HRP970395A2 - New triazolopurines, method for preparing them and their use as drugs - Google Patents

Abstract

1,2,4-TriazoloÄ1,5-aÜpurin-9-one derivatives of formula (I), and their racemates, enantiomers, diastereomers and/or acid addition salts are new. R1 or R3 and R4 or R5 = H, Z, COOZ, SO2Z, SO2A, COZ, aralkyl, aralkenyl, aralkynyl, A, COOA, SO2A, COA, CONHR or (all optionally substituted) benzyloxycarbonyl, benzylsulphonyl, 4-8C cycloalkenyl, 6-8C cycloalkynyl, benzyl, or benzylcarbonyl; Z = 1-10C alkyl, 3-8C cycloalkyl, 6-10C aryl, heteroaryl (all optionally substituted), 2-10C alkenyl or 2-10C alkynyl; A = optionally substituted 5-7 membered heterocycle (containing one or more of N, S and O as heteroatom(s) and bonded via C); R = H, or phenyl, benzyl or 3-6C cycloalkyl (all optionally substituted), or alkyl, alkenyl or alkynyl (all of up to 10C and optionally substituted by OH, optionally substituted phenyl or optionally substituted amino); R2 = H, OH, NH2, halo, NO2, CF3, COOH, SH, 1-6C alkylthio, SO2Z, benzylsulphonyl, OSO2Z, NHSO2Z, CONHZ, di-(1-10C alkyl or 2-10C alkenyl)-aminocarbonyl, N-(1-10C alkyl)-N-(2-10C alkenyl or alkynyl)-aminocarbonyl, NHCOOZ, OCONHZ, C(=NH)NHZ, OZ, COOZ, OCOZ, SZ, optionally substituted amino, preferably NR8R9, or (all optionally substituted) 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, 3-8C cycloalkyl, 5-8C cycloalkanone, 4-8C cycloalkenyl, 6-8C cycloalkynyl, 6-10C aryl, aryl-(1-6C)alkyl, aryl-(2-6C)alkenyl, aryl-(2-6C)alkynyl, cycloalkyl-(1-6C)alkyl, cycloalkyl-(2-6C)alkenyl, cycloalkyl-(2-6C)alkynyl, 5-7 membered heterocycle (containing one or more of O, S and optionally substituted N as heteroatom(s) and linked via C- or N- or via a 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl bridge), or (all optionally substituted) 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, 3-8C cycloalkyl, 5-8C cycloalkanone, 4-8C cycloalkenyl, 6-8C cycloalkynyl, 6-10C aryl, aryl-(1-6C)alkyl, aryl-(2-6C)alkenyl, aryl-(2-6C)alkynyl, cycloalkyl-(1-6C)alkyl, cycloalkyl-(2-6C)alkenyl, cycloalkyl-(2-6C)alkynyl, 5-7 membered heterocycle (containing one or more of O, S and optionally substituted N as heteroatom(s) and linked via C- or N- or via a 1-6C alkyl, 2-6C alkenyl or 2-6C alkynyl bridge), methylenedioxyphenyl, ethylenedioxyphenyl, fluorenyl or optionally substituted group of formula (a)-(e); R6 = as for R2 or CHO; x = 1 or 2; y = 0-2; dotted lines in (a) = optional bonds; Q = H or 1-6C alkyl, but cannot be alkyl if the ring system in (a) contains two double bonds; Y = bond, 1-6C alkylene, 2-6C alkenylene or 2-6C alkynylene; R8, R9 = 1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl (optionally substituted by OH, optionally substituted phenyl, optionally substituted benzyl, optionally substituted amino or 1-6C alkoxy), H, optionally substituted 3-6C cycloalkyl, (CH2)mNHCOOR4; or NR8R9 = saturated or unsaturated 5- or 6- membered ring (optionally containing another O, S or N heteroatom and optionally substituted by 1-4C alkyl, (CH2)nPh, (CH2)nNH2, oxo, ketal (preferably OCH2CH2O), (CH2)nNH-(1-4C alkyl), (CH2)nN(1-8C alkyl)2, (CH2)nNHCOOR10, halo, OR10, CN, NO2, NH2, CH2NR8R9 (sic), OH, COOH, SO3H, COOR10, CONR8R9 (sic) or SO2R10); m = 1-4; n = 2-4; R10 = H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, or benzyl or phenyl (both optionally substituted by one or more OMe).

Description

The invention relates to new derivatives of triazolpurine as well as to the basic structure of triazolpurine, to procedures for their production and their use as medicine.

New triazolpurine derivatives have a structure of the general formula (I)

[image]

where

R1 or R3 represents hydrogen, optionally substituted C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C3-C8-cycloalkenyl or optionally substituted C6- C8-cycloalkynyl;

R1 or R3 represents optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C6-C10- aryl- or optionally substituted heteroaryl, optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby the heterocycle is connected via the carbon atom of the ring;

R1 or R3 represents optionally substituted C1-C10-alkyloxycarbonyl, optionally substituted C2-C10-alkenyloxycarbonyl, optionally substituted C2-C10-alkynyloxy-carbonyl, optionally substituted C3-C8-cycloalkyloxy-carbonyl, optionally substituted C6 -C10-aryloxycarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkyloxycarbonyl, A-O-CO- where A has the meaning of optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms can contain one or more atoms from the group they consist of nitrogen, oxygen or sulfur, where A is connected through a carbon atom of the ring;

R1 or R3 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl, C2-C10-alkynyl-sulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted C6- C10-aryl-C1-C6-alkylsulfonyl,

the residue A-SO2- in which A has the above meaning and is connected through a carbon atom of the ring;

R1 or R3 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl, optionally substituted C2-C10-alkynylcarbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl, residue A-O-CO-, where A has the previously stated meaning;

R1 or R3 represents the remainder of the formula

[image]

where

R represents hydrogen, phenyl, substituted phenyl, optionally substituted benzyl, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched C1-C10-alkyl, preferably C1-C4-alkyl, C2-C10-alkenyl or C2 -C10-alkynyl group, which can be substituted with hydroxy, phenyl, substituted phenyl, amino or substituted amino if necessary;

R2 represents hydrogen, hydroxy, amino, halogen, nitro, CF3, COOH, mercapto, C1-C6-alkylmercapto, optionally substituted C1-C10-alkyl, optionally substituted C2-C10-alkenyl, optionally substituted C2-C10-alkynyl , optionally substituted C3-C8-cycloalkyl, optionally substituted C5-C8-cycloalkanone, optionally substituted C4-C8-cycloalkenyl, optionally substituted C6-C8-cycloalkynyl, optionally substituted C6-C10-aryl, optionally substituted C6 -C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8 -cycloalkyl-C2-C6-alkenyl, or C3-C8-cycloalkyl-C2-C6-alkynyl;

R2 represents, if necessary, a substituted five-membered, six-membered or seven-membered heterocycle, which as a heteroatom can contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby nitrogen can be substituted if necessary and the heterocycle can be connected via a carbon atom or a nitrogen atom directly or via a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl bridge;

R2 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl or C2-C10-alkynylsulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted heteroarylsulfonyl or optionally substituted C6-C10-aryl-C1-C6-alkylsulfonyl;

R2 represents optionally substituted C1-C10-alkylsulfonyloxy, C2-C10-alkenylsulfonyloxy or C2-C10-alkynylsulfonyloxy, optionally substituted C3-C8-cycloalkylsulfonyloxy, optionally substituted C6-C10-arylsulfonyloxy, optionally substituted C6-C10- aryl-C1-C6-alkylsulfonyloxy or optionally substituted heteroaryl-sulfonyloxy;

R2 represents optionally substituted C1-C10-alkylsulfonylamino, C2-C10-alkenylsulfonylamino or C2-C10-alkynylsulfonylainino, optionally substituted C3-C8-cycloalkylsulfonylamino, optionally substituted C6-C10-arylsulfonylamino, optionally substituted C6- C10-aryl-C1-C6-alkylsulfonylamino or optionally substituted heteroarylsulfonylamino;

R2 represents optionally substituted C1-C10-alkylaminocarbonyl, C1-C10-dialkylaminocarbonyl, C1-C10-alkyl-C2-C10-alkenylaminocarbonyl, C2-C10-alkenylaminocarbonyl, C2-C10-dialkenylaminocarbonyl, C2-C10-alkynylaminocarbonyl or C1-C10-alkyl-C2-C10-alkynylaminocarbonyl, optionally substituted C3-C8-cycloalkylaminocarbonyl, optionally substituted C6-C10-arylaminocarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkylaminocarbonyl or optionally substituted heteroarylaminocarbonyl;

R2 represents optionally substituted C1-C10-alkyloxycarbonylamino, C2-C10-alkenyloxycarbonylamino or C2-C10-alkynyloxycarbonylamino, optionally substituted C3-C8-cycloalkyloxycarbonylamino, optionally substituted C6-C10-aryloxycarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonylamino or optionally substituted heteroaryloxycarbonylamino;

R2 represents optionally substituted C1-C10-alkylaminocarbonyloxy, C2-C10-alkenylaminocarbonyloxy or C2-C10-alkynylaminocarbonyloxy, optionally substituted C3-C8-cycloalkylaminocarbonyloxy, optionally substituted C6-C10-arylaminocarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonyloxy or optionally substituted heteroarylaminocarbonyloxy;

R2 represents optionally substituted C1-C10-alkyl-N-amidino, C2-C10-alkenyl-N-amidino or C2-C10-alkynyl-N-amidino, optionally substituted C3-C8-cycloalkyl-N-amidino, optionally substituted C6-C10-aryl-N-amidino, optionally substituted C6-C10-aryl-C1-C6-alkyl-N-amidino or optionally substituted heteroaryl-N-amidino;

R2 represents optionally substituted C1-C10-alkyloxy, C2-C10-alkenyloxy or C2-C10-alkynyloxy, optionally substituted C3-C8-cycloalkyloxy, optionally substituted C6-C10-aryloxy. optionally substituted C6-C10-aryl-C1-C6-alkyloxy or optionally substituted heteroaryloxy;

R2 represents optionally substituted C1-C10-alkyloxycarbonyl, C2-C10-alkenyloxycarbonyl or C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonyl or optionally substituted heteroaryloxycarbonyl;

R2 represents optionally substituted C1-C10-alkylcarbonyloxy, C2-C10-alkenylcarbonyloxy or C2-C10-alkynylcarbonyloxy, optionally substituted C3-C8-cycloalkylcarbonyloxy, optionally substituted C6-C10-arylcarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylcarbonyloxy or optionally substituted heteroaryl-carbonyloxy;

R2 represents optionally substituted C1-C10-alkylthio, C2-C10-alkenylthio or C2-C10-alkynylthio, optionally substituted C3-C8-cycloalkylthio, optionally substituted C6-C10-arylthio, optionally substituted C6-C10-aryl- C1-C6-alkylthio or optionally substituted heteroarylthio;

R2 represents an optionally substituted amine, preferably NR8R9;

R2 represents an optionally substituted residue of the formula

[image]

R2 represents an optionally substituted residue of the formula

[image]

where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4 carbon atoms in the chain;

R2 represents an optionally substituted residue of the formula

[image]

where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4 carbon atoms in the chain;

R2 represents an optionally substituted residue of the formula

[image]

[image]

where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4 carbon atoms in the chain;

R4 or R5 represents hydrogen, optionally substituted C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C4-C8-cycloalkenyl or optionally substituted C6- C8-cycloalkynyl, optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C6-C10- aryl or optionally substituted heteroaryl;

R4 or R5 represents an optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby the heterocycle is connected via a carbon atom of the ring;

R4 or R5 represents optionally substituted C1-C10-alkyloxycarbonyl, optionally substituted C2-C10-alkenyloxycarbonyl, optionally substituted C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6 -C10-aryl-C1-C6-alkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl;

R4 or R5 represents A-O-CO-, where A has the meaning of optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms can contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur;

R4 or R5 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl, C2-C10-alkynyl-sulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, residue A-SO2- wherein A is as defined above and is linked through a ring carbon atom;

R4 or R5 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl, optionally substituted C2-C10-alkynylcarbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , an optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl, a residue A-CO in which A has the previously stated meaning;

R4 or R5 represents the rest of the formula

[image]

where

R represents hydrogen, phenyl, substituted phenyl, optionally substituted benzyl, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched C1-C10-alkyl, preferably C1-C4-alkyl, C2-C10-alkenyl or C2 -C10-alkynyl group which, if necessary, can be substituted with hydroxy, phenyl, substituted phenyl, amino, substituted amino;

R6 represents hydrogen, hydroxy, -CHO, amino, halogen, nitro, CF3, COOH, mercapto, C1-C6-alkylmercapto, optionally substituted C1-C10-alkyl, optionally substituted C2-C10-alkenyl, optionally substituted C2- C10-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C5-C8-cycloalkanone, optionally substituted C4-C8-cycloalkenyl, optionally substituted C6-C8-cycloalkynyl, optionally substituted C6-C10-aryl, per optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C3-C8-cycloalkyl-C1-C6 -alkyl, C3-C8-cycloalkyl-C2-C6-alkenyl or C3-C8-cycloalkyl-C2-C6-alkynyl;

R6 represents an optionally substituted five-membered, six-membered or seven-membered heterocycle, which as a heteroatom may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby nitrogen may be substituted as necessary and the heterocycle may be connected via a carbon atom or a nitrogen atom directly or via a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl bridge;

R6 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl or C2-C10-alkynylsulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted C6-C10- aryl-C1-C6-alkylsulfonyl or optionally substituted heteroarylsulfonyl;

R6 represents optionally substituted C1-C10-alkyl-sulfonyloxy, C2-C10-alkenylsulfonyloxy or C2-C10-alkynyl-sulfonyloxy, optionally substituted C3-C8-cycloalkyl-sulfonyloxy, optionally substituted C6-C10-arylsulfonyl-oxy, by optionally substituted C6-C10-aryl-C1-C6-alkyl-sulfonyloxy or optionally substituted heteroaryl-sulfonyloxy;

R6 represents optionally substituted C1-C10-alkylsulfonylamino, C2-C10-alkenylsulfonylamino or C2-C10-alkynylsulfonylamino, optionally substituted C3-C8-cycloalkylsulfonylamino, optionally substituted C6-C10-arylsulfonylamino, optionally substituted C6- C10-aryl-C1-C6-alkylsulfonylamino or optionally substituted heteroarylsulfonylamino;

R6 represents optionally substituted C1-C10-alkylaminocarbonyl, C1-C10-dialkylaminocarbonyl, C1-C10-alkyl-C2-C10-alkenylaminocarbonyl, C2-C10-alkenylaminocarbonyl, C2-C10-dialkenylaminocarbonyl, or C1-C10-alkynylaminocarbonyl. or C1-C10-alkyl-C2-C10-alkynylaminocarbonyl, optionally substituted C3-C8-cycloalkyl aminocarbonyl, optionally substituted C6-C10-arylaminocarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkylaminocarbonyl or optionally substituted heteroarylaminocarbonyl;

R6 represents optionally substituted C1-C10-alkylaminocarbonylamino, C2-C10-alkenylaminocarbonylamino or C2-C10-alkynylaminocarbonylamino, optionally substituted C3-C8-cycloalkylaminocarbonylamino, optionally substituted C6-C10-arylaminocarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonylamino or optionally substituted heteroarylaminocarbonylamino;

R6 represents optionally substituted C1-C10-alkyloxycarbonylamino, C2-C10-alkenyloxycarbonylamino or C2-C10-alkynyloxycarbonylamino, optionally substituted C3-C8-cycloalkyloxycarbonylamino, optionally substituted C6-C10-aryloxycarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonylamino or optionally substituted heteroaryloxycarbonylamino;

R6 represents optionally substituted C1-C10-alkylaminocarbonyloxy, C2-C10-alkenylaminocarbonyloxy or C2-C10-alkynylaminocarbonyloxy, optionally substituted C3-C8-cycloalkylaminocarbonyloxy, optionally substituted C6-C10-arylaminocarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonyloxy or optionally substituted heteroarylaminocarbonyloxy;

R6 represents optionally substituted C1-C10-alkyl-N-amidino, C2-C10-alkenyl-N-amidino or C2-C10-alkynyl-N-amidino, optionally substituted C3-C8-cycloalkyl-N-amidino, optionally substituted C6-C10-aryl-N-amidino, optionally substituted C6-C10-aryl-C1-C6-alkyl-N-amidino or optionally substituted heteroaryl-N-amidino;

R6 represents optionally substituted C1-C10-alkyloxy, C2-C10-alkenyloxy or C2-C10-alkynyloxy, optionally substituted C3-C8-cycloalkyloxy, optionally substituted C6-C10-aryloxy, optionally substituted C6-C10-aryl- C1-C6-alkyloxy or optionally substituted heteroaryloxy;

R6 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl or optionally substituted C2-C10-alkynyl-carbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl;

R 6 represents the residue A-CO-, in which A has the previously defined meaning;

R6 represents optionally substituted C1-C10-alkyloxycarbonyl, C2-C10-alkenyloxycarbonyl or C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonyl or optionally substituted heteroaryloxycarbonyl;

R6 represents optionally substituted C1-C10-alkyl-carbonyloxy, C2-C10-alkenylcarbonyloxy or C2-C10-alkynyl-carbonyloxy, optionally substituted C3-C8-cycloalkyl-carbonyloxy, optionally substituted C6-C10-arylcarbonyloxy, optionally substituted C6-C10-aryl-C1-C6-alkyl-carbonyloxy or optionally substituted heteroaryl-carbonyloxy;

R6 represents optionally substituted C1-C10-alkylthio, C2-C10-alkenylthio or C2-C10-alkynylthio, optionally substituted C3-C8-cycloalkylthio, optionally substituted C6-C10-arylthio, optionally substituted C6-C10-aryl- C1-C6-alkylthio or optionally substituted heteroarylthio;

R6 represents optionally substituted C1-C10-alkyl-carbonyloxy-C1-C6-alkyl, C2-C10-alkenylcarbonyloxy-C1-C6-alkyl or C2-C10-alkynylcarbonyloxy-C1-C6-alkyl, optionally substituted C3-C8- cycloalkynylcarbonyloxy-C1-C6-alkyl, optionally substituted C6-C10-arylcarbonyloxy-C1-C6-alkyl, C6-C10-aryl-C1-C6-alkylcarbonyloxy-C1-C6-alkyl or hetero arylcarbonyl-C1-C6-alkyl ;

R6 represents an optionally substituted residue of the formula

R10-O-B-(CH2)n-

with n = 1, 2, 3 or 4, wherein B represents C6-C10-aryl or a single bond;

R6 represents an optionally substituted amine, preferably NR8R9;

R6 represents an optionally substituted residue of the formula

[image]

R6 represents an optionally substituted residue of the formula

[image]

[image]

where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4 carbon atoms in the chain;

R6 represents an optionally substituted residue of the formula

[image]

where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4 carbon atoms in the chain;

R8 represents an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl/alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkyl group having 1-4 carbon atoms, which can be substituted with hydroxy , phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or with C1-C8-alkyloxy, preferably with C1-C4-alkyloxy, -(CH2)m,-NHCOOR10 with m = 1, 2, 3 or 4;

R8 represents a five-membered, six-membered or seven-membered heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which can contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be single or multiply, preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R8 represents a bicyclic heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which may contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, may be single or multiple, preferably single substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10;

R9 represents an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkyl group having 1-4 carbon atoms, which can be substituted with hydroxy , phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or with C1-C8-alkyloxy, preferably with C1-C4-alkyloxy, -(CH2)m-NHCOOR10 with m = 1, 2, 3 or 4;

R9 represents a five-membered, six-membered or seven-membered heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which can contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be single or multiply, preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R9 represents a bicyclic heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which may contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, may be single or multiple, preferably single substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR , -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10;

or

R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen, oxygen or sulfur as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group with 1 to 4 carbon atoms/ preferably with methyl or may carry one of the following residues

-(CH2)n-phenyl,

-(CH2)n-NH2, =O, ketal, preferably -O-CH2-CH2-O-,

- (CH2)nNH-C1-C4-alkyl,

- (CH2)n-N(C1-C8-alkyl) 2,

-(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen,

-OR10, -CN, -NO2, -NH2, -CH2NR8R9;

-OH, -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10;

R10 represents hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkynyl, benzyl or phenyl residue, which can be singly or multiply substituted with OCR^, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and, if necessary, their pharmacologically unambiguous acid addition salts.

Compounds of the general formula (I) form the following isomers:

[image]

whereby preference is given to isomers of the general formulas (Ia) and (Ib), especially those in which R1 or R3 represent C1-C4-alkyl. Particular preference is given to the compounds of the general formulas (Ia) and (Ib), in which R1 or R3 represents hydrogen - in this case the isomers (Ia) and (Ib) are tautomers.

Preferred compounds of general formulas (Ia) to (Ib) are those in which

R1 or R3 represent hydrogen, C1-C4-alkyl, benzyl, preferably hydrogen;

R2 represents hydrogen, C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN,

-CH2NR8R9, OH (multiple substitution is also possible),

-OR10, -NR8R9, -NHCOR10, -NHCONR8R9, -NHCOOR10, halogen, -COOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, - OCH2CH2OH, -SO2-CH2CH2-O-COR10, -OCH2-CH2-NR8R9, -SO2-CH2CH2-OH, -CONHSO2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, - SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, =O,

-COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9, if necessary single or multiple, preferably single methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 represents phenyl-C1-C6-alkyl-, preferably phenyl-C1-C4-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted directly, or via alkylene bridge having 1 to 4 carbon atoms, with one or more, preferably with one of the residues –C1-C3-alkyl-, -CN, -NR8R9, -NO2, OH, -OR10, -CH2-NH-SO2-R10 . -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH =NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10,

-CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9, if necessary singly or multiply, preferably singly methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 represents C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkyl-C2-C6-alkenyl, C3-C7-cycloalkyl-C2-C6-alkynyl, whereby the cycloalkyl residue can be substituted directly if necessary, or via an alkylene bridge having 1 to 4 C atoms, with one or more, preferably with one of the residues -CN, -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7 -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -OCH2, -COOH, -COOR10, -CONR8R9, -CH2OH, -CH2OR10, - CHO, -SR10,

-SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11,

-CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9;

methyl-substituted 1, 3-dioxolane or 1,3-dioxane;

R2 represents a residue of the formula A-C1-C6-alkyl, A-CONH-C2-C6-alkyl-, A-CONH-C2-C6-alkenyl-, A-CONH-C2-C6-alkynyl-, A-NH-CO -C1-C6-alkyl, A-NH-CO-C2-C6-alkenyl, A-NH-CO-C2-C6-alkynyl, A-C2-C6-alkenylene, A-C2-C6-alkynylene or A-, where A represents a five-membered, six-membered or seven-membered heterocycle connected via a carbon or nitrogen atom, which contains one or more heteroatoms from the nitrogen, oxygen or sulfur group and can be singly or multiply, preferably singly substituted with benzyl, substituted benzyl if necessary, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, O, ketal, ethylene ketal, -COOH, -SO3H, -COOR10, -CONR8R9, -COR11, -SO2R10 or –CONR8R9;

R2 represents C3-C7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which is optionally substituted with =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl;

R2 represents phenyl which is optionally substituted with -OH, halogen, -OR10, C1-C4-alkyl, preferably with -CH3, -NH2, -COOH, -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9;

R2 represents, if necessary, a C1-C4-alkyl, preferably methyl-substituted residue of norbornene, norbornene, C3-C6-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane;

R2 represents -CH=CH-phenyl, whereby the phenyl ring can be mono- or multi-substituted with methoxy, hydroxy or halogen;

R 2 represents [3,3,0]-bicyclooctane, preferably [3,3,0]-bicyclooctan-2-yl;

R2 represents piperidine or furan connected through carbon;

R2 represents an amine of the general formula NR8R9;

R4 or R5 represents hydrogen, optionally a branched C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN, -CH2NR8R9, OH (multiple substitution is also possible), -OR10 . CH2CH2-O-COR, -OCH2-CH2-NR8R9, -SO2-CH2CH2-OH, -CONHSO 2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, -SOR10, -SO2R10 . -SO3H, -SO2 NR8R9, -OCH2-CH2OCOR10, =O, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9 ,

if necessary singly or multiply, preferably singly substituted with methyl 1,3-dioxolane or 1,3-dioxane;

R4 or R5 represents phenyl-C1-C6-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, wherein the phenyl ring is optionally substituted directly, or via an alkylene bridge having 1 to 4 C-atom, with one or more, preferably with one of the residues –C1-C3-alkyl, -CN, -NR8R9, -NO2, -OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONRR , halogen, -OCOR , -OCO -pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2,R7 -OCH2-CONR8R9 -OCH2CH2OH, -OCH2- CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, if necessary single or multiply, preferably singly methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R4 or R5 represents an optionally substituted C3-C7-cycloalkyl radical;

R4 or R5 represents C3-C7-cycloalkyl-C1-C6-alkyl-, C3-C7-cycloalkyl-C2-C6-alkenyl- or C3-C7-cycloalkyl-C2-C6-alkynyl-, whereby the cycloalkyl radical can be optionally substituted directly, or via an alkylene bridge having 1 to 4 C atoms, with -CN, -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl , -OCH; COOH, -OCH2COOR10, -OCH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -OCH2- CH2 OR, -COOH, -COOR10, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, if necessary single or multiple, preferably single with methyl substituted 1,3-dioxolane or 1,3- dioxane;

R4 or R5 represents the rest of the formula

A-C1-C6-alkyl, A-CONH-C1-C6-alkyl-,

A-CONH-C2-C6-alkenyl-, A-CONH- C2-C6-alkynyl-,

A-NH-CO-C1-C6-alkyl,

A-NH-CO- C2-C6-alkenyl,

A-NH-CO-C2-C6-alkynyl,

A- C2-C6-alkenyl, A- C2-C6-alkynyl, where A represents a heterocycle connected via a carbon or nitrogen atom, which contains one or more heteroatoms from the nitrogen, oxygen or sulfur group and can be singly or multiply substituted if necessary with C1-C4-alkyl, halogen, -OR10, -CN, -NO C2-C6, -NH6, -CH6NR8R9, -OH, =O, ketal, ethylene ketal, -COOH, -SO3H, -COOR10, -CONR8R9, - COR11, -SO2R10 or -CONR8R9;

R6 represents hydrogen, C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN, -CH2NR8R9, OH (multiple substitution is also possible), -OR10, -NR8R9, - NHCOR10, -NHCONR8R9, -NHCOOR10, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2- CH2-O-COR10, -OCH2-CH2-NR8R9, -SO2-CH2CH2-OH, -CONHSO2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2R8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9, if necessary single or polymethyl substituted 1,3-dioxolane or 1,3-dioxane;

R6 represents phenyl-C1-C6-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted if necessary directly, or via an alkylene bridge having 1 to 4 C -atom, with one or more residues –C1-C3-alkyl, -CN, -NR8R9, -NO2, OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, - OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9 , -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2R8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9, -CO-R10, -C1-C4-alkyl-NR8R9 , optionally mono- or multi-methyl substituted 1,3-dioxolane or 1,3-dioxane;

R6 represents C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkyl-C2-C6-alkenyl-, C3-C7-cycloalkyl-C2-C6-alkynyl-, whereby the cycloalkyl residue can be directly substituted if necessary , or via an alkylene bridge having 1 to 4 C atoms, with one or more residues -CN, -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO- pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2- NR8R9, -OCH2CH2OR10, -COOH, - COOR10, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO2H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR10, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9 or methyl substituted 1,3-dioxolane or 1,3-dioxane;

R represents the rest of the formula

A-C1-C6-alkyl, A-CONH- C1-C6-alkyl-,

A-CONH- C2-C6-alkenyl-, A-CONH- C1-C6-alkynyl-, A-NH-CO- C1-C6-alkyl,

A-NH-CO- C1-C6-alkenyl, A-NH-CO- C2-C6-alkynyl, A- C1-C6-alkenyl, A- C1-C6-alkynyl or A-, where A represents five-membered, six-membered or a seven-membered heterocycle connected through carbon or nitrogen, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be mono- or multi-substituted, preferably mono-substituted with benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, ketal, ethyl ketal, -COOH, -SO3H, -COOR10, -CONR8R9, -COR11, -SO2R10 or –CONR8R9;

R6 represents -CHO, -COOR10 or -CONR8R9;

R6 represents C3-C7-cycloalkyl, which is optionally substituted with =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl;

R6 represents phenyl which is optionally substituted with -OH, halogen, -OR10, C1-C4-alkyl, preferably with -CH3, -NH2,

-COOH. -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9;

R6 represents a residue of norbornene, norbornene, C3-C6-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane, optionally substituted with C1-C4-alkyl;

R6 represents -CH=CH-phenyl, whereby the phenyl ring can be mono- or multi-substituted with methoxy, hydroxy or halogen;

R6 represents [3,3,0]-bicyclooctan-, preferably [3,3,0]-bicyclooctan-2-yl, ;

R 6 represents carbon-linked piperidine or furan;

R7 represents C1-C4-alkyl, which is optionally substituted with -OH, -OCOR10, -OCO-pyridyl, NH2, -NR8R9 or NHCOR10, preferably –CH2CH2OH, -CH2CH2OCOR10, -CH2-CH2-CH2OH or -CH2-CH2CH2OCOR10 ;

R8 represents hydrogen, optionally a substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkynyl group having from 1 to 4 carbon atoms, which may be substituted with hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1-C8-alkyloxy, preferably C1-C4-alkyloxy, - (CH2)m-NHCOOR10 with m = 1, 2, 3 or 4;

R8 represents a five-membered, six-membered or seven-membered heterocycle connected directly via a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be single or multiple if necessary , preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R represents a bicyclic heterocycle connected directly via a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, which contains one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be singly or multiply, preferably singly substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R9 represents hydrogen, optionally a substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkynyl group having 1 to 4 carbon atoms, which can be substituted if necessary with hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, C1-C8-alkyloxy, preferably C1-C4-alkyloxy, -(CH2)m, -NHCOOR10 with m = 1, 2, 3 or 4;

R9 represents a five-membered, six-membered or seven-membered heterocycle connected directly by a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, which contains one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be single or multiple if necessary, preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10;

R9 represents a bicyclic heterocycle connected directly by a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be singly or multiply, preferably singly substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10;

or

R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen, oxygen or sulfur as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl , or may carry one of the following residues

-(CH2)n-phenyl,

- (CH2)n-NH2, =O, ketal, preferably -O-CH2-CH2-O-,

- (CH2)n-NH-C1-C4-alkyl,

-(CH2)n-N(C1-C8-alkyl)2,

-(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen,

-OR10, -CN, -NO2, -NH2, -CH2NR8R9,

-OH, -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10;

R10 represents hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, benzyl or phenyl residue, which can be singly or multiply substituted with OCH3, if necessary,

R11 represents C1-C4-alkyl, C2-C4-alkenyl, optionally substituted phenyl, optionally substituted benzyl, C3-C6-cycloalkyl;

R12 represents -COOR10, -CH2OR10, -CONR8R9, hydrogen, C1-C3-alkyl, optionally substituted phenyl or -CH2NR8R9, optionally in the form of their racemates, their enantiomers, their diastereomers or their mixture, and optionally their pharmacologically unambiguous acidic addition salts.

Preferred compounds of general formulas (Ia) to (Ib)

[image]

in which

R1 or R3 represents hydrogen, C1-C4-alkyl, benzyl;

R2 represents hydrogen, C1-C8-alkyl, preferably 1-C6-alkyl;

R2 represents phenyl which is optionally substituted with halogen, preferably with fluorine or chlorine, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9;

R2 represents phenyl-C1-C6-alkyl-, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, wherein the phenyl ring is optionally substituted with halogen, preferably with fluorine or chlorine, C1 -C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9;

R2 represents a substituted amine, preferably NR8R9;

R2 represents a five- or six-membered heterocycle connected directly through C or N, or through an alkylene bridge having 1 to 4 C atoms, containing one or more heteroatoms from the group consisting of nitrogen or sulfur and which can be substituted with benzyl or with C1-C4 -alkyl;

R 2 represents C 3 -C 6 -cycloalkyl which, if necessary, can be substituted with =O, hydroxy, with C 1 -C 4 -alkyl or C 1 -C 4 -alkyloxy;

R 2 represents C 3 -C 6 -cycloalkyl which, if necessary, can be substituted with =O, hydroxy, with C 1 -C 4 -alkyl or C 1 -C 4 -alkyloxy;

R2 represents, if necessary, C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane;

R4 or R5 represents hydrogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted with halogen , preferably chlorine or fluorine, hydroxy, C1-C4-alkyl,

C1-C4-alkyloxy or NR8R9;

R6 represents hydrogen, C1-C8-alkyl, wherein the alkyl chain can be substituted with halogen, hydroxy, =O, C1-C4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-C1-C4-alkyloxy, benzyloxy, -O -benzyl-C1-C4-alkyloxy, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl , -CHO, =NHOH, -COOH, -COO- C1-C4 -alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NH-CO- C1-C4-alkyl, -NHCO-phenyl, -CO - C1-C4 - alkyl-NR8R9, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl;

R6 represents phenyl which is optionally substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl, - C1-C4-alkyl-NH2, - C1-C4-alkyl-OH, - C1-C4 -alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4-alkyl-NH2, -SO2-OH, -SO2- C1 -C4-alkyl or -SO2-phenyl;

R6 represents phenyl-C1-C6-alkyl-, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1 -C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl, - C1-C4-alkyl-NR8R9, - C1-C4-alkyl-OH, - C1-C4-alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO -phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4alkyl-NH2, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl;

R6 represents a five-membered or six-membered heterocycle, directly connected through C or N or through an alkylene bridge having 1 to 4 C atoms, which can contain one, two or three heteroatoms from the group consisting of nitrogen or sulfur and which can be single or multiple if necessary substituted with benzyl or with C1-C4-alkyl;

R6 represents a C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C4-alkyl residue which can be substituted with =O, hydroxy, C1-C4-alkyl or C1-C4-alkyloxy if necessary;

R6 represents optionally with C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane;

R6 represents -CHO, -COOH, -COO-C1-C4-alkyl, -COO-phenyl, -COO-benzyl or -CONR8R9;

R6 represents an amine of the general formula NR8R9;

R8 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms;

R represents a five-membered or six-membered heterocycle, connected through C, containing one, two or three heteroatoms from the group consisting of nitrogen or sulfur and is optionally substituted with benzyl, C1-C4-alkyl, halogen, -CN, -NO2, -NH2, -OH or =O;

R9 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms;

- CN, -NO2, -NH2, -OH or =O;

or

R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen or oxygen as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably with methyl or may be substituted with one - (CH 2 ) 1-4-phenyl residue, preferably with benzyl, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, as if necessary their pharmacologically certain acid addition salts.

Preferred compounds of general formulas (Ia) to (Ib)

[image]

are those in which

R1 or R3 represents hydrogen, C1-C4-alkyl, preferably C1-C4-alkyl, benzyl;

R2 represents hydrogen, C1-C6-alkyl, preferably C1-C4-alkyl;

R 2 represents cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane;

R2 represents a morpholine residue which is optionally substituted with C1-C4-alkyl, preferably with methyl, a piperidinyl residue, a piperazinyl residue which is optionally substituted with benzyl or with C1-C4-alkyl, preferably with methyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furil;

R2 represents a phenyl radical which is optionally substituted with C1-C4-alkyl, halogen or hydroxy;

R2 represents phenyl-C1-C4-alkyl, preferably benzyl, wherein the phenyl ring is optionally substituted with halogen, preferably with fluorine or chlorine, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9;

R2 represents an amine of the general formula NR8R9;

R4 represents optionally with C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane;

R4 represents hydrogen, C1-C7-alkyl, preferably C1-C5-alkyl, phenyl-C1-C3-alkyl, preferably benzyl, wherein the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4- alkyl, C1-C4-alkyloxy or NR8R9;

R6 represents hydrogen, C1-C6-alkyl, preferably C1-C4-alkyl, wherein the alkyl chain can be substituted with halogen, hydroxy, =O, C1-C4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-O- C1 -C4-alkyloxy, benzyloxy, -O-benzyl-O- C1-C4-alkyloxy, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -O-C2-C4 -alkylene, -CO- C1-C4-alkyl,

-CHO, =NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO- C1-C4-alkyl, -NHCO-phenyl, -CO- C1- C4-alkyl-NR8R9, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl;

R6 represents phenyl, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy or NR8R9;

R6 represents phenyl-C1-C3-alkyl-, preferably benzyl, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, - OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-C4-alkylene, -CO- C1-C4-alkyl, -C1-C4-alkyl-NR8R9, - C1-C4-alkyl-OH, - C1-C4-alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4- alkyl-NR8R9, -SO2-OH, -SO2-C1-C4-alkyl or -SO2-phenyl;

R6 represents cyclopentyl, cyclohexyl, cyclohexyl-C1-C3-alkyl, preferably cyclohexylmethyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked by a single bond or via an alkylene chain having 1 to 4 C atoms;

R6 represents furan, tetrahydrofuran, α-pyran, γ-pyran, dioxolane, tetrahydro-pyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, linked by a single bond or via an alkylene chain having 1 to 4 C atoms. pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine/pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole or pyrazolidine;

R6 represents -CHO, -COOH, -COO-C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CO-NH-C1-C4-alkyl, -CO-N(C1-C4-alkyl); or -CONH-phenyl;

R6 represents an amine of the general formula NR8R9;

R8 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms;

R8 represents carbon-linked and, if necessary, chlorine, bromine, C1-C4-alkyl, C1-C4-alkyloxy, -NO2, -NH2, -OH substituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole , pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole;

R9 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms;

R9 represents carbon-bonded and optionally chlorine, bromine, C1-C4-alkyl, C1-C4-alkyloxy, -NO3, -NH2, -OH substituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole , pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole, or

R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen or oxygen as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably with methyl, or it may be substituted with one - (CH 2 ) 1-4-phenyl radical, preferably with benzyl, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixtures, as if necessary their pharmacologically certain acid addition salts.

Preference is also given to compounds of the general formula (Ib)

[image]

where

R2 represents hydrogen, C1-C4-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted with fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzyl-piperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl , adamantyl, noradamantyl, norbornyl or norbornenyl;

R 4 represents hydrogen, C 1 -C 4 -alkyl or benzyl;

R 4 represents hydrogen, C 1 -C 5 -alkyl or benzyl;

R6 represents hydrogen, C1-C4-alkyl, preferably methyl which can be substituted with OH, chlorine, bromine, C1-C4 -alkyloxy or NR8R9, -CHO, -COOH, -COO- C1-C4-alkyl, preferably - COOCH3, phenyl, optionally with fluorine or benzyloxy-substituted phenyl-C1-C3-alkyl, preferably benzyl, optionally with methoxy-substituted phenyloxy-C1-C3-alkyl, preferably phenyloxymethyl, optionally with methoxy-substituted benzyloxy-C1-C3- alkyl, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl;

R 8 represents hydrogen, C 1 -C 4 -alkyl or pyridyl;

R9 can be hydrogen, C1-C4-alkyl or pyridyl, optionally in the form of their racemates, their enantiomers, their diastereomers or their mixtures, and optionally their pharmacologically unambiguous acid addition salts.

Preference is also given to compounds of the general formula (Ia)

[image]

where

R 1 represents hydrogen, C 1 -C 3 -alkyl or benzyl;

R2 represents hydrogen, C1-C4-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted with fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzyl-piperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl , adamantyl, noradamantyl, norbornyl or norbornenyl;

R 4 represents hydrogen, C 1 -C 5 -alkyl or benzyl;

R6 represents hydrogen, C1-C4-alkyl, preferably methyl which can be substituted with OH, chlorine, bromine, C1-C4-alkyloxy or NR8R9, -CHO, -COOH, -COO- C1-C4-alkyl, preferably - COOCH3, phenyl, optionally with fluorine or benzyloxy substituted phenyl-C1-C3-alkyl, preferably benzyl, optionally with methoxy-substituted phenyloxy-Ci-C3-alkyl, preferably phenyloxymethyl, optionally with methoxy-substituted benzyloxy-C1-C3 -alkyl, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl;

R 8 represents hydrogen, C 1 -C 4 -alkyl or pyridyl;

R9 can be hydrogen, C1-C4-alkyl or pyridyl, optionally in the form of their racemates, their enantiomers, their diastereomers or their mixtures, and optionally their pharmacologically unambiguous acid addition salts.

Compounds of the general formula (Ic) are also interesting.

[image]

where

R 1 represents hydrogen or C 1 -C 3 -alkyl;

R 2 represents hydrogen, C 1 -C 4 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;

R5 represents C1-C6-alkyl, preferably C1-C4-alkyl, especially useful methyl, ethyl or tert.butyl;

R 6 represents hydrogen, benzyl or cyclopentyl; if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

Compounds of the general formula (Id) are also interesting.

[image]

where

R 1 represents C 1 -C 3 -alkyl;

R 2 represents hydrogen, C 1 -C 4 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;

R5 represents C1-C6-alkyl, preferably C1-C4-alkyl, especially useful methyl, ethyl or tert.butyl;

R 6 represents hydrogen, benzyl or cyclopentyl; if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

Preference is also given to compounds of the general formula (Ib)

[image]

where

R2 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-morpholinonyl, N-piperazinyl, 4-benzyl- piperazinyl, 2-furyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R 4 represents hydrogen, methyl, ethyl, n-propyl or benzyl;

R 4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl, or benzyl;

R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, phenylethyl, N-morpholinonylmethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, PhCO-O-CH2,-, pyridyl-CO-O-CH2-, Ph-O-CH2-, (4-MeO-Ph) -O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, (4-Ph-CH2 -O- Ph) -CH2-, 4-F-Ph-CH2-, 3,4-F -Ph-CH2-, -COOH, -COOMe, -CH2-OH, -CH2-OMe, -CH2-OEt or -CH2-NMe2,

if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

Particular preference is also given to compounds of the general formula (Ia)

[image]

where

R 1 represents hydrogen, methyl, ethyl, n-propyl or benzyl;

R2 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidyl, N-morpholinonyl, N-piperazinyl, 4-benzyl- piperazinyl, 2-furyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl;

R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, phenylethyl, N-morpholinonylmethyl, N-pyrrolylmethyl, (3-pyridyl) -NH-CH2,-, PhCO-O-CH2-, pyridyl-CO-O-CH2-, Ph-O-CH2-, (4-MeO-Ph) -O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, (4-Ph-CH2-O-Ph) -CH2-,

4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -COOH, -COOMe, -CH2-OH, -CH2-OMe, -CH2-OEt or -CH2-NMe2,

if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

Preference is also given to compounds of the general formula (Ib)

[image]

where

R2 represents hydrogen, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-piperidinyl, N-morpholinonyl, N-piperazinyl, 4-benzylpiperazinyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R 3 represents hydrogen;

R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl;

R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, 2- phenylethyl, N-morpholinonylmethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2,-, PhCO-O-CH2,-, 3-pyridyl-COO-CH2,-, Ph-O-CH2,-, (4 -MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, 4-F-Ph-CH2,-, 3,

4-F-Ph-CH2,-, -CH2-OH, -CH2-OH, -CH2-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH,

if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

Particular preference is also given to compounds of the general formula (Ia)

[image]

where

R1 represents hydrogen;

R2 represents hydrogen, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-piperidinyl, N-morpholinonyl, N-piperazinyl, 4-benzylpiperazinyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl;

R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, 2- phenylethyl, N-morpholinonylmethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-,

Ph-COO-O-CH2-, 3-pyridyl-COO-CH2-, Ph-O-CH2-, (4-MeO-Ph)-O-CH2-, (4-MeO-Ph) -CH2-O- CH2,-, 4-F-Ph-CH2-,

3, 4-F-Ph-CH2,-, -CH2-OH, -CH2-OH, -CH2-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH,

if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and if necessary their pharmacologically unambiguous acid addition salts.

The invention also relates to a class of new compounds containing the basic structure of the general formulas (Ia) to (Id).

[image]

Preferred derivatives of the general formula

[image]

are those that carry one substituent in positions 2, 4 and 6.

If necessary, the compounds of the general formulas (Ia) to (Id) can be translated into their salts, and especially for pharmaceutical use they can be translated into their physiologically tolerable salts with inorganic or organic acids. For this purpose, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid can be used. Mixtures of the above-mentioned acids can also be used.

Alkyl groups (also if they are a component of other residues) are branched or unbranched alkyl groups with from 1 to 10 carbon atoms, preferably from 1 to 4 carbon atoms, and include, for example, methyl, ethyl, n- propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, heptyl and octyl.

Unless otherwise stated, substituted alkyl groups (also if they are a component of other residues) can for example carry one or more of the following substituents: halogen, hydroxy, mercapto, C1-C6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, = O, -CHO, -COOH, -COO-C1-C6-alkyl, -S-C1-C6-alkyl.

Branched or unbranched alkenyl groups that have from 2 to 10 carbon atoms, preferably from 2 to 3 carbon atoms, and if they have at least one double bond can also be designated as alkenyl groups (also if they are a component of other residues). the above alkyl groups if they have at least one double bond, such as vinyl (if no unstable enamine or enol ether is formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.

If not described otherwise, substituted alkenyl groups (even if they are part of other residues) can for example carry one or more of the following substituents: halogen, hydroxy, mercapto, C1-C6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, = O, -CHO, -COOH, -COO-C1-C6-alkyl, -S-C1-C6-alkyl.

Alkynyl groups (also if they are an integral part of other residues) are designated alkynyl groups that have from 2 to 10 carbon atoms, and if they have at least one triple bond, they are, for example, ethynyl, propargyl, butynyl, pentynyl, hexynyl.

If not described otherwise, substituted alkynyl groups (even if they are a component of other residues) can, for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, C1-C6-alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, = O, -CHO, -COOH, -COO- C1-C6-alkyl, -S- C1-C6-alkyl.

As cycloalkyl residues with 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which can also be substituted with branched or unbranched alkyl having 1 to 4 carbon atoms, with hydroxy and/or halogen or can be substituted as is previously defined. Halogen is generally defined as fluorine, chlorine, bromine or iodine.

The term aryl refers to an aromatic ring system having 6 to 10 carbon atoms and which, unless otherwise described, may bear one or more of the following substituents: C1-C6-alkyl, C1-C6-alkyloxy, halogen, hydroxy, mercapto, amino, alkylamino, dialkylamino, CF3, cyano, nitro, -CHO, -COOH, -COO- C1-C6-alkyl, -S- C1-C6-alkyl. A preferred aryl residue is phenyl.

Examples of the N-linked cyclic residue of the general formula NR8R9 are: pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(n-propyl)-piperazine, N-benzylpiperazine, morpholine, thiomorpholine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, preferably morpholine, N-benzylpiperazine, piperazine and piperidine, wherein the mentioned heterocycles can also be substituted with alkyl having 1 to 4 carbon atoms, preferably with methyl, or as specified in the definitions.

As five-membered or six-membered heterocyclic rings connected by a carbon atom that can contain nitrogen, oxygen or sulfur as heteroatoms, examples are furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolane , tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine , thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole, pyrazolidine, wherein the heterocycle may be substituted as indicated in the definitions.

"=O" means an oxygen atom connected by a double bond.

The compounds according to the invention show affinity for adenosine receptors and thus represent a new class of adenosine antagonists. In general, adenosine antagonists may show therapeutically beneficial effects in cases where diseases or pathological conditions are associated with activation of adenosine receptors.

Adenosine is an endogenous neuromodulator with predominantly inhibitory (suppressive) action in the central nervous system, kidneys and other organs. The effects of adenosine are mediated by at least three receptor subtypes:

adenosine A1-, A2- and A3-receptor.

In the central nervous system, adenosine develops an inhibitory effect mainly by activating A1-receptors: presynaptically by suppressing synaptic transmission (suppressing the release of neurotransmitters such as acetylcholine, dopamine, noradrenaline, serotonin, glutamine and others), postsynaptically by suppressing neural activity.

A1-antagonists increase the inhibitory action of adenosine and neural transmission and neural activity.

A1-antagonists are therefore very interesting for the therapy of degenerative diseases of the central nervous system, such as senile dementia Morbus Alzheimer type and other accompanying memory and learning disorders.

In addition to forgetfulness in a milder form and complete helplessness and the absolute need for care in more severe forms, the disease includes a number of other accompanying symptoms such as sleep disorders, motor coordination disorders, up to the picture of Morbus Parkinson, further increased mental lability, as well as depressive symptoms. The disease is progressive and can lead to death. The current therapy is not satisfactory. So far, there is a complete lack of specific therapeutics. Trials of therapy with acetylcholinesterase inhibitors show efficacy only in a small number of patients, however, they are associated with a high number of side effects.

The pathophysiology of Alzheimer's disease and SDAT is characterized by severe damage to the cholinergic system, but other transmitter systems are also encountered. With the loss of presynaptic cholinergic and other neurons and the resulting insufficient availability of neurotransmitters, neural transmission and neural activity of brain areas essential for learning and memory are noticeably prevented.

Selective adenosine-A1-receptor antagonists transmit neural transmission with increased neurotransmitter readiness, increase the excitability of postsynaptic neurons and thus can act symptomatically against the disease.

The high receptor affinity and receptor selectivity of several compounds, for which patent protection is sought, should, with lower doses, enable the treatment of M. Alzheimer's and SDAT so that it is calculated with minimal side effects, which are not reduced to A1-receptor blockade.

Another indication for adenosine-Ai-antagonists acting on the central nervous system is depression. The success of antidepressant drug therapy appears to be related to A1-receptor regulation. Ai-antagonists can lead to the regulation of adenosine-A1-receptors and thus offer a new therapeutic agent for the treatment of depressed patients.

Further areas of use, especially for A2-selective adenosine receptors, are neurodegenerative diseases such as Parkinson's disease, and furthermore migraine. Adenosine inhibits the release of dopamine from central synaptic terminals by interacting with dopamine-D2-receptors. A2-antagonists increase the release and availability of dopamine and thus offer a new therapeutic principle for the treatment of Parkinson's disease.

A2-receptor mediated vasodilatation of cerebral blood vessels seems to be involved in migraine. Selective A2-antagonists suppress vasodilation and thus may be useful for the treatment of migraine.

Adenosine antagonists can also be used for the therapy of peripheral indications.

For example, activation of A1-receptors in the lungs can lead to bronchoconstriction. Selective adenosine A1-antagonists relax the tracheal smooth muscles, promote bronchodilation and thus can be useful as an anti-asthma agent.

Through the activation of A2-receptors, adenosine can, among other things, cause respiratory depression and cessation of breathing. A2-antagonists cause respiratory stimulation. For example, adenosine antagonists (theophylline) are used to treat colic and to prevent "sudden infant death" in premature infants.

An important area of therapy for adenosine deficiency is also cardiovascular disease and kidney disease.

By activating the A1-receptor, adenosine on the heart causes inhibition of electrical and contractile activity. Associated with coronary vasodilatation mediated through the A2-receptor, adenosine has a negative chronotropic, inotropic, dromotropic, bathmotropic, bradycardic effect and lowers cardiac output.

Adenosine A1-receptor-antagonists enable the prevention of heart and lung injuries caused by ischemia and subsequent reperfusion. Therefore, adenosine antagonists can be used for the prevention or earlier treatment of heart injuries caused by ischemia-reperfusion, eg after coronary bypass surgery, heart transplantation, angioplasty or thrombolytic therapy of the heart and similar procedures. The same applies to the lungs.

On the kidneys, the activation of A1-receptors causes vasoconstriction of afferent arterioles and thereby causes a decrease in renal blood flow and glomerular filtration.

A1-antagonists act on the kidneys as strong potassium-sparing diuretics and thus can be used for kidney protection as well as for the treatment of edema, renal insufficiency and acute renal failure.

Based on adenosine antagonism on the heart and diuretic action, A1-antagonists can be effectively used in various cardiovascular diseases, such as heart failure, arrhythmias (bradyarrhythmias) accompanied by hypoxia or ischemia, flow disorders, hypertension, ascites in liver failure (hepato- renal syndrome) and as an analgesic in blood circulation disorders.

Several compounds according to the invention show a surprising affinity for the A3-adenosine-receptor. A3-antagonists suppress the degranulation of fat cells caused by the activation of A3-receptors and they are therefore therapeutically useful in all diseases and pathological conditions associated with the degranulation of fat cells: for example as anti-inflammatory substances, in hypersensitivity reactions such as bpr. for asthma, allergic rhinitis, urticaria, myocardial reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases, etc.

Cystic fibrosis - also known as cystic fibrosis - is a significant metabolic disorder caused by a genetic defect in a certain chromosome. Increased production and increased viscosity of mucus gland secretions in the bronchi can lead to severe complications in the respiratory tract. The first studies showed that A1-antagonists increase the efflux of chloride ions, for example, in CF PAC cells. Proceeding from this finding, it can be expected that in patients suffering from cystic fibrosis (mucoviscidosis), the compounds according to the invention regulate the disturbed content of electrolytes in the cells and alleviate the symptoms of the disease.

The obtained A1-receptor binding values were determined analogously to the description of Ensinger et al. in "Cloning and functional characterization of human A1-adenosine Receptor -Biochemical and Biophysical Communications, Vol 187, No. 2, 919-926, 1992" and are listed in Table 20.

The A3-receptor binding values listed in Table 21 were determined analogously to the description of Salvatore et al., "Molecular cloning and characterization of human A3-adenosine receptor" (Proc. Natl. Acad. Sci. USA 90, 10365-10369, 1993).

The new compounds of general formula (Ia) to (Id) can be administered orally, transdermally, by inhalation or parenterally. The compounds according to the invention are therefore proposed as active ingredients in the usual forms for administration, for example in compositions consisting mainly of an inert pharmaceutical carrier and an effective dose of the active substance, such as tablets, dragees, capsules, sheets, powder, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems, etc. Effective doses of the compounds according to the invention for oral administration range between 1 and 100, preferably between 1 and 50, especially between 5 and 30 mg per dose, for intravenous or intramuscular administration range from 0.001 to 50, preferably between 0.1 and 10 mg per dose. Solutions according to the invention containing from 0.01 to 1.0, preferably from 0.1 to 0.5% of the active substance are suitable for inhalation. For application by inhalation, the use of powder is preferred. The compounds according to the invention can also be used as infusion solutions, preferably in a physiological solution of table salt or a solution of edible salt.

The compounds according to the invention can be produced by the following procedures. For the synthesis of both isomers

[image]

of general formulas (Ia) and (Ib), wherein the substituents have the previously stated meaning, is done as follows.

In the first step, aminoguanidine (1) is chemically converted with a carboxylic acid derivative of the general formula (2) into a triazole of the general formula (3) (scheme 1). This reaction can be carried out according to the description from the articles published in J. Chem. Soc. 1929, 816; J. Org. Chem. 1926, 1729 or Org. Synthesis 26, 11.

[image]

Scheme 1:

Then, in the second step, the triazole of the general formula (3) is chemically converted with an alkyl ester of cyanoacetic acid, in a ring-closing reaction under alkaline conditions, into a triazolpyrimidine of the general formula (4) (scheme 2).

[image]

Scheme 2:

Alkaline or alkaline earth alcoholates, for example methanol, ethanol, isoproplanol, n-, sec-, tert-butyl alcohol, are suitable bases. Suitable alkali and alkaline earth metals are, for example, lithium, sodium, potassium, magnesium, calcium. Sodium methanolate, sodium ethanolate, sodium isopropionate and potassium tert.butylate are preferred bases. Furthermore, according to the invention, alkaline and alkaline earth hydrides come into consideration as bases. The hydrides of sodium, lithium, potassium as well as magnesium and calcium are preferred. Suitable inert solvents are dimethylformamide, dimethylacetamide, methylene chloride, tetrahydrofuran. Alkaline or alkaline earth hydroxides of lithium, sodium, potassium as well as magnesium, calcium, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcoholic or aqueous solutions can also be used.

In addition to alkyne esters of cyanoacetic acid, cyanoacetic acid can also be used. The thus obtained mixture is stirred for 0.5 to 4 hours, preferably for 1 to 2 hours at room temperature and then mixed with the compound of general formula (3) and stirred for 2 to 12, preferably from 4 to 6 hours, preferably under reflux. The reaction mixture is then mixed with water at room temperature and adjusted with acid, and then the solid substance is filtered off, washed and dried. Suitable acids are, for example, formic acid, acetic acid, or mineral acids such as hydrochloric acid or sulfuric acid.

In the third step, the residues R and R are introduced into the triazolopyrimidine of the general formula (4) and compounds of the general formulas (5) and (12) are obtained (scheme 3).

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Scheme 3:

For this purpose, the compound of the general formula (4) is dissolved in a five-fold to 40-fold, preferably 10- to 20-fold, amount of a polar solvent, such as dimethylformamide, dimethyllactamide, methylene chloride, tetrahydrofuran, preferably dimethylformamide and particularly advantageously anhydrous, if necessary absolute dimethylformamide. The thus obtained solution is mixed with a base and with a suitable alkylating agent. Alkaline or alkaline earth carbonates, for example lithium, sodium, potassium, calcium, cesium, such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, and primarily potassium carbonate, come into consideration as bases.

Hydrogen carbonates of lithium, sodium and potassium can also be used. Alkaline and alkaline earth hydroxides of lithium, sodium, potassium, magnesium, calcium, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or in water can also be used. Alkaline and alkaline earth metal alcoholates already mentioned in step 2 can be used as further bases. Furthermore, the previously mentioned alkali and alkaline earth hydrides can be used in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran and toluene. Alkyl halides such as alkyl chloride, alkyl bromide, especially alkyl iodide, as well as alkyl tosylates, mesylates, triflates, dialkyl sulfates are suitable alkylating agents.

The alkyl radicals of the alkylating agent correspond to the definitions given earlier for R4 and R5. The reaction mixture is stirred for 0.5 to 4 days, preferably 1 to 4 days at room temperature and concentrated to dryness. The treatment can be carried out by mixing the residue with water and a solvent, for example with a halogenating agent, such as carbon tetrachloride, methylene chloride, preferably methylene chloride, whereby the compound of general formula (5) can be isolated by filtration as a solid. The compound of general formula (12) can be obtained from the filtrate by removing the solvent. In the event that no solid substance is deposited, the isolation of the compound of general formula (12) from the filtrate can be carried out by separating the filtrate phases: the aqueous solution is extracted with a halogenating agent, preferably methylene chloride, and the combined organic phases are dried and processed. Chromatographic purification of the residue yields compounds of general formulas (5) and (12) (scheme 3).

By nitrosating the compound of general formula (5) in the fourth step, the compound of general formula (6) is obtained (scheme 4).

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Scheme 4:

Here, according to the invention, two versions are possible.

Level 4, Version A:

The compound of the general formula (5) is dissolved or suspended in a polar solvent, whereby the previously mentioned solvents come into consideration as polar solvents, while preference is given to dimethylacetamide or alcohol, for example methanol, ethanol, propanol, isopropanol and butanol. Particular preference is given to dimethylformamide. The selected solvent is recommended to be used anhydrous. The resulting mixture is cooled below 0°C, preferably below -5°C. A nitrosating agent is added to this mixture, for example alkyl nitrite such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, tert.butyl and pentyl nitrite, but preferably isoamyl nitrite, whereby the temperature must not rise above 0 °C. At this temperature, it is mixed for 2 to 48 hours, preferably 4 to 24 hours, especially 8 to 12 hours. Finally, if necessary for complete conversion, the reaction mixture is further stirred at room temperature. The solvent is removed in a vacuum, the residue is taken up in a solvent, for example diethyl ether, filtered, washed with water and the residue thus obtained is dried (in a vacuum).

Level 4, Version B:

The compound of the general formula (5) is mixed with aqueous acid, whereby the acids used are organic acids, formic acid, acetic acid, propionic acid, preferably acetic acid, and inorganic acids, for example hydrochloric acid or dilute sulfuric acid, preferably hydrochloric acid as and their mixtures. The mixture is heated to 30 to 100, preferably to 50 to 80, particularly useful to 70°C and mixed with a nitrosating agent, preferably to sodium nitrite, especially useful to sodium nitrite in water and kept for 0.5 to 2 hours, preferably 1 hour at the above temperature and 0.5-2 hours, preferably one hour per 0 to 20, especially 5 to 15, especially useful at 10°C. The product is filtered off, the residue is washed and dried in a vacuum.

In the fifth step, the reduction of the nitroso compound (6) into a diamine derivative of the general formula (7) follows (Scheme 5).

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Scheme 5:

The following versions can be applied here. Level 5, Version A:

The nitroso compound (6) is suspended with stirring in water and mixed with a suitable reducing agent. A suitable reducing agent is dithionite in an acidic or alkaline solution. Ammonium sulfite, lithium, sodium, potassium hydrogen sulfite, triethyl phosphite, triphenyl phosphine, or lithium aluminum hydride may also be used. The nitroso group can be catalytically hydrogenated using transition metals as catalysts, for example palladium, platinum, nickel or rhodium, with hydrogen gas or transfer hydrogenation, for example with cyclohexene or ammonium formate as a hydrogen source. The use of sodium dithionite is preferred. In addition to the previously used aqueous ammonia solution, solutions of alkaline or alkaline earth hydroxides can also be used as bases, for example lithium, sodium, potassium hydroxide solutions or magnesium, calcium, barium hydroxide solutions, preferably diluted solutions. Methyl, ethyl, isopropyl, n-propyl, iso-butyl, tert-butyl, n-butyl alcoholates of the previously mentioned alkali and alkaline earth metals can also be used. These suspensions are heated to 20 to 100°C, preferably to 50 to 90°C, particularly usefully to 60 to 80°C and mixed with the acid, preferably at the beginning, and especially usefully mixed within the first 30 minutes. Possible acids are inorganic acids, for example hydrochloric acid and sulfuric acid, as well as organic acids, for example formic acid and acetic acid, and their mixtures, whereby preference is given to sulfuric acid, and special preference is given to 50% sulfuric acid. The mixture thus obtained is heated until complete conversion at the reflux temperature. The product is precipitated by cooling as a semi-sulphate. Furthermore, the product can be extracted by neutralization with an aqueous base, for example with lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably with caustic soda, especially useful with 30% caustic soda and filtered off as the free base.

Level 5, version B:

The nitroso compound (6) is added to the mixture of water base and alcohol while stirring. Then, after dissolving or suspending the nitroso compound, a reducing agent is added, preferably in solution. As a reducing agent, the reducing agents listed in method A come into consideration, whereby it is particularly useful to use an aqueous solution of sodium dithionite. It is then mixed for 0.5 to 6, preferably 1 to 4, especially usefully 1.5 to 3 hours at room temperature. The secreted product is isolated by filtration.

In the sixth step, isomeric compounds (8) are prepared from diamines of the general formula (7) (scheme 6).

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Grade 6

In this phase, the amino compound of the general formula (7) is suspended in an organic solvent and mixed with an organic base. After that, the mixture is kept for 40 to 60 minutes, preferably 20 to 50 minutes, especially useful for 25 to 45 minutes at room temperature, then the mixture is cooled to 0 to 15°C, preferably to 5 to 10°C and mixed with one derivative of carbon acid in which the residue R2 corresponds to the previously defined. Suitable organic solvents are dimethylformamide, dimethylacetamide, methylene chloride, toluene and tetrahydrofuran, whereby preference is given to dimethylformamide, and special preference is given to anhydrous, if necessary, absolute dimethylformamide. Suitable organic bases are dimethylaminopyridine, pyridine, tertiary amines, for example trimethylamine, triethylamine, diisopropylethylamine, DBU (diazabicycloundecane) or some of the previously mentioned inorganic bases, especially alkali or alkaline earth carbonates or hydrogen carbonates. However, dimethylaminopyridine is particularly suitable as a base. According to the invention, carboxylic acid derivatives are carboxylic acid halides, primarily carboxylic acid chlorides, but also carboxylic acids if they are activated in a suitable manner. This can be carried out, for example, by conversion with esters of chloroformic acid, carbonyl diimidazole, carbodiimides, for example dicyclohexylcarbodiimidoin, EDAC, or with benzotriazoles, for example with HOBt (1-hydroxy-1-H-benzotriazole) and TBTU. Also, instead of a carboxylic acid derivative, a suitable aldehyde can be used and the intermediate product is oxidized with iron(II) chloride, azodicarboxylic acid esters and other oxidizing agents. Then the mixture is stirred from 0/5 to 4 hours, preferably 1 to 3 hours, especially 2 hours at 5 to 20, preferably at 7 to 15, especially at 10°C and overnight at room temperature. At the end, the solvent is removed in a vacuum, the residue is taken up in water, the solid substance is filtered off, washed and, if necessary, recrystallized or purified by chromatography, preferably by column chromatography.

In the seventh step, the ring-closing reaction of the compound of general formula (6), (7) or (8) into the compound of general formula (9) is carried out according to methods A to C (scheme 7).

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Scheme 7:

Level 7, Method A:

The compound of general formula (8) is suspended in alcohol and heated with a base for 24 hours under reflux. When it cools, the reaction mixture is acidified, the solid substance is filtered off and dried. If necessary, the product is purified by recrystallization or chromatography, preferably column chromatography. Alkaline and alkaline earth hydroxides, for example lithium, sodium, potassium, calcium and barium hydroxides, as well as their mixtures in the form of an aqueous solution or, if necessary, as a mixture with alcohol and/or ether mixed with water, come into consideration here as bases. Suitable alcohols are methanol, ethanol, n-propanol, isopropanol, n-butanol and tert.butanol. Particularly suitable ethers are cyclic ethers, for example tetrahydrofuran and dioxane. The ring closure can be carried out by an analogous procedure also with inorganic acid chlorides such as thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, as well as with phosphoric acid.

A further analogous procedure consists in converting the carboxylic acid amide under acidic conditions with mineral acid/methanol, preferably hydrochloric acid/methanol or under basic conditions with an alkali metal/methanol, preferably with sodium/methanol and then thermally cyclizing.

Level 7, method B:

By the following procedure, compound (9), in which R represents hydrogen, can be produced starting with diamine (7). For this purpose, compound (7) is mixed with an equimolar amount, preferably with an excess of formamide for 0.5 to 3 hours, preferably from 1 to 2 hours, especially 1.5 hours at 50 to 250°C, preferably at 100 to 225° C, especially at 180-200°C. The remaining formamide is removed by vacuum distillation and the residue is taken up in water. The resulting solid substance is filtered off, washed with water and the product thus obtained is purified, if necessary, by recrystallization or chromatography, preferably column chromatography.

Level 7, method C:

The compound of the general formula (9) is further available directly from the nitroso compound of the general formula (6) if R 2 represents the residue NR 8 R 9 , wherein R 8 and R 9 have the previously stated meaning.

Phosphorus oxide is added to a solution of the desired N-formylamine in diglyme at minus 10 to plus 20°C, preferably at minus 5 to plus 5°C, especially at 0°C. It is then mixed in an ice bath and the nitroso compound (6) is added. The mixture is stirred for 15 to 120 minutes, preferably 30 to 80 minutes, especially 40 to 60 minutes at 30 to 120°C, preferably at 50 to 100°C, especially at 70 to 80°C and then poured onto ice. The solid product is filtered off, washed and dried and, if necessary, purified by recrystallization or chromatography, preferably column chromatography.

The compounds of general formula (Ia) and (Ib) can be obtained in the eighth step from the compound of general formula (9) (scheme 8).

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Scheme 8:

Here, the starting compound is taken up in an organic solvent and converted with a base and a suitable alkylating agent. The reaction mixture was stirred overnight at room temperature. If necessary, it can be worked at an elevated temperature. Under certain conditions, the reaction can last up to a week. At the end of the reaction, the reaction mixture is concentrated to dryness. The residue is taken up in an aqueous alkaline solution, with lithium hydroxide, sodium hydroxide, potassium hydroxide, primarily sodium hydroxide, and especially 2N sodium hydroxide as a base. At the end, the solution is washed with a non-polar organic solvent, such as benzene, toluene, xylene, preferably toluene, and adjusted to a pH value of 6. The excreted solid fcvar is filtered and, if necessary, purified by chromatography, preferably by column chromatography. In this way, both dialkylation products and monoalkylation products of compounds of general formulas (Ia) and (Ib) can be produced and isolated.

Suitable organic solvents for the alkylation reaction include inert solvents such as dimethylformamide, dimethylacetamine, methylene chloride, alkyl ethers, especially diethyl ether, tetrahydrofuran, benzene, toluene, xylene, and especially dimethylformamide. As bases, carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, as well as hydrogen carbonates of the previously mentioned alkali and alkaline earth metals, as well as their hydroxides and alcoholates, are considered. Preference is given to alcoholates of the aforementioned alkali and alkaline earth metals with methanol, isopropanol, tert.butanol, whereby sodium methanolate is particularly preferred. In the case of carbonates, hydrogen carbonates, alcoholates and hydroxides, it may be useful to use alcohol or water as a solvent. Sodium hydride, lithium hydride, calcium hydride in the aforementioned inert solvents are suitable as further bases for alkylation. Also suitable as alkylating agents are hydrocarbon halides such as alkyl chlorides, alkyl bromides, alkyl iodides as well as alkyl hydrocarbon tosilates, mesylates, triflates and alkyl sulfates, preferably alkyl iodides.

The invention further relates to a process for the production of compounds of the general formulas (Id) and (Ic).

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Starting from the compound of the general formula (12) in accordance with the previously described conversion from (5) to (6) (compare scheme 4, step 4) the compound of the general formula (13) can be obtained (scheme 9).

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Scheme 9:

According to the regulation from step 5 (compare scheme 5), it can be translated into a compound of general formula (14) (scheme 10).

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Scheme 10:

In accordance with the previously described version of the procedure for converting compound (7) into (8) (compare scheme 6, step 6) compounds of general formula (14) can be converted into compounds of general formula (15) (scheme 11).

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Scheme 11

From this further, compounds of general formula (16) (Scheme 12) can be obtained by variants of the ring-closing reaction (compare Scheme 7) described in step 7 (Scheme 12).

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Scheme 12:

From this, the alkylation reaction, described in steps 3 and 8, can produce compounds of the general formulas (Ic) and (Ic), which, if necessary, are isolated by suitable cleaning or disassembly procedures, for example by crystallization or column chromatography (scheme 13).

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Scheme 13:

By introducing suitably substituted residues R1, R2, R3, R4, R5 or R6, using generally known procedures, triazolpurines (Ia), (Ib), (Ic) and (Id), which can be produced by the previously described procedures, can be made maximally effective. Suitable protecting groups can be used for this purpose if necessary. The following scheme 14 explains, for example, the resulting possibilities of modifying the compounds (Ib) according to the invention on the residue R6.

The reactions shown in scheme 14 lead to reactive triazolpurines that can serve as starting compounds for further structural variants (esterification, alkylation, substitution, etc.). According to the invention, individual residues R1, R2, R3, R4, R5 or R6 can be functionalized. These modifications are not limited to the compounds of the general formula (Ib), but can also be transferred to the triazolpurines of the general formulas (Ia), (Ic) and (Id). Scheme 14 serves, for example, to explain possible structural variants of triazolpurines (Ia), (Ib), (Ic) and (Id), without limiting the invention to the reaction sequences shown here.

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Scheme 14:

The proposed invention will be explained in more detail with examples of regulations for the synthesis of triazolpurine. These examples serve to illustrate and do not limit the scope of the invention.

Step 1: Synthesis of 5-substituted 3-amino-1,2,4-triazoles

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Unsubstituted 3-amino-1,2,4-triazole is commercially available, and the required 5-substituted 3-amino-1,2,4-triazoles can be produced by methods known from the literature, which are for example published in J. Chem. , Soc. 1929, 816, J. Org. Chem. 1926,, 1729 or in Org. Synthesis 26, 11. Carbonic acids R6-COOH, i.e. nitriles R6-CN can be purchased or can be produced by methods known from the literature.

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Step 2: Synthesis of 2-substituted derivatives of 4H-5-amino-1,2,4-triazol[1,5-a]pyrimidin-7-one (4)

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General work regulation

2.3 g (0.1 mol) of sodium are dissolved in 10 ml of abs. of ethanol, then 14.7 g (0.13 mol) of cyanoacetic acid ethyl ester are added. The mixture is stirred for 1-2 hours at room temperature, then mixed with 0.1 mol of the desired 5-substituted 3-aminotriazole and heated for 4-6 hours under reflux. The cooled reaction mixture is mixed with water and adjusted to acid with stirring, then the solid substance is filtered off, washed and dried.

This process produced, among others, the following compounds:

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Stage 3: Synthesis of alkylated triazolpyrimidine derivatives

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General work regulation:

66 moles of the corresponding 5-amino-1,2,4-triazol[1,5-a]-pyrimidin-7-one (4) are dissolved in ten to twenty times the amount of anhydrous dimethylformamide and mixed with 76 mmol of potassium carbonate and 76 mmol of of the desired alkyl iodide. The reaction mixture is stirred for 1-2 days at room temperature and thickened to dryness. The residue is mixed with water and methylene chloride. In many cases, after this treatment, compounds (5) can be filtered out and thus isolated as a solid substance. The isomer (12) can then be obtained from the filtrate as described below.

If no solid substance precipitates during mixing, i.e. to isolate compound (12) from the filtrate, the filtrate phases are separated, the aqueous phase is stirred with methylene chloride, and the combined organic phases are dried over magnesium sulfate and concentrated to dryness. Chromatographic purification of the residue isolates compound (5) and, if necessary, compound (12). The required alkyl halides R'-X (with R' = R4, R5) are commercially available or can be produced by methods known from the literature.

This process produced, among others, the following compounds:

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Stage 4: Synthesis of nitroso compounds (6) or (13)

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General work regulations (version A):

10 mmol of 5-amino-1,2,4-triazol[1,5-a]pyrimidin-7-one (4), (5) or (12) are dissolved or suspended in 10 - 30 ml of anhydrous dimethylformamide and the mixture is cool to -5°C. 20 mmoles of isoamyl nitrite are added so that the temperature does not rise above OOC and it is stirred at that temperature for 4 - 24 hours, and then, if necessary, it is stirred at room temperature until the end of the reaction. The solvent is removed under vacuum, the residue is mixed with efcer, filtered, washed with water and dried under vacuum.

This process produced, among other things, the following substances:

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General work regulation (version B):

20 mmoles of 5-amino-1,2,4-triazol[1,5-a]pyrimidin-7-one (4), (5) or (12) are suspended in 80 - 100 ml of glacial acetic acid. The mixture is heated to 70°C, mixed with a solution of 20 mmol of sodium nitrite in 2 - 4 ml of water and stirred for 0.5 - 2 hours at 70°C, and then for a further 0.5 - 2 hours at 10°C . The product is filtered, washed with water and dried in a vacuum. This process produced, among other things, the following compound:

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Stage 5: Synthesis of diamines (7) and (14)

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General work regulations (version A):

12.7 mmol of the nitroso compound (6) or (13) are suspended with stirring in 86 ml of water and mixed with 4.9 g (2.9 mol) of Na2S2O4. The suspension is heated to 80°C and 15 ml of 50% sulfuric acid is added over 30 minutes. The mixture is boiled under reflux until complete conversion. When cooled, in most cases the product is excreted as semisulfate. If no excretion occurs, neutralize with 30% sodium lye and filter out the excreted free base.

General work regulations (version B):

To a mixture of 175 ml of 25% aqueous ammonia and 36 ml of ethanol, 11.5 inmol of nitroso compound (6) or (13) are added with stirring. It is then stirred at 30°C until the nitroso compound is maximally dissolved, a solution of 6.1 g (34.7 mmol) of Na2S2O4 in 57 ml of water is added dropwise and stirred for another 1.5-3 hours at room temperature. If the starting compound is still present, add another 10% of the above amount of Na2S2O4 and mix until the conversion is complete. The product is isolated by filtration.

According to this version (A or B, see table 5), among other things, the compounds described in table 5 were produced.

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Stage 6: Synthesis of amide (8) or (15)

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General working profile (version A):

30 mmoles of the diamino compound (7) or (14) are suspended in 165 ml of anhydrous dimethylformamide and mixed with 45 mmoles (78 mmoles in the case of semisulfate) of 4-dimethylaminopyrimidine. It is stirred for 30 minutes at room temperature, the mixture is cooled to 5-10°C and a solution of 39 mmol of the desired carboxylic acid chloride in 16 ml of anhydrous dimethylformamide is added. It is then stirred for 2 hours at 10°C and overnight at room temperature. Then the solvent was removed in vacuo. The residue is transferred to water, the solid substance is filtered off, washed and, if necessary, purified by recrystallization and column chromatography.

The necessary chlorides of carboxylic acids are commercially available or can be produced by methods known from the literature.

This process produced, among other things, the compounds of formulas (8) and (15) which are described in table 6a:

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General work regulation (version B):

6.6 mmol of diamine (7) or (14) is suspended in 7.3 mmol of the corresponding carboxylic acid in 15-25 ml of acetonitrile. 7.3 mmol of N-methylmorpholine is slowly added with stirring. Then, at 20-25°C, a solution of 7.3 mmol of isobutyl ester of chloroformic acid in 6-7 ml of acetonitrile is added dropwise for 10-20 minutes. The obtained suspension is stirred for 4-6 hours at room temperature. For treatment, it is filtered and washed with acetonitrile. The resulting filtrate is concentrated and chromatographed on silica gel.

This procedure produced, among other things, the compounds of formulas (8) and (15) described in table 6b:

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Step 7: Ring closing reaction to triazolpurines (9) or (16)

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General work regulation (method A, version A):

14.4 mmol of compound (8) or compound (15) are suspended in 75.5 ml of water and 37.8 ml of ethanol and boiled for 24 hours under reflux with 17.4 ml of 50% NaOH and 4.82 g (65 mmol) Ca(OH)2. The reaction mixture is allowed to cool, acidified, the solid substance is filtered off and dried. If necessary, the product is purified by recrystallization or chromatography.

This procedure produced, among other things, the compounds of general formulas (9) and (16) which are described in table 7a.

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General work regulation (method A, version B):

4 mmol of amide (8) or (15) is mixed for 14 days at 45-65°C in 10-15 ml of tetrahydrofuran and 25-35 ml of water with 46 mmol of lithium hydroxide monohydrate. After that, acidify with 6 N hydrochloric acid and suction. The crude product is recrystallized from methanol. The obtained product is separated by chromatography on a silica gel column.

This process produced, among other things, the compounds of general formula (9) which are described in table 7b:

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General work regulation (method B):

10.1 mmoles of (7) and (14) are mixed for 1.5 hours at 200°C in 34 ml of formamide. The remaining formamide is distilled off in a vacuum, and the residue is mixed with water. The solid is filtered off, washed with water and the product is purified by recrystallization or chromatography.

Compounds (9) and (16), which are described in table 7c, were produced by this process, among others.

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General work regulation (method C):

0.66 ml (7.2 mmol) of phosphorus oxychloride is added to a solution of 6.8 mmol of the desired N-formylamine in 6 ml of diglyne at 0°C. Stir for 30 minutes in an ice bath and then add 4.8 mmol of the nitroso compound (6) or (13). The mixture is stirred for 30-60 minutes at 80°C and poured over ice water, the solid product is filtered off, washed and dried. For purification, it is recrystallized or purified by chromatography.

Compounds (9), which are described in table 7d, were produced by this process, among others.

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The required formylamines can be produced by methods known from the literature by converting amines with 88% formic acid and acetic anhydride.

Step 8: Alkylation reactions General working regulation (version A):

4 mmol of 1,2,4-triazol[1,5-a]purin-9-one [compound (9) with R4 = H; compound (16) with R = H], unsubstituted in positions 4 and 5, is placed in 26 ml of anhydrous dimethylformamide and first mixed with a solution of 0.1 g (4.2 immol) of sodium in 4 ml of anhydrous ethanol, and then with 4.2 mmol of the desired alkyl iodide. The mixture is stirred overnight at room temperature and then concentrated to dryness. The residue is dissolved in 2n NaOH, the solution is washed with toluene and then adjusted to pH 6. The separated solid is filtered off and purified by chromatography. If necessary, the di-alkylation products (la) and (Ib) can also be isolated.

Compounds (9), among others, were produced by this process:

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In addition, the following compounds (Ia) and (Ib) can also be obtained by this process:

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General work regulation (version B):

20.4 mmol of 1,2,4-triazol[1,5-a]purin-9-one [(9) with R4 = H; (16) with R5 = H], unsubstituted in positions 4 and 5, is mixed for 7 days at 70°C together with 40.8 mmol of potassium carbonate and 40.8 mmol of tert.butyl bromide in 100 ml of anhydrous dimethylformamide. It is concentrated to dryness, the residue is mixed with 100 ml of 2 n NaOH, the aqueous phase is thoroughly washed with toluene and neutralized. The precipitate is filtered off, extracted with CH2Cl2/CH3OH 9:1 and the extract is evaporated. Chromatography on silica gel with CH2Cl2/CH3OH 95:5 isolated the isomeric alkylation products (9) and (16) (table 8c).

The following compounds were produced by this process, among others

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General work regulation (version C):

0.05 mol of the starting compound (9) is dissolved in 500 ml abs. of dimethylformamide and mixed overnight at room temperature with 0.055 moles of potassium carbonate and 0.055 moles of benzyl bromide. For processing, the solvent is distilled off in a vacuum and the residue is taken up in methylene chloride/water. The organic phase is separated, washed once with water, dried over magnesium sulfate and evaporated. The residue crystallizes with ether. The thus obtained compounds (Ia/Ib) are listed in Table 8d.

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IX. Functionalization of triazolpurine of general formula (I):

IXa. Deblocking of triazolpurine (Ia)/(Ib) with a protected hydroxyl functional group:

General scheme of synthesis on the example of compounds of general formula (Ib):

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DDQ: 2,3-dichloro-5,6-dicyano-benzoquinone

The above reaction was carried out based on a procedure known from the literature (Tetrahedron 1986, 42, 3021). By this process the following compound was obtained, among others.

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IXb. Unblocking triazolpurine (Ia)/(Ib) with a protected amino functional group in the side chain:

General scheme of synthesis on the example of compounds of general formula (Ib):

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0.83 mmol of 2-(4-N-benzyl-1-pyrazinyl)-1,2,4-triazol-[1,5-a]purin-9-one is placed in 30 ml of glacial acetic acid

and at 60°C and under 5 bar, it is hydrogenated for 6 hours in the presence of 0.1 g of 10% Pd on charcoal. The catalyst is filtered off, the residue is concentrated to dryness and mixed with CH3OH. The solid residue is filtered off, washed and dried. Through this process, among other things, the following was obtained:

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IXc. Detachment of amino protecting groups from the structural core of triazolpurine

General scheme of synthesis on the example of compounds of general formula (Ib):

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The 3-N-benzylated triazolpurine of the general formula (I) is dissolved in methanol or in absolute glacial acetic acid and hydrogenated for 2.5 to 40 hours in a hydrogen atmosphere (1-5 bar) at 25-80°C using palladium as a catalyst (eg Pd/C). The catalyst is sucked off, evaporated and the residue is purified on silica gel. The purified eluates crystallize first with ether and then, if possible, crystallize as a salt (preferably methane sulfonate).

In this way, among others, the following compounds were obtained:

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IXd. Alkylation of hydroxy-substituted triazolpurines:

General scheme of synthesis on the example of compounds of general formula (Ib):

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3 mmol of hydroxyalkyl- or hydroxyaryl-substituted triazolpurine of the general formula (Ia), (Ib), (Ic) or (Id) are dissolved in 30 ml of dimethylformamide, mixed with 3.6 mmol of sodium hydride (60% suspension in mineral oil), stirred for 1 hour at room temperature, mixed with 3.6 mmol of alkyl iodide and stirred for 1-2 days at 25-60°C. To complete the conversion, add another 50% each of sodium hydride and alkyl iodide. For processing, the reaction mixture is evaporated to a residue which is taken up in methylene chloride and water, acidified with 2 N hydrochloric acid, the aqueous phase is extracted once more with methylene chloride, the combined organic phases are washed with common salt solution, dried over magnesium sulfate and evaporated .

The residue is purified on silica gel and the eluate is crystallized from ether.

The following compounds were produced by this process, among others.

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IXe. Acylation of hydroxy-substituted triazolpurine

General scheme of synthesis on the example of compounds of general formula (Ib):

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The hydroxyl compound is taken up in pyridine and mixed with a stoichiometric amount of acid chloride while cooling with ice. After completion of the conversion, the reaction mixture is transferred to ice water and acidified with 2N hydrochloric acid. The aqueous phase is extracted several times with methylene chloride. The combined organic phases are washed with common salt solution, dried over magnesium sulfate and evaporated. The residue is purified on silica gel and the eluate is crystallized from ether.

This process produced, among others, the following compounds:

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IXf. Halogenation of hydroxy substituted triazolpurine

General scheme of synthesis on the example of compounds of general formula (Ib):

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Conventionally, the hydroxylated triazolpurine is converted to the corresponding halide with halogenating reagents such as SOCl 2 , SOBr 2 , POCl 3 , etc., in inert solvents in the presence of a base (eg NEt 3 ).

Accordingly, among other things, the following compound was produced:

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9th century Nucleophilic substitution on halogen-substituted triazolpurines

General scheme of synthesis on the example of compounds of general formula (Ib):

[image]

X: chlorine, bromine, iodine

Using a well-known standard procedure, halogen-substituted triazolpurine derivatives can be converted into corresponding amines and alkyloxy-/aryloxy-compounds by conversion with nucleophiles (eg alcohol, amine) in the presence of a base. For the preparation of amines, reference is made to the previously described stage 8 of the synthesis regulations.

Alkyloxy-/aryloxy-compounds can be synthesized according to the general procedure described under item IXd. The following compounds, among others, were suitably produced.

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IXh. Oxidation of hydroxy-substituted triazolpurines

General scheme of synthesis on the example of compounds of general formula (Ib):

[image]

Using a well-known standard procedure (eg Tetrahedron Letters, 1979, 5, 399-402), derivatives of hydroxy-substituted triazolpurine can be converted into triazole-purines with a functional group of a higher oxidation state (eg aldehydes, carboxylic acids). The following compounds were suitably produced, among others:

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IXi. Derivatization of triazolpurine-carboxylic acids

General scheme of synthesis on the example of compounds of general formula (Ib):

[image]

By the procedure known from the literature, triazolpurine-carboxylic acids can be converted into a large number of carboxylic acid derivatives (e.g. halides, anhydrides, amides, esters, etc.). For the preparation of the corresponding triazolpurine-carboxylic acid methyl ester, the following general work rule can be used:

0.003 mol of triazolpurine carboxylic acid is suspended in a 1 molar solution of SOCl2 (1.5 eq.) in MeOH. The resulting clear solution is stirred at room temperature. At the end of the reaction, the solvent is distilled off in a vacuum and the remaining precipitate is purified by chromatography on silica gel. This process produced, among other things:

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IXk. Reductive amination of triazolpurine-aldehyde

General scheme of synthesis on the example of compounds of general formula (Ib):

[image]

By applying a well-known standard procedure, triazolpurine-aldehydes can be converted into the corresponding amines by chemical conversion with primary or secondary amines and final reduction or hydrogenation of the intermediate Schiffschen bases. Accordingly, the following compound was produced among others:

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The following table shows the binding values of receptors KiA1 (human) and KiA2 (rat).

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The following table shows the KiA3 (human) receptor binding values.

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The compounds of the general formula (I) can be used alone or in combination with other active substances according to the invention, if necessary also in combination with further pharmacologically active substances. Suitable administration forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powders. Suitable tablets can be obtained, for example, by mixing the active substance or active substances with known excipients, for example with inert diluents, such as calcium carbonate, calcium phosphate, or milk sugar, with a dissolving agent, such as corn starch or alginic acid, with binders such as starch or gelatin, sliding. with agents such as magnesium stearate or talc, and/or with agents for achieving a depot effect, such as carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. Tablets can also consist of several layers.

Suitable dragees can be produced by coating cores produced analogously to tablets using conventional dragee coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to reduce incompatibility, the core should consist of several layers. Also, the coating of the dragee to achieve the depot effect can consist of several layers, whereby the excipients mentioned above for tablets can be used.

Juices of active substances according to the invention, i.e. combinations of active substances, may additionally contain sweeteners such as saccharin, cyclamate, glycerin or sugar, as well as an agent for improving taste, for example, aromatic substances such as vanillin or orange extract. In addition, they may contain suspended auxiliary substances or a thickening agent, such as sodium carboxymethylcellulose, a leavening agent, for example a condensation product of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoate.

Injection solutions are produced in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoate or stabilizers such as alkaline salts of ethylenediaminetetraacetic acid and are filled into injection vials or ampoules. Capsules containing one or more active substances, or a combination of active substances, can be produced, for example, by mixing the active substance with inert carriers, such as milk sugar or sorbitol, and thereby filling gelatin capsules.

Suitable suppositories can be produced, for example, by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol, or its derivatives. The therapeutically effective daily dose for an adult is between 1 and 800 mg, preferably 10-300 mg.

The following examples illustrate the proposed invention, whereby the invention is not limited to the listed examples.

Examples of pharmaceutical formulations

AND)

Tablets Per tablet

active substance 100 mg

milk sugar 140 mg

corn starch 240 mg

polyvinylpyrrolidone 15 mg

magnesium stearate 5 mg

500 mg

Finely ground active substance, milk sugar and part of corn starch are mixed. The mixture is sieved, then the mixture is moistened with an aqueous solution of polyvinyl pyrrolidone, crushed, wet granulated and dried. The granulate, cornstarch residue and magnesium stearate are sieved and mixed. The mixture is pressed into tablets of a suitable shape.

B)

Tablets Per tablet

active substance 80 mg

corn starch 190 mg

milk sugar 55 mg

microcrystalline cellulose 35 mg

polyvinylpyrrolidone 15 mg

sodium-carboxymethyl-starch 23 mg

magnesium stearate 2 mg

400 mg

Finely ground active substance, part of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone are mixed. The mixture is sieved and then, with the rest of the cornstarch and water, it is processed into a granulate, which is dried and sieved. Sodium carboxymethyl starch and magnesium stearate are added to this and the mixture is pressed into tablets of a suitable size.

C)

Dragees By dragees

active substance 5 mg

corn starch 41.5 mg

milk sugar 30 mg

polyvinylpyrrolidone 3 mg

magnesium stearate 0.5 mg

80 mg

The active substance, corn starch, milk sugar and polyvinylpyrrolidone are mixed well and moistened with water. The wet mass is pushed through a sieve with a mesh size of 1 mm, dried at approx. 45°C and the granulate is then sifted through the same sieve. When magnesium stearate is mixed in, rounded cores of 6 mm diameter dragees are pressed on a tablet press. The dragee cores produced in this way are coated in a known way with a layer consisting mainly of sugar and talc. Finished dragees are polished with wax.

D)

Capsules Per capsule

active substance 50 mg

corn starch 268.5 mg

magnesium stearate 1.5 mg

320 mg

The active substance and corn starch are mixed and moistened with water. The wet mass is sieved and dried. The dry granulate is sieved and magnesium stearate is mixed in. Hard gelatin capsules of size 1 are filled with the final mixture.

E)

Solution for ampoules

active substance 50 mg

sodium chloride 50 mg

water for inj. 5 ml

At its own pH value or at pH 5.5 to 6.5, the active substance is dissolved in water and mixed with sodium chloride as an isotonant. The solution thus obtained is filtered without pyrogens and the filtrate is filled into ampoules under aseptic conditions, finally sterilized and sealed. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

F)

Suppositories

active substance 50 mg

Adeps solidus 1650 mg

1700 mg

The hard fat melted. At 40°C, the ground active substance is homogeneously dispersed. Cool to 38°C and pour into slightly cooled suppository molds.

MR)

Oral suspension

active substance 50 mg

hydroxymethylcellulose 50 mg

sorbic acid 5 mg

sorbitol (70% alcohol) 600 mg

glycerin 200 mg

fragrance 15 mg

water ad 5 ml

Distilled water is heated to 70°C. Hydroxyethyl cellulose is dissolved in it with stirring. After adding the sorbitol and glycerine solution, cool to room temperature. Sorbic acid, fragrance and active substance are added at room temperature. For degassing, the suspension is evacuated with stirring.

Claims (18)

1. Triazolpurines of the general formula (I) [image] indicated by the fact that R1 or R3 represents hydrogen, optionally substituted C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, optionally substituted C3-C8-cycloalkyl, by optionally substituted C3-C8-cycloalkenyl or optionally substituted C6-C8-cycloalkynyl; R1 or R3 represents optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C6-C10- aryl- or optionally substituted heteroaryl, optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby the heterocycle is connected via a carbon atom of the ring; R1 or R3 represents optionally substituted C1-C10-alkyloxycarbonyl, optionally substituted C2-C10-alkenyl-oxycarbonyl, optionally substituted C2-C10-alkynyloxy-carbonyl, optionally substituted C3-C8-cycloalkyloxy-carbonyl, optionally substituted C6-C10-aryloxycarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkyloxycarbonyl, A-O-CO- where A has the meaning of optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms may contain one or more atoms from the group consisting of nitrogen, oxygen or sulphur, where A is connected through a ring carbon atom; R1 or R3 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl, C2-C10-alkynyl-sulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted C6- C10-aryl-C1-C6-alkylsulfonyl, the residue A-SO2- in which A has the above meaning and is connected through a ring carbon atom; R1 or R3 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl, optionally substituted C2-C10-alkynylcarbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl, residue A-O-CO-, where A has the previously stated meaning; R1 or R3 represents the rest of the formula [image] in which R represents hydrogen, phenyl, substituted phenyl, optionally substituted benzyl, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched C1-C10-alkyl, preferably C1- C4-alkyl, C2-C10-alkenyl or C2-C10-alkynyl group, which can be substituted with hydroxy, phenyl, substituted phenyl, amino or substituted amino if necessary; R2 represents hydrogen, hydroxy, amino, halogen, nitro, CF3, COOH, mercapto, C1-C6-alkylmercapto, optionally substituted C1-C10-alkyl, optionally substituted C2-C10-alkenyl, optionally substituted C2-C10-alkynyl , optionally substituted C3-C8-cycloalkyl, optionally substituted C5-C8-cycloalkanone, optionally substituted C4-C8-cycloalkenyl, optionally substituted C6-C8-cycloalkynyl, optionally substituted C6-C10-aryl, optionally substituted C6 -C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, C3-C8-cycloalkyl-C1-C6-alkyl, C3-C8 -cycloalkyl-C2-C6-alkenyl, or C3-C8-cycloalkyl-C2-C6-alkynyl; R2 represents, if necessary, a substituted five-membered, six-membered or seven-membered heterocycle, which as a heteroatom can contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby nitrogen can be substituted if necessary and the heterocycle can be connected via a carbon atom or a nitrogen atom directly or via a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl bridge; R2 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl or C2-C10-alkynylsulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted heteroarylsulfonyl or optionally substituted C6-C10-aryl-C1-C6-alkylsulfonyl; R2 represents optionally substituted C1-C10-alkylsulfonyloxy, C2-C10-alkenylsulfonyloxy or C2-C10-alkynylsulfonyloxy, optionally substituted C3-C8-cycloalkylsulfonyloxy, optionally substituted C6-C10-arylsulfonyloxy, optionally substituted C6-C10 -aryl-C1-C6-alkylsulfonyloxy or optionally substituted heteroaryl-sulfonyloxy; R2 represents optionally substituted C1-C10-alkylsulfonylamino, C2-C10-alkenylsulfonylamino or C2-C10-alkynylsulfonylainino, optionally substituted C3-C8-cycloalkylsulfonylamino, optionally substituted C6-C10-arylsulfonylamino, optionally substituted C6-C10- aryl-C1-C6-alkylsulfonylamino or optionally substituted heteroarylsulfonylamino; R2 represents optionally substituted C1-C10-alkylaminocarbonyl, C1-C10-dialkylaminocarbonyl, C1-C10-alkyl-C2-C10-alkenylaminocarbonyl, C2-C10-alkenylaminocarbonyl, C2-C10-dialkenylaminocarbonyl, C2-C10-alkynylaminocarbonyl or C1 -C10-alkyl-C2-C10-alkynylaminocarbonyl, optionally substituted C3-C8-cycloalkylaminocarbonyl, optionally substituted C6-C10-arylaminocarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkylaminocarbonyl or optionally substituted heteroarylaminocarbonyl; R2 represents optionally substituted C1-C10-alkyloxycarbonylamino, C2-C10-alkenyloxycarbonylamino or C2-C10-alkynyloxycarbonylamino, optionally substituted C3-C8-cycloalkyloxycarbonylamino, optionally substituted C6-C10-aryloxycarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonylamino or optionally substituted heteroaryloxycarbonylamino; R2 represents optionally substituted C1-C10-alkylaminocarbonyloxy, C2-C10-alkenylaminocarbonyloxy or C2-C10-alkynylaminocarbonyloxy, optionally substituted C3-C8-cycloalkylaminocarbonyloxy, optionally substituted C6-C10-arylaminocarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonyloxy or optionally substituted heteroarylaminocarbonyloxy; R2 represents optionally substituted C1-C10-alkyl-N-amidino, C2-C10-alkenyl-N-amidino or C2-C10-alkynyl-N-amidino, optionally substituted C3-C8-cycloalkyl-N-amidino, optionally substituted C6-C10-aryl-N-amidino, optionally substituted C6-C10-aryl-C1-C6-alkyl-N-amidino or optionally substituted heteroaryl-N-amidino; R2 represents optionally substituted C1-C10-alkyloxy, C2-C10-alkenyloxy or C2-C10-alkynyloxy, optionally substituted C3-C8-cycloalkyloxy, optionally substituted C6-C10-aryloxy. optionally substituted C6-C10-aryl-C1-C6-alkyloxy or optionally substituted heteroaryloxy; R2 represents optionally substituted C1-C10-alkyloxycarbonyl, C2-C10-alkenyloxycarbonyl or C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonyl or optionally substituted heteroaryloxycarbonyl; R2 represents optionally substituted C1-C10-alkylcarbonyloxy, C2-C10-alkenylcarbonyloxy or C2-C10-alkynylcarbonyloxy, optionally substituted C3-C8-cycloalkylcarbonyloxy, optionally substituted C6-C10-arylcarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylcarbonyloxy or optionally substituted heteroaryl-carbonyloxy; R2 represents optionally substituted C1-C10-alkylthio, C2-C10-alkenylthio or C2-C10-alkynylthio, optionally substituted C3-C8-cycloalkylthio, optionally substituted C6-C10-arylthio, optionally substituted C6-C10-aryl- C1-C6-alkylthio or optionally substituted heteroarylthio; R2 represents an optionally substituted amine, preferably NR8R9; R2 represents an optionally substituted residue of the formula [image] R2 represents an optionally substituted residue of the formula [image] where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4, carbon atoms in the chain; R2 represents an optionally substituted residue of the formula [image] where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4, carbon atoms in the chain; R2 represents an optionally substituted residue of the formula [image] [image] where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4, carbon atoms in the chain; R4 or R5 represents hydrogen, optionally substituted C1-C10-alkyl, C2-C10-alkenyl or C2-C10-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C4-C8-cycloalkenyl or optionally substituted C6- C8-cycloalkynyl, optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C6-C10- aryl or optionally substituted heteroaryl; R4 or R5 represents an optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby the heterocycle is connected via a carbon atom of the ring; R4 or R5 represents optionally substituted C1-C10-alkyloxycarbonyl, optionally substituted C2-C10-alkenyloxycarbonyl, optionally substituted C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6 -C10-aryl-C1-C6-alkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl; R4 or R5 represents A-O-CO-, where A has the meaning of optionally substituted five-membered, six-membered or seven-membered heterocycle, which as heteroatoms can contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur; R4 or R5 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl, C2-C10-alkynyl-sulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, residue A-SO2- wherein A is as defined above and is linked through a ring carbon atom; R4 or R5 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl, optionally substituted C2-C10-alkynylcarbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , an optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl, a residue A-CO in which A has the previously stated meaning; R4 or R5 represents the rest of the formula [image] in which R represents hydrogen, phenyl, substituted phenyl, optionally substituted benzyl, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched C1-C10-alkyl, preferably C1- C4-alkyl, C2-C10-alkenyl or C2-C10-alkynyl group which can be substituted with hydroxy, phenyl, substituted phenyl, amino, substituted amino if necessary; R6 represents hydrogen, hydroxy, -CHO, amino, halogen, nitro, CF3, COOH, mercapto, C1-C6-alkylmercapto, optionally substituted C1-C10-alkyl, optionally substituted C2-C10-alkenyl, optionally substituted C2- C10-alkynyl, optionally substituted C3-C8-cycloalkyl, optionally substituted C5-C8-cycloalkanone, optionally substituted C4-C8-cycloalkenyl, optionally substituted C6-C8-cycloalkynyl, optionally substituted C6-C10-aryl, per optionally substituted C6-C10-aryl-C1-C6-alkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl-C2-C6-alkynyl, optionally substituted C3-C8-cycloalkyl-C1-C6 -alkyl, C3-C8-cycloalkyl-C2-C6-alkenyl or C3-C8-cycloalkyl-C2-C6-alkynyl; R6 represents an optionally substituted five-membered, six-membered or seven-membered heterocycle, which as a heteroatom may contain one or more atoms from the group consisting of nitrogen, oxygen or sulfur, whereby nitrogen may be substituted as necessary and the heterocycle may be connected via a carbon atom or a nitrogen atom directly or via a C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl bridge; R6 represents optionally substituted C1-C10-alkylsulfonyl, C2-C10-alkenylsulfonyl or C2-C10-alkynylsulfonyl, optionally substituted C3-C8-cycloalkylsulfonyl, optionally substituted C6-C10-arylsulfonyl, optionally substituted C6-C10- aryl-C1-C6-alkylsulfonyl or optionally substituted heteroarylsulfonyl; R6 represents optionally substituted C1-C10-alkyl-sulfonyloxy, C2-C10-alkenylsulfonyloxy or C2-C10-alkynyl-sulfonyloxy, optionally substituted C3-C8-cycloalkyl-sulfonyloxy, optionally substituted C6-C10-arylsulfonyl-oxy, by optionally substituted C6-C10-aryl-C1-C6-alkyl-sulfonyloxy or optionally substituted heteroaryl-sulfonyloxy; R6 represents optionally substituted C1-C10-alkylsulfonylamino, C2-C10-alkenylsulfonylamino or C2-C10-alkynylsulfonylamino, optionally substituted C3-C8-cycloalkylsulfonylamino, optionally substituted C6-C10-arylsulfonylamino, optionally substituted C6-C10- aryl-C1-C6-alkylsulfonylamino or optionally substituted heteroarylsulfonylamino; R6 represents optionally substituted C1-C10-alkylaminocarbonyl, C1-C10-dialkylaminocarbonyl, C1-C10-alkyl-C2-C10-alkenylaminocarbonyl, C2-C10-alkenylaminocarbonyl, C2-C10-dialkenylaminocarbonyl, or C1-C10-alkynylaminocarbonyl or C1-C10-alkyl-C2-C10-alkynylaminocarbonyl, optionally substituted C3-C8-cycloalkylaminocarbonyl, optionally substituted C6-C10-arylaminocarbonyl, optionally substituted C6-C10-aryl-C1-C6-alkylaminocarbonyl or optionally substituted heteroarylaminocarbonyl; R6 represents optionally substituted C1-C10-alkylaminocarbonylamino, C2-C10-alkenylaminocarbonylamino or C2-C10-alkynylaminocarbonylamino, optionally substituted C3-C8-cycloalkylaminocarbonylamino, optionally substituted C6-C10-arylaminocarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonylamino or optionally substituted heteroarylaminocarbonylamino; R6 represents optionally substituted C1-C10-alkyloxycarbonylamino, C2-C10-alkenyloxycarbonylamino or C2-C10-alkynyloxycarbonylamino, optionally substituted C3-C8-cycloalkyloxycarbonylamino, optionally substituted C6-C10-aryloxycarbonylamino, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonylamino or optionally substituted heteroaryloxycarbonylamino; R6 represents optionally substituted C1-C10-alkylaminocarbonyloxy, C2-C10-alkenylaminocarbonyloxy or C2-C10-alkynylaminocarbonyloxy, optionally substituted C3-C8-cycloalkylaminocarbonyloxy, optionally substituted C6-C10-arylaminocarbonyloxy, optionally substituted C6-C10-aryl- C1-C6-alkylaminocarbonyloxy or optionally substituted heteroarylaminocarbonyloxy; R6 represents optionally substituted C1-C10-alkyl-N-amidino, C2-C10-alkenyl-N-amidino or C2-C10-alkynyl-N-amidino, optionally substituted C3-C8-cycloalkyl-N-amidino, optionally substituted C6-C10-aryl-N-amidino, optionally substituted C6-C10-aryl-C1-C6-alkyl-N-amidino or optionally substituted heteroaryl-N-amidino; R6 represents optionally substituted C1-C10-alkyloxy, C2-C10-alkenyloxy or C2-C10-alkynyloxy, optionally substituted C3-C8-cycloalkyloxy, optionally substituted C6-C10-aryloxy, optionally substituted C6-C10-aryl- C1-C6-alkyloxy or optionally substituted heteroaryloxy; R6 represents optionally substituted C1-C10-alkylcarbonyl, optionally substituted C2-C10-alkenyl-carbonyl or optionally substituted C2-C10-alkynyl-carbonyl, optionally substituted C3-C8-cycloalkylcarbonyl, optionally substituted C6-C10-arylcarbonyl , optionally substituted C6-C10-aryl-C1-C6-alkylcarbonyl; R 6 represents the residue A-CO-, in which A has the previously defined meaning; R6 represents optionally substituted C1-C10-alkyloxycarbonyl, C2-C10-alkenyloxycarbonyl or C2-C10-alkynyloxycarbonyl, optionally substituted C3-C8-cycloalkyloxycarbonyl, optionally substituted C6-C10-aryloxycarbonyl, optionally substituted C6-C10-aryl- C1-C6-alkyloxycarbonyl or optionally substituted heteroaryloxycarbonyl; R6 represents optionally substituted C1-C10-alkyl-carbonyloxy, C2-C10-alkenylcarbonyloxy or C2-C10-alkynyl-carbonyloxy, optionally substituted C3-C8-cycloalkyl-carbonyloxy, optionally substituted C6-C10-arylcarbonyloxy, optionally substituted C6-C10-aryl-C1-C6-alkyl-carbonyloxy or optionally substituted heteroaryl-carbonyloxy; R6 represents optionally substituted C1-C10-alkylthio, C2-C10-alkenylthio or C2-C10-alkynylthio, optionally substituted C3-C8-cycloalkylthio, optionally substituted C6-C10-arylthio, optionally substituted C6-C10-aryl- C1-C6-alkylthio or optionally substituted heteroarylthio; R6 represents optionally substituted C1-C10-alkyl-carbonyloxy-C1-C6-alkyl, C2-C10-alkenylcarbonyloxy-C1-C6-alkyl or C2-C10-alkynylcarbonyloxy-C1-C6-alkyl, optionally substituted C3-C8- cycloalkynylcarbonyloxy-C1-C6-alkyl, optionally substituted C6-C10-arylcarbonyloxy-C1-C6-alkyl, C6-C10-aryl-C1-C6-alkylcarbonyloxy-C1-C6-alkyl or heteroarylcarbonyl-C1-C6-alkyl; R6 represents an optionally substituted residue of the formula R10-O-B-(CH2)n- with n = 1, 2, 3 or 4, where B represents C6-C10-aryl or a single bond; R6 represents an optionally substituted amine, preferably NR8R9; R6 represents an optionally substituted residue of the formula [image] R6 represents an optionally substituted residue of the formula [image] [image] where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4, carbon atoms in the chain; R6 represents an optionally substituted residue of the formula [image] where Y represents a single bond or alkylene, alkenylene or alkynylene which has up to 6, preferably up to 4, carbon atoms in the chain; R8 represents an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl/alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkyl group having 1-4 carbon atoms, which can be substituted with hydroxy , phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or with C1-C8-alkyloxy, preferably with C1-C4-alkyloxy, -(CH2)m,-NHCOOR10 with m = 1, 2, 3 or 4; R8 represents a five-membered, six-membered or seven-membered heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which can contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be single or multiply, preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10; R8 represents a bicyclic heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which may contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and may be single or multiple, preferably single substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10; R9 represents an optionally substituted cycloalkyl group having 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkyl group having 1-4 carbon atoms, which may be substituted with hydroxy , phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or with C1-C8-alkyloxy, preferably with C1-C4-alkyloxy, -(CH2)m-NHCOOR10 with m = 1, 2, 3 or 4; R9 represents a five-membered, six-membered or seven-membered heterocycle, connected through a carbon atom directly or through an alkyl chain having 1 to 4 C-atoms, which can contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be single or multiply, preferably monosubstituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10; R9 represents a bicyclic heterocycle, connected via a carbon atom directly or via an alkyl chain having 1 to 4 C-atoms, which may contain one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, may be single or multiple, preferably single substituted with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR , -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10; or R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen, oxygen or sulfur as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group with 1 to 4 carbon atoms/ preferably with methyl or can carry one of the following residues -(CH2)n-phenyl, -(CH2)n-NH2, =O, ketal, preferably -O-CH2-CH2-O-, - (CH2)nNH-C1-C4- alkyl, - (CH2)n-N(C1-C8-alkyl) 2, -(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9 ; -OH, -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10; R10 represents hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkynyl, benzyl or phenyl residue, which can be singly or multiply substituted with OCR^, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, and, if necessary, their pharmacologically unambiguous acid addition salts. 2. Compounds of general formulas (Ia) to (Id) [image] [image] indicated by that R1 or R3 represents hydrogen, C1-C4-alkyl, benzyl; R2 represents hydrogen, C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN, -CH2NR8R9, OH (multiple substitution is also possible), -OR10, -NR8R9, - NHCOR10, -NHCONR8R9, -NHCOOR10, halogenim, -COOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2CH2O-COR10, -OCH2-CH2-NR8R9, -SO2-CH2CH2-OH, -CONHSO2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2R8R9, -OCH2-CH2OCOR10, -CH=NOH -CH=NOR10, =O, -COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9, if necessary singly or multiply, preferably singly methyl-substituted 1, 3-dioxolane or 1,3-dioxane; R2 represents phenyl-C1-C6-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted directly, or via an alkylene bridge having 1 to 4 carbon atoms, with one or more, preferably with one of the residues –C1-C3-alkyl-, -CN, -NR8R9, -NO3, OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2,R10, -SO2H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9, if necessary single or multiply, preferably monosubstituted with methyl, 1,3-dioxolane or 1,3-dioxane; R2 represents C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkyl-C2-C6-alkenyl, C3-C7-cycloalkyl-C2-C6-alkynyl, whereby the cycloalkyl residue can be substituted directly if necessary, or via an alkylene bridge with 1 to 4 C atoms, with one or more, preferably with one of the residues -CN, -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2R8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR89, -CH2-O-CONR8R9, -CH2-CH2O-CONR8R9, methyl substituted 1,3-dioxolane or 1,3-dioxane; R2 represents a residue of the formula A-C1-C6-alkyl, A-CONH-C1-C6-alkyl-, A-CONH- C2-C6-alkenyl-, A-CONH- C2-C6-alkynyl-, A-NH-CO- C1-C6-alkyl, A-NH-CO- C2-C6-alkenyl, A-NH-CO-C2-C6-alkynyl, A-C1-C6-alkenylene, A-C1-C6-alkynylene or A-, where A represents a five-membered, six-membered or seven-membered heterocycle connected via a carbon or nitrogen atom, which contains one or more heteroatoms from the nitrogen, oxygen or sulfur group and can be singly or multiply substituted with benzyl, optionally substituted benzyl, C1-C4 -alkyl, halogen, -OR, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, ketal, ethylene ketal, -COOH, -SO2H, -COOR10, -CONR8R9, -COR11, -SO2R10 or -CONR8R9; R2 represents C3-C7-cycloalkyl, which is optionally substituted with =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl; R2 represents phenyl which is optionally substituted with -OH, halogen, -OR10, C1-C4-alkyl, -NH2, -COOH, -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9; R2 represents a residue of norbornene, norbornene, C3-C6-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane, optionally substituted with C1-C4-alkyl; R2 represents -CH=CH-phenyl, whereby the phenyl ring can be mono- or multi-substituted with methoxy, hydroxy or halogen; R 2 represents [3,3,0]-bicyclooctane; R2 represents piperidine or furan connected through carbon; R2 represents an amine of the general formula NR8R9; R4 or R5 represents hydrogen, optionally a branched C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN, -CH2NR8R9, OH (multiple substitution is also possible), -OR10 , -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2CH2-O-COR10, - OCH2-CH2-NR8R9, -SO2-CH2CH2-OH, -CONHSO2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, =O, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9, if necessary singly or multiply, preferably singly substituted with methyl 1,3-dioxolane or 1,3-dioxane; R4 or R5 represents phenyl-C1-C6-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, wherein the phenyl ring is optionally substituted directly, or via an alkylene bridge having 1 to 4 C-atom, with one or more, preferably with one of the residues –C1-C3-alkyl, -CN, -NR8R9, -NO2, OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2CH, -OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2-CH2OR10, -COOH, -COOR10, - CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO2H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, - COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally mono- or multi-methyl substituted 1,3-dioxolane or 1,3-dioxane; R4 or R5 represents an optionally substituted C3-C7-cycloalkyl radical; R4 or R5 represents C3-C7-cycloalkyl-C1-C6-alkyl-, C3-C7-cycloalkyl-C2-C6-alkenyl- or C3-C7-cycloalkyl-C2-C6-alkynyl-, whereby the cycloalkyl radical can be optionally substituted directly, or via an alkylene bridge having 1 to 4 C atoms, with -CN, -NR R , =O, -OH, -OR, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO- pyridyl, -OCH2COOH, -OCH2COOR10, -OCH2OCOR, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -OCH2-CH2OR, -COOH, -COOR10, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally mono- or multi-methyl substituted 1,3-dioxolane or 1,3-dioxane; R4 or R5 represents the rest of the formula A-C1-C6-alkyl, A-CONH- C1-C6-alkyl-, A-CONH- C2-C6-alkenyl-, A-CONH- C2-C6-alkynyl-, A-NH-CO- C1-C6 -alkyl, A-NH-CO-C2-C6-alkenyl, A-NH-CO-C2-C6-alkynyl, A-C2-C6-alkenyl or A-C2-C6-alkynyl, where A represents a heterocycle connected through a carbon or nitrogen of atoms, which contains one or more heteroatoms from the nitrogen, oxygen or sulfur group and can be singly or multiply, preferably singly substituted with C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9 , -OH, =O, ketal, ethylene ketal, -COOH, -SO3H, -COOR10, -CONR8R9, -COR11, -SO2R10 or -CONR8R9; R represents hydrogen, C1-C8-alkyl, C2-C8-alkenyl or C2-C8-alkynyl residue, which is substituted by -CN, -CH2NR8R9, OH (multiple substitution is also possible), -OR10, -NR8R9, - NHCOR10, -NHCONR8R9, -NHCOOR10, halogenim, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7 -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2-CH2-O-COR10, -OCH2-CH2-NR8R9, -SOV-CH2CH2-OH, -CONHSO2R10, -CH2CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -CH=CH-R12, OCONR8R9, if necessary single or multiple, preferably mono-methyl-substituted 1, 3-dioxolane or 1,3-dioxane; R6 represents phenyl-C1-C6-alkyl-, preferably phenyl-C1-C4-alkyl-, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be directly substituted if necessary, or via an alkylene bridge having 1 to 4 C-atoms, with one or more residues –C1-C3-alkyl, -CN, -NR8R9, -NO2, OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10 , -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -CONHSO2R10, -OCH2CH2OR10, -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO3H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10)2, -NHCOOR10, -CH2CONHSO2R10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9, -CO- R10, -CO-C1-C4-alkyl-NR8R8, if necessary singly or multiply, preferably singly methyl-substituted 1,3-dioxolane or 1,3-dioxane; R6 represents C3-C7-cycloalkyl-C1-C6-alkyl, C3-C7-cycloalkyl-C2-C6-alkenyl-, C3-C7-cycloalkyl-C2-C6-alkynyl-, whereby the cycloalkyl residue can be directly substituted if necessary , or via an alkylene bridge having 1 to 4 C atoms, with one or more, preferably with one of the residues -CN, -NR8R9, =O, -OH, -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, - OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH2OCOR10, -SO2R7, -OCH2-CONR8R9, -OCH2CH2OH, -OCH2-CH2-NR8R9, -OCH2CH2OR10, -COOH, -COOR10, -CONR8R9, -CH2OH, - CH2OR10, -CHO, -SR10, -SOR10, -SO2R10, -SO2H, -SO2NR8R9, -OCH2-CH2OCOR10, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CONHSO2R10, -CH(OR10)2, -NHCOOR10, -CH=CH-R12, -OCONR8R9, -CH2-O-CONR8R9, -CH2CH2-O-CONR8R9 or methyl substituted 1,3-dioxolane or 1,3- dioxane; R6 represents a residue of the formula A-C1-C6-alkyl, A-CONH- C1-C6-alkyl-, A-CONH- C2-C6-alkenyl-, A-CONH- C2-C6-alkynyl-, A-NH-CO - C1-C6-alkyl, A-NH-CO- C2-C6-alkenyl, A-NH-CO- C2-C6-alkynyl, A- C2-C6-alkenyl, A- C2-C6-alkynyl or A-, where A represents a five-membered, six-membered or seven-membered heterocycle connected via carbon or nitrogen, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be singly or multiply, preferably singly substituted with benzyl, C1-C4- alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, ketal, ethyl ketal, -COOH, -SO2H, -COOR10, -CONR8R9, -COR11, -SO2R10 or -CONR8R9; R6 represents -CHO, -COOR10 or -CONR8R9; R6 represents C3-C7-cycloalkyl, preferably cyclopentyl or cyclohexyl, which is optionally substituted with =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl; R6 represents phenyl which is optionally substituted with -OH, halogen, -OR10, C1-C4-alkyl, preferably with -CH2, -NH2, -COOH. -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9; R6 represents, if necessary, a residue of norbornene, norbornene, C3-C6-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane substituted with C1-C4-alkyl, preferably methyl; R6 represents -CH=CH-phenyl, whereby the phenyl ring can be mono- or multi-substituted with methoxy, hydroxy or halogen; R6 represents [3,3,0]-bicyclooctane-; R 6 represents carbon-linked piperidine or furan; R7 represents C1-C4-alkyl, which is optionally substituted with -OH, -OCOR10, -OCO-pyridyl, NH2, -NR8R9 or NHCOR10, preferably -CH2CH2OH, -CH2CH2OCOR10, -CH2-CH2-CH2-OH or -CH2 -CH2CH2OCOR10; R8 represents hydrogen, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which can optionally be substituted with hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1-C8-alkyloxy, preferably C1-C4-alkyloxy, - (CH2)m, -NHCOOR10 with m = 1, 2, 3 or 4; R8 represents a five-membered, six-membered or seven-membered heterocycle connected directly via a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be single or multiple if necessary substituted with benzyl, optionally substituted with benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10; R8 represents a bicyclic heterocycle connected directly via a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, which contains one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be mono- or multi-substituted with benzyl if necessary, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10; R9 represents hydrogen, optionally substituted cycloalkyl group having 3 to 6 carbon atoms, branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which may optionally be substituted with hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, C1-C8-alkyloxy, preferably C1-C4-alkyloxy, - (CH2)m, -NHCOOR10 with m = 1, 2, 3 or 4; R9 represents a five-membered, six-membered or seven-membered heterocycle connected directly by a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and can be singly or multiply substituted if necessary with benzyl, optionally substituted benzyl, C1-C4-alkyl, halogen, -OR, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10; R9 represents a bicyclic heterocycle connected directly by a carbon atom, or via an alkyl chain having 1 to 4 C-atoms, containing one or more heteroatoms from the group consisting of nitrogen, oxygen or sulfur and, if necessary, can be mono- or multi-substituted with benzyl, by optionally substituted with benzyl, C1-C4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, -COOR10; or R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen, oxygen or sulfur as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, or can carry one of the following residues -(CH2)n-phenyl, -(CH2)n-NH2, =O, ketal, preferably -O-CH2-CH2-O-, - (CH2)n-NH-C1-C4-alkyl, -(CH2)n-N(C1-C8-alkyl)2, -(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10; R10 represents hydrogen, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, benzyl or phenyl residue, which can be mono- or multi-substituted with OCH2 if necessary, R11 represents C1-C4-alkyl, C2-C4-alkenyl, optionally substituted phenyl, optionally substituted benzyl, C3-C6-cycloalkyl; R12 represents -COOR10, -CH2OR10, -CONR8R9, hydrogen, C1-C3-alkyl, optionally substituted phenyl or -CH2NR8R9, optionally in the form of their racemates, their enantiomers, their diastereomers or their mixture, and optionally their pharmacologically unambiguous acidic addition salts. 3. Compounds of general formulas (Ia) to (Id) [image] indicated by that R1 or R3 represents hydrogen, C1-C4-alkyl, benzyl; R2 represents hydrogen, C1-C8-alkyl, preferably 1-C6-alkyl; R2 represents phenyl which is optionally substituted with halogen, preferably with fluorine or chlorine, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9; R2 represents phenyl-C1-C6-alkyl-, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, wherein the phenyl ring is optionally substituted with halogen, preferably with fluorine or chlorine, C1 -C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9; R2 represents a substituted amine, preferably NR8R9; R2 represents a five- or six-membered heterocycle connected directly through C or N, or through an alkylene bridge having 1 to 4 C atoms, containing one or more heteroatoms from the group consisting of nitrogen or sulfur and which can be substituted with benzyl or with C1-C4 -alkyl; R 2 represents C 3 -C 6 -cycloalkyl which, if necessary, can be substituted with =O, hydroxy, with C 1 -C 4 -alkyl or C 1 -C 4 -alkyloxy; R 2 represents C 3 -C 6 -cycloalkyl which, if necessary, can be substituted with =O, hydroxy, with C 1 -C 4 -alkyl or C 1 -C 4 -alkyloxy; R2 represents, if necessary, C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane; R4 or R5 represents hydrogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted with halogen , preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy or NR8R9; R6 represents hydrogen, C1-C8-alkyl, wherein the alkyl chain can be substituted with halogen, hydroxy, =O, C1-C4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-C1-C4-alkyloxy, benzyloxy, -O -benzyl-C1-C4-alkyloxy, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl , -CHO, =NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NH-CO- C1-C4-alkyl, -NHCO-phenyl, -CO- C1-C4-alkyl-NR8R9, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl; R6 represents phenyl which is optionally substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl, - C1-C4-alkyl-NH2, - C1-C4-alkyl-OH, - C1-C4 -alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4-alkyl-NH2, -SO2-OH, -SO2- C1-C4-alkyl or -SO2- phenyl; R6 represents phenyl-C1-C6-alkyl-, preferably benzyl, phenyl-C2-C6-alkenyl- or phenyl-C2-C6-alkynyl-, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1 -C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O- C2-C4-alkylene, -CO- C1-C4-alkyl, - C1-C4-alkyl-NR8R9, - C1-C4-alkyl-OH, - C1-C4-alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4alkyl-NH2, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl; R6 represents a five-membered or six-membered heterocycle, directly connected through C or N or through an alkylene bridge having 1 to 4 C atoms, which can contain one, two or three heteroatoms from the group consisting of nitrogen or sulfur and which can be single or multiple if necessary substituted with benzyl or with C1-C4-alkyl; R6 represents a C3-C6-cycloalkyl or C3-C6-cycloalkyl-C1-C4-alkyl residue which can be substituted with =O, hydroxy, C1-C4-alkyl or C1-C4-alkyloxy if necessary; R6 represents optionally with C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane; R6 represents -CHO, -COOH, -COO-C1-C4-alkyl, -COO-phenyl, -COO-benzyl or -CONR8R9; R6 represents an amine of the general formula NR8R9; R8 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms; R represents a five-membered or six-membered heterocycle, connected through C, containing one, two or three heteroatoms from the group consisting of nitrogen or sulfur and is optionally substituted with benzyl, C1-C4-alkyl, halogen, -CN, -NO2, -NH2, -OH or =O; R9 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms; - CN, -NO2, -NH2, -OH or =O; or R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen or oxygen as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably with methyl or may be substituted with one - (CH 2 ) 1-4-phenyl residue, preferably with benzyl, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, as if necessary their pharmacologically certain acid addition salts. 4. Compounds of general formulas (la) to (Ib) [image] indicated by that R1 or R3 represents hydrogen, C1-C4-alkyl, preferably C1-C4-alkyl, benzyl; R2 represents hydrogen, C1-C6-alkyl, preferably C1-C4-alkyl; R 2 represents cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane; R2 represents a morpholine residue which is optionally substituted with C1-C4-alkyl, preferably with methyl, a piperidinyl residue, a piperazinyl residue which is optionally substituted with benzyl or with C1-C4-alkyl, preferably with methyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furil; R2 represents a phenyl radical which is optionally substituted with C1-C4-alkyl, halogen or hydroxy; R2 represents phenyl-C1-C4-alkyl, preferably benzyl, wherein the phenyl ring is optionally substituted with halogen, preferably with fluorine or chlorine, C1-C4-alkyl, C1-C4-alkyloxy, hydroxy or NR8R9; R2 represents an amine of the general formula NR8R9; R4 represents optionally with C1-C4-alkyl, preferably methyl-substituted norbornene, norbornene, adamantane or noradamantane; R4 represents hydrogen, C1-C7-alkyl, preferably C1-C5-alkyl, phenyl-C1-C3-alkyl, preferably benzyl, wherein the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4- alkyl, C1-C4-alkyloxy or NR8R9; R6 represents hydrogen, C1-C6-alkyl, preferably C1-C4-alkyl, wherein the alkyl chain can be substituted with halogen, hydroxy, =O, C1-C4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-O- C1 -C4-alkyloxy, benzyloxy, -O-benzyl-O- C1-C4-alkyloxy, -OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -O-C2-C4 -alkylene, -CO- C1-C4-alkyl, -CHO, =NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO- C1-C4-alkyl, -NHCO-phenyl, -CO- C1- C4-alkyl-NR8R9, -SO2-OH, -SO2- C1-C4-alkyl or -SO2-phenyl; R6 represents phenyl, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy or NR8R9; R6 represents phenyl-C1-C3-alkyl-, preferably benzyl, whereby the phenyl ring can be substituted with halogen, preferably chlorine or fluorine, hydroxy, C1-C4-alkyl, C1-C4-alkyloxy, benzyloxy, phenyloxy, NR8R9, - OCO- C1-C4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-C4-alkylene, -CO- C1-C4-alkyl, -C1-C4-alkyl-NR8R9, - C1-C4-alkyl-OH, - C1-C4-alkyl=NHOH, -COOH, -COO- C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO- C1-C4- alkyl-NR8R9, -SO2-OH, -SO2-C1-C4-alkyl or -SO2-phenyl; R6 represents cyclopentyl, cyclohexyl, cyclohexyl-C1-C3-alkyl, preferably cyclohexylmethyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked by a single bond or via an alkylene chain having 1 to 4 C atoms; R6 represents furan, tetrahydrofuran, α-pyran, γ-pyran, dioxolane, tetrahydro-pyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, linked by a single bond or via an alkylene chain having 1 to 4 C atoms. pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine/pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole or pyrazolidine; R6 represents -CHO, -COOH, -COO-C1-C4-alkyl, -COO-phenyl, -COO-benzyl, -CO-NH-C1-C4-alkyl, -CO-N(C1-C4-alkyl); or -CONH-phenyl; R6 represents an amine of the general formula NR8R9; R8 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms; R8 represents carbon-linked and, if necessary, chlorine, bromine, C1-C4-alkyl, C1-C4-alkyloxy, -NO2, -NH2, -OH substituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole , pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole; R9 represents hydrogen, a branched or unbranched alkyl group having from 1 to 4 carbon atoms; R9 represents carbon-bonded and optionally chlorine, bromine, C1-C4-alkyl, C1-C4-alkyloxy, -NO3, -NH2, -OH substituted pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole , pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole, or R8 and R9 together with the nitrogen atom form a saturated or unsaturated five-membered or six-membered ring which can contain nitrogen or oxygen as further heteroatoms, whereby the heterocycle can be substituted with one branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably with methyl, or it may be substituted with one - (CH 2 ) 1-4-phenyl radical, preferably with benzyl, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixtures, as if necessary their pharmacologically certain acid addition salts. 5. Compounds of general formula (Ib) [image] indicated by that R2 represents hydrogen, C1-C4-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted with fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzyl-piperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl , adamantyl, noradamantyl, norbornyl or norbornenyl; R 3 represents hydrogen, C 1 -C 3 -alkyl or benzyl; R 4 represents hydrogen, C 1 -C 5 -alkyl or benzyl; R6 represents hydrogen, C1-C4-alkyl, which is optionally substituted with OH, chlorine, bromine, C1-C4-alkyloxy or NR8R9, -CHO, -COOH, -COO-C1-C4-alkyl, phenyl, if necessary with fluorine or with benzyloxy substituted phenyl-C1-C3-alkyl, if necessary with methoxy substituted phenyloxy-v-alkyl, if necessary with methoxy substituted benzyloxy - C1-C3-alkyl, benzyloxybenzyl, benzoyloxymethyl pyridylcarbonyloxy-methyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl; R 8 represents hydrogen, C 1 -C 4 -alkyl or pyridyl; R 9 can be hydrogen, C 1 -C 4 -alkyl or pyridyl, optionally in the form of their racemates, their enantiomers, their diastereomers or mixtures thereof, as optionally their pharmacologically unambiguous acid addition salts. 6. Compounds of general formula (Ia) [image] indicated by that R 1 represents hydrogen, C 1 -C 3 -alkyl or benzyl; R2 represents hydrogen, C1-C4-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted with fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzyl-piperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl , adamantyl, noradamantyl, norbornyl or norbornenyl; R4 represents hydrogen, C1-C5-alkyl or benzyl; R6 represents hydrogen, C1-C4-alkyl, which can be substituted with OH, chlorine, bromine, C1-C4-alkyloxy or NR8R9, -CHO, -COOH, -COO- C1-C4-alkyl, phenyl, if necessary with fluorine or with benzyloxy-substituted phenyl-C1-C3-alkyl, optionally with methoxy-substituted phenyloxy-C1-C3-alkyl, optionally with methoxy-substituted benzyloxy-C1-C3-alkyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxy-methyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl; R 8 represents hydrogen, C 1 -C 4 -alkyl or pyridyl; R 9 can be hydrogen, C 1 -C 4 -alkyl or pyridyl, optionally in the form of their racemates, their enantiomers, their diastereomers or mixtures thereof, as optionally their pharmacologically unambiguous acid addition salts. 7. Compounds of general formula (Ic) [image] indicated by that R 1 represents hydrogen or C 1 -C 3 -alkyl; R 2 represents hydrogen, C 1 -C 4 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl; R5 represents C1-C6-alkyl; R 6 represents hydrogen, benzyl or cyclopentyl, optionally in the form of their racemates, their enantiomers, their diastereomers or mixtures thereof, as optionally their pharmacologically unambiguous acid addition salts. 8. Compounds of the general formula (Id) [image] indicated by that R 1 represents C 1 -C 3 -alkyl; R2 represents hydrogen, C1-C4-alkyl, cyclopentyl, cyclopentanone/hydroxycyclopentane, furan or benzyl; R5 represents C1-C6-alkyl; R 6 represents hydrogen, benzyl or cyclopentyl; if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, as if necessary their pharmacologically unambiguous acid addition salts. 9. Compounds of general formula (Ib) [image] indicated by that R2 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzyl- piperazinyl, 2-furyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R 3 represents hydrogen, methyl, ethyl, n-propyl or benzyl; R 4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl, or benzyl; R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, PhCO-O-CH2-, pyridyl-CO-O-CH2-, Ph-O-CH2-, (4-MeO-Ph)- O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, (4-Ph-CH2-O-Ph)-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -COOH, -COOMe, -CH2-OH, -CH2-OMe, -CHV-OEt or -CHV-NMC2, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, as if necessary their pharmacologically unambiguous acid addition salts. 10. Compounds of general formula (Ia) [image] indicated by that R 1 represents hydrogen, methyl, ethyl, n-propyl or benzyl; R2 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidyl, N-morpholinyl, N-piperazinyl, 4-benzyl- piperazinyl, 2-furyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl; R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, phenylethyl, N-morpholinomethyl, N-pyrrolyl-methyl, (S-pyridyl-NH-CH2-, PhCO-O-CH2-, pyridyl-CO-O-CH2,-, Ph-O-CH2-, (4-MeO-Ph )-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, (4-Ph-CH2-O-Ph)-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -COOH, -COOMe, -CH2-OH, -CH2-OMe, -CH2-OEt or -CH2-NMe2, if necessary in the form their racemates, their enantiomers, their diastereomers or mixtures thereof, as well as their pharmacologically unambiguous acid addition salts as appropriate. 11. Compounds of general formula (Ib) [image] indicated by that R2 represents hydrogen, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R 3 represents hydrogen; R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl; R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, 2- phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, PhCO-O-CH2-, S-pyridyl-COO-CH2-, Ph-O-CH2-, (4-MeO-Ph )-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -CH2-OH, -CH2-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixtures, as well as their pharmacologically indubitable acid addition salts as needed. 12. Compounds of general formula (Ia) [image] indicated by that R1 represents hydrogen; R2 represents hydrogen, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 3-terahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R4 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, phenyl or benzyl; R6 represents hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexylmethyl, 2- phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2,-, PhCO-O-CH2-, S-pyridyl-COO-CH2,-, Ph-O-CH2-, (4-MeO -Ph)-O-CH2,-, (4-MeO-Ph)-CH2-O-CH2-, 4-F-Ph-CH2-, 3,4-F-Ph-CH2-, -CH2-OH, -CH2-OH, -CH2-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, if necessary in the form of their racemates, their enantiomers, their diastereomers or their mixture, as well as their pharmacologically unequivocal acid addition salts, if necessary. 13. Use of a compound according to one of claims 1 to 12, characterized in that it is used as a medicine. 14. Use of a compound according to one of claims 1 to 12, characterized in that it is used as a drug with adenosine-antagonistic action. 15. Pharmaceutical preparations, characterized in that they contain as an active substance one or more compounds according to one of claims 1 to 12 or its pharmaceutically acceptable acid addition salt in combination with usual auxiliary and/or carrier substances. 16. Process for the production of triazolpurine derivatives of the general formula (I) [image] where R1, R2, R3, R4, R5 and R6 have the meaning defined in claims 1 to 12, indicated that a) compound of general formula (9) [image] or a tautomer thereof, wherein R2, R4 and R6 are as defined above, chemically converted in a suitable organic solvent or solvent mixture under basic conditions with a suitable alkylating agent of the general formula R1-X or R3-X, wherein R1 and R3 have the above the given meaning, and X represents the starting group, or se b) compound of general formula (16) [image] or a tautomer thereof, wherein R2, R5 and R6 are as defined above, chemically converted in a suitable organic solvent or solvent mixture under basic conditions with a suitable alkylating agent of the general formula R1-X or R3-X, wherein R1 and R3 have the above the given meaning, and X represents the starting group, or se c) for R4=R1 compound of the general formula [image] or a tautomer thereof, in which R2 and R6 are defined as above, chemically converted to monoalkylated compounds (9) or directly to dialkylated compounds (I) in a suitable organic solvent or solvent mixture under basic conditions with a suitable alkylating agent of the general formula R1-X or R 3 -X, wherein R 1 and R 3 have the above meaning and X represents a leaving group. 17. Process for the production of triazolpurine derivatives of the general formula (9) [image] or its tautomers, wherein R2, R4 and R6 are defined as in claims 1 to 12, characterized in that a) combination of general formulas [image] where R 2 , R 4 and R 6 are defined as above, under basic, acidic or dehydration conditions, they are cyclized into tricyclic triazolpurine derivatives of the general formula (9), or b) for R2=H, diamine of the general formula [image] in which R4 and R6 are defined as previously, by thermal chemical conversion with formamide it is converted into a tricyclic triazolpurine derivative of the general formula (9), or c) for R2 = NR8R9, with the aforementioned meanings for R8 and R9, a nitroso compound of the general formula [image] in which R4 and R6 are defined as previously, under dehydration conditions, chemically converted with N-formylamines into tricyclic triazolpurine derivatives of the general formula (9). 18. Process for the production of triazolpurine derivatives of the general formula (16) [image] or their tautomers, wherein R2, R5 and R6 are defined as in claims 1 to 12, characterized in that a) a compound of the general formula [image] where R2, R5 and R6 are defined as above, under basic, acidic or dehydration conditions, it is cyclized into a tricyclic triazolpurine derivative of the general formula (16), or b) for R2=H, diamine of the general formula [image] in which R5 and R6 are defined as above, converted by thermal chemical conversion with formamide into a tricyclic triazolpurine derivative of the general formula (16), or c) for R2 = NR8R9, with the aforementioned meanings for R8 and R9, a nitroso compound of the general formula [image] in which R5 and R6 are defined as before, under dehydration conditions it is chemically converted with N-formylamine into a tricyclic triazolpurine derivative of the general formula (16).