WO1998009668A2 - Inhibiteurs de la synthese de la phosphatidylcholine - Google Patents

Inhibiteurs de la synthese de la phosphatidylcholine Download PDF

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WO1998009668A2
WO1998009668A2 PCT/GB1997/002410 GB9702410W WO9809668A2 WO 1998009668 A2 WO1998009668 A2 WO 1998009668A2 GB 9702410 W GB9702410 W GB 9702410W WO 9809668 A2 WO9809668 A2 WO 9809668A2
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carbon atoms
formula
straight
sulfur
oxygen
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PCT/GB1997/002410
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WO1998009668A3 (fr
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George Simon Attard
Christopher Mcguigan
Patrick Anthony Riley
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University Of Southampton
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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7024—Esters of saccharides
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • 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 System
    • 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
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • 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 System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Definitions

  • the present application relates to compounds which act as inhibitors of phosphatidylcholine synthesis, and which can be used in, for example, the treatment of cancers.
  • amphiphilic compounds as anti-neoplastic agents is attractive because they represent a class of non-DNA interactive therapeutic agents and may therefore be non-serotoxic.
  • certain amphiphilic compounds such as the phospholipid analogues Edelfosine and Mitelfosine (trade marks) are able to induce cytostasis in cancer cell cultures at micromolar concentrations. It has also been shown that at these concentrations the non-cancerous cells are relatively unaffected by these compounds.
  • CT phosphatidylcholine
  • the present invention relates to compounds which inhibit phosphatidylcholine synthesis and which can be used, for example, in the treatment of cancers.
  • the compounds may have higher activity than known amphiphilic compounds such as edelfosine and mitelfosine.
  • the present invention provides the use of an amphiphilic compound in the manufacture of a medicament for the inhibition of phosphatidylcholine synthesis, said amphiphilic compound have the following properties: i) the compound comprises a non-ionic, cationic or anionic hydrophilic head group and a hydrophobic tail group, ii) the head group has a cross section A and the tail group has a cross section B such that the ratio B:A is less than 0.7:1, iii) the tail group comprises a straight hydrocarbon chain having from 8 to 18 carbon atoms , and iv) the amphiphilic compound has a membrane/water partition coefficient of more than 1 x 10 "3 .
  • an amphiphilic compound is to be understood as being a compound having a hydrophilic head attached to a hydrophobic tail, although there may be more than one hydrophobic tail.
  • the heads of two amphiphilic compounds each having a single head and a single tail may be joined either directly or via a short linking group such as an alkylene group having from 1 to 6, preferable 1 to 4, carbon atoms which does not materially affect the hydrophilicity of the head groups.
  • Amphiphilic compounds having a cationic head group have generally been found to have the best phosphatidylcholine synthesis inhibition activity. However, amphiphilic compounds having a non-ionic head group may have better properties in other areas. For example, they may have less haemolytic activity in vivo .
  • the ratio B:A is preferably as small as possible. For example it may be less than 0.5:1, preferably less than 0.3:1. From a synthetic viewpoint, it is difficult to obtain compounds having a ratio B:A of less than 0.25:1. Amphiphilic compounds having this characteristic are sometimes referred to as "type I amphiphiles" because they form normal topology liquid crystalline phases when mixed with water.
  • the tail group is a straight chain hydrocarbon group containing from 8 to 18 carbon atoms. It is preferably an alkyl group, although it may contain one or more carbon-carbon double bonds. In order to ensure that the tail has a small cross section, these bonds must be in the trans configuration.
  • the tail preferably contains from 12 to 16 carbon atoms, and may contain, for example, 13, 14 or 15 carbon atoms, and none, one or two carbon-carbon double bonds.
  • the membrane/water partition coefficient of the amphiphilic compound is more than l x 10 '3 ,and is preferably as large as possible, ie. preferably more than 5xl0 '3 , more preferably more than lxlO "2 , even more preferably more than lxlO "1 .
  • This coefficient is the ratio of the concentration of the compound in the membrane/concentration of the compound in the solution. The coefficients may be measured in accordance with the method of E.E. Kelley, E.J. Modest, C.P. Burns (1993), Biochemical Pharmacology, vol. 45, pp 435-2439.
  • amphiphilic compounds which can be used in the present invention are as follows:
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms, and n is from 6 to 12, preferably 8 to 10.
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is hydrogen or a straight or branched alkyl group containing up to 5 carbon atoms
  • R j is hydrogen, a monovalent cation [insert examples] or a choline group,
  • X is oxygen, sulfur or NH
  • Y is oxygen, sulfur or NH
  • V is oxygen or sulfur.
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 , R 3 and R 4 which may be identical or different, are each a methyl, ethyl or straight or branched propyl group, and A " is a pharmaceutically acceptable anion.
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is methyl, m and n are integers such that the ring contains from 5 to 8 ring atoms, preferably 6 ring atoms, and A ' is a pharmaceutically acceptable anion.
  • R 1 is a straight hydrocarbon group containing from 8 to 18 carbon atoms
  • X is hydrogen
  • a " is a pharmaceutically acceptable anion.
  • R 1f R 3 , R 4 and R s which may be identical or different, are each methyl or ethyl,
  • R 2 and R 6 which may be identical or different, are each straight hydrocarbon groups containing from 10 to 18 carbon atoms p is from 2 to 4 , preferably 3 , and each A " which may be identical or different, is a pharmaceutically acceptable anion.
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 , R 3 and R 4 which may be the same or different, are each methyl, ethyl or straight or branched propyl groups , and A " is a pharmaceutically acceptable anion.
  • R is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 , R 3 and R 4 are each hydrogen, and A " is a pharmaceutically acceptable anion.
  • An alkylpyridiniu compound of formula (X) is
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is hydrogen
  • a " is a pharmaceutically acceptable anion
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is hydrogen or a straight or branched alkyl group containing not more than 5 carbon atoms
  • R 3 and R 4 which may be identical or different, are each a straight or branched alkyl group containing not more than 5 carbon atoms, m and n are integers such that the ring contains from 5 to 8 ring atoms, preferably 6 ring atoms,
  • X is oxygen, sulfur or NH
  • Y is oxygen, sulfur or NH
  • V is oxygen or sulfur
  • W is oxygen or sulfur
  • R 2 is a straight or branched alkyl group containing not more than 5 carbon atoms
  • R 3 is a straight or branched alkyl group containing not more than 5 carbon atoms, and n are integers such that the ring contains from 5 to 8 ring atoms, preferably 6 ring atoms,
  • X is oxygen, sulfur or NH
  • Y is oxygen, sulfur or NH
  • V is oxygen or sulfur
  • W is oxygen or sulfur
  • R 1 is a straight hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is hydrogen or a straight or branched alkyl group containing not more than 5 carbon atoms
  • R 3 and R 4 which may be identical or different, are each a straight or branched alkyl group containing not more than 5 carbon atoms
  • X is oxygen, sulfur or NH
  • Y is oxygen, sulfur or NH V is oxygen or sulfur
  • W is oxygen or sulfur.
  • R is a hydrocarbon group containing from 10 to 18 carbon atoms
  • R 2 is hydrogen or a straight or branched alkyl group containing not more than 5 carbon atoms, m is from 2 to 6, preferably 3 to 5, most preferably 4,
  • X is oxygen, sulfur or NH
  • Y is oxygen
  • sulfur or NH V is oxygen or sulfur
  • W is oxygen or sulfur
  • a ' is a pharmaceutically acceptable anion
  • a glycolipid analogue of formula (XV) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl) :
  • R is an amino, trimethyl ammonium, triethyl ammonium or phosphate group
  • R 2 is a hydroxy or phosphate group
  • R 3 is a hydroxy or phosphate group
  • R is hydrogen
  • one of R 5 and R 6 is methyl, ethyl or straight or branched propyl and the other is a straight hydrocarbon group containing from 8 to 18 carbon atoms .
  • R 1 , R 7 and R 10 which may be identical or different, is each an amino, trimethyl ammonium, triethyl ammonium or phosphate group, R 13 is a hydroxy or phosphate group,
  • R 3 , R, and R 12 which may be identical or different, is each a hydroxy or phosphate group
  • R 4 , R g and R n is each hydrogen, and one of R. and R 6 is methyl, ethyl or straight or branched propyl and the other is a straight hydrocarbon group containing from 8 to 18 carbon atoms.
  • R v R 7 and R 10 in formulae (XV) and (XVI) is a trimethyl ammonium or a triethyl ammonium group, it contains a balancing anion.
  • This anion may be an anion A ' as herein defined.
  • the pharmaceutically acceptable anion A ' may be inorganic or organic.
  • inorganic anions are halides such as fluoride, chloride and bromide.
  • organic anions are methylsulfate, toluenesulfate and acetate.
  • the straight hydrocarbon groups are generally alkyl groups. They may optionally contain one, two or more trans carbon-carbon double bonds.
  • the groups containing from 10 to 18 carbon atoms or 8 to 18 carbon atoms preferably contain from 12 to 18 carbon atoms, more preferably from 14 to 18 carbon atoms, most preferably 16 carbon atoms.
  • the hydrocarbon group containing from 8 to 18 carbon atoms in the compound of formula (V) preferably has from 10 to 16 carbon atoms, more preferably from 10 to 14 carbon atoms, most preferably 12 carbon atoms.
  • the alkyl groups containing from 1 to 5 carbon atoms may be straight or branched. Examples are methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl and n-pentyl .
  • the present invention also provides a method of inhibiting phosphatidylcholine synthesis in a subject, which comprises administering to a subject in need of such inhibition an effective amount of an amphiphilic compound as herein defined.
  • amphiphilic compounds used in the present invention may be used, for example, to treat a cancer.
  • the compounds may be administered, for example, by intravenous (i.v.) injection or topically. They may also be used in autologous bone marrow transplantation.
  • the compounds may be administered in any conventional form. Thus they may be administered in the form of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or diluent.
  • the compounds may be used singly or in a combination of two or more.
  • the compounds may also be administered either together or separately with other compounds useful in the treatment of cancers.
  • the amphiphilic compounds may be used to treat a variety of cancers. They may be used, for example, for the treatment of leukemias, breast cancer skin metastasis, cutaneous ly phomas, mammary carcinomas, fibrosarcomas, melanomas and lung carcinomas. They may also be used as purging agents for autologous bone marrow transplantation.
  • the amphiphilic compounds may be administered, for example, to humans by injection at a dose of 5 to 15 mg/kg body weight per injection, or by topical application in an amount of not less than 50, preferably 80, mg/kg body weight. They may also be used in an amount of not less than 3, preferably 10, more preferably 20, micromoles per 10 6 lymphocytes for bone marrow purging.
  • amphiphilic compounds used in the present invention can be obtained from commercial sources, although they may require further purification, for example by column chromatography or by recrystallization before use.
  • amphiphilic compounds used in the present invention are novel. These include the compounds of formulae (II) , (XI) , (XII) , (XIV) , (XV)and(XVI) .
  • the compounds of formula (II) may be prepared by alkylation of diethyl alonate using the appropriate 1- bromoalkanes.
  • An example of a synthesis method is given in Example 2.
  • Other compounds of formula (II) can be prepared by analogous methods.
  • the present invention also provides an amphiphilic compound as defined above for use in a method of treatment of the human or animal body by therapy.
  • the present invention is now further described in the following Examples.
  • HL60, Ramos and Daudi cancer cell lines were cultivated in RPMI 1640 medium supplemented with 10% foetal bovine serum and 2 illimolar glutamine. The cells were maintained in a humidified atmosphere with 5% carbon dioxide at 37 degrees Celsius. Cell viability as a function of different concentrations of amphiphilic compounds was determined using a colorimetric assay. Cells were seeded at 4 x 10 5 cells per illilitre for HL60 cells, 8 x 10 5 per millilitre for Daudi cells and 2 x 10 5 cells per millilitre for Ramos cells. All of the amphiphilic compounds were made up as 11 millimolar stock solutions in medium.
  • a number of compounds of formula (II) were synthesised by alkylation of diethyl malonate using the appropriate 1-bromoalkanes according to literature procedures.
  • the alkyl diethylmalonate was reduced to produce the diol which was phosphorylated using phosphorus oxychloride.
  • Salts were prepared by reacting the product with, for example, sodium ethoxide.
  • Other compounds of formula (II) may be prepared by analogous methods.
  • a solution of sodium ethoxide was prepared by carefully dissolving sodium metal (1.85g, 0.08 mol) in dry ethanol (20 ml). Diethyl malonate (13.28g, 0.083 mol) was introduced dropwise, followed by the addition of 1-bromododecane (20g, O.OSmol). The mixture was refluxed under dry N 2 overnight. Ethanol was removed from the mixture by rotary evaporator, and dichloromethane (100ml) was used to redissolve the residue. The mixture was washed with water (100ml), then dried with MgS0 A , and concentrated to given an orange oil (23.56g). Some of the residual diethyl malonate was removed by short path distillation. The remaining crude product was purified by column chromatography (1:1 ethyl acetate/petroleum ether) to yield the product (A) as a colourless solid (20.27g, 74% yield) .
  • Lithium aluminium hydride (2.17g, 0.57mol) was carefully introduced into a dry flask under N 2 and mixed thoroughly with dry ether (200ml) .
  • Diethyl dodecylmalonate (A) (17.93g, 0.55mol) was cautiously added to the lithium aluminium hydride mixture with vigorous stirring. Traces of the added ester were washed into the reaction vessel with dry ether. Further portions of dry ether (4x50ml) were added to facilitate stirring as the mixture became more viscous. After 3 hours of stirring, the excess aluminium hydride was decomposed by the controlled addition of water (100ml) . Chloroform (200ml) was added and the aqueous layer was separated. The organic extract was dried with MgS0 4 and concentrated. The residual solid was recrystallised from methanol to yield the desired product (B) as a white solid (9.55g, 71% yield) .
  • Phosphorus oxychloride (0.28g, 1.84mrool, 1.5eq) in dry dichloromethane (100ml) was introduced dropwise into a solution of 2-dodecyl-l , 3-propanediol (B) (0.30g,
  • HC 50 values The haemolytic activity of a number of amphiphilic compounds was determined This was expressed as HC 50 values, which was the concentration that produced 50% haemolysis as determined by a standard colorimetric assay following 2 minutes incubation with fresh mouse red blood cells.
  • the HC 50 data are given below:
  • amphiphilic compounds used in the present invention induce less haemolysis than mitelfosine. They may therefore, if desired, be administered i.v. at higher concentrations than Mitelfosine.
  • Mitelfosine was tested at 3 micromolar for 72 hours.
  • the compound of formula (III) was one in which
  • Mitelfosine does not appear to change the proportions of the cells in the different phases of the cell cycle.
  • the non- ionic compound (I) and the cationic compound (III) appear to block cells in the S phase.
  • the cationic compound (XIV) appears to block cells in the Gl phase.
  • Samples for mass spectrometry were dissolved in 5 millimolar sodium hydroxide dissolved in chloroform/methanol (2:1).
  • the mobile phase employed consisted of methanol/chlorofor /water (80:10:10).
  • the PE lipids were quantitated using the negative ionization mode while the PC lipids were quantitated as their sodium adducts using the positive ionization mode.
  • Example 9 The reduction in PC synthesis of various compounds used in the present application was determined.
  • amphiphilic compounds used in the present invention are potent inhibitors of the enzyme CTP: phophocholine cytidylyltransferase (CT) .
  • CTP phophocholine cytidylyltransferase
  • amphiphilic compounds which are used in the present invention were synthesised.
  • a number of compounds of formula (IV) as defined above were synthesised by the alkylation of a N-methyl heterocycles with the appropriate 1-bromoalkanes.
  • a number of compounds of formula (VI) as defined above were synthesised by the alkylation of (N,N,N',N' ⁇ tetraalkyl (alkane diamine) with the appropriate 1- bromoalkanes.
  • a number of compounds of formula (IX) as defined above were synthesised by the alkylation of pyridine or its derivatives with the appropriate 1-bromoalkanes.
  • reaction mixture was allowed to stir at room temperature for about 2h under N 2 , monitoring the progress of reaction by tic (using ethyl acetate as eluant) .
  • the solvent and excess P0C1 3 and NEt 3 were evaporated off at high vacuum to yield the crude phosphorodichloridate (E) as a waxy solid.
  • compound (E) was dissolved in CH 2 C1 2 (20ml) and NEt 3 (0.05g, 0.5mmol).
  • 1,4-butanediamine (44mg, O. ⁇ mmol, 2eq.) in CH 2 C1 2 (2ml) was introduced into a solution of 1-0- dichlorophosphate-2- ⁇ -methyl-3-0-hexadecyl-rac- glycerol (E) and was allowed to stir at room temperature (20°C) under N 2 overnight.
  • the crude product was obtained as a waxy whitish solid after solvent removal under vacuum, which on purification by chromatographic column (silica gel, 100% ethyl acetate) yielded the target compound as a waxy white solid (52mg, 45%).
  • 1,3-propanediamine (37mg, 0.5mmol 2eq.) in CH 2 C1 2 (2ml) was introduced into a solution of l-O- dichlorophosphate-2-0-methyl-3-0-hexadecyl-rac- glycerol (E) and was allowed to stir at room temperature (20°C) under N 2 overnight.
  • the crude product was obtained as a waxy whitish solid after solvent removal under vacuum, which on purification by chromatographic column (silica gel. 100% ethyl acetate) yielded the target compound as a waxy white solid (52mg,48%) .
  • N,N'-dimethyl-l, 3-propanediamine (51mg, 0.50mmol, 2eq.) in CH 2 C1 2 (2ml) was introduced dropwise into a solution of l-0-dichlorophosphate-2-0-methyl-3-0- hexadecyl-rac-glycerol (E) was stirred at 0°C under N 2 for 2h. Evaporation of the solvent and NEt 3 under vacuum gave the crude product as a waxy whitish solid, which after purification by flash chromatography column over silica gel (petroleum ether: ethyl acetate 1:1) yielded target compound as a waxy white solid (20mg, 15%).
  • intermediate D (intermediate D) (132mg, 0.4mmol) was dissolved in 5ml dry pyridine. To this solution was added bis(2,2,2- trichloroethyl) phosphorochloridate (228mg, 0.6mmol) dissolved in dry pyridine (1ml) . The mixture was stirred under nitrogen for 2 hours. A further quantity (228mg, 0.6mmol) of bis (2 , 2 , 2-trichloroethyl) - phosphorochloridate dissolved in dry pyridine (1ml) was added to the reaction mixture. The mixture was stirred under nitrogen for a further 4 hours. Pyridine was removed under vacuum using short path distillation to afford a yellowish oil.
  • Cesium fluoride (1.30g, 8.56mmol) was added and the reaction was stirred at 6°C for 4 days with rigorous exclusion of moisture. Excess ethylamine was evaporated and 20ml absolute ethanol was added. The mixture was allowed to stir for a further 3 days at room temperature (20°C) . Excess ethanol was removed from under vacuum and the residue was purified by column chromatograph using silica gel and petroleum ether/ethyl acetate (1:1) as eluant. The target compound was obtained as a colourless oil (0.02g, 11% yield) .
  • N-octyl- ⁇ -glucopyranosylamine was synthesised as described by Attard G.S, Blackaby W.P. and Leach A.R.
  • P-Toluenesulphonyl chloride (0.41g, 2.15mmol) was dissolved in 5ml dry pyridine. The solution was added dropwise with stirring to a solution of N-octyl-(l- octadecylamido) - ⁇ -D-glucopyranoside (A) (l.Og, l. ⁇ mmol) in 20ml dry pyridine at 0°C. After warming to room temperature (20°C) over a period of 6 hours the solvent was removed under vacuum and residual pyridine was removed by co-evaporation with toluene. Diethyl ether (25ml) was added and the precipitate was removed by filtration.

Abstract

L'invention porte sur l'utilisation d'un composé amphiphile pour la fabrication d'un médicament inhibant la synthèse de la phosphatidylcholine. Ledit composé amphiphile présente les propriétés suivantes: (i) il comporte un groupe hydrophile de tête non ionique, cationique ou anionique, et un groupe hydrophobe de queue, (ii) le groupe de tête présente une section A et le groupe de queue présente une section B telles que le rapport B:A est inférieur à 0,7:1, (iii) le groupe de queue comporte une chaîne droite d'hydrocarbures présentant de 8 à 18 atomes de carbone, et (iv) le composé amphiphile présente un coefficient de séparation membrane/eau supérieur à 1 x 10-3.
PCT/GB1997/002410 1996-09-06 1997-09-08 Inhibiteurs de la synthese de la phosphatidylcholine WO1998009668A2 (fr)

Priority Applications (1)

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AU41285/97A AU4128597A (en) 1996-09-06 1997-09-08 Phosphatidylcholine synthesis inhibitors

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GB9618634.1 1996-09-06
GBGB9618634.1A GB9618634D0 (en) 1996-09-06 1996-09-06 Anti cancer drugs

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WO1998009668A3 WO1998009668A3 (fr) 1998-06-25

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WO2000052015A2 (fr) * 1999-03-05 2000-09-08 Metabasis Therapeutics, Inc. Nouveaux promedicaments a teneur en phosphore
EP1125927A1 (fr) * 2000-02-14 2001-08-22 Wako Pure Chemical Industries, Ltd. Procédé de préparation d'un sel d'ammonium quaternaire
FR2818646A1 (fr) * 2000-12-22 2002-06-28 Oreal Nouveaux derives c-glycoside et utilisation
EP1263752A2 (fr) * 2000-03-17 2002-12-11 The University Of Tennessee Research Corporation Agonistes et antagonistes du recepteur lpa et procedes d'utilisation de ces derniers
EP1634886A2 (fr) * 1999-03-05 2006-03-15 Metabasis Therapeutics, Inc. Nouveaux promedicaments a teneur en phosphore
US7205404B1 (en) 1999-03-05 2007-04-17 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
US7303739B2 (en) 1999-09-08 2007-12-04 Metabasis Therapeutics, Inc. Prodrugs for liver specific drug delivery
US7351399B2 (en) 1998-03-06 2008-04-01 Metabasis Therapeutics, Inc. Prodrugs for phosphorus-containing compounds
US7732414B2 (en) 2000-12-22 2010-06-08 L'oreal S.A. C-glycoside compounds for stimulating the synthesis of glycosaminoglycans
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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US7351399B2 (en) 1998-03-06 2008-04-01 Metabasis Therapeutics, Inc. Prodrugs for phosphorus-containing compounds
WO2000052015A2 (fr) * 1999-03-05 2000-09-08 Metabasis Therapeutics, Inc. Nouveaux promedicaments a teneur en phosphore
US8664195B2 (en) 1999-03-05 2014-03-04 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
US8080536B2 (en) 1999-03-05 2011-12-20 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
US7205404B1 (en) 1999-03-05 2007-04-17 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
US7816345B2 (en) 1999-03-05 2010-10-19 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
WO2000052015A3 (fr) * 1999-03-05 2001-02-15 Mets Asis Therapeutics Inc Nouveaux promedicaments a teneur en phosphore
EP1634886A2 (fr) * 1999-03-05 2006-03-15 Metabasis Therapeutics, Inc. Nouveaux promedicaments a teneur en phosphore
EP1634886A3 (fr) * 1999-03-05 2006-03-29 Metabasis Therapeutics, Inc. Nouveaux promedicaments a teneur en phosphore
EP1724276A1 (fr) * 1999-03-05 2006-11-22 Metabasis Therapeutics, Inc. Nouveaux promédicaments à téneur en phosphore
US7303739B2 (en) 1999-09-08 2007-12-04 Metabasis Therapeutics, Inc. Prodrugs for liver specific drug delivery
EP1125927A1 (fr) * 2000-02-14 2001-08-22 Wako Pure Chemical Industries, Ltd. Procédé de préparation d'un sel d'ammonium quaternaire
US6414159B2 (en) 2000-02-14 2002-07-02 Wako Pure Chemical Industries, Ltd. Method for preparation of a quaternary ammonium salt
EP1263752A2 (fr) * 2000-03-17 2002-12-11 The University Of Tennessee Research Corporation Agonistes et antagonistes du recepteur lpa et procedes d'utilisation de ces derniers
US6875757B2 (en) 2000-03-17 2005-04-05 University Of Tennessee Research Foundation LPA receptor agonists and antagonists and methods of use
EP1263752A4 (fr) * 2000-03-17 2003-07-30 Univ Tennessee Res Corp Agonistes et antagonistes du recepteur lpa et procedes d'utilisation de ces derniers
EP1918287A3 (fr) * 2000-03-17 2008-08-20 The University Of Tennessee Research Corporation Agonistes et antagonistes du récepteur lpa et méthodes d'utilisation
KR100874392B1 (ko) 2000-03-17 2008-12-17 유니버시티 오브 테네시 리서치 파운데이션 Ｌｐａ 수용체 아고니스트 및 안타고니스트, 및 사용 방법
WO2002051803A2 (fr) * 2000-12-22 2002-07-04 L'oreal Nouveaux derives c-glycoside et utilisation
WO2002051803A3 (fr) * 2000-12-22 2002-12-27 Oreal Nouveaux derives c-glycoside et utilisation
US7732414B2 (en) 2000-12-22 2010-06-08 L'oreal S.A. C-glycoside compounds for stimulating the synthesis of glycosaminoglycans
FR2818646A1 (fr) * 2000-12-22 2002-06-28 Oreal Nouveaux derives c-glycoside et utilisation
US10449210B2 (en) 2014-02-13 2019-10-22 Ligand Pharmaceuticals Inc. Prodrug compounds and their uses
US11278559B2 (en) 2014-02-13 2022-03-22 Ligand Pharmaceuticals Incorporated Prodrug compounds and their uses
US9994600B2 (en) 2014-07-02 2018-06-12 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
US10150788B2 (en) 2014-07-02 2018-12-11 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses thereof
US11970482B2 (en) 2018-01-09 2024-04-30 Ligand Pharmaceuticals Inc. Acetal compounds and therapeutic uses thereof

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