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  • C07D405/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• R x represents an alkyl group
• V represents a hydrogen atom or a linear or branched alkyl group, cycloalkyl, cycloalkylmethyl, phenylalkyl optionally substituted on the phenyl ring, carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally monosubstituted or disubstituted on nitrogen
• W represents a carboxymethyl group, alkoxycarbonylmethyl optionally monosubstitutes or disubstitutes on nitrogen, a cyclic group having from 4 to 7 vertices and optionally containing an oxygen or sulfur atom, a pyridin-2-ylmethyl group, a pyridin-3-ylmethyl group, a pyridin group 4-ylmethyl, an 1-methylpyrrol-2-ylmethyl group, a furan-2-ylmethyl group, a thien-2-ylmethyl group or a 1, 3-thiazol-2-ylmethyl group, or alternatively
• V and W together form, and with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl or 1,2,3,4-tetrahydroisoquinoline group.
• the compounds of the invention more particularly correspond to one of the general formulas (IA), (IB), (IC) and (ID)
• R x represents a hydrogen atom or a linear or branched (C 2 -C 4 ) alkyl group, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkylmethyl or phenyl ( ⁇ 3 ) alkyl optionally substituted on the phenyl ring,
• R 2 represents a hydrogen atom or a (C 1 -C 4 ) linear or branched alkyl group, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkylmethyl or phenyl (C 1 -C 3 ) alkyl optionally substituted on the phenyl ring
• R 3 represents a hydroxy group or (C- L -C) alkoxy or a group of general formula NR 4 R 5 in which R and R 5 , independently of one another, each represent a hydrogen atom, a (C- L -C ⁇ linear or branched alkyl group, a (C 3 -C 5 ) cycloalkyl group or a (C 3 -C 6 ) cycloalkylmethyl group.
• the compounds of general formula (IA) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; they may also exist in the form of free bases or of addition salts with acids.
• the compounds of general formula (IA) can be prepared by various methods described below.
• the amide of formula (IIA) is subjected to a dealkylation in the presence of sodium sulfide, in a polar aprotic solvent, for example N-methylpyrrolidone, at a temperature of 100 to 150 ° C, to obtain the amide of formula (IIIA), according to a method described in J. Am. Chem. Soc. (1976) 98 3237.
• a polar aprotic solvent for example N-methylpyrrolidone
• the latter is then hydrolyzed in a basic medium, for example sodium hydroxide, in a protic solvent, for example water or an aliphatic alcohol, at a temperature of 25 to 100 ° C., to obtain the corresponding primary amine, then it is treated the latter either with an aldehyde of general formula
• R 6 -CH0 in which R 6 is the lower homolog of group R 2 , in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, under reductive amination conditions known to man of career, to obtain an amine of general formula (VA).
• a reducing agent such as sodium borohydride or sodium cyanoborohydride
• the amine of general formula (VA) is then reacted with ethyl bromoacetate, to obtain a compound of general formula (IA) in which R 1 and R 2 represent an alkyl, cycloalkyl, cycloalkylalkyl or phenylalkyl group and R 3 represents an ethoxy group.
• the compound thus obtained can then be saponified to transform it into the corresponding acid, or it can be reacted with an amine of general formula HNR 4 R 5 , in which R 4 and R 5 are such as defined above, to transform it into an amide.
• the conditions for these reactions are conventional and are well known to those skilled in the art.
• the amines of general formula (VA) can be prepared in which R x represents a cyclopropylmethyl group and R 2 represents an alkyl or phenylalkyl group either by reduction of the corresponding alkanamides, described in patent application EP-461958, or by hydrolysis into primary amine of said alkanamides, then by treatment of these amines under N-monoalkylation conditions. All these reactions are carried out according to methods well known to those skilled in the art.
• a compound of general formula (IA) can be prepared in which R 1 represents a hydrogen atom by demethylation, using sodium sulphide in N, N-dimethylformamide, of the corresponding compound, in the formula of which R represents a methyl group, described in patent application FR-2742152.
• the dash "-” is part of the name, and the dash “_” is only used for breaking at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.
• Example IA Compound No. 2A.
• 0.23 ml (2.6 mmol) of cyclopropylmethanamine, 20 ml of dioxane and 0.36 ml of triethylamine are introduced into a 250 ml flask, a solution of 0.21 ml (2, 6 mmol) of chloroacetyl chloride in 5 ml of dioxane, and the mixture is stirred at room temperature for 8 h. 30 ml of water, 1 g of potassium carbonate and 1.0 g (2.7 mmol) of 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] - N-ethyl - 1, 3-dioxane are added.
• Example 2A (Compound ⁇ ° 3A). N-Cyclopropyl -2 - [[3- [5- [6- (cyclopropylmethoxy) naphthalen-1- yl] -1, 3-dioxan-2-yl] propyl] ethylamino] acetamide.
• aqueous phase is concentrated under reduced pressure, the residue is taken up with ethanol, which again provides 1.22 g of white solid, ie a total of 1.92 g of compound which is used as it is in the next step.
• 0.69 g (1.87 mmol) of 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] -N-ethyl - 1,3-dioxane-2-propanamine in solution is introduced into a 100 ml flask. 20 ml of acetonitrile, 0.37 g (2.77 mmol) of 2-chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate, and the mixture is heated at 70 ° C. for 4 hours.
• Example 3A (Compound No. 17A). 2- [[3- [5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1, 3-dioxan-2- yl] propyl] methylamino] -N- (cyclopropylmethyl) acetamide.
• the solvent is evaporated under reduced pressure, the residue is taken up in toluene and it is evaporated under reduced pressure, and the residue is dried.
• 0.24 ml (2.81 mmol) of cyclopropanemethanamine, 20 ml of dioxane, and 0.4 ml of triethylamine are introduced into a 250 ml flask, and a solution of 0.22 ml is added dropwise ( 2.81 mmol) of chloroacetyl chloride) in 10 ml of dioxane, and the mixture is stirred at room temperature for 9 h. 30 ml of water, 1 g of potassium carbonate and 1 g (2.81 mmol) of 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] -N- methyl-1,3-dioxane-2 are added.
• Example 4A (Compound ⁇ ° 19A).
• the organic phases are combined, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate.
• the solvent is filtered and evaporated under reduced pressure, and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol.
• 4.5 g (13.7 mmol) of N- [3- [5- (6-hydroxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] are introduced into a 250 ml flask acetamide dissolved in 70 ml of N, N-dimethylformamide, 2.8 g of potassium carbonate and 1.53 ml (20.5 mmol) of bromoethane, and the mixture is stirred at room temperature overnight.
• the hydrochloride is prepared from a 0.1N solution of hydrochloric acid in propan-2-ol. Melting point: 180-183 ° C.
• the solvent is evaporated off under reduced pressure, the white residue is taken up with water and ethyl acetate, the organic phase is washed twice with water and once with ethyl acetate, dried over magnesium sulfate, filtered, the solvent is evaporated off under reduced pressure, and the residual oil is purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol.
• the mixture is allowed to cool, water and ethyl acetate are added, the organic phase is separated, the aqueous phase is extracted once more, the organic phase is washed twice with water and once with a saturated aqueous solution of sodium chloride, it is dried over magnesium sulphate, it is filtered, the solvent is evaporated under reduced pressure, and the residue is purified by chromatography on a column of silica gel, eluting with a 99 / 1 of dichloromethane and methanol.
• Example 5A (Compound No. 20A). 2- [[3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] _ (phenylmethyl) amino] -N-methylacetamide.
• the solvent is evaporated off under reduced pressure, and
• Example 6A (Compound No. 23A). 2- [[3- [5- [6- (Cyclopentyloxy) naphthalen-1-yl] -1, 3-dioxan-2yl] propyl] (phenylmethyl) amino] acetamide.
• N- [3- [5- [(6-Phenylmethoxy) naphthalen-1-yl] -1, 3-dioxan-2-yl] propyl] acetamide From 4.2 g (12.75 mmol) of N- [3- [5- (6-hydroxy_ naphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] acetamide and 1.82 ml (15.3 mmol) of (bromomethyl) benzene, and operating under conditions analogous to those described in Example 4A.2, 4.67 g of product are obtained, of which 0.3 g is recrystallized from a mixture 6 / 4 ethanol and water, to obtain 0.15 g of white solid. Melting point: 138-140 ° C.
• cC 3 H 5 represents a cyclopropyl group
• cC 5 H 9 represents a cyclopentyl group
• C 6 H 5 represents a phenyl group.
• R represents either a hydrogen atom or a group of general formula CH 2 C0Y in which Y represents a hydroxy group or a (C 1 -C 4 ) alkoxy group, or also a group of general formula C ⁇ CONR ⁇ in wherein R x and R 2 , independently of each other, each represent a hydrogen atom or a (C- L -C, ⁇ ) alkyl group,
• X represents an oxygen or sulfur atom or a CH 2 group
• m represents 0 or 1
• n 0, 1 or 2.
• the compounds of general formula (IB) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; on the other hand, certain compounds, due to the chirality of the cycle linked to the nitrogen atom, can exist in the form of diastereoisomers and / or enantiomers. They can also exist in the form of free bases or of addition salts with acids.
• the compounds of general formula (IB) can be prepared by a process illustrated by scheme B which follows.
• the 2- (6-methoxynaphthalen-1-yl) propane-1, 3-diol of formula (IIB) is reacted with 4, 4-diethoxybutanamine of formula (IIIB) at reflux of a non-protic solvent such as toluene and in the presence of dry hydrochloric acid in solution in diethyl ether as catalyst to obtain 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-propanamine of formula (IVB), then reacts the latter with a ketone of general formula (VB), in which X, m and n are as defined above, in the presence of a reducing agent such as sodium borohydride or any other equivalent agent, in the medium neutral or acid, under reducing amination conditions well known to those skilled in the art.
• a compound of general formula (IBa) is obtained which corresponds to the general formula (IB) when
• the compound of general formula (IBb) can then be reacted with an amine of general formula HNR X R 2 , in which R x and R 2 are as defined above, to obtain an amide of general formula (IBc).
• the conditions for this reaction are conventional and are well known to those skilled in the art.
• An amide of general formula (IBc) can also be obtained directly from a compound of general formula (IBa) by alkylation with a halide of general formula Z-CH 2 -CO-NR- L R 2 , in which Z represents a chlorine or bromine atom and R ⁇ and R 2 are as defined above, in a polar aprotic solvent, for example N, N-dimethylformamide, in the presence of a base, for example of potassium carbonate.
• a polar aprotic solvent for example N, N-dimethylformamide
• the mixture is cooled, 2 g of sodium borohydride are added, the mixture is stirred for 1 h, 100 ml of water are added, the mixture is extracted four times with 75 ml of ethyl acetate, the solvent is evaporated under pressure reduced and the residue is dried under reduced pressure.
• hydrochloride is prepared using 5 ml of a 0.1 M solution of hydrochloric acid in propan-2-ol. After washing with diisopropyl ether and drying, 0.08 g of hydrochloride is obtained. Melting point: 172-173 ° C.
• HCl means a hydrochloride; the acid: base molar ratio is indicated in parentheses.
• R- L represents either a hydrogen atom or a group of general formula CH 2 C0Y in which Y represents a hydroxy group or a (C 1 -C 4 ) alkoxy group, or also a group of general formula CH 2 CONR 4 R 5 in which R 4 and R 5 , independently of each other, each represent a hydrogen atom or a (C 1 -C 4 ) alkyl group, and
• R 2 represents a pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, an l-methylpyrrol-2-yl group, a furan-2-yl group, a thien-2 group -yle or a group 1, 3-thiazol-2-yl, the respective formulas of which are as follows:
• the compounds of general formula (IC) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; they may also exist in the form of free bases or of addition salts with acids.
• a compound of general formula (ICa) is obtained which corresponds to the general formula (IC) when R represents a hydrogen atom.
• the latter can be saponified under conditions well known to those skilled in the art to obtain a compound of general formula (ICb) in which Y represents a hydroxy group.
• the general formula (ICb) corresponds to the general formula (IC) when R x represents a group of general formula CH 2 C0Y.
• the compound of general formula (ICb) can then be reacted with an amine of general formula HNR 4 R 5 , in which R 4 and R 5 are as defined above, to obtain an amide of general formula (ICc).
• the conditions for this reaction are conventional and are well known to those skilled in the art.
• An amide of general formula (ICc) can also be obtained directly from a compound of general formula (ICa) by alkylation using a halide of general formula Z-CH 2 -CO-NR 4 R 5 , in which Z represents a chlorine or bromine atom and R 4 and R 5 are as defined above in an aprotic polar solvent, for example N, N-dimethylformamide, in the presence of a base, for example potassium carbonate.
• aprotic polar solvent for example N, N-dimethylformamide
• the general formula (ICc) corresponds to the general formula (IC) when R x represents a group of general formula CH 2 CONR 4 R 5
• Example 2C (Compound No. 3C). 2- [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (pyridin-4-ylmethyl) amino] acetamide dihydrochloride
• the mixture is allowed to cool, 140 ml of water are added and the mixture is extracted with four times 50 ml of ethyl acetate. After evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol, and 0.3 g of pure base is obtained.
• the base is salified by means of 8 ml of 0.1 N solution of hydrochloric acid in propan-2-ol. After washing with ethyl acetate and drying, 0.17 g of dihydrochloride is obtained.
• Example 3C (Compound No. 19C). 5- (6-methoxynaphthalen-1-yl) -N- (thiazol-2-ylmethyl) -1,3-dioxan-2-propanamine hydrochloride.
• the methanol is evaporated under reduced pressure, the residue is taken up with water and ethyl acetate, the organic phase is separated, washed and dried over magnesium sulfate, and the solvent is evaporated off reduced pressure.
• C 5 H 4 N-2- represents a pyridin-2-yl group
• C 5 H 4 N-3- represents a pyridin-3-yl group
• C 5 H 4 N-4- represents a pyridin-4-yl group
• CH 3 -lC 4 H 3 N-2- represents a l-methylpyrrol-2-yl group
• C 4 H 3 0-2- represents a furan-2-yl group
• C 4 H 3 S-2- represents a thien-2-yl group
• C 3 H 2 NS-2- represents a 1, 3-thiazol-2-yl group.
• Y represents a hydroxy group, a (C 1 -C 4 ) alkoxy group, or a group of general formula NR 4 R 5 in which R 4 and R 5 , independently of one another, each represent an atom of hydrogen or a (C 1 -C 4 ) alkyl group, and
• R- L and R 2 form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine cycle, a piperidine cycle or a 1,2,3,4-tetrahydroisoquinoline cycle.
• the compounds of general formula (ID) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; moreover, and because of the asymmetric carbon atom in ⁇ of the group -C (0) Y, they can exist in the form of pure enantiomers or mixtures of enantiomers. They can also exist in the form of free bases or of addition salts with acids.
• the 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol of formula (IID) is reacted with 2- (3-chloropropyl) -1, 3-dioxolane of formula (IIID), in the medium acid and in an aprotic solvent, to obtain 2- (3-chloropropyl) -5- (6-methoxynaphthalen-1-yl) -1, 3-dioxolane of formula (IVD), and finally the latter is reacted with a amine of general formula (VD), in which Y, R and R 2 are as defined above, in the presence of an organic or inorganic base, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature from 20 to 110 ° C.
• aprotic solvent for example N, N-dimethylformamide
• Example 2D (Compound N ° 2D). 1- [3- [5- (6-Methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] -L- prolinamide.
• Example 3D (Compound ⁇ ° 6D). 2- [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] -N-methyl oxalate - 1,2,3,4-tetrahydroisoquinoline-3-carbox_ amide.
• the compounds according to the invention have been the subject of pharmacological tests which have demonstrated their interest as therapeutic substances.
• the entry of calcium caused by a depolarizing stimulus into the cortical synaptosomes of the rat can be measured using a fluorescent probe, according to the method described by A. Deffois et al. in Neurosciences Letters (1996) 220 117-120.
• a sodium channel agonist such as veratridine (10 ⁇ M)
• IC 50 concentration inhibiting the response by 50%
• the results are expressed by the DA 50 , a dose which protects 50% of the animals, calculated according to the method of JT Lichtfield and F. Wilcoxon [J. Pharm. Exp. Ther. , 96, 99-113 (1949)), using the Probit TM software, from 3 or 4 doses each administered to a group of 8 mice.
• the DA 50 of the most active compounds range from 1 to 10 mg / kg.
• the compounds were subjected to the global cerebral ischemia test in mice.
• the ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride.
• the "survival time” that is to say the interval between the time of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system.
• Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.
• Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention.
• the results are given in the form of the difference between the survival time measured in a group of 10 mice having received the compound and the survival time measured in a group of 10 mice having received the carrier liquid.
• the relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.
• This curve allows the calculation of the "effective dose 3 seconds" (DE 3 .J, that is to say the dose (in mg / kg) which produces a 3 second increase in survival time compared to the control group. of 10 untreated mice. An increase in survival time of 3 seconds is both statistically significant and reproducible.
• the ED 3 habof the most active compounds of the invention are of the order of 0.05 to 0.2 mg / kg intravenously.
• the antinociceptive activity is evaluated in the rat, during the second phase of a formal test adapted from the work of Tjolsen A., Berge O.-G., Hunskaar S., Rosland J. H. and
• Formalin (5%) is injected subcutaneously (100 ⁇ l) into the arch of the left hind paw.
• the nociception is quantified, after injection, by the measurement, for the injected paw, of the total duration of licks, between +20 and +35 min, and by the number of tremors, measured by sequences of 2 min, every 5 min , between +35 and +60 min.
• the compounds are administered at doses of 30 and 60 mg / kg, in suspension (water + 1% Tween 80), orally (5 ml / kg), 30 min before the formalin injection.
• the activity threshold for the compounds of the invention corresponds to reductions of 35 to 40%. The most active compounds cause a reduction of 50% at a dose of 30 mg / kg orally.
• the results of the tests show that the compounds according to the invention have neuroprotective properties, and that they can therefore be used for the preparation of medicaments useful in the treatment or prevention of cerebrovascular disorders of ischemic or hypoxic origin (infarction). cerebral, cranial or medullary trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia), glaucoma, progressive neurodegenerative diseases (senile dementias such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.) and in the prevention of ischemic strokes associated with cardiac and vascular surgery and endovascular therapy.
• the compounds of the invention can be presented in all forms of pharmaceutical compositions suitable for enteral or parenteral administration, such as tablets, dragees, capsules, suspensions or oral or injectable solutions such as syrups, ampoules, etc., associated with suitable excipients, and dosed to allow daily administration of 1 to 1000 mg of active substance.

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• 1998
  • 1998-06-03 CN CN98807817A patent/CN1265658A/zh active Pending
  • 1998-06-03 AU AU80251/98A patent/AU8025198A/en not_active Abandoned
  • 1998-06-03 PL PL98337234A patent/PL337234A1/xx unknown
  • 1998-06-03 EE EEP199900560A patent/EE9900560A/xx unknown
  • 1998-06-03 KR KR1019997011436A patent/KR20010013435A/ko not_active Application Discontinuation
  • 1998-06-03 JP JP50172399A patent/JP2002502412A/ja active Pending
  • 1998-06-03 IL IL13324298A patent/IL133242A0/xx unknown
  • 1998-06-03 TR TR1999/03022T patent/TR199903022T2/xx unknown
  • 1998-06-03 AR ARP980102585A patent/AR012908A1/es unknown
  • 1998-06-03 BR BR9810742-9A patent/BR9810742A/pt not_active IP Right Cessation
  • 1998-06-03 SK SK1661-99A patent/SK166199A3/sk unknown
  • 1998-06-03 EP EP98928419A patent/EP0986552A1/de not_active Withdrawn
  • 1998-06-03 HU HU0002166A patent/HUP0002166A3/hu unknown
  • 1998-06-03 WO PCT/FR1998/001113 patent/WO1998055474A1/fr not_active Application Discontinuation
  • 1998-06-03 CA CA002290695A patent/CA2290695A1/en not_active Abandoned
  • 1998-06-04 CO CO98031750A patent/CO4940480A1/es unknown
• 1999
  • 1999-11-30 BG BG103937A patent/BG103937A/xx unknown
  • 1999-12-03 NO NO995966A patent/NO995966L/no not_active Application Discontinuation

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