WO2001079152A1 - Sphingolipides - Google Patents

Sphingolipides Download PDF

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Publication number
WO2001079152A1
WO2001079152A1 PCT/IL2001/000361 IL0100361W WO0179152A1 WO 2001079152 A1 WO2001079152 A1 WO 2001079152A1 IL 0100361 W IL0100361 W IL 0100361W WO 0179152 A1 WO0179152 A1 WO 0179152A1
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disease
compound
group
pharmaceutical composition
cells
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PCT/IL2001/000361
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Arieh Dagan
Shimon Gatt
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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Priority to AU2001252506A priority Critical patent/AU2001252506A1/en
Priority claimed from PCT/IL2001/000909 external-priority patent/WO2003027058A1/fr
Publication of WO2001079152A1 publication Critical patent/WO2001079152A1/fr
Priority to US10/273,664 priority patent/US6756504B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/04—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
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    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/24—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and acyclic
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/34—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton and at least one hydroxy group bound to another carbon atom of the carbon skeleton
    • C07C215/36—1-Aryl-2-amino-1,3-propane diols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C07C215/38—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • Sphingolipids comprise a group of lipids having ceramide, i.e., iV-acylsphingosine as the basic group.
  • ceramide i.e., iV-acylsphingosine
  • phosphoSL phosphoSL
  • glycoSL glycol
  • the former have one main component, i.e., sphingomyelin (ceramide-phosphorylcholine)
  • the glycosphingolipids comprise a wide group.
  • SLs are present in practically every cell type and tissue and particularly abound in the nervous system. The relative composition of the SL may change with age; thus, it has been shown that the ratio of sphingomyelin to lecithin increases with age.
  • Glycosphingolipids have a high binding potential and act as specific receptors for a number of external agents, e.g., lectins, toxins, hormones and viruses.
  • external agents e.g., lectins, toxins, hormones and viruses.
  • SPM is generally considered as the primary metabolic source of ceramide whose generation in a particular location in the cell, (e.g., the membrane) makes it suitable for mediating cellular signaling processes.
  • An increased de novo synthesis of ceramide has also been described as a potential source for signaling [Bose et al, Cell 82, 405-414, (1995)].
  • ceramide in cell killing by apoptosis as well as its effect on important cellular events such as proliferation, differentiation and reaction to stress conditions.
  • cell-permeable (e.g., C2 or Co) ceramides evoke biological responses that lead to cell killing.
  • Other studies, using the precursor of ceramide, i.e., sphingosine have shown its effects on cell growth and viability.
  • sphingosine was shown to inhibit protein kinase C and increase the intracellular concentration of calcium ions.
  • sphingosine- 1-phos hate has been shown to be a potent activator of phospholipase D.
  • di- or tri- methylated sphingosine was shown to inhibit growth of cancer cells [Endo et al, Cancer Research 51, 1613-1618, (1981)].
  • ceramide The involvement of ceramide and sphingolipid metabolism in cancer has been studied. It have been demonstrated that apoptosis induced by administration of a variety of chemotherapeutic agents is mediated by ceramide [Strum et al, J. Biol. Chem. 269, 15493-15497 (1994); Maurer et al, J. Natl. Cancer List. 91, 1138-1146 (1999); Suzuki et ⁇ Z., Exp. Cell Res. 233, 41-47 (1997)]- Anthracyclins (e.g., daunorubicin) have been shown to induce ceramide accumulation which subsequently led to death of cancer cells [Bose et al, Cell 82, 405-414 (1995)].
  • Anthracyclins e.g., daunorubicin
  • HePC hexadecylphosphocholine
  • This is an antiproliferative drug, which is currently used for the treatment of extraneous metastases of mammary carcinoma and has been shown to induce apoptosis at a concentration of 25 ⁇ M.
  • HePC which inhibits the biosynthesis of phosphatidylcholine exerts a secondary effect by decreasing the biosynthesis of sphingomyelin and consequently increasing the levels of ceramide and it is probably the latter that is responsible for the proapoptotic properties of HePC.
  • Another major aspect of the metabolism of the sphingolipids is their accumulation in organs of patients afflicted with the genetic lipid storage diseases, such as Gaucher disease ( ⁇ -glucosidase), Tay-Sachs disease ( ⁇ -iV-acetyl hexosaminidase); Niemann-Pick disease (acid sphingomyelinase), Krabbe disease ( ⁇ -galactosidase), Metachromatic leuko dystrophy (arylsulfatase A), Fabry disease (ceramidase) and Farber disease ( ⁇ -galactosidase).
  • Gaucher disease ⁇ -glucosidase
  • Tay-Sachs disease ⁇ -iV-acetyl hexosaminidase
  • Niemann-Pick disease as acid sphingomyelinase
  • Krabbe disease ⁇ -galactosidase
  • Metachromatic leuko dystrophy arylsulfatase A
  • Each of these diseases is due to a mutation in a gene encoding a lysosomal sphingolipid hydrolase (shown in brackets). Consequently, the activity of the respective hydrolase is considerably reduced resulting in accumulation of the respective sphingolipid in the patients' organs.
  • Enzyme replacement therapy in which the enzyme involved is purified and infused into the patients for the rest of their lives; this approach is currently applied to patients with Gaucher disease, in which the patients are infused with ⁇ -glucosidase purified from human placentae or, alternatively, a recombinant form of the enzyme.
  • Gene therapy in which a gene encoding the normal enzyme will be cloned and administered into the patients; this is currently in the stage of planning. 3.
  • Sphingolipids are of the general structure:
  • CH3(CH2)i4-22 and R 2 may be a hydrogen atom, phosphoryl- choline; glucose, galactose or an oligosaccharide.
  • the compound PDMP for example, the compound PDMP
  • sphinglipids affect cell growth and differentiation.
  • N,N,N-trimethyl sphingosine has been shown to inhibit cell growth [Endo et al, Cancer Research, 51, 1613-1618 (1991)].
  • Cs ceramide in which the amide group was replaced by — NH — (CH ⁇ CHs: CH 3 (CH 2 )i2— CH CH— CHOH— CHNH[(CH )7CH 3 ]— CH2OH induced apoptosis [Karasavvas et al., Eur. J. Biochem. 236, 729-731 (1996)].
  • Hexadecylphosphocholine induced a ceramide-mediated apoptosis [Wieder et al., J. Biol. Chem. 273, 11025-11031 (1998)].
  • the invention relates to compounds of the general formula (I):
  • n is an integer of
  • X represents hydrogen or the group — OR 4 in which R 4 is a linear or branched, saturated or unsaturated Ci-C ⁇ alkyl or alkenyl chain which may be optionally substituted with hydroxy;
  • Y represents — NH , NHR X wherein R x is hydrogen, a linear or branched alkyl or alkenyl chain which may be optionally substituted with
  • Ri, R 2 and R 3 which may be identical or different each represent Ci- ⁇ alk l or Ci-ealkenyl, a group
  • n is zero or an integer of from 1
  • polymer designates a natural or synthetic biocompatible polymer having a molecular weight between 10 3 and 10 6 daltons;
  • Z represents hydrogen, — OH, a mono- or disaccharide, a monosaccharide sulfate and choline phosphate; with the proviso that
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound of formula (I) wherein the substituents are as defined in claiml, and optionally further comprising pharmaceutically acceptable carrier, adjuvant or diluent.
  • compositions of the invention may be used for reducing accumulation of sphinglipids, and thus for the treatment of lipid storage diseases such as Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, Krabbe disease, Metachromatic leukodystrophy, Fabry disease and Farber disease.
  • lipid storage diseases such as Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, Krabbe disease, Metachromatic leukodystrophy, Fabry disease and Farber disease.
  • novel compounds of formula (I) may be used as inhibitors of acidic, neutral and alkaline sphingomyelinases, acidic, neutral and alkaline ceramidases, ⁇ -galactosyl synthetase, ceramide synthetase, sphingomyelin synthetase and glycocer amides synthetase.
  • compositions of the invention may also be used for the treatment of cancerous diseases, for killing of wild type and drug-resistant cancer cells.
  • compositions of the invention may also be used for the treatment of parasitic, viral, bacterial, fungal and prion diseases.
  • the invention relates to a method of treating a lipid storage disease or a cancerous disease in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound of formula (I) or of pharmaceutical composition comprising the same.
  • AD-2646 Abbreviations: Via (viable), C (cells), Contr (control), Inhi (inhibitor), Cone (concentration).
  • the cytotoxic effect of AD-2646 was examined using increasing concentrations of AD-2646 for two days. The total protein content was measured. Abbreviations: Prot (protein).
  • FIG. 3 Effect of AD-2646 on sphingolipids metabolism (SPM) HL60 cells were incubated with increasing concentrations of AD-2646 for 3 hours in the presence of 2.5 ⁇ M Bodipy-C3-ceramide. After extraction, the lipids were applied onto a thin layer chromatography plate, and the fluorescence of Bodipy-C3 - sphingomyelin (SPM) was quantified.
  • SPM sphingolipids metabolism
  • FIG. 4 Effect of AD-2646 on sphingolipids metabolism (GC) HL60 cells were incubated with increasing concentrations of AD-2646 for 3 hours in the presence of 2.5 ⁇ M Bodipy-C3-ceramide. After extraction, the lipids were applied on a thin layer chromatography plate, and the fluorescence of Bodipy-C3-cerebroside (GC) was quantified.
  • GC Bodipy-C3-cerebroside
  • FIG. 5 -AD-2646 inhibits SPM synthesis in TSU-PR1 cells
  • TSU-PR1 cells were incubated for 3 hours in the presence of increasing concentrations of AD-2646 and the fluorescence of Bodipy-C3 - sphingomyelin (SPM) was quantified.
  • SPM Bodipy-C3 - sphingomyelin
  • HL60 cells were incubated with the different compounds AD-2672, AD-2673 and AD-2674, each at 5 and 10 ⁇ M.
  • the effect of the different compounds on synthesis of Bod3-SPM and Bod3-GC was examined.
  • the relative quantity of the SPM and GC is shown in the fluorescent image of the plate Abbreiations: Cont (control).
  • NH-adamantane from 1 to 20, NH-adamantane, or a group — NH— t-BOC, — NH— FMOC, or NH-CBZ;
  • X represents hydrogen or the group — OR 4 in which R is a linear or branched, saturated or unsaturated CI-CG alkyl or alkenyl chain which may be optionally substituted with hydroxy;
  • Y represents — NH2, NHR X wherein R x is hydrogen, a linear or branched alkyl or alkenyl chain which may be optionally substituted with s s
  • R 1; R 2 and R 3 which may be identical or different each represent Ci-calkyl or Ci-calkenyl, a group
  • n is zero or an integer of from 1
  • Z represents hydrogen, — OH, a mono- or disaccharide, a monosaccharide sulfate and choline phosphate; with the proviso that
  • Preferred compounds of formula (I) are those in which R designates aminophenyl or nitrophenyl.
  • amino protecting groups may be any suitable amino protecting groups as known to the man of skill in the art, particularly BOC (tertiary, butyloxy carbonyl), FMOC (fluorenylmethoxycarbonyl) or CBZ (benzyloxycarbonyl).
  • the novel synthetic compounds of the invention are capable of inhibiting degradation as well as biosynthesis of sphingolipids.
  • these compounds may be used in the treatment of lipidoses, particularly genetic lipid storage diseases in which sphingolipids accumulate in organs of afflicted patients, such as Gaucher disease, Tay-Sachs disease, Niemann-Pick disease, Krabbe disease, Metachromatic leukodystrophy, Fabry disease and Farber disease.
  • Pharmaceutical compositions for the treatment of lipid storage diseases are also within scope of the present invention.
  • the invention thus also relates to pharmaceutical compositions for the treatment of cancerous diseases, comprising as active ingredients the compounds of the invention, optionally in combination with at least one other anti-cancer drug. Still further, the compounds of the invention may be used in the treatment of parasitic diseases such as malaria and leishmania. Pharmaceutical compositions for the treatment of such parasitic diseases are also within scope of the present invention.
  • compositions are for use by injection or by oral uptake.
  • compositions- of the invention generally comprise a buffering agent, an agent which adjusts the osmolarity thereof, and optionally, one or more carriers, excipients and/or additives as known in the art, e.g., for the purposes of adding flavors, colors, lubrication, or the like to the pharmaceutical composition.
  • Each carrier should be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the subject to be treated.
  • formulations include those suitable for rectal, nasal, preferred formulations are intended for oral or parenteral administration, including intramuscular, intradermal, subcutaneous and specifically intravenous administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the art of pharmacy.
  • Carriers may include starch and derivatives thereof, cellulose and derivatives thereof, e.g., microcrystalline cellulose, xantham gum, and the like.
  • Lubricants may include hydrogenated castor oil and the like.
  • a preferred buffering agent is phosphate-buffered saline solution (PBS), which solution is also adjusted for osmolarity.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated.
  • a preferred pharmaceutical formulation is preferably used for administration by injection, including intravenous injection.
  • compositions of the invention may be administered in a variety of ways.
  • the composition may be delivered by injection intravenously, intramuscularly, or intraperitoneally. Intravenous administration, for example, is advantageous.
  • the pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred method of preparation are vacuum-drying and freeze drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the composition of the invention may be mixed with nutritive feed material or water supplies for the subject to be treated. It is contemplated however that the effective composition can either be mixed with the nutritive feed material or water or fed to the subject separately.
  • compositions are well known in the art and has been described in many articles and textbooks, see e.g., Remington's Pharmaceutical Sciences, Gennaro A.R. ed., Mack Publishing Company, Easton, Pennsylvania, 1990, and especially pages 1521-1712 therein.
  • Additives may also be designed to enhance uptake of the active agent across cell membranes. Such agents are generally agents that will enhance cellular uptake of the molecules of the invention.
  • the compounds of the invention may be enclosed within liposomes.
  • liposomes e.g., using particular transfection reagents, is well known in the art.
  • Other methods of obtaining hposomes include the use of Sendai virus or of other viruses.
  • the above-mentioned lipid agents may also improve the stability of the active compounds that have been taken up by the cell.
  • the dose of the active agent may vary. The dose would generally depend on the disease, the state of the disease, age, weight and sex of the patient, and is to be determined by the attending physician.
  • the invention also relates to a method for the treatment or prevention of a lipid storage disease, a cancerous disease or a parasitic disease, comprising administering a compound or a pharmaceutical composition of the invention or of any of the preferred embodiments thereof, to a patient in need thereof.
  • HL60 Human leukemia cell line (ATCC CCL-240).
  • TSU-PR1 Prostate cancer cells (available at the ATCC).
  • MCF7-AdrR Human breast cancer cells, drug resistant (available at the ATCC).
  • MCF7-NCi Human breast cancer cells, drug sensitive (available at the ATCC).
  • U937 Myeloid Leukemic cells (available at the ATCC).
  • the lower phase was collected, the aqueous-methanol phase was extracted twice with 50 ml 3:1 dichloromethane:methanol, the 3 lower phases were combined and shaken with 75 ml H 2 O.
  • the organic phase was dried with MgSO , filtered and evaporated to dryness.
  • the residue was dissolved in a small volume of dichloromethane: methanol, 1:1, and loaded onto a 50 x 2 cm silica gel column.
  • BOC was linked to 4 gr 2R, 3S-2-amino-l-(4-nitrophenyl)-l,3-propanediol as in the preparation of AD2502 (4).
  • 2 grams of the BOC derivative were reduced by hydrogen as in AD2516 (2).
  • 1 gr of the product, i.e., the respective amino phenyl derivative was reacted with 1 gr hexadecanoic acid in 50 ml dichloromethane:methanol, 2:1, by addition of 1 gr EDAC.
  • the reaction mixture was stirred overnight, evaporated to dryness, the residue was dissolved in 4 ml dichloromethane-methanol, 1:1 and loaded onto a 50 x 1.5 cm silica gel column prepared in dichloromethane.
  • sphingosine were dissolved in 10 ml dichloromethane:methanol, 2:1, in a 25 ml Erlenmeyer flask. 200 ⁇ l of butylsulfonylchloride were added and the solution was stirred for 10 min. 300 ⁇ l of triethylamine were then added in 50 ⁇ l portions during 1 h and the solution was stirred overnight. The solution was transferred to a 250 ml separatory funnel, a mixture of 50 ml dichloromethane, 15 ml methanol and 25 ml water were added and the solution was shaken in the separatory funnel.
  • sphingosylphosphorylcholine 100 mg were dissolved in 10 ml methanokwater, 2:1, in a 25 ml Erlenmeyer flask. To the stirred solution were added 100 mg of tertiary butyl isothiocyanate. The solution was stirred for 10 min, then 2.5 ml of IN sodium bicarbonate were added. The solution was left to stir for 48 hours, transferred to a separatory funnel and 80 ml dichloromethane, 30 ml methanol and 40 ml water were added. The organic phase was washed with 40 ml of water, then dried over MgSO 4 , filtered and evaporated to dryness.
  • the compound was purified by preparative TLC using dichloromethane:methanol:water, 65:35:5 for development.
  • BOC was finked to 3 gr (2R, 3S)-2-amino-l-(4-nitrophenyl)-l,3-propanediol as was done in the preparation of AD-2502 (4).
  • Three grams of the BOC derivative were reduced by hydrogen as in the preparation of AD-2516 (2).
  • AD-2646 The effect of AD-2646 on cell viability was analyzed by measuring cell mortality (viable cell count) and/or total protein quantity.
  • HL60 cells grown in RMPI plus 10% fetal calf serum were incubated with increasing concentrations of (2R,3R)-2-( V-tetradecylamine)-l-(4-nitro- phenyl)-l, 3-propanediol (AD-2646) in 6- or 24-well dishes.
  • the compound was added as solutions in dimethylsulfoxide (DMSO), ensuring that the concentration of this solvent did not exceed 0.1% of the volume of the culture medium.
  • DMSO dimethylsulfoxide
  • Fig. 1 indicates an IC50 value of 5 ⁇ M.
  • HL60 cells were incubated with 40 ⁇ M of AD-2646 for 1, 3, 5 and 7 hours. Already after 1 hour a reduction of 60% of the viable cell number was observed.
  • AD-2646 compound The effect of the AD-2646 compound on cell viability was further supported when the total protein content was quantified.
  • HL60 cells were incubated as described above, with different concentrations of AD-2646. After 2 days the cells were collected, washed twice with saline, dispersed and following a short pulsing with a probe-sonicator their protein content was quantified by the Bradford procedure. Similarly to the viable cell counting results, the protein measurements indicated an IC50 value of 5 ⁇ M.
  • TSU-PR1 cells prostate cancer cells
  • AD-2646 concentration of AD-2646.
  • the protein content measurements shown in Fig. 2 indicate'that the cells were killed with an IC50 of 6-7 ⁇ M.
  • Myeloid, leukemic U937 cells were incubated for 24 hours in the absence or in the presence of 5 ⁇ M AD-2672 and AD-2665. Cells were then collected and the percent of apoptotic cells was determined using a kit quantifying the DEVDase, caspase 3 activity. The number of apoptotic cells incubated with AD-2672 exceeded 6-fold those in the control cells. Cells incubated with AD-2665 exceeded 2.8- fold those in the control cells.
  • HL60 cells The apoptotic effect of three different compounds was further examined on HL60 cells using a flow cytometry method.
  • Cells were incubated with AD-2646, AD-2665 or AD-2687 at 3 and 24hr and increasing compound concentrations, collected and washed. Washed cells were then treated with 5% Triton and stained with propidium iodide 0.5% mg in 0.1% sodium citrate pH 7.4. Analysis was performed using a Becton Dickinson Fluorescence Activated Cell Sorter (FACS).
  • FACS Becton Dickinson Fluorescence Activated Cell Sorter
  • results of incubation for 3 hours with low concentration of the AD-2646 compound (10 ⁇ M) indicate 12% of apoptotic cells, at 20 ⁇ M 18% of the cells were apoptotic, and at 40 ⁇ M, 26% of the cells were apoptotic. Incubation for longer period (24 hours) revealed already at the lower concentration (10 ⁇ M) about 50% apoptotic cells.
  • AD-2687 When AD-2687 was used, after 3 hours of incubation at 15 ⁇ M, only 9% of the cells were apoptotic, while after 24 hours of incubation at a low concentration (2.5 ⁇ M), close to 50% of the cells were apoptotic.
  • Plates were developed as follows: For medium: in chloroform -me thanol-H 2 O, 75:25:4 by volume. For cells: plates were first developed with chloroform-methanol, 9:1, then dried and re-run in chloroform-methanol: H 2 0, 65:35:4.
  • Bodipy-C3-ceramide Bodipy-C3-glucosylceramide (Bod3-GC) and Bodipy C3 sphingomyelin (Bod3-SPM) were used as markers.
  • the fluorescence of the respective Bod3-SPM and Bod3-GC spots was quantified using a Fuji FLA- 2000 scanner.
  • Fig. 6 is a fluorescent image, indicating that AD-2672 strongly reduces the level of Bod3-SPM but not of Bod3-GC. In contrast, AD-2673 and AD-2674 at 10 ⁇ M show a low inhibition of Bod3-SPM but a much stronger reduction of the level of Bod3-GC. ,
  • MCF-NCi drug-sensitive
  • MCF-AdrR Adriamycin-resistant
  • AD-2144 ⁇ -hexyl-sphingosyl phosphorylcholine
  • sphingomyelinases acidic (i.e., with an optimum at about pH 5) or neutral (with a pH optimum at about pH 7.4).
  • a sonicate of HL60 leukemic cells was used as enzyme source.
  • Increasing concentrations of AD-2144 were dispersed by a mixture of fluorescent and non-fluorescent sphingomyelin (Bodipy-C12-SPM:SPM, 1:19), buffer and 0.25% Triton-XlOO in a volume of 100 ⁇ l.
  • AD-2144 causes reduction of Bodipy-C12-ceramide
  • AD-2646 compound displays significant specific cell mortality by inducing apoptotic mechanism. This apoptotic phenomenon is probably mediated by inhibition of sphingolipids metabolism.
  • an in vivo toxicity study was performed in mice.

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Abstract

L'invention concerne des composés de la formule générale (I), comme définie dans le descriptif, ainsi que des compositions pharmaceutiques les contenant. Ces composés, qui sont des inhibiteurs de divers enzymes associés aux lipides, peuvent servir à réduire l'accumulation de sphingolipides et, par conséquent, à traiter des dyslipidoses. Ces composés peuvent également servir à traiter des cancers et à tuer des cellules cancéreuses de type sauvage et pharmacorésistantes.
PCT/IL2001/000361 2000-04-19 2001-04-18 Sphingolipides WO2001079152A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1287815A1 (fr) * 2001-08-31 2003-03-05 Cosmoferm B.V. Utilisation d'une base sphingoide pour inhiber l'activité de la céramidase
WO2003027058A1 (fr) * 2001-09-26 2003-04-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sphingolipides
WO2004019900A1 (fr) * 2002-08-27 2004-03-11 Societe Des Produits Nestle Prevention ou traitement d'une lesion de l'epithelium ou de la perte des cheveux
US6756504B2 (en) 2000-04-19 2004-06-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sphingolipids
WO2005051891A1 (fr) * 2003-11-25 2005-06-09 Consejo Superior De Investigaciones Científicas Utilisation de derives de cyclopropenylesfingosine pour la production d'une composition pharmaceutique modulant l'activite de ceramidases et leurs applications
EP1814841A2 (fr) * 2004-10-29 2007-08-08 MUSC Foundation For Research Development Ceramides et ligands de signalisation de l'apoptose
WO2009060457A1 (fr) * 2007-11-08 2009-05-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Nouveaux analogues synthétiques de sphingolipides
US8093393B2 (en) 2004-10-29 2012-01-10 Musc Foundation For Research Development Cationic ceramides, and analogs thereof, and their use for preventing or treating cancer
US8586564B2 (en) * 2003-09-30 2013-11-19 Enzo Therapeutics, Inc. Synthetic glycolipid analogues and derivatives for the treatment of pathologic disorders
US8697379B2 (en) 2008-11-06 2014-04-15 Musc Foundation For Research Development Lysosomotropic inhibitors of acid ceramidase
CN105287608A (zh) * 2015-09-30 2016-02-03 山东大学 神经鞘氨醇磷脂酰胆碱在制备抗乳腺癌药物中的应用
US9717754B2 (en) 2003-02-27 2017-08-01 Enzo Therapeutics, Inc. Glucocerebroside treatment of disease
US9744185B2 (en) 2003-02-27 2017-08-29 Enzo Therapeutics, Inc. Glucocerebroside treatment of liver disorders

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Publication number Priority date Publication date Assignee Title
EP0072286A1 (fr) * 1981-08-03 1983-02-16 FIDIA S.p.A. Composés d'amides organiques dérivés de lipides azotes
EP0398340A1 (fr) * 1989-05-17 1990-11-22 THERA - Patent Verwaltungs-GmbH Dérivés céramide et leur utilisation comme inhibiteurs de la synthèse sphingolipide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0072286A1 (fr) * 1981-08-03 1983-02-16 FIDIA S.p.A. Composés d'amides organiques dérivés de lipides azotes
EP0398340A1 (fr) * 1989-05-17 1990-11-22 THERA - Patent Verwaltungs-GmbH Dérivés céramide et leur utilisation comme inhibiteurs de la synthèse sphingolipide

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US6756504B2 (en) 2000-04-19 2004-06-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sphingolipids
EP1287815A1 (fr) * 2001-08-31 2003-03-05 Cosmoferm B.V. Utilisation d'une base sphingoide pour inhiber l'activité de la céramidase
WO2003027058A1 (fr) * 2001-09-26 2003-04-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Sphingolipides
AU2003266313B2 (en) * 2002-08-27 2009-10-22 Societe Des Produits Nestle S.A. Preventing or treating epithelial tissue damage or hair loss
WO2004019900A1 (fr) * 2002-08-27 2004-03-11 Societe Des Produits Nestle Prevention ou traitement d'une lesion de l'epithelium ou de la perte des cheveux
JP2006511462A (ja) * 2002-08-27 2006-04-06 ソシエテ デ プロデユイ ネツスル ソシエテ アノニム 上皮組織損傷又は脱毛症の予防又は治療
US10639324B2 (en) 2003-02-27 2020-05-05 Enzo Therapeutics, Inc. Glucocerebroside treatment of disease
US9907810B1 (en) 2003-02-27 2018-03-06 Enzo Therapeutics, Inc. Glucocerebroside treatment of liver disorders
US9744185B2 (en) 2003-02-27 2017-08-29 Enzo Therapeutics, Inc. Glucocerebroside treatment of liver disorders
US9717754B2 (en) 2003-02-27 2017-08-01 Enzo Therapeutics, Inc. Glucocerebroside treatment of disease
US8592394B2 (en) * 2003-09-30 2013-11-26 Enzo Therapeutics, Inc. Synthetic derivatives beta glycolipids and compositions thereof for the treatment of pathologic disorders
US8586564B2 (en) * 2003-09-30 2013-11-19 Enzo Therapeutics, Inc. Synthetic glycolipid analogues and derivatives for the treatment of pathologic disorders
WO2005051891A1 (fr) * 2003-11-25 2005-06-09 Consejo Superior De Investigaciones Científicas Utilisation de derives de cyclopropenylesfingosine pour la production d'une composition pharmaceutique modulant l'activite de ceramidases et leurs applications
EP1814841A4 (fr) * 2004-10-29 2011-03-16 Musc Found For Res Dev Ceramides et ligands de signalisation de l'apoptose
US8592419B2 (en) 2004-10-29 2013-11-26 Musc Foundation For Research Development Ceramides and apoptosis-signaling ligand
US8093393B2 (en) 2004-10-29 2012-01-10 Musc Foundation For Research Development Cationic ceramides, and analogs thereof, and their use for preventing or treating cancer
EP1814841A2 (fr) * 2004-10-29 2007-08-08 MUSC Foundation For Research Development Ceramides et ligands de signalisation de l'apoptose
US8962891B2 (en) 2007-11-08 2015-02-24 Hadasit Medical Research Services & Development Limited Synthetic analogs of sphingolipids
US9340488B2 (en) 2007-11-08 2016-05-17 Hadasit Medical Research Services & Development Limited Synthetic analogs of sphingolipids
JP2011503050A (ja) * 2007-11-08 2011-01-27 イッサム リサーチ ディべロップメント カンパニー オブ ザ ヘブライ ユニバーシティー オブ エルサレム，リミテッド スフィンゴリピドの新規合成アナログ
WO2009060457A1 (fr) * 2007-11-08 2009-05-14 Yissum Research Development Company Of The Hebrew University Of Jerusalem Nouveaux analogues synthétiques de sphingolipides
US8697379B2 (en) 2008-11-06 2014-04-15 Musc Foundation For Research Development Lysosomotropic inhibitors of acid ceramidase
CN105287608A (zh) * 2015-09-30 2016-02-03 山东大学 神经鞘氨醇磷脂酰胆碱在制备抗乳腺癌药物中的应用

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