WO1994003169A1 - Melange d'un intercepteur de radicaux libres et d'un chelateur du fer utilise dans le traitement de la depranocytose - Google Patents

Melange d'un intercepteur de radicaux libres et d'un chelateur du fer utilise dans le traitement de la depranocytose Download PDF

Info

Publication number
WO1994003169A1
WO1994003169A1 PCT/GB1993/001626 GB9301626W WO9403169A1 WO 1994003169 A1 WO1994003169 A1 WO 1994003169A1 GB 9301626 W GB9301626 W GB 9301626W WO 9403169 A1 WO9403169 A1 WO 9403169A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxy
group
aliphatic
hydroxypyrid
mixture according
Prior art date
Application number
PCT/GB1993/001626
Other languages
English (en)
Inventor
Catherine Anne Rice-Evans
Original Assignee
British Technology Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by British Technology Group Limited filed Critical British Technology Group Limited
Priority to AU47197/93A priority Critical patent/AU4719793A/en
Publication of WO1994003169A1 publication Critical patent/WO1994003169A1/fr

Links

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

  • This invention is in the field of treatment of sickle cell disease and other conditions resulting from the modification of the normal red blood cell morphology. Description of the prior art
  • Sickle cell disease comprises a group of disorders resulting from a hereditary defect which causes a modification of the normal AA haemoglobin to haemoglobin of the SS, SC, SD or S ⁇ thal form and leads to a polymerisation of the haemoglobin when in the deoxy state to form a linear polymer of a sickle shape.
  • the sickle cells are less readily able to pass througji the capillaries resulting in repeated painful crises for the patients, leading to greater deoxygenation of red cells in neighbouring blood vessels and further sickling. Peroxidation of the membrane lipids and oxidative modification of the membrane proteins have also been reported for the sickle erythrocyte.
  • non-haem iron-containing compounds in membrane preparations from sickle erythrocytes poses the possibility that such compounds may play a catalytic role in the processes leading to membrane oxidation.
  • the non-haem iron retained by sickle erythrocyte membranes has been suggested to comprise both iron contained within ferritin and an unidentified component able to catalyse the breakdown of lipid hydroperoxides.
  • Studies indicate that the non-haem iron-containing compounds are associated with the membrane cytoskeleton and possibly also with polar lipid headgroups on the cytoplasmic face of the membrane. Moore et al_.
  • N-acetylcysteine is a compound reported to be a scavenger of hydroxyl and ferrylmyoglobin radical species. It has been found that this compound is able to penetrate the membrane of erythrocytes and is highly effective as an antioxidant in sickle erythrocytes, modulating oxidative stress and attenuating oxidative damage.
  • the present invention comprises a mixture of a free radical scavenger containing a thiol group and a membrane-permeable iron chelator.
  • the preferred thiol-containing free radical scavengers of the current invention have the general formula (I) below
  • R' in which R is hydrogen, a group CH3(CH ) n c 0 in which n is 0 or 1, or a group HS(CH2)m C0 i n which m is 1 or 2 and R 1 is hydrogen or a mercaptomethyl , methyl or ethyl group with the proviso that the compound of formula (I) contains a single SH group, the compound optionally being in the form of a physiologically acceptable salt.
  • Preferred compounds are those in which R is other than hydrogen and/or R' is hydrogen or mercaptomethyl.
  • cysteine (R is H, R' is a mercaptomethyl group)
  • N-mercaptoacetylglycine R is HSCH2CO, R 1 is H
  • N-mercaptopropionylglycine R is HSCH 2 CH2C0, R' is H
  • N-acetylcysteine R is CH3CO, R 1 is a mercaptomethyl group
  • NAC N-acetylcysteine
  • MPG 2-mercaptopropionylglycine
  • non-haem iron-containing compounds in membrane preparations from sickle erythrocytes poses the possibility that such compounds may play a catalytic role in the processes leading to membrane oxidation.
  • the non-haem iron retained by sickle erythrocyte membranes has been suggested to comprise both iron contained within ferritin and an unidentified component able to catalyse the breakdown of lipid hydroperoxides.
  • Studies indicate that the non-haem iron-containing compounds are associated with the membrane cytoskeleton and possibly also with polar lipid headgroups on the cytoplas ic face of the membrane.
  • Suitable iron chelators for incorporation into the mixture of the invention are hydroxypyridone compounds.
  • Hydroxypyridone chelators may take various forms as described, for example in UK Patents 2118176B, 2136807B, 2146990B and 2146989B, and in their equivalents, for example US Patents 4840958, 4585780, 4587240, 4666927 and 4912118, the disclosure of all of which is incorporated herein.
  • Preferred hydroxypyridone chelators are:
  • a 3-hydroxypyrid-2-one or 3-hydroxypyrid-4-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, cycloalkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic acyl, alkoxy, cycloalkoxy, aliphatic amide, aliphatic ester, halogen or hydroxy group, by an aliphatic hydrocarbon group, or by an aliphatic hydrocarbon group substituted by an alkoxy, cycloalkoxy, aliphatic ester, halogen or hydroxy group, or a physiologically acceptable salt thereof;
  • Hydroxypyridone compounds of types (1), (2) and (3) are described in detail in UK patents GB 2118176B and 2136807B; GB 2146990B; and GB 2146989B, respectively, which relate to the use of such compounds for the removal of toxic amounts of metal from the body, and the various preferred and specific types of compound described in these patents may be used in the present invention. Certain compounds of types (2) and (3) are also described in U.S. Patent 4,698,431, the disclosure of which is incorporated herein.
  • the size of the aliphatic hydrocarbon and alkyl or cycloalkyl moieties in such groups is conveniently in a range of C-j_8, particularly C ⁇ _6, for example C ⁇ —4, such as methyl and ethyl.
  • C-j_8 particularly C ⁇ _6, for example C ⁇ —4, such as methyl and ethyl.
  • C ⁇ _6 for example C ⁇ —4, such as methyl and ethyl.
  • the aliphatic hydrocarbon groups are conveniently of 1 to 6 carbon atoms, especially 1 to 4 and more especially 1 to 3 carbon atoms, when these groups are not themselves substituted.
  • Acyclic rather than cyclic groups are preferred, as are saturated rather than unsaturated groups, the preferred unsubstituted aliphatic hydrocarbon groups and those in the aliphatic amide groups being the alkyl groups ethyl and particularly methyl.
  • the substituted aliphatic hydrocarbon groups are conveniently of 1 to 6 carbon atoms, preferably of 1 to 4 carbon atoms, especially of 1 , 2 or 3 carbon atoms.
  • the preferred substituted aliphatic hydrocarbon groups being substituted methyl, ethyl, isopropyl and n-propyl groups, the three latter alkyl groups conveniently being substituted terminally.
  • Alkoxy groups are preferred to cycloalkoxy groups and the former are conveniently of 1 to 6 carbon atoms, preferably of 1 to 4 carbon atoms and especially of 1 or 2 carbon atoms.
  • Aliphatic amide groups conveniently contain no more than one aliphatic hydrocarbon group which may, for example, be ethyl or especially methyl .
  • substituted aliphatic hydrocarbon group substituents are hydroxymethyl , 2-hydroxyethyl , 3-hydroxypropyl , methoxymethyl , 2-methoxyethyl , 3-methoxypropyl , 2-methoxy-l- methylethyl, ethoxymethyl , 2-ethoxyethyl , 3-ethoxypropyl , and
  • a first preferred group of compounds consists of single ring 3-hydroxypyrid-4-ones in which the carbon atoms of the ring each separately are either unsubstituted or are substituted by an aliphatic hydrocarbon group, for example as described above, conveniently at the 6 or more preferably at the 2 position.
  • aliphatic hydrocarbon group as used herein includes both acyclic and cyclic groups which may be unsaturated or more preferably saturated, the acyclic groups having a branched or more preferably a straight chain.
  • Groups of 1 to 6 carbon atoms, particularly of 1 to 4 and more particularly of 1 to 3 carbon atoms are of more interest.
  • the nitrogen atom is preferably substituted either by an aliphatic hydrogen group, particularly a methyl or ethyl group or by a hydroxy-substituted or more particularly an alkoxy, for example methoxy or ethoxy, substituted aliphatic hydrocarbon group of 1 to 6 carbon atoms, particularly an ethyl, propyl or isopropyl group substituted at the 2- or 3-position (as appropriate).
  • an aliphatic hydrogen group particularly a methyl or ethyl group or by a hydroxy-substituted or more particularly an alkoxy, for example methoxy or ethoxy, substituted aliphatic hydrocarbon group of 1 to 6 carbon atoms, particularly an ethyl, propyl or isopropyl group substituted at the 2- or 3-position (as appropriate).
  • 3-hydroxy-l-(2'-hydroxyethyl)- 2-methylpyrid-4-one and 3-hydroxy-l-(2'-hydroxy-l '-methylethyl)-2- methylpyrid-4-one and salts thereof are particularly preferred.
  • analogues of the compounds described above in which the methyl group at the 2-position is replaced by an ethyl group and salts thereof a preferred group of compounds again being those in which the hydrogen atom attached to the nitrogen atom is replaced by a hydroxy-substituted or alkoxy-substituted aliphatic hydrocarbon group, for example 3-hydroxy-l-(2-hydroxyethyl)-2-ethylpyrid-4-one and 3-hydroxy-l-(2-hydroxy-l '-methylethyl)-2-ethylpyrid-4-one.
  • the particularly preferred compounds are those hydroxypyridones of type (1) in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms, particularly that at the 2-position, are replaced by an aliphatic hydrocarbon group, particularly 1 ,2-diethyl-3-hydroxypyrid-4-one and its salts.
  • a second preferred group of compounds consists of single ring l-hydroxypyrid-2-ones in which the carbon atoms of the ring are substituted, conveniently at the 6- or 4-position by an alkoxy, alkoxyalkoxy or aliphatic amide substituent.
  • Specific examples of such compounds are l-hydroxy-4-(2'-methoxyethoxy)-pyrid-2-one, l-hydroxy-4-(2'-ethoxyethoxy)-pyrid-2-one, and 6-carbamoyl-l- hydroxypyrid-2-one and its 6-(N-methylcarbamoyl) and 6-(N-ethylcarbamoyl) analogues, and salts thereof.
  • a third preferred group of compounds, of poly(hydroxypyridone) compounds consists of compounds containing three 3-hydroxypyrid-2- or -4-one rings in which the carbon and nitrogen atoms of the rings are either unsubstituted apart from linking groups or are substituted by an aliphatic hydrocarbon group, for example as described above, particularly at the 6-, or especially at the 2-position in the case of the 4-ones.
  • a fourth preferred group, of poly(hydroxypyridone) compounds consists of compounds containing three l-hydroxypyrid-2-one rings in which the carbon atoms of the rings are either unsubstituted apart from linking groups or are substituted by an aliphatic hydrocarbon group or an aliphatic amide group, for example as described above, particularly at the 6- or 4-position.
  • Linkage of the rings through the carbon atoms thereof or particularly through the nitrogen atoms thereof for the 3-hydroxypyridones is conveniently effected by linking groups which are of an aliphatic hydrocarbon nature or which additionally contain one or more groups
  • the hydroxypyridones may be prepared by procedures described in the earlier patents referred to hereinbefore.
  • the C-carbamoyl and C-alkylated-carbamoyl 1-hydroxypyridones may be prepared as described in US Patent 4,698,431 and the N-alkoxyalkyl and N-hydroxyalkyl 3-hydroxypyrid-4-one compounds may be prepared as described in UK patent GB 2136807B.
  • This latter route involves reaction of a corresponding 3-hydroxy-4-pyrone, or a 3-hydroxy-4- pyrone containing groups convertible to the C-substituents present in the desired hydroxypyridone, with a compound R'NI.2 in which R' represents the group present on the nitrogen atom of the desired compound or a group convertible thereto, the reaction being carried out in the presence of a base, for example an alkali metal hydroxide such as sodium hydroxide.
  • a base for example an alkali metal hydroxide such as sodium hydroxide.
  • salts may be formed between the anion produced by the loss of the hydroxy group proton and a cation such as an alkali metal ion, for example Na + , quaternary ammonium ions or protonated amines such as tris
  • a cation such as an alkali metal ion, for example Na + , quaternary ammonium ions or protonated amines such as tris
  • the nitrogen atom of a 3-hydroxypyridone ring may be sufficiently basic, particularly in the case of the 3-hydroxypyrid-4-ones, for salt formation to be effected through reaction with an acid such as hydrochloric acid.
  • the proportion of membrane-permeable iron chelator, for example a hydroxypyridone compound, to the thiol-containing free radical scavenger may vary.
  • a ratio by weight of the hydroxypyridone or other chelator.thiol-containing compound is from 5:1 to 0.2:1, particularly from 3:1 to 0.5:1, for example 1:1, is often-suitable (when salts of iron chelators are used similar ratios apply but based upon the amount of the compound in the salt).
  • more than one hydroxypyridone compound may be used, for example both a single ring bidentate compound and a three ring hexadentate compound, the proportions given then applying to the total of hydroxypyridone compounds, and more than one thiol- containing compound may be used in the mixture.
  • the mixture may consist only of the iron chelator, for example the hydroxypyridone(s) and the thiol-containing compound(s), but in many other instances the mixture may contain other ingredients.
  • a mixture of a free radical scavenger containing a thiol group and a membrane-permeable iron chelator in therapy.
  • the use of the mixture of thiol-containing free radical scavenger and a membrane-permeable iron chelator is preventative, i.e. administered to the patient before a pain crisis occurs, but may be curative, i.e. administered during or after the occurrence of pain crises.
  • the thiol-containing free radical scavenger may, if desired, be used in the form of a physiologically acceptable salt, particularly one formed with a physiologically acceptable base.
  • suitable bases are the alkali metal hydroxides, for example sodium hydroxide, quaternary ammonium hydroxides and amines such as tris (tris representing 2-amino-2-hydroxymethyl propane 1 ,3-diol) .
  • the mixture of thiol-containing free radical scavenger and the membrane-permeable iron chelator may be administered to the recipient by a route selected from oral, parenteral (including subcutaneous, intrader al, intramuscular and intravenous) and rectal.
  • Particular compositions are those in an orally digestible or sterile injectable form including forms suitable for delayed release.
  • Solid forms include powders, tablets, granules, capsules, sachets and suppositories.
  • Liquid forms include solutions, suspensions and emulsions.
  • the formulation may be administered in unit dosage form, or in multiple unit dosage form to provide the desired therapeutic effects.
  • the present invention finds particular use in the treatment of patients suffering from sickle cell anaemia or other blood disorder characterised by a change in normal red blood cell morphology and/or oxidative damage of red blood cells which comprises administering to a patient in need thereof a therapeutically effective dosage of a mixture of a free radical scavenger containing a thiol group and a membrane-permeable iron chelator.
  • This effective amount may vary depending on a number of factors including the physical status of the patient and the type of blood disorder and the severity thereof involved.
  • a further formulation of the mixture of thiol-containing free radical scavenger and a membrane-permeable iron chelator according to the invention is a form suitable for the extra-corporeal treatment of blood from the patient.
  • such treatment may be conducted in a batch-wise manner by removing an appropriate volume of blood, admixing it with the compound and transfusing the treated blood back into the patient.
  • the treatment may be on a continuous basis, analogous to the well-known techniques for haemodialysis, whereby for a period of time blood is continuously withdrawn, admixed with the compound and passed back into the patient. Both procedures should be conducted under sterile conditions and may be repeated as often as necessary.
  • an effective blood concentration of thiol-containing free radical scavenger will generally be in the range 2 to 20 mg/kg, preferably in the range 4 to 15 and most preferably in the range 5 to 10 mg/kg with an optimum concentration of 8 mg/kg.
  • the present invention therefore further includes a pharmaceutical composition which comprises a mixture of a free radical scavenger containing a thiol group and an iron chelator, preferably a hydroxypyridone compound, for example as described hereinbefore, together with a physiologically acceptable diluent or carrier.
  • 'Avicel' microcrystalline cellulose 38 polyvinylpyrrolidone 3 alginic acid 6 magnesium stearate 3
  • the micronised mixture is mixed with 'Avicel' and polyvinylpyrrolidone is added, dissolved in sufficient industrial methylated spirits (74° OP) to produce a mass suitable for granulating.
  • the mass is granulated through a 20 mesh sieve and the resultant granules are dried at a temperature not exceeding 50°C.
  • the dried granules are passed through a 20 mesh sieve and the alginic acid and magnesium stearate are then added and mixed with the granules.
  • the product is compressed into tablets each weighing 300 mg on 3/8 inch flat bevelled edge divided punches.
  • N-acetylcysteine and 1 ,2-diethyl-3-hydroxypyrid-4-one mixture (1:1 w/w; micronised) 250 'Avicel' (microcrystalline cellulose) 134 polyvinylpyrrolidone 4 alginic acid 8 magnesium stearate 4
  • the tablets are prepared by essentially the same procedure as described in (A) and are compressed at a tablet weight of 400 mg on 7/16 inch flat bevelled edge punches.
  • N-acetylcysteine and 1 ,2-diethyl-3-hydroxypyrid-4-one mixture (1:1 w/w; micronised) 250 lactose (300 mesh) 19 maize starch 15 gelatine 10 magnesium stearate 6
  • the micronised mixture is mixed with lactose and half the total quantity of maize starch required, and a 5% solution of gelatine in water is added to the mass.
  • the product is granulated through a 16 ⁇ mesh sieve, and the resultant granules are dried to constant weight at a temperature not exceeding 50°C.
  • the dried granules are passed through a 20 mesh sieve and mixed with magnesium stearate and the remainder of the maize starch.
  • the product is compressed at a 300 mg tablet weight on 3/8 inch flat bevelled edge divided punches.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Des intercepteurs de radicaux libres contenant un groupe thiol présentent une efficacité dans le traitement de la dépranocytose et autres troubles du sang caractérisés par une modification de la morphologie normale des érythrocytes et/ou par une altération oxydative des érythrocytes, les composés étant utilisés en combinaison avec un chélateur du fer perméable à la membrane.
PCT/GB1993/001626 1992-08-04 1993-08-02 Melange d'un intercepteur de radicaux libres et d'un chelateur du fer utilise dans le traitement de la depranocytose WO1994003169A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47197/93A AU4719793A (en) 1992-08-04 1993-08-02 Mixture of a free radical scavenger and an iron chelator for the treatment of sickle cell disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929216506A GB9216506D0 (en) 1992-08-04 1992-08-04 Improvements in or relating to the treatment of sickle cell disease
GB9216506.7 1992-08-04

Publications (1)

Publication Number Publication Date
WO1994003169A1 true WO1994003169A1 (fr) 1994-02-17

Family

ID=10719768

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/001626 WO1994003169A1 (fr) 1992-08-04 1993-08-02 Melange d'un intercepteur de radicaux libres et d'un chelateur du fer utilise dans le traitement de la depranocytose

Country Status (4)

Country Link
AU (1) AU4719793A (fr)
GB (2) GB9216506D0 (fr)
WO (1) WO1994003169A1 (fr)
ZA (1) ZA935647B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0768302A2 (fr) * 1995-09-29 1997-04-16 Novartis AG Hydroxypyridinones
US6087398A (en) * 1996-03-01 2000-07-11 South Alabama Medical Science Foundation Sickle cell anemia treatment
WO2000064421A2 (fr) * 1999-04-21 2000-11-02 Zambon Group S.P.A. Utilisation de la n-acetylcysteine pour la preparation d'un medicament a administrer par voie intraveineuse pour prevenir le stress oxydatif chez les patients sous dialyse
CN102190644A (zh) * 2011-03-31 2011-09-21 浙江大学 手性3-羟基吡啶-4-酮类衍生物及其合成和用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10160796A1 (de) * 2001-12-11 2003-06-26 Wulf Droege Verwendung einer Cystein-haltigen Substanz zur Steigerung der Atmungsaktivität und Erythropoetin-Produktion
WO2010045220A1 (fr) 2008-10-14 2010-04-22 Edison Pharmaceuticals, Inc. Traitement d'affections liées au stress oxydatif, notamment de la néphropathie aux produits de contraste, des radiolésions et des perturbations de la fonction des globules rouges
EP3960168A1 (fr) * 2020-08-28 2022-03-02 Université de Genève Compositions et procédés comprenant de la d-cystéine ou un de ses dérivés

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Blood, vol. 79, no. 5, 1 March 1992, R.B. MOORE et al.: "Increased susceptibility of the sickle cell membrane Ca2+ + Mg2+ -ATPase tp t-butylhydroxyperoxyde: protective effects of ascorbate and desferal", pages 1334-1341, see abstract *
The Biochemical Journal, vol. 237, no. 1, 1 July 1986 (London, GB), C. RICE-EVANS et al.: "Sickle cell membranes and oxidative damage", pages 265-270, see abstract *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0768302A2 (fr) * 1995-09-29 1997-04-16 Novartis AG Hydroxypyridinones
EP0768302A3 (fr) * 1995-09-29 1998-02-25 Novartis AG Hydroxypyridinones
US6087398A (en) * 1996-03-01 2000-07-11 South Alabama Medical Science Foundation Sickle cell anemia treatment
WO2000064421A2 (fr) * 1999-04-21 2000-11-02 Zambon Group S.P.A. Utilisation de la n-acetylcysteine pour la preparation d'un medicament a administrer par voie intraveineuse pour prevenir le stress oxydatif chez les patients sous dialyse
WO2000064421A3 (fr) * 1999-04-21 2001-10-11 Zambon Spa Utilisation de la n-acetylcysteine pour la preparation d'un medicament a administrer par voie intraveineuse pour prevenir le stress oxydatif chez les patients sous dialyse
US6627659B1 (en) 1999-04-21 2003-09-30 Zambon Group S.P.A. Methods of decreasing the effects of oxidative stress using N-acetylcysteine
AU771390B2 (en) * 1999-04-21 2004-03-18 Zambon S.P.A. Use of N-acetylcysteine for the preparation of a medicament suitable for the intravenous administration to prevent oxidative stress in dialysed patients
CN102190644A (zh) * 2011-03-31 2011-09-21 浙江大学 手性3-羟基吡啶-4-酮类衍生物及其合成和用途
WO2012129942A1 (fr) * 2011-03-31 2012-10-04 浙江大学 Dérivé chiral de 3-hydroxypyrid-4-one et synthèse et utilisation de celui-ci
CN102190644B (zh) * 2011-03-31 2012-11-21 浙江大学 手性3-羟基吡啶-4-酮类衍生物及其合成和用途
EP2692724A1 (fr) * 2011-03-31 2014-02-05 Zhejiang University Dérivé chiral de 3-hydroxypyrid-4-one et synthèse et utilisation de celui-ci
EP2692724A4 (fr) * 2011-03-31 2014-08-27 Univ Zhejiang Dérivé chiral de 3-hydroxypyrid-4-one et synthèse et utilisation de celui-ci

Also Published As

Publication number Publication date
ZA935647B (en) 1995-02-06
GB2269748A (en) 1994-02-23
AU4719793A (en) 1994-03-03
GB9316004D0 (en) 1993-09-15
GB9216506D0 (en) 1992-09-16

Similar Documents

Publication Publication Date Title
KR950005866B1 (ko) Edrf 효능 또는 그 생성을 차단하는 쇽 치료용 약제
CA1161362A (fr) Composes pharmaceutiques contenant un corticosteroide
CA2053277C (fr) Utilisation de la lipoxine a4 et de ses derives comme antagonistes des substances a reaction differee de l'anaphylaxie (s.r.s.a.)
WO2001028568A1 (fr) Traitements fondes sur le fait que la synthase d'oxyde nitrique est une diaphorase du paraquat
EP0668760A1 (fr) UTILISATION D'UN TAMPON DE CALCIUM A PERMEATION DE MEMBRANE CELLULAIRE POUR REDUIRE DES LESIONS DE CELLULES DE MAMMIFERE $i(IN VIVO)
WO1994003169A1 (fr) Melange d'un intercepteur de radicaux libres et d'un chelateur du fer utilise dans le traitement de la depranocytose
DE2900203A1 (de) Krebshemmendes und krebsmetastasen verhinderndes arzneimittel
DE69911350T2 (de) Vorbeugung und behandlung einer durch einen immunschwächevirus ausgelösten infektion
EP0542807B1 (fr) Utilisation de 2-phenyl-1,2-benzisoselenazol-3(2h)-one
US5276044A (en) Leukotriene receptor antagonist and antihistamine complex pharmaceutical compositions
JPH06500537A (ja) アテローム硬化症の治療のためのアリールヒドロキシ尿素化合物の使用
US5534523A (en) Anti-aids virus composition
CA2207943A1 (fr) Agent therapeutique pour les maladies articulaires
US4271191A (en) Method of treating hyperuricemia and gout
US4923877A (en) Composition and method for treating glaucoma
US4895874A (en) Tumor treatment process and composition
JP2900580B2 (ja) 活性酸素障害防御剤
Pierson et al. Modulation by taurine of the toxicity of taumustine, a compound with antitumor activity
SE451070B (sv) Anvendning av ett karbostyrilderivat for framstellning av ett lekemedel for behandling av glaukom
WO1992020332A1 (fr) Composition pharmaceutique comprenant de la purpurogalline utilisee comme agent cytoprotecteur et antioxydant
CA1307740C (fr) Preparation pharmaceutique et methode permettant d'inhiber la replication du htlv-iii (sida)
EP0038060B1 (fr) Composition pharmaceutique contenant du L-alpha méthyl-dihydroxy-3,4 phénylalanine et du salicylamide pour le traitement de l'hypertension
WO1992004026A1 (fr) Utilisation de 4-hydroxyphenyl-thioethers pour stimuler la production de superoxyde
DE2844534C2 (fr)
US5461072A (en) Use of aryl hydroxyurea compounds for the treatment of atherosclerosis

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase