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WO1996016663A1 - Derives de thionophosphate, procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Derives de thionophosphate, procede de preparation et compositions pharmaceutiques les contenant Download PDF

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Publication number
WO1996016663A1
WO1996016663A1 PCT/US1995/015199 US9515199W WO9616663A1 WO 1996016663 A1 WO1996016663 A1 WO 1996016663A1 US 9515199 W US9515199 W US 9515199W WO 9616663 A1 WO9616663 A1 WO 9616663A1
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compound
optionally substituted
pharmaceutical composition
formula
group
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PCT/US1995/015199
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WO1996016663B1 (fr
Inventor
Oren Tirosh
Joshua Katzhendler
Isaac Ginsburg
Yehezkel Barenholz
Ron Kohen
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem
Kohn, Kenneth, I.
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Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem, Kohn, Kenneth, I. filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority to AU44081/96A priority Critical patent/AU4408196A/en
Priority to EP95942875A priority patent/EP0813415A4/fr
Priority to US08/849,122 priority patent/US6200962B1/en
Publication of WO1996016663A1 publication Critical patent/WO1996016663A1/fr
Publication of WO1996016663B1 publication Critical patent/WO1996016663B1/fr

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    • 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
    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2458—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the invention relates to novel thionophosphate organic derivatives, their preparation and pharmaceutical compositions containing them, particularly suitable for treating and/or preventing oxidative damage.
  • ROS Reactive Oxygen Species
  • the antioxidants defense system is composed of several lines of defense. These lines of defense include macromolecular molecules (mainly enzymes such as superoxide dis utase (SOD), catalase glutathione peroxidase and other protecting enzymes) and low molecular weight antioxidants [Halliwell. B. ( 1990) Free Rad. Res. Comm. 9:1-327].
  • macromolecular molecules mainly enzymes such as superoxide dis utase (SOD), catalase glutathione peroxidase and other protecting enzymes
  • low molecular weight antioxidants [Halliwell. B. ( 1990) Free Rad. Res. Comm. 9:1-327].
  • Antioxidants can be classified according to their partition between aqueous and lipid compartments (lipoproteins and membranes) [Dean, R.T., et al. (1991) Free Radical Biology &. Medicine 11:161-168: Niki. E.. et al. (1984) J. Biol. Chem. 259:4177- 4182]. Most of the natural antioxidants cannot cross biological membranes and cannot move freely by spontaneous diffusion between aqueous and lipid environments. Some of them are ionized at natural physiologic pH, a fact that also restricts their movement.
  • Antioxidants should not have any pro-oxidative effects, i.e. thiols group produced superoxide radicals causing LDL oxidation and NO radical distraction or ascorbic acid that induced free radical production when coupled with a transition metal [Heinecke, J. et al. (1993) J. Lipid Res. 34:2051-2061 ; Jackson, R.L., et al. (1993) Medicinal Research Reviews 13:161-182; Ingold, K.U., et al. (1993) Proc. Natl. Acad. Sci. USA 90:45-49];
  • N.N'-dimethyl thiourea is a well known antioxidant and a potent hydroxyl radical scavenger, also capable of removing hydrogen peroxide and superoxide radicals [Kelner, M.J., et al. (1990) J. Biol. Chem. 265:1306-1311; Dey, G.R., et al. (1994) J. Chem. Soc. Perkin Trans 2:1625-1629]. Notwithstanding their antioxidative properties, various DMTU-derived compounds are relatively highly toxic (e.g., lung, liver and thyroid toxicity) and considered carcinogenic substances.
  • the present invention relates to compounds of the general formula:
  • X ⁇ and X 2 each independently represents an oxygen or nitrogen atom; p, m and n are each independently an integer of at least 2; R, R ⁇ and R 2 each independently represents a hydrogen atom; a halogen atom; an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group R3O in which R3 is a hydrogen atom, an optionally substituted acyl group or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted aryl or heteroaryl; a group R4 ⁇ (0)C in which R4 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -SR5 in which R5 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical
  • A is a halogen atom selected from chlorine, bromine and iodine and X ⁇ , X 2 , R ⁇ , R 2 , m and n are as defined above with an amine of the formula
  • the invention further relates to pharmaceutical compositions comprising as active ingredient at least one compound of formula I in a suitable pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical compositions of the invention are particularly suitable for preventing and/or treating oxidative damage associated with inflammatory disorders, atherosclerosis, ischemia, traumatic shock, degenerative brain disease, skin disorders, septic shock, lung disease, malignant disease, damages caused by ionizing or non-ionizing radiation and poisonings by xanobiotics which generates reactive oxygen species.
  • the invention relates to methods of preventing and/or treating oxidative damage in a patient in need of such treatment by administering to said patient a therapeutically effective amount of at least one compound of formula I or of a pharmaceutical composition according to the invention
  • the invention relates to antioxidative additives comprising as active ingredient at least one compound of formula I in a suitable carrier or diluent.
  • Concentration dependent scavenging rate of superoxide radicals by increasing concentration of compound B detected spectrophoto- metrically by following the reduction of cytochrome C.
  • Lipid Hydroperoxide was measured as described under Materials and
  • Control 1 (3* 10 5 ) or control 2 ( 1.5* 10 6 ) were stimulated by cationized streptococci in the presence of various concentrations of compound B and 2mM DMTU.
  • Control 1 compound B (0.2mM), compound B (0.5mM), compound B (ImM), Control 2, Compound B (2mM), Compound B (4mM), Compound B (6mM), Compound B (8mM) and DMTU (2mM) are as shown.
  • SLS streptolysin S
  • GO glucose oxidase
  • the present invention relates to compounds of the general formula:
  • X] and X 2 each independently represents an oxygen or nitrogen atom; p, m and n are each independently an integer of at least 2; R, R ⁇ and R each independently represents a hydrogen atom; a halogen atom; an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group R3O in which R3 is a hydrogen atom, an optionally substituted acyl group or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; optionally substituted aryl or heteroaryl; a group R4 ⁇ (0)C in which R4 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical; a group -SR5 in which R5 is a hydrogen atom or an optionally substituted straight-chained or branched alkyl, alkenyl or alkynyl radical;
  • alkyl, alkenyl, alkynyl, acyl, aryl and heteroaryl radicals and groups can be optionally subsituted by one or more substitutents which may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, acyl, acyloxy, ether, ester, halogen, phosphate, amino, amido, thio, lipid, phospholipid, peptide, vitamin and other suitable substitutents.
  • Preferred compounds of formula I are those in which Xi and X 2 are both oxygen, R ⁇ and R 2 are both alkyl, preferably lower alkyl such as ethyl, and p, m, and n are 2. Particularly preferred such compounds are those in which R is an alkyl, hydroxy or carboxy group.
  • the invention also relates to a method for the preparation of compounds of formula I. comprising reacting a dialkyl halothiophosphate of the formula
  • A is a halogen atom selected from chlorine, bromine and iodine and Xj , X 2 ,
  • R] , R 2 , m and n are as defined above with an amine of the formula
  • Another unique property of the new ATMP functional group in the compounds of the invention is that the thionophosphate group can be monitored by 3 IP NMR.
  • the typical chemical shift of an AMTP molecule is about 72 ppm, which differs from other biological phosphates ( Figure 1 ). This unique property makes the tracing and examination of these compounds very simple.
  • novel organic thionophosphates of the invention are capable of reacting with hydroxyl radical, sodium hypochlorite, hydrogen peroxide, superoxide and lipid hydroperoxide. While the compounds of the invention are not capable of inhibiting lipid peroxidation by free radical chain breaking, neither scavenging peroxyl radicals, they can limit lipid peroxidation to a certain degree by preventing the initiation phase through the scavenging of hydroxyl radicals. Estimation of rate constants of AMTPs shows that by the scavenging mechanism they can prevent hydroxyl radical damage to biological systems, and that they are also capable of removing the less reactive ROS (H 2 0 2 , Or-) that can lead to hydroxyl radical production.
  • ROS H 2 0 2 , Or-
  • the compounds of the invention are extremely efficient scavengers of sodium hypochlorite, an oxidant produced by neutrophils at the site of inflammation and was recently shown by Stocker et al. [ibid.] to increase LDL uptake by macrophages and to cause protein damage to apo B 100. [Fig. 3].
  • the compounds of the invention also inhibit the flux of oxygen free radicals from activated neutrophils, a finding that has implications on the prevention of synergistic cell damage in inflamed tissues [Ginsburg et al. (1992) ibid.].
  • the compounds of the invention were used to prevent synergistic killing of cell cultures by H?0 2 and streptolysin S.
  • Compound B (Preparatory Example 2) (unionized) was much more efficient than compound C (Preparatory Example 3) (ionized) in preventing cell damage.
  • the finding that the novel compounds react with hydrogen peroxide in a time scale of hours may indicate that they probably contributed to the survival of the cell cultures by hydroxyl radical scavenging from outside the cell (compounds B and C) and from the cell interior (compound B).
  • oxidized AMTPs have one to two major oxidation products that contain phosphorus.
  • the products are very much similar to biological phosphates.
  • the thionophosphates of the invention did not show acute toxicity to Sabra rats at 500mg/kg.
  • novel thionophosphate molecules can be designed to meet specific needs as antioxidants. Hence, they need not be limited by an ionized active group, as is the case with other antioxidants such as ascorbic acid.
  • the lipophilicity of the compounds of the invention can be controlled, by varying the different subsituents on the thionophosphate core, they can be designed to move freely by spontaneous diffusion in different environments, and to cross biological barriers such as membranes, and targeted to specific organs.
  • novel compounds are incapable of reducing transition metals and oxygen, since they do not possess any pro-oxidative properties like conventional antioxidants.
  • Table 1 A cyclic voltmeter scanning up to 2 volts with glass carbon as a working electrode revealed no reducing power of these molecules, hence, no oxygen reduction to free radicals is possible.
  • the novel compounds of the invention are superior to the thiourea family of molecules (which are also considered powerful antioxidants) because they lack the relatively high toxicity of the thiourea molecules (e.g., lung, liver and thyroid toxicity).
  • ⁇ -naphthyl- thiourea has an LD50 of about lOmg/kg and DMTU is also considered a toxic compound [Boyd, M.R. and Neal, R.A. (1976) Drug Metabolism and Disposition 4:314].
  • the compounds of the invention may be advantageously used in preventing and/or treating oxidative damage.
  • oxygen free radicals are considered to be responsible for oxidative toxicity in mammals and the resulting biological damage.
  • the production of oxygen reactive metabolites can occur in various systems such as mitochondria, phagocytes, liver Kupfer cells, monocytes, basophyls, eosinophyls and mast cells.
  • phagocytes are incapable of producing the oxygen radicals and consequently patients suffer recurring infections which may lead to death [Johnston, Jr., R.B. et al. (1975) J. Clin. Invest. 55:1357].
  • Another source for free radicals are enzymes such as prolyl hydrolase, lipoxygenase and cycloxygenase, which during their catalytic activity produce oxygen free radicals [Halliwell and Gutteridge ibid.].
  • enzymes such as prolyl hydrolase, lipoxygenase and cycloxygenase, which during their catalytic activity produce oxygen free radicals [Halliwell and Gutteridge ibid.].
  • autoimmune diseases such as Hashimoto's thyroiditis, systemic lupus erythematosus, myastenia gravis, chronic autoimmune gastritis, dermatomyositis, etc.
  • degenerative brain diseases such as epilepsy, Parkinsonism, Wilson's disease and Alzheimer's disease
  • eye disease such as cataract and retinopathy
  • lung diseases such as Adult Respiratory Distress Syndrome (ARDS) and emphysema
  • malignant diseases and age related disease such as amyloid generation, age pigmentation and neuro
  • Exposure of humans to free radicals is not limited to the endogenous oxygen free radicals, but also to exogenous sources.
  • Various substances which are xanobiotics producing reactive oxygen species for examples agrochemicals like ParaquatTM, can serve as free radical generation systems, causing poisonings.
  • Other substances such as alloxan, isouramil, cigarette smoke, air pollutants, carcinogenic and mutagenic agents and many drugs, as well as ionizing and non-ionizing radiation, can also generate oxygen free metabolites and cause biological damage.
  • the novel compounds of the invention are particularly useful for treating and or preventing the above pathological conditions.
  • the invention relates to pharmaceutical compositions comprising as active ingredient at least one compound of Formula (I), in a pharmaceutically acceptable carrier or diluent.
  • compositions of the invention may -be particularly useful for preventing and/or treating oxidative damage associated with inflammatory disorders such as rheumatoid arthritis, atherosclerosis, post-ischemic brain and muscle damage, traumatic shock, degenerative brain disease such as Parkinson's disease and Alzheimer's disease, skin disorders such as eczema, pyodermes, dermatitis, allergies and urticaria, septic shock, lung disease, ⁇ eye disease such as Adult Respiratory Distress Syndrome and emphysema, ionizing radiation damage, particularly skin and eye damage, eye diseases such as cataract and retinopathy, and malignant diseases.
  • inflammatory disorders such as rheumatoid arthritis, atherosclerosis, post-ischemic brain and muscle damage, traumatic shock, degenerative brain disease such as Parkinson's disease and Alzheimer's disease, skin disorders such as eczema, pyodermes, dermatitis, allergies and urticaria, septic shock, lung disease, ⁇ eye disease
  • the pharmaceutical composition of the invention may contain, in addition to the active ingredient, conventional pharmaceutically acceptable carriers, diluents and the like and may be prepared in any suitable dosage form.
  • Such forms include solid compositions for oral administration such as tablets, capsules, pills and the like , which may be coated or otherwise compounded with pharmaceutically acceptable substances known in the art of pharmacy to provide a dosage form affording prolonged or sustained release.
  • Liquid forms may be prepared for oral administration or for administration by injection, the term including sub-cutaneous, transdermal, intravenous, intra ⁇ muscular intratechal, etc. administration.
  • the liquid compositions for oral administration may include aqueous solutions, flavoured syrups, aqueous or oil suspensions and the like.
  • the liquid compositions may also be prepared in the form of eye drops and as aerosols for intra- nasal and like administration. Preparations in ointment or cream base are also envisaged.
  • the active dose for humans would be determined by the attending physician in accordance with the disease to be treated or prevented, mode of administration, patient's age, sex, weight, counter indications and the like.
  • the invention further relates to a method of preventing and/or treating oxidative damage in a patient in need of such treatment by administering to said patient a therapeutically effective amount of at least one compound of formula I or of a pharmaceutical composition according to the invention.
  • the method of the invention may be particularly suitable for preventing and/or treating oxidative damage associated with inflammatory disorders such as rheumatoid arthritis, atherosclerosis, post-ischemic brain and muscle damage, traumatic shock, degenerative brain disease such as Parkinson's disease and Alzheimer's disease, skin disorders, septic shock, lung disease such as Adult Respiratory Distress Syndrome and emphysema, ionizing and non-ionizing radiation damage, particularly skin and eye damage, eye diseases such as cataract and retinopathy, malignant diseases and poisonings caused by xanobiotics which produce reactive oxygen species.
  • inflammatory disorders such as rheumatoid arthritis, atherosclerosis, post-ischemic brain and muscle damage, traumatic shock, degenerative brain disease such as Parkinson's disease and Alzheimer's disease, skin disorders, septic shock, lung disease such as Adult Respiratory Distress Syndrome and emphysema, ionizing and non-ionizing radiation damage, particularly skin and eye damage, eye diseases such as
  • the compounds of the invention may be used as antioxidative additives, preventing deterioration of various food, cosmetic and other chemical industrial product due to oxidative damage.
  • the invention further relates to an antioxidative additive comprising as active ingredient at least one compound of formula I in a suitable carrier or diluent. While only few compounds will be described in detail on hand oTthe following Examples, these are illustrative only and do not in any sense limit the invention, which is only defined by the scope of the appended claims.
  • the reaction mixture was incubated for lh at 37°C. Scavenging of hydroxyl radical was done by various concentrations of AMTP (compound C), and color was developed by reaction with thiobarbituric acid as described [Halliwell, B. et al., ibid.]
  • Chemiluminescence (CL) was measured in mixtures of H 2 0 2 , NTA- Fe2 + and HRP (Horseradish peroxidase) systems in a LUMAC/3M BIOCONTER M2010 connected to a linear recorder as described [Ginsburg, I. et al. (1993) Inflammation 17:227-243].
  • the scavenging of hydroxyl radicals was done by various concentrations of AMTP (compound C dissolved in reaction buffer).
  • Superoxide radicals were produced from reactions of xanthine/xanthine oxidase [Mccord, J.M. and Fridovich I. (1969) J. Biol. Chem. 244:6049-6055].
  • the enzyme unit was adjusted to produce a linear flux of superoxide radicals which gave a slope of 0.12OD/min at 550 nm. by reduction of cyt-C.
  • Various concentrations of AMTP (compound B) were added to protect the protein.
  • BAS 0.5mg/ml
  • HEPES buffer 1ml
  • AAPH 2,2'-azobis-(2- amidinopropane)-HCL
  • fluorescence was measured [Hazell, L. and Stocker, R. (1993) Biochem. J. 290:165-172].
  • the protein was dialyzed for 2h against 2x500 vol of HEPES buffer to remove free sodium hypochlorite.
  • 301 DTNB 0.015M in water was then added to the protein solution and color was measured at 420nm.
  • AMTPs were added to the protein sample to protect it against sodium hypochlorite [Hazell and Stocker, ibid.].
  • Lipid hydroperoxides were monitored by a modified micromolar sensitive spectroscopic method [Siddiqi, A.M. and Tappel, A.L. (1955) Chemist Analyst 44:52]. 50 ⁇ of lipids (liposomes or emulsion) were dissolved in 1ml ethanol. 50 ⁇ of 50%) potassium iodide solution were then added and the mixture was incubated for half an hour in the dark. The developed color was read in a spectrophotometer at 400 nm.
  • PMNs Human neutrophils
  • AMTP compound B
  • Radiolabeled cell monolayers were prepared by the addition of l O ⁇ Ci/ml of [51Cr]NaCr ⁇ 4 (New England Nuclear) to 100ml of trypsinized cells grown in 75-ml tissue culture bottles. The cells were then dispensed into 24-well tissue culture plates (Nunc, Roskilde, Denmark) and grown to confluency in a C0 2 incubator.
  • the toxicity of compound B was tested by injecting 75mg/kg, 150mg/kg, 300mg/kg, 500mg/kg, 700mg/kg and lOOOmg/kg i.p. to groups of eight Sabra mice.
  • the LD50 was found to be around 700mg/kg. No mortality was observed at doses up to 500mg/kg nor were there any significant changes in the average weight of the mice in comparison to a saline injected control group after monitoring of 30 days.
  • a repetitive i.p. injection of 75mg/kg/day which was conducted on eight mice over a period of two weeks did not lead to any mortality or weight differentiation compared to the control.
  • reaction rate constant of hydroxyl radicals with compound C was calculated from equation 1 and was found to be 1.5xl ⁇ " M ' ⁇ S " 1 * Equation 1 : A ' ⁇ Ao "1 ⁇ 1+K[S] x (KDR[DR]) _ 1 ⁇
  • Lipid peroxidation was measured after the initiation of hydroxyl radicals in 1% emulsions by Fe 2+ (l OO ⁇ M) vit C (lOO ⁇ M) and H 0 2 (ImM). After lh of incubation amounts of thiobarbituric reactive species were measured. AMTPs added at concentrations of lOmM inhibited the accumulation of thiobarbituric reactive species ( Figure 9). The more lipophilic the compound, the better it was in preventing peroxidation.
  • SUV Liposomes (12.5mM) with certain degrees of oxidation were incubated with 5mM AMTP molecules for period of 24h.
  • Peroxidation number (PN) was measured with potassium iodide in ethanol. AMTPs were able to decompose lipid hydroperoxide and to reduce the peroxidation number (PN).
  • Compound C was more efficient in the first few hours of the incubation time with the liposomes but after 24h the more lipophilic compounds of A and B were more effective in reducing PN ( Figure 10).
  • BSA's tryptophan oxidation and BSA's cystine oxidation were the models for protein damage by NaOCI ( Figure 1 1 and Figure 12 respectively).
  • BSA fluorescence intensity decreased following oxidative stress of NaOCI (1 mM).
  • AMTPs molecules showed strong protection of fluorescent amino acid residues on the protein (tryptophan and tyrosine).
  • A the most lipophilic
  • a and B the more lipophilic AMTP molecules protects the BSA lipophilic amino acid residues (tryptophan and cystine) by site specific defense mechanisms due to hydrophobic interaction with the protein and higher local concentration surrounding it.
  • Control 2 represents 1.5* 10" cells per 1ml HBSS activation of the cells by cationized streptococcus produced between 50,000-63,000 light units at the peak. 8mM of compound B reduced the light measurements to the base level of 3500 light units.
  • Fibroblasts in culture were exposed to a synergistic killing mechanism (streptolysin S in combination with an oxidant glucose oxidase) in a D-MEM culture medium that contained lmg/ml of glucose (about 0.5-lmM of H 2 0 2 was produced after 1 hour of o incubation at 37 C). This system caused about 60% chromium released within an hour.
  • Compounds B and C themselves did not show any toxic effects on the cell at concentrations of up to 20mM but were able to induce 50-60% protection against cell killing at concentrations up to lOmM (Figure 14).
  • Compound A was not soluble in the D-MEM medium at concentrations above 2 mM but showed a protection of 10%) at this concentration ( Figure 14).
  • the positive controls were DMTU and catalase.

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Abstract

L'invention traite d'un composé de la formule (I) dans laquelle X1 et X2 représentent chacun indépendamment un atome d'oxygène ou d'azote; p, m et n représentent chacun indépendamment un nombre entier d'une valeur d'au moins 2; R, R1 et R2 représentent indépendamment un atome d'hydrogène; un atome halogène; un radical alkyle, alcényle ou alcynile éventuellement substitué, à chaîne droite ou ramifié; un groupe R3O dans lequel R3 est un atome d'hydrogène, un radical alkyle, alcényle ou alcynile éventuellement substitué, à chaîne droite ou ramifié; un acyle éventuellement substitué ou un aryle ou un hétéroaryle éventuellement substitué; un groupe R4O(O)C dans lequel R4 est un atome d'hydrogène ou un radical alkyle, alcényle ou alcynile éventuellement substitué, à chaîne droite ou ramifié; un groupe -SR5 dans lequel R5 est un atome d'hydrogène ou un radical alkyle, alcényle ou alcynile éventuellement substitué, à chaîne droite ou ramifié; un groupe -NR6R7 dans lequel R6 et R7 représentent indépendamment un atome d'hydrogène, un radical alkyle, alcényle ou alcynile éventuellement substitué, à chaîne droite ou ramifié; un acyle éventuellement substitué ou un groupe d'ester phosphorique éventuellement substitué. Cette invention traite également des procédés de préparation de composés de la formule susmentionnée et de compositions pharmaceutiques les contenant.
PCT/US1995/015199 1994-11-28 1995-11-13 Derives de thionophosphate, procede de preparation et compositions pharmaceutiques les contenant WO1996016663A1 (fr)

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AU44081/96A AU4408196A (en) 1994-11-28 1995-11-13 Thionophosphate derivatives, process for their preparation and pharmaceutical compositions containing them
EP95942875A EP0813415A4 (fr) 1994-11-28 1995-11-13 Derives de thionophosphate, procede de preparation et compositions pharmaceutiques les contenant
US08/849,122 US6200962B1 (en) 1994-11-28 1995-11-13 Thionophosphate derivatives, process for their preparation and pharmaceutical compositions containing them

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IL11179794A IL111797A0 (en) 1994-11-28 1994-11-28 Thionophosphate derivatives, process for their preparation and pharmaceutical compositions containing them
IL111,797 1994-11-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8034769B2 (en) * 2000-10-20 2011-10-11 Hamburger Stiftung Zur Foerderung Von Wissenschaft Und Kultur Oxidized proteins and oxidized protein inhibitor compositions and methods of use thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3087955A (en) * 1960-02-08 1963-04-30 Dow Chemical Co O-haloalkyl o-alkyl phosphoramidothioates
US3251675A (en) * 1961-12-28 1966-05-17 Dow Chemical Co Method of inhibiting plant growth
US3337656A (en) * 1963-01-11 1967-08-22 Continental Oil Co N-(2-chloroalkyl)-phosphoramidothionates
US3531550A (en) * 1965-08-12 1970-09-29 Monsanto Co Phosphorus ester amides
US3597476A (en) * 1968-12-04 1971-08-03 Dow Chemical Co Process for preparing tris (2-mercaptoethylamino) phophine oxides and sulfides
US3702332A (en) * 1969-02-20 1972-11-07 Pechiney Progil Sa N-furfuryl-monophosphoryl ethylene diamines

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3670057A (en) * 1969-11-10 1972-06-13 Sumitomo Chemical Co S(alkllthio ethyl) phosphorothioamidate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3087955A (en) * 1960-02-08 1963-04-30 Dow Chemical Co O-haloalkyl o-alkyl phosphoramidothioates
US3251675A (en) * 1961-12-28 1966-05-17 Dow Chemical Co Method of inhibiting plant growth
US3337656A (en) * 1963-01-11 1967-08-22 Continental Oil Co N-(2-chloroalkyl)-phosphoramidothionates
US3531550A (en) * 1965-08-12 1970-09-29 Monsanto Co Phosphorus ester amides
US3597476A (en) * 1968-12-04 1971-08-03 Dow Chemical Co Process for preparing tris (2-mercaptoethylamino) phophine oxides and sulfides
US3702332A (en) * 1969-02-20 1972-11-07 Pechiney Progil Sa N-furfuryl-monophosphoryl ethylene diamines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0813415A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8034769B2 (en) * 2000-10-20 2011-10-11 Hamburger Stiftung Zur Foerderung Von Wissenschaft Und Kultur Oxidized proteins and oxidized protein inhibitor compositions and methods of use thereof

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CA2206374A1 (fr) 1996-06-06
EP0813415A4 (fr) 1998-05-06
AU4408196A (en) 1996-06-19
IL111797A0 (en) 1995-01-24
EP0813415A1 (fr) 1997-12-29

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