching agent for peripheral blood stem cell transplantation therapy by G—CSF comprising at least one glycoside compound or a salt thereof represented by the following formula:
  • RR g is a substituent selected to be applicable in any of the following i) to v);
  • R 4 is H, ⁇ H, NH 2 , NHCOCH 3 or
  • R 5 is 0 H
  • R 7 is 0 H
  • R q is H, CHCH 2 ⁇ H or
  • RR 6 and R 7 are both H
  • RR 5 and R 9 are the same as defined in i), respectively.
  • RR 6 and R 7 are both H
  • R 5 and R 9 are the same as defined in i)
  • R 3 is H, ⁇ HNHNHCOCH 3 or
  • R 8 is ⁇ H or T
  • RR 5 and R 7 are both H
  • RR 6 and R 8 are both 0 H
  • R 9 is H, CH 3 or CH 20 H, or
  • RR 5 and R 7 are both H
  • RR 6 and R 8 are both ⁇ H
  • R g is H, CH 3 or CH 2 ⁇ H]
  • a peripheral blood stem cell enriching agent in peripheral blood stem cell transplantation therapy by G-CSF comprising at least one glycoside compound or a salt thereof represented by the following formula:
  • Glycoside compounds as defined by Formula A or B consist of a sugar moiety and an aglycone moiety, some of which are in the form of a hyselev mouth side or a single glycan. Also referred to as co-silcer lamid, hi-glu co-silcer amid, single-glu co-ser-b-side, single-glu-co-sel-bro-side or single-glu-co-to-sil-se-lamid It is called. These compounds are characterized by the fact that they have an anomeric configuration.
  • R 3 , R 6 and R 8 are all H, R 4 , R 5 and R 7 are all 0 H, and R 9 is preferably CH 2 OH, that is, the sugar moiety is preferably 1-galactovilanosyl.
  • R 2 is preferably a substituent (b), (c) or (e). It is even more preferred that R i is H (meaning that it is a kerasin type) and R 2 is a substituent (b).
  • X is preferably 21 to 25, and Y is preferably 11 to 15. Preferred examples of the glycoside compound are listed below.
  • W 094/2 4 1 4 2 means to refer to each.
  • the conjugated compound 14 immediately, (2S, 3S, 4R)-1- (HIIC-D—galacto-vilano-siloxy)- 2-Hexacosanoylamino 3, 4-The most preferred is decandiol (hereinafter referred to as KRN700).
  • KRN700 decandiol
  • Glycoside compounds as defined by Formula A or B may be capable of forming acid addition salts with pharmaceutically acceptable acids.
  • Acids that form acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or acetic acid, propionic acid, maleic acid, oleic acid, and pallic acid. Mitic acid, citric acid, conodic acid, tartaric acid, fumaric acid, glutamate, pantothenic acid, raurylsulfonate, methansulfonate, Organic acids such as phthalic acid can be mentioned.
  • the compound of the present invention can be obtained by subjecting the above compound 14) to known chemical techniques, if necessary, using known raw materials in the same manner as shown in the following Production Examples and Reaction Schemes. They can be combined and combined.
  • the present invention relates to a G-CSF and a glycoside defined by formula A or B Also provided is a pharmaceutical composition for increasing peripheral blood stem cells, which comprises at least one compound or a salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides a peripheral blood stem cell expansion comprising a G-CSF and at least one glycoside compound or a salt thereof as defined by Formula A or B.
  • a peripheral blood stem cell expansion comprising a G-CSF and at least one glycoside compound or a salt thereof as defined by Formula A or B.
  • the G-CSF according to the present invention has the following amino acid sequence, or lacks or substitutes one or more amino acid residues in the sequence.
  • a polypeptide having an added and / or inserted amino acid sequence and having G-CSF activity can be obtained.
  • a convenient method for obtaining such a G-CSF is disclosed in, for example,
  • G-CSF having the amino acid sequence shown below (SEQ ID NO: 1) is particularly suitable.
  • n nig "ID OJJ S IH SXQ ngq s q J jqi B IV ⁇ 9 s nio ujg
  • deletion, substitution, addition and / or insertion of an amino acid residue is carried out, for example, by DFMark et al., Proc. Natl. Acad. Sci. USA, Vol. .5662-5666, 1984, S. Inouy et al., Proc. Natl. Acad. Sci. USA, Vol. 79: p. 3438-3441, 1982, PCT W085 / 00817, published February 28, 1985, RP Wharton. Et al., Nature, Vol. 316, p. 601-605, Aug. 15, 1985, which is a well-known technique prior to the filing of the present application, and which is implemented by a site-specific mutagenesis method or the like. And can be done.
  • the agent for increasing peripheral blood stem cells according to the present invention may be administered by any administration route that meets its purpose.
  • methods such as intraperitoneal administration, subcutaneous administration, intravenous administration to a vein or artery, and local administration by injection are possible.
  • intravenous administration, intraarterial administration, local administration by injection, intraperitoneal or pleural administration, subcutaneous administration, intramuscular administration, sublingual administration, transdermal administration Alternatively, it can be administered by rectal administration.
  • the drug of the present invention is administered in an appropriate dosage form determined by the administration method and administration purpose, specifically, in the form of injections, suspensions, emulsifiers, ointments, creams, etc. can do .
  • These preparations contain additives such as carriers or diluents which are pharmaceutically acceptable, specifically, solvents, solubilizers, isotonic agents, preservatives, antioxidants, excipients and the like. Excipient, binding Additives, stabilizers, etc. can be added.
  • additives include serum albumin and mannitol, as well as site potions, such as human IL-11, human IL-13, and human IL-13. Includes IL-11, human SCF, human LIF, human EPO, human GM-CSF and human M-CSF.
  • Each active ingredient in the medicament of the present invention can be administered continuously or intermittently according to individual circumstances. Specific dosages will vary depending on the mode of administration, patient conditions, eg, age, weight, sex, sensitivity, time of administration, concomitant medications, etc. In general, the dose required for the expression of the glycoside compound activity is, for example, about 0.01 to 1 Omg per day for a human adult by intravenous administration; ⁇ 1 mg is preferred. The dose required for the expression of G-CSF activity is different for allogeneic and autologous transplantation, but is about 1 to 20 mg / kg / day for humans. There have been many reports of subcutaneous administration of 2 to 16 mg / kg for 4 to 6 days.
  • glycoside compounds may be separately administered in any order (sequentially, simultaneously, separately), but include the glycoside compound, G-CSF, and a pharmaceutically acceptable carrier. It is preferable to use a pharmaceutical composition for increasing peripheral blood stem cells.
  • the glycoside compound is contained in a weight ratio of 1:10 to 10: 1 with G-CSF. --
  • compositions for increasing peripheral blood stem cells which are described above are suitable, and moreover, glycoside compounds are almost always contained in the same amount by weight as G—CSF. I like it.
  • G—CSF glycoside compound
  • the present invention therefore relates to the use of G-CSF in combination with at least one glycoside compound defined by formula A or B or a salt thereof to increase peripheral blood stem cells. It also includes methods for treating humans or other animals in need thereof.
  • the present invention also relates to at least one glycoside compound or a salt thereof defined by formula A or B for the manufacture of a medicament having a peripheral blood stem cell-enhancing action.
  • the agent for increasing peripheral blood stem cells of the present invention is used for increasing stem cells when collecting peripheral blood stem cells.
  • peripheral blood stem cells are collected from a healthy subject, the timing of administration can be arbitrarily selected before that.
  • it is collected from a patient such as a cancer patient, it is preferable to set the recovery period from the cytopenia period.
  • radiation / chemotherapy It may be used before or immediately after legal action.
  • KRN 7000 (2 S, 3 S, 4 R)-1-(Hiichi D-Garakto Villano Silo Kishi) 1, 2-Hexacosanoylamino 1, 3-4-year old Kutadecanediol
  • Tridecane triphenylphosphine bromide (962 g, 1.16 mol; 1-bromotridecane, triphenylphosphine was heated to 140 ° C for 4.5 hours.
  • a 2.5 M hexane solution of n-butyllithium (462 mL; 1.16 mol) was added dropwise at 0 ° C to a THF solution (prepared) of THF (1500 ml) under argon atmosphere. After completion of the dropwise addition, the mixture was stirred for 15 minutes, and a THF solution (450 ml) of G2 (250 g, 579 mmol) was added dropwise. The mixture was stirred for 18 hours while gradually raising the temperature to room temperature.
  • reaction solution was concentrated under reduced pressure, and a residue mixture of hexane: methanol: water (10: 7: 3, 1000 ml) was added to the residue, and the mixture was washed with a saturated aqueous solution of ammonium chloride.
  • the aqueous layer was extracted with hexane (500 ml), and all the organic layers were combined, dried over magnesium sulfate anhydride, and concentrated under reduced pressure to obtain a crude G3 product.
  • Hexacosanoic acid (22.4 g, 56.5 mmol) and WSC hydrochloride (12.6 g, 64.6 mmol) were added to a methylene chloride solution (300 ml) of G10, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure. Ethyl acetate (500 ml) was added to the residue, and the mixture was washed with a 0.5 M aqueous hydrochloric acid solution, a saline solution, a saturated aqueous sodium hydrogen carbonate solution, and further with a saline solution. All the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude G11 product. Yield 53.2g (88%). The obtained Gil was used for the next step without further purification.
  • the analytical sample was purified by silica gel chromatography using hexane: ethyl acetate (100: 1) as the el
  • KRN7000, G—CSF is present. Increase in hematopoietic progenitor cells in peripheral blood by in vivo administration of both KRN7000 and G—CSF.
  • the experiment was performed using a C57BL / 6 mouse purchased from SLC Japan.
  • KRN7000 was used as a representative glycoside compound in the following experiments.
  • G-CSF sugar-free G-CSF (generic name: Gran, manufactured by Kirin Brewery) was used.
  • mice C57BL / 6 mice (6 weeks old, female) were divided into the following four groups to conduct experiments. That is, (A) a control (unprocessed) group. (B) KRN7000 (100 g / kg) was administered intravenously on day-and G-CSF (100 juLg / H) was administered on days -3, -2, -1, and 0 (4 hours before blood collection).
  • Subcutaneously administered group (KRN7000 + G-CSF group), (C) KRN7000 (100 / g / kg) intravenously administered on day-(KRN7000 group), (D) G-CSF (100 g / kg) kg) was administered subcutaneously on days -3, -2, -1, and 0 (4 hours before blood collection) (G-CSF sc group).
  • Peripheral blood was aseptically collected from the mouse's heart using parylene, and the blood in each group was removed. After diluting this blood two-fold using RPMI 1640 medium, the blood is overlaid on Linholite M (Sedaren) and centrifuged to remove mononuclear cells from erythrocytes. A spherical layer was obtained.
  • the resulting mononuclear cells were diluted to 8 x 10 5 cells / ml and contained mouse I 3 20 ng / ml and erythropoietin 2 U / l. After culturing in 0.8% methylcellulose semi-solid medium lm1 for 6 days, the formed leukocyte cell mass (hematopoietic progenitor cells
  • CFU-GM CFU-GM
  • a There is a significant difference at 5% risk relative to control.
  • b Indicates that there is a significant difference at a risk rate of 5% with respect to KRN7000.
  • c Indicates that there is a significant difference at a risk rate of 5% with respect to G-CSF.
  • administration of KRN7000 and administration of G-CSF significantly increased CFU-GM in peripheral blood.
  • co-administration of KRN7000 and G-CSF significantly increased the CFU-GM in peripheral blood compared to KRN7000 or G-CSF alone.
  • Pharmacological test 2 Effect of donor blood from peripheral blood administered KRN7000 and G-CSF on the survival time of whole-body irradiated recipient mice
  • mice C57BL / 6 mice (6 weeks old, female) were used as donor mice, and the experiments were performed in the following seven groups. That is, the (A) content port (unprocessed) group.
  • B KRN7000 (100 ⁇ g / kg) administered intravenously on day-and G-CSF (100 / g / kg) on days -3, -1, -1, -1 and 0 (4 hours before blood collection) ) Subcutaneously (KRN7000 + G-CSF group), (C) KRN7000 (lOO / zg / kg) intravenously on day-(KRN7000 group), (D) G-CSF (lOO g / kg) was administered subcutaneously on days -3, -2, -1 and 0 (4 hours before blood collection) (G-CSF sc group), as well as positive control.
  • Recipient mice (6 weeks old, C57BL / 6 mouse, Mess, 10 mice per group) were subjected to 9 Gy (900 rad) X-ray whole-body irradiation, and 2 days after irradiation.
  • Peripheral blood (100 1 / mouse) collected from each group as described above was transferred by vein into the recipient mouse within the above time. Then, the survival of each recipient mouse was observed. The results are shown in Figure 1.
  • peripheral blood from (A) control group, (C) KRN7000 group, (D) G-CSF sc group, and (G) SCF group was transferred to peripheral blood. All point mice died within 20 days after whole body irradiation with X-rays. Also, 40 days after whole body irradiation with X-rays, (F) G-CSF iv group And (E) In the mice receiving peripheral blood from the G-CSF + SCF group, one and two mice were observed to survive. (B) Five (50%) mice survived in the recipient mice to which peripheral blood was transferred from the KRN7000 + G-CSF group. This result indicates that among the seven groups described above, there is more hematopoietic progenitor cells in the peripheral blood of donor mice treated with KRN7000 + G-CSF I suggest this.
  • the recipient mice to which the peripheral blood of (A) the control group, (C) the KRN7000 group, and (G) the SCF group were transferred were: All died within 15 days after whole body irradiation with X-rays. Also, 40 days after whole-body irradiation with X-rays, in the recipient mice to which peripheral blood of (D) G-CSF sc group and (F) G-CSF iv group had been transferred, Survival of one of them was observed. Then, (E) peripheral blood of G-CSF + SCF group was ⁇
  • Fig. 3 shows the survival time of the recipient mice to which the peripheral blood of each group was transferred.
  • FIG. 4 shows the results of PCR performed on the positive and negative control mice and mice, and the blood of the surviving mouse (nine mice) in group (B) 150 days after irradiation. The results are shown.
  • Organism name Homo sapiens

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Abstract

Agents augmentant le nombre de cellules souches du sang périphérique, qui peuvent être utilisés dans les greffes de cellules souches du sang périphérique utilisant le G-CSF, et qui contiennent comme principe actif au moins un composé glucoside représenté par la formule générale (A) ou son sel, de préférence le (2S,3S,4R)-1-(α-D-galactopyranosiloxy)-2-hexacosanoylamino-3,4-octadécanediol; et compositions médicales ou trousses médicales destinées à augmenter le nombre de cellules souches du sang périphérique, qui contiennent lesdits agents associés au G-CSF.
PCT/JP1997/003698 1996-10-14 1997-10-14 Agents augmentant le nombre de cellules souches du sang peripherique et contenant des glucosides WO1998016235A1 (fr)

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Application Number Priority Date Filing Date Title
AU44732/97A AU4473297A (en) 1996-10-14 1997-10-14 Peripheral blood stem cell-increasing agents containing glycosides

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JP29114896A JP2002226377A (ja) 1996-10-14 1996-10-14 配糖体含有末梢血幹細胞増加剤
JP8/291148 1996-10-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1619199A4 (fr) * 2003-02-14 2009-12-16 Daiichi Asubio Pharma Co Ltd Derives de glycolipide, leur procede de production, intermediaires pour la synthese associee, et procede de production desdits intermediaires

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Publication number Priority date Publication date Assignee Title
JPH0276820A (ja) * 1988-06-15 1990-03-16 Ajinomoto Co Inc 骨髄移植療法支持剤
WO1994002168A1 (fr) * 1992-07-16 1994-02-03 Kirin Beer Kabushiki Kaisha Nouvelle composition medicamenteuse
WO1994028919A1 (fr) * 1993-06-08 1994-12-22 Ajinomoto Co., Inc. Accelerateur de la proliferation des cellules hematopietiques
WO1995006475A1 (fr) * 1993-09-02 1995-03-09 Celtrix Pharmaceuticals, Inc. Augmentation du nombre des cellules parentes hematopoïetiques dans le sang peripherique au moyen du facteur transformant de croissance beta
JPH08506091A (ja) * 1992-11-13 1996-07-02 ボード オブ リージェンツ オブ ユニバーシティ オブ ワシントン 造血幹細胞の末梢化

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0276820A (ja) * 1988-06-15 1990-03-16 Ajinomoto Co Inc 骨髄移植療法支持剤
WO1994002168A1 (fr) * 1992-07-16 1994-02-03 Kirin Beer Kabushiki Kaisha Nouvelle composition medicamenteuse
JPH08506091A (ja) * 1992-11-13 1996-07-02 ボード オブ リージェンツ オブ ユニバーシティ オブ ワシントン 造血幹細胞の末梢化
WO1994028919A1 (fr) * 1993-06-08 1994-12-22 Ajinomoto Co., Inc. Accelerateur de la proliferation des cellules hematopietiques
WO1995006475A1 (fr) * 1993-09-02 1995-03-09 Celtrix Pharmaceuticals, Inc. Augmentation du nombre des cellules parentes hematopoïetiques dans le sang peripherique au moyen du facteur transformant de croissance beta

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOL. PHARM. BULL., Vol. 19, No. 7, (July 1996), K. MOTOKI et al., "Effects of Alpha-Galactosylceramides on Bone Marrow Cells In Vitro and Hematopoiesis In Vivo", pages 952-955. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1619199A4 (fr) * 2003-02-14 2009-12-16 Daiichi Asubio Pharma Co Ltd Derives de glycolipide, leur procede de production, intermediaires pour la synthese associee, et procede de production desdits intermediaires
US7732583B2 (en) 2003-02-14 2010-06-08 Japan As Represented By President Of National Center Of Neurology And Psychiatry Glycolipids and synthetic method thereof as well as their synthetic intermediates, and synthetic intermediates, and synthetic method thereof
EP2343306A1 (fr) * 2003-02-14 2011-07-13 Japan as represented by President of National Center of Neurology and Psychiatry Ministry of Health Dérivés de glycolipide, procédé de production associé, intermédiaires pour synthèse associés et procédé de production des intermédiaires
US8034908B2 (en) 2003-02-14 2011-10-11 Japan As Represented By President Of National Center Of Neurology And Psychiatry Glycolipids and synthetic method thereof as well as their synthetic intermediates, and synthetic method thereof

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