WO2005118522A1 - Monomethylphytosphingosine- polyethylenegly col et composition anti-cancereuse contenant ledit compose - Google Patents

Monomethylphytosphingosine- polyethylenegly col et composition anti-cancereuse contenant ledit compose Download PDF

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Publication number
WO2005118522A1
WO2005118522A1 PCT/KR2005/001438 KR2005001438W WO2005118522A1 WO 2005118522 A1 WO2005118522 A1 WO 2005118522A1 KR 2005001438 W KR2005001438 W KR 2005001438W WO 2005118522 A1 WO2005118522 A1 WO 2005118522A1
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WIPO (PCT)
Prior art keywords
group
cancer
monomethylphytosphingosine
mmps
derivative
Prior art date
Application number
PCT/KR2005/001438
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English (en)
Inventor
Dae-Seog Lim
Jinwook Kim
Sungjin Park
You-A Hwang
Changseo Park
Ho-Jae Lee
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Doosan Corporation
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Publication of WO2005118522A1 publication Critical patent/WO2005118522A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine

Definitions

  • the present invention relates to a derivative of sphingolipid having an anti-cancer activity and a composition containing the same, and more particularly to a monomethylphytosphingosine-polyethyleneglycol (MMPS-PEG) derivative formed by combining monomethylphytosphingosine (MMPS), which is a derivative of sphingolipid, with polyethyleneglycol (PEG) or a pharmaceutically acceptable salt thereof and a composition containing the same.
  • MMPS-PEG monomethylphytosphingosine-polyethyleneglycol
  • Sphingolipid was firstly found by Thudichum in 1884 and named as a sphinx like substance. It was known as a substance playing a substantial role in life phenomena as well as regulating cell growth, proliferation and differentiation.
  • the sphingolipid in a human body has sphingosine, phytosphingosine or sphinganine backbones and 300 or more kinds of derivatives including ceramide having fatty acids connected to the backbones.
  • the sphingolipid is a main ingredient constituting a cell membrane together with phospholipid and has polar and non-polar parts.
  • Ceramide having a fatty acid connected to sphingolipid is known as a substance playing an important role in causing various action mechanisms occurring in a cell. In particular, it takes part in a cell proliferation, a cell differentiation, a temporary growth arrest of the cell proliferation and an apoptosis.
  • the ceramide is a substance causing an apoptosis which is an importance mechanism for a cancer treatment and thus development of an anti-cancer drug is focused on the ceramide. It is analyzed that many anti-cancer drugs, which are being currently used or developed, influence on a biosynthesis pathway of the ceramide and thus exhibit their effects.
  • ceramide and ceramide derivative and analog are directly treated to the cancer cell or a substance inducing or starting a de novo synthesis of ceramide may be used as an anti-cancer drug.
  • P-drug which has been actively researched as an anti-cancer drug in recent years, is a ceramide analog of aminoalcohols.
  • PDMP D-threo-l-phenyl-2-decanoylamino-3-mo holino-l-propanol
  • PDMP D-threo-l-phenyl-2-decanoylamino-3-mo holino-l-propanol
  • PPMP D-1hreo-l-phenyl-2-palmitoylamino-3-mo ⁇ holino-l-propanol
  • PPPP P4D-1hreo-l-phenyl-2-palmitoylamino-3-pyrrolidino-l-propanol
  • the P-drug is expected to exhibit an anti-cancer effect for a general cancer cell and to inhibit a synthesis of GlcCer relating to tolerance to the anti-cancer drug, thereby contributing to a prevention of drug resistance.
  • B13 or N-oleoylethanolamine which are ceramidase inhibitors, is also a ceramide analog and inhibits a decomposition of the ceramide to induce a death of the cancer cell.
  • ceramide biosynthesis inhibitors having a structure similar to those of sphingolipid and ceramide, such as FTY-720, fumonisin and myriosin, etc.
  • DMS dimethylsphingosine
  • the polyethylene glycol above mentioned is a substance having a structure of HO- (CH CH O) CH CH -OH, and often used in foods or cosmetics. In addition, since it 2 2 n 2 2 retards decomposition of an active ingredient, it has been much used in prescription of drug.
  • the polyethylene glycol is a substance suitable for such purposes since it is a non-toxic polymer, has a good solubility and no antigenicity in a human body and is easily removed in the body.
  • polyethylene glycol Since the polyethylene glycol has a hydroxyl group at both ends thereof, monomethoxy polyethylene glycol (CH 3 O-(CH 2 CH 2 O) n CH 2 CH 2 -OH) having one end blocked is much used in PEGylation and its molecular weight is used up to 30,000 Daltons.
  • a hydroxyl group at one end having no methoxy connected thereto is activated and connected using various chemicals.
  • MMPS-PEG monomethylphytosphingosine- polyethyleneglycol
  • the object of the present invention is to inhibit a growth of tumor xenografted to a mammal using a derivative of sphingolipid, i.e., a monomethylphytosphingosine-polyethyleneglycol (MMPS-PEG) derivative formed by combining monomethylphytosphingosine (MMPS) with polyethyleneglycol (PEG), thereby treating or preventing a cancer or a cancer-related disease.
  • Another object of the invention is to inhibit an activity of promoting a cell proliferation, thereby treating or preventing a hyper-proliferative disease such as a cancer and psoriasis.
  • the object of the invention is to provide a tumor inhibiting composition, an anti-cancer composition or composition for treating or preventing a hyper-proliferative disease, which compositions have the above-mentioned efficacies.
  • MMPS-PEG monomethylphy- tosphingosine-polyethyleneglycol
  • R is independently hydrogen, alkyl group of C , alkenyl group of C , alkynyl group of C , acyl group or aryl group, in a case of acyl group (COR ), R is alkyl group, alkenyl group, alkynyl group or aryl group, a substituent X is a medium used to combine with sphingolipid and -NR -, -O-, -S-, or X -alk-X , R is hydrogen, alkyl group of C 1-6 , acyl group or aryl group, X 1 and X2 are independently amino group, amido group, carboxyl group, carbamate group, carbonyl group, urea or phosphoro, and alk is alkylene of C .
  • the polyethyleneglycol has a molecular weight of 550 ⁇ 10,000, more preferably, 750 ⁇ 5,000 and an end replaced with methoxy.
  • a representative example of the monomethylphytosphingosine-polyethyleneglycol derivatives according to the invention is one wherein R is independently hydrogen, alkyl group or acyl group, X is succinate and the polyethyleneglycol has a molecular weight of 750 ⁇ 5,000 and an end replaced with methoxy group.
  • a tumor inhibiting composition containing the monomethylphytosphingosine-polyethyleneglycol (MMPS-PEG) derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • MMPS-PEG monomethylphytosphingosine-polyethyleneglycol
  • the tumor inhibiting composition is used to treat or prevent a cancer or cancer-related disease.
  • an anti-cancer composition for treating or preventing a cancer containing the monomethylphytosphingosine- polyethyleneglycol (MMPS-PEG) derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • MMPS-PEG monomethylphytosphingosine- polyethyleneglycol
  • composition for treating or preventing a hyper-proliferative disease containing the monomethylphytosphingosine- polyethyleneglycol (MMPS-PEG) derivative or a pharmaceutically acceptable salt thereof as an effective ingredient.
  • MMPS-PEG monomethylphytosphingosine- polyethyleneglycol
  • the hyper-proliferative disease is psoriasis.
  • composition of the invention containing the monomethylphytosphingosine- polyethyleneglycol (MMPS-PEG) derivative or a pharmaceutically acceptable salt thereof can be used in a medicine.
  • the salt is not specifically limited if it is pharmaceutically acceptable.
  • hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and naphthalene sulfonic acid, etc. can be used.
  • the monomethylphytosphingosine-polyethyleneglycol derivative having the chemical formula 1 according to the invention can be prepared by reacting monomethylphytosphingosine having a following chemical formula 2 with polyethyleneglycol which is activated in advance in a solvent under presence of catalyst.
  • the MMPS-PEG derivative or the pharmaceutically acceptable salt thereof according to the invention highly inhibits a growth of tumor xenografted to the mammal, thereby treating or preventing a cancer or a cancer-related disease.
  • a solubility of the monomethylphytosphingosine is improved and a toxicity thereof influencing on the human body is reduced, thereby remarkably expanding the application ranges thereof. Accordingly, the composition containing the same can be efficiently used as a tumor inhibiting composition, an anti- cancer composition for treating or preventing a cancer or a cancer-related disease or a composition for treating or preventing a hyper-proliferative disease.
  • FIG. 1 is a graph showing an anti-cancer efficacy of a MMPS-PEG derivative in a nude mouse.
  • FIG. 2 is a graph showing a survival rate of a nude mouse having a tumor grafted thereto which is treated with the MMPS-PEG derivative.
  • a detailed description of a method of manufacturing the monomethylphy- tosphingosine-polyethyleneglycol derivative having the chemical formula 1 is as follows. Firstly, polyethyleneglycol is activated. Succinic anhydride is added to the polyethyleneglycol under presence of an organic solvent, thereby converting an alcohol group into a carboxyl group. An acid part of the polyethyleneglycol having carboxyl group replaced is activated using triethylamine and p-toluenesulfonylchloride and then a small amount of monomethylphytosphingosine is added to the activated solution a small amount by a small amount, thereby completing a 24 hours reaction under warming conditions.
  • the compound having the chemical formula 1 prepared as described above is extracted using an organic solvent such as chloroform or a mixed solution of chloroform and methanol and then purified with an adsorption chromatography by silica gel.
  • the purified monomethylphytosphingosine-polyethyleneglycol derivative can be used in a medicine as it is or in a form of pharmaceutically acceptable salt.
  • the salt is not specifically limited if it is pharmaceutically acceptable.
  • hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid and naphthalene sulfonic acid, etc. can be used.
  • the polyethyleneglycol has preferably a molecular weight of 550 ⁇ 10,000, more preferably 700 ⁇ 5,000.
  • the range of the molecular weight is the most optimal range for achieving a purpose of combining the polyethyleneglycol.
  • a pharmaceutical composition containing the monomethylphy- tosphingosine-polyethyleneglycol derivative or the pharmaceutically acceptable salt thereof preferably contains 0.001 ⁇ 20 wt.% of the compound in a total composition.
  • concentration is less than 0.001 wt.%, it is difficult to obtain the efficacy and when the concentration is more than 20 wt.%, it can cause an abnormality of a generative function.
  • the monomethylphytosphingosine-polyethyleneglycol derivative of the invention inhibits a growth of tumor grafted in a living mammal and has an increased solubility and a decreased toxicity.
  • the inventors measured an in vivo anti-cancer activity using a derivative of sphingolipid, i.e., the monomethylphytosphingosine-polyethyleneglycol derivative (MMPS-PEG) having the chemical formula 1 formed by combining monomethylphytosphingosine (MMPS) with polyethyleneglycol (PEG).
  • MMPS-PEG monomethylphytosphingosine-polyethyleneglycol derivative
  • PEG polyethyleneglycol
  • a pharmaceutical composition containing the monomethylphytosphingosine-polyethyleneglycol derivative and the pharmaceutically acceptable salt thereof may further comprise proper carrier, excipient and diluent typically used to prepare the pharmaceutical composition.
  • the compound of the invention can be pharmaceutically administrated in a form of a pharmaceutically acceptable salt thereof. Further, it can be administrated solely or in conjunction with and in a proper combination with other pharmaceutically acceptable active compounds.
  • the pharmaceutical composition containing the compound of the invention can be used in forms of oral formulation such as acida, granulum, tablet, capsule, suspension, emulsion, syrup and aerosol, external preparations such as ointment and cream, suppository and sterilizing injection solution according to typical methods. Further, it can be formulated in any forms suitable for pharmaceutical preparations.
  • a preferable dosage of the compound according to the invention varies with ages, sexes, weights, symptoms and degrees of diseases of administration subjects, drug forms, administration routes and administration periods, it can be properly selected by a skilled person in the art. However, considering a preferable efficacy, it is preferred that the compound of the invention is administrated in an amount of 0.001 ⁇ 1000 mg/kg per a day. The administration can be performed one time or many times per a day. In addition, the dosage can be increased or decreased according to the ages, sexes, weights, degrees of diseases and administration routes, etc. Accordingly, the dosage does not limit a scope of the invention in any way.
  • the compound of the invention can be administrated to a mammal such as a rat, a mouse, a domestic animal and a human through various routes, for example, non-oral and oral administrations. All types of the administration can be expected. For instance, it can be administrated with oral, rectum or vein, muscle, hypodermic, and intrauterine dura mater or intracerebroventricular injections.
  • Example 1 synthesis of monomethylphytosphingosine-polyethylenegl col (MMPS-PEG) derivative
  • a sufficient amount of human breast cancer cell line i.e., MDA-MB-231 (obtained from Korea Institute of Radiological and Medical Sciences, Gongneung- dong, Seoul) was cultivated and about 10 of cells were injected into nude mouses (6-week of age, about 20 g, 6 (six) per group, SLC, Japan). After few days, when a size of tumor was increased to about 3 mm, the MMPS-PEG derivative of the Example 1 was injected in the nude mouse (125 mg/kg, three times of intraperitoneal administration) and fractionation-injection conditions of test materials were set while measuring the tumor size.
  • MDA-MB-231 obtained from Korea Institute of Radiological and Medical Sciences, Gongneung- dong, Seoul
  • the tumor size was measured using calipers per day and a survival rate of the treatment group was evaluated.
  • phosphate buffered solution PBS
  • TAXOL TAXOL
  • MMPS-PEG derivative 125 mg/kg, three times of intraperitoneal administration
  • TAXOL 30 mg/kg, three times of intraperitoneal administration
  • MMPS-PEG derivative was added to a solution of hydroxypropyl b-cyclodextrin in purified water while stirring it. Hydrochloric acid was added to be a solution and then sodium hydroxide was added to be pH 6.0. This solution was added to a dispersion solution of carrageenan PJ in propylene glycol while mixing it. The mixture was heated to 50 °C while slowly mixing, and added with ethyl alcohol and then cooled to about 35 °C. A remaining amount of purified water was added to the mixture and then the mixture was mixed to be homogeneous.
  • Migliol 812, MMPS-PEG derivative and polysorbate 80 were mixed. Phosphatidyl choline was dissolved in ethanol and then added to the mixture to obtain a homogeneous clear liquid. [85] [86] Table 4 MMPS-PEG derivative nano-dispersion solution water phase
  • a water phase containing MMPS-PEG derivative (for example, 94.54 g) was stirred and kept at 50 °C in a receptacle.
  • a liquid nano-dispersion solution inversion phase (for example, 5.46 g) was stirred and added to the water phase.
  • the MMPS-PEG derivative or the pharmaceutically acceptable salt thereof according to the invention highly inhibits a growth of tumor xenografted to the mammal, thereby treating or preventing a cancer or a cancer-related disease.
  • a solubility of the monomethylphytosphingosine is improved and a toxicity thereof influencing on the human body is reduced, thereby remarkably expanding the application ranges thereof. Accordingly, the composition containing the same can be efficiently used as a tumor inhibiting composition, an anti- cancer composition for treating or preventing a cancer or a cancer-related disease or a composition for treating or preventing a hyper-proliferative disease.

Abstract

L'invention concerne un dérivé de monométhylphytosphingosine-polyéthylèneglycol (MMPS-PEG) formé par combinaison de monométhylphytosphingosine (MMPS), qui est un dérivé d'un sphingolipide, et de polyéthylèneglycol (PEG) ou d'un sel acceptable d'un point de vue pharmaceutique de celui-ci, et une composition contenant ledit dérivé. Ledit composé inhibe la croissance d'une tumeur xénogreffée chez un mammifère, afin de traiter ou de prévenir un cancer ou une maladie associée à un cancer. Ledit composé peut également inhiber une activité favorisant la prolifération cellulaire, afin de traiter ou de prévenir une maladie hyperproliférative telle que le cancer ou le psoriasis. La solubilité de la monométhylphytosphingosine est, de plus, améliorée et sa toxicité sur le corps humain est réduite, son champ d'application étant ainsi significativement étendu.
PCT/KR2005/001438 2004-06-01 2005-05-17 Monomethylphytosphingosine- polyethylenegly col et composition anti-cancereuse contenant ledit compose WO2005118522A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2004-0039704 2004-06-01
KR1020040039704A KR100736145B1 (ko) 2004-06-01 2004-06-01 모노메틸파이토스핑고신-폴리에틸렌글리콜 및 그를 함유하는 항암 조성물

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WO2005118522A1 true WO2005118522A1 (fr) 2005-12-15

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5820873A (en) * 1994-09-30 1998-10-13 The University Of British Columbia Polyethylene glycol modified ceramide lipids and liposome uses thereof
KR20030014780A (ko) * 2001-08-13 2003-02-20 주식회사 참 존 항암활성을 가지는 파이토스핑고신 유도체
WO2003092667A1 (fr) * 2002-05-02 2003-11-13 Doosan Corporation Composition permettant de traiter le cancer comprenant n,n-dimethylphytosphingosine
WO2003101937A1 (fr) * 2002-05-31 2003-12-11 Bundle David R Methodes de synthese permettant la production a grande echelle a partir de glucose d'analogues de sphingosine, azidosphingosine, ceramides, lactosylceramides, et glycosyle phytosphingosine
WO2004054963A1 (fr) * 2002-12-13 2004-07-01 Doosan Corporation Derives de sphingolipides modifies par du polyethylene glycol et composition contenant ces derives

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60117900D1 (de) 2001-09-05 2006-05-11 Charmzone Co Phytosphingosinderivate mit Antitumorwirkung
KR100459484B1 (ko) * 2002-05-20 2004-12-03 한국원자력연구소 엔-아세틸 파이토스핑고신과 다이메틸 파이토스핑고신을유효 성분으로 포함하는 방사선 치료 민감제 조성물
KR20050051862A (ko) * 2003-11-28 2005-06-02 주식회사 두산 스핑고지질-폴리에틸렌글리콜 중합체 및 그를 함유한 피부외용제 조성물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5820873A (en) * 1994-09-30 1998-10-13 The University Of British Columbia Polyethylene glycol modified ceramide lipids and liposome uses thereof
KR20030014780A (ko) * 2001-08-13 2003-02-20 주식회사 참 존 항암활성을 가지는 파이토스핑고신 유도체
WO2003092667A1 (fr) * 2002-05-02 2003-11-13 Doosan Corporation Composition permettant de traiter le cancer comprenant n,n-dimethylphytosphingosine
WO2003101937A1 (fr) * 2002-05-31 2003-12-11 Bundle David R Methodes de synthese permettant la production a grande echelle a partir de glucose d'analogues de sphingosine, azidosphingosine, ceramides, lactosylceramides, et glycosyle phytosphingosine
WO2004054963A1 (fr) * 2002-12-13 2004-07-01 Doosan Corporation Derives de sphingolipides modifies par du polyethylene glycol et composition contenant ces derives

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KR20050114478A (ko) 2005-12-06
KR100736145B1 (ko) 2007-07-06

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