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EP0799211A1 - 2-carbamoyl-1,4,5,6-tetrahydropyrazines - Google Patents

2-carbamoyl-1,4,5,6-tetrahydropyrazines

Info

Publication number
EP0799211A1
EP0799211A1 EP95929045A EP95929045A EP0799211A1 EP 0799211 A1 EP0799211 A1 EP 0799211A1 EP 95929045 A EP95929045 A EP 95929045A EP 95929045 A EP95929045 A EP 95929045A EP 0799211 A1 EP0799211 A1 EP 0799211A1
Authority
EP
European Patent Office
Prior art keywords
carbamoyl
acid
group
formula
tetrahydropyrazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95929045A
Other languages
German (de)
English (en)
Inventor
Christof Kandzia
Michael Henningsen
Sven Doye
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF SE
Original Assignee
BASF SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by BASF SE filed Critical BASF SE
Publication of EP0799211A1 publication Critical patent/EP0799211A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom

Definitions

  • the present invention relates to 2-carbamoyl-1,4,5,6-tetrahydropyrazine of the general formula I.
  • R 1 , R 2 and R 3 are identical or different and in each case represent a straight-chain or branched C 1 to C 8 alkyl group, a C 5 to C 6 cycloalkyl group, a C 6 to C 7 methylene cycloalkyl group, a C 6 - to C 10 aryl group or a C 7 - to C 12 aralkyl group or in which the radicals R 1 and R 2 are connected to one another and together with the exocyclic, non-carbonylic carbon atom C 1 a 5- form to 6-membered, cycloaliphatic ring and R 3 has the abovementioned meaning or in which R 3 represents hydrogen and R 1 and R 2 are identical or different and have the abovementioned meaning, a process for their preparation and their use.
  • EP-A 541 168 describes a number of different ones
  • HIV-1 protease inhibitors whose structure is characterized by a piperazine-2-carbamoyl group.
  • a particularly preferred HIV protease inhibitor is, inter alia, the compound of the formula VI
  • the piperazin-2-tert. contains -butyl-carboxamide group as a structural component.
  • the HIV protease inhibitor VI an anti-AIDS drug, is also known as the active ingredient "L-735,524". Its synthesis is described in EP-A 541 168 and by Askin et al, Tetrahedron Lett. 35, 673 (1994).
  • R 1 , R 2 and R 3 are identical or different and in each case represent a straight-chain or branched C 1 to C 8 alkyl group, a C 5 to C 6 cycloalkyl group, a C 6 to C 7 methylene cycloalkyl group, a C 6 - to C 10 aryl group or a C 7 - to C 12 aralkyl group or in which the radicals R 1 and R 2 are connected to one another and together with the exocyclic, non-carbonylic carbon atom C 1 a 5- form to 6-membered, cycloaliphatic ring and R 3 has the abovementioned meaning or in which R 3 represents hydrogen and R 1 and R 2 are identical or different and have the abovementioned meaning.
  • R 5 hydrogen is a straight-chain or branched C 1 - to C 7 -alkyl, C 5 - bis
  • C 6 cycloalkyl group a C 6 to C 10 aryl or a C 7 to C 12 aralkyl group and Z is one of the Brönsted mentioned and / or Lewis-acidic conditions means removable leaving group.
  • the radicals R 1 , R 2 and R 3 which may be the same or different, represent straight-chain or branched C 1 -C 8 -alkyl groups, for example the methyl, ethyl, n-propyl, Isopropyl, n-butyl, 2-butyl, isobutyl, n-pentyl, or the 2-ethylhexyl group, particularly preferably for the methyl group, or for the methylene-cyclopentyl group or the methylene-cyclohexyl group, or for C 5 - to
  • C 6 -cycloalkyl groups such as the cyclopentyl or cyclohexyl group, or for C 6 - to Cio-aryl groups, such as the phenyl or naphthyl group, preferably the phenyl group, or for C 7 - to
  • C 12 aralkyl groups preferably the benzyl group.
  • radicals R 1 and R 2 can also be linked to one another and, together with the exocyclic, non-carbonylic carbon atom C 1, form a 5- to 6-membered cycloaliphatic ring, for example a cyclopentyl or cyclohexyl ring.
  • the radical R 3 can also be different from R 1 and R 2 and stand for hydrogen, where R 1 and R 2 can have the meaning given above.
  • a particularly preferred compound is 2-tert-butylaminocarbonyl-1,4,5,6-tetrahydropyrazine of the formula II
  • the radicals R 1 , R 2 and R 3 have , of course, the meaning given above for the explanation of the compounds according to general formula I.
  • the group Z stands for a leaving group which can be split off under Bronsted and / or Lewis acidic conditions, the splitting off of which forms the intermediate carbocation under the reaction conditions specified here in situ in the reaction mixture, which immediately forms with the starting compound II to form the compounds of the invention in general Formula I reacts.
  • the leaving groups Z are, for example, the hydroxyl group OH, ether groups OR 4 or ester groups as well as halogen atoms, such as chlorine, bromine or iodine atoms. While the oxygen-containing leaving groups are preferably split off using Bronsted acids or mixtures of Bronsted and Lewis acids, a Lewis acid or the mixture of one is preferably used to split off the halogen atoms
  • R 4 of the leaving groups Z can in principle be chosen as desired, since they generally have no particular significance for the ability to split off the group Z.
  • R 4 for a straight-chain or branched C 1 - to C 20 -, preferably a C 1 - to C 8 -alkyl group, a C 3 - to C 8 -, preferably a C 5 - to C 6 -cycloalkyl group, a C 6 to C 10 aryl group, preferably the phenyl group or a C 7 to C 12 aralkyl group, preferably the benzyl group.
  • the radicals R 4 can be chosen as desired, since they generally have no particular significance for the ability to split off the group Z.
  • R 4 for a straight-chain or branched C 1 - to C 20 -, preferably a C 1 - to C 8 -alkyl group, a C 3 - to C 8 -, preferably a C 5 - to C 6 -cycloalkyl group,
  • Preferred compounds IV are, for example, tertiary alcohols, tertiary ethers, such as methyl tert-butyl ether, or trimethyl methane halides, such as trimethyl methane chloride. Tert-butanol is particularly preferably used as compound IV.
  • the compounds of general formula V H are, for example, tertiary alcohols, tertiary ethers, such as methyl tert-butyl ether, or trimethyl methane halides, such as trimethyl methane chloride.
  • Tert-butanol is particularly preferably used as compound IV.
  • R5 R 2 can be used in the process according to the invention, the under
  • the radicals R 1 and R 2 can be identical or different and have the meanings given above for R 1 and R 2 .
  • the radical R 5 can be hydrogen, a straight-chain or branched C 1 to C 7 alkyl group, a C 5 to C 6 cycloalkyl group, a C 6 to C 10 aryl group or a C 7 to C 11 aralkyl group stand.
  • a particularly preferred compound V is isobutene.
  • the Bronsted or Lewis acid or the mixture of Bronsted and Lewis acid is expediently used with respect to the cyanopyrazine III in excess, for example in a single to five-fold molar excess, preferably in an approximately three-fold molar excess. It is also possible to use higher molar excesses of these acids with respect to III without disadvantage. For example, it is possible to use the Bronsted acids as solvents in the process according to the invention, so that these acids are present in a 10 to 100-fold molar excess with respect to compound III.
  • the order of addition of the compounds III, IV or V to the reaction mixture is generally not critical and can be chosen as desired.
  • the Bronsted or Lewis acids can be placed in the reactor or in addition to those placed in the reactor
  • Reactants III, IV and V are dosed.
  • Brönsted acids which are preferably used are those which have a pKa value of less than or equal to 4.
  • the pKs value is a measure of the acid level and for example in HR Christians, Fundamentals of general and inorganic chemistry, 7th edition, pp. 357-365, Otto Salle Verlag, Frankfurt 1982 or in
  • Suitable Bronsted acids are, for example, hydrohalic acids, such as hydrofluoric acid, hydrochloric acid or hydrobromic acid, sulfuric acid, phosphoric acid, heteropolyacids, such as dodecamolybdatophosphoric acid (H 3 PMO 12 O 40 .nH 2 O), dodecamolybdatosilicic acid
  • Halogen carboxylic acids such as formic acid, trifluoroacetic acid or trichloroacetic acid, sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, tetrafluoroboric acid or perchloric acid.
  • sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, tetrafluoroboric acid or perchloric acid.
  • These Bronsted acids can also advantageously be used in a mixture with other Bronsted acids, including weaker Bronsted acids, that is to say those with a pKa value of greater than 4.
  • Mixtures of sulfuric acid and acetic acid are very suitable for the process according to the invention.
  • the Bronsted acids can be used undiluted, dissolved or in a mixture with a solvent which is inert under the reaction conditions, for example an ether such as tetrahydrofuran, dioxane, dibutyl ether or dimethoxyethane, a halogenated hydrocarbon, for example carbon tetrachloride, or an aliphatic or aromatic hydrocarbon, for example benzene become.
  • a solvent which is inert under the reaction conditions
  • a solvent which is inert under the reaction conditions
  • a solvent which is inert under the reaction conditions
  • a solvent which is inert under the reaction conditions for example an ether such as tetrahydrofuran, dioxane, dibutyl ether or dimethoxyethane, a halogenated hydrocarbon, for example carbon tetrachloride, or an aliphatic or aromatic hydrocarbon, for example benzene become.
  • heterogeneous Bronsted acids such as acidic ion exchange resins such as sulfonated styrene-divinylbenzene copolymers, sulfonated polystyrene, Nafion ® resins, sulfonated carbon or zeolites, such as pentasils, such as ZSM-5 or ZSM-10 zeolites, Mordenites, ⁇ -zeolites or Y-zeolites, acidic aluminum phosphates, or zirconium dioxide impregnated with sulfuric acid, phosphoric acid or heteropolyacids can be used as heterogeneous Bronsted acids.
  • acidic ion exchange resins such as sulfonated styrene-divinylbenzene copolymers, sulfonated polystyrene, Nafion ® resins, sulfonated carbon or zeolites, such as pentasils, such as ZSM-5 or Z
  • Lewis acids commonly used for carrying out organic reactions can be used in the process according to the invention, for example aluminum chloride, titanium halides such as titanium tetrachloride, zirconium halides such as zirconium tetrachloride, tin (IV) chloride, organotin halides such as tributyltin chloride , tributyltin bromide, tributyltin iodide, titanium (IV) alkoxides, such as Titantetramethanolat, titanium tetraethoxide or titanium tetraisopropoxide, zinc halides such as zinc chloride, zinc bromide or zinc iodide, silicon halides such as silicon tetrachloride, boron halides, and the addition complex with alcohols or ethers, such as boron trifluoride, boron trifluoride diethyl etherate,
  • the Lewis acids can be used undiluted, dissolved or mixed with one of the solvents previously mentioned in connection with the use of Bronsted acids or in a mixture with one or more Bronsted acids.
  • weaker Bronsted acids such as acetic acid or higher carboxylic acids, can advantageously also be used, for example boron trifluoride-acetic acid mixtures.
  • the process according to the invention is advantageously carried out under essentially anhydrous conditions.
  • the yield of I decreases with increasing water content of the reaction mixture.
  • a water content of the reaction mixture of 3% by weight, based on the entire reaction mixture, no disadvantageous consequences for the process result have yet been found.
  • Bronsted acids which have a strong tendency to attach water molecules to the acid molecule, such as sulfuric acid or phosphoric acid, higher ones can also be used
  • Water contents of the reaction mixture can be tolerated without disadvantages, since the water of the reaction mixture is removed by hydrating the acid.
  • commercially available concentrated sulfuric or phosphoric acid can be used in the process according to the invention.
  • the process according to the invention is generally carried out at temperatures from -70 to + 130 ° C., preferably at -20 to + 30 ° C., in particular at 0 to + 5 ° C., under atmospheric pressure or elevated pressure, preferably under the autogenous pressure of the reaction system.
  • the process according to the invention can be carried out batchwise, e.g. in stirred tanks, or continuously, e.g. in stirred tank cascades or tubular reactors.
  • the reaction mixture is advantageously worked up by hydrolysis with water, ice or ice water at temperatures between -20 ° C. and 40 ° C.
  • Any base can be used to neutralize the excess acid.
  • Organic bases which are water-soluble or partially water-soluble are advantageous, for example lower aliphatic amines, pyridine, piperidine or inorganic bases such as ammonia, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide and others.
  • aqueous Al is particularly preferred Potash hydroxide solutions in concentrations from 0.5 to 40%, at temperatures below 5 ° C.
  • the product of value I can be isolated by the customary techniques such as sedimentation, filtration, centrifugation or phase separation, in particular by extraction with solvents which are immiscible with water at least in the presence of salts or, to a limited extent, are water-soluble. Continuous extraction with solvents which are immiscible with water, such as methyl tert-butyl ether or ethyl acetate, is particularly preferred. However, any other limited water-soluble solvent in which the product of value I has sufficient solubility can also be used.
  • the product of value I can be purified by recrystallization from organic solvents, water or mixtures of water and / or organic solvents or by distillation.
  • the 2-carbamoyl-tetrahydropyrazines according to the invention of the general formula I, in particular 2-tert-butylaminocarbonyl-1,4,5,6-tetrahydropyrazine of the formula II, have the advantage that they can be obtained in a simple manner from inexpensive starting materials. Furthermore, by using the
  • the piperazine derivatives of the general formula VII are consequently accessible starting from inexpensive and readily available starting materials in a total of only 3 synthesis steps, the preparation of the 2-cyano-1,4,5,6-tetrahydropyrazine of the formula III being included in the payment .
  • the catalytic hydrogenation of the 2-carbamoyl-1,4,5,6-tetrahydropyrazine I to the 2-carbamoyl-piperazine derivatives of the formula VII can be carried out in a conventional manner using heterogeneous or homogeneous hydrogenation catalysts.
  • all hydrogenation catalysts which are suitable for the hydrogenation of CC double bonds can be used as heterogeneous hydrogenation catalysts.
  • Commercial hydrogenation catalysts which contain at least one element from group VIIIB of the Periodic Table of the Elements, such as platinum, rhodium or palladium supported catalysts or Raney nickel, in particular rhodium-on-activated carbon, rhodium-on-aluminum oxide, are preferably used.
  • Sulfonic acid for example malic acid, almond acid or camphorsulfonic acid
  • the corresponding diastereomeric salts of these acids are obtained in situ with the racemate of the 2-carbamoyl-piperazine derivatives VII obtained, which are subsequently e.g. by fractional crystallization and cleavage of the acid from ⁇ en salts isolated in the corresponding enantiomeric 2-CarDamoyl-piperazine derivatives VII can be separated.
  • Supported catalysts suitable for 2-carbamoyl-tetrahydropyrazine generally contain 0.1 to 10% by weight, preferably 0.5 to 8% by weight, based on the total weight of the catalyst, of the platinum metal concerned and, if they are not commercially available, be produced in a conventional manner by impregnating the carrier material in question with a platinum metal compound.
  • catalysts which contain an element from Group VIIIB of the Periodic Table of the Elements and in which this element is complexed with identical or different ligands, preferably carboxyl and / or phosphine ligands, can likewise be used as homogeneous hydrogenation catalysts.
  • ligands preferably carboxyl and / or phosphine ligands
  • Rh (PPh 3 ) 3 Ci Rh (PPh 3 ) 3 Ci, HRuCl (PPh 3 ) 3 , HRuCl (CO) (hexyldiphenylphosphine) 3 , RuH 2 (CO) (PPh 3 ) 3 or RuH 2 (PPh 3 ) 3 , where the abbreviation PPh 3 is tripnenylphosphine means.
  • an ⁇ ere phosphine ligands can be used instead of triphenyl phosphine, such as trimethylphosphine, Triethylpnosphin, tripropylphosphine, Trusopropylphosphin, Tributylpnosphin, Trioctylpnosphin, Tridecylphosphin, tricyclopentylphosphine, Tricyciohexylphosphin, tritolylphosphine, Cyclohexyldipnenylphosphin, Tetraphenyldiphosphinomethan, 1,2-bis (diphenylphosphino) ethane, Tetramethyldiphosphinomethan, Tetraethyldipnosphinomethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylpnosphino) butane, tetra-t-butyldiphospninomethane, 1,2-bis (dimethylp
  • alkyl or arylphosphine ligands can be prepared by methods which are conventional per se, for example according to the methods described in
  • racemate of the 2-carbamoyl-piperazine VII in question is also formed in the hydrogenation, which in the manner described e.g. can be split into its enantiomers by means of optically active carboxylic or sulfonic acids.
  • 2-Carbamoyl-tetrahydropyrazine I also optically active, homogeneous hydrogenation catalysts are used, which enable the enantioselective hydrogenation of the compounds I to the corresponding 2-carbamoyl-piperazines VII desired configuration.
  • Palladium- or platinum-containing homogeneous catalysts with optically active phosphine ligands are available which are used to carry out the enantioselective hydrogenation of the C-C double bond of the
  • Compounds I are suitable, for example optically active rhodium, ruthenium, palladium or platinum complexes with the chiral phosphine ligands, 4, 5-bis (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane (DIOP) , 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (BINAP) or bis (diphenyiphosphino) butane (CHIRAPHOS).
  • DIOP 5-bis (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane
  • BINAP 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl
  • CHIRAPHOS bis (diphenyiphosphino) butane
  • the homogeneous catalysts are generally used in an amount of 0.0001 to 0.1 mol catalyst / mol I with respect to the 2-carbamoyl-tetrahydropyrazine I to be hydrogenated. Of course, smaller or larger amounts of the homogeneous catalyst can also be used, which leads to an increase or decrease in the hydrogenation time.
  • the hydrogenation of the CC double bond of the compounds I can be carried out continuously or batchwise. If heterogeneous hydrogenation catalysts are used, the hydrogenation can be carried out, for example, in a batch mode Stirred kettle by means of a suspension in the reaction medium
  • Hydrogenation catalyst or in a loop reactor in which the hydrogenation catalyst can be present in suspended form or preferably in a fixed bed arrangement In the continuous mode of operation, the hydrogenation can e.g. Stirred tank cascades, loop reactors or tubular reactors can be carried out, the heterogeneous catalyst also being in suspended form or, if loop or tubular reactors are used, in a fixed bed arrangement. If a fixed bed arrangement of the heterogeneous catalyst is used, the hydrogenation can be carried out either in the bottom or in the trickle mode.
  • the hydrogenation of the C-C double bond of the 2-carbamoyl-tetrahydropyrazine I by means of homogeneous catalysts can be carried out batchwise or continuously in stirred tanks or tubular reactors.
  • Compounds VII can advantageously in the presence of a solvent which is inert under the hydrogenation conditions used, for example water, aliphatic or aromatic hydrocarbons, ethers such as diethyl ether, methyl tert-butyl ether, dimethoxyethane, tetrahydrofuran or dioxane or alcohols such as methanol, ethanol, propanol or butanol , be performed.
  • the hydrogenation conditions are chosen so that only the CC double bond in the 2-carbamoyl-tetrahydropyrazines I is hydrogenated and there are no side reactions. In general, the hydrogenation is carried out at from 0 to 200.degree. C., preferably from 10 to 100.degree.
  • the 2-carbamoyl-piperazines can be isolated from the hydrogenation by conventional work-up methods such as crystallization or distillation.
  • the 2-carbamoyl-piperazines VII thus obtained can then be prepared in a manner known per se, for example as in EP-A 541 168 or in Tetrahedron Lett. 35, 673 (1994), for the synthesis of the HIV protease inhibitors according to EP-A 541 168, in particular for the synthesis of the active ingredient L-735,524 of the formula VI. example 1
  • the reaction discharge was slowly poured onto a mixture of 600 g of ice and 100 g of 50% strength by weight aqueous sodium hydroxide solution and stirred for a further 2.5 hours.
  • the resulting aqueous phase was extracted overnight with 300 g of methyl tert-butyl ether. After the methyl tert-butyl ether phase had cooled to 5 ° C., the product was obtained as a yellow salt. After filtering off under nitrogen and drying in vacuo, 6.9 g of crystalline product were obtained.

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Abstract

La présente invention concerne des 2-carbamoyl-1,4,5,6-tétrahydropyrazines ayant la formule générale (I), dans laquelle R<1>, R<2> et R<3> sont identiques ou différents et représentent chacun un groupe alcoyle C1 à C8 à chaîne droite ou ramifiée, un groupe cycloalcoyle C5 ou C6, un groupe méthylène-cycloalcoyle C6 ou C7, un groupe aryle C6 à C10 ou un groupe aralcoyle C7 à C12, ou dans laquelle les radicaux R<1> et R<2> sont reliés entre eux et, avec l'atome de carbone C<1> exocyclique, non carbonyle, forment un anneau cycloaliphatique à 5 ou 6 éléments, et R<3> a la signification indiquée ci-dessus, ou dans laquelle R<3> est l'hydrogène et R<1> et R<2> sont identiques ou non et ont la signification indiquée ci-dessus. L'invention concerne aussi un procédé de fabrication de ces composés et leur utilisation.
EP95929045A 1994-12-22 1995-08-01 2-carbamoyl-1,4,5,6-tetrahydropyrazines Withdrawn EP0799211A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4446025 1994-12-22
DE4446025A DE4446025A1 (de) 1994-12-22 1994-12-22 2-Caroxamido-1,4,5,6-tetrahydropyrazine
PCT/EP1995/003063 WO1996019460A1 (fr) 1994-12-22 1995-08-01 2-carbamoyl-1,4,5,6-tetrahydropyrazines

Publications (1)

Publication Number Publication Date
EP0799211A1 true EP0799211A1 (fr) 1997-10-08

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP95929045A Withdrawn EP0799211A1 (fr) 1994-12-22 1995-08-01 2-carbamoyl-1,4,5,6-tetrahydropyrazines

Country Status (5)

Country Link
EP (1) EP0799211A1 (fr)
JP (1) JPH10510818A (fr)
CN (1) CN1170408A (fr)
DE (1) DE4446025A1 (fr)
WO (1) WO1996019460A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0805803B1 (fr) * 1995-01-23 2002-10-30 Lonza AG Procede pour la production d'amides d'acide 1,4,5,6-tetrahydropyrazine-2-carboxylique

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2195027C (fr) * 1991-11-08 2000-01-11 Joseph P. Vacca Inhibiteurs de la protease du vih utiles pour le traitement du sida
WO1995002584A2 (fr) * 1993-07-16 1995-01-26 Merck & Co., Inc. Procede de fabrication d'inhibiteurs de la protease de vih
US5734055A (en) * 1993-11-22 1998-03-31 Koei Chemical Co. Ltd. Process for preparing N-tert-butyl-2-pyrazinecarboxamide and N-tert-butyl-2-piperazinecarboxamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9619460A1 *

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Publication number Publication date
DE4446025A1 (de) 1996-06-27
CN1170408A (zh) 1998-01-14
WO1996019460A1 (fr) 1996-06-27
JPH10510818A (ja) 1998-10-20

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