CA2256736A1 - New triazolopurines, method of preparing them and their use as drugs - Google Patents

Abstract

The invention pertains to triazolopurines of formula (I). The claimed compounds show an affinity to adenosine receptors and thus represent a new class of adenosine antagonists. Generally, adenosine antagonists can have a therapeutically useful effect in cases where diseases or pathological situations involve activation of adenosine receptors.

Description

FIL~ J~ T'II~AM~E~
-'I L, ,~ N -LA

S016-974PCT.200 Case 1/1024-Dr. Wy/ks New triazolopurines, processes for preparing them and their use as ph~r~-ceutical compositions The invention relates to new triazolopurine derivatives and fundamental triazolopurine substances, processes for preparing them and their use as pharmaceutical compositions.

-,' The new triazolopurine derivatives have the structure of general formula (I):

NX~,~R2 (I) wherein Rl or R3 denotes hydrogen, an optionally substituted ~- Cll0-alkyl, C2l0-alkenyl or C2l0-alkynyl, an optionally substituted C38-cycloalkyl, an optionally substituted C48-cycloalkenyl or an optionally substituted C68-cycloalkynyl;
Rl or R3 denotes an optionally substituted C6l0-aryl-Cl6-alkyl~ C6l0-aryl-c2-6-alkenyll C6l0-aryl-C26-alkynyl, an optionally substituted C6l0-aryl or an optionally substituted heteroaryl, an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms from the group comprising CA 022~6736 1998-12-02 nitrogen, oxygen or sulphur, the heterocycle being linked via a carbon atom of the ring;

R1 or R3 denotes an optionally substituted Cl10-alkyloxycarbonyl, an optionally substituted C2l0-alkenyloxycarbonyl, an optionally substituted C210-alkynyloxycarbonyl, an optionally substituted C3a-cycloalkyloxy-carbonyl, an optionally substituted C610-aryloxycarbonyl, an optionally substituted C6l0-aryl-Cl6-alkyloxycarbonyl, A-O-CO- wherein A
denotes an optionally substituted 5-, 6- or 7-} membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein A is linked via a carbon atom of the ring, Rl or R3 is an optionally substituted C110-alkyl-sulphonyl, C210-alkenylsulphonyl, C210-alkynylsulphonyl, an optionally substituted C3a-cycloalkylsulphonyl, an optionally substituted C6l0-arylsulphonyl, an optionally substituted C610-aryl-C16-alkylsulphonyl, a group A-SO2- wherein A is as hereinbefore defined and is linked via a carbon atom of the ring;

R1 or R3 denotes an optionally substituted C110-alkylcarbonyl, an optionally substituted C210-alkenylcarbonyl, an optionally substituted C210-alkynylcarbonyl, an optionally substituted C38-cycloalkylcarbonyl, an optionally substituted C610-arylcarbonyl, an optionally substituted C610-aryl-C16-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined;

R1 or R3 denotes a group of general formula CA 022~6736 1998-12-02 H~

wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C36-cycloalkyl group, a branched or unbranched Cl10-alkyl, preferably Cl4-alkyl, C2l0-alkenyl or C2l0-alkynyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino;
1, .
R2 denotes hydrogen, hydroxy, amino, halogen, nitro, CF3, COOH, mercapto, Cl6-alkylmercapto, an optionally substituted Cll0-alkyl, an optionally substituted C2l0-alkenyl, an optionally substituted C210-alkynyl, an optionally substituted C38-cycloalkyl, an optionally substituted C58-cycloalkanone, an optionally substituted C48-cycloalkenyl, an optionally substituted C68-cycloalkynyl, an optionally substituted C6l0-aryl, an optionally substituted C6l0-aryl-Cl6-alkyl, C6l0-aryl-'~ C26-alkenyl, C6-lo-aryl-c2-6-alkynyl~
C38-cycloalkyl-Cl6-alkyl, C38-cycloalkyl-C26-alkenyl, or C38-cycloalkyl-C26-alkynyl;

R2 denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatom one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein the nitrogen may optionally be substituted and the heterocyclic group may be linked via a carbon or nitrogen atom directly or via a Cl6-alkyl, C26-alkenyl or C26-alkynyl ~ 35 bridge;

CA 022~6736 1998-12-02 R2 denotes an optionally substituted C110-alkylsulphonyl, C210-alkenylsulphonyl or C210-alkynylsulphonyl, an optionally substituted C38-cycloalkylsulphonyl, an optionally substituted C610-arylsulphonyl, an optionally substituted heteroarylsulphonyl or an optionally substituted C610-aryl-C16-alkylsulphonyl;

R2 denotes an optionally substituted Cl1O-alkylsulphonyloxy, C2l0-alkenylsulphonyloxy or C210-alkynylsulphonyloxy, an optionally - substituted C38-cycloalkylsulphonyloxy, an optionally substituted C610-arylsulphonyloxy, an optionally substituted C610-aryl-C16-alkylsulphonyloxy or an optionally substituted heteroarylsulphonyloxy;

R2 denotes an optionally substituted Cl1O-alkylsulphonylamino, C2l0-alkenylsulphonyl-amino or C210-alkynylsulphonylamino, an optionally substituted C3B-cycloalkyl-sulphonylamino, an optionally substituted . C610-arylsulphonylamino, an optionally ,j substituted C610-aryl-C16-alkylsulphonylamino, or an optionally substituted heteroarylsulphonyl-amino;

R2 denotes an optionally substituted Cl1O-alkylaminocarbonyl, Cl1O-dialkylamino-carbonyl, C110-alkyl- C2-1o- alkenylaminocarbonyl, C2l0-alkenylaminocarbonyl, C2l0-dialkenylamino-carbonyl, C210-alkynylaminocarbonyl or C11O-alkyl-C210-alkynylaminocarbonyl, an optionally substituted C38-cycloalkyl-aminocarbonyl, an optionally substituted C610-arylaminocarbonyl, an optionally substituted C610-aryl-C16-alkylaminocarbonyl, or CA 022~6736 1998-12-02 an optionally substituted heteroarylamino-carbonyl;

R2 denotes an optionally substituted C110-alkyloxycarbonylamino, C210-alkenyloxy-carbonylamino or C210-alkynyloxycarbonylamino, an optionally substituted C38-cycloalkyloxy-carbonylamino, an optionally substituted C610-aryloxycarbonylamino, an optionally substituted C6-10 - aryl- Cl-6 - alkyloxycarbonylamino or an optionally substituted heteroaryloxy-. carbonylamino;
i R2 denotes an optionally substituted C110-alkylaminocarbonyloxy, C210-alkenylamino-carbonyloxy or C210-alkynylaminocarbonyloxy, an optionally substituted C38-cycloalkylamino-carbonyloxy, an optionally substituted C610-arylaminocarbonyloxy, an optionally substituted C610-aryl-C16-alkylaminocarbonyloxy or an optionally substituted heteroarylamino-carbonyloxy;

R2 denotes an optionally substituted C110-alkyl-N-i 25 amidino, C210-alkenyl-N-amidino or C210-alkynyl-N-amidino, an optionally substituted C38-cycloalkyl-N-amidino, an optionally substituted C610-aryl-N-amidino, an optionally substituted C610-aryl-C16-alkyl-N-amidino or an optionally substituted heteroaryl-N-amidino;

R2 denotes an optionally substituted C110-alkyloxy, C210-alkenyloxy or C2-10-alkynyloxy, an optionally substituted C38-cycloalkyloxy, an optionally substituted C610-aryloxy, an optionally sub~tituted C610-aryl-C16-alkyloxy or an optionally substituted heteroaryloxy;

CA 022~6736 1998-12-02 .. . . . ..

R2 denotes an optionally substituted C110-alkyloxycarbonyl, C210-alkenyloxycarbonyl or C210-alkynyloxycarbonyl, an optionally substituted C38-cycloalkyloxycarbonyl, an optionally substituted C610-aryloxycarbonyl, an optionally substituted C6-10-aryl-C16-alkyloxy-carbonyl or an optionally substituted heteroaryloxycarbonyl;
R2 denotes an optionally substituted - C110-alkylcarbonyloxy, C210-alkenylcarbonyloxy or C210-alkynylcarbonyloxy, an optionally substituted C38-cycloalkylcarbonyloxy, an optionally substituted C610-arylcarbonyloxy, an optionally substituted C610-aryl-C16-alkyl-carbonyloxy or an optionally substituted heteroarylcarbonyloxy;

20 R2 denotes an optionally substituted C1l0-alkylthio, C2l0-alkenylthio or C210-alkynylthio, an optionally substituted C38-cycloalkylthio, an optionally substituted C610-arylthio, an optionally substituted C610-aryl-C16-alkylthio or an optionally ~~ substituted heteroarylthio;

R2 denotes an optionally substituted amine, preferably NR8R9;
R2 denotes an optionally substituted group of the formula ~ , (CH2)1,2 ~ (~1 CA 022~6736 1998-12-02 R2 denotes an optionally substituted group of the formula (CH2)1.2 ('-H2)-,2 (CH2),,2 -Y~ _y~ -Y~G~

wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, - preferably up to 4 carbon atoms in the chain;
..
10 R2 denotes an optionally substituted group of the formula (CH2),,2 (~H2)-,2 -Y~ -Y~

C,-C6-AIkY C,-C6-AIkYI

wherein Y is a single bond or an alkylene, an ~ alkenylene or an alkynylene ha~ing up to 6, '~ preferably up to 4 carbon atoms in the chain;

R2 denotes an optionally substituted group of the formula CA 022~6736 1998-12-02 _yZ~ CH2)0,1,2 ~ 12 ~ Y ~

wherein Y is a single bond or an alkylene, an ~ alkenylene or an alkynylene having up to 6, preferably up to 4 carbon atoms in the chain;

R4 or R5 denotes a hydrogen atom, an optionally substituted Cl10-alkyl, C2l0-alkenyl or C2l0-alkynyl, an optionally substituted C38-cycloalkyl, an optionally substituted C48-cycloalkenyl or an optionally substituted C68-cycloalkynyl, an optionally substituted C6-lo~arYl~Cl6~alkYl~ C6-lo-aryl-c2-6-alkenyll C6l0-aryl-C26-alkynyl, an optionally substituted C6l0-aryl or an optionally substituted heteroaryl;

: 20 R4 or Rs denotes an optionally substituted 5-, 6- or 7-~ membered heterocyclic group which contains as heteroatoms one of more atoms selected from the group comprising nitrogen, oxygen or sulphur, the heterocyclic group being bound via a carbon atom of the ring;

R4 or Rs denotes an optionally substituted Cl10-alkyloxycarbonyl, an optionally substituted C2l0-alkenyloxycarbonyl, an optionally substituted C2l0-alkynyloxycarbonyl, an optionally substituted C38-cycloalkyloxy-carbonyl, an optionally substituted C6l0-aryl-CA 022~6736 l998-l2-02 C16-alkyloxycarbonyl, an optionally substituted C6_10 - aryloxycarbonyl;

R4 or R5 denotes A-0-C0- wherein A denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur;

R4 or Rs denotes an optionally substituted Cl1O-alkylsulphonyl, C2l0-alkenylsulphonyl, . C2l0-alkynylsulphonyl, an optionally substituted ( C38-cycloalkylsulphonyl, an optionally substituted C6l0-arylsulphonyl, a group A-S02-wherein A is as hereinbefore defined and is linked via a carbon atom of the ring;

R4 or R5 denotes an optionally substituted C110-alkylcarbonyl, an optionally substituted C210-alkenylcarbonyl, an optionally substituted C210-alkynylcarbonyl, an optionally substituted C38-cycloalkylcarbonyl, an optionally substituted C610-arylcarbonyl, an optionally substituted C6l0-aryl-Cl6-alkylcarbonyl, a group - 25 A-C0- wherein A is as hereinbefore defined;

R4 or R5 denotes a group of general formula H~
,N ~
R O
wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C36-cycloalkyl group, a branched or unbranched C110-alkyl, preferably C14-alkyl, C210-alkenyl or C210-alkynyl group, which may CA 022~6736 1998-12-02 optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino;

R6 denotes hydrogen, hydroxy, -CHO, amino, halogen, nitro, CF3, COOH, mercapto, Cl6-alkylmercapto, an optionally substituted Cll0-alkyl, an optionally substituted C2l0-alkenyl, an optionally substituted C2l0-alkynyl, an optionally substituted C38-cycloalkyl, an optionally substituted Cs8-cycloalkanone, an optionally substituted C48-cycloalkenyl, an optionally substituted C68-cycloalkynyl, an optionally substituted C6l0-aryl, an optionally substituted C6l0-aryl-Cl6-alkyl, C6l0-aryl-C26-alkenyl, C6l0-aryl-C26-alkynyl, an optionally substituted C38-cycloalkyl-Cl6-alkyl, C38-cycloalkyl-C26-alkenyl or C38-cycloalkyl-C2 6-alkynyl;

20 R6 denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatom one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein the nitrogen may optionally be substituted and the heterocyclic group may be linked via a carbon atom or N-atom directly or via a Cl6-alkyl, C26-alkenyl or C26-alkynyl bridge;

30 R6 denotes an optionally substituted C,l0-alkylsulphonyl, C2l0-alkenylsulphonyl or C2,0-alkynylsulphonyl, an optionally substituted C38-cycloalkylsulphonyl, an optionally substituted C6,0-arylsulphonyl, an optionally substituted C6,0-aryl-Cl6-alkylsulphonyl or an optionally sub~tituted heteroarylsulphonyl;

CA 022~6736 1998-12-02 R6 denotes an optionally substituted Cl1O-alkylsulphonyloxy, C2l0-alkenylsulphonyloxy or C2l0-alkynylsulphonyloxy, an optionally substituted C38-cycloalkylsulphonyloxy, an optionally substituted C6l0-arylsulphonyloxy, an optionally substituted C6l0-aryl-Cl6-alkyl-sulphonyloxy or an optionally substituted heteroarylsulphonyloxy;

10 R6 denotes an optionally substituted Cl-10-alkylsulphonylamino, C2-10-alkenylsulphonyl-amino or C2l0-alkynylsulphonylamino, an optionally substituted C38-cycloalkylsulphonyl-amino, an optionally substituted C6l0-arylsulphonylamino, an optionally substituted C610-aryl-C16-alkylsulphonylamino or an optionally substituted heteroarylsulphonyl-amino;

20 R6 denotes an optionally substituted Cl10-alkyl-aminocarbonyl, Cl10-dialkylaminocarbonyl, Cl-lo-alkyl-c2-lo-alkenylaminocarbonyl~
C2l0-alkenylaminocarbonyl, C2l0-dialkenylamino-carbonyl, C210-alkynylaminocarbonyl or Cl10-alkyl-C2l0-alkynylaminocarbonyl, an optionally substituted C38-cycloalkylamino-carbonyl, an optionally substituted C6l0-arylaminocarbonyl, an optionally substituted C6l0-aryl-Cl6-alkylaminocarbonyl or an optionally substituted heteroarylamino-carbonyl;

R6 denotes an optionally substituted Cl10-alkylaminocarbonylamino, C2l0-alkenylaminocarbonylamino or C2l0-alkynylaminocarbonylamino, an optionally substituted C38-cycloalkylaminocarbonylamino, an CA 022~6736 1998-12-02 ........... ... .

optionally substituted C610-arylaminocarbonyl-amino, an optionally substituted C6l0-aryl-Cl6-alkylaminocarbonylamino or an optionally substituted heteroarylaminocarbonylamino;

R6 denotes an optionally substituted C110-alkyloxycarbonylamino, C2l0-alkenyloxycarbonylamino or C2l0-alkynyloxycarbonylamino, an optionally substituted C38-cycloalkylcarbonylamino, an optionally substituted C610-aryloxycarbonyl-amino, an optionally substituted C610-aryl-C16-alkyloxycarbonylamino or an optionally substituted heteroaryloxycarbonylamino;
R6 denotes an optionally substituted C110-alkylaminocarbonyloxy, C2l0-alkenylaminocarbonyloxy or C210-alkynylaminocarbonyloxy, an optionally substituted C38-cycloalkylaminocarbonyloxy, an optionally substituted C610-arylamino-carbonyloxy, an optionally substituted C610-aryl-Cl6-alkylaminocarbonyloxy or an optionally substituted heteroarylamino-carbonyloxy;
. ~ ., R6 denotes an optionally substituted C110-alkyl-N-amidino, C210-alkenyl-N-amidino or C210-alkynyl-N-amidino, an optionally substituted C38-cycloalkyl-N-amidino, an optionally substituted C610-aryl-N-amidino, an optionally substituted C6l0-aryl-Cl-6- alkyl-N-amidino or an optionally substituted heteroaryl-N-amidino;

35 R6 denotes an optionally substituted C110-alkyloxy, C2l0-alkenyloxy or C2l0-alkynyloxy, an optionally substitutea C38-cycloalkyloxy, an optionally CA 022~6736 1998-12-02 substituted C610-aryloxy, an optionally substituted C610-aryl-C16-alkyloxy or an optionally substituted heteroaryloxy;

5 R6 denotes an optionally substituted Cl10-alkylcarbonyl, an optionally substituted C2l0-alkenylcarbonyl, an optionally substituted C2l0-alkynylcarbonyl, an optionally substituted C38-cycloalkylcarbonyl, an optionally substituted C6l0-arylcarbonyl, an optionally substituted C6l0-aryl-Cl6-alkylcarbonyl;

i R6 denotes a group A-C0- wherein A is as hereinbefore defined;
R6 denotes an optionally substituted Cll0-alkyloxycarbonyl, C2l0-alkenyloxycarbonyl or C2l0-alkynyloxycarbonyl, an optionally substituted C38-cycloalkyloxycarbonyl, an optionally substituted C6l0-aryloxycarbonyl, an optionally substituted C6l0-aryl-Cl6-alkyloxycarbonyl or an optionally substituted heteroaryloxycarbonyl;

~ 25 R6 denotes an optionally substituted ~ Cll0-alkylcarbonyloxy, C2l0-alkenylcarbonyloxy or C2l0-alkynylcarbonyloxy, an optionally substituted C38-cycloalkylcarbonyloxy, an optionally substituted C6l0-arylcarbonyloxy, an optionally substituted C610-aryl-Cl6alkyl-carbonyloxy or an optionally substituted heteroarylcarbonyloxy;

R6 denotes an optionally substituted Cll0-alkylthio, C2l0-alkenylthio or C2l0-alkynylthio, an optionally substituted C38-cycloalkylthio, an optionally substituted CA 022~6736 1998-12-02 C610-arylthio, an optionally substituted C610-aryl-C16-alkylthio or an optionally substituted heteroarylthio;

5 R6 denotes an optionally substituted Cl1O-alkylcarbonyloxy-Cl6-alkyl, C210-alkenylcarbonyloxy-C16-alkyl or C210-alkynylcarbonyloxy-C16-alkyl, an optionally substituted C38-cycloalkylcarbonyloxy-C16-alkyl, an optionally substituted C610-arylcarbonyloxy-Cl6-alkyl, C6l0-aryl-Cl6-alkylcarbonyloxy-- C16-alkyl or heteroarylcarbonyloxy-C16-alkyl;

R6 denotes an optionally substituted group of the formula R10O-B-(CH) -wherein n=1, 2, 3 or 4, where B denotes a C610-aryl or a single bond;

R6 denotes an optionally substituted amine, preferably NR9R9;

! 1 . 25 R6 denotes an optionally substituted group of the formula ~ ~(CH2)1,2 ~
R6 denotes an optionally substituted group of the formula CA 022~6736 1998-12-02 .. . . ...

(CH2)1.2 (~H2)1,2 (~CH2)-,2 -Y~ -Y~ -Y~G~

(~H2)-,2 (CH2)1,2 -y~ -y~

C~-C6-Alkyl C,-C6-AIkY

wherein Y is a single bond or an alkylene, an ~ alkenylene or an alkynylene having up to 6, preferably 4 carbon atoms in the chain;

R6 is an optionally substituted group of the formula _y~\ ~CH2)0,1,2 ~7 ~CH2)0,1,2 ~ )0,12 ~ Y ~

wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably 4 carbon atoms in the chain;

R8 denotes hydrogen, an optionally substituted C36-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atom~, preferably an alkyl group having 1 to 4 carbon atoms which may optionally be CA 022~6736 l998-l2-02 substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, Cl8-, preferably Cl4-alkyloxy, or -(CH2)m-NHCOORl~ wherein m = 1, 2, 3 or 4;

R8 denotes a 5-, 6- or 7-membered heterocyclic group which is carbon linked directly or via a Cl4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally ~ be mono- or polysubstituted, preferably ( monosubstituted, by benzyl, optionally substituted benzyl, Cl4-alkyl, halogen, -ORl~, - CN, -NO2, NH2, -OH, =O, -COOH, -SO3H or -COORl~;

R8 denotes a bicyclic heterocyclic group which is C-linked directly or via a Cl4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, Cl_4- alkyl, halogen, -ORl~, - CN, -NO2, -NH2, -OH, =0, - COOH, -SO3H, - COORl~;

R9 denotes hydrogen, an optionally substituted C36-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10, preferably 1 to 4 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, Cl8-, preferably Cl4-alkoxy, or -(CH2)m-NHCOORl~ wherein m equals 1, 2, 3 or 4;

CA 022~6736 1998-12-02 R9 denotes a 5-, 6- or 7-membered heterocyclic group which is carbon linked directly or via a Cl4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, Cl4-alkyl, halogen, -ORl~, -CN~ -NO2, NH2, -OH, =0, -COOH, -SO3H or -COOR10;

R9 denotes a bicyclic heterocyclic group which is carbon linked directly or via a Cl4-alkyl chain ~:J and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, Cl4-alkyl, halogen, -ORl~, -CN~ -NO2~ -NH2, -OH~
=0, ~ COOH, ~ SO3H, ~ COORl~;
or RB and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain as further heteroatoms nitrogen, oxygen or sulphur, whilst the -, 25 heterocyclic group may be substituted by a '~~ branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or may carry one of the following groups 3 0 - ( CH2 ) n ~ phenyl, -(CH2)n-NH2, =O, a ketal - preferably -O-CH2-CH2-~-~
- (CH2)nNH-Cl 4-alkyl, - (CH2)n~N(Cl a~alkYl)2~
- (CH2)n-NHCOORl~, (n = 2, 3 ~ 4) ~ halogen, - ORl~ ~ - CN ~ - NO2 ~ -NH2 ~ - CH2NRaR9 ~
-OH -COOH, -S03H, -COORl~, -CONRBR9~ -SO2-Rl~;

CA 022~6736 1998-12-02 , ., . , , . ~ , ,, .. ,, , . , . ~

R10 denotes hydrogen Cl4-alkyl, C24-alkenyl, C24-alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH3, optionally in the form of the racemates, the enantiomers and diastereomers thereof and their mixtures, as well as optionally the pharmacologically acceptable acid addition salts thereof.

It will be appreciated that the dotted lines linking pairs of nitrogen atoms in formula (I) indicate the presence of i a double bond in one of two alternative positions, such that both of R1 and R3, or of R4 and R5 are not simultaneously present.

CA 022~6736 1998-12-02 The compounds of general formula (I) form the following isomers:

R6~/ ~ R2 R6~/ 1~R\~R2 (Ia) (Ib) ( ) R'~ /~R R6~1 1 \~R

(Ic) (Id) the isomers of general formulae (Ia) and (Ib) being preferred, particularly those wherein Rl or R3 denotes hydrogen or C14-alkyl. Compounds of general formula (Ia) and (Ib) wherein Rl and R3 denote hydrogen are particularly preferred; in this case isomers (Ia) and (Ib) are tautomers.

~ Preferred compounds are the compounds of general formulae '~~ (Ia) to (Id) wherein Rl or R3 denotes hydrogen, Cl4-alkyl, benzyl, preferably hydrogen;

R2 denotes hydrogen, a Cl8-alkyl, C28-alkenyl or C28-alkynyl group which may optionally be substituted, by -CN, -CH2NR8R9, -OH
(polysubstitution also possible), -ORl~, -NR8R9, -NHCORl~, -NHCONR8R9, -NHCOORl~, halogen, -OCORl~, -OCO-pyridyl, -OCH2COOH, -OCH2COORl~, -So2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, CA 022~6736 1998-12-02 - S~2 - CH2 - CH2 - O - CORl~, - OCH2 - CH2 - NR8R9, -SO2-CH2-CH2-OH, -CONHSO2Rl~, -CH2CONHSO2Rl~, -OCH CH ORl~ -COOH, -COORl~, -CONR8R9, -CHO, -SR , -SORl~, -SO2Rl~, -SO3H, -SO2NR8R9, -OCH2-CH2OCORl~, -CH=NOH -CH=NORl~, =O, -CORll, -CH(OH)R , -CH(ORl~) 2~ -CH=CH-R12, OCONR8R9, optionally mono-or poly-substituted, preferably mono-methyl-substituted, 1,3-dioxolane or 1,3-dioxane;

10 R2 denotes phenyl-C16-alkyl, preferably phenyl-C14-alkyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, wherein the phenyl ring is ' optionally substituted either directly or via a C14-alkylene bridge by one or more, preferably one, of the groups -C13-alkyl, -CN, -NR8R9, -NO2, -OH, -OR , -CH2-NH-SO2-Rl~, -NHCORl~, -NHCONR8R9 halogen, -OCOR10, -OCO-pyridyl, -OCH2 COOH, - OCH2COORl~, - CH20CORl~, - So2R7, - OCH2 - CONR8R9, -OCH2CH20H, -OCH2-CH2-NR8R9, -CONHSO2Rl~, -OCH2CH2ORl~, -COOH, -COORl~, -CF3, cycl opropyl, -CONR8R9, -CH2OH, -CH2ORl~, -CHO, -SRl~, -SORl~, -SO2Rl~, -SO3H, -SO2NR8R9, -OCH2-CH2OCORl~, -CH=NOH, CH NORl~ -CORll -CH(OH)Rll, -CH(OR ) 2~
-NHCOORl~, -CH2CONHSO2Rl~, -CH=CH-Rl2, OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally ~- mono- or poly- preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 denotes C37- cycloalkyl-C16-alkyl, C37-cycloalkyl-C26-alkenyl, C37-cycloalkyl-C26-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C1~-alkylene bridge by one or more, preferably one, of the groups -CN, NR8R9, =O, -OH, -ORl~, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR1~, -CH20COR1~, - So2R7, - OCH2 - CONR8R9, - OCH2 CH20H, - OCH2 - CH2 - NR8R9, CA 022~6736 1998-12-02 ~ . .... ..

-OCH2CH20Rl~, -COOH, -COORl~, -CONR8R9, -CH20H, -CH20R~, -CHO, -SRl~, -SORl~, -SO Rl~ -SO H
-SO2NR8R9, -OCH2-CH20CORl~, -CH=NOH, -CH=NORl~, -COR , -CH(OH)Rll, -CONHSO2Rl~, -CH(ORl~) -NHCOORl~, -CH=CH-Rl2, -OCONR8R9, -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 denotes a group of the formula A-Cl6-alkyl, A-CONH-Cl6-alkyl, A-CONH-C26-alkenyl, A-CONH-C26-alkynyl, A-NH-CO-Cl6-alkyl, A-NH-CO-C26-alkenyl, ~ A-NH-CO - C2 - 6 - alkynyl, A - C2 - 6 - alkenylene, A-C2 6-alkynylene or A-, wherein A is a C- or N-linked 5-, 6- or 7-membered heterocyclic group which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or poly-, preferably monosubstituted by benzyl, optionally substituted benzyl, C14-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, - COOH, - SO3H, - COORl~, - CON8R9, - CORll SO Rl~ or CONR8R9;
. 25 denotes C37-cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by =O, -OH, -OR10, OCOR10 or ~ -OCO-pyridyl;
R2 denotes phenyl which is optionally substituted by -OH, halogen, -OR10, C14-alkyl, preferably -CH3, -NH2, -COOH, -SO3H, -COORl~, -OCH2COORl~, - CN
or - oCH2CONR8R9;
R2 denotes a norbornane, norbornene, - C36-dicycloalkylmethyl, preferably CA 022~6736 1998-12-02 dicyclopropylmethyl, adamantane or noradamatane group optionally substituted by Cl4-alkyl, preferably methyl;

5 R2 denotes -CH=CH-phenyl in which the phenyl ring is mono- or polysubstituted by methoxy, hydroxy or halogen;

R2 is a [3.3.0]-bicyclooctane, preferably a [3.3.0]-bicyclooctan-2-yli R2 is a C-linked piperidine or furan;

R2 is an amine of general formula NRaR9;
R4 or Rs denotes hydrogen, an optionally branched Cl8-alkyl, C28-alkenyl or C28-alkynyl group which is substituted by -CN, -CH2NR8R9, -OH
(polysubstitution also possible), -ORl~, -NR8R9, -NHCORl~, -NHCONR8R9, halogen, -OCORl~, -OCO-pyridyl, -OCH2COOH, -OCH2COORl~, -So2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH20H, - S~2 - CH2 - CH2 - O - CORl ~, - OCH2 - CH2 - NR8R9, -SO2-CH2-CH2-OH, -CONHSO2Rl~, -CH2CONHSO2Rl~, i .25 -OCH2CH20Rl~, -COOH, -COORl~, -CONR8R9, -CHO, -SRl~, ~ -SORl~, -SO2Rl~, -SO3H, -SO2NR8R9, -OCH2-CH20CORl~, =O -CH=NOH -CH=NORl~, -CORll, -CH(OH)R , -CH(ORl~) 2~ -CH=CH-Rl2, -OCONR8R9, optionally mono-or poly-, preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R4 or Rs denotes phenyl-Cl6-alkyl, preferably phenyl-Cl4-alkyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a Cl4-alkylene bridge by one or more, preferably one of the groups, Cl3-alkyl, -CN, -NR8R9, -NO2, CA 022~6736 1998-12-02 , OR , -CH2-NH-SO2-Rl~, -NHCORl~ NHCO 8 9 halogen, -OCORl~, -OCO-pyridyl, -OCH2COOH, -OCH2COORl~, -CH20CORl~, -So2R7, -oCH2-CoNR8R9, -OCH2CH20H, -OCH2-CH2-NRBR9, -CONHSO2Rl~, -OCH2CH2ORl~, -COOH, -COOR10, -CF3, cyclopropyl, -CONR8R9, -CH2OH, -CH2ORl~, -CHO, -SR10, -SOR10, -SO2R1~, -SO3H, -So2NR5R9, -OCH2-CH2OCOR1~, -CH=NOH, CH NoR10 -COR11 -CH(OH)R11, -CH(OR ) 2 ' -NHCOOR10, -CH2CONHSO2R1~, -CH=CH-R12, -OCONR9R9, -CH2-O-CONR8R9, -CH2-CH2-o-CoNR5R9, optionally mono- or poly-, preferably mono-methyl-- substituted 1,3-dioxolane or 1,3-dioxane;

R4 or Rs denotes an optionally substituted C37-cycloalkyl group;

R4 or R5 denotes C37-cycloalkyl-C16-alkyl, C37-cycloalkyl-C26-alkenyl, C37-cycloalkyl-C26-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a Cl4-alkylene bridge by -CN, -NR9R9, =O, -OH, -ORl~, -NR5R9, -NHCORl~, -NHCoNR5R9, halogen, -OCORl~, -OCO-pyridyl, -OCH2COOH, -OCH2COORl~, - CH20CORl~, - So2R7, - OCH2 - CONR9R9, - OCH2CH20H, -OCH2-CH2-NR8R9, -OCH2CH2OR1~, -COOH, -COOR10, -CONR8R9, -CH2OH, -CH2OR1~, -CHO, -SR10, -SORl~, -SO2Rl~, -SO3H, -SO2NR8R9, -OCH2-CH2OCORl~, -CH=NOH, -CH=NOR10 -CORll, -CH(OH)Rll, -CONHSO2Rl~, CH(OR ) 2, -NHCOORl~~ -CH=CH-Rl2 OCONR8 9 -CH2-O-CONR8R9, -CH2-CH2-O-CONR8R9, optionally mono- or poly-, preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R4 or R5 denotes a group of the formula A-Cl6-alkyl, A-CONH-Cl6-alkyl, A-CONH-C26-alkenyl, A-CONH-C26-alkynyl, .

CA 022~6736 1998-12-02 A-NH-CO-Cl6-alkyl, A-NH-CO-C26-alkenyl, A-NH-CO-C26-alkynyl, A-C26-alkenyl or A-C26-alkynyl, wherein A is a C- or N-linked heterocyclic group which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by C14-alkyl, halogen, -ORl~, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, -COOH, -SO3H, -COORl~, -CONR8R9, -COR11 SO R10 or CONR8R9;

: R denotes hydrogen, a C18-alkyl, C28-alkenyl or C28-alkynyl group which is substituted by -CN, -CH2NRaR9, -OH (polysubstitution also possible), -ORl~, -NR8R9, -NHCORl~, -NHCONR8R9, -NHCOORl~, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR1~, -So2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH20H, -SO2-CH2-CH2-O-CORl~, -OCH2-CH2-NR8R9, -SO2-CH2-CH2-OH, -CONHSO2R1~, -CH2CONHSO2R1~, -OCH2CH20R1~, -COOH, -COORl~, -CONR8R9, -CHO, -SR10, -SORl~, -S02Rl~, -SO H
-SO2NR8R9, -OCH2-CH20COR1~, -CH=NOH, -CH=NOR10, -COR11 -CH(OH)R11, -CH(OR10) 2/ -CH=CH-R12~
-OCONR8R9, optionally mono- or poly-, preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R6 denotes phenyl-C16-alkyl, preferably phenyl-C14-alkyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a C14-alkylene bridge by one or more of the groups, -C13-alkyl, -CN, -NR8R9, -NO2, -OH, -OR10, -CH2-NH-SO2-R1~, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR1~, -CH20CORl~, -So2R7, -OCH2-CONR8R9, -OCH2CH20H, CA 022~6736 1998-12-02 -OCH2-CH2-NR8R9, -CONHSO2R1~, -OCH2CH20R1~, -COOH, -COOR10, -CF3, cyclopropyl, -CONRaR9, -CH20H, -CH20R1~, -CHO, -SR10, -SOR10, -S02R1~, -S03H
-SO2NR8R9, -OCH2-CH20COR1~, -CH=NOH, -CH=NOR10, -COR11, -CH(OH)R11, -CH(OR10) 2~ -NHCOORl~~
-CH2CONHSO2Rl~, -CH=CH-Rl2, -OCONR8R9 - CH2 - O - CONR8R9, - CH2 - CH2 - O - CONR8R9, - CO - Rl~, -CO-C14-alkyl-NR8R9, optionally mono- or poly-, preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R6 denotes C37-cycloalkyl-C16-alkyl, C37-cycloalkyl-C26-alkenyl, C37-cycloalkyl-C26-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C14-alkylene bridge by one or more, preferably one, of the groups -CN, NR8R9, =0, -OH, -OR10, ~ -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR1~, -CH20COR1~, -So2R7, -OCH2-CONR8R9, -OCH2CH20H, -OCH2-CH2-NR8R9, -OCH2CH20R1~, -COOH, -COOR10, -CONR8R9, -CH20H, -CH20R1~, -CHO, -SR10, -SOR10, -SO R10 -SO H
-SO2NR8R9, -OCH2-CH20COR1~, -CH=NOH, -CH=NOR10, -COR , -CH(OH)R11, -CONHSO2R1~, -CH(OR10) , 25 -NHCOOR~, -CH=CH-R12, -OCONR8R9, -CH -O-CONR8R9 -CH2-CH2-O-CONR8R9, methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R6 denotes a group of the formula A-C16-alkyl, A-coNH-cl-6-alkyl~
A-CONH-C26-alkenyl, A-CONH-C26-alkynyl, A-NH-CO-Cl6-alkyl, A-NH-CO-C26-alkenyl, A-NH-CO-C26-alkynyl, A-C26-alkenyl or A-C26-alkynyl or A-, wherein A is a C- or N-linked 5-, 6- or 7-membered heterocyclic group which contains one CA 022~6736 1998-12-02 or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl optionally substituted benzyl, Cl4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, -COOH, -SO3H, -COORl~, -CONR8R9, ~ -CORll, -SO2-Rl~ or -CONR8R9;

10 R6 denotes -CHO, -COORl~, -CONR8R9;

R6 denotes C37-cycloalkyl, preferably cyclopentyl or cyclohexyl, optionally substituted by =O, -OH, -ORl~, OCOR10 or -OCO-pyridyl;
R6 denotes phenyl optionally substituted by -OH, halogen, -ORl~, Cl4-alkyl, preferably -CH3, -NH2, -COOH, -SO3H, -COORl~, -OCH2COORl~, -CN or -OCH2CONR8R9;
R6 denotes a norbonane, norbornene, C36-dicyclo-alkylmethyl, preferably dicyclopropylmethyl, ~ adamantane or noradamantane group optionally substituted by Cl4-alkyl, preferably methyl;
' R6 denotes -CH=CH-phenyl, wherein the phenyl ring may be mono- or polysubstituted by methoxy, hydroxy or halogen;

30 R6 denotes a [3.3.0]-bicyclooctane, preferably a [3.3.0]-bicyclooctan-2-yl;

R6 denotes a C-linked piperidine or furan;

35 R7 denotes Cl4-alkyl which is optionally substituted by -OH, -OCORl~, -OCO-pyridyl, -NH2, CA 022~6736 1998-12-02 -NR8R9 or -NHCOR10, preferably -CH2-CH2-OH, - CH2- CH2OCORl~, - CH2- CH2- CH2- OH or - CH2- CH2CH2OCORl~;

R8 denotes hydrogen, an optionally substituted C36-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably a C14-alkyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C18-alkoxy, preferably C14-alkoxy, or -(CH2)~-NHCOOR1~ where m = 1, 2, 3 or 4;
( R3 denotes a 5-, 6- or 7-membered heterocyclic group which is C-linked directly or via a C14-alkyl chain, and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted by benzyl, optionally substituted benzyl, C14-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R8 denotes a bicyclic heterocyclic group C-linked ~- 25 directly or via a C14-alkyl chain, which ' contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted by benzyl, optionally substituted benzyl, C14-alkyl, halogen, -ORl~, - CN, - NO2, - NH2, - OH, = O, - COOH, - SO3H or -COORl~;

R9 denotes hydrogen, an optionally substituted C36-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably a C14-alkyl group, which may optionally be substituted by hydroxy, CA 022~6736 1998-12-02 phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or Cla-alkoxy, preferably Cl4-alkoxy, or -(CH2)m-NHCOORl~ wherein m is 1, 2, 3 or 4, preferably hydrogen;

R9 denotes a 5-, 6- or 7-membered heterocyclic group which is C-linked directly or via a Cl4-alkyl chain, and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably -~ monosubstituted by benzyl, optionally substituted benzyl, Cl4-alkyl, halogen, -ORl~, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COORl~;
R9 denotes a bicyclic heterocyclic group C-linked directly or via a Cl4-alkyl chain, which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted by benzyl, optionally substituted benzyl, Cl4-alkyl, halogen, -ORl~, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COORl~, or ,- 25 R8 and R9 together with the nitrogen atom form a .~ , saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen or sulphur as additional heteroatoms, whilst the heterocyclic group may be substituted by a branched or unbranched Cl4-alkyl group, preferably methyl, or may carry one of the following groups:

- ( CH2 ) n-phenyl, -(CH2)n-NH2, =O, a ketal - preferably -O-CH2-CH2-O-~
-(CH2)nNH-C14-alkyl, - (CH2) n~N (Cl-8-alkyl ) 2 ~

CA 022~6736 1998-12-02 -(CH2)n-NHCOOR1~, (n = 1, 2, 3, 4), halogen, -OR10, -CN, -NO2, -NH2, -CH2NR3R9, -OH, -COOH, -SO3H, -COORl~, -CONR9R9, -SO2-Rl~;

R10 denotes hydrogen, C14-alkyl, C24-alkenyl, C24-alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH3;

Rll denotes Cl4-alkyl, C24-alkenyl, C24-alkynyl, optionally substituted phenyl, optionally substituted benzyl, C36-cycloalkyl;

R12 denotes -COOR10, -CH20R1~, -CoNR3R9, hydrogen, C13-alkyl, optionally substituted phenyl or - CH2NR3R9, optionally in the form of the racemates, enantiomers and diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Also preferred are compounds of general formula (Ia) to (Id) N~N1 - N N~NJ~ N
N ~r~N~ R~/ ~ \~R2 (Ia) (Ib) CA 022~6736 1998-12-02 R6~,N ' N ~ N~ R2 R6~N ~ N ~ N'~ R2 Nl N N N ~' N

(Ic) (Id) wherein Rl or R3 denotes hydrogen, C14-alkyl or benzyl;

. R2 denotes hydrogen, C18-alkyl, preferably Cl6-alkyl;
R2 denotes phenyl which is optionally substituted by halogen, preferably fluorine or chlorine, Cl4-alkyl, Cl4-alkyloxy, hydroxy or NR9R9;

15 R2 denotes phenyl-Cl6-alkyl, preferably benzyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, Cl4-alkyl, C14-alkyloxy, hydroxy or NR8R9;
i: i '~~~ R2 denotes an optionally substituted amine, preferably NR8R9;
.

25 R2 denotes a 5- or 6-membered heterocyclic group which is optionally C- or N-linked either directly or via a C14-alkylene bridge, containing one or more heteroatoms selected from the group comprising nitrogen or oxygen and optionally substituted by benzyl or Cl4-alkyl;

R2 denotes a C36-cycloalkyl which may optionally be substituted by =0, hydroxy, Cl4-alkyl or Cl4-alkyloxy;

CA 022~6736 1998-12-02 R2 denotes norbornane, norbornene, adamantane or noradamantane optionally substituted by Cl4-alkyl, preferably methyl;

R4 or R5 denotes hydrogen, C18-alkyl, phenyl-Cl4-alkyl, preferably benzyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably chlorine or fluorine, hydroxy, C14-alkyl, Cl4-alkyloxy or NR8R9;

R6 denotes hydrogen, Cl8-alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy, =O, C14-alkyloxy, NRaR9, phenyloxy, -O-phenyl-C14-alkyloxy, benzyloxy, -O-benzyl-O-C14-alkyloxy, -OCO-C14-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C24-alkylene, -CO-C14-alkyl, -CHO, =NOH, -COOH, -COO-Cl4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO-Cl4-alkyl, -NHCO-phenyl, -CO-C14-alkyl-NR8R9, -SO20H, -SO2-C14-alkyl or -SO2-phenyl;

25 R6 denotes phenyl which may optionally be substituted by halogen, preferably chlorine or fluorine, hydroxy, C14-alkyl, C14-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO-Cl 4- alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C24-alkylene, -CO-Cl4-alkyl, -Cl4-alkyl-NH2, -C14-alkyl-OH, -C14-alkyl=NOH, -COOH, -COO-C14-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO-Cl4-alkyl-NH2, -SO20H, -SO2-Cl~-alkyl or -SO2-phenyl;
R6 denotes phenyl-Cl4-alkyl, preferably benzyl, phenyl-C26-alkenyl or phenyl-C26-alkynyl, CA 022~6736 1998-12-02 wherein the phenyl ring may be optionally substituted by halogen, preferably chlorine or fluorine, hydroxy, C14-alkyl, C14-alkoxy, benzyloxy, phenyloxy, -NR8R9, -OCO-C14-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C24-alkylene, -CO-C14-alkyl, -C14-alkyl-NR8R9, -C14-alkyl-OH, -C14-alkyl=NOH, -COOH, -COO-C14-alkyl, -COO-phenyl, -COO-benzyl, - CONR8R9, - CO - Cl _4 - alkyl-NH2, -SO2OH, -SO2-C14-alkyl or -SO2-phenyl;

. R6 denotes a 5- or 6-membered heterocyclic group c optionally C- or N-linked either directly or via a C14-alkylene bridge, which contains one, two or three heteroatoms selected from nitrogen or oxygen and is optionally mono- or polysubstituted by benzyl or Cl4-alkyl;

R6 denotes a C36-cycloalkyl or C36-cycloalkyl-C14-alkyl group which may optionally be substituted by =O, hydroxy, Cl4-alkyl or Cl4-alkyloxy;

R6 denotes norbornyl, norbornenyl, adamantyl or noradamantyl optionally substituted by Cl4-alkyl, preferably methyl;

R6 denotes -CHO, -COOH, -COO-Cl4-alkyl, -COO-phenyl, -COO-benzyl or -CONR8R9;
R6 denotes an amine of general formula NR8R9;

R8 denotes hydrogen, a branched or unbranched Cl4-alkyl group;
R8 denotes a C-linked 5- or 6-membered heterocyclic ~ group which contains one, two or three CA 022~6736 1998-12-02 heteroatoms selected from the group comprising nitrogen, oxygen and sulphur and is optionally substituted by benzyl, C14-alkyl, Cl4-alkyloxy, halogen, -CN, -NO2, -NH2, -OH or =O;

R9 denotes hydrogen, a branched or unbranched Cl4-alkyl group;

R9 denotes a C-linked 5- or 6-membered heterocyclic group which contains one, two or three heteroatoms selected from the group comprising - nitrogen, oxygen or sulphur and is optionally ~: substituted by benzyl, C14-alkyl, C14-alkyloxy, halogen, -CN, -NO2, -NH2, -OH or =O;
or R8 and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as additional heteroatoms, whilst the heterocyclic group may be substituted by a branched or unbranched C14-alkyl group, preferably methyl, or by a -(CH2)14-phenyl group, preferably benzyl, optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Also preferred are compounds of general formulae (Ia) and (Ib) N_N~ N N_N~ N
R6~ ~ R2 r r (Ia) (Ib) CA 022~6736 1998-12-02 ~ , _, ,.. .~

wherein ~1 or R3 denotes hydrogen, C14-alkyl, preferably C13-alkyl and benzyl;

R2 denotes hydrogen, C16-alkyl, preferably C14-alkyl;

R2 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydrocyclohexane;
. .
' R2 denotes a morpholine group optionally substituted by C14-alkyl, preferably methyl, a piperidinyl group, a piperazinyl group optionally substituted by benzyl or C14-alkyl, preferably methyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furyl;

20 R2 denotes a phenyl group optionally substituted by C14-alkyl, halogen or hydroxy;

R2 denotes a phenyl-C14-alkyl, preferably benzyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, Cl4-alkyl, C14-alkyloxy, hydroxy or NR8R9;

R2 denotes an amine of general formula NR3R9;
R2 denotes a norbornenyl, norbornyl, adamantyl or noradamantyl optionally substituted by Cl4-alkyl, preferably methyl;

35 R4 denotes hydrogen, Cl7-alkyl, preferably Cl5-alkyl, phenyl-Cl3-alkyl, preferably benzyl, wherein the phenyl ring may be substituted by CA 022~6736 1998-12-02 halogen, preferably chlorine or fluorine, hydroxy, C14-alkyl, Cl4-alkyloxy or NR8R9;

R6 denotes hydrogen, C16-alkyl, preferably C14-alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy, =O, C14-alkyloxy, NR8R9, phenyloxy, -O-phenyl-O-C14-alkyloxy, benzyloxy, -O-benzyl-O-C14-alkyloxy, -OCO-C14-alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -O-C2 _4 - alkylene, -CO-C1 4 - alkyl, - CHO, =NOH, -COOH, -COO-C14-alkyl; -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO- Cl_4- alkyl, - NHCO -phenyl, -CO-Cl 4- alkyl-NR8R9, -SO20H, -SO2-C1 4- alkyl or -SO2-phenyl;

R6 denotes phenyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, C14-alkyl, C14-alkyloxy or NR8R9;

R6 denotes phenyl-C13-alkyl, preferably benzyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, C14-alkyl, C14-alkyloxy, benzyloxy, phenyloxy, NR8R9, -OCO-C14-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C24-alkylene, -CO-C14-alkyl, -C14-alkyl-NR8R9, -C14-alkyl -OH, -C14-alkyl =NOH, -COOH, -COO - Cl_4 - alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO-Cl 4- alkyl-NR8R9, -SO20H, -SO2-C1 4- alkyl or -SO2-phenyl;

R6 denotes a cyclopentyl, cyclohexyl, cyclohexyl-C13-alkyl, preferably cyclohexylmethyl, cyclopentanone, cyclohexanone, CA 022~6736 1998-12-02 hydroxycyclopentane or hydroxycyclohexane linked via a single bond or via a C14-alkylene chain;

R6 denotes a furan, tetrahydrofuran, a-pyran, ~-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole ~ or pyrazolidine linked via a single bond or via a Cl4-alkylene chain;

R6 denotes -CHO, -COOH, -COO-C14-alkyl;
-COO-phenyl, -COO-benzyl, -CO-NH-C14-alkyl, -CO-N(C14-alkyl) 2 or -CO-NH-phenyl;

20 R6 denotes an amine of general formula NR8R9;

R8 denotes hydrogen, a branched or unbranched C14-alkyl group;

i 25 R8 denotes a C-linked pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, ~ imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole optionally substituted by chlorine, bromine, C14-alkyl, C14-alkyloxy, NO2, NH2 or OH;

R9 denotes hydrogen, a branched or unbranched C14-alkyl group;

CA 022~6736 1998-12-02 ..... .. . . ..

R9 denotes a C-linked pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole optionally substituted by chlorine, bromine, C14-alkyl, C14-alkyloxy, NO2, NH2, OH, or R8 and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring -~ which may contain nitrogen or oxygen as additional heteroatoms, wherein the heterocyclic group may be substituted by a branched or unbranched C14-alkyl group, preferably methyl, or by a -(CH2)14-phenyl group, preferably benzyl, optionally in the form of the racemates, the enantiomers and the diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Other preferred compounds are those of general formula (Ib) o R ~ --1~ ~ R
N ~ N

(Ib) ~ wherein 30 R2 denote~ hydrogen, C14-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted by fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, CA 022~6736 1998-12-02 furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;

R3 denotes hydrogen, C13-alkyl or benzyl;

R4 denotes hydrogen, C15-alkyl or benzyl;

R6 denotes hydrogen, C14-alkyl, preferably methyl, which may optionally be substituted by OH, chlorine, bromine, C14-alkyloxy or NR8R9, -CHO, -COOH, -coo-cl-4-alkyl~ preferably -COOCH3, phenyl, phenyl-C13-alkyl optionally substituted by fluorine or benzyloxy, preferably benzyl, phenyloxy-cl-3-alkyl optionally substituted by methoxy, preferably phenyloxymethyl, benzyloxy-Cl3-alkyl optionally substituted by methoxy, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolyl-methyl or N-morpholinomethyl;

R8 denotes hydrogen, C14-alkyl or pyridyl;
'~ J 25 R9 denotes hydrogen, C14-alkyl or pyridyl, optionally in the form of the racemates, the enantiomers and the diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

Other preferred compounds are those of general formula (Ia) CA 022~6736 l998-l2-02 ~ . . .. . . ..

,~ R1 N N N

(Ia) wherein R1 denotes hydrogen, C13-alkyl or benzyl;

- R2 denotes hydrogen, C14-alkyl, phenyl, benzyl, '- wherein the phenyl ring is optionally fluorine-substituted, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;
R4 denotes hydrogen, Cl_5 - alkyl or benzyl;

R6 denotes hydrogen, C14-alkyl, preferably methyl, which may optionally be substituted by OH, chlorine, bromine, C14-alkyloxy or NR8R9, -CHO, -COOH, -COO-C14-alkyl, preferably -COOCH3, phenyl, phenyl-C13-alkyl optionally substituted - by fluorine or benzyloxy, preferably benzyl, phenyloxy-Cl3-alkyl optionally substituted by methoxy, preferably phenyloxymethyl, benzyloxy-C13-alkyl, optionally substituted by methoxy, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl;

R8 denotes hydrogen, C14-alkyl or pyridyl;' CA 022~6736 1998-12-02 R9 may denote hydrogen, Cl4-alkyl or pyridyl, optionally in the form of the racemates, the enantiomers, the diastereomers thereof and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Also of interest are compounds of general formula (Ic) Nl N N

(Ic) wherein 15 Rl denotes hydrogen or C13-alkyl;

R2 denotes hydrogen, C14-alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;
Rs denotes C16-alkyl, preferably C14-alkyl, most preferably methyl, ethyl or tert.-butyl;

R6 denotes hydrogen, benzyl or cyclopentyl, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically ~ acceptable acid addition salts thereof.

Also of interest are compounds of general formula (Id) CA 022~6736 1998-12-02 R6~/N 1~ N'~ R2 Nl N ,N3 (Id) ~ wherein 5 R1 denotes hydrogen or C13-alkyl;

R2 denotes hydrogen, C14-alkyl, cyclopentyl, - cyclopentanone, hydroxycyclopentane, furan or benzyl;
R5 denotes C16-alkyl, preferably C14-alkyl, most preferably methyl, ethyl or tert.-butyl;

R6 denotes hydrogen, benzyl or cyclopentyl, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically ~ acceptable acid addition salts thereof.

Also preferred are compounds of general formula (Ib) : O

N r r (Ib) wherein R2 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-~ morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, CA 022~6736 1998-12-02 2-furyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R3 denotes hydrogen, methyl, ethyl, n-propyl or benzyl;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;
., ~.. .
R6 denotes 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-morpholino-methyl, 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, -CH2OEt or -CH2-NMe2~
optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Of particular interest are compounds of general formula (Ia) R~

N N N

(Ia) CA 022~6736 1998-12-02 wherein R1 denotes hydrogen, methyl, ethyl, n-propyl or benzyl;

R2 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 2-furyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, ~~ cyclohexyl, adamantan-l-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

15 R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes 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-morpholino-methyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, : . 25 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, -CH20Et or - CH2 - NMe2 ~
optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Also preferred are compounds of general formula (Ib) CA 022~6736 1998-12-02 N r r R4 R (Ib) wherein R2 denotes 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-benzyl-f - piperazinyl, 3-tetrahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R3 denotes hydrogen;

15 R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, t- cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl-methyl, 2-phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, Ph-COO-CH2-, 3-pyridyl-COO-CH2-, Ph-O-CH2-, (4-MeO-Ph)-O-CH2-, (4-MeO-Ph)-CH2-O-CH2-, 4-F-Ph-CH2-, 3,4F-Ph-CH2-, -CH2-OH, -CH2-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

CA 022~6736 1998-12-02 ~ ~ . . . .....

Also of particular interest are compounds of general formula (Ia) ~ R1 R6~/ ~ /~ R2 (Ia) wherein R1 denotes hydrogen;

R2 denotes 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-benzyl-piperazinyl, 3-tetrahydrofuranyl, 4-tetrahydro-pyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;
J R6 denotes hydrogen, methyl, ethyl, n-propyl, ~ i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, cyclohexyl-methyl, 2-phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH2-, Ph-COO-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-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures CA 022~6736 1998-12-02 .

thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

In addition, the invention relates to a new category of compounds which contain basic structures of general formulae (Ia) to (Id).

~<,N - N ~~<,N ' N J~ N,~

~, , (Ia) (Ib) O ~ O
~<,N 1~ N~ ~ ~<N - N ~ N
N N N N N IN
~ ~ ~
(Ic) (Id) Preferred compounds are derivatives of general formula N N N, ~ H
which have a substituent in positions 2, 4 and 6.

If required, the compounds of general formulae (Ia) to (Id) may be converted into the salts thereof, particularly, for pharmaceutical use, into the physiologically acceptable salts thereof with an inorganic or organic acid. Suitable acids for this purpose include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, CA 022~6736 1998-12-02 tartaric acid or maleic acid. Moreover, mixtures of these acids may be used.

The alkyl group~ meant here (including those which are components of other groups) are branched and unbranched alkyl groups having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, such as: methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec.-butyl, tert.-butyl, pentyl, iso-pentyl, hexyl, heptyl and octyl.
Unless otherwise specified, substituted alkyl groups ,~ (including those which are components of other groups) may, for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, Cl6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =O, -CHO, -COOH, -COO-Cl6-alkyl, -S-Cl6-alkyl.

Alkenyl groups (including those which are components of other groups) are the branched and unbranched alkenyl groups with 2 to 10 carbon atoms, preferably 2 to 3 carbon atoms, provided that they have at least one double bond, e.g. the alkyl groups mentioned above provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are 'J 25 formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.

Unless otherwise specified, substituted alkenyl groups, (including those which are components of other groups), may for example carry one or more of the following substituents: halogen, hydroxy, mercapto, Cl6-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =O, -CHO, -COOH, -coo-Cl6-alkyl, -s-cl6-alkyl-The term alkynyl groups (including those which arecomponents of other group~) refers to alkynyl groups having 2 to 10 carbon atoms provided that they have at CA 022~6736 1998-12-02 ,, . . , ,, , , , _, .

least one triple bond, e.g. ethynyl, propargyl, butynyl, pentynyl and hexynyl.

Unless otherwise specified, substituted alkynyl groups, (including those which are components of other groups), may for example carry one or more of the following substituents: halogen, hydroxy, mercapto, C16-alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, =O, -CHO, - COOH, - COO -Cl-6- alkyl, -S-C16-alkyl.

Examples of cycloalkyl groups having 3 to 6 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, which may also be substituted by branched or unbranched C14-alkyl, hydroxy and/or halogen or as hereinbefore defined. The term halogen generally refers to fluorine, chlorine, bromine or iodine.

The word aryl denotes an aromatic ring system having 6 to 10 carbon atoms which, unless otherwise specified, may carry one or more of the following substituents, for example: C16-alkyl, C16-alkyloxy, halogen, hydroxy, mercapto, amino, alkylamino, dialkylamino, CF3, cyano, nitro, -CHO, -COOH, -COO-C16-alkyl, -S-C16-alkyl. The preferred aryl group is phenyl.
~ Examples of N-linked cyclic groups of general formula NR3R9 are as follows: 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 above-mentioned heterocycles may also be substituted by C14-alkyl, preferably methyl, or may be substituted as in the definitions.

CA 022~6736 1998-12-02 .

.. . .,, , , ~ ._, . , .. . . _ Examples of C-linked 5- or 6-membered heterocyclic rings which may contain nitrogen, oxygen or sulphur as heteroatoms include, for example, furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylfuran, tetrahydrofuranone, r-butyrolactone, a-pyran, ~-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 and pyrazolidine, whilst the heterocycle may be substituted as in the definitions.
"=O" means an oxygen atom linked by a double bond.

The compounds according to the invention have an affinity for adenosine receptors and thus constitute a new category of adenosine antagonists. In general, adenosine antagonists may exhibit a therapeutically useful activity in cases where diseases or pathological situations are connected with the activation of adenosine receptors.

Adenosine is an endogenous neuromodulator with predominantly inhibitory effects on the CNS, heart, kidneys and other organs. The effects of adenosine are mediated through at least three receptor subtypes:
adenosine Al, ~ and A3 receptors.
In the CNS, adenosine develops inhibitory effects predominantly by activating Al receptors: presynaptically by inhibiting synaptic transmission (inhibiting the release of neurotransmitters such as acetylcholine, dopamine, noradrenalin, serotonin, glutamate, etc.), and postsynaptically by inhibiting neuronal activity.

CA 022~6736 1998-12-02 Al antagonists cancel out the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.

Al antagonists are therefore of great interest in the treatment of degenerative diseases of the central nervous system such as senile dementia of the Alzheimer's type and age-associated disorders of memory and learning performance.
The disease includes, in addition to forgetfulness in its mild form and total helplessness and absolute dependence '; on care in the most severe form, a range of other accompanying systems such as sleep disorders, motor-coordination disorders up to the clinical picture of Parkinson's disease as well as increased lability affect and depressive symptoms. The disease is progressive and can result in death. Therapy up till now has been unsatisfactory. Hitherto, there has been a complete absence of specific therapeutic agents. Attempts at therapy with acetylcholinesterase inhibitors exhibit some effect in a small proportion of patients but are connected with a high level of side effects.

, The pathophysiology of Alzheimer's disease and SDAT is characterised by a severe impairment of the cholinergic system, but other transmitter systems are also affected.
As a result of the loss of presynaptic cholinergic and other neurons and the resulting lack of provision of neurotransmitters, neuronal transmission and neuronal activity is significantly reduced in the areas of the brain essential for learning and memory.

Selective adenosine Al receptor antagonist~ promote neuronal transmission by increased provision of neurotransmitters, they increa~e the excitability of CA 022~6736 1998-12-02 postsynaptic neurons and can thus counteract the symptoms of the disease.

The high receptor affinity and selectivity of some of the compounds claimed should make it possible to treat Alzheimer's disease and SDAT with low doses, so that hardly any side effects can be expected which cannot be attributed to the blockade of A1 receptors.

Another indication for centrally acting adenosine Al ~ antagonists is depression. The therapeutic success of antidepressant substances appears to be connected to the regulation of A1 receptors. A1 antagonists may lead to the regulation of adenosine A1 receptors and thus present a new therapeutic approach to the treatment of depressive patients.

Other fields of use particularly for A2-selective adenosine antagonists are neurodegenerative diseases such as Parkinson's disease and also migraine. Adenosine inhibits the release of dopamine from central synaptic nerve endings by interaction with dopamine-D2 receptors.
A2 antagonists increase the release and availability of dopamine and thus offer a new therapeutic principle for treating Parkinson's disease.

In migraine, vasodilation of cerebral blood vessels mediated by A2 receptors appears to be involved.
Selective A2 antagonists inhibit vasodilation and may thus be useful in treating migraine.

Adenosine antagonists may also be used in the treatment of peripheral indications.

For example, the activation of Al receptors in the lungs may lead to bronchoconstriction. Selective adenosine Al antagoniqts relax the smooth muscle of the trachea, cause CA 022~6736 1998-12-02 bronchodilation and may thus be useful as antiasthmatic agents.

By activating A2 receptors, adenosine may also lead, under certain circumstances, to respiratory depression and stoppage of breathing. A2 antagonists cause respiratory stimulation. For example, adenosine antagonists (theophyllin) are used for treating respiratory distress and for preventing "sudden infant death" in premature babies.

Important fields of therapy for adenosine antagonists are also cardiovascular diseases and kidney diseases.

In the heart, adenosine causes inhibition of electrical and contractile activity by activating Al receptors. In conjunction with coronary vasodilation mediated by A2 receptors, adenosine has a negative chronotropic, ionotropic, dromotropic, bathmotropic and bradycardiac effect and lowers the minute output.

Adenosine Al receptor antagonists are able to prevent damage to the heart and lungs caused by ischaemia and subsequent reperfusion. Consequently, adenosine , 25 antagonists may be used for the prevention and early treatment of damage to the heart caused by ischaemic reperfusion, e.g. after coronary bypass surgery, heart transplants, angioplasty or thrombolytic treatment of the heart and similar interventions. The same is true of the lungs.

In the kidneys, the activation of A1 receptors causes vasoconstriction of afferent arterioles and, consequently, a fall in renal blood flow and glomerular filtration. Al antagonists act as powerful potassium-saving diuretics on the kidneys and can thus be used for kidney protection and CA 022~6736 1998-12-02 for the treatment of oedema, renal insufficiency and acute renal failure.

Because of the adenosine antagonism on the heart and the - 5 diuretic activity, Al antagonists may be used to therapeutic effect for various cardiovascular diseases, such as cardiac insufficiency, arrhythmias (bradyarrhythmias) associated with hypoxia or ischaemia, conduction disorders, hypertension, ascites in liver failure (hepato-renal syndrome) and as an analgesic in circulatory disorders.
.~.
! ~
Surprisingly, some of the compounds according to the invention display an affinity for the A3-adenosine receptor. A3 antagonists inhibit the degranulation of mast cells caused by activation of the A3 receptor and are therefore therapeutically useful in all diseases and pathological situations connected with mast cell degranulation; e.g. as anti-inflammatory substances in hypersensitivity reactions such as asthma, allergic rhinitis, urticaria, in myocardial reperfusion injury, scleroderma, arthritis, autoimmune diseases, inflammatory bowel diseases, and the like. Cystic fibrosis - also known as mucoviscidosis - is a congenital metabolic ,~ ) 25 disorder caused by a genetic defect on a certain chromosome. As a result of increased production and increased viscosity of the secretions of the mucous glands in the bronchi, there may be severe complications in the airways. Early investigations have shown that A1 antagonists increase the efflux of chloride ions, e.g. in CF PAC cells. On the basis of these findings it is to be expected that the compounds according to the invention will regulate the disrupted electrolyte bands of the cells and alleviate the symptoms of the disease in patients - 35 suffering from cystic fibrosis (mucovicidosis).

CA 022~6736 1998-12-02 ~ .. . ,.. . , , .. . _.

The A1 receptor binding values obtained have been determined analogously with Ensinger et al. in "Cloning and functional characterisation of human A1 adenosine receptor - Biochemical and Biophysical Communications, Vo.187, No. 2, 919-926, 1992" and are assembled in Table 20.

The A3 receptor binding values assembled in Table 21 were determined analogously to Salvatore et al. "Molecular 10 cloning and characterization of the human A3-adenosine receptor" (Proc. Natl. Acad. Sci. USA 90, 10365-10369, 1993).

The new compounds of general formula (Ia) to (Id) may be 15 administered orally, transdermally, by inhalation or parenterally. The compounds according to the invention are present as active ingredients in conventional preparations, e.g. in compositions consisting essentially of an inert pharmaceutical carrier and an effective dose 20 of the active substance, such as for example plain or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal systems, etc. An effective dose of the compounds according to the invention is between 1 and 100, J 25 preferably between 1 and 50, most preferably between 5 and 30 mg/dose for oral use, between 0.001 and 50, preferably between 0.1 and 10 mg/dose for intravenous or intramuscular use. According to the invention, solutions containing 0.01 to 1.0, preferably 0.1 to 0.5~ active 30 substance are suitable for inhalation. It is preferable to use powders for administration by inhalation. It is also possible to use the compounds according to the invention as a solution for infusion, preferably in physiological saline or nutrient saline solution.

CA 022~6736 1998-12-02 The compounds according to the invention may be prepared by the following methods. In order to synthesise the two isomers N N N R6~/ ~C \~R~

(Ia) (Ib) . .
of general formula (Ia) and (Ib), wherein the substituents are as hereinbefore defined, the following procedure is used.

In a first step, aminoguanidine (1) is reacted with a carboxylic acid derivative of general formula (2) to obtain a triazole of general formula (3) (diagram 1).
This reaction may be carried out in accordance with the procedures published in J. Chem. Soc. 1929, 816; J. Org.
Chem 1926, 1729 or Org. Synthesis 26, 11.

, H2N~NH ~ NH + ~r Step1 R6~/ -~H

, (1) (2) (3) Diaqram 1:

Then, in a second step, the triazole of general formula (3) is reacted with alkylcyanoacetate in a cyclising reaction under alkaline conditions to obtain a triazolopyrimidine of general formula (4) (Diagram 2).

CA 022~6736 1998-12-02 .. ... . , , , . ., . , . _. . ~ .

R ~/ 1~ Step2 R6~/

(3) (4) Diaqram 2:

The base may be an alkali or alkaline earth metal alkoxide, e.g. of methanol, ethanol, isopropanol, n-, sec-or tert.-butyl alcohol. Suitable alkali and alkaline earth metals include for example lithium, sodium, potassium, magnesium and calcium. Sodium methoxide, sodium ethoxide, sodium isopropoxide and potassium tert.-butoxide are particularly preferred as the base.
Furthermore, alkali or alkaline earth metal hydrides may be used as bases. The hydrides of sodium, lithium, potassium, magnesium and calcium are preferred. Suitable inert sol~ents are dimethylformamide, dimethylacetamide, methylene chloride and tetrahydrofuran. Additionally, alkali or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium and calcium may also be used, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcoholic or aqueous solution.

In addition to the alkylcyanoacetates, cyanoacetic acid may also be used. The mixture thus obtained is stirred at ambient temperature for 0.5 to 4 hours, preferably 1 to 2 hours and then mixed with a compound of general formula (3) and stirred for 2 to 12, preferably 4 to 6 hours, preferably at reflux temperature. The reaction mixture is then mixed with water at ambient temperature and acidified, after which the solid is filtered off, washed and dried. Examples of suitable acids are formic acid, CA 022~6736 1998-12-02 acetic acid or inorganic acids such as hydrochloric or sulphuric acid.

In a third step, the groups R4 and R5 are introduced into the triazolopyrimidine of general formula (4) and the compounds of general formulae (5) and (12) are obtained (Diagram 3).

O O O
R6~/ ~3~ Step 3 R6~/ ~'13~ N--N~

H R
(5) (1 2) Diaqram 3:

For this, a compound of general formula (4) is dissolved in 5 to 40 times, preferably 10 to 20 times the amount of a polar solvent, such as dimethylformamide, dimethylacetamide, methylene chloride or tetrahydrofuran, preferably dimethylformamide, and most preferably anhydrous, possibly absolute dimethylformamide. The resulting solution is combined with a base and a corresponding alkylating agent. Suitable bases include the alkali or alkaline earth metal carbonates of lithium, sodium, potassium and calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. Moreover, the hydrogen carbonates of lithium, sodium and potassium may be used. It is also possible to use the alkali or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium or calcium, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or water. Other bases which may be consid~red are the alkoxides of the alkali and alkaline earth metals already mentioned in step (2).

CA 022~6736 1998-12-02 . . .

Furthermore, the above-mentioned alkali and alkaline earth metal hydrides may be used, preferably in inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, ethers, tetrahydrofuran and toluene. Suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide, especially alkyl iodide and alkyl tosylates, mesylates, triflates and dialkylsulphates. The alkyl groups of the alkylating agents correspond to the definitions for R4 and R5 given hereinbefore. The reaction mixture is stirred at ambient temperature for 0.5 to 4 days, preferably 1 to 2 days and evaporated to dryness. The product can be worked up, on the one hand, ~--' by stirring the residue with water and a solvent, e.g. a ~ halogenated solvent such as carbon tetrachloride, methylene chloride, preferably methylene chloride, whereupon the compound of general formula (5) can be isolated as a solid by filtering. The compound of general formula (12) can be obtained from the filtrate by removing the solvent. Moreover, in the event that no solid is obtained, in order to isolate the compound of general formula (12) from the filtrate, the phases of the filtrate may be separated, the aqueous solution may be extracted with an halogenated solvent, preferably methylene chloride, and the combined organic phases may be dried and worked up. The compounds of general formulae (5) and (12) are obtained by chromatographic purification of the residue (Diagram 3).

~ By nitrosing a compound of general formula (5), a compound of general formula (6) is obtained in the fourth step (Diagram 4).

CA 022~6736 1998-12-02 .,, . ~

o o --N~ R~ --1~
N Nl NH2 N N NH2 (5) (6) Dia~ram 4:

According to the invention, there are two alternative processes which may be used.

Step 4, alternative A:
A compound of general formula (5) is dissolved or suspended in a polar solvent, the polar solvent possibly consistlng of any of the above-mentioned solvents and dimethylacetamide or an alcohol, e.g. methanol, ethanol, ~ propanol, isopropanol and butanol. Dimethylformamide is particularly preferred. It is advisable to use the chosen solvent as an anhydrous, optionally absolute solvent. The mixture thus obtained is cooled to below 0~C, preferably -5~C. A nitrosing agent, e.g. an alkyl nitrite such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl and pentyl nitrite, but preferably isoamyl nitrite, is added to this mixture, whilst the temperature should not rise above 0~C. The mixture is stirred at this temperature for 2 to 48, preferably 4 to 24, most preferably 8 to 12 hours. Then stirring is continued at ambient temperature if required to finish off the reaction. The solvent is eliminated in vacuo, the residue is filtered with a solvent, e.g. diethylether, washed with water and the residue thus obtained is dried ( in vacuo) .

Ste~ 4 alternative B:
A compound of general formula (5) is mixed with an aqueous acid, the acid being an organic acid, formic acid, acetic acid, propionic acid, preferably acetic acid or an CA 022~6736 1998-12-02 inorganic acid, e.g. hydrochloric acid or dilute sulphuric acid, preferably hydrochloric acid and mixtures thereof.
The mixture is heated to 30 to 100, preferably 50 to 80, most preferably 70~C and mixed with a nitrosing agent, preferably sodium nitrite, most preferably sodium nitrite in water and kept at the above temperature for 0.5 to 2 hours, preferably 1 hour, and then kept for 0.5 to 2 hours, preferably 1 hour, at 0 to 20, preferably 5 to 15, most preferably 10~C. The product is filtered, the residue is washed and dried in vacuo.

In the fifth step the nitroso compound (6) is reduced to form a diamine derivative of general formula (7) (Diagram 5) O O
N_ ~ NO N~N ~ NH2 R6 ~/ ~ ~ Step 5 R6 (6) (7) Diaqram 5:

The following alternative methods may be used for this purpose.

Step 5, alternative A:
The nitroso compound (6) is suspended in water with stirring and combined with a suitable reducing agent.
Suitable reducing agents are dithionite in acid or alkaline solution. Also ammonium sulphite, lithium, sodium or potassium hydrogen sulphite, triethylphosphite, triphenylphosphine or lithium aluminium hydride can be used. Moreover, the nitroso group may be catalytically hydrogenated using transition metal catalysts based on palladium, platinum, nickel or rhodium or by transfer CA 022~6736 1998-12-02 hydrogenation, e.g. with cyclohexane or ammonium formate as the hydrogen source. However, it is preferable to use sodium dithionite. Apart from the aqueous ammonia solution which is preferably used, alkali or alkaline earth metal hydroxide solutions, e.g. lithium, sodium, potassium hydroxide or magnesium, calcium and barium hydroxide solutions, but preferably the dilute solutions, may be used as bases. Furthermore, the methyl, ethyl, isopropyl, n-propyl, isobutyl, tert.-butyl and n-butyl alkoxides of the above-mentioned alkali and alkaline earth metals may be used. This suspension is heated to 20 to 100~C, preferably 50 to 90~C, most preferably 60 to 80~C
~ and mixed with an acid, preferably at the beginning, but most preferably within the first 30 minutes. Possible acids are inorganic acids, hydrochloric and sulphuric acid and organic acids such as formic acid and acetic acid and mixtures thereof, sulphuric acid being preferred whilst 50~ sulphuric acid is particularly preferred. The resulting mixture is refluxed until the reaction is complete. On cooling, the product is precipitated as a hemisulphate. Moreover, the product can be precipitated by neutralising with an aqueous base, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide solution, most preferably 30 by weight sodium hydroxide solution by neutralising and then filtered off as a free base.

Step 5, alternative B:
The nitroso compound (6) is added to a mixture of aqueous base and an alcohol, with stirring. Then, after the nitroso compound has been dissolved or suspended, the reducing agent is added, preferably in solution. Possible reducing agents are those mentioned in Method A, an aqueous solution of sodium dithionite being particularly preferred. Then the mixture is stirred at ambient temperature for 0.5 to 6, preferably 1 to 4, most CA 022~6736 1998-12-02 .. , . . , .. . . . _ ..

preferably 1.5 to 3 hours. The product precipitated is isolated by filtering.

In the sixth step, the isomeric compounds (8) are prepared from the diamines of general formula (7) (Diagram 6).
O O O
N_NJ~NH2 N_ J~,NHCOR2 N_ NJ~NH2 Step 6 R6~/ 1 ~ + R~

(7) (8) Diaqram 6:

For this, the amino compound of general formula (7) is suspended in an organic solvent and mixed with an organic base. After the mixture has been kept at ambient temperature for 40 to 60 minutes, preferably 20 to 50 minutes, most preferably 25 to 45 minutes, the mixture is cooled to 0 to 15~C, preferably 5 to 10~C and combined with a carboxylic acid derivative wherein the group R2 is as hereinbefore defined. Suitable organic solvents are -- dimethylformamide, dimethylacetamide, methylene chloride, toluene and tetrahydrofuran, of which dimethylformamide is preferred and anhydrous, optionally absolute dimethylformamide is particularly preferred. Suitable organic bases are dimethylaminopyridine, pyridine, tert.-amines, such as trimethylamine, triethylamine, diisopropylethylamine, DBU (diazabicycloundecene) or one of the inorganic bases mentioned earlier, particularly alkali or alkaline earth metal carbonates or hydrogen carbonates. However, dimethylaminopyridine is particularly suitable as the base. Carboxylic acid derivatives which may be used according to the invention are the carboxylic acid halides, preferably carboxylic acid chlorides or carboxylic acids if they are suitably CA 022~6736 1998-12-02 activated. This may be done, for example, by reacting with chloroformic acid esters, carbonyldiimidazole, carbodiimides, such as dicyclohexylcarbodiimide, EDAC, or benzotriazoles, such as HOBt (1-hydroxy-1-H-benzotriazole) 5 and TBTU. Similarly, the corresponding aldehyde may also be used instead of the carboxylic acid derivative and the ~ intermediate product may be oxidised with iron(II)chloride, azodicarboxylic acid esters and other oxidising agents. The mixture is then stirred at ambient temperature for 0.5 to 4 hours, preferably 1 to 3 hours, most preferably 2 hours, at 5 to 20~C, preferably 7 to f 15~C, most preferably 10~C and overnight at ambient temperature and the solvent is then eliminated in vacuo.
The residue is taken up in water, the solid is filtered 15 off, washed and optionally purified by recrystallisation or chromatography, preferably column chromatography.

In the seventh step, a compound of general formula (6), (7) or (8) is cyclised to form the compound of general 20 formula (9) in accordance with methods A to C (Diagram 7).

~ ~.

CA 022~6736 1998-12-02 N_ N ~NHCOR2 S
--1 Method A
N Nl NH2 R (8) O O
N-N ~ NH2 Step7,~ N-N ~ N
N 1 N NH2 Method BN--1 N N~ R
-~ R4 (7) R4 H
(9) o ~ N-N ~ NO Step 7l R _l I Method C
N N ~ NH2 R (6) Diagram 7:

5 Step 7, Method A:
A compound of general formula (8) is suspended in an alcohol and refluxed with a base for 24 hours. After -- cooling, the mixture is made alkaline, the solid is filtered off and dried. If desired, the product is purified by recrystallisation or chromatography, preferably column chromatography. Bases which may be used here include the alkali metal and alkaline earth metal hydroxides, e.g. the hydroxides of lithium, sodium, potassium, calcium and barium and mixtures thereof in the form of aqueous solutions or optionally in admixture with an alcohol and/or with a water-miscible ether. Suitable alcohols are methanol, ethanol, n-propanol, isopropanol, n-butanol and tert.-butanol. Suitable ethers include, in particular, cyclic ethers, e.g. tetrahydrofuran and dioxane. By analogous methods, cyclisation may also be CA 022~6736 1998-12-02 ~ carried out with inorganic acid chlorides such as thionyl chloride, phosphorusoxychloride or phosphorus pentachloride and with polyphosphoric acid.

5 Another analogous method consists of reacting the carboxylic acid amide under acid conditions with inorganic acid/methanol, preferably hydrochloric acid/methanol or under basic conditions with alkali metal/methanol, preferably sodium/methanol and then carrying out thermal 10 cyclisation.

Step 7, Method B:
In another process it is possible to prepare the compound (9) wherein R2 is hydrogen starting from the diamine (7).
15 To do this, (7) is stirred with an equimolar amount, ~ preferably with an excess of formamide for 0.5 to 3 hours, preferably 1 to 2 hours, most preferably 1.5 hours at 50 to 250~C, preferably 100 to 225~C, most preferably 180 -200~C. The formamide remaining is distilled off in vacuo and the residue is taken up in water. The solid thus obtained is filtered off, washed with water and the resulting product is purified optionally by recrystallisation or chromatography, preferably column chromatography.
Step 7, Method C:
Moreover, the compound of general formula (9) may be obtained directly from the nitroso compound of general formula (6) if R2 denotes a group NR8R9, wherein R8 and R9 are as hereinbefore defined. To a solution of the desired ~ N-formylamine in diglyme, phosphorusoxychloride is added at -10 to +20~C, preferably -5 to +5~C, most preferably 0~C. Then the mixture is stirred 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, most preferably 40 to 60 minutes, at 30 to 120~C, preferably 50 to 100~C, most preferably 70 to 80~C and then added to ice CA 022~6736 1998-12-02 , . . , ., _ . .. , . ., ,. , . __ water. The solid product is filtered off, washed and dried and optionally purified by recrystallisation or purified by chromatography, preferably column chromatography.

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

R' R6~' 1~ /~ R2 O N N N
--N~ \~R2 Step 8 R4 R4 H R6~ R
(9) N N N~ 3 o (Ib) Diaqram 8:
For this, the starting compound is taken up in an organic ' solvent and reacted with a base and a suitable alkylating '~- agent. The reaction mixture is stirred overnight at ambient temperature. If required, the reaction may also be carried out at elevated temperature. The duration of the reaction may be up to one week under certain circumstances. When the reaction has ended the mixture is evaporated to dryness. The residue is taken up in an aqueous alkaline solution, whilst the base may be lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide and most preferably 2N sodium hydroxide solution. The solution is then washed with a non-polar organic solvent such as benzene, toluene or xylene, preferably toluene and adjusted to a pH of 6. The solid precipitated i~ filtered off and optionally purified CA 022~6736 1998-12-02 by chromatography, preferably column chromatography. In this way, both the dialkylation products and the monoalkylation products of the compounds of general formula (Ia) and (Ib) may be prepared and isolated.

Suitable organic solvents for the alkylation include inert solvents such as dimethylformamide, dimethylacetamide, methylene chloride, alkylether, preferably diethylether, tetrahydrofuran, benzene, toluene, xylene and particularly dimethylformamide. Suitable bases include carbonates such ~ as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate and hydrogen carbonates of the above-mentioned alkali metals and alkaline earth metals as well as the hydroxides and alkoxides thereof.
The alkoxides of the above-mentioned alkali and alkaline earth metals with methanol, isopropanol and tert.-butanol are preferred, sodium ethoxide being particularly preferred. In the case of the carbonates, hydrogen carbonates, alkoxides and hydroxides, it may be advantageous to use alcohol or water as solvent. Other bases which may be used for alkylation are sodium hydride, potassium hydride, lithium hydride and calcium hydride in the above-mentioned inert solvents. Moreover, suitable alkylating agents are hydrocarbon halides such as alkyl chlorides, alkyl bromides and alkyl iodides as well as hydrocarbon or alkyl tosylates, -mesylates and -triflates and the alkyl sulphates, alkyl iodides being preferred.

The invention further relates to a process for preparing compounds of general formula (Id) and (Ic) O

R6~N ~CN\~R2 R6~, _~N~R2 r N N~ ~N N N

(Id) (Ic) CA 022~6736 1998-12-02 ~ Starting from a compound of general formula (12) a compound of general formula (13) may be obtained (Diagram 9) in accordance with the reaction of (5) to obtain (6) described hereinbefore (cf. Diagram 4, Step 4).

O O

R6 ~/ l ~ Step 4 R6 (12) (13) Diaqram 9:
This may be converted in accordance with the method of Step 5 (cf. Diagram 5) into a compound of general formula ~(14) (Diagram 10).

O O
N_NJ~,NO N_NJ' NH2 R~ 1~ ~ R~ ~

(13) (14) Diaqram 10:
In accordance with the alternative methods described hereinbefore for reacting compound (7) to obtain compound (8) (cf. Diagram 6, Step 6) the compounds of general formula (14) may be converted into the compounds of general formula (15) (Diagram 11).

CA 022~6736 1998-12-02 O O O
N_ N ~NH2 N_ NJ~,NHCOR2 N_NJ' NH2 ,NlN~NH2 Nl~N~NH Nl~N~NHCOR2 (14) (15) Diaqram 11:

From this, the compounds of general formula (16) may be obtained (Diagram 12) in Step 7 in accordance with the ( alternative reactions of cyclisation described above (cf.
Diagram 7).

N-N ~ NHCOR2 Ste rl~ Me~od A

R5 (1 5) O O
Rs~/ l ~ Step 7, ' RC~/ l ~ \~ R2 R5 (14) R5 H
(16) o N-N ~ NO Step R5 (13) Diaqram 12:

From these, the compounds of general formulae (Ic) and (Id) may be obtained by the alkylation reactions described ,,, _., in Steps 3 and 8 and may then be isolated if required by suitable methods of purification or separation, e.g.
crystallisation or column chromatography (Diagram 13).

,R
R6~/N ~ N ~ N~ 2 O N N N

--N~ \~R2 SteP 8 R +
jN N N~ O
._ 5 H N_N~ N

(16) ~Nl~ ~N~
R R3 (~) Diaqram 13:

By introducing suitably substituted groups Rl, R2, R3, R4, R5 or R6, the triazolopurines (Ia), (Ib), (Ic) and (Id) which may be prepared by the methods described above can be further functionalised using generally known methods.
If desired, suitable protecting groups may be used.
Diagram 14 which follows illustrates, by way of example, possible modifications to the group R6 of the compounds (Ib) which may arise according to the invention.

The reactions outlined by way of example in Diagram 14 lead to reactive triazolopurines which may be used as starting compounds for further structural variations (esterifications, alkylations, substitutions etc.).
According to the invention, all the groups R1, R2, R3, R4, R5 or R6 may be functionalised. These modifications are not restricted to compounds of general formula (Ib) but may also be transferred to the triazolopurines of general formulae (Ia), (Ic) and (Id). Diagram 14 serves as an explanation by way of example of possible structural variations of the triazolopurines (Ia), (Ib), (Ic) and CA 022~6736 1998-12-02 , . . ,, ~ ~ . . ...

(Id), without restricting the invention to the reaction sequences shown.

R~ ~N\~ 2 R6 MeO~CH2--O-CH2Alcyl--N N N~ 3(b) [Oxidation ]
O O
N ~ N ~Halogena~on~ N ~ N

R': -CH2AIkYI-, [ Oxidation ] R': -CH2Alky~, [Oxidation ] ~ X: Halogen, O O
H N J~ N HO N~ N
,~ R~ R ,~ R~ R
O N N N~ ~ N N N
R4 R3 R":-Alkyl-, R4 R3 Diagram 14:

The present invention is explained more fully by means of descriptions of synthesis of triazolopurines given by way of example. These Examples serve as an illustration without restricting the invention to their scope.

. . _, .

Step 1: SYnthesis of 5-substituted 3-amino-1,2,4-triazoles (3):

N ' N' H

(3) The unsubstituted 3-amino-1,2,4-triazole is commercially obtainable, the 5-substituted 3-amino-1,2,4-triazoles required may be prepared in accordance with methods known from the literature as published, for example, in J. Chem.
Soc. 1929, 816, J. Org. Chem. 1926, 1729 or Org. Synthesis 26, 11. The carboxylic acids R6-COOH and nitriles R6-CN
are commercially obtainable or may be prepared by methods known from the literature.

Table 1:

No. R6 Yield M (~C) (%) 1.1. -H commercially obtainable 1.2.-Methyl 76 145-148 - 1.3. -Ethyl 75 152 ~-- 1.4.-n-Propyl 62 140-143 1.5.-i-Propyl 67 103-104 1.6.-n-Butyl 62 118 1.7.-t-Butyl 39 130-131 1.8.Benzyl- 70 167-169 1.9.Cyclopentyl- 64 168-172 1.10.2-Furyl- (Hemisulfate) 76 207-208 1.11.Phenyl- 68 185-186 1.12.Cyclohexylmethyl- 51 186-188 1.13.2-Phenylethyl- 53 139-140 1.14.(4-MeO-Ph)-O-cH2- 41 1.15.(4-MeO-Ph)-CH2-O-CH2 54 153 CA 022~6736 1998-12-02 ., _ . .

1.16. (4-Ph-CH2O-Ph)-CH2- 57 196-200 1.17. 4-Fluorobenzyl- 100 163-164 1.18. 3,4-Difluorobenzyl- 81 135-137 1.19. 3-Pyridylmethyl- 58 192-196 SteP 2: SYnthesis of 2-substituted 4H-5-amino-1,2,4-triazolo[l,5-a]pyrimidin-7-one derivatives (4) R ~ N~
H (4) General method:
2.3g (0.1 mol) of sodium are dissolved in 10 ml of abs.
ethanol, then 14. 7 g (0.13 mol) of ethyl cyanoacetate are added. The mixture is stirred for 1 - 2 hours at ambient temperature, then mixed with 0.1 mol of the desired 5-substituted 3-aminotriazole and refluxed for 4 - 6 hours.
The cooled reaction mixture is mixed with water and made acidic with stirring, then the solid is filtered off, washed and dried.
- Using thls process the following compounds were prepared:
Table 2:

No R6 Yield Mp (~C) (%) 2.1. -H 73 ~370 2.2. -Methyl 76 ~300 2.3. -Ethyl 81 ~300 2.4. -n-Propyl 80 290 (Decomp.) ~ 2.5. -i-Propyl 81 294 (Decomp.) 2.6. -n-Butyl 77 256 2.7. -t-Butyl 78 ~300 2.8. Benzyl- 82 300 (Decomp.) CA 022~6736 l998-l2-02 , .. . . .. .

2.9. Cyclopentyl- 83 310 (Decomp.) 2.10. 2-Furyl- 61 2.11. Phenyl- 75 2.12. Cyclohexylmethyl- 81 > 300 2.13. 2-Phenylethyl- 83 295-296 2.14. (4-MeO-Ph)-O-cH2- 68 302 2.15. (4-MeO-Ph)-CH2-O-CH2 89 245 ~ 2.16. (4-PhCH2O-Ph)-CH2- 96 296-298 No R6 Yield Mp (~C) (%) ....~
2.17. 4-Fluorbenzyl- 79 300-302 2.18. 3,4-Difluorbenzyl- 62 290-292 2.19. 3-Pyridylmethyl- 82 ~300 Step 3: SYnthesis of the alkylated triazoloPYrimidine derivatives (5) and (12):

O O

R~N~ 3~ N-N~

(5) (12) General method:
66 mMol of the relevant 5-amino-1,2,4-triazolo[1,5-a]-pyrimidin-7-one (4) are dissolved in 10 - 20 times the quantity of anhydrous dimethylformamide and mixed with 76 mMol of potassium carbonate and 76 mMol of the desired alkyl iodide. The reaction mixture is stirred at ambient temperature for one 1 - 2 days and evaporated to dryness.
The residue is stirred with water and methylene chloride.
In many cases, after this treatment, compound (5) can be filtered off as a solid and isolated in this way. The isomer (12) can then be obtained from the filtrate as described below. If no solid is obtained during stirring CA 022~6736 1998-12-02 , . .. ... _ _--. .. .. . .. .

or in order to isolate compound (12) from the filtrate, the phases of the filtrate are separated, the aqueous phase is extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate and evaporated to dryness. Compound (5) and optionally (12) are isolated by chromatographic purification of the residue. The alkyl halides required R'-X (wherein R' =
R4, R5) are commercially obtainable or may be prepared by methods known from the literature.
Using this method the following substances were prepared:
~, CA 022~6736 1998-12-02 ~ , . . .

Table 3:

No. R6 R4 R5 Yield Mp (~C) (%) 3.1 -H -Methyl - 80310(Decomp.) 3.2 -H -n-Propyl - 58 184- 186 3.3 -H - -n-Propyl 18 183 3.4-Methyl -n-Propyl - 61 228 3.5 -Ethyl -n-Propyl - 65 194 3.6-n-Propyl -n-Propyl - 69 170 3.7-i-Propyl -n-Propyl - 50 138 3.8 -Butyl -n-Propyl - 62 167 3.9-t-Butyl -n-Propyl - 64 164- 165 3.102-Furyl- -n-Propyl - 45 260 - 262 3.11Cyclopentyl- -n-Propyl - 64 148- 150 3.12Cyclopentyl- - -n-Propyl 22 173 3.13Benzyl- -n-Propyl - 60 208 3.14Benzyl- -Methyl - 52 296 3.15Benzyl- -Ethyl - 58 213 3.16Benzyl -i-Propyl - 29 232 3.17Benzyl- -n-Butyl - 55 175 3.18Benzyl- -Pentyl - 63 188 3.19Benzyl- Benzyl- - 51 180- 181 t 3.20Phenyl- -n-Propyl - 30 270 - 2713.21Cyclohexylmethyl- -Ethyl - 67 210-212 3.222-Phenylethyl- -Ethyl - 29 173-174 3.23(4-MeO-Ph)-O-CH2- -Ethyl - 58 177-180 3.24(4-MeO-Ph)-CH2-O-CH2- -Ethyl - 100 *
8.25(4-PhCH2-O-Ph)-CH2- -Ethyl - 63 240-242 3.264-Fluorobenzyl- -Ethyl - 53 3.273,4-Difluorobenzyl- -Ethyl - 61 228 ~ 3.283-Pyridylmethyl- -Ethyl - 94 186-188 *Isomer sepd,dlion in r~ /,;.,9 step CA 022~6736 1998-12-02 Ste~ 4: Synthesis of the nitroso compounds (6) and (13) RB~,N - N ~ N ~ N ~NO

(6) (13) 1~ General methods (alternative A):
10 mMol of 5-amino-1,2,4-triazolo[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 cooled to -5~C. 20 mMol of isoamyl nitrite are added in such a way that the temperature does not rise above 0~C and the mixture is stirred at this temperature for 4 - 24 hours, then as necessary at ambient temperature until the reaction is complete. The solvent is eliminated in vacuo, the residue is stirred with ether, filtered off, washed with water and dried in vacuo.

- 20 The following substances were prepared by this method:

Table 4a:

No. R6 R4 R5 Yield (%) Mp (~C) 4.1 -H -H - 85 >350 4.2 -H -Methyl - 79 248 4.3 -H -n-Propyl - 81 211 (Decomp.) 4.4 -Methyl -n-Propyl - 88 226 (Decomp.) 4.5 -Ethyl -n-Propyl - 94 190 CA 022~6736 1998-12-02 4.6 -n-Propyl -n-Propyl - 96 206 (Decomp.) 4.7 i Plopyl -n-Propyl - 72 210 (Decomp.) 4.8 -n-Butyl -n-Propyl - 95 196 (Decomp.) 4.9 -t-Butyl -n-Propyl - 93 200 (Decomp.) 4.10 2-Furyl- -n-Propyl - 85 261 4.11Cyclopentyl- -n-Propyl - 97 224 (Decomp.) ..
4.12Cyclopentyl- -H - 89 225 (Decomp.) 4.13 Benzyl- -H - 97 238 (Decomp.) 4.14 Benzyl- -n-Propyl - 95 208 (Decomp.) No. R6 R4 R5 Yield (%) Mp (~C) 4.15 Benzyl- -Methyl - 96 233 (Decomp.) 4.16 Benzyl- -Ethyl - 97 226 (Decomp.) 4.17 Benzyl -i-Propyl - 88 190 (Decomp.) 4.18 Benzyl- -n-Butyl - 93 196 4.19 Benzyl- -n-Pentyl - 74 190 (Decomp.) 4.20 Benzyl- Benzyl- - 96 236 4.21 Phenyl- -n-Propyl - 92 257 - 258 (Decomp.) 4.22 -H - -n-Propyl 63 206 (Decomp.) 4.23Cyclopentyl- - -n-Propyl 74 146 4.24Cyclohexylmethyl- -Ethyl - 83 208-209 4.252-Phenylethyl- -Ethyl - 90 200-201 CA 022~6736 1998-12-02 , . ... .. , .. , . . _ . , .

4.26(4-MeO-Ph)-O-CH2- -Ethyl - 93 214-216 4 27(4-Meo-ph)-cH2-o-cH2- -Ethyl - 56 156-158 4.28(4-phcH2-o-ph)-cH2- -Ethyl - 97 201 (Decomp.) 4.294-Fluorobenzyl- -Ethyl - 89 241-242 4.303,4-Difluorobenzyl- -Ethyl - 97 234-236 4.313-Pyridylmethyl- -Ethyl - 44 229 General method (alternative B):
~ 20 mMol of 5-amino-1,2,4-triazolo[1,5-a]pyrimidin-7-one (4), (5) or (12) are suspended in 80 to 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 H2O and stirred for 0.5-2 hours at 70~C, then for a further 0.5-2 hours at 10~C. The product is filtered off, washed and dried in vacuo. Using this process the following 10 compounds were prepared:

Table 4b:

No. R6 R4 R5 Yield (%) Mp (~C) 4.32 Benzyl- -H 65 236 (Decomp.) SteP 5: SYnthesis of the diamines (7) and (14):
~, ~NH ~Nl'~NH

(7) (14) General method (alternative A):
12.7 mMol of the nitroso compound (6) or (13) are suspended in 86 ml of H2O with stirring and 4.9 g (2.9 mMol) of Na2S2O4 are added. The suspension is heated to 80~C and within 30 minutes 15 ml of 50~ H2SO4 are added.

CA 022~6736 1998-12-02 The mixture is refluxed until the reaction is complete.
After cooling, the product is usually obtained as a hemisulphate. If no solid is precipitated, the mixture is neutralised with 30~ sodium hydroxide solution and the S free base precipitated is filtered off.

General method (alternative B):
11.5 mMol of nitroso compound (6) or (13) are added to a mixture of 175 ml of 25~ aqueous ammonia and 36 ml of ethanol, with stirring. Then the mixture is stirred at 30~C until the nitroso compound has substantially dissolved, a solution of 6.1 g (34.7 mMol) of Na2S2O4 in 57 ml of H2O is added dropwise and stirring is continued for a further 1.5 to 3 hours at ambient temperature. If some starting compound is still present, 10~ of the above quantity of Na2S2O4 are added and stirring is continued until the reaction is complete. The product is isolated by filtering.

The compounds described in Table 5, inter alia, were prepared by one of these methods (A or B, see Table 5):

CA 022~6736 1998-12-02 ., .. . ~ . . . . . ....

Table 5:
~, No. R6 R4 R5 Alter- YieldSalt formMelting point in native in % ~C
5.1 -H -H - A 73 Hemisulfate ~300 5.2 -H -Methyl - A 65 - 267 (Deco",p.) 5.3 -H -n-Propyl - A 65 - 185-188 5.4 -Methyl -n-Propyl - A 70 - 174 5.5 -Ethyl -n-Propyl - A 78 - 170-172 5.6 -n-Propyl -n-Propyl - A 82 - 148-150 5.7 -i-Propyl -n-Propyl - A 52 - 193 5.8 -n-Butyl -n-Propyl - A 71 - 140-142 5.9 -t-Butyl -n-Propyl - B 90 - 168 5.10 Cyclopentyl- -H - A 74 Hemisulfate 224 5.11 Cyclopentyl- -n-Propyl - A 48 Hemisulfate 195-197 5.12 2-Furyl- -n-Propyl - B 75 - 204-205 5.13 Benzyl -i-Propyl - A 8 Hemisulfate 223 5.14 Benzyl- -n-Propyl - A 62 Hemisulfate 217 5.15 Benzyl- -Methyl - B 91 - 248 o Ul No. R6 R4 R5 Alter- Yield Salt form Melting point ~, native in % in ~C
5.16Benzyl- -Ethyl - B 95 - 175 5.17Benzyl- -n-Butyl - A 48Hemisulfate 203-205 5.18Benzyl- -n-Pentyl - B 92 - 146 5.19Benzyl- -H - A 47Hemisulfate 218-220 5.20Benzyl- Benzyl- - B 80 - 273 5.21Phenyl- -n-Propyl - A 79Hemisulfate 260 5.22 -H - -n-Propyl A 81 - 222-224 5.23Cyclopentyl- - -n-Propyl A 86 - 175 5.24Cyclohexylmethyl- -Ethyl - B 94 - 158-160 5.252-Phenylethyl- -Ethyl - B 94 - 204-205 5.26(4-MeO-Ph)-O-CH2- -Ethyl - B 86 - 154-156 5.27(4-MeO-Ph)-CH2-O-cH2- -Ethyl - B 88 - 133-139 5.28(4-phcH2-o-ph)-cH2- -Ethyl - B 84 - 155 5.294-Fluorobenzyl- -Ethyl - B 88 - 202-205 5.303,4-Difluorobenzyl- -Ethyl - B 95 - 209-212 5.303-Pyridylmethyl- -Ethyl - B 82 - 179-180 SteD 6: Synthesis of amides (8) and (15):

~ R ~ N ~' + +
o R~ J~ N-N~NH2 (8) (15) General method (alternative A):
30 mMol of diamino compound (7) or (14) are suspended in 165 ml of anhydrous dimethylformamide and mixed with 45 mMol (or in the case of hemisulphates 78 mMol) of 4-dimethylaminopyridine. The mixture is stirred for 30 . minutes at ambient temperature, 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. Then the mixture is stirred for 2 hours at 10~C and overnight at ambient temperature, after which the solvent is eliminated in vacuo. The residue is added to water, the solid is filtered off and washed and optionally purified by recrystallisation or chromatography.

The carboxylic acid chlorides required are commercially available or may be prepared by methods known from the literature.

CA 022~6736 1998-12-02 Using this method the compounds of formulae (8) and (15) described in Table 6a were prepared, inter alia:

:

ulTable 6a:
No. R6 R4 R5 R2 Yield inMeltingpointin ~, % ~C
6.1 -H -H Cyclopentyl- 86284 (Decomp.) O 6.2 -H -Methyl - Benzyl- 35 306 6.3 -H -n-Propyl - Benzyl- 65 178 6.4 -H -n-Propyl -Cyclopentyl- 95 192 6.5 -Methyl -n-Propyl -Cyclopentyl- 71 208 6.6 -Ethyl -n-Propyl -Cyclopentyl- 72 209 6.7 -Ethyl -n-Propyl - -Ethyl 77 6.8 -n-Propyl -n-Propyl -Cyclopentyl- 90 210 6.9 -n-Propyl -n-Propyl - Phenyl- 68 205 6.10 -n-Propyl -n-Propyl -4-Fluorobenzyl- 84 200 6.11 -i-Propyl -n-Propyl -Cyclopentyl- 71 148 6.12 -n-Butyl -n-Propyl -Cyclopentyl- 66 173 6.13 -t-Butyl -n-Propyl -Cyclopentyl- 60 100 6.14 Cyclopentyl- -n-Propyl - -Ethyl 76 205 6.15 Cyclopenlyl- -n-Propyl - -Methyl 70 243 6.16 Cyclopentyl- -n-Propyl - Benzyl- 76 160 6.17 2-Furyl- -n-Propyl -Cyclopentyl- 74 6.18 2-Furyl- -n-Propyl - -Ethyl 73 6.19 Benzyl- -H -Cyclopentyl- 51 254-257 6.20 Benzyl- Benzyl- -Cyclopentyl- 90 6.21 Benzyl- -Ethyl -3-Tetrahydrofuranyl- 60 227 6.22 Benzyl- -Ethyl -4-Tetrahydropyranyl- 65 237 No. R6 R4 R5 R2 Yield inMelting pointin % ~C
6.23Benzyl- -Ethyl - 2-Pyridyl- 63 223 6.24Benzyl- -Ethyl - 4-Pyridyl- 55 6.25Benzyl- -n-Propyl - -Ethyl 61 183 6.26Benzyl- -n-Propyl - -n-Propyl 62 166 6.27Benzyl- -Methyl - Cyclopentyl- 88 205-208 6.28Benzyl- -Ethyl - Cyclopentyl- 90 188-189 6.29Benzyl- -n-Propyl - Cyclopentyl- 77 170 6.30Benzyl- -n-Butyl - Cyclopentyl- 60 163 6.31Benzyl- -n-Pentyl - Cyclopentyl- 67 162 6.32Phenyl- -n-Propyl - -Ethyl 47 165-166 6.33Phenyl- -n-Propyl - Cyclopentyl- 68 >300 6.34 -H - -n-PropylCyclopentyl- 69 248 6.35Benzyl- -Ethyl - 2-Pyridyl- 40 223 6.36Benzyl- -Ethyl - 4-Pyridyl- 55 6.37Benzyl- -Ethyl - 3-Pyridyl- 88 206 6.38Benzyl- -Ethyl - Cyclohexyl- 86 186-187 6.39Benzyl- n-Butyl- - -H 84 231-232 6.40Benzyl- -H - Phenyl- 72 276-279 6.41Benzyl- -H - 2-Furyl- 69 305-307 6.423-Pyridylmethyl--Ethyl - Cyclopentyl- 73 163-165 6.433-Pyridylmethyl--Ethyl - -Ethyl 71 186-187 6.442-Furyl- -n-Propyl - 2-Furyl- 81 228 No.R6 R4 R5 R2 Yield inMelting pointin % ~C
6.45 Cyclohexylmethyl--Ethyl - -Ethyl 81 204-207 6.46 Cyclohexylmethyl--Ethyl - Cyclopentyl-70 196-198 6.47 2-Phenylethyl- -Ethyl - -Ethyl 95 182-183 6.48 2-Phenylethyl- -Ethyl - Cyclopentyl-81 155-156 6.49 Cyclopentyl- -n-Propyl - 3-Tetrahydrofuranyl- 65 179-180 6.50 Cyclopentyl- -n-Propyl - Cyclopentyl-41 306-308 6.51 (4-MeO-Ph)- OCH2- -Ethyl - -Ethyl 93 160-164 6.52 (4-MeO-Ph)- OCH2- -Ethyl - Cyclopel,lyl-76 176-178 6.53 (4-MeO-Ph)-CH2-O-cH2--Ethyl - Cyclopentyl-91 133-136 6.54 (4-PhCH2O-Ph)-cH2- -Ethyl - Cyclopentyl-86 190 6.55 Cyclohexylmethyl--Ethyl - ", ~ 98 6.56 4-Fluorobenzyl- -Ethyl - Cyclopentyl-62 206-208 6.57 4-Fluorobenzyl- -Ethyl - tert.-Butyl- 53 6.58 4-Fluorobenzyl- -Ethyl - ~ 75 6.59 4-Fluorobenzyl- -Ethyl - ,~ 91 6.60 3,4-Difluorobenzyl--Ethyl - Cyclopentyl-100 222-224 6.61 3,4-Difluorobenzyl--Ethyl - ,~ 100 6.62 Benzyl- -Ethyl - ,~ 87 6.63 3-Pyridylmethyl- -Ethyl - ,~ 79 134-137 General procedure (alternative B):
6.6 mMol of a diamine (7) or (14) are suspended with 7.3 mol of the correqponding carboxylic acid in 15-25 ml of acetonitrile. 7.3 mMol of N-methylmorpholine are slowly added with stirring. Then a solution of 7.3 mMol of isobutyl chloroformate in 6-7 ml of acetonitrile is added dropwise at 20-25~C within 10-20 minutes. The suspension obtained is stirred for 4-6 hours at ambient temperature. For processing, the suspension is filtered and washed with acetonitrile. The resulting filtrate is concentrated and chromatographed over silica gel.
_, Using this process, the compounds of formula (8) and (15) described in Table 6b were prepared:
Table 6b:

No. R6 R4 R5 R2 Yield in %

6.64 4-fluorobenzyl- Ethyl- - ,~ 26 SteD 7: Reactions of cyclisation to obtain the triazoloPurines (9) and (16) R6~ l ~ \~ R2 R~ \~ R2 (9) (16) General method (Method A. alternative A):
14.4 mMol of (8) or (15) are suspended in 75.5 ml of H2O
and 37.8 ml of ethanol and refluxed with 17.4 ml of 50 NaOH and 4.82 g (65 mMol) of Ca(OH) 2 for 24 hours. The mixture is allowed to cool, made acidic, the solid is CA 022~6736 1998-12-02 filtered off and dried. The product is optionally purified by recrystallisation or chromatography.

Using this process the compounds of general formulae (9) and (16) described in Table 7a were prepared, inter alia.

CA 022~6736 1998-12-02 o ul Table 7a-No. R6 R4 R5 R2 Yield inMellin~ point % in ~C
7.1 -H -H -Cyclopentyl- 80 >360 O 7.2 -H -Methyl - Benzyl- 35 306 7.3 -H -n-Propyl - Benzyl- 68 222-223 7.4 -H -n-Propyl -Cyclopentyl- 59 250 7.5 -Methyl -n-Propyl -Cyclopentyl- 62 262-264 7.6 -Ethyl -n-Propyl -Cyclopentyl- 58 253 7.7 -Ethyl -n-Propyl - -Ethyl 68 229 7.8 -n-Propyl -n-Propyl -Cyclopentyl- 75 256 7.9 -n-Propyl -n-Propyl - Phenyl- 49300 (Decomp.) 7.10-n-Propyl -n-Propyl -4-Fluorbenzyl- 65 221 7.11i Plopyl -n-Propyl -Cyclopentyl- 62 260-261 7.12-n-Butyl -n-Propyl -Cyclopentyl- 72 246 7.13-t-Butyl -n-Propyl -Cyclopentyl- 64 310 7.14Cyclopentyl- -n-Propyl - -Ethyl 85 245-248 7.15Cyclopentyl- -n-Propyl - -Methyl 56 248-250 7.16Cyclopentyl- -n-Propyl - Benzyl- 70 233 7.172-Furyl- -n-Propyl -Cyclopentyl- 61>300(Decomp.) 7.182-Furyl- -n-Propyl - -Ethyl 44>300(Decomp.) 7.19Benzyl- -H Cyclopentyl- 40270 (Decomp.) 7.20Benzyl- Benzyl- -Cyclopentyl- 13 270 7.21Benzyl- -Ethyl -3-Tetrahydrofuranyl-60 227 t~ - ' }

o Ul No. R6 R4 R5 R2 Yield in Melting point ~, % in~C
7.22 Benzyl- -Ethyl - 4-Tetrahydropyranyl- 64 237 7.23 Benzyl- -Ethyl - 2-Pyridyl- 21 287 7.24 Benzyl- -Ethyl - 4-Pyridyl- 8 346 7.25 Benzyl- -n-Propyl - -Ethyl 57 223 7.26 Benzyl- -n-Propyl - -n-Propyl 53 202 7.27 Benzyl- -Methyl - Cyclopentyl- 13 265-267 7.28 Benzyl- -Ethyl - Cyclopentyl- 56 242 7.29 Benzyl- -n-Propyl - Cyclopentyl- 67 234-235 7.30 Benzyl- -n-Butyl - Cyclopentyl- 53 238-240 7.31 Benzyl- -n-Pentyl - Cyclopentyl- 56 231-236 7.32 Phenyl- -n-Propyl - -Ethyl 97 ~300 (Decomp.) 7.33 Phenyl- -n-Propyl - Cyclopentyl- 78 ~300 (Decomp.) 7.34 -H - -n-Propyl Cyclopentyl- 36 217-220 7.35 -H - -Ethyl Cyclopentyl- 2 4 260 7.36 Benzyl- -Ethyl - 3-Pyridyl- 11 331-332 7.37 Benzyl- -Ethyl - Cyclohexyl- 74 260-262 7.383-Pyridylmethyl- -Ethyl - Cyclopentyl- 60 261-263 7.393-Pyridylmethyl- -Ethyl - -Ethyl 62 225-227 7.40 2-Furyl- -n-Propyl - 2-Furyl- 9 385-387 7.41 Benzyl- -H - 2-Furyl- 14 352-354 7.42Cyclohexylmethyl- -Ethyl - -Ethyl 73 230-232 7.43Cyclohexylmethyl- -Ethyl - Cyclope"lyl- 62 273-274 o Ul No.R6 R4 R5 R2 Yield inMelting point ~, % in ~C
7.44 2-Phenylethyl--Ethyl - -Ethyl 31 282-283 7.45 2-Phenylethyl--Ethyl - Cyclopentyl-53 292-294 7.46 Cyclopentyl-n-Propyl -3-Tetrahydrofuranyl- 56 289-290 7.47 Cyclopentyl-n-Propyl - Cyclopentyl- 41 306-308 7.48 (4-MeO-Ph)-OCH2--Ethyl - -Ethyl 47 225 7 49 (4-MeO-Ph)-OCH2--Ethyl - Cyclopentyl-20 234-236 7 50 (4-MeO-Ph)-CH2-O-CH2- -Ethyl - Cyclopentyl- 70 1827.51 (4-PhCH2O-Ph)-CH2--Ethyl - Cyclopentyl-70 251 7.52 4-Fluorobenzyl--Ethyl - Cyclopentyl-71 252-254 7.53 4-Fluorobenzyl--Ethyl - -tert.-Butyl 73 262-264 7.54 4-Fluorobenzyl--Ethyl - ~ 53 337-339 7.55 4-Fluorobenzyl--Ethyl - ,~ 45 325-327 7.56 3,4-Difluorobenzyl- -Ethyl - Cyclopentyl- 60 264-2667.57 3,4-Difluorobenzyl- -Ethyl - ~ 58 315-317 7.58 Benzyl- -Ethyl - ,~ 67 320-322 7.59 3-Pyridylmethyl--Ethyl - ,~ 57 330-332 General method (Method A. alternative B):
4 mMol of an amide (8) or (15) are stirred in 10-15 ml of tetrahydrofuran and 25-35 ml of H20 with 46 mMol of lithium hydroxide monohydrate at 45-65~ for 14 days. Then 5 the mixture is acidified with 6 N hydrochloric acid and suction filtered. The crude product is recrystallised from methanol. The resulting product is separated by chromatography on a silica gel column.

10 The compounds of general formula (9) described in Table 7b were prepared by this method.

Table 7b:

No. R6 R4 R2 Yield (%)Mp (~C) 7.62 Cyclohexylmethyl- Ethyl- ""OE~ 10 246-248 7.63 Cyclohexylmethyl- Ethyl- ~) 3258-260(Decomp.) General method (Method B):
10.1 mMol of (7) or (14) are stirred into 34 ml of formamide for 1.5 hours at 200~C. The remaining formamide 20 is distilled off in vacuo and the residue is stirred with water. The solid is filtered off, washed with water and the product is purified by recrystallisation or chromatography.

25 Using this process, the compounds (9) and (16) listed in Table 7c were prepared:

CA 022~6736 1998-12-02 ~ No. R6 R4 R5 R2 Yield Mp (~C) (%) 7.64-Ethyl -n-Propyl - -H 84 >300 7.65Cyclopentyl- -H - -H 53 215 7.66Cyclopentyl- -Methyl - -H 7 ~300 7.673-Pyridylmethyl- -Ethyl - -H 58 328-330 7.68Cyclopentyl- -n-Propyl - -H 58287 (Decomp.) 7.692-Furyl- -n-Propyl - -H 74~300 (Decomp.) 7.70Benzyl- -Methyl - -H 9 ~300 .~ 7.71Benzyl- -n-Propyl - -H 75 ~300 7.72Benzyl- -i-Propyl - -H 90 ~300 7.73Benzyl- -n-Butyl - -H 75 ~300 7.74Benzyl- -H - -H 63 ~300 7.75Phenyl- -n-Propyl - -H 75 295-296 (Decomp.) 7.76Cyclopentyl- - -n- -H 35 202-203 Propyl 7.773-Pyridylmethyl- -Ethyl - -H 58 328-330 7.78Cyclohexylmethyl- -Ethyl - -H 87 328-330 7.792-Phenylethyl- -Ethyl - -H 84 273 General method (Method C):
At 0~C, 0.66 ml (7.2 mMol) of phosphorusoxychloride are added to a solution of 6.8 mMol of the desired N-formylamine in 6 ml of diglyme. The mixture is stirred for 30 minutes in an ice bath and then 4.8 mMol of nitroso compound (6) or (13) are added. The mixture is stirred at 80~C for 30 - 60 minutes and added to ice water, the solid product is filtered off, washed and dried. The product is ~ purified by crystallisation or by chromatography.

Using this process, compounds (9) described in Table 7d were prepared:

CA 022~6736 1998-12-02 . . ., ~, . .

Table 7d:

No. R6 R4 R2 Yield (%) Mp (~C) 7.80Benzyl- -n-Propyl N-Morpholinyl- 21 298 7.81Benzyl- -n-Propyl4-Benzyl-1-piperazinyl- 21 266-268 7.82Benzyl- -n-Propyl Dimethylamino- 9 272-274 ~ 7.83Benzyl- -n-Propyl N-Piperidinyl- 22 294-297 The formylamines required are prepared by methods known from the literature by reacting the amines with 88% formic acid and acetic anhydride.

Step 8: Reactions of alkYlation General method (alternative A):
4 mMol of 1,2,4-triazolo[1,5-a]purin-9-one unsubstituted in the 4- and 5-position [(9) with R4 = H; (16) with Rs =
H] are taken up in 26 ml of anhydrous dimethylformamide and mixed first with a solution of 0.1 g (4.2 mMol) of sodium in 4 ml of anhydrous ethanol, then with 4.2 mMol of the desired alkyliodide. The mixture is stirred overnight ~ at ambient temperature and then evaporated to dryness.
The residue is dissolved in 2 N of NaOH, the solution is ~~- washed with toluene and then adjusted to pH 6. The solid~-- 20 precipitated is filtered off and purified by chromatography. If required, the dialkylation products (Ia) and (Ib) may be isolated.

The following compounds (9) were prepared using this method:

CA 022~6736 1998-12-02 Table 8a:
No. R6 R4 R5 R2 Yield (%) Mp (~C) 8.1Benzyl- -Methyl - -H 9 ~300 8.2Cyclopentyl- -Methyl - -H 7 >300 8.3 -H -Methyl - Cyclopentyl- 44 285 8.4 -H -Ethyl - Cyclopentyl- 57 249-253 8.5 -H -n-Propyl - Cyclopentyl- 52 255 8.6 -H -n-Butyl - Cyclopentyl- 45 243 8.7 -H -t-Butyl - Cyclopentyl- 10 190-191 8.8 Benzyl- -Ethyl - -t-Butyl 24 243-244 8.9 Benzyl- -Ethyl - Phenyl- 24 343-345 8.10 -H -n-Butyl - Cyclopentyl- 45 243 8.11 -H - -t-Butyl Cyclopentyl- 4 149-150 Moreover, the following compounds (Ia) and (Ib) could be obtained by this method:

~ R' O
N_N~N N_NJ~ N
~N lN~N~ N N N, ~...

: (Ia) (Ib) 10 Table 8b:

No R6 R4 R1 orR3 R2 Yield Mp (~C) (%) 8.12 Benzyl- -Ethyl -Ethyl -H 4 ~300 8.13 -H -Methyl -Methyl Cyclopentyl- 4 206 8.14Cyclopentyl- -n-Propyl -n-Propyl -H 10 146 8.15Cyclopentyl- -n-Propyl -n-Propyl -H 5 151 8.16 Benzyl- -Ethyl -Ethyl 2-Furyl- 16 187-189 CA 022~6736 1998-12-02 General method (alternative B):
20.4 mMol of 1,2,4-triazolo[1,5-a]purin-9-one unsubstituted in the 4- and 5-position [(9) with R4 = H;
(16) with Rs = H] are stirred together with 40.8 mMol of potassium carbonate and 40.8 mMol of tert.-butylbromide in 100 ml of anhydrous dimethylformamide at 70~C for 7 days.
The mixture is evaporated to dryness, the residue is combined with 100 ml of 2N NaOH, the aqueous phase is washed thoroughly with toluene and neutralised. The precipitate is filtered off, extracted with CH2Cl2/CH3OH
9:1 and the extract is evaporated down. The isomeric alkylation products (9) and (16) are isolated by chromatography on silica gel with CH2C12/CH3OH 95:5 (Table 8c). The following compounds were prepared using this method.

T a ble 8 c:

N ~ R 6 R 4 R 5 R 2 Yield M p (~ C) (%) 8.1 7 -H -t-B utyl - C yclo p e ntyl- 1 0 1 9 0-1 91 8.1 8 -H - -t-B utylC yclo p e ntyl- 5 1 4 9-1 5 0 - 20 General method (alternative C):
0.05 Mol of starting compound (9) are dissolved in 500 ml of absolute dimethylformamide and stirred with 0.055 Mol of potassium carbonate and 0.055 Mol of benzyl bromide overnight at ambient temperature. For processing, the solvent is distilled off in vacuo and the residue is taken up in methylene chloride/water. The organic phase is separated off, washed once with water, dried over magnesium sulphate and evaporated down. The residue is crystallised with ether. The compounds (Ia/Ib) thus obtained are listed in Table 8d.

CA 022~6736 1998-12-02 , . . , . . ... , ~

Tabl~ 8d:
No. R6 R4 R1 or R2 Yield Mp (~C) R (%) 8.19 (4-MeO-Ph)-CH2-o-cH2- Ethyl-Benzyl- Cyclopentyl- 85 127-128 8.20 (4-PhcH2o-ph)-cH2- Ethyl-Benzyl- Cyclopentyl- 66 138-140 IX. Functionali~ation of the triazolopurine~ of general formula (I):

IX.a. Deblocking of triazoloPurines (Ia/Ib) with Protected hydroxyl functions:
~...
General diagram of synthesis taking as example the compounds of general (formula Ib):
O O

Y~ R2 ~ ~ R2 DDQ: 2,3-Dichloro-5,6-dicyano-benzoquinone The above reaction was carried out using a method known from the literature (Tetrahedron 1986, 42, 3021). The following compounds were obtained, inter alia:

Tabl~ 9:

No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 9.1 HO-CH2- Ethyl- Benzyl- Cyclopentyl- 97 204-207 IX.b. Deblockinq of triazolopurines (Ia)/(Ib) with protected amine functions in the side chain:
General diagram of synthesis taking as example the ~ compounds of general formula (Ib):

CA 022~6736 1998-12-02 .. ~ ... .. ..

o o 6~/N--N ~ N~ A H2 R6~/ N ~ \~ N NH
R4 R ~ Cat. R4 R3 0.83 mMol of a 2-(4-N-benzyl-1-piperazinyl)-1,2,4-triazolo[1,5-a]purin-9-one are taken up in 30 ml of glacial acetic acid and hydrogenated at 60~C and at 5 bar for 6 hours in the presence of 0.1 g of 10% Pd on ~ charcoal. The catalyst is filtered off, the residue is evaporated to dryness and stirred with CH30H, the solid product is filtered off, washed and dried. Using this method the following was obtained:

Tabl~ 10:
No. R6 R4 R1 or R2 Yield SaltformMp (~C) R3 (%) 10.1 Benzyl- n-Propyl- H- 1-Piperazinyl- 53 Acetate 260 IX.c. Cleavinq of Protective amine groups from the triazolopurine core structure:
General diagram of synthesis taking as example the ! compounds of general formula (Ib):
O O

R6~ R2 H2, R6~ R2 N N N Cat. N N NH
R4 \~ R4 3-N-benzylated triazolopurines of general formula (I) are dissolved in methanol or absolute glacial acetic acid and hydrogenated under a hydrogen atmosphere (1-5 bar) at 25-80~C with the help of a palladium catalyst (e.g. Pd/C) over a period of 2.5-40 hours. The catalyst is filtered CA 022~6736 1998-12-02 . . .

off, the filtrate is evaporated down and the residue is purified over silica gel. The purified product is crystallised from the eluate, preferably with ether and then, if possible, crystallised as a salt (preferably methanesulphonate). In this way the following compounds were obtained.

Tabl~
No. R6 R4 R2 Salt form Yield Mp (~C) %

11.1Methoxymethyl- Ethyl- Cyclopentyl- - 27 246-248 11.2Ethoxymethyl- Ethyl- Cyclopentyl- - 45 224-225 11.3Hydroxymethyl- Ethyl- Cyclopentyl- - 37 305-307 11.4Benzoyloxymethyl- Ethyl- Cyclopentyl- - 54 238-239 ~ .

CA 022~6736 1998-12-02 No. R6 R4 R2 Salt form Yield Mp % (~C) 11.5 Dimethylaminomethyl- Ethyl- Cyclopentyl- Methanesulfonate 29 224-11.6 N-Morpholinyl-methyl- Ethyl- Cyclopentyl- Methanesulfonate 47 184 11.7 Phenoxymethyl-Ethyl- Cyclopentyl- - 40 229 IX.d. Alkylation of hydroxy-substituted triazolopurine:
General diagram of synthesis taking as example the compounds of general formula (Ib):
, i .
O O

--<'N1~ \~R2 -- R6~ R2 IN4 ~R3 N N N~

3 mMol of hydroxyalkyl- or hydroxyaryl-substituted triazolopurines of general formula (Ia), (Ib), (Ic) or (Id) are dissolved in 30 ml of anhydrous dimethylformamide, mixed with 3.6 mMol of sodium hydride (60% suspension in mineral oil), stirred for 1 hour at ~~ ambient temperature, mixed with 3.6 mMol of alkyliodide and stirred for 1-2 days at 25-60~. To complete the reaction, 50% sodium hydride and alkylhalide are added.
For processing, the reaction mixture is evaporated down to leave the residue which is taken up in ethylene chloride and water, acidified with 2N hydrochloric acid, the aqueous phase is extracted once more with methylene chloride, the combined organic phases are washed with saline solution and dried over magnesium sulphate and then evaporated down. The residue is purified over silica gel and the eluate is crystallised from ether.
The following compounds were prepared using this method:

CA 022~6736 1998-12-02 , . . , . , ., . ~ , ,, . ,, , , . _ , .. .. .. .

TablP 12:
No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 12.1 Methoxymethyl- Ethyl-Benzyl- Cyclopentyl- 37 116-118 12.2 Ethoxymethyl- Ethyl-Benzyl- Cyclopentyl- 36 120-123 IX.e. Acylation of hydroxy-substituted triazolo~urines:
General diagram of synthesis taking as example the compounds of general formula (Ib):
O O
HO N ~ N ~ N pyridine N _ ~U~ N
N N N carboxylic acid N N N
R4 ~R3 chloride R4 ~R3 The hydroxyl compound is taken up in pyridine and, whilst it is being cooled with ice, stoichiometric quantities of acid chloride are added. When conversion is complete the mixture is added 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 saline solution, dried over magnesium sulphate and evaporated down. The residue is purified over silica gel and the eluate is crystallised from ether.

The following compounds were prepared by this method:

Table 13:
No. R6 R4 R1 or R2 Yield R3 (%) 12.1 ~ Ethyl- Benzyl- Cyclopentyl- 73 O - CH~
12.2 ~ Ethyl- Benzyl- Cyclopentyl- 93 .N O-CH~-CA 022~6736 1998-12-02 .... . .... . ..

IX.f. Halogenation of hydroxy-substituted triazolopurines:
General diagram of synthesis taking as example the compounds of general formula (Ib):
O O

N~N~ NEt3 ~Nl~N'R~R2 The hydroxylated triazolopurines are converted into the corresponding halides in the usual way with halogenating reagents such as SOCl2, SOBr2, POCl3 in inert solvents in the presence of bases (e.g. NEt3).

The following compounds were prepared analogously:

Tabl~ 14:
No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 14.1 Br-CH2- Ethyl-Benzyl- Cyclopentyl- 66 188-189 IX.q. Nucleo~hilic substitution in haloqen-substituted ~ . .
trlazolopurlnes:
General diagram of synthesis taking as example the compounds of general formula (Ib):

o Alcoholor ~
y ~ R2 ~ R6~ RZ

X:C~orine,bro~e,io~ne Using generally known standard procedures, halogen-substituted triazolopurine derivatives may be converted into the corresponding amines and alkyloxy/aryloxy compounds by reacting with nucleophiles (e.g. alcohols, amines) in the presence of a base. For preparation of the amines, please see the methods of synthesis described for Step 8 hereinbefore. The alkyloxy/aryloxy compound may be synthesised in accordance with the general method under point IX.d. The following compounds were prepared 10 analogously:

Tabl~ 15:
No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 15.1 (CH3)2N-CH2- Ethyl- Benzyl-Cyclopentyl- 100 15.2 N-Morpholinomethyl-Ethyl- Benzyl- Cyclopentyl- 96 15.3 Phenyloxymethyl- Ethyl-Benzyl- Cyclopentyl- 86 155 IX.h. Oxidation of hydroxy-substituted triazolopurines:
General diagram of synthesis taking as example the compounds of general formula (Ib):
O O
- HO N _ N ~ N Oxidation N _ J~ N
</ 1 J~ \~ R2 R6~ R2 Using generally known standard procedures (e.g.
Tetrahedron Letters 1979, 5, 399-402) hydroxy-substituted triazolopurine derivatives may be converted into triazolopurines with functionalities of a higher oxidation state (e.g. aldehydes, carboxylic acids). The following compounds were prepared analogously:

CA 022~6736 1998-12-02 . . ~ _ ~ ., Tabl~ 16:
No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 16.1 -CHO Ethyl- Benzyl- Cyclopentyl- 48 153-154 16.2 -COOH Ethyl- Benzyl- Cyclopentyl- 38 157-158 IX.i. Derivatisation of triazolopurine carboxylic acids:
General diagram of synthesis taking as example the compounds of general formula (Ib):
O O
o N_ J~ N N_ J~ N
~<' I~ ~ '~ R2 R6~/ ~ R2 Using methods known from the literature, triazolopurine carboxylic acids may be converted into a plurality of carboxylic acid derivatives (e.g. halides, anhydrides, amides, ester, etc.). The following general method may be used to prepare the corresponding triazolopurine-methyl carboxylates:
0.003 mol of triazolopurine carboxylic acid are suspended in a 1 molar solution of SOCl2 (1 . 5 eq) in MeOH. The resulting clear solution is stirred at ambient temperature. After the reaction is complete the solvent is distilled off in vacuo and the residue remaining is purified by chromatography on silica gel. Using this process the following were prepared:

Tabl~ 17:
No. R6 R4 R1 or R2 Yield Mp (~C)R3 (%) 17.1 -COOCH3 Ethyl- Benzyl- Cyclopentyl- 71 155-157 CA 022~6736 1998-12-02 .. ... . . .

IX.k. Reductive amination of triazolopurine aldehydes:
General diagram of synthesis taking as example the compounds of general formula (Ib):

O , O

~ R2 ) R6~ R2 O N N N~ 2)Red. N N N~

Using generally known standard procedures, triazolopurine aldehydes may be converted into the corresponding amines by reaction with primary or secondary amines and subsequent reduction or hydrogenation of the Schiff's base formed as an intermediate. The following compounds were prepared accordingly:

Tabl~ 18:
No. R6 R4 R1 or R2 Yield Mp (~C) R3 (%) 18.1 ~NH CH2- Ethyl- Benzyl- Cyclopentyl-CA 022~6736 1998-12-02 2 o ~ u~

s E G N 3 N G

~ _ sO 2 s 2 r N N a~ N a7 N a~ N O~
.C ~ .C ~ ,C ~ ,C
o m m, m, m, m, a) ~ C .C O O O O O
O ~ C ~') ~ ~ ~ ~ O

1~
CJ~ N
O ~
~ ~'Z, ~'Z'~
~ O~z 'k ~C
C/ In r-Z~Z U~c~ ~ I l ' ' ~D~
~0 ~~; o ~ 2 -I I I I I
~ , _C
U~
~"

E Q~ c~ I I I I I
~n 0 ~
a~ tD ~ O ~ N C') ~t U7 U~

. .

~ N ~ N e ~ I ~

$ 2 c a~ c 0 c a~ p N ~ ~
t~S ~' O ~;~ O Q c~Q ~ Q 3 Q ~ ~ Q ~ Q ~
Z ~ C t~I a) C O ~' r c O
~, c ~ ,_ c~ N ~C ~ ~ N c~ ~
E N _ N _ N O N O ~ O N O n Q N ~ N , N
~ m ~- m ~ m ~~ m, ~~ m 1~a m ~~ ~~ ~ m ~ m OQ m ~

C ~ l N N C~l ~ ~~
o o C~

o ~ ' ' ' ' ' ' ' ' ' ' ~ ~ ~' o ';? ~3 o ~ G

~ ~ ~ ~ ~ z~ ~Z) [z~

- o~ I I I I I I I I I I

Q
E z ~ ~ ~ C~
~L~

E ~ 3 ' ~ t ~ ~ ~
Z ~ p ~ y ~~ ~ a) 2. w ~ ~
3 q N C~ ,~
E ~ ~ a ~ 'C ~ ON ~ m ~ m, ,~J

~) C Q Q O 0 , ~ C ~ 1~ o ~ IS) o1~ 0 N ~1 C~ C'~l 5 r~ ~J) A ~C) ~ ~ N
~ ~ N
~ ~

o . . I I . . . . .
ll ll ~ s s ~ ~ C 2 ' 2 2 ~, . . . . .

o ~"
~y I I I I I I I I I I

$: o ~D ~ co ~ O ~ ~ ~ ~ U~

..... . ... . .... _ . ... .. . .

~ ~ o ~c ~ ~

E~ q ~ q ~. $ ~ ~ 5 ~ o ZE a) ~ 'n ~ ~ a) ~ a~ ~ a~ a) o ~ ~ Q a~
~ t . t c a a) c a c ~ c ~ ~ a~ In- ', a) ~' ~ .C ,,~ r) N~ ~ ~ g ~
- 5 ~ ~ A C~ ~ A N

C~ I I I I I I o S .
o C! ' ~ I

lY

I 2 ~ ~ ~ ~ ~' 2 2 ~
c 5 ' c ' c c C

C! ~ ~ ~ O ~ ~ O ~ I

'- C~ I I I I I I I I I I

~ O C~ O ~ C~l C~

.... . . . .. . . ..

E ~ C ~ c ~ c ~ c ~ ~ 2 ~ ' a, ~ ~ 2 ' ~ ~ t a~ c cn ~
g ~ - ~D U') N U~ Q ~C Q 1~ ~ C Q ~
E ~ o ~ ~ m o ~ ~ ~ ~ c~ ~ c~ ~ ' w c ~ o ~

~ .,.~ ._ ._ ._ , , , g co c~ o o E ~ c~ 8 ~ 8 E
-- 0 ~ ~ O ~ C~ ~ C~ o ~ o ~ o ~ C, C~

~1 Q Q Q Q Q Q Q Q Q Q
~ ,0 ,0 , , ,0 0 0 0 0 0 ' c c c ~ c ~ ~ ~ c c O ~ s I ~lC~ ~

~ C~
I I I I I I I I I I

o ~ ~ o~ a~ o ~ ~ c~ ~ u~
~ z ~ ~ ~ ~ ~ ~ ~ ~ ~ ~

E ~ c ~ ~C ~ C ~a ~ C a t~ C ,0 2'Q ~ ~ ,o ~ U) ,0 U) o C~) lo ~~ Io ~ lo Z q ~~ ~ a) O ~ a) ~ o~
~C ~ ~ a~ D C OC C C C C C - C C C
o g o g ~ c O Qg ~ g ~ N Q g Q

C ~ ~, ~ E ~ E ~ E C~l o ~ '~ '~ ~ ~
~A a) A OA a) 1~ A ~ A O

o ~o ~o O I I I I

~' ~

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-- ~>.O o 0. Qo ~ ~ ~) s ~ I s o ~" Q
~~ I I I ~ s~

~ o ~D ~ co a~ o ~ c~

~ .
D
Example-R1 or Melting No. -R3 -R2 -R4 -R5 R6 pointin Chemical Name ~ ~C
56 -n-Propyl -H -n-Propyl - O 146 6-Cyclopentyl-1,4-di-n-propyl-1,2,4-O l,i ~1~ [1,5-a]purin-9-one 57 -n-Propyl -H -n-Propyl - ~ 151 6-Cyclopentyl-3,4-di-n-propyl-1,2,4-[1 ,5-a]purin-9-one 58 -H ~ -n-Butyl - -H 243 2-Cyclopentyl-4-n-butyl-1,2,4-~i -'c [1,5-a]purin-9-one 59 -H ~3 -Ethyl - \~ 287 6-Benzyl-4-ethyl-2-(2-pyridyl)-1,2,4-l, - I [1 ,5-a]purin-9-one -H ~N -Ethyl \_ ~3 346 6-Benzyl-4-ethyl-2-(4-pyridyl)-1,2,4-l,i '- [1,5-a]purin-9-one 61 -H G ~ -H 149-150 2-Cyclope"tyl 5-tert.-butyl-1,2,4-triazolo-[1 ,5-a]purin-9-one 62 -H ~ ~ - -H 190-191 2-Cyclopentyl4-tert.-butyl-1 ,2,4-triazolo-[1 ,5-a]purin-9-one 63 -H ~ -Ethyl - \~ 331-332 6-Benzyl-4-ethyl-2-(3-pyridyl)-1,2,4-ll Nc [1,5-a]purin-9-one 64 -H ~ -n-Propyl - ~ 385-387 2,6-Di-(2-furyl)-4-n-propyl-1,2,4-triazolo-[1 ,5-a]purin-9-one -H -N(CH3)2 -n-Propyl - \~ 272-274 6-Benzyl-2-dimethylamino-4-n-propyl-1,2,4-lli ~'~ [1,5-a]purin-9-one D
o Example -R1 or Melting No. -R3 R2 -R4 -R5 R6 pointin Chemical Name ~ ~C
66 -H ~ -Ethyl - \~) 260-262 6-Benzyl-2-cyclohexyl ~ cthyl-1,2,4-O t~ [1,5-a]purin-9-one 67 -H - N~ -n-Propyl - \~ 294-297 6-Benzyl-2-(N-piperidinyl)4-n-propyl-1,2,4-t~ 1,5-a]purin-9-one 68 -H ~ -Ethyl - \~3 243-244 6-Benzyl-2-tert.-butyl4-ethyl-1,2,4-triazolo-[1 ,5-alpurin-9-one 69 -H ~ -Ethyl - \~3 343-345 6-Benzyl4-ethyl-2-phenyl-1,2,4-tri~olo-11 ,5-alpurin-9-one -H ~ -Ethyl - \~ 261-263 2-Cyclopent~rl q cthyl4-(3-pyridylmethyl)-1,2,4-l~ [1,5-a]purin-9-one 71 -H -Ethyl -Ethyl - \~) 225-227 2,4-Diethyl-6-(3-pyridylmethyl)-1,2,4-N

lli :'- [1,5-alpurin-9-one 72 -Ethyl ~ -Ethyl - \~ 187-189 6-Benzyl-1 ,4-diethyl-2-(2-furyl)-1,2,4-l,' :'~ [1,5-alpurin-9-one 73 -H -H -Ethyl - \~ 328-330 4-Ethyl-6-(3-pyridylmethyl)-1,2,4-triazolo-[1 ,5-alpurin-9-one 74 -H -H -Ethyl - \ 0 328-330 6-Cyclohexylmethyl4-ethyl-1,2,4-triazolo-[1 ,5-a]purin-9~ne -H -Ethyl -Ethyl - \ 0 230-232 6-Cyclohexy'~"ell,yl-2,4~iethyl-1,2,4-[1 ,5-a]purin-9-one ~ c g 5 f~ O ~ e ~ g ~ 5 E C ~ a~ $ ~ o ~ ~~ a) E ~, o ~, ~ 3~ ~

Q _ C C o Q~ N ~ ., C ~ ~ ~ 3 _ ~ ~

N llJ Q ~ U~ ~ 0 ~ C ~ ~ C N o Q
C) ~ 1- ~ N --- ~D 2 C~ l E ~ Q 1~ ~ E
c ~ ~) ~ o a~

5 ~ ~ c~ o~ a) o c~

I
$ ~ ~
~o ~o o J

U~

a~: S S S S o o s s s .

I s ~ s ~ O

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Il~

,, .. , , , . . , . . .,, . _ c c , ~,a E c, ~P

E ~ c c ~ C C,~ C ~ ~ C s u~

E a) ~ o ~ c u~ o ~ q c ~ c q S 9~ q ~, c S
Z ~ ~ C ~ ~ ac~ 2' ~ q ~ ~ ~ ~ ~ ~Q ~
~ c ' ~ ~ ~ ~' a) ~ ~Q 8 ~ 8 ~ c ~Q 8 c ~-~ N~ N~ o ~ ~~ S, N ~ ~ S
~ a~ Q m ~ , m g~ O~
~ n~ ~ n ~ ~ ~ c a~ n ~' ~ In c~ o o ._ O , a) ~ ~ O

o ~ [~ ~ IL 1 O O
J

Lt') a~ ' ' ' ~ ~ S S S

o ~

a o U~ cc~ 1~ oo 0 o ~ ~
~ z ~ a~ 0 0 0 Il~

.. ~, . . . . . .. . . .

c ~ ~ s ~ E ~ I ~ o ~
U~ C o ~ o ~ _ o -- C
~ ~ O o N Q c Q S O S ~
s O s ~ t ~ , ~ s, lo 9' ~ E ~

a~ -- I S ~ O ~ ~ ~ aS~ NO ~ NO ~ ~~ a~ U~
q ~ q '_ ~ S q S ~ ~ ~ ~ C N C~l C ~ ~D N
c ~ c 7 c o ~ ~ L) ~ ~ 7 ~ ~ ~ N
~) ~) C O~D C O ~ ~ N ~ C~l C ~ ~C ~) C t~ ~1 ao ~
C ~--._ ~C ~ l ~ O
~D ~-- ~ ~ 0~ ~.) O ~ 00 c ~ '~ ~ N C~

~Y g ~ O 0 0~ 0~ 0 0 o o ~ ~
r~

~ s s s s s s s s 0 [~

Q ~ un ~ ~ oo cn ~
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llJ

CA 02256736 1998~12~02 .. . .. .

u~

c ~ e E ~ S
Z ~ c a~ ~ C ~ ~ ~ ~ ~ ~ ~ a y C a~ O

s ~1~ E ~ ~ E c ~ s ~ ~ s ~ ' N ~ c ~ ~ ~ C

o o u~

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u~

s s s s s s ~ s '~ l l l l l l l l C! I ~ I I I ~ I I

a) ~ ~ O O O O O O O o . . .. . . .

c ~ E ~~ ~ W

_ Q ~ c ~ a) o c ~ Q ~
:~ ~ c , O ~ C ~ n a~ q N

~ ~ E C~l Q E; ~~ Q C ~- ~ --O ~~
E ~ ~O ~ a~ 0~ ~ ~L ~ E ~ o .;. o N

g , ~,1 ~ ~C-- ~ ON tl;~ ~ N NO
~, ~ N ~ Q N _. N ~- N C N ~- N C N E
u~ ~, m ~ m ~ m C m ~ m C m C m E a) C~ ~ E ~ Q' ~ O

c ~ ~ U~
_ O O r-- U) U~ ~n ~'~J ~~ O G I ~ z ~J
$ ' r u) s s s s s s s s ~ ~

53 ~3 5 3 5 3 5 3 5~ 3 ~

C O a~ O
Z

The structures of the examples of compounds (Ia) to (Id) synthesised hereinbefore were confirmed by NMR-spectroscopy.

NMR-spectroscopic data of selected compounds:

Example (3) H-NMR (DMSO-d6): ~ = 14.10 (lH, s, broad, NH); 8.24 (lH, s, H2); 7.35-7.14 (5H, m, Aryl-H); 4.12 (2H, t, J =
7.5 Hz; N-CH2CH2CH3)i 4.09 (2H, s, -CH2-Phenyl); 1-73 (2H~
m, N-CH2CH2CH3); 0.89 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

- Example (4) lH-NMR (DMSO-d6): ~ = 13.28 (lH, s, broad, NH); 8.24 (lH, s, H2); 7.35-7.14 (5H, m, Aryl-H); 4.15 (2H, t, J =
7.5 Hz, N-CH2CH2CH2CH3); 1.68 (2H, m, N-CH2CH2CH2CH3);
1.32 (2H, m, N-CH2CH2CH2CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2cH2cH2cH3 ) -Example (5) H-NMR (DMSO-d6): ~ = 13.22 (lH, s, broad, NH); 8.25 (lH, s, H2); 7.35-7.14 (5H, m, Aryl-H);5.33 (lH, m, CH-Isopropyl); 4.09 (2H, s, -CH2-Phenyl);
1.55 (6H, d, J = 7.0 Hz, (CH3)2-Isopropyl).

Example (6) H-NMR (DMSO-d6): ~ = 13.66 (lH, s, broad, NH); 7.34-7.14 (5H, m, Aryl-H);
4.11 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 4.07 (2H, s, -CH2-Phenyl);
2.79 (2H, qu, J = 7.5 Hz, -CH2CH3); 1.71 (2H, m, N-CH2cH2cH3)i 1.29 (3H, t, J = 7.5 Hz, -CH2-CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (7) CA 022~6736 1998-12-02 H-NMR (DMSO-d6): ~ = 13.70 (lH, s, broad, NH); 7.43-7.14 (5H, m, Aryl-H);
4.09 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 4.07 (2H, s, -CH2-Phenyl);
2.75 (2H, t, J = 7.5 Hz, -CH2CH2CH3); 1.74 (4H, m, N-CH2CH2CH3i -CH2CH2CH3)i 0.92 (6H, m, N-CH2CH2CH3; -CH2cH2cH3)-Example (8) 1H-NMR (DMSO-d6): ~ = 7.34-7.12 (5H, m, Aryl-H); 4.07 (2H, s, CH2-Phenyl);
- 3.55 (3H, s, N-CH3); 3.23 (lH, m, CH-Cyclopentyl); 2.14-1.52 (8H, m, CH2-Cyclopentyl).

Example (9) 1H-NMR (DMSO-d6): ~ = 13.68 (lH, s, broad, NH); 7.40-7.14 (5H, m, Aryl-H);
4.19 (2H, qu, J = 7.5 Hz, N-CH2CH3); 4.09 (2H, s, CH2-Aryl); 3.24 (lH, m, CH-Cyclopentyl); 2.26-1.50 (8H, m, CH2-Cyclopentyl); 1.26 (3H, t, J = 7.5 Hz, N-CH2CH3).

Example (10) H-NMR (DMSO-d6): ~ = 13.65 (lH, s, broad, NH); 7.38-7.14 (5H, m, Aryl-H);
4.11 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 4.08 (2H, s, Phenyl-CH2-); 3.23 (lH, m, CH-Cyclopentyl); 2.14-1.49 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3); 0.89 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (11) H-NMR (DMSO-d6): ~ = 13.85 (lH, s, broad, NH); 7.62-7.33 (5H, m, Aryl-H);
4.34 (2H, t, J = 7.5 Hz, N-CH2); 4.28 (2H, s, CH2-Phenyl);
3.43 (lH, m, CH-Cyclopentyl); 2.33-1.38 (12H, m, CH2-Cyclopentyl; N-CH2-_2CH2-CH3);
1.10 (3H, t, J = 7.5 Hz, N-(CH2)3-CH3).

Example (12) CA 022~6736 1998-12-02 .. , . , . .. . .. . ., . . ~

H-NMR (DMSO-d6): ~ = 12.58 (lH, s, broad, NH); 7.52-7.14 (10 H, m, Aryl-H);
5.52 (2H, s, N-CH2-Aryl); 4.18 (2H, s, -CH2-Aryl); 3.31 (lH, m, CH-Cyclopentyl);
2.21-1.50 ~8H, m, CH2-Cyclopentyl).

Example (13) lH-NMR (DMSO-d6): ~ = 12.38 (lH, s, broad, NH); 7.34-7.14 (5H, m, Aryl-H);
4.08 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 4.6 (2H, s, -CH2-Phenyl); 3.69; 3.59 (8H, m, morpholin-H); 1.70 (2H, m, N-CH2CH2CH3); 0.88 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (14) lH-NMR (DMSO-d6): ~ = 12.26 (lH, s, broad, NH); 7.38-7.14 (10 H, m, Aryl-H);
4.08 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 4.06 (2H, s, CH2-Phenyl); 3.57; 2.46 (8H, m, -CH2-Piperaz.); 3.52 (2H, s, N-CH2-Phenyl); 1.70 (2H, m, N-CH2CH2CH3);
0.88 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (15) H-NMR (DMSO-d6): ~ = 7.40-7.14 (5H, m, Aryl-H); 4.76 (3H, s, broad, NH, NH2);
4.08 (2H, t, J = 7.5 Hz; N-CH2CH2-CH3); 4.06 (2H, s, -CH2-Phenyl); 3.48; 2.79 (8H, 2m, CH2-Piper.); 1.90 (3H, s, CH3COOH); 1.70 (2H, m, N-CH2CH2-CH3) ; 0.88 (3H, t, J = 7.5 Hz, N-CH2CH2-CH3).

Example (16) lH-NMR (DMSO-d6): ~ = 13.82 (lH, s, broad, NH); 7.34-7.14 (5H, m, Aryl-H);
4.19 (2H, qu, J = 7.0 Hz, N-CH2CH3); 4.08 (2H, s, -CH2-Phenyl); 3.93; 3.43 (4H, 2m, 2 CH2-0); 3.09 (lH, m, -CH-THP); 2.00-1.68 (4H, m, 2-CH2-THP); 1.25 (3H, t, J = 7.0 Hz, N-CH2CH3).

Example (17) CA 022~6736 1998-12-02 . _ , . .. .... ..

lH-NMR (DMSO-d6): ~ = 13.84 (lH, s, broad, NH); 7.34-7.14 (5H, m, Aryl-H);
4.18 (2H, qu, J = 7.0 Hz, N-CH2CH3); 4.08 (2H, s, -CH2-Phenyl); 4.08-3.74 (4H, m, 2 CH2-0-3THF); 3.62 (lH, m, CH-3 THF); 2.29 (2H, m, CH2- 3 THF); 1.25 (3H, t, J = 7.0 Hz, N CH2CH3).

Example (18) lH-NMR (DMSO-d6): ~ = 13.64; 12.76 (2H, 2s, broad, 2NH); 7.35-7.14 (5H, m, Aryl-H); 4.02 (2H, s, -CH2-Phenyl); 3.23 (lH, m, CH-Cyclopentyl); 2.14-1.50 (8H, m, CH2-Cyclopentyl).

Example (19) lH-NMR (DMSO-d6): ~ = 13.42; 13.20 (2H, 2s, broad, 2 NH); 8.24 (lH, s, H2);
3.20 (lH, m, CH-Cyclopentyl); 2.17-1.50 (lH, m, CH2-Cyclopentyl).

Example (20) H-NMR (DMSO-d6): ~ = 13.86 (lH, s, broad, NH); 8.22 (lH, s, H2); 3.58 (3H, s, N-CH3); 3.23 (lH, m, CH-Cyclopentyl); 2.14-1.52 (8H, m, CH2-cylcopentyl).

Example (21) H-NMR (DMSO-d6): ~ = 14.04 (lH, s, broad, NH); 8.24 (lH, s, H2); 4.13 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.21 (lH, m, CH-Cyclopentyl); 2.14-1.52 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2cH2cH3)-Example (22) H-NMR (DMSO-d6): ~ = 13.68 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz, N-CH2-CH2CH3)j3.20 (lH, m, CH-Cyclopropyl); 2.45 ~3H, s, -CH3); 2.12-1.52 (10 H, m, CH2-Cyclopentyl); 0.89 (3H, t, J = 7.5 Hz, N-CH2-CH2CH3).

Example (23) CA 022~6736 1998-12-02 H-NMR (DMSO-d6): ~ = 13.64 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz, N-CH2-CH2CH3)j3.20 (lH, m, CH-Cyclopentyl); 2.80 (2H, qu, J = 7.5 Hz, -CH2-CH3);
2.13-1.52 (10 H, m, CH2-Cyclopentyl; N-CH2-CH2CH3); 1.29 (3H, t, J = 7.5 Hz, -CH2-CH3)i 0.90 (3H, t, J = 7.5 Hz, -N-cH2-cH2cH3)-Example (24) lH-NMR (DMSO-d6): ~ = 13.88 (lH, s, broad, NH); 7.35-7.14 (5H, m, Aryl-H);
4.13 (2H, s, -CH2-Phenyl); 4.11 (2H, t, J = 7.5 Hz, N-- CH2CH2CH3); 3.19 (lH, m, CH-Cyclopentyl); 2.09-1.52 (l=H, m, cH2-cyclopentyl; N-CH2CH2CH3);
0.89 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (25) lH-NMR (DMSO-d6): ~ = 13.60 (lH, s, broad, NH); 7.43-7.14 (5H, m, Aryl-H);
4.36 (2H, t, J = 7.5 Hz, N-CH2(CH2)3-CH3); 4.19 (2H, s, -CH2-Phenyl); 3.40 (lH, m, CH-Cyclopentyl); 2.31-1.24 (14H, m, CH2-Cyclopentyl; N-CH2(CH2)3-CH3);
0.89 (3H, m, N-(CH2)4-CH3).

Example (26) lH-NMR (DMSO-d6): ~ = 13.85 (lH, s, broad, NH); 8.16 (lH, s, H6); 7.35-7.14 (5H, m, Aryl-H); 4.15 (2H, s, -CH2-Phenyl); 3.59 (3H, s, N-CH3).

Example (27) lH-NMR (DMSO-d6): ~ = 14.02 (lH, s, broad, NH); 8.19 (lH, s, H6); 7.35-7.14 (5H, m, Aryl-H); 4.18 (2H, s, -CH2-Phenyl); 4.15 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 1.75 (2H, m, N-CH2CH2CH3); 0.93 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (28) lH-NMR (DMS0-d6): ~ = 13.50, 12.92 (2H, 2s, broad, 2NH); 8.10 (lH, s, H6);

CA 022~6736 1998-12-02 3.24 (lH, m, CH-Cyclopentyl); 2.17-1.52 (8H, m, CH2-Cyclopentyl).

Example (29) lH-NMR (DMSO-d6): ~ = 13.70 (lH, s, broad, NH); 8.18 (lH, s, H6); 3.59 (3H, s, C-CH3); 3.25 (lH, m, CH-Cyclopentyl); 2.15-1.52 (8H, m, CH2-Cyclopentyl).

Example (30) lH-NMR (DMSO-d6): ~ = 13.70 (lH, s, broad, NH); 8.20 (lH, s, H6); 4.25 (2H, qu, J = 7.0 Hz, N-CH2-CH3); 3.27 - (lH, m, CH-Cyclopentyl); 2.21-1.52 (8H, m, CH2-Cyclopentyl); 1.29 (3H, t, J = 7.0 Hz, N-CH2-CH3).

Example (31) H-NMR (DMSO-d6): ~ = 13.74 (lH, s, broad, NH); 8.18 (lH, s, H6); 4.14 (2H, t, J = 7.5 Hz, N-CH2-CH2CH3); 3.25 (lH, m, CH-Cyclopentyl); 2.15-1.54 (10 H, m, CH2-Cyclopentyl; N-CH2-CH2CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2-CH2CH3).

Example (33) H-NMR (DMSO-d6): ~ = 13.62 (lH, s, broad, NH); 4.11 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.23 (lH, m, CH-Cyclopentyl); 2.37 (3H, s, -CH3); 2.14-1.50 (10 H, m, CH2-Cyclopentyl, N-CH2CH2CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2cH2cH3)-Example (34) lH-NMR (DMSO-d6): ~ = 8.22 (lH, s, Hz); 4.13 (2H, t, J
= 7.5 Hz, N-CH2CH2CH3)i 2.75 (2H, qu, J = 7.5 Hz, -CH2CH3); 1.74 (2H, m, N-CH2CH2CH3); 1.29 (3H, t, J = 7.5 Hz, CH2-CH3); 0.92 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (35) CA 022~6736 1998-12-02 H-NMR (DMSO-d6): ~ = 13.62 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.25 (lH, m, CH-Cyclopentyl); 2.74 (2H, qu, J = 7.5 Hz, -CH2CH3);
2.17-1.51 (10 H, m, CH2-Cyclopentyli N-CH2CH2CH3); 1.29 (3H, t, J = 7.5 Hz, -CH2CH3); 0.90 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (36) lH-NMR (DMSO-d6): ~ = 13.58 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.24 (lH, m, CH-Cyclopentyl)j2.69 (2H, t, J = 7.5 Hz, -CH2CH2CH3);
2.15-1.50 (12H, m, CH2-Cyclopentyl; (CH2CH2CH3)2); 0.95;
~- o.90 (6H, 2t, J = 7.5 Hz, (CH2CH2CH3)2)-Example (37) H-NMR (DMSO-d6): ~ = 13.62 (lH, s, broad, NH); 4.13 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.24 (lH, m, CH-Cyclopentyl); 3.05 (lH, m, CH-Isoprop.);
2.14-1.50 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3); 1.32 (6H, d, J = 7.5 Hz, CH3-Isoprop.); 0.90 (3H, t, J = 7.5 Hz, CH2CH2CH3).

Example (38) H-NMR (DMSO-d6): ~ = 13.62 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.24 (lH, m, Cyclopentyl-H); 2.70 (2H, t, J = 7.5 Hz, CH2-CH2CH2CH3);
2.15-1.26 (14H, m, CH2-Cyclopentyl; N-CH2CH2-CH3, CH2-CH2CH2CH3); 0.90 (6H, m, N-CH2CH2CH3); (-CH2)3-CH3).

Example (39) lH-NMR (CDC13): ~ = 4.36 (2H, t, J = 7.5 Hz, N-CH2CH2CH3);
3.40 (lH, m, CH -Cyclopentyl); 2.32-1.63 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3); 1.46 (9H, s, C(CH3)3; 1.02 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).
Example (40) H-NMR (DMSO-d6): ~ = 14.28 (lH, s, broad, NH); 8.26-7.45 (5H, m, Aryl-H);

CA 022~6736 1998-12-02 4.14 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 2.71 (2H, t, J =
7.5 Hz, -CH2CH2CH3);
1.76 (4H, m, (-CH2CH2CH3)2); 0.98; 0.93 (6H, 2t, (-CH2CH2CH3)2)-Example (41) H-NMR (DMSO-d6): ~ = 7.44-7.05 (4H, m, Aryl-H); 4.13 (2H, s, CH2-Phenyl);
4.11 (2H, t, J = 7.5 Hz, N-CH2CH2-CH3); 2.68 (2H, t, J =
7.5 Hz, -CH2CH2-CH3)i 1.74 (4H, m, (-CH2CH2-CH3)2); 0.95; 0.89 (6H, 2t, J = 7.5 Hz, (cH2cH2-cH3)2)-Example (42) lH-NMR (DMSO-d6): ~ = 13.64 (lH, s, broad, NH); 4.12 (2H, t, J = 7.5 Hz; N-CH2CH2CH3); 2.76 (4H, m, (CH2CH3)2);

1.73 (2H, m, N-CH2CH2CH3));
2.29 (6H, m, (CH2-CH3)2); 0.90 (3H, t, J = 7.5 Hz, N-CH2cH2cH3)-Example (43) H-NMR (DMS0-d6): ~ = 14.19 (lH, s, broad, NH); 8.31 (lH, s, H2);
8.16-7.38 (5H, m, Aryl-H); 4.21 (2H, t, J = 7.5 Hz, N-CH2CH2CH3)i 1.83 (2H, m, N-CH2CH2CH3); 0.98 (3H, t, J = 7.5 Hz, N-CH2cH2cH3)-Example (44) lH-NMR (DMS0-d6): ~ = 13.78 (lH, s, broad, NH); 8.19-7.43 (5H, m, Aryl-H);
4.21 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 2.83 (2H, qu, J =
7.5 Hz, -CH2CH3)i 1.81 (2H, m, N-CH2CH2CH3); 1.33 (3H, t, j = 7.5 Hz, -CH2CH3)i 0.95 (3H, t, J = 7.5 Hz, -N-CH2CH2CH3).

Example (45) CA 022~6736 1998-12-02 H-NMR (DMSO-d6): ~ = 13.70 (lH, s, broad, NH); 8.19-7.38 (5H, m, Aryl-H);
4.21 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.28 (lH, m, CH-Cyclopentyl);
2.19-1.50 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3); 0.94 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (46) lH-NMR (DMSO-d6): ~ = 8.26 (lH, s, Hz); 7.84; 7.10;
6.69 (3H, 3m, Furyl-H);
4.10 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 1.81 (2H, m, N-CH2CH2CH3) i 0.98 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (47) lH-NMR (DMSO-d6): ~ = 13.56 (lH, s, broad, NH); 7.70;
6.91; 6.50 (3H, 3m, Furyl-H); 4.00 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 2.66 (2H, qu, J = 7.5 Hz, -CH2CH3);
1.61 (2H, m, N-CH2-CH2-CH3); 1.14 (3H, t, J = 7.5 Hz, N-CH2cH2cH3)i 0.77 (3H, t, J = 7.5 Hz, -CH2CH3).

Example (48) lH-NMR (DMSO-d6): ~ = 13.84 (lH, s, broad, NH); 8.00;
. ~
7.18; 6.78 (3H, 3m, Furan-H); 4.26 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.37 (lH, m, CH-Cyclopentyl);
2.28-1.62 (10 H, m, CH2-Cyclopentyl; N-CH2CH2CH3);
1.04 (3H, t, J = 7.5 Hz; N-CH2CH2CH3).

Example (49) H-NMR (DMSO-d6): ~ = 12.84 (lH, s, broad, NH); 8.26 (lH, s, H2);
4.32 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.18 (lH, m, CH-Cyclopentyl);
2.09-1.52 (10 H,m, CH2-Cyclopentyli N-CH2CH2CH3);
0.83 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

CA 022~6736 1998-12-02 Example (50) lH-NMR (DMSO-d6): ~ = 8.28 (lH, s, H6); 8.15 (lH, s, H2);

13.35 (2H, s, broad).

Example (51) H-NMR (DMSO-d6): ~ = 13.74 (lH, s, broad, NH); 8.34 (lH, s, H6);
4.63 (2H, qu, J = 7.5 Hz, N-CH2CH3); 3.33 (lH, m, CH-Cyclopentyl);
2.24-1.57 (8H, m, CH2-Cyclopentyl); 1.47 (3H, t, J = 7.5 Hz, N-cH2cH3)-Example (52) lH-NMR (DMSO-d6): ~ = 13.72 (lH, s, broad, NH); 8.34 (lH, s, H6);
4.53 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.34 (lH, m, CH-Cyclopentyl);
2.20-1.57 (8H, m, CH2-Cyclopentyl); 1.87 (2H, m, N-CH2CH2CH3)i 1.06 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

Example (53) lH-NMR (DMSO-d6): ~ = 8.19 (lH, s, H6); 4.00 (3H, s, N-CH3)i 3.58 (3H, s, N-CH3); 3.42 (lH, m, CH-Cyclopentyl); 2.18-1.57 (8H, m, CH2-Cyclopentyl).

Example (55) H-NMR (DMS0-d6): ~ = 14.12 (lH, s, broad, NH); 8.44 (lH, s, Hz);
4.53 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.28 (lH, m, CH-Cyclopentyl);
2.17-1.55 (8H, m, CH2-Cyclopentyl)i 1.87 (2H, m, N-CH2CH2CH3)i 1.05 (3H, t, J = 7.5 Hz, N-CH2CH2CH3).

CA 022~6736 1998-12-02 Example (56) lH-NMR (DMSO-d6): ~ = 8.28 (lH, s, H2); 4.36 (2H, t, J
= 7.5 Hz, N-CH2CH2CH3)i 4.12 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.21 (lH, m, CH-Cyclopentyl).
2.12-1.57 (12H, m, CH2-Cyclopentyl; (N-CH2CH2CH3)2);
0.92; 0.87 (6H, 2t, J = 7.5 Hz, (N-CH2CH2CH3)2).

Example (57) lH-NMR (DMSO-d6): ~ = 8.02 (lH, s, H2); 4.45 (2H, t, J
= 7.5 Hz, N-CH2CH2CH3)i 4.14 (2H, t, J = 7.5 Hz, N-CH2CH2CH3); 3.24 (lH, m, CH-Cyclopentyl);
2.14-1.57 (12H, m, CH2-Cyclopentyl; (N-CH2CH2CH3)2;
0.93; 0.89 (6H, 2t, J = 7.5 Hz, (N-CH2CH2CH3)2;

CA 022~6736 1998-12-02 ... ~ .. . .. . . .... .

The following Table contains KiA1 (human) and KiA2 (rat) receptor binding values.

Table 20:
Example KjA1 KjA2 No.: [rM] [nV]
7 ,1 '5 ~ g v~
c ,4 '0 ',7 ,vO
3~5 '3 5" 2 ''5 1(,3 1''31 ~,0 8,~ 3292 36 5,8 731 37 6,~ .~07 38 6,~ ~2 39 6,(~ ~9 48 11,4 4455 The following Table contains KiA1 (human) receptor binding values.

Table 21:
Example KjA3 No. [r M]
v ~,7 ",3 ~2 20 ~9 3,8 ~3 2 ''5 26 v8 22 ~8 30 ;8 5,3 The compounds of general formula (I) may be used on their own or combined with other active substances according to the invention, possibly also together with other pharmacologically active substances. Suitable preparations include, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Corresponding tablets may be obtained, for example, by mixing the active substance or substances with known excipients such as inert diluents, e.g. calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate ' or talc, and/or agents for achieving delayed release such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also be made up of several layers.

Coated tablets may be prepared analogously by coating cores produced in the same way as the tablets with agents conventionally used in tablet coatings, e.g. collidone or shellack, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities, the core may also be made up of several layers. Similarly, the tablet coating may be made up of several layers to - 25 achieve delayed release, in which case the excipients used for the tablets may be used.

Syrups of the active substances according to the invention or combinations of active substances may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavouring improving agent, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g.
condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

CA 022~6736 1998-12-02 Injectable solutions are produced in the usual way, e.g.
by adding preservatives such as p-hydroxybenzoates or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid and are transferred into injection vials or ampoules.

The capsules containing one or more active substances or combinations of active substances may be produced by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

! Suitable suppositories may be prepared, for example, by mixing with carriers intended for this purpose such as neutral fats or polyethyleneglycol or derivatives thereof.

A therapeutically active daily dose is between 1 and 800 mg, preferably 10 to 300 mg per adult.

The Examples which follow illustrate the invention without restricting its scope:

Examples of pharmaceutical formulations 25 A) Tablets per Tablet Active substance 100 mg Lactose 140 mg Corn starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate 5 mq 500 mg The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, and then moistened with a solution of polyvinylpyrrolidone in water, kneaded, moist-granulated and dried. The granules, the remaining corn starch and CA 022~6736 1998-12-02 the magnesium stearate are screened and mixed together.
The mixture is compressed into tablets of suitable shape and size.

5 B) Tablets per Tablet Active substance 80 mg Corn starch 190 mg Lactose 55 mg Microcrystalline cellulose35 mg Polyvinylpyrrolidone 15 mg ~~ Sodium carboxymethyl starch 23 mg Magnesium stearate 2 mq 400 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and processed with the remaining corn starch and water to form a granulated material which is dried and screened. The sodium carboxymethyl starch and the magnesium stearate are added to this, then mixed together and the mixture is compressed to form tablets of suitable slze .
C) Coated tabletsper coated tablet Active substance 5 mg Corn starch 41.5 mg Lactose 30 mg Polyvinylpyrrolidone3 mg Magnesium stearate0.5 mq 80 mg The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is pressed through a 1 mm mesh screen, dried at about 45~C and the granules are then CA 022~6736 1998-12-02 passed through the same screen again. After the addition of magnesium stearate, curved tablet cores measuring 6 mm in diameter are pressed out in a tablet making machine.
The tablet cores thus produced are coated in known manner with a covering consisting essentially of sugar and talc.
The finished coated tablets are polished with wax.

D) Ca~sules per caPsule Active substance 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mg 320 mg The substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The finished mixture is packed into size 1 hard gelatine capsules.

CA 022~6736 1998-12-02 E) Ampoule solution Active substance 50 mg Sodium chloride 50 mg Water for injections 5 ml The active substance is dissolved at its own pH or optionally at pH 5.5 to 6.5 in water and sodium chloride is added to render the solution isotonic. The resulting solution is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules ~~ which are subsequently sterilised and sealed by fusion.
The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

F) Suppositories Active substance 50 mg Solid fat 1650 mq 1700 mg The hard fat is melted. At 40~C the ground active substance is homogeneously dispersed therein. It is cooled to 38~C and poured into slightly chilled suppository moulds.

G) Oral Sus~ension Active substance 50 mg Hydroxyethylcellulose 50 mg Sorbic acid 5 mg (70~) Sorbitol 600 mg Glycerol 200 mg Flavouring 15 mg 3 5 Water ad 5 ml Distilled water is heated to 70~C. Hydroxyethylcellulose is dissolved therein with stirring. After the addition of CA 022~6736 1998-12-02 sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient temperature the sorbic acid, flavouring and substance are added. To eliminate air from the suspension it is evacuated with stirring.

;'':

CA 022~6736 1998-12-02

Claims (18)

Claims

1. Triazolopurines of general formula (I) wherein R1 or R3 denotes hydrogen, an optionally substituted C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl, an optionally substituted C3-8-cycloalkyl, an optionally substituted C4-8-cycloalkenyl or an optionally substituted C6-8-cycloalkynyl;
R1 or R3 denotes an optionally substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl, an optionally substituted C6-10-aryl or an optionally substituted heteroaryl, an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms from the group comprising nitrogen, oxygen or sulphur, the heterocycle being linked via a carbon atom of the ring;
R1 or R3 denotes an optionally substituted C1-10-alkyloxycarbonyl, an optionally substituted C2-10-alkenyloxycarbonyl, an optionally substituted C2-10-alkynyloxycarbonyl, an optionally substituted C3-8-cycloalkyloxy-carbonyl, an optionally substituted C6-10-aryloxycarbonyl, an optionally substituted C6-10-aryl-C1-6-alkyloxycarbonyl, A-O-CO- wherein A
denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein A is linked via a carbon atom of the ring, R1 or R3 is an optionally substituted C1-10-alkyl-sulphonyl, C2-10-alkenylsulphonyl, C2-10-alkynylsulphonyl, an optionally substituted C3-8-cycloalkylsulphonyl, an optionally substituted C6-10-arylsulphonyl, an optionally substituted C6-10-aryl-C1-6-alkylsulphonyl, a group A-SO2- wherein A is as hereinbefore defined and is linked via a carbon atom of the ring;
R1 or R3 denotes an optionally substituted C1-10-alkylcarbonyl, an optionally substituted C2-10-alkenylcarbonyl, an optionally substituted C2-10-alkynylcarbonyl, an optionally substituted C3-8-cycloalkylcarbonyl, an optionally substituted C6-10-arylcarbonyl, an optionally substituted C6-10-aryl-C1-6-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined;

R1 or R3 denotes a group of general formula wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched C1-10-alkyl, preferably C1-4-alkyl, C2-10-alkenyl or C2-10-alkynyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino;

R2 denotes hydrogen, hydroxy, amino, halogen, nitro, CF3, COOH, mercapto, C1-6-alkylmercapto, an optionally substituted C1-10-alkyl, an optionally substituted C2-10-alkenyl, an optionally substituted C2-10-alkynyl, an optionally substituted C3-8-cycloalkyl, an optionally substituted C5-8-cycloalkanone, an optionally substituted C4-8-cycloalkenyl, an optionally substituted C6-8-cycloalkynyl, an optionally substituted C6-10-aryl, an optionally substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl, or C3-8-cycloalkyl-C2-6-alkynyl;
R2 denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatom one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein the nitrogen may optionally be substituted and the heterocyclic group may be linked via a carbon or nitrogen atom directly or via a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl bridge;

R2 denotes an optionally substituted C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl or C2-10-alkynylsulphonyl, an optionally substituted C3-8-cycloalkylsulphonyl, an optionally substituted C6-10-arylsulphonyl, an optionally substituted heteroarylsulphonyl or an optionally substituted C6-10-aryl-C1-6-alkylsulphonyl;

R2 denotes an optionally substituted C1-10-alkylsulphonyloxy, C2-10-alkenylsulphonyloxy or C2-10-alkynylsulphonyloxy, an optionally substituted C3-8-cycloalkylsulphonyloxy, an optionally substituted C6-10-arylsulphonyloxy, an optionally substituted C6-10-aryl-C1-6-alkylsulphonyloxy or an optionally substituted heteroarylsulphonyloxy;

R2 denotes an optionally substituted C1-10-alkylsulphonylamino, C2-10-alkenylsulphonylamino or C2-10-alkynylsulphonylamino, an optionally substituted C3-8-cycloalkyl-sulphonylamino, an optionally substituted C6-10-arylsulphonylamino, an optionally substituted C6-10-aryl-C1-6-alkylsulphonylamino, or an optionally substituted heteroarylsulphonylamino;
R2 denotes an optionally substituted C1-10-alkylaminocarbonyl, C1-10-dialkylaminocarbonyl, C1-10-alkyl-C2-10-alkenylaminocarbonyl, C2-10-alkenylaminocarbonyl, C2-10-dialkenylaminocarbonyl, C2-10-alkynylaminocarbonyl or C1-10-alkyl-C2-10-alkynylaminocarbonyl, an optionally substituted C3-8-cycloalkyl-aminocarbonyl, an optionally substituted C6-10-arylaminocarbonyl, an optionally substituted C6-10-aryl-C1-6-alkylaminocarbonyl, or an optionally substituted heteroarylaminocarbonyl;

R2 denotes an optionally substituted C1-10-alkyloxycarbonylamino, C2-10-alkenyloxy-carbonylamino or C2-10-alkynyloxycarbonylamino, an optionally substituted C3-8-cycloalkyloxy-carbonylamino, an optionally substituted C6-10-aryloxycarbonylamino, an optionally substituted C6-10-aryl-C1-6-alkyloxycarbonylamino or an optionally substituted heteroaryloxy-carbonylamino;

R2 denotes an optionally substituted C1-10-alkylaminocarbonyloxy, C2-10-alkenylamino-carbonyloxy or C2-10-alkynylaminocarbonyloxy, an optionally substituted C3-8-cycloalkylamino-carbonyloxy, an optionally substituted C6-10-arylaminocarbonyloxy, an optionally substituted C6-10-aryl-C1-6-alkylaminocarbonyloxy or an optionally substituted heteroarylamino-carbonyloxy;

R2 denotes an optionally substituted C1-10-alkyl-N-amidino, C2-10-alkenyl-N-amidino or C2-10-alkynyl-N-amidino, an optionally substituted C3-8-cycloalkyl-N-amidino, an optionally substituted C6-10-aryl-N-amidino, an optionally substituted C6-10-aryl-C1-6-alkyl-N-amidino or an optionally substituted heteroaryl-N-amidino;

R2 denotes an optionally substituted C1-10-alkyloxy, C2-10-alkenyloxy or C2-10-alkynyloxy, an optionally substituted C3-8-cycloalkyloxy, an optionally substituted C6-10-aryloxy, an optionally substituted C6-10-aryl-C1-6-alkyloxy or an optionally substituted heteroaryloxy;

R2 denotes an optionally substituted C1-10-alkyloxycarbonyl, C2-10-alkenyloxycarbonyl or C2-10-alkynyloxycarbonyl, an optionally substituted C3-8-cycloalkyloxycarbonyl, an optionally substituted C6-10-aryloxycarbonyl, an optionally substituted C6-10-aryl-C1-6-alkyloxy-carbonyl or an optionally substituted heteroaryloxycarbonyl;

R2 denotes an optionally substituted C1-10-alkylcarbonyloxy, C2-10-alkenylcarbonyloxy or C2-10-alkynylcarbonyloxy, an optionally substituted C3-8-cycloalkylcarbonyloxy, an optionally substituted C6-10-arylcarbonyloxy, an optionally substituted C6-10-aryl-C1-6-alkyl-carbonyloxy or an optionally substituted heteroarylcarbonyloxy;

R2 denotes an optionally substituted C1-10-alkylthio, C2-10-alkenylthio or C2-10-alkynylthio, an optionally substituted C3-8-cycloalkylthio, an optionally substituted C6-10-arylthio, an optionally substituted C6-10-aryl-C1-6-alkylthio or an optionally substituted heteroarylthio;

R2 denotes an optionally substituted amine, preferably NR8R9;

R2 denotes an optionally substituted group of the formula R2 denotes an optionally substituted group of the formula wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably up to 4 carbon atoms in the chain;
R2 denotes an optionally substituted group of the formula wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably up to 4 carbon atoms in the chain;
R4 or R5 denotes a hydrogen atom, an optionally substituted C1-10-alkyl, C2-10-alkenyl or C2-10-alkynyl, an optionally substituted C3-8-cycloalkyl, an optionally substituted C4-8-cycloalkenyl or an optionally substituted C6-8-cycloalkynyl, an optionally substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl, an optionally substituted C6-10-aryl or an optionally substituted heteroaryl;
R4 or R5 denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one of more atoms selected from the group comprising nitrogen, oxygen or sulphur, the heterocyclic group being bound via a carbon atom of the ring;

R4 or R5 denotes an optionally substituted C1-10-alkyloxycarbonyl, an optionally substituted C2-10-alkenyloxycarbonyl, an optionally substituted C2-10-alkynyloxycarbonyl, an optionally substituted C3-8-cycloalkyloxycarbonyl, an optionally substituted C6-10-aryl-C16-alkyloxycarbonyl, an optionally substituted C6-10-aryloxycarbonyl;
R4 or R5 denotes A-O-CO- wherein A denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur;
R4 or R5 denotes an optionally substituted C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl, C2-10-alkynylsulphonyl, an optionally substituted C3-8-cycloalkylsulphonyl, an optionally substituted C6-10-arylsulphonyl, a group A-SO2- wherein A is as hereinbefore defined and is linked via a carbon atom of the ring;
R4 or R5 denotes an optionally substituted C1-10-alkylcarbonyl, an optionally substituted C2-10-alkenylcarbonyl, an optionally substituted C2-10-alkynylcarbonyl, an optionally substituted C3-8-cycloalkylcarbonyl, an optionally substituted C6-10-arylcarbonyl, an optionally substituted C6-10-aryl-C1-6-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined;
R4 or R5 denotes a group of general formula wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched C1-10-alkyl, preferably C1-4-alkyl, C2-10-alkenyl or C2-10-alkynyl group, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino;

R6 denotes hydrogen, hydroxy, -CHO, amino, halogen, nitro, CF3, COOH, mercapto, C1-6-alkylmercapto, an optionally substituted C1-10-alkyl, an optionally substituted C2-10-alkenyl, an optionally substituted C2-10-alkynyl, an optionally substituted C3-8-cycloalkyl, an optionally substituted C5-8-cycloalkanone, an optionally substituted C4-8-cycloalkenyl, an optionally substituted C6-8-cycloalkynyl, an optionally substituted C6-10-aryl, an optionally substituted C6-10-aryl-C1-6-alkyl, C6-10-aryl-C2-6-alkenyl, C6-10-aryl-C2-6-alkynyl, an optionally substituted C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkyl-C2-6-alkenyl or C3-8-cycloalkyl-C2-6-alkynyl;

R6 denotes an optionally substituted 5-, 6- or 7-membered heterocyclic group which contains as heteroatom one or more atoms selected from the group comprising nitrogen, oxygen or sulphur, wherein the nitrogen may optionally be substituted and the heterocyclic group may be linked via a carbon atom or nitrogen atom directly or via a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl bridge;

R6 denotes an optionally substituted C1-10-alkylsulphonyl, C2-10-alkenylsulphonyl or C2-10-alkynylsulphonyl, an optionally substituted C3-8-cycloalkylsulphonyl, an optionally substituted C6-10-arylsulphonyl, an optionally substituted C6-10-aryl-C1-6-alkylsulphonyl or an optionally substituted heteroarylsulphonyl;

R6 denotes an optionally substituted C1-10-alkylsulphonyloxy, C2-10-alkenylsulphonyloxy or C2-10-alkynylsulphonyloxy, an optionally substituted C3-8-cycloalkylsulphonyloxy, an optionally substituted C6-10-arylsulphonyloxy, an optionally substituted C6-10-aryl-C1-6-alkyl-sulphonyloxy or an optionally substituted heteroarylsulphonyloxy;

R6 denotes an optionally substituted C1-10-alkylsulphonylamino, C2-10-alkenylsulphonyl-amino or C2-10-alkynylsulphonylamino, an optionally substituted C3-8-cycloalkylsulphonyl-amino, an optionally substituted C6-10-arylsulphonylamino, an optionally substituted C6-10-aryl-C1-6-alkylsulphonylamino or an optionally substituted heteroarylsulphonyl-amino;

R6 denotes an optionally substituted C1-10-alkyl-aminocarbonyl, C1-10-dialkylaminocarbonyl, C1-10-alkyl-C2-10-alkenylaminocarbonyl, C2-10-alkenylaminocarbonyl, C2-10-dialkenylamino-carbonyl, C2-10-alkynylaminocarbonyl or C1-10-alkyl-C2-10-alkynylaminocarbonyl, an optionally substituted C3-8-cycloalkylamino-carbonyl, an optionally substituted C6-10-arylaminocarbonyl, an optionally substituted C6-10-aryl-C1-6-alkylaminocarbonyl or an optionally substituted heteroarylamino-carbonyl;

R6 denotes an optionally substituted C1-10-alkylaminocarbonylamino, C2-10-alkenylaminocarbonylamino or C2-10-alkynylaminocarbonylamino, an optionally substituted C3-8-cycloalkylaminocarbonylamino, an optionally substituted C6-10-arylaminocarbonyl-amino, an optionally substituted C6-10-aryl-C1-6-alkylaminocarbonylamino or an optionally substituted heteroarylaminocarbonylamino;

R6 denotes an optionally substituted C1-10-alkyloxycarbonylamino, C2-10-alkenyloxycarbonylamino or C2-10-alkynyloxycarbonylamino, an optionally substituted C3-8-cycloalkyloxycarbonylamino, an optionally substituted C6-10-aryloxycarbonyl-amino, an optionally substituted C6-10-aryl-C1-6-alkyloxycarbonylamino or an optionally substituted heteroaryloxycarbonylamino;

R5 denotes an optionally substituted C1-10-alkylaminocarbonyloxy, C2-10-alkenylaminocarbonyloxy or C2-10-alkynylaminocarbonyloxy, an optionally substituted C3-8-cycloalkylaminocarbonyloxy, an optionally substituted C6-10-arylamino-carbonyloxy, an optionally substituted C6-10-aryl-C1-6-alkylaminocarbonyloxy or an optionally substituted heteroarylamino-carbonyloxy;

R6 denotes an optionally substituted C1-10-alkyl-N-amidino, C2-10-alkenyl-N-amidino or C2-10-alkynyl-N-amidino, an optionally substituted C3-8-cycloalkyl-N-amidino, an optionally substituted C6-10-aryl-N-amidino, an optionally substituted C6-10-aryl-C1-6-alkyl-N-amidino or an optionally substituted heteroaryl-N-amidino;

R6 denotes an optionally substituted C1-10-alkyloxy, C2-10-alkenyloxy or C2-10-alkynyloxy, an optionally substituted C3-8-cycloalkyloxy, an optionally substituted C6-10-aryloxy, an optionally substituted C6-10-aryl-C1-6-alkyloxy or an optionally substituted heteroaryloxy;

R6 denotes an optionally substituted C1-10-alkylcarbonyl, an optionally substituted C2-10-alkenylcarbonyl, an optionally substituted C2-10-alkynylcarbonyl, an optionally substituted C3-8-cycloalkylcarbonyl, an optionally substituted C6-10-arylcarbonyl, an optionally substituted C6-10 - aryl- C1-6-alkylcarbonyl;

R6 denotes a group A-CO- wherein A is as hereinbefore defined;

R6 denotes an optionally substituted C1-10-alkyloxycarbonyl, C2-10-alkenyloxycarbonyl or C2-10-alkynyloxycarbonyl, an optionally substituted C3-8-cycloalkyloxycarbonyl, an optionally substituted C6-10-aryloxycarbonyl, an optionally substituted C6-10-aryl-C1-6-alkyloxycarbonyl or an optionally substituted heteroaryloxycarbonyl;

R6 denotes an optionally substituted C1-10-alkylcarbonyloxy, C2-10-alkenylcarbonyloxy or C2-10-alkynylcarbonyloxy, an optionally substituted C3-8-cycloalkylcarbonyloxy, an optionally substituted C6-10-arylcarbonyloxy, an optionally substituted C6-10-aryl-C1-6alkyl-carbonyloxy or an optionally substituted heteroarylcarbonyloxy;

R6 denotes an optionally substituted C1-10-alkylthio, C2-10-alkenylthio or C2-10-alkynylthio, an optionally substituted C3-8-cycloalkylthio, an optionally substituted C6-10-arylthio, an optionally substituted C6-10-aryl-C1-6-alkylthio or an optionally substituted heteroarylthio;

R6 denotes an optionally substituted C1-10-alkylcarbonyloxy-C1-6-alkyl, C2-10-alkenylcarbonyloxy-C1-6-alkyl or C2-10-alkynylcarbonyloxy-C1-6-alkyl, an optionally substituted C3-8-cycloalkylcarbonyloxy-C1-6-alkyl, an optionally substituted C6-10-arylcarbonyloxy-C1-6-alkyl, C6-10-aryl-C1-6-alkylcarbonyloxy-C1-6-alkyl or heteroarylcarbonyloxy-C1-6-alkyl;

R6 denotes an optionally substituted group of the formula R10O-B-(CH2)n~

wherein n=1, 2, 3 or 4, where B denotes a C6-10-aryl or a single bond;

R6 denotes an optionally substituted amine, preferably NR8R9;

R6 denotes an optionally substituted group of the formula R6 denotes an optionally substituted group of the formula wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably 4 carbon atoms in the chain;

R6 is an optionally substituted group of the formula wherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably 4 carbon atoms in the chain;

R3 denotes hydrogen, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1-8-alkyloxy, preferably C1-4-alkyloxy, or -(CH2)m-NHCOOR10 wherein m = 1, 2, 3 or 4;

R8 denotes a 5-, 6- or 7-membered heterocyclic group which is carbon linked directly or via a C1-4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R8 denotes a bicyclic heterocyclic group which is C-linked directly or via a C1-4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, - CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H, - COOR10;

R9 denotes hydrogen, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10, preferably 1 to 4 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, C1-8-, preferably C1-4-alkoxy, or -(CH2)m-NHCOOR10 wherein m equals 1, 2, 3 or 4;

R9 denotes a 5-, 6- or 7-membered heterocyclic group which is carbon linked directly or via a C1-4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, - CN, - NO2, NH2, - OH, =O, -COOH, -SO3H or -COOR10;

R9 denotes a bicyclic heterocyclic group which is C-linked directly or via a C1-4-alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, C1-4-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 5- or 6-membered ring which may contain as further heteroatoms nitrogen, oxygen or sulphur, whilst the heterocyclic group may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, or may carry one of the following groups -(CH2)n-phenyl, -(CH2)n-NH2, =O, a ketal - preferably -(CH2)nNH-C1-4-alkyl, - (CH2)n-N(C1-8-alkyl) 2, -(CH2)n-NHCOOR10, (n = 2, 3, 4), halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, - OH, - COOH, - SO3H, - COOR10, - CONR8R9, - SO2-R10;

R10 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH3, optionally in the form of the racemates, the enantiomers and diastereomers thereof and their mixtures, as well as optionally the pharmacologically acceptable acid addition salts thereof.

2. Compounds of general formulae (Ia) to (Id) wherein R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;

R2 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which may optionally be substituted, by -CN, -CH2NR8R9, -OH
(polysubstitution 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-CH2-CH2-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, OCONR3R9, optionally mono- or poly-substituted, preferably mono-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a C1-4-alkylene bridge by one or more, of the group C1-3-alkyl, -CN, -NR8R9, -NO2, -OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH20COR10, -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, -CH2-CH2-O-CONR8R9, optionally mono- or poly-methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R2 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C1-4-alkylene bridge by one or more, of the groups -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, -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 denotes a group of the formula A-C1-6-alkyl, A-CONH-C1-6-alkyl, A-CONH-C26-alkenyl, A-CONH-C26-alkynyl, A-NH-CO-Cl6-alkyl, A-NH-CO-C26-alkenyl, A-NH-CO-C26-alkynyl, A-C26-alkenylene, A-C2-6-alkynylene or A-, wherein A is a C- or N-linked 5-, 6- or 7-membered heterocyclic group which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or poly-substituted by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, -COOH, -SO3H, -COOR10, -CON8R9, -COR11, -SO-R10 or -CONR8R9;

R2 denotes C3-7-cycloalkyl, which may optionally be substituted by =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl;

R2 denotes phenyl which is optionally substituted by -OH, halogen, -OR10, C1-4-alkyl, -NH2, -COOH, -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9;

R2 denotes a norbornane, norbornene, C3-6-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamatane group optionally substituted by C1-4-alkyl;

R2 denotes -CH=CH-phenyl in which the phenyl ring is mono- or polysubstituted by methoxy, hydroxy or halogen;

R2 is a [3.3.0]-bicyclooctane;

R2 is a C-linked piperidine or furan;

R2 is an amine of general formula NR8R9;
R4 or R5 denotes hydrogen, an optionally branched C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which is substituted by -CN, -CH2NR8R9, -OH
(polysubstitution also possible), -OR10, -NR8R9, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -SO2R7, -S-R7, -NHCONH-phenyl, -OCH2-CONR8R9, -OCH2CH2OH, -SO2-CH2-CH2-O-COR10, -OCH2-CH2-NR8R9, -SO2-CH2-CH2-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, optionally mono- or poly-, methyl-substituted 1,3-dioxolane or 1,3-dioxane;
R4 or R5 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a C1-4-alkylene bridge by one or more, preferably one of the groups, -C1-3- alkyl, - CN, -NR8R9, -NO2, -OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCO-pyridyl, -OCH2COOH, -OCH2COOR10, -CH20COR10, - 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, -CH2-CH2-O-CONR8R9, optionally mono- or poly-, methyl-substituted 1,3-dioxolane or 1,3-dioxane;
R4 or R5 denotes an optionally substituted C3-7-cycloalkyl group;
R4 or R5 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl, C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C1-4-alkylene bridge by -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, -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 poly-, methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R4 or R5 denotes a group of the formula A-C1-6-alkyl, A-CONH-C1-6-alkyl, A-CONH-C2-6-alkenyl, A-CONH-C2-6-alkynyl, A-NH-CO-C1-6-alkyl, A-NH-CO-C2-6-alkenyl, A-NH-CO-C2-6-alkynyl, A-C2-6-alkenyl or A-C2-6-alkynyl, wherein A is a C- or N-linked heterocyclic group which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted by C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, -COOH, -SO3H, -COOR10, -CONR8R9, -COR11, -SO2-R10 or -CONR8R9;

R6 denotes hydrogen, a C1-8-alkyl, C2-8-alkenyl or C2-8-alkynyl group which is substituted by -CN, -CH2NR8R9, -OH (polysubstitution 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-CH2-CH2-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, optionally mono- or poly-, methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R6 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a C1-4-alkylene bridge by one or more of the groups, C1-3-alkyl, - CN, NR8R9, -NO2, -OH, -OR10, -CH2-NH-SO2-R10, -NHCOR10, -NHCONR8R9, halogen, -OCOR10, -OCOpyridyl, -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, -CH2-CH2-O-CONR8R9, -CO-R10, -CO-C1-4-alkyl-NR8R9, optionally mono- or poly-methyl-substituted 1,3-dioxolane or 1, 3-dioxane;

R6 denotes C3-7-cycloalkyl-C1-6-alkyl, C3-7-cycloalkyl-C2-6-alkenyl or C3-7-cycloalkyl-C2-6-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C1-4-alkylene bridge by one or more of the groups -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, -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 or methyl-substituted 1,3-dioxolane or 1,3-dioxane;

R6 denotes a group of the formula A-C1-6-alkyl, A-CONH-C1-6-alkyl, A-CONH-C2-6-alkenyl, A-CONH-C2-6-alkynyl, A-NH-CO-C1-6-alkyl, A-NH-CO-C2-6-alkenyl, A-NH-CO-C2-6-alkynyl, A-C2-6-alkenyl or A-C2-6-alkynyl or A-, wherein A is a C- or N-linked 5-, 6- or 7-membered heterocyclic group which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH, =O, a ketal, ethyleneketal, -COOH, -SO3H, -COOR10, -CONR8R9, -COR11, -SO2-R10 or -CONR8R9;

R6 denotes -CHO, -COOR10, -CONR8R9;

R6 denotes C3-7-cycloalkyl optionally substituted by =O, -OH, -OR10, -OCOR10 or -OCO-pyridyl;

R6 denotes phenyl optionally substituted by -OH, halogen, -OR10, C1-4-alkyl, preferably -CH3, -NH2, -COOH, -SO3H, -COOR10, -OCH2COOR10, -CN or -OCH2CONR8R9;

R6 denotes a norbonane, norbornene, C3-6-dicyclo-alkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane group optionally substituted by C1-4-alkyl;

R6 denotes -CH=CH-phenyl, wherein the phenyl ring may be mono- or polysubstituted by methoxy, hydroxy or halogen;

R6 denotes a [3.3.0]-bicyclooctane;

R6 denotes a C-linked piperidine or furan;

R7 denotes C1-4-alkyl which is optionally substituted by -OH, -OCOR10, -OCO-pyridyl, -NH2, -NR8R9 or -NHCOR10, preferably -CH2-CH2-OH, -CH2CH2OCOR10, -CH2-CH2-CH2-OH or -CH2-CH2CH2OCOR10;

R8 denotes hydrogen, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1-8-alkoxy, preferably C1-4-alkoxy, or -(CH2)m-NHCOOR10 where m = 1, 2, 3 or 4;

R8 denotes a 5-, 6- or 7-membered heterocyclic group which is C-linked directly or via a C1-4-alkyl chain, and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, - COOH, -SO3H or -COOR10;

R3 denotes a bicyclic heterocyclic group C-linked directly or via a C1-4-alkyl chain, which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, - COOH, - SO3H or -COOR10;

R9 denotes hydrogen, an optionally substituted C3-6-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 10 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1-8-alkoxy, preferably C1-4-alkoxy, or -(CH2)m-NHCOOR10 wherein m is 1, 2, 3 or 4;

R9 denotes a 5-, 6- or 7-membered heterocyclic group which is C-linked directly or via a C1-4-alkyl chain, and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10;

R9 denotes a bicyclic heterocyclic group C-linked directly or via a C1-4-alkyl chain, which contains one or more heteroatoms from the group comprising nitrogen, oxygen or sulphur and may optionally be mono- or polysubstituted, by benzyl, optionally substituted benzyl, C1-4-alkyl, halogen, -OR10, -CN, -NO2, -NH2, -OH, =O, -COOH, -SO3H or -COOR10, or R8 and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen, oxygen or sulphur as additional heteroatoms, whilst the heterocyclic group may be substituted by a branched or unbranched C1-4-alkyl group, or may carry one of the following groups:

- (CH2)n-phenyl, - (CH2)n-NH2, =O, a ketal - preferably -O-CH2-CH-O-, - (CH2)nNH-C1-4-alkyl, - (CH2)n-N(C1-8-alkyl)2, - (CH2)n-NHCOOR10, (n = 1, 2, 3, 4), halogen, -OR10, -CN, -NO2, -NH2, -CH2NR8R9, -OH -COOH, -SO3H, -COOR10, -CONR8R9, -SO2-R10;

R10 denotes hydrogen, C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH3;

R11 denotes C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, optionally substituted phenyl, optionally substituted benzyl or C3-6-cycloalkyl;

R12 denotes -COOR10, -CH2OR10, -CONR8R9, hydrogen, C1-3-alkyl, optionally substituted phenyl or -CH2NR8R9, optionally in the form of the racemates, enantiomers and diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

3. Compounds of general formulae (Ia) to (Id) wherein R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;

R2 denotes hydrogen, C1-8-alkyl, preferably C1-6-alkyl;

R2 denotes phenyl which is optionally substituted by halogen, C1-4-alkyl, C1-4-alkyloxy, hydroxy or NR8R9;

R2 denotes phenyl-C1-6-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, C1-4-alkyl, C1-4-alkyloxy, hydroxy or NR8R9;

R2 denotes an amine of formula NR8R9;

R2 denotes a 5- or 6-membered heterocyclic group which is optionally C- or N-linked either directly or via a C1-4-alkylene bridge, containing one or more heteroatoms selected from the group comprising nitrogen or oxygen and optionally substituted by benzyl or C1-4-alkyl;

R2 denotes a C3-6-cycloalkyl which may optionally be substituted by =O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;

R2 denotes norbornane, norbornene, adamantane or noradamantane optionally substituted by C1-4-alkyl;
R4 or R5 denotes hydrogen, C1-8-alkyl, phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl- C2-6-alkynyl, wherein the phenyl ring is optionally substituted by halogen, hydroxy, C1-4-alkyl, C1-4-alkyloxy or NR8R9;

R6 denotes hydrogen, C1-8-alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy, =O, C1-4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-C1-4-alkyloxy, benzyloxy, -O-benzyl-O-C1-4-alkyloxy, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl, -CHO, =NOH, -COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO-C1-4-alkyl, -NHCO-phenyl, -CO-C1-4-alkyl-NR8R9, -SO2OH, -SO2-C1-4-alkyl or -SO2-phenyl;

R6 denotes phenyl which may optionally be substituted by halogen, hydroxy, C1-4-alkyl, C1-4-alkyloxy, benzyloxy, phenyloxy, -NR8R9, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl, -C1-4-alkyl-NH2, -C1-4- alkyl-OH, -C1-4-alkyl=NOH, -COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO-C1-4-alkyl-NH2, -SO2OH, -SO2-C1-4-alkyl or -SO2-phenyl;

R6 denotes phenyl-C1-4-alkyl, phenyl-C2-6-alkenyl or phenyl-C2-6-alkynyl, wherein the phenyl ring may optionally substituted by halogen, hydroxy, C1-4-alkyl, C1-4-alkoxy, benzyloxy, phenyloxy, -NR8R9, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl, -C1-4-alkyl-NR8R9, -C1-4-alkyl-OH, -C1-4-alkyl=NOH, -COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO-C1-4-alkyl-NH2, -SO2OH, -SO2-C1-4-alkyl or -SO2-phenyl;

R6 denotes a 5- or 6-membered heterocyclic group optionally C- or N-linked either directly or via a C1-4-alkylene bridge, which contains one, two or three heteroatoms selected from nitrogen or oxygen and is optionally mono- or polysubstituted by benzyl or C1-4-alkyl;

R6 denotes a C3-6-cycloalkyl or C3-6-cycloalkyl-C1-4-alkyl group which may optionally be substituted by =O, hydroxy, C1-4-alkyl or C1-4-alkyloxy;

R6 denotes norbornyl, norbornenyl, adamantyl or noradamantyl optionally substituted by C1-4-alkyl;

R6 denotes -CHO, -COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl or -CONR8R9;

R6 denotes an amine of general formula NR8R9;

R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group;

R8 denotes a C-linked 5- or 6-membered heterocyclic group which contains one, two or three heteroatoms selected from the group comprising nitrogen, oxygen and sulphur and is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, -CN, -NO2, -NH2, -OH or =O;

R9 denotes hydrogen, a branched or unbranched C1-4-alkyl group;

R9 denotes a C-linked 5- or 6-membered heterocyclic group which contains one, two or three heteroatoms selected from the group comprising nitrogen, oxygen or sulphur and is optionally substituted by benzyl, C1-4-alkyl, C1-4-alkyloxy, halogen, -CN, -NO2, -NH2, -OH or =O;
or R8 and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as additional heteroatoms, whilst the heterocyclic group may be substituted by a branched or unbranched C1-4-alkyl group, preferably methyl, or by a -(CH2)1-4-phenyl group, preferably benzyl, optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

4. Compounds of general formulae (Ia) and (Ib) wherein R1 or R3 denotes hydrogen, C1-4-alkyl or benzyl;

R2 denotes hydrogen or C1-6-alkyl, R2 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydrocyclohexane;

R2 denotes a morpholine group optionally substituted by C1-4-alkyl, a piperidinyl group, a piperazinyl group optionally substituted by benzyl or C1-4-alkyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furyl;

R2 denotes a phenyl group optionally substituted by C1-4-alkyl, halogen or hydroxy;

R2 denotes a phenyl-C1-4-alkyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, C1-4-alkyl, C1-4-alkyloxy, hydroxy or NR8R9;

R2 denotes an amine of general formula NR8R9;

R2 denotes a norbornenyl, norbornyl, adamantyl or noradamantyl optionally substituted by C1-4-alkyl;

R4 denotes hydrogen, C1-7-alkyl, phenyl-C1-3-alkyl, preferably benzyl, wherein the phenyl ring may be substituted by halogen, hydroxy, C1-4-alkyl, C1-4-alkyloxy or NR8R9;

R6 denotes hydrogen, C1-6-alkyl wherein the alkyl chain may be substituted by halogen, hydroxy, =O, C1-4-alkyloxy, NR8R9, phenyloxy, -O-phenyl-O-C1-4-alkyloxy, benzyloxy, -O-benzyl-O-C1-4-alkyloxy, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -O-C2-4-alkylene, -CO-C1-4-alkyl, -CHO, =NOH, -COOH, -COO-C1-4-alkyl; -COO-phenyl, -COO-benzyl, -CONR8R9, -NHCO-C1-4-alkyl, -NHCO-phenyl, -CO-C1-4-alkyl-NR8R9, -SO2OH, -SO2-C1-4-alkyl or -SO2-phenyl;

R6 denotes phenyl, wherein the phenyl ring may be substituted by halogen, hydroxy, C1-4-alkyl, C1-4-alkyloxy or NR8R9;

R6 denotes phenyl-C1-3-alkyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, C1-4-alkyl, C1-4-alkyloxy, benzyloxy, phenyloxy, -NR8R9, -OCO-C1-4-alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C2-4-alkylene, -CO-C1-4-alkyl, -C1-4-alkyl-NR8R9, -C1-4-alkyl-OH, -C1-4-alkyl=NOH, -COOH, -COO-C1-4-alkyl, -COO-phenyl, -COO-benzyl, -CONR8R9, -CO-C1-4-alkyl-NR8R9, -SO2OH, -SO2-C1-4-alkyl or -SO2-phenyl;

R6 denotes a cyclopentyl, cyclohexyl, cyclohexyl-C1-3-alkyl, preferably cyclohexylmethyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked via a single bond or via a C1-4-alkylene chain;

R6 denotes a furan, tetrahydrofuran, .alpha.-pyran, .gamma.-pyran, dioxolane, tetrahydropyran, dioxane, thiophene, thiolane, dithiolane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, morpholine, thiomorpholine, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole or pyrazolidine linked via a single bond or via a C1-4-alkylene chain;

R6 denotes -CHO, -COOH, -COO-C1-4-alkyl;
-COO-phenyl, -COO-benzyl, -CO-NH-C1-4-alkyl, -CO-N(C1-4-alkyl)2 or -CO-NH-phenyl;

R6 denotes an amine of general formula NR8R9;

R8 denotes hydrogen, a branched or unbranched C1-4-alkyl group;

R8 denotes a C-linked pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole optionally substituted by chlorine, bromine, C1-4-alkyl, C1-4-alkyloxy, -NO2, -NH2 or -OH;

R9 denotes hydrogen, a branched or unbranched C1-4-alkyl group;

R9 denotes a C-linked pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, thiazole, isothiazole or thiadiazole optionally substituted by chlorine, bromine, C1-4-alkyl, C1-4-alkyloxy, -NO2, -NH2, -OH, or R8 and R9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring which may contain nitrogen or oxygen as additional heteroatoms, wherein the heterocyclic group may be substituted by a branched or unbranched C1-4-alkyl group, or by a -(CH2)1-4-phenyl group, optionally in the form of the racemates, the enantiomers and the diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

5. Compounds of general formula (Ib) wherein R2 denotes hydrogen, C1-4-alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted by fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR8R9, cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;

R3 denotes hydrogen, C1-3-alkyl or benzyl;

R4 denotes hydrogen, C1-5-alkyl or benzyl;

R6 denotes hydrogen, C1-4-alkyl, which may optionally be substituted by OH, chlorine, bromine, C1-4-alkyloxy or NR8R9, -CHO, -COOH, -COO-C1-4-alkyl, phenyl, phenyl-C1-3-alkyl optionally substituted by fluorine or benzyloxy, optionally methoxy-substituted phenyloxy-C1-3-alkyl, optionally methoxy-substituted benzyloxy-C1-3-alkyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolyl-methyl, or N-morpholinomethyl;

R8 denotes hydrogen, C1-4-alkyl or pyridyl;

R9 denotes hydrogen, C1-4-alkyl or pyridyl, optionally in the form of the racemates, the enantiomers and the diastereomers thereof and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

6. Compounds of general formula (Ia) wherein R1 denotes hydrogen, C1-3-alkyl or benzyl;

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

R4 denotes hydrogen, C1-5-alkyl or benzyl;

R6 denotes hydrogen, C1-4-alkyl, which may optionally be substituted by OH, chlorine, bromine, C1-4-alkyloxy or NR8R9, -CHO, -COOH, -COO-C1-4-alkyl, phenyl, phenyl-C1-3-alkyl optionally substituted by fluorine or benzyloxy, optionally methoxy-substituted phenyloxy-C1-3-alkyl, optionally methoxy-substituted benzyloxy-C1-3-alkyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl;

R8 denotes hydrogen, C1-4-alkyl or pyridyl;

R9 may denote hydrogen, C1-4-alkyl or pyridyl, optionally in the form of the racemates, the enantiomers, the diastereomers thereof and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

7. Compounds of general formula (Ic) wherein R1 denotes hydrogen or C1-3-alkyl;

R2 denotes hydrogen, C1-4-alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;

R5 denotes C1-6-alkyl;

R6 denotes hydrogen, benzyl or cyclopentyl, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

8. Compounds of general formula (Id) wherein R1 denotes hydrogen or C1-3-alkyl;

R2 denotes hydrogen, C1-4-alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;

R5 denotes C1-6-alkyl;

R6 denotes hydrogen, benzyl or cyclopentyl, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

9. Compounds of general formula (Ib) wherein R2 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 2-furyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R3 denotes hydrogen, methyl, ethyl, n-propyl or benzyl;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes 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-, Ph-CO-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, -CH2OEt or -CH2-NMe2, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

10. Compounds of general formula (Ia) wherein R1 denotes hydrogen, methyl, ethyl, n-propyl or benzyl;

R2 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, 4-fluorobenzyl, pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 2-furyl, 3-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes 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-, Ph-CO-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, -CH2OEt or -CH2-NMe2, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof.

11. Compounds of general formula (Ib) wherein R2 denotes 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-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R3 denotes hydrogen;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes 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-, Ph-COO-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-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

12. Compounds of general formula (Ia) wherein R1 denotes hydrogen;

R2 denotes 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-tetrahydrofuranyl, 4-tetrahydropyranyl, -NMe2, cyclopentyl, cyclohexyl, adamantan-1-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl;

R4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;

R6 denotes 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-, Ph-COO-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-OMe, -CH2-OEt, -CH2-NMe2, -COOMe or -COOH, optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

13. Use of a compound according to one of claims 1 to 12 as a pharmaceutical composition.

14. Use of a compound according to one of claims 1 to 12 as a pharmaceutical composition having an andenosine-antagonistic activity.

15. Pharmaceutical preparations containing as active substance one or more compounds according to one of claims 1 to 12 or the physiologically acceptable acid addition salts thereof combined with conventional excipients and/or carriers.

16. Process for preparing triazolopurine derivatives of general formula (I) wherein R1, R2, R3, R4, R5 and R6 are defined as in claims 1 to 12, characterised in that a) a compound of general formula (9) or a tautomer thereof, wherein R2, R4 and R6 are as hereinbefore defined, is reacted in a suitable organic solvent or mixture of solvents under basic conditions with a suitable alkylating agent of general formula R1-X or R3-X, wherein R1 and R3 are as hereinbefore defined and X
denotes a leaving group, or b) a compound of general formula (16) or a tautomer thereof, wherein R2, R5 and R6 are as hereinbefore defined, is reacted in a suitable organic solvent or mixture of solvents under basic conditions with a suitable alkylating agent of general formula R1-X or R3-X, wherein R1 and R3 are as hereinbefore defined and X
denotes a leaving group, or c) for R4=R1 a compound of general formula or a tautomer thereof, wherein R2 and R6 are as hereinbefore defined, is reacted in a suitable organic solvent or mixture of solvents under basic conditions with a suitable alkylating agent of general formula R1-X or R3-X to form the monoalkylated compounds (9) or directly to form the dialkylated compounds (I), wherein R1 and R3 are as hereinbefore defined and X denotes a leaving group.

17. Process for preparing triazolopurine derivatives of general formula (9) or the tautomers thereof, wherein R2, R4 and R6 are defined as in claims 1 to 12, characterised in that a) a compound of general formulae or wherein R2, R4 and R6 are as hereinbefore defined, is cyclised under basic, acidic or dehydrating conditions to obtain the tricyclic triazolopurine derivatives of general formula (9), or b) for R2=H, a diamine of general formula wherein R4 and R6 are as hereinbefore defined, is converted by thermal reaction with formamide into triazolopurine derivatives of general formula (9), or c) for R2=NR8R9, wherein R8 and R9 are as hereinbefore defined, a nitroso compound of general formula wherein R4 and R6 are as hereinbefore defined, is reacted under dehydrating conditions with N-formylamines to obtain triazolopurine derivatives of general formula (9).

18. Process for preparing triazolopurine derivatives of general formula (16) or the tautomers thereof, wherein R2, R5 and R6 are defined as in claims 1 to 12, characterised in that a) a compound of general formula or wherein R2, R5 and R6 are as hereinbefore defined, is cyclised under basic, acidic or dehydrating conditions to obtain the tricyclic triazolopurine derivatives of general formula (16), or b) for R2=H, a diamine of general formula wherein R5 and R6 are as hereinbefore defined, is converted by thermal reaction with formamide into triazolopurine derivatives of general formula (16), or c) for R2=NR8R9 wherein R8 and R9 as hereinbefore defined, a nitroso compound of general formula wherein R5 and R6 are as hereinbefore defined, is reacted with N-formylamines under dehydrating conditions to obtain triazolopurine derivatives of general formula (16).