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WO1998034609A1 - Produits cardioprotecteurs - Google Patents

Produits cardioprotecteurs Download PDF

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Publication number
WO1998034609A1
WO1998034609A1 PCT/HU1998/000003 HU9800003W WO9834609A1 WO 1998034609 A1 WO1998034609 A1 WO 1998034609A1 HU 9800003 W HU9800003 W HU 9800003W WO 9834609 A1 WO9834609 A1 WO 9834609A1
Authority
WO
WIPO (PCT)
Prior art keywords
groups
stands
general formula
nitroxide
alkylene
Prior art date
Application number
PCT/HU1998/000003
Other languages
English (en)
Inventor
László FRANK
Olga H. Hankovszky
Kálmán HIDEG
Original Assignee
Icn Hungary R.T.
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 Icn Hungary R.T. filed Critical Icn Hungary R.T.
Priority to AU57750/98A priority Critical patent/AU5775098A/en
Publication of WO1998034609A1 publication Critical patent/WO1998034609A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide

Definitions

  • Object of the present invention is a cardioprotective pharmaceutical containing nitroxides and/or hydroxyl amine derivatives and optionally along with these containing amine derivatives having an antiarrythmic activity as well as preparation and use of the pharmaceutical product.
  • R2 stands for an aryl - group , or a 5- or 6- membered hetero-aryl group , containing one or more nitrogen, oxigen and/or sulfur atoms whereby the said aryl or hetero-aryl groups are optionally substituted by halogen atoms, C [ ⁇ -n ) alkoxy groups, trifluoro-methyl groups or C ( 2-5 ) aliphatic acylamino groups,
  • R3 stands for a hydrogen atom or C ( ]__4 ) al yl group
  • - A stands for a single bond or a C ( 1-5 ) alkylene group optionally substituted by hydroxy groups or alkylene-thio- groups or alkylene- oxy- groups,
  • - R stands for a 5- or 6- membered aromatic or hetero-aromatic ring , optionally substituted by one or more hydroxy-, C ( ]__4 ) alkyl and/or C ( _4 ) alkoxy and/or methylene dioxy groups and/or halogen atom and where the alkyl groups can also be unsaturated,
  • R 1 stands for a C(i_ ) alkyl group
  • the object of the present invention is a cardioprotective pharmaceutical composition containing a nitroxide and/or hydroxyl amine derivative of the general formula II having a radical scavanger activity and optionally also containing an amine derivative of the general formula I .
  • a further object of the invention consists m the new chemical compounds of the general formula II as well as methods for their preparation.
  • a specific object of the present invention resides in the pharmaceutical combination having a cardioprotective activity and comprising as active ingredients an amine derivative of the general formula I together with the corresponding nitroxide and/or hydroxyl amine derivative of the general formula II and which is located on the place of action of the cardioprotective activity.
  • a further object of the present invention is the method of application of at least one of the compounds of the general formulae I and/or II as cardioprotective pharmaceuticals .
  • the basis of the present invention is the recognition according to which the most effective transformation metabolite of these compounds is a stable paramagnetic molecule. This finding was also shown by electronic spin resonance (ESR) spectrosopical measurements. The found ESR spectrum contained an isotrope triplette sign which indicates the presence of pyrroline- or pyrrolidme-N-oxyl groups. These compounds were reproduced by metal catalysed oxidation with hydrogen peroxideof the starting bioactive secondary amine basic molecules. The compounds thus obtained were of the same type and had the same chemical properties as the paramagnetic transformation products found in the course of metabolism.
  • ESR electronic spin resonance
  • the product prepared also in vi tro does not contain that part of the molecule of basical character which is characteristic for the pharmaceutical molecule having and influence on circulation. Thus it does not show the known characteristic electrophysiological parameters of the antiarrythmic compounds belonging to the activity class I.
  • the general toxicity of these products is generally several orders of magnitude less than the corresponding molecule before metabolism.
  • the compounds are oxidized into the toxic metabolits by way of scavangmg the reactive intermediates formed on the course of reactions catalysed by metalo enzymes.
  • the peroxides formed on the course of ischemia are transformed into radicals when undergoing a catalase type oxidation with the starting bioactive molecule. Therefore they reduce the effect of hydroxy- and alkoxy radicals appearing on the course of reperfusion causing further ischemical damage.
  • the sterically inhibited alicyclic antiarrythmic nitrogen heterocyclic compounds are molecules showing a combination of activities on the heart and whereby the following transformation procedure is generally characteristic.
  • Preferred compounds suitable to be used according to the invention having the general formula I and their physico chemical properties are shown in Table I and some compounds according to the general formula II and their physico chemical properties are shown in Table II.
  • the compounds according to the general formula I show an excellent antiarrythmic activity both m enteral and parenteral use. Their ventricular and auricular fibrillation activity is good, their therapeutic index favourable. The compounds reach their antiarrythi ical effect by way of their influence on the electro-physiological parameters of the heart.
  • the nitroxide- and/or hydroxyl amine derivatives of the general formula II - not used or proposed hetherto as pharmaceuticals - play their role m the compositions according to the invention m the first line as scavangers of radicals.
  • the corresponding amines of the general formula I having the same substituents they do not show any activity on the electro-physiological paramters of the heart: they do not change the action potential of the heart and do not raise the electric stimilus threshold of the myocardial cells, they do not prolongate the effective refractive period and do not dimmish the conductive velocity.
  • the nitroxide- and/or hydroxyl amine derivatives of the general formula II do not possess a direct antiarrythmic activity
  • Toxicity of the nitroxide- and/or hydroxyl amine derivatives of the general formula II is a magnitude less than the toxicity of molecules according to the general formula I.
  • the amines of the general formula I are oxidized m the organism into atoxic nitroxide- and/or hydroxyl amme derivatives of the general formula II thereby scavanging the reactive intermediates which are formed on the course of reactions catalysed by metalo-enzymes .
  • a further object of the present invention are pharmaceutical combinations containing the compounds of the general formulae I and II together.
  • This pharmaceutical combination may optionally be administered into the body already as a combination. It is a preferred embodyment of the invention to apply the combination by way of forming the combination n vivo m the organism: administering a member of the compound family of the general formula I into the organism - which is then transformed - carrying out its antiarrythmic effect - into a cardioprotective, radical-scavangmg nitroxid- and/or hydroxyl amine derivative of the general formula II thereby ensuring the presence of the latter in the necessary amount .
  • a medicament for control of cardial rythmic disturbances having a dualistic character which s theoretically new per se, not known m therapy.
  • the combination influences the electrophysiological parameters of the heart favourably and thus stops already manifested auricular and ventricular arrythmiae while exhibiting a protective effect by way of detoxificating the reactive oxigen intermediates when oxidizing the spherically inhibited amines.
  • N- [2- (2, 2 , 5, 5-tetramethyl-3- pyrroline-3-carbonyl) aminoethyl] -phthalimide is used as the compound of general formula I in order to show the process according to the invention, the new combination originated as well as its biological effect.
  • EPR spectra were recorded using a Varian E-109 spectrometer operating at X-band frequency equipped with a TE102 cavity.
  • the modulation frequency was 100 KHz.
  • 100 ⁇ L samples were loaded into Teflon tubing (15 cm long, 0.8 mm ID, 0.03 mm wall thickness) and the EPR spectra measured at 9.4 GHz resonant frequency, 10 mlW incident microwave power, 1 G modulation amplitude.
  • the height of the high field peak was plotted as a function of time irradiation to determine the rate of reaction of the nitroxides with carbon- centered radicals.
  • mice 12 to 20 weeks old, were anesthetized by inhalation of 1 - 3 % isoflurane in 30 % C>2 , 70 % N2O and maintained under anesthesia during the entire experiment.
  • the inhalation of the anesthetic was continuously monitored throughout the experiment.
  • a conical tube was used as the animal holder by cutting a hole in the conical end and cutting a window in the side through which intraperitoneal injections could be administered to the mouse under anesthesia with the tail positioned in the cavity (TE]_Q2) of the EPR spectrometer.
  • the mouse can be kept alive and anesthetized for several hours while the tail, secured in the plastic tube and inserted into the cavity of the EPR spectrometer and continuously monitored for free radicals continuously in a non-invasive manner in real time.
  • the EPR spectrometer though operating at X-band frequency can be tuned with the mouse tail in the cavity, presumably because of its relatively low water content compared to other tissues.
  • the microwave power was 10 mW.
  • the vase line were recorded before the injection of the drug.
  • the drugs were dissolved in phosphate buffered saline (PBS) at a concentration of 2.6 mg/ml. Because of its inherent low water solubility, (III) was first dissolved in volume 100 % ethanol, then diluted with PBS. All drugs were injected intra-peritoneally at a dose of 39 mg/kg body weight, while spectra were continuously recorded.
  • PBS phosphate buffered saline
  • Alkyl radical reactions with the test compounds were studied by exposing de-aerated aqueous solutions containing 3 % DMSO to gamma-rays at a dose rate of 110 Gy/min from a 60 Co source (Gamma Cell 220, Atomic Energy of Canada) for various time intervals.
  • Alkyl peroxy radicals were generated by temperature- induced homolytic cleavage of AAPH in an aerobic environment (25) .
  • test compounds I and II at 10 mM were exposed to 25 mM AAPH at 37 °C and the EPR signal intensity was monitored at different time intervals.
  • III a concentration of 100 ⁇ M was used, all other conditions being identical.
  • Superoxide radicals were produced by the aerobic hypoxanthine / xanthine oxidase (5mM/0.1 U/ml) reaction in phosphate buffered solutions (pH 7.4, 100 mM) .
  • Catalase and DETAPAC (100 ⁇ M) were included in the reaction to minimize any metal mediated oxidation reactions in the presence of H 2 0 2 .
  • Dissolved oxygen was measured using a Clark electrode based Gilson 5/6 oxigraph.
  • Deaerated phosphate buffer pH 7.4, 100 mM was injected into the chamber of the Clark electrode. As indicated, myoglobin and H2O2 were injected in the same sequence to achieve a final concentration of 10 ⁇ M and 1.0 mM, respectively. The basal evolution of oxygen was monitored and then the test compounds (I) or (II) or (III) were injected into the reaction mixture and oxygen evolution monitored.
  • Figure 1 shows the EPR spectrum obtained when the distal portion of the anesthetized mouse after the drug (39 mg/kg) was administered.
  • the three lined radical APR signal detected after l.p. injection of the anti- arrhythmic drug is characteristic of a nitroxide free radical based on the hyperfme coupling constant a ⁇ ( 1.6 ⁇ iT), which is the separation between two adjacent lines n the EPR spectrum.
  • a ⁇ 1.6 ⁇ iT
  • pyrrolme/pyrrolidme derivatives for anti-arrhythmic action is based on the lonizibal ty of the ammo group in the pH range 8-9, to mamtama proper proton gradient.
  • Alicyclic amines piperidme, pyrroline and pyrrolidme
  • piperidmes can undergo oxidation in microsomal incubations to the correspon-ding nitroxide free radical through mixed function amine oxidase pathways.
  • the m vivo oxidation of the amine to the nitroxide and its biologic consequences have not been considered so far.
  • the direct detection of the nitroxide lends strong support to the in vivo oxidation of the drug to the nitroxide and the role for the oxidation products to mediate further biologic roles.
  • EPR spectroscopic measurements on anaesthetized mice after administering I provided direct evidence for the conversion of the drug to the corresponding nitroxide free radical.
  • the hydroxylamine also was found to undergo oxidation relatively more efficiently.
  • the in vivo half life of the nitroxide was estimated and found to be longer than 1 hour and hence is expected to be n circulation for significant times.
  • the hydroxylammes were also tested for anti-arrhythmic effects and were found to be active, though relatively to a lesser extent than the secondary amines. Chemically, the amines and the hydroxylammes were found to be oxidized to the corresponding nitroxide using several model oxidation reactions.
  • nitroxides The in vivo fate of nitroxides has been determined and found that, in general, they are reduced by enzyme mediated pathways to the corresponding hydroxylammes.
  • the stability of nitroxides was found to be dependent on the ring size; five membered ring nitroxides (pyrrolidme, pyrroline) are in general more stable than the corresponding six-membered nitroxides.
  • the in vivo oxidation of the hyxdroxylammes can also readily occur. Consequently, once the anti-arrhythmic drug is oxidized to the nitroxide, a distribution between the nitroxide and the hydroxylamme is established in vivo and can mediate biologic effects .
  • the sterically hindered amine can be oxidized to the corresponding nitroxide in vivo and accumulate in the blood to provide anti-oxidant defense against free radical mediated injury as can occur in ischemia/reperfusion as well as against progressive oxidation which contributes to atherosclerosis .
  • the isolated left atrium and papillary muscle were electrically driven by rectangular electric impulses of 1 msec duration and 100/mm frequency. During the trials the following parameters were determined; electrical threshold and effective refractory period at stimulus intensity three times the threshold value. The test compound and control substances were directly added to the circulating nutrient solution.
  • the acute LD50 values of the test compounds were determined on CFLP mice weighing 18 - 22 g each, with the application of at least five doses, for each dose using 6 animals.
  • the test compounds were dissolved in a physiological salt solution and injected intravenously in the tail veins of animals. The observation period was 14 days.
  • the LD50 values were calculated with regression analysis. Table IB Effect on the Ventricular Electrical Fibrillation Threshold in the Cat Heart
  • Mexiletine 20 0.52 ⁇ 0.04 0.75 ⁇ 0.06** + 44 95 ⁇ 4 140 ⁇ 15
  • Drug Dose n Control value Change from control in per cent following mg/1 IwAJ 15 ' 30' 45 ' 60' n exposure to the drug c
  • Drug Dose Control value Change from control in per cent following mg/l /msec/ 30 ' 60 ' cn exposure to the drug c
  • Drug Dose n Control value Change from control in per cent following mg/1 /msec/ 30 ' 60 ' n exposure to the drug c
  • mice The ur ⁇ ne of untreated mice and that of mice treated with tnp pro ⁇ uct h-25.5 - N- .2- (2 , 2 , 5, 5-tetramethyl-3-pyrroline-3- carbonyl ) -ammo-ethyl] -pn ali ide - were collected for 16 hours ana tne ESR spectra of the urine were taken. The spectrum is encicse ⁇ as Figure 5.
  • Example 4 The ⁇ SI mass spectroscop cal comparison appearing in the plasma after administration of the oxyl derivative of formula II prepared synthetically from N- [2- (2, 2, 5, 5-tetramethyl-3- pyrrolme-3-carDonyl) -amir.o-etnyl ] -phtalimide (H-2954) and of tne metabolite (P-2) appearing in the plasma after administration of - [2- (2, 2, 5, 5-tetramethyl-3-pyrroline-3- carbonyl ) -ammo-ethyl ] -phtalimide are shown n Figures 6.A and 6.B.
  • Example 5 The HPLC chromatograms are compared and shown in Figure 4 with the curves A and B as appearing in the plasma after administration of the oxyl derivative of formula II prepared synthetically from N- [2- (2, 2 , 5, 5-tetramethyl-3-pyrroline-3- caroonyl) -ammo-ethyl] -phtalimide (H-2954) and of the metabolite (P-2) appearing m the plasma after administration of N- [2- (2, 2, 5, 5-tetramethyl-3-pyrroline-3-carbonyl) -amino- ethyl] -phtalimide .

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  • 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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention se rapporte à une composition pharmaceutique cardioprotectrice, à un procédé pour sa préparation et à un procédé de traitement antiarythmique et cardioprotecteur utilisant cette composition, qui contient un dérivé de D3-carboxamide-2,2,5,5-tétraméthylpyrroline ou de 2,2,5,5-tétraméthylpyrrolidine et/ou ses produits de N-oxydation, ayant des effets de piégeage des radicaux libres.
PCT/HU1998/000003 1997-02-10 1998-01-10 Produits cardioprotecteurs WO1998034609A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57750/98A AU5775098A (en) 1997-02-10 1998-01-10 Cardioprotective products

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9700392A HUP9700392A1 (hu) 1997-02-10 1997-02-10 Egy vagy két hatóanyagot tartalmazó kardioprotektív hatású gyógyszerkészítmények
HUP9700392 1997-02-10

Publications (1)

Publication Number Publication Date
WO1998034609A1 true WO1998034609A1 (fr) 1998-08-13

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PCT/HU1998/000003 WO1998034609A1 (fr) 1997-02-10 1998-01-10 Produits cardioprotecteurs

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AU (1) AU5775098A (fr)
HU (1) HUP9700392A1 (fr)
WO (1) WO1998034609A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103613A2 (fr) * 2007-02-22 2008-08-28 Othera Holding, Inc. Composés d'hydroxylamine et leurs procédés d'utilisation
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984002907A1 (fr) * 1983-01-21 1984-08-02 Alkaloida Vegyeszeti Gyar Nouveaux derives de diamines d'alcoyle
WO1984002906A1 (fr) * 1983-01-20 1984-08-02 Alkaloida Vegyeszeti Gyar Nouveaux aminoderives de 2- adn-(2,2,5,5-tetramethyle-3-pyrroline-3-carbonyle) bd
DD215538A5 (de) * 1984-01-20 1984-11-14 Alkaloida Vegyeszeti Gyar Verfahren zur herstellung von neuen carboxamiden
US5714510A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1984002906A1 (fr) * 1983-01-20 1984-08-02 Alkaloida Vegyeszeti Gyar Nouveaux aminoderives de 2- adn-(2,2,5,5-tetramethyle-3-pyrroline-3-carbonyle) bd
WO1984002907A1 (fr) * 1983-01-21 1984-08-02 Alkaloida Vegyeszeti Gyar Nouveaux derives de diamines d'alcoyle
DD215538A5 (de) * 1984-01-20 1984-11-14 Alkaloida Vegyeszeti Gyar Verfahren zur herstellung von neuen carboxamiden
US5714510A (en) * 1985-07-18 1998-02-03 Proctor; Peter H. Topical proxyl composition and method

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Title
HANKOVSZKY ET AL.: "New Antiarrhythmic Agents. 2,2,5,5,-tetramethyl-3-pyrroline-3-carboxamides and 2,2,5,5-tetramethylpyrrolidine-3-carboxamides", J. MED. CHEM., vol. 29, no. 7, 1986, pages 1138 - 1152, XP002068557 *
LANCRISCINA ET AL.: "A General Method for Phospholipid Polar Head Spin Labeling", ANALYTICAL BIOCHEMISTRY, vol. 76, no. 1, 1976, pages 292 - 299, XP002068559 *
MIHALY ET AL.: "Az A-2545 antiaritmias gyogyszerjelölt kemiajahoz I. Hidrolizisvizgalatok", ACTA PHARMACEUTICA HUNGARICA, vol. 67, no. 5, 1997, pages 175 - 178, XP002068560 *
SUBCHINSKY ET AL.: "Study of the Interaction Between Spin Probes and Membranes of Submitochondrial Particles", BIOFIZIKA, vol. 23, no. 1, 1978, pages 57 - 60, XP002068558 *
TWOMEY ET AL.: "DIRECT EVIDENCE FOR IN VIVO NITROXIDE FREE RADICAL PRODUCTION FROM A NEW ANTIARRHYTHMIC DRUG BY EPR SPECTROSCOPY", FREE RADICAL BIOL. MED., vol. 22, no. 5, 1997, pages 909 - 916, XP002068561 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008103613A2 (fr) * 2007-02-22 2008-08-28 Othera Holding, Inc. Composés d'hydroxylamine et leurs procédés d'utilisation
WO2008103613A3 (fr) * 2007-02-22 2009-07-30 Othera Holding Inc Composés d'hydroxylamine et leurs procédés d'utilisation
JP2010519259A (ja) * 2007-02-22 2010-06-03 オセラ ホールディングス、インク． ヒドロキシルアミン化合物およびそれらの使用方法
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation

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HU9700392D0 (en) 1997-03-28
HUP9700392A1 (hu) 1999-09-28
AU5775098A (en) 1998-08-26

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