WO1991014679A1 - Derives heterocycliques n-substitues, leur preparation, les compostions pharmaceutiques en contenant - Google Patents

Derives heterocycliques n-substitues, leur preparation, les compostions pharmaceutiques en contenant Download PDF

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Publication number
WO1991014679A1
WO1991014679A1 PCT/FR1991/000224 FR9100224W WO9114679A1 WO 1991014679 A1 WO1991014679 A1 WO 1991014679A1 FR 9100224 W FR9100224 W FR 9100224W WO 9114679 A1 WO9114679 A1 WO 9114679A1
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alkyl
group
phenyl
formula
ppm
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PCT/FR1991/000224
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English (en)
French (fr)
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Claude Bernhart
Jean-Claude Breliere
Jacques Clement
Dino Nisato
Pierre Perreaut
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Sanofi
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Priority claimed from FR9003563A external-priority patent/FR2659967B1/fr
Priority claimed from FR9010144A external-priority patent/FR2665702B1/fr
Priority to KR1019910701647A priority Critical patent/KR0175310B1/ko
Priority to HU603/91A priority patent/HU221188B1/hu
Priority to SU5010343/04A priority patent/RU2099331C1/ru
Application filed by Sanofi filed Critical Sanofi
Priority to PL91293015A priority patent/PL165945B1/pl
Priority to UA5010343A priority patent/UA42669A/uk
Priority to HU9302497A priority patent/HU223141B1/hu
Publication of WO1991014679A1 publication Critical patent/WO1991014679A1/fr
Priority to NO914528A priority patent/NO301977B1/no
Priority to FI915458A priority patent/FI103407B/fi
Priority to LVP-93-147A priority patent/LV10439B/en
Priority to NO1998021C priority patent/NO1998021I1/no

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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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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
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • N-substituted heterocyclic derivatives Their preparation.
  • the present invention relates to N-substituted heterocyclic derivatives, their preparation and pharmaceutical compositions containing them.
  • the compounds according to the invention antagonize the action of Angiotensin II which is a peptide hormone of formula:
  • Angiotensin II is a powerful vasopressor agent which is the biologically active product of the renin-angiotensin system: renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted into angiotensin II by the action of angiotensin I converting enzyme
  • the compounds of the present invention are non-peptide compounds, angiotensin II antagonists.
  • angiotensin II antagonists By inhibiting the action of angiotensin II on its receptors, the compounds according to the invention notably prevent the increase in blood pressure produced by the hormone-receptor interaction, they also have other physiological actions at the level of the system. central nervous.
  • the compounds according to the invention are useful in the treatment of cardiovascular conditions such as hypertension, heart failure as well as in the treatment of central nervous system conditions and in the treatment of glaucoma and diabetic retinopathy.
  • R 1 and R 2 are similar or different and each independently represent hydrogen or a group chosen from alkyl in C 1 -C 6 , C 1 -C 4 alkoxy, amino, aminomethyl, carboxy, alkoxycarbonyl in which the alkoxy is C 1 -C 4 , cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino , trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyano-acetamide, N-hydroxy-acetamide, N - ((carboxy-4) thiazol-1,3-yl-2) acetamide, ureido, cyano-2 guanidinocarbonyl , 2-cyano guanidinomethyl, imidazol-1-yl-carbonyl, 3-cyano-2-methyl-isothioureidomethyl, provided that at least one of the substituents R 1 or R 2 is
  • R 3 represents hydrogen, C 1 -C 6 alkyl, unsubstituted or substituted by one or more halogen atoms, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, phenyl, phenylalkyl in which the alkyl is C 1 -C 3 , a phenylalkenyl in which the alkenyl is in C 2 -C 3 , said phenyl groups being unsubstituted or substituted one or more times by a halogen atom, an alkyl C 1 -C 4 haloalkyl C 1 -C 4 polyhaloalkyl, C 1 -C 4 alkyl, hydroxyl or alkoxy, C 1 -C 4 alkyl;
  • R 4 and R 5 each independently represent a C 1 -C 6 alkyl, a phenyl, a phenylalkyl in which the alkyl is C 1 -C 3 , said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or several halogen atoms or by a group chosen from a C 1 -C 4 perfluoroalkyl, a hydroxyl, a C 1 -C 4 alkoxy;
  • R 4 and R 5 linked together represent either a group of formula (CH 2 ) n , or a group of formula (CH 2 ) p Y (CH 2 ) q , in which Y is, or an oxygen atom , either a sulfur atom, or a carbon atom substituted by a C 1 -C 4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C 1 -C 3 , or a NR 6 group in which R 6 represents a hydrogen, a C 1 -C 4 alkyl, a phenylalkyl in which the alkyl is C 1 -C 3 , a C 1 -C 4 alkylcarbonyl, a
  • C 1 -C 4 haloalkylcarbonyl a polyhaloalkylcarbonyl C 1 -C 4 , a benzoyl, an alpha aminoacyl or an N-protecting group, or R 4 and R 5 linked together with the carbon atom to which they are bonded constitute an indane or an adamantane;
  • - n is an integer between 2 and 11;
  • - m is an integer between 2 and 5;
  • - X represents an oxygen atom or sulfur atom
  • the invention comprises the 2 optical isomers of this compound.
  • the salts of the compounds of formula (I) according to the present invention include those with mineral or organic acids which allow suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or a optically active acid, for example a mandelic acid or a camphosulfonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methanesulfonate, the methyl sulfate, the maleate, the fumarate, the
  • the salts of the compounds of formula (I) also include the salts with organic or inorganic bases, for example the salts of alkali or alkaline earth metals such as the sodium, potassium, calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine, such as trometamol, or else the salts of arginine, of lysine, or of any physiologically acceptable amine.
  • organic or inorganic bases for example the salts of alkali or alkaline earth metals such as the sodium, potassium, calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine, such as trometamol, or else the salts of arginine, of lysine, or of any physiologically acceptable amine.
  • halogen atom is meant a bromine, chlorine or fluorine atom
  • N-protecting group also designated by Pr
  • Pr means a group conventionally used in peptide chemistry to allow temporary protection of the amino function, for example a Boc, Z, Fmoc group or a benzyl group
  • esteerified carboxy group means a labile ester under appropriate conditions, such as for example a methyl, ethyl, benzyl or tert-butyl ester.
  • alkyl is meant the residues of saturated, straight or branched aliphatic hydrocarbons.
  • NBS N-bromo-succinimide
  • DIPEA diisopropylethylamine
  • the present invention also relates to the process for the preparation of the compounds (I). Said method is characterized in that:
  • Lawesson's reagent bis (4-methoxyphenyl) -2,4 1,3-dithia-2,4-diphosphetane-2,4 disulfide];
  • R 3 represents hydrogen, C 1 -C 6 alkyl, unsubstituted or substituted by one or more halogen atoms, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, phenyl, phenylalkyl in which the alkyl is C 1 -C 3 , a phenylalkenyl in which the alkenyl is in C 2 -C 3 , said phenyl groups being unsubstituted or substituted one or more times by a halogen atom, an alkyl C 1 -C 4 haloalkyl C 1 -C 4 polyhaloalkyl, C 1 -C 4 alkyl, hydroxyl or alkoxy, C 1 -C 4 alkyl; - R 4 and R 5 each independently represent a C 1 -C 6 alkyl, a phenyl, a phenylalkyl in which the alkyl is C 1 -C 3 , said al
  • R 7 represents hydrogen, C 1 -C 4 alkyl or phenyl
  • R 8 represents C 1 alkyl - C 4 or phenyl
  • R 4 and R 5 linked together represent either a group of formula (CH 2 ) n , or a group of formula (CH 2 ) p Y (CH 2 ) q , in which Y is, or an atom of oxygen, either a sulfur atom or a carbon atom substituted by a C 1 -C 4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is C 1 -C 3 , or a NR 6 group in which R 6 represents a hydrogen, a C 1 -C 4 alkyl, a phenylalkyl in which the alkyl is C 1 -C 3 , a C 1 -C 4 alkylcarbonyl, a
  • haloalkylcarbonyl C 1 -C 4 polyhalogenoalkylcarbonyl a C 1 -C 4 alkyl, benzoyl, alpha-aminoacyl or an N-protecting group, or R 4 and R 5 bonded together with the carbon atom to which they are bonded, form a indane or an adamantane;
  • - n is an integer between 2 and 11;
  • - m is an integer between 2 and 5;
  • - X represents an oxygen atom or sulfur atom
  • R 4 and R 5 are other than:
  • the alkyl is C 1 -C 3 , said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or more halogen atoms or by a group chosen from a C 1 -C 4 perfluoroalkyl, a hydroxyl, an alkoxy C 1 -C 4 ; • or R 4 and R 5 linked together are other than a group NR 6 in which R 6 represents a hydrogen, a C 1 -C 4 alkyl, a phenylalkyl in which the alkyl is C 1 -C 3 ,
  • R 4 and R 5 are each different from methyl.
  • X represents an oxygen atom or a sulfur atom and R 3 represents a hydrogen, a C 1 -C 6 alkyl, unsubstituted or substituted by one or more halogen atoms, a C 2 -C alkenyl 6 , a C 3 -C 7 cylcoalkyl, a phenyl, a phenylalkyl in which the alkyl is C 1 -C 3 , a phenylalkenyl in which the alkenyl is C 2 -C 3 , said phenyl groups being unsubstituted or substituted one or more times with a halogen atom, a C 1 -C 4 haloalkyl C 1 -C 4 polyhaloalkyl, C 1 -C 4 alkyl, hydroxyl or alkoxy, C 1 -C 4 .
  • R 3 represents a hydrogen, a C 1 -C 6 alkyl, unsubstituted or
  • halogen atoms C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, phenyl, phenylalkyl in which C 1 -C 3 alkyl, phenylalkenyl in which l alkenyl is C 2 -C 3 , said phenyl groups being unsubstituted or substituted one or more times by a halogen atom, a C 1 -C 4 alkyl, a C 1 -C 4 haloalkyl, a polyhaloalkyl C 1 -C 4 , hydroxyl or C 1 -C 4 alkoxy;
  • R 4 and R 5 each independently represent a C 1 -C 6 alkyl, a phenyl, a phenylalkyl in which the alkyl is C 1 -C 3 , said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted by one or several halogen atoms or by a group chosen from a C 1 -C 4 perfluoroalkyl, a hydroxyl, a C 1 -C 4 alkoxy;
  • R 7 represents hydrogen, C 1 -C 4 alkyl or phenyl
  • R 8 represents C 1 alkyl - C 4 or phenyl
  • R 4 and R 5 linked together represent either a group of formula (CH 2 ) n or a group of formula (CH 2 ) p Y (CH 2 ) q , in which Y is either an oxygen atom, either a sulfur atom or a carbon atom substituted by a C 1 -C 4 alkyl group, a phenyl or phenylalkyl in which the alkyl is C 1 -C 3 , or a NR 6 group in which R 6 represents hydrogen, C 1 -C 4 alkyl, a phenylalkyl in which the alkyl is C 1 -C 4 alkylcarbonyl, C 1 -C 4, a haloalkylcarbonyl C 1 -C 4 polyhalogenoalkylcarbonyl a C 1 -C 4 , a benzoyl, an alpha aminoacyl or an N-protecting group, or R 4 and R 5 linked together with the carbon atom to which they are linked constitute an indane or
  • - n is an integer between 2 and 11;
  • - m is an integer between 2 and 5;
  • - X represents an oxygen atom or a sulfur atom
  • R 3 is other than phenyl when R 4 and R 5 each represent methyl
  • Derivatives 2 are prepared by known methods. For example, one can use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 3, 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373) and cause an alkyl imidate to act on an amino acid or its ester, according to the following reaction scheme:
  • R represents a C 1 -C 4 alkyl
  • R ' represents hydrogen or a C 1 -C 4 alkyl
  • R 3 , R 4 , R 5 , z and t are as defined above for (I) .
  • This reaction is carried out in an acid medium, by heating in an inert solvent such as xylene or toluene.
  • compound 2 can be prepared by the action in an acid medium of an aminoalkylamide (5 ") on an alkyl ortho-ester (10) according to the following reaction scheme:
  • R represents a C 1 -C 4 alkyl
  • Hal represents a halogen, preferably chlorine.
  • the reaction is carried out in basic medium.
  • compound 2 is prepared by a process characterized in that: action is taken on a compound of formula:
  • A represents an OH group, an NH 2 group or an OR 'group, R' being hydrogen or a C 1 -C 4 alkyl, a compound of formula:
  • R being a C 1 -C 4 alkyl and Hal denoting a halogen atom, preferably chlorine;
  • the compound thus obtained is treated with the Lawesson reagent (bis / 4-methoxyphenyl) -2.4 dithia-1,3 diphosphophetane-2,4 disulfide.
  • R ' 1 and / or R' 2 represents an esterified carboxy group.
  • R ' 1 and / or R' 2 can represent either a tetrazolyl protected for example by a trityl group, or a cyano group which will then be replaced by a tetrazolyl group possibly protected by a trityl.
  • the conversion of the cyano group into a tetrazolyl can be carried out with an azide, for example tributyl tin azide or with sodium azide.
  • R ′ 1 and / or R ′ 2 such as the nitro, carboxy, cyano or acid chloride groups and then to transform them by reactions well known to those skilled in the art to obtain groups.
  • R 1 and / or R 2 as defined for the compound (I).
  • R ′ 1 and / or R ′ 2 represents a carboxy
  • it can be transformed into R 1 and / or R 2 representing an imidazol-1-yl carbonyl, or else into N- [(carboxy-4) thiazol- 1.3 yl-2)] acetamide.
  • R ' 1 and / or R' 2 representing an acid chloride can be transformed into R 1 and / or R 2 representing N-hydroxy-acetamide, N-cyanoacetamide, ureido or cyano-2 guanidinocarbonyl.
  • R ′ 1 and / or R ′ 2 representing a nitro can be transformed into amino from which R 1 and / or R 2 are prepared, such as methylsuifonylamino, trifluorornethylsuifonylamino and trifluoromethylsulfonylaminomethyl.
  • the group R ' 1 and / or R' 2 representing a cyano can be transformed into aminomethyl from which a 3-cyano-2-methyl isothio- is prepared.
  • ureidomethyl accordinging to C. Gordon et Al., J. Org. Chem., 1970, 35 (6), 2067-2069
  • a cyano-2 guanidinomethyl accordinging to RW Turner, Synthesis, 1975, 332
  • Step a1) is carried out in an inert solvent such as DMF, DMSO or THF, in basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate, or triethylamine.
  • an inert solvent such as DMF, DMSO or THF
  • basic medium for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate, or triethylamine.
  • Step b1) is carried out by heating under nitrogen in a solvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061.
  • the compounds (I) can be prepared according to another process which is also an object of the present invention. This process is characterized in that:
  • R ' 1 and R' 2 respectively represent either R 1 and R 2 , or a precursor group of R 1 and R 2 ;
  • Lawesson reagent bis (4-methoxy-phenyl) -2,4 1,3-dithia-2,4-diphosphetane-2,4 disulfide];
  • Step a2) is carried out under the usual conditions for the coupling of an acid with an amino, for example in the presence of BOP and DIPEA.
  • Step b2) which is the cyclization of compound 9. in the presence of 10 is carried out according to Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373).
  • the method comprising steps a2 to d2 is called method 2.
  • step b2 an intermediate 9 ′ of formula can optionally be isolated:
  • Hal represents a halogen atom and R ' 1 and R' 2 respectively represent either R 1 and R 2 , or a precursor group of R 1 and R 2 , in the presence of oxygen and UV irradiation, in basic environment;
  • the imidazole derivative 11 is either commercial or known, or is prepared by known methods, indicated above for the preparation of compounds 2.
  • Step a3) is carried out in an inert solvent such as DMF for example; to facilitate the reaction, it is possible to add a photosensitizing product such as methylene blue.
  • process 3 the process comprising steps a3) to c3) is called process 3.
  • the compounds (I) according to the invention in which R 4 and R 5 linked together represent a group of formula (CH 2 ) p Y (CH 2 ) q in which Y is an NH group, can be prepared by catalytic hydrogenolysis d 'a corresponding compound (I) in which Y is an NR 6 group, R 6 being a benzyl.
  • the affinity of the products according to the invention for the angiotensin II receptors was studied on a test for binding of angiotensin II labeled with iodine 125 to membrane receptors of rat liver. The method used is that described by S. KEPPENS et al. in Biochem. J., 1982, 208, 809-817.
  • the IC 50 is measured: concentration which gives 50% displacement of the labeled angiotensin II, linked specifically to the receptor.
  • the IC 50 of the compounds according to the invention is less than 10 -6 M.
  • angiotensin II of the products according to the invention has been observed in different animal species in which the renin-angiotensin system has been activated beforehand (C. LACOUR et al., J. Hypertension, 1989, 7 (suppl. 2), S33-S35).
  • the compounds according to the invention are active after administration by various routes, in particular by oral route.
  • the compounds according to the invention can be used in the treatment of various cardiovascular affections, in particular hypertension, cardiac failure, venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathies, and of various affections of the system central nervous system, anxiety, depression, memory deficits or Alzheimer's disease for example.
  • the present invention also relates to pharmaceutical compositions containing an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt and suitable excipients.
  • Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, or their possible salts, may be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of above disorders or diseases.
  • Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
  • the compounds according to the invention can be used in creams, ointments or lotions.
  • the dose of active principle can vary between 0.01 and 50 mg per kg of body weight per day.
  • Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.
  • the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose,. magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose,. magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose, a cellulose derivative, or other suitable materials or they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a quantity predetermined active ingredient.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate dye.
  • a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate dye.
  • Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or agents wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors.
  • Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
  • the active ingredient can also be formulated in the form of
  • microcapsules possibly with one or more carriers or additives.
  • compositions of the present invention may contain, in addition to the products of formula I above or of a pharmaceutically acceptable salt thereof, other active ingredients such as, for example, tranquilizers or other medicaments which may be useful in the treatment of the disorders or diseases indicated above.
  • compositions containing several active principles in combination one of which is a compound according to the invention and the other (s) may be a beta-blocking compound, a calcium antagonist, a diuretic, an anti-inflammatory non steroid or a tranquilizer.
  • d means density
  • TA room temperature
  • KHSO 4 -K 2 SO 4 means an aqueous solution containing 16.6 g of potassium bisulfate and 33.3 g of potassium sulfate per 1 liter.
  • the melting points (Fc) are given in degrees Celsius; unless otherwise indicated, they were measured without recrystallization of the product.
  • im means imidazole.
  • z and t are zero, except when the compound prepared is a pyrimidinone.
  • n-butyl-2 spirocyclopentane-4 [(tei-butoxycarbonyl-2 'biphenyl-4-yl) methyl] -1 imidazoline-2 one-5.
  • the product obtained in the previous step is dissolved in 10 ml of DMF, then 1 ml of diethylamine is added and the mixture is stirred for 1 hour 15 minutes at RT.
  • the reaction medium is taken up in 100 ml of ethyl acetate and 20 ml of water, then the organic phase is washed once with water, once with a saturated solution of sodium chloride, then dried over sodium sulfate. and evaporated to dryness.
  • the ethyl ester of 1-amino-cyclopentane carboxylic acid is prepared according to ADKINS and BILLICA (J. Amer. Chem. Soc, 1948, 70, 3121).
  • Ethyl valeridate is prepared according to Mac ELVAIN (J. Amer. Chem. Soc, 1942, 64 1825-1827) then released from its hydrochloride by the action of potassium carbonate and extraction with DCM.
  • n-butyl-2 spirocyclopentane-4 imidazoline-2 one-5 prepared in step A can also be obtained according to another procedure described below, using cyclopentanone as starting material.
  • This step is carried out according to A. Strecker (Org. Synth., 1955, 3) 1.97 g of sodium cyanide are dissolved in 3.9 ml of water in a flask and a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% ammonia, finally 3 g of cyclopentanone in 3.8 ml of methanol are added to the flask. After 1 hour and a half with stirring, the mixture is brought to 60 ° C. for 45 minutes then the heating is stopped, stirring is continued for 45 minutes and then cooled to 25 ° C. Extraction is carried out several times with methylene chloride. Dried over sodium sulfate, filtered and concentrated in vacuo. 4 g of the expected product are obtained in oily form.
  • the amino-1 cyclopentane nitrile obtained is dissolved in 300 ml of acetone and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added, with stirring. The precipitate formed is drained, washed with acetone and then dried,
  • This compound is 1-amino cyclopentane nitrile hemioxalate.
  • This step is carried out according to J. Zabicky, (The Chemistry of Amides, Intersciences, New-York, 1970, 119).
  • This step is carried out according to H. Takenaka et al., Heterocycles, 1989, 29 (6), 1185-89.
  • the residue obtained is taken up in 40 ml of water and extracted with 10 ml of ethyl acetate and then twice with 5 ml of ethyl acetate.
  • the combined organic phases are dried over sodium sulfate and filtered.
  • the filtrate is concentrated to dryness. 4.85 g of the expected product are obtained.
  • the NMR spectrum is similar to that described above.
  • the hydrochloride of this compound can be prepared by adding concentrated hydrochloric acid. The hydrochloride melts at 240 ° C while sublimating.
  • This compound is obtained by treatment in an acid medium as described in the last step of Example 1 and of Example 2.
  • the physicochemical data are identical to those obtained for the same compound prepared by methods 1 or 2.
  • the N.O.E. (Nuclear Overhauser Effect) confirms the position of the 5-one and 4,4-dimethyl substitutions on imidazolinone.
  • -2spirocyclopentane-4 imidazoline-2 one-5 (prepared in Example 2, step A) in 10 ml of DMF.
  • the mixture is stirred for 30 minutes at RT and then a solution of 1.5 g of 4-bromomethyl-2-cyano-2 'biphenyl in 10 ml of DMF is added.
  • the N.O.E. confirms the position of the 5-one substitution on imidazole.
  • N-Butyl-2 trifluoroacetate [(2-carboxy-biphenyl-4-yl) methyl.] -1 (spirotetrahydropyran-4) -4 imidazoline-2 one-5. and n-butyl-2 (spirotetrahydropyran-4) -4 [(tert-butoxycarbonyl-2 'biphenyl-4-yl) methyl] -1 imidazoline-2 one-5 - Method 2.
  • A) 4-amino acid tetrahydropyrannecarboxylic-4 is prepared from tetrahydropyrannone-4 according to the method described in German patent DE-2 215 721.
  • N- (benzyloxycarbonyloxy) succinimide dissolved in 12 ml of acetonitrile. After 1 hour 15 minutes, the reaction medium is diluted with 70 ml of ethyl acetate and 10 ml of water and the mixture is brought back to pH2 with a saturated solution of potassium bisulfate.
  • a mixture containing 0.9 g of the compound obtained in step D, 327 mg of methyl esterovalate and 2 drops of acetic acid is heated for 3 hours at 110 ° C.
  • the reaction medium is taken up in 100 ml of ethyl acetate and then washed with a saturated solution of sodium bicarbonate, a saturated solution of sodium chloride and then dried over sodium sulfate and the ethyl acetate is evaporated.
  • the residue obtained is chromatographed on silica, eluting with an ethyl acetate / toluene mixture (2/1, v / v). 550 mg of the expected product are obtained in the form of a wax.
  • A) 4-amino-1-benzyl piperidinecarboxylic-4 acid is prepared from N-benzyl piperidone-4 according to the method described in German patent DE-2 215 721.
  • step A 3.80 g of the compound prepared in step A are added to a solution of 13 g of hydrochloric acid in 50 ml of ethanol at 0 ° C and then brought to reflux for 5 hours. After concentration in vacuo, the residue is washed with ether and then dissolved in an ether-water mixture to which a saturated potassium carbonate solution is added to reach pH 9. The phase ethereal is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to dryness. 3.50 g of the expected product are obtained in the form of an oil.
  • the ethyl valeridate is prepared as in Example 2, step A. 2.06 g of ethyl valeridate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid are mixed in 15 ml of xylene and heated to reflux for 6 hours. After concentration under vacuum, the residue is chromatographed on silica gel, eluting with a mixture
  • step C To 2.78 g of the compound obtained in step C, dissolved in 25 ml of DMF, 513 mg of sodium methylate is added and, after 15 minutes, 4.16 g of bromomethyl-4 (tert-butoxycarbonyl-2 ' ) biphenyl. It is heated to 40 ° C for 5 hours then the reaction medium is taken up in 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution. The organic phase is decanted, washed again with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo.
  • N-butyl-2-ditrifluoroacetate [(2-carboxy-biphenyl-4-yl methyl] -1 (spiropiperidine-4) -4 imidazoline-2 one-5.
  • step D 300 mg of the compound of example 7, step D are dissolved in 10 ml of methanol. 180 mg of 10% palladium on carbon are added and hydrogenation is carried out for 3 hours at atmospheric pressure. The catalyst is filtered and the filtrate is concentrated in vacuo. 200 mg of the expected product are obtained.
  • step A 160 mg of the product obtained in step A are stirred in 3 ml of
  • This compound is prepared according to the usual method by acting on the compound prepared in step B of 4-bromomethyl (2-tert-butoxycarbonyl) biphenyl, in the presence of sodium methylate in DMF.
  • Cyclopentylidene acetic acid is prepared according to G.A.R. KON and R.P.
  • a mixture containing 310 mg of the compound obtained in step B, 348 mg of ethyl valerididate, 10 ml of xylene and 6 drops of acetic acid is brought to reflux. Again, after 2 hours and 18 hours, 348 mg of ethyl valerididate and after 24 hours of reflux in total, the reaction medium is evaporated and then chromatographed on silica eluting with a DCM-methanol mixture (97/3 , v / v). 153 mg of the expected product are obtained.
  • a mixture of 10 ml of DMF and 40 mg of 80% sodium hydride in oil is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in step C, dissolved in 5 ml of DMF, are added dropwise at room temperature. After 30 minutes with stirring, 288 mg of 4-bromomethyl-2-tert-butoxycarbonyl-2 'biphenyl dissolved in 5 ml of DMF is added. The mixture is left stirring for 2 hours then evaporated, the residue taken up in water and extracted with ethyl acetate.
  • n-butyl-2 spirocyclopentane-4 [(tert-butoxycarbonyl-2 'biphenyl-4-yl) methyl] -1 imidazoline-2 thione-5.
  • A) 2-amino-indane-2 carboxylic acid is prepared according to R.M. Pinder, J. Med. Chem., 1971, 14, 9, 892, and the corresponding ethyl ester is then prepared according to Adkins (ref. Cited in Example 2A).
  • n-butyl-2 [((imidazolyl-1 carbonyl) -2 'bi ⁇ henyl-4-yl) methyl] -1 spirocyclopentane-4 imidazoline-2 one-5.
  • n-butyl-2 [((cyano-3 methyl-2 isothioureidomethyl) -2 'biphenyl-4-yl) methyl] -1 spirocyclopentane-4 imidazoline-2 one-5.
  • This compound is obtained by hydrogenation of the compound, prepared in Example 5.
  • n-butyl-2 [((2-cyano guanidinomethyl) -2 'biphenyl-4-yl) methyl] -1 spirocyclopentane-4 imidazoline-2 one-5.
  • This compound is obtained from the compound, prepared in the previous example. 200 mg of the compound are placed in 10 ml of absolute ethanol, saturated with ammonia at 10 ° C, then heated at 80 ° C in an autoclave for 1 night. After dry concentration of the reaction medium, a chromatographed on silica, eluting with a DCM-methanol mixture (95/5, v / v). 130 mg of the expected product are obtained.
  • a mixture containing 260 mg of sodium hydride at 80% in 5 ml of DMF is prepared and 500 mg of n-butyl-2-spirocyclopentane-4 imidazoline-2 one-5 is prepared at room temperature under nitrogen, prepared at Example 2 step A.
  • 901 mg of 4-bromomethyl-2-nitro-biphenyl is added in 5 ml of DMF and the mixture is stirred for 24 hours.
  • the reaction medium is concentrated to dryness, taken up in a water-ethyl acetate mixture.
  • the organic phase is decanted, dried over sodium sulfate and filtered, then the ethyl acetate is evaporated.
  • the product obtained is chromatographed on silica, eluting with a DCM / ethyl acetate mixture (9/1, v / v). 500 mg of the expected product are obtained.
  • n-butyl-2 [((N-hydroxy-acetamide) -2 'biphenyl-4-yl) methyl] -1 spirocyclopentane-4 imidazoline-2 one-5.
  • the compound prepared in Example 2 is freed from its salt d trifluoroacetic acid by taking up this compound in an ethyl acetate-water mixture and bringing the solution to pH 6 by addition of a saturated solution of sodium hydrogen carbonate.
  • the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give the free base in the form of a white solid.
  • step A 16 g of imidate obtained in step A are dissolved in 100 ml of dichloromethane and 50 ml of water and 15 g of potassium carbonate are added. After decantation, the dichloromethane is dried over potassium carbonate and then evaporated to dryness without heating.
  • 1-Amino cyclohexane carboxylic acid is commercially available. 15 g of this amino acid are added at 0 ° C to a solution of 23 g of hydrochloric gas in 150 ml of anhydrous ethanol. The mixture is heated to reflux for 5 hours, then the reaction mixture is concentrated to dryness and it is taken up in ether. The white solid obtained is filtered, washed with ether and then dissolved in a mixture of 300 ml of ether and 100 ml of water. The pH is brought to 9 by adding a solution of potassium carbonate. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to dryness. 14 g of the expected product are obtained in the form of an oil.
  • step C 14 g of the product obtained in step C are dissolved in 200 ml of xylene containing 0.6 ml of acetic acid.
  • Half of the imidate obtained in step B is added and the mixture is heated to reflux. After 1 hour and a half, add the half of the imidate remaining then the last quarter after 4 hours. After a total of 7 hours of reflux, the medium is evaporated to dryness. The solid obtained is taken up in hexane, filtered, washed with ether and then dried.
  • imidazolinone-5 based on the values of the IR bands.
  • step D To 0.24 g of 80% sodium hydride in oil, suspended in 10 ml of dimethylformamide, 970 mg of imidazolinone obtained in step D is added. After 20 minutes of stirring under nitrogen, add in 5 minutes 1.91 g of bromomethyl-4 tert-butoxycarbonyl-2 'biphenyl, prepared according to European patent application 324377. After 1 hour of stirring, the medium is concentrated in half vacuum and taken up in 100 ml of acetate ethyl then with 20 ml of water. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and then concentrated in vacuo. The residue is chromatographed on silica, eluting with an ethyl acetate-toluene mixture. 2.10 g of the expected product are obtained in the form of a wax.
  • reaction medium is diluted with 150 ml of ethyl acetate, 20 ml of water and brought to pH 5 with acetic acid, the organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated dried up. The residue is chromatographed on silica, eluting with a chloroform / methanol / acetic acid mixture (90/8/2, v / v). 160 mg of the expected product are obtained in solid form.
  • This compound is prepared from the compound obtained in Example 20.
  • the 2-amino-4-ethoxycarbonyl-1,3-thiazole is prepared according to B. Plouvier et al., J. Heterocycl. Chem., 1989, 26 (6), 1646.
  • n-butyl-2 [((2-cyano guanidinocarbonyl) -2 'biphenyl-4-yl) methyl] - 1 spirocyclopentane-4 imidazoline-2 one-5.
  • the acid chloride of the compound obtained in Example 2 is prepared: 1 g of this compound is placed in 20 ml of DCM in the presence of 1.8 ml of thionyl chloride and stirred at room temperature for 2 hours. After concentration of the medium, it is taken up in benzene and then concentrated again. The isolated crude product is then used. It is mixed with 417 mg of dicyanodiamide, 0.5 ml of 10N sodium hydroxide, 0.5 ml of water and 10 ml of dioxane and then left to stir for 5 hours. The reaction medium is taken up in water and ethyl acetate, potassium carbonate is added and then concentrated. The residue obtained is chromatographed on silica eluting with a DCM-methanol mixture (95/5, v / v). 100 mg of the expected product are isolated.
  • N-Boc ⁇ -dehydro (L) phenylalanine N-carboxyanhydride of ⁇ -dehydro (L) phenylalanine is prepared according to R. Jacquier et al., Tetrahedron Lett., 1984, 25 (26), 2775. p.
  • step A benzylidene-4 n-butyl-2 [(tert-bytoxycarbonyl-2 'biphenyl-4-yl) methyl] -1 imidazoline-2 one-5.
  • 440 mg of the compound obtained in step A are dissolved in 1 ml of acetic acid and heated for 30 minutes at 100 ° C.
  • a mixture containing 500 mg of the compound obtained in the preceding step, 570 mg of 4-aminomethyl-2-biphenyl-tert-butyl carboxylate and 10 ml of pyridine is heated at 110 ° C. for 3 hours. It is evaporated in vacuo, taken up in chloroform and then evaporated again. The residue is chromatographed on silica, eluting with a hexane-ethyl acetate mixture (3/1 then 2/1, v / v). 106 mg of the expected product are obtained in the form of a yellow solid.
  • n-butyl-2 spirocyclopentane-6 [((tetrazolyl-5) -2 'bi ⁇ henyl-4-yl) methyl] -34 (1H) -dihydro-5,6 pyrimidinone-4.
  • 150 ml of gaseous ammonia are added to 20 g of cyclopentylidene ethyl acetate prepared previously and the mixture is heated at 150 ° C. for 72 hours.
  • the product obtained after evaporation is purified by chromatography on silica, eluting with a DCM-methanol-ammonia mixture at 20% (90/10/1, v / v / v).
  • the product obtained is dissolved in DCM, dried over sodium sulfate.
  • the DCM is filtered and evaporated to obtain 7.2 g of the expected product.
  • This compound is prepared according to Helv. Chim. Acta, 1952, 35. (7), 2561. 9.2 g of sodium are dissolved in 200 cm 3 of absolute ethanol. Half of the sodium ethylate solution formed is poured into an ampoule. To the remaining half, 24.88 g of ethyl cyanoacetate are added and the mixture is brought to reflux.
  • This compound is prepared by catalytic hydrogenation of ethyl cyano-1 cyclopentane carboxylate.
  • a mixture containing 13.12 g of the compound obtained in the preceding step and 13.5 g of ethyl valerididate in 100 ml of xylene containing a few drops of acetic acid is brought to reflux for 13 hours.
  • the reaction medium is evaporated, taken up in ethyl acetate and a 10% sodium carbonate solution, then dried and concentrated.
  • 250 ml of the terbutyl ester prepared in the previous step are dissolved in 10 ml of DCM. It is cooled in an ice-water bath and then 5 ml of cold trifluoroacetic acid is added and the mixture is left to stir for one hour under cold conditions, then 1 hour at room temperature. It is evaporated under reduced pressure. The residue is taken up in ethyl ether and then evaporated. The operation is repeated 3 times then the evaporation residue is taken up in hexane, triturated then decanted hexane. It is taken up in ethyl ether and the precipitate is filtered.

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PCT/FR1991/000224 1990-03-20 1991-03-20 Derives heterocycliques n-substitues, leur preparation, les compostions pharmaceutiques en contenant WO1991014679A1 (fr)

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HU9302497A HU223141B1 (hu) 1990-03-20 1991-03-20 Új imidazol- és pirimidinszármazékok és eljárás előállításukra
UA5010343A UA42669A (uk) 1990-03-20 1991-03-20 Антагоністи ангіотензину ii, спосіб їх отримання (варіанти), проміжна сполука (варіанти), спосіб їх отримання та фармацевтична композиція
PL91293015A PL165945B1 (pl) 1990-03-20 1991-03-20 Sposób wytwarzania N-podstawionych pochodnych lmidazolu lub pirymidyny PL PL PL PL PL PL
HU603/91A HU221188B1 (en) 1990-03-20 1991-03-20 N-substituted imidazole and pyrimidine derivatives, pharmaceutical compositions comprising such compounds as active ingredients and process for producing them
SU5010343/04A RU2099331C1 (ru) 1990-03-20 1991-03-20 N-замещенные гетероциклические производные или их соли, промежуточные производные пиримидина и имидазолина и фармацевтическая композиция на основе замещенных гетероциклических производных
KR1019910701647A KR0175310B1 (ko) 1990-03-20 1991-03-20 N-치환 복소환식 유도체, 그의 제조방법 및 그를 함유하는 약학 조성물
NO914528A NO301977B1 (no) 1990-03-20 1991-11-19 Analogifremgangsmåte for fremstilling av N-substituerte heterocykliske derivater, samt mellomprodukter for deres fremstilling
FI915458A FI103407B (fi) 1990-03-20 1991-11-19 Menetelmä terapeuttisesti aktiivisten N-substituoitujen pyrimidiini- j a imidatsoliinijohdannaisten valmistamiseksi ja välituotteina käyttöke lpoisia pyrimidiini- ja imidatsoliinijohdannaisia
LVP-93-147A LV10439B (en) 1990-03-20 1993-02-25 N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them
NO1998021C NO1998021I1 (no) 1990-03-20 1998-09-16 Irbesartan

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FR9010144A FR2665702B1 (fr) 1990-08-08 1990-08-08 Derives heterocycliques n-substitues, leur preparation, les compositions pharmaceutiques en contenant.
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CS74591A3 (en) 1991-11-12
AU641005B2 (en) 1993-09-09
PL165945B1 (pl) 1995-03-31
IL110820A0 (en) 1994-11-11
NO914528L (no) 1992-01-17
NO301977B1 (no) 1998-01-05
SK280096B6 (sk) 1999-08-06
CA2057913A1 (en) 1991-09-21
HUT61284A (en) 1992-12-28
CZ287064B6 (cs) 2000-08-16
JPH04506222A (ja) 1992-10-29
PT97078B (pt) 1997-07-31
HUT67648A (en) 1995-04-28
EP0454511A1 (fr) 1991-10-30
LU90279I2 (fr) 1998-10-21
LV10439B (en) 1995-08-20
NZ237476A (en) 1994-01-26
LU90371I2 (fr) 1999-05-12
ES2119764T3 (es) 1998-10-16
HU9302497D0 (en) 1993-11-29
JPH10279566A (ja) 1998-10-20
FI915458A0 (fi) 1991-11-19
ATE167475T1 (de) 1998-07-15
PL166403B1 (pl) 1995-05-31
NL990006I2 (nl) 1999-10-01
IE910913A1 (en) 1991-09-25
FI103407B1 (fi) 1999-06-30
HU221188B1 (en) 2002-08-28
FI103407B (fi) 1999-06-30
AU7561091A (en) 1991-10-21
PL166581B1 (pl) 1995-06-30
IL97612A (en) 1995-08-31
RU2099331C1 (ru) 1997-12-20
HK1008918A1 (en) 1999-05-21
PL293015A1 (en, 2012) 1993-02-08
UA42669A (uk) 2001-11-15
NO1998021I1 (no) 1998-10-05
HU223141B1 (hu) 2004-03-29
IL110820A (en) 1995-11-27
EP0454511B1 (fr) 1998-06-17
HU913603D0 (en) 1992-07-28
DE19975029I2 (de) 2002-05-08
MY115638A (en) 2003-08-30
DE69129606T2 (de) 1998-12-17
JP2868313B2 (ja) 1999-03-10
NL980039I1 (nl) 1999-02-01
DK0454511T3 (da) 1999-04-06
TW201738B (en, 2012) 1993-03-11
CZ287225B6 (cs) 2000-10-11
SK283197B6 (sk) 2003-03-04
PT97078A (pt) 1991-11-29
DE69129606D1 (de) 1998-07-23
SG49053A1 (en) 1998-05-18
NL980039I2 (nl) 1999-09-01
CA2057913C (en) 1997-07-08
NL990006I1 (nl) 1999-05-03
NO914528D0 (no) 1991-11-19
KR0175310B1 (ko) 1999-02-18
LV10439A (lv) 1995-02-20
MX9203586A (es) 1992-07-01
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KR920702349A (ko) 1992-09-03
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