Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
  • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
  • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
  • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• the present invention relates to new therapeutically active compounds and salts and esters thereof as well as new intermediates.
• the 5 invention also relates to pharmaceutical compositions containing these compounds as active ingredients.
• the compounds of the invention have phospholamban inhibiting properties and are useful in the treatment of heart failure and stunned myocardium.
• Ri is hydrogen, alkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, halogenalkyl, alkoxy, COR-
• rjRl 1 where R 0 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, hydroxyalkyl, halogenalkyl, alkoxy or hydroxy and R- ⁇ 1 is hydrogen, 5 alkyl, aryl, arylalkyl, alkoxy, aryloxy, hydroxy or acyl, or in case where X is NR1 1 , can Ri also be carboxylalkyl,
• R6 is hydrogen, alkyl, alkenyl, aryl, arylalkyl
• R2 and R7 mean hydrogen, alkyl, aryl, arylalkyl, alkenyl, COR10, CONR10R11 , halogen, trifluoromethyl, nitro or cyano, where R10 and R11 are defined as above
• R3 is hydrogen, alkyl, aryl or arylalkyl
• A means alkyl or substituted alkyl
• m is 0-2 and n is 1-3
• Y means O, NR11 or S, where R11 is the same as above, X means O, NR11 or S, where R11 is the same as above, R4, R5, R8 and Rg mean independently one of the following groups:
• R4, R5, Rs and Rg also independently mean HOOC-, R12OOC-, H2NCO- or HOHNCO- wherein R-
• R2 is hydrogen
• R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C ⁇ -10 aryl. C7-12 arylalkyl, C1 -6 hydroxyalkyl, C1-6 halogenalkyl or C-
• Y is O or S, preferably O; and X is O.
• Y is O or S, preferably O; and X is NR11 , where R11 is hydrogen, C1 -6 alkyl, C6-10 aryl, C7-12 arylalkyl, C1 -6 alkoxy, C-6-10 aryloxy, hydroxy, C1-6 alkanoyl or C-
• R3 is hydrogen, C1 -6 alkyl, C6-10 aryl, or C7-12 arylalkyl, preferably C1 -6 alkyl, most preferably methyl.
• A is preferably straight-chain or branched C-
• compounds have formula (II) wherein R7 is hydrogen.
• R6 is hydrogen, C1-6 alkyl, C-6-10 aryl, C7-12 arylalkyl; and n is 1 , 2 or 3, preferably 1 or 2.
• Y is O or S, preferably O; and X is O.
• Y is O or S, preferably O; and X is NR11 , where R11 is hydrogen, C1 -6 alkyl, C-6-10 aryl, C7-12 arylalkyl, C1-6 alkoxy, C-6-10 aryloxy, hydroxy, C-
• A is preferably straight-chain or branched C1-4 alkylene.
• Each aryl residue in each of these preferred classes of compounds may be substituted by 1 to 3, preferably 1 or 2, most preferably one of fluorine, chlorine, bromine, iodine, trifluoromethyl, amino, C1 -4 alkyl, C1-4 alkoxy, phenyl, naphthyl, halophenyl, halonaphthyl, benzyl, phenethyl, halobenzyl, halophenethyl, naphthylmethyl, naphthylethyl, C4-7 cycloalkyl, C1 -4 alkyl (C4-7)cycloalkyl, hydroxy, mono- (Ci-4)alkylamino, di-(C-
• FIG. 1 A shows the effect of the compound of Example 1c (50 and 100 ⁇ M) on the Ca 2+ uptake rate into the cardiac muscle SR vesicles.
• FIG. 1 B shows the effect of the compound of Example 1c (50 and 100 ⁇ M) on the Ca 2+ uptake rate into the fast skeletal muscle SR vesicles.
• FIG. 2A shows the development of stunned myocardium and the subsequent decrease in the left ventricular systolic pressure.
• FIG. 2B shows the complete inhibition of the development of stunned myocardium by the compound of Example 8g.
• the compounds of the invention can be prepared from the 1 ,3- dihydroxy substituted heteroaromatics by alkylation of the dihydroxy compounds by suitable alkylating agents, for example by chloroacetonitrile or bromoacetic ester according to the following Scheme 1 , wherein R-
• the cyano compound (IV) described above is used to prepare the 1 ,2,4- oxadiazole and 1 ,2,4-thiadiazole derivatives using the methods described in J. Med. Chem. 1996, 39, 5228-5235.
• the dihydroxyaromatics (III) are made by use of the literature methods.
• the coumarins (XIV), (XVI) and (XX) are made by the use of the Knoevenagel condensation or von Pechmann reaction as presented in Scheme 3 and 4, where R-
• the quinolinones are prepared by the Knorr reaction as described in Scheme 5, wherein Ri , Ri 1 and R3 are the same as defined above, X is a halogen. SCHEME 5.
• the cyclic compounds (II) can be prepared correspondingly from compound (XXXI) which can be prepared according to the Scheme 6, wherein R2 and R6 are the same as defined above, R ' is a protecting group for the hydroxyls e.g. methyl, benzyl or tetrahydropyranyl.
• Cyclic quinolinone compounds (II) can be prepared correspondingly from (XXVI) using Scheme 5.
• Salts and esters of the compounds when applicable, may be prepared by known methods.
• Physiologically acceptable salts are useful as active medicaments, however, preferred are the salts with alkali or alkaline earth metals.
• Physiologically acceptable esters are also useful as active medicaments. Examples are the esters with aliphatic or aromatic alcohols.
• alkyl as employed herein by itself or as part of another group includes both straight, branched and cyclized chain radicals of up to 18 carbon atoms, preferably 1 to 8 carbon atoms, most preferably 1 to 4 carbon atoms.
• lower alkyl as employed herein by itself or as part of another group includes straight, branched and cyclized chain radicals of 1 to 7, preferably 1 to 4, most preferably 1 or 2 carbon atoms.
• Specific examples for the alkyl and lower alkyl residues, respectively, are methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, octyl, decyl and dodecyl including the various branched chain isomers thereof.
• acyl as employed herein by itself or as part of another group refers to an alkylcarbonyl or alkenylcarbonyl group, the alkyl and alkenyl groups being defined above.
• aryl as used herein by itself or as part of another group refers to a monocyclic or bicyclic group containing from 6 to 10 carbon atoms in the ring portion. Specific examples for aryl groups are phenyl, naphtyl and the like. "Aroyl” means in a corresponding way an arylcarbonyl group.
• alkoxy as employed herein by itself or as part of another group includes an alkyl group as defined above linked to an oxygen atom.
• Aryloxy means in a corresponding way an aryl group linked to an oxygen atom.
• substituted refers to halogen substituents, such as fluorine, chlorine, bromine, iodine or trifluoromethyl group, amino, alkyl, alkoxy, aryl, alkyl-aryl, halogen- aryl, cycloalkyl, alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, or aikylthio substituents.
• the "substituted” groups may contain 1 to 3, preferably 1 or 2, most preferably 1 of the above mentioned substituents.
• Compounds of the invention may be administered to a patient in therapeutically effective amounts which range usually from about 0.1 to 500 mg per day depending on the age, weight, condition of the patient, administration route and the phospholamban inhibitor used.
• the compounds of the invention can be formulated into dosage forms using the principles known in the art. It can be given to a patient as such or in combination with suitable pharmaceutical excipients in the form of tablets, dragees, capsules, suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art.
• compositions containing the active compound can be given enteraily or parenterally, the oral route being the preferred way.
• the contents of the active compound in the composition is from about 0.5 to 100 %, preferably from about 0.5 to about 20 %, per weight of the total composition.
• the inhibitory effect of a given compound on phospholamban can be demonstrated by measuring the effect of the compound on calcium uptake into the SR vesicles prepared from cardiac tissue and into SR vesicles prepared from fast skeletal muscle (psoas m.). Both kind of SR vesicles contain Ca 2+ -ATPase but the vesicles from the fast skeletal muscle do not contain phospholamban (Hoh JFY, "Muscle fiber types and function", Current Opinion in Rheumatology, 4:801 -808, 1992).
• Guinea pigs (10-12) were decapited. Their hearts or the psoas muscles were excised, washed in ice-cold 0.9 % NaCI and cut into pieces in a buffer containing 20 mM Tris-maleate, 0.3 M sucrose, pH 7.0. Thereafter tissue pieces were homogenized with Polytron and further with Potter (10 strokes). The homogenate was centrifugated at 1000 g for 15 min at 4 °C. The supernatant was collected and the pellet was resuspended into 5 ml of the buffer (20 mM Tris-maleate, 0.3 M sucrose, pH 7.0) and recentrifugated at 1000 g for 10 min at 4 °C.
• the obtained supernatant was combined with the earlier collected supernatant and centrifugated once again at 10 000 g for 20 min at 4 °C.
• the final supernatant was filtered into a bottle equipped with a magnetic stirrer. KCI was added to the filtered supernatant to achieve the final concentration of 0.6 M (at 4 °C).
• the obtained solution was centrifugated at 100 000 g for 60 min at 4 °C.
• the pellet was suspended in 5 ml of the buffer containing 20 mM Tris-maleate, 0.3 M sucrose, pH 7.0 and centrifugated at 100 000 g for 60 min at 4 °C.
• the obtained pellet was suspended in 5 ml of buffer containing 20 mM Tris-maleate, 0.3 M sucrose, 0.1 M KCI, pH 7.0 and stored at -80 °C until use.
• the protein concentration was also measured in order to standardise the separately prepared vesicle preparations.
• the fluorescent indicator, fluo-3 was used to detect the decrease of the extravesicular Ca 2+ -concentration, when the SR Ca 2+ ATPase was transferring Ca 2+ from the extravesicular space into the SR-vesicles.
• the SR-vesicles obtained above were pre- incubated with or without the test compound at 37 °C for 5 min in the assay buffer containing 40 mM imidazole, 95 mM KCI, 5 mM NaN3, 5 mM MgCI , 0.5 mM EGTA, 5 mM potassium oxalate, 2 ⁇ M ruthenium red, 5 ⁇ M fluo-3, pH 7.0.
• the free calcium was adjusted to 0.1 ⁇ M or to 0.04 ⁇ M by CaCl 2 .
• the reaction was initiated by adding ATP (5 mM).
• the final reaction volume was 1.5 ml.
• the fluorescence of reaction mixture was measured for 3 min by using the excitation and emission wavelengths of 510 nm and 530 nm, respectively.
• Figures 1A and 1 B show the effect of the compound of Example 1c (50 and 100 ⁇ M) on the Ca 2+ uptake rate into the cardiac (A) and fast skeletal muscle (B) SR vesicles. It can be seen that the compound of the invention accelerated the calcium uptake into the cardiac SR vesicles but did not change the calcium uptake into the SR vesicle prepared from the fast skeletal muscle.
• Table 1 shows the effects of various other phospholamban inhibitors of formula (I) or (II) on the Ca 2+ uptake rate into the cardiac (A) and fast skeletal muscle (B) SR vesicles.
• the experiments were carried out at 0.1 ⁇ M and 0.04 ⁇ M free calcium concentrations, respectively.
• Guinea-pigs of either sex weighing 300-400 g were used in the study. After the guinea-pig was sacrificed by a blow on the skull and decapitated the heart was rapidly excised. The heart was then rinsed in cold oxygenated perfusion buffer. A cannula was inserted into the aorta and secured with a ligature. Retrograde perfusion began as soon as the heart was placed in a thermostatically controlled moist chamber of the Langendorff apparatus. Modified Tyrode solution (37 °C), equilibrated in a thermostatically controlled bulb oxygenator with carbogen (95 % O2 and 5% CO2) was used as a perfusion buffer.
• Modified Tyrode solution 37 °C
• carbogen 95 % O2 and 5% CO2
• the composition of the Tyrode solution was (in mM): NaCI 135; MgCI 2 x 6H 2 O 1 ; KCI 5; CaCI 2 x 2H 2 O 2; NaHCO 3 15; Na 2 HPO 4 x 2H 2 0 1 ; glucose 10; pH 7.3-7.4.
• the experiments were carried out under constant pressure condition (50 mmHg). After a short prestabiiization (10 min) a latex balloon (size 4) was carefully placed into the left ventricle through the left pulmonary vein and the left atrium. The latex balloon was attached to a stainless-steel cannula coupled with a pressure transducer.
• the latex balloon, the cannula and the chamber of the pressure transducer were filled with ethylene glycol / water (1 :1) mixture avoiding any air-bubble.
• the isovolumetric left ventricular pressure was recorded through the pressure transducer.
• the volume of the balloon was adjusted to obtain a diastolic pressure of approximately 5 mmHg.
• the heart was allowed to stabilise further for 30 - 50 min with vehicle (0.1 % DMSO) in the perfusion buffer.
• Guinea-pigs of either sex weighing 300-400 g were used in the study. After the guinea-pig was sacrificed by a blow on the skull and decapitated the heart was rapidly excised. The heart was then rinsed in oxygenated perfusion buffer. A cannula was inserted into the aorta and secured with a ligature. Retrograde perfusion began as soon as the heart was placed in a thermostatically controlled moist chamber of the Langendorff apparatus. Modified Tyrode solution (37 °C), equilibrated in a thermostatically controlled bulb oxygenator with carbogen (95 % O 2 and 5% CO ) was used as a perfusion buffer.
• the composition of the Tyrode solution was (in mM): NaCI 135; MgCI 2 x 6H 2 O 1 ; KCI 5; CaCI 2 x 2H 2 O 2; NaHCO 3 15; Na 2 HPO 4 x 2H 2 0 1 ; glucose 10; pH 7.3-7.4.
• the experiments were carried out under constant pressure condition (50 mmHg). After a short prestabilization (10 min) a latex balloon attached through the stainless-steel cannula to a pressure transducer was carefully placed into the left ventricle through the left pulmonary vein and the left atrium.
• the latex balloon, the cannula and the chamber of the pressure transducer were filled with ethylene glycol / water (1 :1 ) mixture avoiding any air-bubble.
• the isovolumetric left ventricular pressure was recorded through the pressure transducer.
• the volume of the balloon was adjusted to obtain the end- diastolic pressure of approximately 5 mmHg.
• the spontaneously beating heart was allowed to stabilise further for 30 - 50 min with vehicle (0.1% DMSO) in the perfusion buffer.
• Example 8g 10 ⁇ M was added to the perfusion buffer.
• the heart was 15 min later exposed to the 8 minute period of global ischemia followed by reperfusion. This procedure was then repeated twice at 35 min intervals.
• Another series of experiments was performed with vehicle instead of compound of Example 8g.
• the vehicle concentration (0.1% DMSO) was kept constant throughout the experiments.
• the baseline value was the average of the two minute recordings obtained just before compound of Example 8g or vehicle was added to the perfusion buffer.
• the preischemia values were the average of the two minute recordings obtained just before each ischemia period and the reperfusion values were the average of the two minute recordings obtained at 8 min during each reperfusion period.
• Figures 2 A and B The results are shown in Figures 2 A and B.
• Figure 2A shows the development of stunned myocardium and the subsequent decrease in the left ventricular systolic pressure in the control group.
• Figure 2B shows that the phospholamban inhibitor of Example 8g completely inhibited the development of stunned myocardium. Givens are mean ⁇ SEM of 2-3 experiments.
• Triethylamine (1.94 ml) was added to a suspension of hydroxylamine hydrochloride (0.97 g) in DMSO (2 ml) and the resulting mixture stirred at room temperature for thirty minutes. The crystals were filtered and washed with THF. The filtrate was concentrated and the product from example 1 b (0.5 g) added. This solution was kept at 75 °C overnight. The reaction mixture was treated with ice water, the pH adjusted to 11 and the solids filtered, washed with water, and dried. Yield 0.5 g. Melting point: 155-160°C.
• Phloroglucinol (1 g) and ethyl 2-oxocyclohexane carboxylate (1.32 g) were stirred in 75 % sulfuric acid (10 ml) overnight, the mixture poured into ice water and filtered. Yield: 1.55 g.
• Example 6 Preparation of 7,8,9, 10-Tetrahydro-1 ,3-bis[(1 H-tetrazol-5- yl)methoxy]-8-phenyl-6H- dibenzo[b,d]pyran-6-one a) 7,8,9,10-Tetrahydro-1 ,3-dihydroxy-8-phenyl-6/--dibenzo[b,d]pyran-
• 3,5-Dimethoxyaniline (5 g) was added in portions to a preheated (160 °C) ethyl 2-benzyl acetoacetate (15 ml) under nitrogen and kept at that temperature for 60 minutes. The cooled solution was diluted with heptane- ethyl ether and filtered. Yield 5.2 g (49 %).

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Veterinary Medicine (AREA)
• Life Sciences & Earth Sciences (AREA)
• Cardiology (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Indole Compounds (AREA)
• Quinoline Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (7)

Publications (1)

Family

ID=27379660

Family Applications (1)

Country Status (18)

Families Citing this family (4)

Family Cites Families (6)

• 1998
  • 1998-09-24 HU HU0003647A patent/HUP0003647A3/hu unknown
  • 1998-09-24 JP JP2000512828A patent/JP2003525838A/ja active Pending
  • 1998-09-24 EP EP98946482A patent/EP1017691A1/de not_active Withdrawn
  • 1998-09-24 EA EA200000352A patent/EA003084B1/ru not_active IP Right Cessation
  • 1998-09-24 IL IL13466298A patent/IL134662A0/xx unknown
  • 1998-09-24 EE EEP200000179A patent/EE04494B1/xx not_active IP Right Cessation
  • 1998-09-24 ID IDW20000564A patent/ID24373A/id unknown
  • 1998-09-24 AU AU93508/98A patent/AU735729B2/en not_active Ceased
  • 1998-09-24 CN CNB98809438XA patent/CN1143857C/zh not_active Expired - Fee Related
  • 1998-09-24 NZ NZ503044A patent/NZ503044A/en unknown
  • 1998-09-24 CA CA002304849A patent/CA2304849A1/en not_active Abandoned
  • 1998-09-24 PL PL98339493A patent/PL339493A1/xx unknown
  • 1998-09-24 BR BR9813216-4A patent/BR9813216A/pt not_active IP Right Cessation
  • 1998-09-24 TR TR2000/00764T patent/TR200000764T2/xx unknown
  • 1998-09-24 WO PCT/FI1998/000755 patent/WO1999015523A1/en not_active Application Discontinuation
  • 1998-09-24 SK SK390-2000A patent/SK3902000A3/sk unknown
  • 1998-09-24 KR KR1020007003094A patent/KR20010015607A/ko not_active Application Discontinuation
• 2000
  • 2000-03-24 NO NO20001569A patent/NO20001569D0/no not_active Application Discontinuation

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events