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WO1999065864A2 - Amines substituees de maniere geminee - Google Patents

Amines substituees de maniere geminee Download PDF

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Publication number
WO1999065864A2
WO1999065864A2 PCT/EP1999/004258 EP9904258W WO9965864A2 WO 1999065864 A2 WO1999065864 A2 WO 1999065864A2 EP 9904258 W EP9904258 W EP 9904258W WO 9965864 A2 WO9965864 A2 WO 9965864A2
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Prior art keywords
group
substituted
alkyl
alkyl group
nitro
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PCT/EP1999/004258
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German (de)
English (en)
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WO1999065864A3 (fr
Inventor
Herwig Buchholz
Urs Welz-Biermann
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Merck Patent Gmbh
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Priority claimed from DE19827165A external-priority patent/DE19827165A1/de
Priority claimed from DE19827164A external-priority patent/DE19827164A1/de
Priority claimed from DE19827163A external-priority patent/DE19827163A1/de
Priority claimed from DE19827161A external-priority patent/DE19827161A1/de
Priority claimed from DE19827166A external-priority patent/DE19827166A1/de
Priority claimed from DE19844194A external-priority patent/DE19844194A1/de
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Publication of WO1999065864A2 publication Critical patent/WO1999065864A2/fr
Publication of WO1999065864A3 publication Critical patent/WO1999065864A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/023—Preparation; Separation; Stabilisation; Use of additives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link
    • B01J31/0212—Alkoxylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
    • B01J31/0235—Nitrogen containing compounds
    • B01J31/0237—Amines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/66—Preparation of compounds containing amino groups bound to a carbon skeleton from or via metallo-organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to geminally substituted amines.
  • the present invention relates to amines substituted with aryl group-containing substituents, combinatorial libraries of such amines and special uses of these amines as intermediates in combinatorial drug synthesis or as drugs in pharmaceuticals.
  • a prerequisite for the combinatorial synthesis of active substance libraries is the accessibility of suitable starting compounds which either already contain a biologically active structural element or form this through combinatorial synthesis. Furthermore, the starting compounds must be suitable to provide as many of the reaction products as possible by law in the same possible yield in order to reduce the influence of the concentration of the individual compounds during screening and to create a combinatorial library that is as complete as possible.
  • the object of the invention is therefore to provide new compounds which contain a special biologically active structural element and which can be used individually or as a library in the combinatorial synthesis of active substances.
  • This object is achieved by providing an amine of the following formula (I) as a pure substance or in a substance library in a mixture with several different amines of the formula (I). It has been found that, surprisingly, the geminal substitution of a preferably tertiary amine can not only provide biological activity, but at the same time its preparation also has advantageous properties in combinatorial active ingredient synthesis. A process is also proposed in which a large number of amines of the general formula (I) can be prepared as a substance library.
  • R 1 and R 2 may be the same or different and each independently represent substituted or unsubstituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl or trialkylsilyl or R 1 and R 2 together with the nitrogen atom to which they are attached can form substituted or unsubstituted cycloalkyl ring which, in addition to the nitrogen atom, can also contain at least one further heteroatom which is selected from the group consisting of nitrogen, oxygen or sulfur,
  • R 3 is selected from hydrogen and methyl, which can optionally be substituted by 1-3 fluorine atoms,
  • R 4 and R 5 may be the same or different and each individually independently of one another represents alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, substituted or unsubstituted aryl or an alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl substituted by substituted or unsubstituted aryl , with the proviso that at least one radical R 4 or R 5 contains an aryl group; or a salt thereof, especially a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention are valuable as ⁇ -sympathicomimetics with a stimulating effect on the central nervous system, in particular in the treatment of depression, obesity, fatigue, allergic disorders and nasal mucosal inflammation.
  • Alkyl is preferably C ⁇ ⁇ alkyl, more preferably C 2 . 8 alkyl.
  • Cycloalkyl is preferably C 3.g -cycloalkyl, more preferably C 3 . 7- cycloalkyl.
  • Alkenyl is preferably C 2.10 alkenyl, more preferably C 2 . 8 alkenyl.
  • Cycloalkenyl is preferably C 3 . ⁇ - Cycloalkenyi, more preferred for C 3 _ 7 -cycloalkenyi.
  • Alkynyl is preferably C 2 . 10 alkynyl, more preferably for C 2 _a alkynyl.
  • Aryl is preferably phenyl, naphthyl, anthryl or phenanthryl.
  • an aryl radical is phenyl, benzyl, p-tolyl, m-tolyl, 4-fluorophenyl, 4-fluoro-3- Methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 2-methyl-2-phenylethyl, 3-phenylprop-2-ynyl, 4-dimethylaminophenyl, naphthalen-1-yl and 3-aminophenyl.
  • an alkyl radical is methyl, ethyl, propyl, butyl, pentyl, hexyl.
  • a cycloalkyl radical is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • an alkenyi radical is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl isobutenyl.
  • R 1 and R 2 are described below, where halogen is fluorine, chlorine, bromine or iodine.
  • R 1 and R 2 can be the same or different and independently of one another for a C ,.
  • Alkyl group a C 3 . 7- cycloalkyl group, one with a C 3 . 7- Cycloalkyl group substituted C ..
  • Poiyhalogen-C 2.6 -alkenyloxy group substituted C ⁇ alkyl group one with a mono-, di- and
  • a phenyl group (provided that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. .6 alkyl group and a
  • C ⁇ alkoxy group a C .. 6 -alkyl group substituted with a phenyl group (with the proviso that such a phenyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,. ⁇ - alkyl group and a C 1 6 alkoxy group), a C-substituted by a phenyl group.
  • C. ⁇ - alkoxy group a C 2 ⁇ -alkynyl group substituted by a phenyl group (with the proviso that such a phenyl group can be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. 6 alkyl group and a C. 6 alkoxy group), one with a
  • Phenoxy group substituted (provided that such a phenoxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C g alkyl group and a C. ⁇ -. alkoxy ), a C, ⁇ - substituted with a phenylthio group
  • Halogen atom a trifluoromethyl group, a nitro group, a C 6 - alkyl group and a C,.
  • a C, 6 -alkoxy group a C, 6 -alkyl group substituted with a phenylsulfinyl group (with the proviso that such a phenylsulfinyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group , a C .. ⁇ - alkyl group and a C ,. s -Alkoxygrupp), one with a
  • Phenylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, one
  • Nitro group one a C, substituted with a benzyloxy group.
  • ⁇ - alkyl group (with the proviso that the phenyl group of such
  • Benzyloxy group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ... 6 alkyl group and one
  • Alkyl group (with the proviso that the phenyl group of such a benzylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. 6 alkyl group and a C. 6 -alkoxy group), a C, substituted by a benzylsulfinyl group.
  • benzylsulfinyl group can be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C. 6 alkyl group and a C. ⁇ - alkoxy group), a C, substituted with a benzylsulfonyl group.
  • 6 -alkyl group (with the proviso that the phenyl group of such a benzylsulfonyl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C Lg -Alkoxy group), a substituted with an amino group which is substituted by a C 1-4 alkylsulfonyl group . 6 alkyl group.
  • rings which are present when the radicals R 1 and R 2 form a cycloalkyl ring which may optionally contain, in addition to N, at least one further heteroatom, preferably N, 0 or S, are as follows: 1-pyrrolidinyl, 1-imidazolinyl , 1 -pyrazolinyl, 1 -piperidyl, 1 -piperazinyl, 4-morpholinyl, 4-thiamorpholinyl.
  • the radicals R 1 and R 2 are particularly preferably each independently of one another methyl, ethyl, isopropyl, n-butyl, isobutyl, phenyl, benzyl, 2-pyridyl or trimethylsilyl, or together with the nitrogen atom to which they are attached are for 1-pyrrolidinyl, 1-piperidyl, 4-methylpiperidyl, or 4-morpholinyl.
  • R 3 particularly preferably represents hydrogen.
  • R 4 and R 5 are described below, where halogen is fluorine, chlorine, bromine or iodine and aryl is phenyl, naphthyl, anthryl or phenanthryl:
  • R 4 and R 5 may be the same or different and independently of one another represent alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, which can have the same meaning as described for R 1 and R 2 , or an aryl group (with the proviso that such aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C ,. 6 - alkyl group and a C ,.
  • alkoxy group ⁇ one with a aryl substituted C ⁇ g alkyl group (with the proviso that such an aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C .. 6 - alkyl and a C, .g-alkoxy group), a C 2 substituted with an aryl group. 7 alkenyl group (with the proviso that such an aryl group may be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C,
  • Alkyl group and a C ⁇ alkoxy group a substituted with an aryl group C 26 alkynyl group
  • Trifluoromethyl group a nitro group, a C, 6 -alkyl group and a C, 6 -alkoxy group
  • a C 1-4 alkyl group substituted with an aryloxy group (with the proviso that such an aryloxy group may be substituted with one or more substituents selected from the group consisting of a haiogen atom, a trifluoromethyl group, a nitro group, a C,
  • Alkyl group (with the proviso that such an arylthio group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 6 - alkyl group and a C 1 6 alkoxy group ), a C, e - alkyl group substituted by an arylsulfmyl group (with the proviso that such an
  • Arylsulfmyl group can be substituted with one or more substituents which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C 1-4 alkyl group and a C 6 alkoxy group), a C substituted with an arylsulfonyl group, 6 -
  • Alkyl group (with the proviso that such an arylsulfonyl group may be substituted with one or more substituents selected from the group consisting of one
  • Halogen atom a trifluoromethyl group, a nitro group, a C, 6 -alkyl group and a C,
  • Trifluoromethyl group Trifluoromethyl group, a nitro group, a C, 6- alkyl group and a C, 6- alkoxy group
  • a C, 6 -alkyl group substituted by a benzylthio group (with the proviso that the aryl group of such a benzylthio group may be substituted by one or more substituents, which are selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, a C, 6 -alkyl group and a C, 6- alkoxy group), one with a
  • R 4 and R 5 are particularly preferably phenyl, benzyl, p-tolyl, m-tolyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 2,6-dimethylphenyl, 2-methyl -2-phenylethyl, 3-phenyl-prop-2-ynyl, 4-dimethylaminophenyl, naphthalene-1-yl and 3-aminophenyl.
  • a combinatorial library in the sense of the present invention contains at least five, preferably at least seven different amines of the general formula (I).
  • the preparation of the compounds of the general formula (I) is not particularly restricted. However, it has been found that the compounds of the general formula (I) can preferably be prepared by one of the following processes.
  • R 1 , R 2 and R 3 have the meaning given above and R 3 particularly preferably represents hydrogen or a methyl group, in a suitable solvent with a compound of the general formula (III)
  • R 1 for F, Cl, Br and I
  • R 1 for an alkyl radical with C ⁇ C. Q
  • R 5 has the meaning given above and n is an integer from 1 to 3.
  • carboxylic acid amides are suitable, in which the radicals R 1 and R 2, identical or different, represent an alkyl radical with C, - C 10, a one by fluorine or polysubstituted, including perfluorinated alkyl radical with C, - C 10 , a cycloalkyl radical with C 3 - C 8 , an aryl radical with C ⁇ - C 20 , an aryl radical which is mono- to pentasubstituted by fluorine, chlorine, bromine, iodine, an alkenyl radical with C 2 - C 10 , an alkynyl radical with C 2 - C 10 , a cycloalkyl ring consisting of the radicals R 1 and R 2 with C 3 - C 8 , which may contain a nitrogen, oxygen or sulfur atom as a further hetero atom, in addition to nitrogen.
  • the radicals R 1 and R 2 identical or different, represent an alkyl radical with C, - C 10, a one
  • a compound of the general formula (III) is used as the Grignard compound or organolithium compound for the reaction.
  • the radical R 4 is preferably a C, -C 10 alkyl radical, a fluorine or polysubstituted by fluorine, including perfluorinated C, - C 10 alkyl radical, a C 3 - C 6 cycloalkyl radical, a C.
  • R 4 radical is particularly preferably a methyl or cyclopropyl radical.
  • R 4 and R 5 preferably have at most one hydrogen atom in the ⁇ position.
  • the radical M in the general formula (III) preferably stands for a -MgX radical with X for Cl or Br or the radical M stands for lithium.
  • the reaction is preferably also carried out with an organotitanium compound.
  • Suitable organotitanium compounds are preferably compounds of the general formula (IV-a) shown above, where n is an integer from 1 to 3, preferably 3, Y is Cl, Br or I, the radicals R '", the same or different, one Alkyl radical with C, - C 10 or an aryl radical with C 6 - C 20 , preferably isopropyl, and R 5 , identical or different from R ⁇ , has the meaning given for R 4 .
  • R 5 Ti (OiPr) 3 is particularly preferably used as the organotitanium compound, where iPr stands for an isopropyl radical.
  • Methyl, phenyl, cyclopropyl or p-fluorophenyl-th-isopropyl titanates are very preferably used.
  • the compounds of the general formula (III) and (IV) should each be present in amounts of 0.7 to 1.3, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II) .
  • the reaction is preferably carried out in a suitable solvent for the compounds of the general formulas (II) and (III) and (IV-a), preferably in a suitable organic solvent, such as, for. B. an aliphatic or aromatic hydrocarbon or ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.
  • a suitable organic solvent such as, for. B. an aliphatic or aromatic hydrocarbon or ether, preferably toluene, tetrahydrofuran, n-hexane, cyclohexane, benzene or diethyl ether.
  • a solution of the compound of the general formula (II) and (IV) and the cocatalyst are very particularly preferably introduced and the compounds of the general formula (III) are metered in slowly. It is advantageous if the addition of the Grignard or lithium compounds is present as a solution in the solvents mentioned and preferably by dropwise addition to the reaction mixture is added. It is also advantageous to stir the reaction mixture during the entire reaction.
  • the process for the preparation of amino compounds of the general formula (I) is preferably carried out at room temperature, i.e. H. at 20 to 25 ° C, carried out under an inert gas atmosphere.
  • the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in the usual way.
  • the products can be used as salts with the help of hydrochloric acid solutions such.
  • hydrochloric acid solutions such.
  • reaction product by removing the organic solvent with the aid of a vacuum and separating the remaining residue by column chromatography to isolate the reaction product.
  • Compounds of the present invention can also be prepared by reacting a compound of the general formula (II) shown above, in which R 1 , R 2 and R 3 have the meanings given for formula (I), with a nucleophilic reagent of the general formula (III), wherein R 4 has the meanings given for formula (I), in the presence of catalytic amounts of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide.
  • the process can also be carried out in the presence of a cocatalyst, where alkylsilyl halides can be used as cocatalysts; namely alkylsilyl halides of the general formula (V)
  • the use of the cocatalyst suppresses the ⁇ and / or 3 elimination which is usually observed in titanium alkyls which have ⁇ and / or ⁇ hydrogen atoms.
  • Catalyst selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, based on the carboxamide, at room temperature under an inert gas atmosphere in a solvent selected from the group consisting of toluene, THF, n-hexane, benzene and diethyl ether,
  • carboxamides of the general formula (II) can be reacted with good yields, in which R 1 , R 2 independently of one another have the following
  • a ie branched or unbranched alkyl having 1 to 10 carbon atoms such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and their suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl or branched or unbranched alkenyl having 2 to 10 carbon atoms, such as allyl, vinyl, isoprop
  • Aralkenyl or aralkynyl where in each case the aryl, alkenyl and alkynyl group can assume the meanings given, such as. B. in phenylethynyl, and R 3 is hydrogen or methyl.
  • R 1 and R 2 together form a cyclic ring with 3 to 8 carbon atoms which, in addition to nitrogen, contains further heteroatoms, such as - S -, - O - or - N -.
  • Particularly preferred here are compounds in which R 1 and R 2 form a simple cyclic ring which includes the nitrogen of the carboxamide or in which R 1 and R 2 form a cyclic ring which contains an oxygen atom as a further hetero atom.
  • R 4 preferably represents an alkyl radical having 1 to 10 carbon atoms, such as methyl, ethyl, n- or i-propyl, n-, sec- or t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like suitable isomers, or cycloalkyl having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or corresponding methyl- or ethyl-substituted cycloalkyl groups or mono- or polyunsaturated cycloalkyl groups, such as cyclopentenyl or cyclopentadienyl or
  • alkenyl radicals with 2 to 10 carbon atoms such as allyl, vinyl, isopropenyl, propenyl or
  • alkynyl radicals having 2 to 10 carbon atoms, such as ethynyl or propynyl.
  • Grignard compounds such as methyl magnesium bromide, ethyl magnesium bromide, n- or i-propyl magnesium bromide, i-, sec- or tert-butyl magnesium bromide, n-hexyl magnesium bromide, cyclohexyl mag nesium chloride, alylyl magnesium bromide, vinyl chloride, vinyl bromide, vinyl chloride , Allyl magnesium bromide used for the reactions.
  • Alkylsilyl halides are suitable as co-catalysts in this reaction.
  • these are the alkylsilyl halides of the general formula (V) or of the general formula (VI) described above.
  • Alkylsilane halides are preferably used, in which R ⁇ v is alkyl having 1 to 6 carbon atoms. Particularly preferred are those in which R ⁇ v is alkyl having 1 to 3 carbon atoms and X is chlorine.
  • Dried commercially available metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide, can be used as the catalyst for carrying out the process.
  • Powdered titanium (IV) oxide (Ti0 2 ) is preferably used. In the simplest case, this can be a technical quality. In order to be able to ensure simple separation after the reaction has taken place, it is advantageous to choose a quality which is not too finely divided.
  • the metal oxide preferably titanium dioxide, which has been predried by heating, is used as a suspension in a suitable, likewise predried organic solvent.
  • suitable solvents are e.g. B. aliphatic or aromatic hydrocarbons or ethers.
  • Solvents selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyciohexane, benzene and diethyl ether are preferably used, which are dried before the reaction by methods known to those skilled in the art. Drying can be done using magnesium sulfate, calcium chloride, sodium, KOH or other methods.
  • a preferred embodiment of the method is that the titanium (IV) oxide used as catalyst in an amount of 1-15, preferably 1.5 to 14, in particular 2 to 10, and very particularly preferably 3-6 mol%, based on a mole of the amide used as starting material is introduced in the form of a suspension which is set to a temperature of 10-30 ° C., preferably 15-25 ° C., particularly preferably a temperature of approximately 20 ° C.
  • the starting material is slowly added dropwise either as such in liquid form or dissolved in a solvent selected from the group consisting of toluene, tetrahydrofuran, n-hexane, cyciohexane, benzene and diethyl ether with stirring. Then an amount of cocatalyst corresponding to the amount of starting material to be reacted, if necessary also taken up in a solvent, is added dropwise. The reaction mixture obtained is stirred for a short time, ie for a few minutes, at a constant temperature.
  • nucleophilic reagent of the general formula (IN) in particular one Grignard reagent, slowly added in excess, that the geminal carbonyl carbon atom can be replaced by two identical substituents, ie, a symmetrical substitution of the geminal carbonyl carbon atom.
  • a nucleophilic reagent according to the invention produced according to methods well known to the person skilled in the art, should take place so slowly that the temperature of the reaction mixture does not exceed 50 ° C. It is advantageous if the nucleophilic reagent, ie the Grignard reagent or the lithium compound, is added with thorough mixing, preferably with intensive stirring.
  • the nucleophilic reagent used preferably a Grignard reagent
  • the nucleophilic reagent used is added in an amount of 2.1 to 3 moles per mole of reactant reactant.
  • the Grignard reagent is preferably added in an amount of 2.2 to 2.6 mol based on 1 mol of starting material.
  • the reaction mixture is stirred for a while at a constant temperature until the reaction is complete.
  • the Grignard reagent is prepared in situ by reacting magnesium with an appropriate halide.
  • the amount of magnesium is preferably 2 to 5 times the molar amount, preferably 2.8 to 3.2 times the molar amount, based on the compounds of the general formula (II) used as starting material and the amount of the halide is 2 to 3.8 times the molar amount, preferably 2.2 to 2.6 times the molar amount, based on the compound of the general formula (II).
  • the reaction temperature can be adjusted to approximately 80 ° C., preferably 60 to 70 ° C., in particular 75 ° C., after the addition of the nucleophilic reagent has been completed and thorough mixing has taken place.
  • reaction mixture can be worked up in a manner known to the person skilled in the art known way.
  • the products can be used as salts with the help of hydrochloric acid solutions, e.g. B. 1 molar ethereal hydrochloric acid solutions, precipitated and filtered, and if necessary, purified by recrystallization.
  • hydrochloric acid solutions e.g. B. 1 molar ethereal hydrochloric acid solutions
  • a suitable amount of saturated ammonium chloride solution and water can be added, for example, and stirring is continued intensively for several hours (1-3 hours).
  • the resulting precipitate is separated off and washed with a little dried ether, preferably diethyl ether.
  • the filtrate is made basic (pH> 10) by adding a suitable alkali, such as a NaOH, KOH, sodium or potassium carbonate solution, preferably sodium hydroxide solution.
  • the phases that form are then separated and the aqueous phase is extracted several times (eg three times with 30 ml each in the special case given above) with diethyl ether.
  • the combined organic phases are washed with (e.g. 15 ml) saturated sodium chloride solution and can be dried over potassium carbonate, magnesium sulfate or sodium sulfate and filtered.
  • the products can be purified in various ways according to methods known to the person skilled in the art, such as e.g. B. in the manner described above.
  • the Grignard reagents can also be replaced by the corresponding lithium compounds.
  • the corresponding lithium compounds like the Grignard compounds, can be prepared by methods generally known to the person skilled in the art and can be reacted in the same manner as described above.
  • the reaction takes place in the presence of an organotitanium compound as a catalyst, which is used in an amount of 0.5 to 5 mol%, preferably 1 to 3.5 mol%, based on the compound of the general formula (II).
  • n is an integer from 1 to 4,
  • R v is an alkyl radical with 1 to 10 C atoms or an aryl radical with 6 to 20
  • organotitanium compounds in which R v is isopropyl are preferably used.
  • the organotitanium compound used is particularly preferably Ti (Oi-Pr) 4 , where i-Pr corresponds to an isopropyl radical.
  • the symmetrically substituted amine compounds of the general formula (I) prepared are preferably not only in the presence of a catalyst, but can also be in the presence of a compound of one of the general formulas (V) or (VI) shown above or a compound of the general formula (VII )
  • M ' is Al, Ca, Na, K, Si or Mg, preferably Mg or Na
  • m is an integer from 1 to 4 and the oxidation state of the metal, prepared as a cocatalyst.
  • a cocatalyst is added to the reaction mixture, it should be used in amounts of 0.7 to 1.2, preferably 0.9 to 1.1 equivalents, based on the compound of the general formula (II).
  • R 4 and R 5 have the meanings given above, where,
  • titanium dioxide Group of titanium dioxide, hafnium dioxide and zirconium dioxide.
  • the catalyst is preferably used in the presence of a cocatalyst, in particular in the presence of an alkylsilane halide as cocatalyst.
  • Suitable alkylsian halides are the compounds of the general formula (V) or of the general formula (VI) described above.
  • titanium dioxide is used as the catalyst for carrying out the process.
  • Metal oxide selected from the group titanium (IV) oxide, hafnium dioxide, zirconium dioxide, based on the carboxamide, at a temperature of 10 to 30 ° C. of the group toluene,
  • THF THF, hexanes, benzene and diethyl ether, b ') at least two different in a solvent selected from the group toluene,
  • R 4 and R 5 have the meanings given above, added dropwise, c ') can be re-reacted with stirring and, after the reaction has ended, worked up in a conventional manner.
  • Process step a) or a ') is carried out at a temperature of 15 to 25 ° C, preferably at room temperature.
  • a catalyst system consisting of a metal oxide selected from the group consisting of titanium dioxide, hafnium dioxide and zirconium dioxide and a co-catalyst of the general formula (V) or (VI) described above has proven particularly advantageous.
  • This catalyst system preferably contains a compound selected from the group
  • a catalyst system containing titanium dioxide as the metal oxide is very particularly preferably used.
  • titanium (IV) oxide (Ti0 2 ) as a suspension in a suitable, dried solvent is selected from the group of toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether in an amount of 1 to 15 mol%, preferably 3-13 mol%, based on the amount of the reacting amide.
  • the suspension is adjusted to a temperature of 15 to 30 ° C, preferably to about 20 ° C.
  • the starting material either as such in liquid form or dissolved in a solvent, selected from the group consisting of tetrahydrofuran, toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether, is slowly added dropwise with stirring.
  • a solvent selected from the group consisting of tetrahydrofuran, toluene, tetrahydrofuran (THF), hexanes, benzene and diethyl ether
  • An amount of cocatalyst corresponding to the amount of starting material to be reacted, likewise taken up in a dried solvent, is added dropwise.
  • the reaction mixture obtained is stirred for a short time, ie for a few minutes, while maintaining the temperature.
  • a mixture consisting of equal amounts of two different Grignard reagents is then added to the reaction mixture obtained so slowly that the temperature of the reaction mixture does not rise above 50.degree.
  • the Grignard reagents are added in excess.
  • the Grignard reagents are preferably used in an amount of at least 1.05 mol to 1.5 mol per 1 mol of starting material.
  • the Grignard reagents are used in an amount of 1.1 to 1.3 mol, based on 1 mol of starting material.
  • Compounds of the present invention are advantageously prepared by reacting a compound of the general formula (II) shown above, where R ⁇ R 2 and R 3 have the meaning given above, in a suitable solvent with at least one compound of the general formula (III- a) and (III-b) in the presence of an organotitanium compound of the general formula (IV-b) as a catalyst.
  • the organotitanium compound used is particularly preferably Ti (OiPr) 4 , where iPr stands for an isopropyl radical.
  • the asymmetrically substituted amine compounds of the general formula (I) prepared according to the invention are preferably prepared not only in the presence of a catalyst, but also in the presence of a compound according to one of the general formulas (V), (VI) or (VII) as a cocatalyst.
  • symmetrically or asymmetrically substituted amino compounds of the general formula (1) is preferably carried out at room temperature, ie at 20 to 25 ° C., under an inert gas atmosphere.
  • room temperature ie at 20 to 25 ° C.
  • inert gas atmosphere ie at 20 to 25 ° C.
  • symmetrically or asymmetrically substituted amino compounds of the general formula (I) can be prepared with sufficient yields within reasonable reaction times, the enamine reaction with ⁇ -elimination and the cyclization reaction with ⁇ -hydride elimination being largely avoided.
  • products of the cyclization reaction with ⁇ -hydride elimination can be prepared by not using a cocatalyst in the process described above.
  • the symmetrically or asymmetrically substituted amino compounds can be purified and isolated in a conventional manner, such as. B. described above.
  • the amines of the general formula (I) can be used as pure substances or several different ones can be used as a combinatorial library in a combinatorial synthesis in which the amines are reacted with one or more reactants to create modified amines of the general formula (I).
  • the structural element of the geminal substitution of the amines is preferably obtained.
  • the combinatorial synthesis to create modified amines of the general formula (I) it is advantageously possible to use those amines which have already been found to be effective in a biological screening process.
  • amines of the general formula (I) with biological activity in the creation of modified amines it is possible to achieve an improved activity by combinatorial synthesis.
  • the process can be carried out catalytically.
  • Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g.
  • oral or rectal or parenteral application or for application in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils, Benzyl alcohols, polyethylene glycols, glycerin acetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.
  • Tablets, coated tablets, capsules, syrups, juices or drops are used in particular for oral use; of particular interest are coated tablets and capsules with enteric coatings or capsule shells.
  • Suppositories are used for rectal administration, solutions are used for parenteral administration, preferably oily or aqueous solutions, further suspensions, emulsions or implants.
  • sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas mixture (e.g. chlorofluorocarbons).
  • a propellant gas mixture e.g. chlorofluorocarbons
  • the active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol.
  • Inhalation solutions can be administered using standard inhalers.
  • the active ingredients claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. can be used for the preparation of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.
  • the compounds of the formula (I) or (Ia) according to the invention are generally administered in analogy to other known, commercially available preparations, but in particular in analogy to the compounds described in US Pat. No. 4,880,804, preferably in doses between about 1 mg and 1 g, in particular between 50 and 500 mg per dosage unit.
  • the daily dosage is preferably between about 0.1 and 50 mg / kg, in particular 1 and 10 mg / kg body weight.
  • the specific dose for each individual patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the administration time and route and on the excretion speed, drug combination and severity of the disease to which the therapy applies. Oral application is preferred.
  • Titanium (IV) oxide induced symmetric dialkylation of carboxylic acid amides with Grignard reagents.
  • the compounds listed in Table 4 were prepared by titanium (IV) oxide-induced asymmetrical disubstitution of carboxylic acid amides with different Gngnard reagent mixtures.
  • an aryl Grignard reagent in the case of asymmetrical dialkylation, a mixture of 6 mmol of two different Grignard reagents (2a and 2b), at least one of the Grignard reagents containing an aryl residue) being added so slowly that the mixture does not exceed 50 ° C warmed.
  • 15 ml of saturated ammonium chloride solution and 15 ml of water are added and the mixture is stirred vigorously for 1-3 hours.
  • the resulting precipitate is separated off and washed with a little dried diethyl ether.
  • the filtrate is made basic (pH> 10) by adding 15% sodium hydroxide solution.
  • the phases are then separated and the aqueous phase is extracted three times with 30 ml of diethyl ether each time.
  • the combined organic phases are washed with 15 ml of saturated sodium chloride solution and dried over potassium carbonate and filtered.
  • the products can be cleaned in various ways (see Table 6):
  • the organic phase is extracted twice with 40 ml of a 0.5 M HCl solution. This extract is adjusted to pH> 10 with 2 M NaOH solution and extracted again with three times 30 ml of dried diethyl ether. The combined organic phases are dried over potassium carbonate and the solvent is removed under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

L'invention concerne une amine de la formule générale (I), où R1 et R2 peuvent être identiques ou différents et désignent chacun indépendamment l'un de l'autre alkyle substitué ou non substitué, cycloalkyle, alkényle, cycloalkényle, alkinyle, aryle ou trialkylsilyle ou R1 et R2 peuvent former conjointement avec l'atome d'azote auquel ils sont liés, un composé cyclique cycloalkyle substitué ou non substitué qui, outre l'atome d'azote, peut contenir un autre hétéroatome, sélectionné dans le groupe comprenant azote, oxygène ou soufre. R3 est sélectionné parmi hydrogène et méthyle pouvant éventuellement être substitué par 1 à 3 atomes de fluor. R4 et R5 peuvent être identiques ou différents et désignent chacun indépendamment l'un de l'autre alkyle, cycloalkyle, alkényle, cycloalkényle, alkinyle, aryle substitué ou non substitué ou un alkyle substitué par aryle substitué ou non substitué, cycloalkyle, alkényle, cycloalkényle ou alkinyle, sous réserve qu'au moins un reste R4 ou R5 contienne un groupe aryle ou un de ses sels.
PCT/EP1999/004258 1998-06-18 1999-06-18 Amines substituees de maniere geminee WO1999065864A2 (fr)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
DE19827165A DE19827165A1 (de) 1998-06-18 1998-06-18 Katalytisch Titan(IV)-oxid-vermittelte geminale unsymmetrische Dialkylierung von Carbonsäureamiden
DE19827164A DE19827164A1 (de) 1998-06-18 1998-06-18 Katalytisch Titan(IV)-oxid vermittelte geminale symmetrische Dialkylierung von Carbonsäureamiden
DE19827165.4 1998-06-18
DE19827163A DE19827163A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen, unsymmetrischen Disubstitution von Carbonsäureamiden mit 2 unterschiedlichen Grignardreagenzien
DE19827161.1 1998-06-18
DE19827164.6 1998-06-18
DE19827163.8 1998-06-18
DE19827167 1998-06-18
DE19827167.0 1998-06-18
DE19827161A DE19827161A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen, symmetrischen Disubstitution von Carbonsäureamiden mit Grignardreagenzien
DE19827166A DE19827166A1 (de) 1998-06-18 1998-06-18 Verfahren zur katalytischen Disubstitution von Carbonsäureamiden mit wenigstens einem Grignardreagenz
DE19827166.2 1998-06-18
DE19844194.0 1998-09-26
DE19844194A DE19844194A1 (de) 1998-06-18 1998-09-26 Verfahren zur symmetrischen oder unsymmetrischen Disubstitution von Carbonsäureamiden mit Organotitanaten und Grignardreagenzien

Publications (2)

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WO1999065864A2 true WO1999065864A2 (fr) 1999-12-23
WO1999065864A3 WO1999065864A3 (fr) 2003-05-22

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PCT/EP1999/004257 WO1999065863A1 (fr) 1998-06-18 1999-06-18 Procede pour preparer des bibliotheques combinatoires d'amines
PCT/EP1999/004256 WO1999065318A2 (fr) 1998-06-18 1999-06-18 Amines substituees de maniere geminee
PCT/EP1999/004255 WO1999065855A2 (fr) 1998-06-18 1999-06-18 Bibliotheques combinatoires d'amines substituees de maniere geminee

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PCT/EP1999/004255 WO1999065855A2 (fr) 1998-06-18 1999-06-18 Bibliotheques combinatoires d'amines substituees de maniere geminee

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044160A3 (fr) * 1999-12-14 2002-03-07 Merck Patent Gmbh Procede d'elaboration de bibliotheques combinatoires d'amines
WO2001044161A3 (fr) * 1999-12-17 2002-04-11 Merck Patent Gmbh Procede d'elaboration de bibliotheques combinatoires d'amines substituees par aryle
JP2015522537A (ja) * 2012-05-18 2015-08-06 ウニヴァーシテテット イ オスロ 心臓障害の治療に用いられる第三級アミン

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103167866B (zh) * 2010-09-20 2015-09-23 瑟纳治疗公司 用于寡核苷酸递送的新型低分子量阳离子脂质

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB807835A (en) * 1955-07-01 1959-01-21 Thomae Gmbh Dr K New tertiary amines and their salts and process for their preparation
US3067101A (en) * 1959-11-25 1962-12-04 Lilly Co Eli Method for controlling hypertension
US4020059A (en) * 1975-06-02 1977-04-26 Nippon Shokubai Kagaku Kogyo Co., Ltd. Process for preparing tertiary amines
BE842528R (fr) * 1976-06-03 1976-12-03 Derives actifs de methylamine, compositions therapeutiques les contenant ainsi que les procedes de preparation de ces derives et compositions
DE2657476A1 (de) * 1976-12-18 1978-06-22 Basf Ag Morpholinderivate
CA2207137A1 (fr) * 1996-06-14 1997-12-14 James Erwin Fritz Procede combinatoire a l'aide d'agent d'elimination pour la preparation de banques d'amine secondaire
US6232467B1 (en) * 1996-06-28 2001-05-15 University Of Southern California Method for the synthesis of amines and amino acids with organoboron derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044160A3 (fr) * 1999-12-14 2002-03-07 Merck Patent Gmbh Procede d'elaboration de bibliotheques combinatoires d'amines
WO2001044161A3 (fr) * 1999-12-17 2002-04-11 Merck Patent Gmbh Procede d'elaboration de bibliotheques combinatoires d'amines substituees par aryle
JP2015522537A (ja) * 2012-05-18 2015-08-06 ウニヴァーシテテット イ オスロ 心臓障害の治療に用いられる第三級アミン
US9951033B2 (en) 2012-05-18 2018-04-24 Universitetet I Oslo Tertiary amines for use in the treatment of cardiac disorders

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JP2003524588A (ja) 2003-08-19
WO1999065318A3 (fr) 2003-04-17
WO1999065855A3 (fr) 2003-12-11
EP1087929A1 (fr) 2001-04-04
WO1999065863A1 (fr) 1999-12-23
EP1088029A1 (fr) 2001-04-04
JP2002518366A (ja) 2002-06-25
WO1999065864A3 (fr) 2003-05-22
WO1999065318A2 (fr) 1999-12-23

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