WO2004050639A2 - Composes nitroso pour traiter l'ischemie - Google Patents

Composes nitroso pour traiter l'ischemie Download PDF

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Publication number
WO2004050639A2
WO2004050639A2 PCT/US2003/037341 US0337341W WO2004050639A2 WO 2004050639 A2 WO2004050639 A2 WO 2004050639A2 US 0337341 W US0337341 W US 0337341W WO 2004050639 A2 WO2004050639 A2 WO 2004050639A2
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WO
WIPO (PCT)
Prior art keywords
piperazinyl
nitroso
pyrimidinyl
alkyl
nitroso compound
Prior art date
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PCT/US2003/037341
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English (en)
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WO2004050639A3 (fr
Inventor
Edward J. Hessler
Harold A. Karnes
Luis H. Toledo
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Epcellon, Inc.
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.)
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Publication date
Application filed by Epcellon, Inc. filed Critical Epcellon, Inc.
Priority to AU2003291141A priority Critical patent/AU2003291141A1/en
Publication of WO2004050639A2 publication Critical patent/WO2004050639A2/fr
Publication of WO2004050639A3 publication Critical patent/WO2004050639A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the Physicians Desk Reference discloses metoprolol is a ⁇ -adrenergic agent useful in treating hypertension, angina pectoris and myocardial infarction.
  • the Physicians Desk Reference discloses carvediol is a ⁇ -adrenergic agent useful in treating hypertension and heart failure.
  • Ischemic diseases are diseases caused by a lack of blood supply and include coronary heart disease, stroke, hemorrhagic shock, peripheral vascular disease (of both the upper and lower extremities), abdominal vascular insufficiency and transplant related surgery. These diseases are the most frequent cause of morbidity and mortality in the industrialized countries. Interruption of blood supply results in ischemia, which activates leukocytes particularly neutrophils, as well as platelets, and rapidly damages metabolically active tissues. Without cooling of the organ, irreversible damage will occur within a matter of minutes depending on the organ type. Paradoxically, restoration of blood flow initiates a cascade of events that may lead to additional cell injury.
  • agents to treat these ischemic diseases include nitrites, nitrates, various non-steroidal anti-inflammatory derivative (NSAIDs) analgesics and agents to treat platelet effects.
  • NSAIDs non-steroidal anti-inflammatory derivative
  • agents to treat platelet effects include nitrites, nitrates, various non-steroidal anti-inflammatory derivative (NSAIDs) analgesics and agents to treat platelet effects.
  • none of these agents are completely effective, they do not fully prevent (transplant) or reduce (after an ischemic event) the damage caused by the ischemic event.
  • the compounds of the invention effectively treat these diseases.
  • nitric oxide given as sodium nitroprusside, demonstrated a protective effect in treating ischemic injury of the kidney in rats which had been subjected to 75 min of renal warm ischemia and contralateral nephrectomy.
  • nitric oxide is a free radical and a mediator of ischemia and reperfusion injury. Further, that nitric oxide is synthesized from the guanidino group of L-arginine by nitric oxide synthases and the nitric oxide synthesized produces organ damage. The authors also report that nitric oxide can act in a tissue-protective manner by scavenging oxygen-derived free radicals and other means. The authors report that there are three strategies to prevent ischemia and reperfusion injury which are, nitric oxide supplementation, antioxidant molecules and neutrophil-endothelial cell blockade.
  • nitric oxide supplementation a number of different approaches are reviewed. These include nitric oxide gas, nitric oxide dissolved in normal or physiological saline, nitric oxide in low concentrations, nitric oxide donors and administration of L-arginine. With regard to nitric oxide donors most were organic nitrates.
  • nitric oxide donors representing many different chemical classes have been tried in vivo. These include, organic nitrates such as glyceryl trinitrate, organic nitrites, diazenium diolates (NONOates) such as spermine NONOate, sydnonimines such as linsidomine and molsidomine, and nitrosothiols such as S-Nitrosoglutathione.
  • NONOates diazenium diolates
  • sydnonimines such as linsidomine and molsidomine
  • nitrosothiols such as S-Nitrosoglutathione.
  • Sodium nitroprusside contains a cyano group and therefore is toxic. Another disadvantage of sodium nitroprusside is that it has a toxic hypotensive effect. At present there are no agents that completely reverse the ischemic disease and are non-toxic. The compounds of the invention have neither a cyano group nor a toxic hypotensive effect as seen with the other compounds.
  • Circulation, 95(1), 83-9 reported on a study of 700 stable coronary patients scheduled for angioplasty.
  • the patients were treated with the nitric oxide donors linsidomine and molsidomine before the angioplasty.
  • Cardiovascular Res., 30(1), 87-96 (1995) reported on a study of a nitric oxide donor, molsidomine, in pigs with regard to smooth muscle proliferation following carotid angioplasty.
  • the authors found that exogenous nitric oxide inhibits smooth muscle cell proliferation following balloon angioplasty in pigs.
  • nitric oxide donors including linsidomine, molsidomine, isosorbide diniitrate, L-arginine, SPM-5185 (a cysteine containing nitric oxide donor), glyceryl trinitrate, SLN-1 (hepatic metabolite of molsidomine, available in systemic form as linsidomine), SNP a nitroprusside dianion consisting of a complex of ferrous ion with five cyanide ions, SNAP a nitrosothiol that directly releases nitric oxide slowly without prior biotransformation, DELTA-NO a diazenium diolate with a 20 hour half-life, and NO aspirins which is a new class nitric oxide donors attached to the aspirin molecule. Yet one of the authors' conclusions:
  • J. Clin. Invest., 96(6), 2630-8 (1995) reports on a study in rabbits using a protein adduct of nitric oxide with regard to inhibition of neointimal proliferation.
  • the nitric oxide adduct was S-nitrososerum albumin a naturally occurring adduct of nitric oxide which has a prolonged biological half-life.
  • the study investigated the effects of locally delivered S- nitroso-bovine serum albumin and a poly thiolated form of bovine serum albumin modified to include several S-nitrosothiol groups.
  • the authors found that local administration inhibited intimal proliferation and platelet deposition after vascular arterial balloon injury. They concluded that the strategy for local delivery of a long-lived nitric oxide adduct has potential for preventing restenosis after angioplasty.
  • HCT-1026 nitric oxide releasing moiety
  • nitric oxide-releasing non-steroidal anti- inflammatory and related nitric oxide-donating pharmaceuticals including nitroflurbiprofen, nitronaproxen, nitropednisolone, nitrofenac, nitrodiclofenac, nitroifuprofen, nitroindomethacin and others. They found that the slow release of nitric oxide from these compounds led to subtle changes in the profile of the pharmacological activity of the parent non-steroidal anti-inflammatory agent.
  • the parent compound of the nitric oxide of the present invention is known only as an intermediate in producing 21-aminosteroids.
  • NitroMed is a company which is trying to prepare nitric oxide pharmaceuticals which when taken in vivo release nitric oxide (NO). They have in development NO-aspirin, NO- diclofenac, NO-naproxen, NO-ketoprofen, NO-ibuprofen and S-NO-diclofenac. None of those compounds is similar to the piperazinyl pyrimidinyl nitroso compounds (H) of the present invention.
  • Nicox a French company, is also involved in developing nitric oxide releasing compounds by attaching nitric oxide onto existing pharmaceuticals.
  • These compounds include nitric oxide derivatives of aspirin, flurbiprofen, hydrocortisone, prednisolone, salbutamol, budesonide, ursodeoxycholic acid, sildenafil and sulindac. None of these compounds are similar to the compounds of this invention.
  • US Patent 6,255,277 discloses a method of preventing an adverse effect associated with the use of a medical device in a patient comprising introducing into the patient a medical device of which at least a portion comprises a nitric oxide adduct, wherein the nitric oxide adduct comprises an S-Nitroso-protein.
  • a method of treating a human who has an ischemic disease selected from the group consisting of coronary heart disease, stroke, hemorrhagic shock, peripheral vascular disease (upper and lower extremities) and transplant related injuries and who is in need of treatment which comprises administering to that human an anti-ischemic effective amount of a piperazinyl pyrimidinyl nitroso compound of formula (H)
  • Nitroso Compounds refers to the piperazinyl pyrimidinyl nitroso compounds (II), N- nitrosometoprolol (IV).
  • the "nitroso compounds” of the invention are prepared from known starting materials, or from compounds which can be readily be prepared from known compounds by those skilled in the art, by means known to those skilled in the art.
  • Ci-C ⁇ alkyl and where (SM)-R 2 . ⁇ and (SM)-R 2 . 2 are taken together with the attached nitrogen atom to form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1 -piperazinyl; where (SM)-R . ⁇ is -H and
  • Ci-C ⁇ alkyl and where (SMJ-ILu and (SM)-R 4 - 2 are taken together with the attached nitrogen atom to form a ring selected from the group consisting of: pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, 1 -piperazinyl.
  • the process is the standard method of producing N-nitroso compounds.
  • the starting material the piperazinyl pyrimidinyl compounds (I)
  • aqueous acid The nature of the aqueous acid is not important, hydrochloric, sulfuric and phosphoric are all operable.
  • Nitrite, N0 2 " in the form of an aqueous solution, preferably either sodium or potassium nitrite, is then added drop wise with stirring to the piperazinyl pyrimidinyl (I)-acid mixture. The mixture is then stirred for some additional time, from about 10 min to about 2 hr, usually about 0.5 to about 1 hr.
  • the reaction can be performed at room temperature (20- 25°), however, it is preferred to add the nitrite solution at about 40° and then stir at 20-25°.
  • the desired piperazinyl pyrimidinyl nitroso product (II) is obtained by extraction with an organic water immiscible solvent, such as ethyl acetate, as is know to those skilled in the art. While performing the extraction it is preferred to add a weak base such as bicarbonate or carbonate. A 5% solution of potassium bicarbonate works well.
  • piperazinyl pyrimidinyl compounds (I) can be nitrosated at the pyrimidinyl C-5 carbon and at a number of secondary amine positions
  • (SM)-R 2 _ ⁇ is -H
  • the group -N[(SM)-R 2 _ ⁇ ][(SM) ⁇ R 2 . 2 ] is -N(-H)(C ⁇ -C 6 alkyl)
  • the piperazinyl pyrimidinyl nitroso compound (II) can have one, two, three or four nitroso groups depending on the substitution of the piperazinyl pyrimidinyl starting compound (I). If one desires a piperazinyl pyrimidinyl nitroso compound (IT) with just one or two nitroso groups it is preferred that (SM)-R 2 . ⁇ and/or (SM ⁇ R ⁇ are not -H nor cyclized to form piperazinyl.
  • One way to control the number of nitroso groups piperazinyl pyrimidinyl nitroso compound (IT) is to control the number of secondary amine groups in the piperazmyl pyrimidinyl starting compound (I). It is easier to control the number of nitroso groups in the piperazinyl pyrimidinyl nitroso compound (II) by controlling the number of secondary amines in the piperazinyl pyrimidinyl starting compound (I) than by controlling the number of equivalents of sodium nitrite added.
  • the piperazinyl pyrimidinyl nitroso compounds (IT) and N-nitrosometoprolol (IV) are amines and as such form pharmaceutically acceptable salts with pharmaceutically acceptable acids.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline.
  • Pharmaceutically acceptable salts are preferred over the corresponding free bases since they produce compounds which are more water soluble, stable and or more crystalline.
  • Pharmaceutically acceptable salts are any salt which retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered.
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the preferred pharmaceutically acceptable salts include salts of the following acids acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate, camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic, estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic, hexamic, hexylresorcinoic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic, malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric, mucic, muconic, napsylic, nitric, oxalic, p-nitrome
  • the piperazinyl pyrimidinyl nitroso compounds (IT) and N-nitrosometoprolol (IV) and pharmaceutically acceptable salts thereof are given initially IV over a period of about 24 hr, preferably a dose every 8 hr for three doses. If needed, the administration can be continued IN. However, if the patient is able to tolerate oral administration, then the piperazinyl pyrimidinyl nitroso compounds (IT) and N-nitrosometoprolol (IN) can be administered orally.
  • the piperazinyl pyrimidinyl nitroso compounds (IT) and ⁇ - nitrosometoprolol (IN) and pharmaceutically acceptable salts are compounded into a sterile aqueous solution, with pH adjusted appropriately as is known to those skilled in the art.
  • the usual oral dosage forms of tablets, capsules, suspension, solution, emulsion are all useful.
  • the piperazinyl pyrimidinyl nitroso compounds (IT) and ⁇ - nitrosometoprolol (IN) and pharmaceutically acceptable salts thereof are compounded into known parenteral and oral dosage forms in the usual manner as is known to those skilled in the art.
  • the invention here is not the pharmaceutical dosage forms but rather the compounds themselves and the manner in which they are used.
  • the dose is from about 5 to about 100 mg/kg/dose (one to four doses daily), preferably from about 25 to about 50 mg/kg/dose.
  • the dose is from about 5 to about 50 mg /kg/dose; preferably from about 10 to about 20 mg/kg/dose.
  • one to four doses are given daily.
  • the piperazinyl pyrimidinyl nitroso compounds (II) and ⁇ -nitrosometoprolol (IN) and pharmaceutically acceptable salts thereof can be given preventively before the surgery.
  • the piperazinyl pyrimidinyl nitroso compounds (II) and ⁇ -nitrosometoprolol (IN) and pharmaceutically acceptable salts thereof are given starting about 48 hr before surgery and during the surgery.
  • the dose is the same as for treating an acute ischemic disease.
  • the exact dosage and frequency of administration depends on the particular piperazinyl pyrimidinyl nitroso compounds (H) and ⁇ -nitrosometoprolol (IN) used, the particular condition being treated, the severity of the condition being treated, the route of administration, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art.
  • the exact dosage and frequency of administration can be more accurately determined by measuring the blood level or concentration of the piperazinyl pyrimidinyl nitroso compounds (IT) and ⁇ -nitrosometoprolol (IN) in the patient's blood and/or the patients' response to the particular condition being treated.
  • Groups Ri and Rj would represent monovalent variable substituents if attached to the formula CH 3 -CH 2 -C(Ri)(Rj)H 2 .
  • variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis.
  • each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses.
  • both R; and R j are bonded to the preceding carbon atom.
  • any molecule with an established system of carbon atom numbering such as steroids
  • these carbon atoms are designated as , where "i" is the integer corresponding to the carbon atom number.
  • C 6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry.
  • Rg represents a variable substituent (either monovalent or bivalent) at the C ⁇ position.
  • the carbon atom content of variable substituents is indicated in one of two ways.
  • the first method uses a prefix to the entire name of the variable such as "C ⁇ -C 4 ", where both "1" and "4" are integers representing the minimum and maximum number of carbon atoms in the variable.
  • the prefix is separated from the variable by a space.
  • C ⁇ -C alkyl represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined.
  • C 2 -C 4 alkoxy- carbonyl describes a group CH 3 -(CH 2 ) n -0-CO- where n is zero, one or two.
  • the carbon atom content of only each portion of the definition is indicated separately by enclosing the " -C j " designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined.
  • this optional convention (C ⁇ -C 3 )alkoxycarbonyl has the same meaning as C 2 -C 4 alkoxycarbonyl because the "C ⁇ -C 3 " refers only to the carbon atom content of the alkoxy group.
  • C 2 -C 6 alkoxyalkyl and (C ⁇ -C 3 )alkoxy(C ⁇ -C 3 )alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms
  • the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
  • Metoprolol refers to l-[4-(2-methoxyethyl)phenoxy]-3-[(l-methylethyl)amino]-2- propanol.
  • Neitroso Compounds refers to the pyrimidinyl nitroso compounds (11) and N- ni rosometoprolol (TV).
  • Chromatography column and flash chromatography refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • NMR nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
  • the ratios of solvents used are volume/volume (v/v).
  • the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
  • 2,4-Di(l-pyrrolidinyl)-6-(l-piperazinyl)pyrimidine (I, 0.7 g, 0.0023 moles), 3- bromopropionic acid methyl ester (0.7 g), sodium iodide (0.1 g), acetonitrile (20 ml) and triethylamine (5 ml) are mixed and stirred at 20-25° for 2 hr. The mixture is then concentrated, ethyl acetate 50 ml are added. The mixture is extracted saline (2 x 100 ml). The mixture is dried and concentrated under reduced pressure to dryness. The solid is crystallized from ether/hexane to give the title compound.
  • N-Nitrosometoprolol (TV) l-[4-(2-Memoxyemyl)phenoxy]-3-[(l-methylemyl)amino]-2-propanol (111, 3.0 mmoles) is added to water (6 ml) and isopropanol (3.5 ml) and hydrochloric acid (0.42 ml). The mixture is stirred at 40°. A solution of sodium nitrite (765 mg) in water (4 ml) is added drop wise and the mixture stirred for 1 hr at 20-25°. Potassium bicarbonate (20%, 25 ml) is added and the mixture is extracted with ethyl acetate (3 x 25 ml).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (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

L'invention concerne des composés pipérazinyl pyrimidinyl nitroso de formule (II) et N-Nitrosométoprolol ainsi que des sels de ceux-ci, acceptables au plan pharmaceutiques, qui sont utiles dans le traitement d'une ou plusieurs des maladies ischémiques suivantes, à savoir la coronaropathie, l'attaque, le choc hémorragique, l'acrosyndrome (des extrémités inférieures et supérieures), l'insuffisance vasculaire abdominale et la chirurgie relative à la transplantation.
PCT/US2003/037341 2002-12-03 2003-11-21 Composes nitroso pour traiter l'ischemie WO2004050639A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003291141A AU2003291141A1 (en) 2002-12-03 2003-11-21 5-nitroso-6-piperazinyl-pyrimidine derivatives for treating ischemia

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43054502P 2002-12-03 2002-12-03
US60/430,545 2002-12-03

Publications (2)

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WO2004050639A2 true WO2004050639A2 (fr) 2004-06-17
WO2004050639A3 WO2004050639A3 (fr) 2004-12-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1997014685A1 (fr) * 1995-10-19 1997-04-24 Gyógyszerkutató Intézet Kft Derives de pyrimidine
WO2000037441A1 (fr) * 1998-12-18 2000-06-29 Centre National De La Recherche Scientifique (Cnrs) Derives de melatonine et medicament comprenant de tels derives
WO2002034705A2 (fr) * 2000-10-26 2002-05-02 Duke University Composes c-nitroso et utilisation associee

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0574906A2 (fr) * 1992-06-17 1993-12-22 Nisshin Flour Milling Co., Ltd. Dérivés de pipérazine et homopipérazine, compositions pharmaceutiques les contenant et procédé pour leur préparation
WO1997014685A1 (fr) * 1995-10-19 1997-04-24 Gyógyszerkutató Intézet Kft Derives de pyrimidine
WO2000037441A1 (fr) * 1998-12-18 2000-06-29 Centre National De La Recherche Scientifique (Cnrs) Derives de melatonine et medicament comprenant de tels derives
WO2002034705A2 (fr) * 2000-10-26 2002-05-02 Duke University Composes c-nitroso et utilisation associee

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
USKINA E V ET AL: "COMPARTATIVE ASSESSMENT OF ANTIOXIDANT SUBSTANCES ACTION ON THE STABILITY OF ERYTHROCYTES MEMBRANES IN ISCHEMIC HEART DISEASE PATIENTS (IN VITRO)" ISRAEL JOURNAL OF MEDICAL SCIENCES, ISRAEL MEDICAL ASSOCIATION, TEL AVIV, IL, vol. 32, no. 10, 1996, page 917, XP001030003 ISSN: 0021-2180 *

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AU2003291141A8 (en) 2004-06-23
WO2004050639A3 (fr) 2004-12-09

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