AU1741899A - New imidazotriazolopyrimidinones, processes for preparing them and their use as pharmaceutical compositions - Google Patents
New imidazotriazolopyrimidinones, processes for preparing them and their use as pharmaceutical compositions Download PDFInfo
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- AU1741899A AU1741899A AU17418/99A AU1741899A AU1741899A AU 1741899 A AU1741899 A AU 1741899A AU 17418/99 A AU17418/99 A AU 17418/99A AU 1741899 A AU1741899 A AU 1741899A AU 1741899 A AU1741899 A AU 1741899A
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- alkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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Description
Our Ref: 685528 P/00/001 Section 29
AUSTRALIA
Patents Act 1990 PATENT REQUEST STANDARD PATENT I/We, being the person/s identified below as the Applicant, request the grant of a patent to the person/s indicated below as the Nominated Person/s, for an invention described in the accompanying standard complete specification.
Full application details follow.
[71] [70] Applicant/s and Nominated Person/s: Boehringer Ingelheim International GmbH, a company organised and existing under the laws of Germany, of Postfach 200, D-55216 Ingelheim am Rhein, GERMANY [54] [72] [74] Invention Title: New triazolopurines, method of preparing them and their use as drugs Name/s of actual inventor/s: (optional) Address for service in Australia: DAVIES COLLISON CAVE, Patent Attorneys Barrack Street, SYDNEY NSW 2000 Attorney Code CA Code: [321 Date: US 25 June 1998 BASIC CONVENTION APPLICATION DETAILS: 311 Appln No: [331 Country: 60/090587 UNITED STATES OF AMERICA DIVISIONAL APPLICATION DETAILS [62] Original application number 36955/97 DATED this NINETEENTH day of FEBRUARY 1999 Boehringer Ingelheim International GmbH By Patent Attorneys DAVIES COLLISON CAVE P'ekc QecrvL Dr. PETER STEARNE, FIPTA Fee: 2140.00 5010 Our Ref: 685528 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Boehringer Ingelheim International GmbH Postfach 200 D-55216 Ingelheim am Rhein
GERMANY
Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 New triazolopurines, method of preparing them and their use as drugs The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 68799.200 Case 1/1024-Dr. Wy/ks New imidazotriazolopyrimidinones, processes for preparing them and their use as pharmaceutical compositions The invention relates to new imidazotriazolopyrimidinone derivatives and fundamental imidazotriazolopyrimidinone substances, processes for preparing them and their use as pharmaceutical compositions.
The new imidazotriazolopyrimidinone derivatives have the structure of general formula 0
RI
R"N N N \A R wherein
R
1 or R 3
R
1 or R 3 denotes hydrogen, an optionally substituted
C
1 10 -alkyl, C2- 10 -alkenyl or C2- 10 -alkynyl, an optionally substituted C 3 _,-cycloalkyl, an optionally substituted
C
4 _,-cycloalkenyl or an optionally substituted
C,_
8 -cycloalkynyl; denotes an optionally substituted C 6 0 -aryl-C, alkyl, C 6 1 0 -aryl-C2-6-alkenyl,
C
6 10 -aryl-
C
2 ,-alkynyl, an optionally substituted
C
6 -o 0 -aryl or an optionally substituted heteroaryl, an optionally substituted 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms from the group comprising R' or R' nitrogen, oxygen or sulphur, the heterocycle being linked via a carbon atom of the ring; denotes an optionally substituted C,.,,.-alkyloxycarbonyl, an optionally substituted
C
2 alkenyloxycarbonyl, an optionally substituted C2iO,-alkynyloxycarbonyl, an optionally substituted
C
3 .,-cycloalkyloxycarbonyl, an optionally substituted Cs-,-aryloxycarbonyl, an optionally substituted C.-I-aryl-CI--alkyloxycarbonyl, A-O-CO- wherein A denotes an optionally substituted 6- or 7membered 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, is an optionally substituted
C
1 10 -alkylsulphonyl,
C
2 1 -alkenylsulphonyl,
C
2 1 -alkynylsulphonyl, an optionally substituted
C
3 .,-cycloalkylsulphonyl, an optionally substituted
C
6 arylsulphonyl, an optionally substituted
C
6 aryl-C 1 -,-alkylsulphonyl, a group A-SO,- wherein A is as hereinbefore defined and is linked via a carbon atom of the ring; denotes an optionally substituted C,.,,-alkylcarbonyl, an optionally substituted
C
2 1 -alkenylcarbonyl, an optionally substituted
C
2 -I.-alkynylcarbonyl, an optionally substituted
C
3 cycloalkylcarbonyl, an optionally substituted
C,
6 arylcarbonyl, an optionally substituted C6-o,-aryl-C 6 alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined; R1 or R R1 or R' R' or R' denotes a group of general formula
H%
R O wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted
C
3 .,-cycloalkyl group, a branched or unbranched C_.-,-alkyl, preferably
C
1 4 -alkyl,
C
2 1 -alkenyl or C 2 1 -alkynyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino;
R
2 denotes hydrogen, hydroxy, amino, halogen, nitro, CF3, COOH, mercapto,
C
1 ._-alkylmercapto, an optionally substituted CIo 1 -alkyl, an optionally substituted C2- 10 -alkenyl, an optionally substituted C2-10-alkynyl, an optionally substituted
C
3 _,-cycloalkyl, an optionally substituted C._,-cycloalkanone, an optionally substituted
C
4 8 -cycloalkenyl, an optionally substituted Cg.
8 -cycloalkynyl, an optionally substituted
C
6 1 -aryl, an optionally substituted C,.o-aryl-C,._-alkyl, C,_,o-aryl-
C
2 .,-alkenyl, C 6 0 -aryl-C 2 a-alkynyl,
C
3 .8-cycloalkyl-CI.,-alkyl,
C
3 .,-cycloalkyl- C2-.-alkenyl, or C 3 ._-cycloalkyl-C2.,-alkynyl;
R
2 denotes an optionally substituted 6- or 7membered 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 C,_ 6 -alkyl, C 2 .,-alkenyl or C2-6-alkynyl bridge; denotes an optionally substituted
C
1 1 0 ,-alkylsulphonyl,
C
2 -1-alkenylsulphonyl or
C
2 i-alkynylsulphonyl, an optionally substituted
C
3 cycloalkylsulphonyl, an optionally substituted
C.
1 -arylsulphonyl, an optionally substituted heteroarylsulphonyl or an optionally substituted C..i-aryl-C,- 6 -alkylsulphonyl; 2 denotes an optionally substituted Ci.o-akylsulphonyloxy,
C
2 or C 2 -10-alkynylsulphonylox,~ an optionally substituted
C
3 -cycloalkylsulphonylox,~ an optionally substituted
C
610 -arylsulphonyloxy, an optionally substituted
C
6 0 -aryl-Cl- 6 alkylsuiphonyloxy or an optionally substituted heteroarylsulphonyloxy;
*R
2 denotes an optionally substituted sulphonyl amino, C,-,i-alkenylsulphonyl amino or C 2 -iO-alkynylsulphonylamino, an optionally substituted
C
3 cycloalkylsuiphonylamino, an optionally substituted C, aryl sulphonyl amino, an optionally substituted C,-ioaryl-C 16 ,-alkylsulphonylamino,_or an optionally substituted heteroarylsulphonylamino; 2 denotes an optionally substituted C,-.,,-alkylaminocarbonyl, Cl-.
1 -dialkylaminocarbonyl, Cl-lo-alkyl-C 2
C
2 -10-alkenylaminocarbonyl,
C,
1 0 -dialkenylaminocarbonyl,
C
2 1 -alkynylaminocarbonyl or Cl-.io-alkyl-C 2 0 alkynylaminocarbonyl, an optionally substituted
C
3 cycloalkylaminocarbonyl, an optionally substituted
C
6 0 -arylaminocarbonyl, an optionally substituted Cr,-O-aryl-Cl- 6 -alkylaminocarbonyl, or an optionally substituted heteroarylaminocarbonyl; R 2 denotes an optionally substituted
C,
1 -,-alkyloxycarbonyl amino, C 2 10 -alkenyloxycarbonylamino or C 2 0 -alkynyloxycarbonylamino, an optionally substituted
C
3 cycloalkyloxycarbonylamino, an optionally substituted
C
6 1 aryloxycarbonyl amino, an optionally substituted
C
6 1 -aryl -C,-.-alkyloxycarbonylamino or an optionally substituted heteroaryloxycarbonylamino; 2 denotes an optionally substituted
C
1 1 0 -alkylaminocarbonyloxy,
C
2 1 0 -alkenylaminocarbonyloxy or C 2 .io,-alkynylaminocarbonyloxy, an optionally substituted
C
3 cycloalkylaminocarbonyloxy, an optionally substituted 6-10arylaminocarbonyloxy, an optionally substituted C 6 -i-arylC- 6 alkylaminocarbonyloxy or an optionally substituted heteroarylaminocarbonyloxy; 2 denotes an optionally substituted
C
1 10 -alkyl-Namidino, 1 -alkenyl-N-amidino or C 2 1 0 -alkynyl- N-amidino, an optionally substituted
C
3 cycloalkyl-N-amidino, an optionally substituted
C
6 10 -aryl-N-amidino, an optionally substituted
C
6 10 -aryl-C 16 -alkyl-N-amidino or an optionally substituted heteroaryl-N-amidino; 2 denotes an optionally substituted C 1 10 -alkyloxy,
C
2 1 0 -alkenyloxy or C 2 10 -alkynyloxy, an optionally substituted
C
3 8 -cycloalkyloxy, an optionally substituted
C
6 0 -aryloxy, an optionally substituted
C
6 1 0 -aryl-C 1 6 -alkyloxy or an optionally substituted heteroaryloxy; R 2denotes an optionally substituted Ci.-o-alkyoxycarbonyl,
C
210 -alkenyloxycarbonyl or
C
2 i-alkynyloxycarbonyl, an optionally substituted C3.-cycloalkyloxycarbonyl, an optionally substituted C,,-o-aryloxycarbonyl, an optionally substituted
C
6 10 -aryl-C 1 6 ,-alkyloxycarbonyl. or an optionally substituted heteroaryloxycarbonyl; R 2 denotes an optionally substituted
C
1 1 -alkylcarbonyloxy,
C
2 1 -alkenylcarbonyloxy or
C
2 1 LO-alkynylcarbonylox,~ an optionally, substituted
C
38 -cycloalkylcarbonyloxy, an optionally substituted Cf.l-arylcarbonyloxy, an optionally substituted
C
6 10 -aryl-Cl- 6 -alkyl carbonyloxy or an optionally substituted heteroarylcarbonyloxy; R 2 denotes an optionally substituted
C
1 10 -alkylthio,
C
2 10 -alkenylthio or
C
2 10 -alkynylthio, an optionally substituted
C
3 cycloalkylthio, an optionally substituted
C
6 1 -arylthio, an optionally substituted
C
6 1 0 -aryl-c] 1 6 r-alkylthio or an optionally substituted heteroarylthio; R 2denotes an optionally substituted amine, pref erably NR 8
R
9 R 2 denotes an optionally substituted group of the formula 0 7
R
2 denotes an optionally substituted group of the formula
(CH
2 )12 (CH 2
(CH
2 )1, 2 -Y -i 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;
R
2 denotes an optionally substituted group of the formula
(CH
2 12
(CH
2 )1, 2 C,-C6-Alkyl CI-C 6 -Alkyl 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;
R
2 denotes an optionally substituted group of the formula
-Y.
(CH
2 0,122 (CH2)0,1,2 2 I I 1Y-
(CH
2 0 1 2 (C .)01,2
NS.
R
4 or R s
R
4 or R 5 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; denotes a hydrogen atom, an optionally substituted C 1 z.
1 -alkyl, C2- 10 -alkenyl or
C
21 -alkynyl, an optionally substituted
C
3 _,-cycloalkyl, an optionally substituted
C
4 8 -cycloalkenyl or an optionally substituted Cg_-cycloalkynyl, an optionally substituted
C
6 g 10 -aryl-C_.
6 -alkyl, C _o 0 -aryl C 2 6- alkenyl,
C
6 1 0 -aryl-C 2 6 -alkynyl, an optionally substituted C6- 1 0 -aryl or an optionally substituted heteroaryl; denotes an optionally substituted 6- or 7membered 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;
R
4 or R 5 denotes an optionally substituted
C
1 z.--alkyloxycarbonyl, an optionally substituted
C
2 10 -alkenyloxycarbonyl, an optionally substituted C2-.o-alkynyloxycarbonyl, an optionally substituted C 3 ._-cycloalkyloxycarbonyl, an optionally substituted C 6 0 o-aryl- R' or R 5
R
4 or R 5
CL-
6 -alkyloxycarbonyl, an optionally substituted Cg 0 aryloxycarbonyl; denotes A-O-CO- wherein A denotes an optionally substituted 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur; denotes an optionally substituted
C
1 1 -alkylsulphonyl,
C
2 10 -alkenylsulphonyl,
C
2 1 0 -alkynylsulphonyl, an optionally substituted
C
3 ,--cycloalkylsulphonyl, an optionally substituted
C,_
0 ,-arylsulphonyl, a group A-SO 2 wherein A is as hereinbefore defined and is linked via a carbon atom of the ring; denotes an optionally substituted
C
1 i 0 -alkylcarbonyl, an optionally substituted
C
2 a-,-alkenylcarbonyl, an optionally substituted
C
2 1 0 -alkynylcarbonyl, an optionally substituted
C
3 _,-cycloalkylcarbonyl, an optionally substituted C_.
1 0 -arylcarbonyl, an optionally substituted
C
6 1 0 -aryl-C,-_-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined; denotes a group of general formula R' or R 5
R
4 or R 5
H
R 0 wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C 3 .,-cycloalkyl group, a branched or unbranched C 1 10 -alkyl, preferably C 1 .4-alkyl, C,_-i-alkenyl or C 2 0 -alkynyl group, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino; R 6 denotes hydrogen, hydroxy, -CH{O, amino, halogen, nitro, CF 3 1 COOH, mercapto,
C
1 alkylmercapto, an optionally substituted
C
1 10 -alkyl, an optionally substituted 1 -alkenyl, an optionally substituted 1 -alkynyl, an optionally substituted cycloalkyl, an optionally substituted C, -cycloalkanone, an optionally substituted cycloalkenyl, an optionally substituted C,..-cycloalkynyl, an optionally substituted an optionally substituted
C
6 10 -aryl 6 -alkyl, C 6 0 -aryl
C
2 6 -alkenyl,
C
6 1 0 -aryl-C 2 6 -alkynyl, an optionally substituted C,_..-cycloalkyl-C 1 6 ,-alkyl,
C
3 cycloalkyl-C,-,-alkenyl or C 3 cycloalkyl-
C
2 alkynyl; R' denotes an optionally substituted 6- or 7membered 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 Cl-,-alkyl,
C
2 alkenyl or C 2 alkynyl bridge; R6 denotes an optionally substituted
C
1 .,,-alkylsulphonyl,
C
2 10 -alkenylsulphonyl or
C
2 1 0 -alkynylsulphonyl, an optionally substituted
C
3 cycloalkylsulphonyl, an optionally substituted 1 -arylsulphonyl, an optionally substituted C..i-aryl-C 1 alkylsulphonyl or an optionally substituted heteroarylsuiphonyl; R' denotes an optionally substituted
C.
1 0 ,-alkylsulphonyloxy,
C
2 .i-alkenylsulphonyloxy or C 2 1 -alkynylsulphonyloxy, an optionally substituted C 3 cycloalkylsulphonyloxy, an optionally substituted 1 -arylsulphonyloxy, an optionally substituted C 6 10 -aryl-C 1 6 alkylsulphonyloxy or an optionally substituted heteroarylsuiphonyloxy; R6 denotes an optionally substituted C.,-alkylsulphonylamino, 1 -alkenylsulphonyl amino or C 210 -alkynylsulphonylamino, an optionally substituted C,-,-cycloalkylsulphonyl amino, an optionally substituted
C
610 -arylsulphonylamino, an optionally substituted C 6 0 aryl C,-,-alkyl sulphonyl amino or an optionally substituted heteroarylsulphonylamino; R' denotes an optionally substituted C, 1 1 0 -alkylaminocarbonyl, Cl-.
1 -dialkylaminocarbonyl,
C
110 o-alkyl-C 210 -alkenylaminocarbonyl,
C
2 10 -alkenylaminocarbonyl, C 2 10 -dialkenylaminocarbonyl, C 2 10 -alkynylaminocarbonyl or
C,-
1 -alkyl-C 2 10 -alkynylaminocarbonyl, an optionally substituted C 3 cycloalkylaminocarbonyl, an optionally substituted
CG.
1 0 -arylaminocarbonyl, an optionally substituted C 6 1 -ary-C--alkylaminocarbonyl or an optionally substituted heteroarylaminocarbonyl; R6 denotes an optionally substituted cj-..
1 alkylaminocarbonyl amino,
C
2 0 -alkenylaminocarbonylamino or
C
2 10 -alkynylaminocarbonylamino, an optionally substituted C 3 cycloalkylaminocarbonylamino, an optionally substituted
C
6 1 -aryaminocarbony..
amino, an optionally substituted C,-2,-aryl-
C.
6 -alkyl aminocarbonyl amino or an optionally substituted heteroarylaminocarbonylamino.
R 6 denotes an optionally substituted Cl 1 .iO-alkyloxycarbonylamino, alkenyloxycarbonylamino or alkynyloxycarbonyl amino, an optionally substituted C3.-cycloalkylcarbonylamino, an optionally substituted
C
610 -aryloxycarbonyl amino, an optionally substituted
C
6 1 0 O-aryl- Ci..-alkyloxycarbonylamino or an optionally substituted heteroaryloxycarbonylamino; 6 denotes an optionally substituted
C
1 1 alkylaiuinocarbonyloxy, alkenylaminocarbonyloxr or
C
2 i-alkynylaminocarbonyloxy, an optionally substituted
C
3 cycloalkylaminocarbonyloxy, an optionally substituted
C
6 10 -arylaminocarbonyloxy, an optionally substituted 6-10aryl -C alkylaminocarbonyloxy or an optionally substituted heteroarylaminocarbonyloxy; 6 denotes an optionally substituted
C
1 1 -alkyl-Namidino,
C
2 10 -alkenyl -N-amidino or C 2 10 -alkynyl N-amidino, an optionally substituted
C
3 cycloalkyl-N-amidino, an optionally substituted
C
6 .l-aryl -N-amidino, an optionally substituted
C,
6 0 -aryl-C 1 alkyl-Namidino or an optionally substituted heteroaryl-N-amidino; R' 6 denotes an optionally substituted
C
1 10 -alkyloxy,
C
2 10 -alkenyloxy or C 2 1 -alkynyloxy, an optionally substituted
C
3 .,-cycloalkyloxy, an optionally substituted
C
6 0 -aryloxy, an optionally substituted C,51-arl-Cl6akoxorn optionally substituted heteroaryloxy; R6 denotes an optionally substituted Cl-,i,-alkylcarbonyl, an optionally substituted
C
2 iaalkenylcarbonyl, an optionally substituted
C
2 iO-alkynylcarbonyl, an optionally substituted
C
38 ,-cycloalkylcarbonyl, an optionally substituted C,5 1 0 -arylcarbonyl, an optionally substituted C,,-rlC-,aklabnl R 6 denotes a group A-CO- wherein A is as hereinbefore defined; R6 denotes an optionally substituted Ci,-iO-alkyloxycarbonyl, C2-1-alkenyloxycarbonyl or C2..lo-alkynyloxycarbonyl, an optionally substituted C3.8,-cycloalkyloxycarbonyl, an optionally substituted
C
610 -aryloxycarbonyl, an optionally substituted
C
610 aryl-C- 6 alkyloxycarbonyl or an optionally substituted heteroaryloxycarbonyl;
R
6 denotes an optionally substituted Cl-.,-alkycarbonylox,~ C2lo,-alkenylcarbonyloxy or
C
2 i-alkynylcarbonyloxy, an optionally substituted C3-,-cycloalkylcarbonyloxy, an optionally substituted
C
6 -iO-arylcarbonyloxcy, an optionally substituted
C,
6 .ia-aryl-C 16 alkyl.
carbonyloxy or an optionally substituted heteroaryl.carbonyloxy;
R
6 denotes an optionally substituted
C
1 10 -alkylthio,
C
2 0 -alkenylthio or
C
2 10 -alkynylthio, an optionally substituted
C
3 cycloalkylthio, an optionally substituted C..-arylthio, an optionally substituted
C,
10 -ary-C 16 -alkylthio or an optionally substituted heteroarylthio;
R
6 denotes an optionally substituted Cl-lo-alkylcarbonyloxy-C,-calkyl,
C
2 o-alkenlcarbonyloxy-C,-..alkyl or
C
2 ,,-alkynylcarbonyloxy-C,,-alkyl, an optionally substituted C,-,-cycloalkylcarbonyloxy-C,-,-alkyl, an optionally substituted C.-I.-arylcarbonylooxy- C,-alkyl,
C
6 1 -aryl-C,-alkylcarbonyloxy C,-,-alkyl or heteroarylcarbonyloxy-C,-,-alkyl
R
6 denotes an optionally substituted group of the formula RI-0-B--(CH)n wherein n=l, 2, 3 or 4, where B denotes a
C
6 10 -aryl or a single bond; R6 denotes an optionally substituted amine, preferably
NR
8
R
9
R
6 denotes an optionally substituted group of the formula R6 denotes an optionally substituted group of the formula
(CH
2 )1,2
-Y
1> I (CH
(CH
2 CH2)1,2(CH 2 12 *YI C 6 -Alkyl Cl-C67lkyl Cl-Cwherein Y is a single bond or an alkylene, an alkenylene or an alkynylene having up to 6, preferably 4 carbon atoms in the chain; is an optionally substituted group of the formula
-Y.
-Y-F
(CH
2 012 (CH2)0,1,2 .4 I IY-
(CH
2 0 ,1,2 (CH2)0,1, .o.i "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; denotes hydrogen, an optionally substituted
C
3 _6-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 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, C 1 preferably
C
1 _,-alkyloxy, or -(CH 2 ).-NHCOOR wherein m 1, 2, 3 or 4; R' denotes a 6- or 7-membered heterocyclic group which is carbon linked directly or via a
C
14 -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, C 1 4 -alkyl, halogen, -OR 10 -CN, -NO 2
NH
2 -OH, -COOH, -SO3H or -COOR 10
R
8 denotes a bicyclic heterocyclic group which is C-linked directly or via a C 1 _,-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,
C
1 4 -alkyl, halogen, -OR 10 -CN, -NO 2
-NH
2
-OH,
-COOH, -S03H, -COOR 10
R
9 denotes hydrogen, an optionally substituted
C
3 .,-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to preferably 1 to 4 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, preferably C,_,-alkoxy, or -(CH 2
),-NHCOOR
0 wherein m equals 1, 2, 3 or 4;
R
denotes a 6- or 7-membered heterocyclic group which is carbon linked directly or via a
C,_
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, C,.
4 -alkyl, halogen, -OR 0 -CN, -NO NH,, -OH, -COOH, -S0 3 H or -COOR 0
R
9 denotes a bicyclic heterocyclic group which is carbon linked directly or via a C,_ 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,
C,
4 -alkyl, halogen, -OR 1 -CN, -NO 2
-NH
2
-OH,
-COOH, -SO 3 H, -COOR'; or
R
8 and R 9 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
-(CH
2 ),-phenyl,
-(CH
2
).-NH
2 a ketal preferably -0-CH 2
-CH
2
(CH
2
NH-C,
4 -alkyl, (C,.-alkyl) 2
-(CH
2
)"-NHCOOR
0 (n 2, 3, halogen,
-OR
1 -CN, -NO 2
-NH
2
-CH
2
NR'R',
-OH, -COOH, -S03H, -COOR"', -CONRR 9
-SO
2
-R
10 R" denotes hydrogen
C
1 4 alkyl, C,- 4 -alkenyl,
C
2 4 -alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH 3 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 indicate the presence of a double bond in one of two alternative positions, such that both of R 1 and R 3 or of R 4 and R 5 are not simultaneously present.
The compounds of general formula MI form the following isomers: 0 R0 N~ N 2 R N N N N N NIa
R
6 ONb 0 1 0 N N N is R6 (1c)
R
6 0dc) the isomers of general formulae (Ia) and (Ib) being preferred, particularly those wherein R1 or R 3 denotes hydrogen or C 1 4 -alkyl. Compounds of general formula (Ia) and (Ib) wherein R' and R 3 denote hydrogen are particularly preferred; in this case isomers (Ia) and (Ib) are tautomers.
Preferred compounds are the compounds of general formulae (Ta) to (Id) wherein Ror R 3 denotes hydrogen,
C
1 4 -alkyl, benzyl, preferably hydrogen; R 2 denotes hydrogen, a C 1 8 ,-alkyl, C 2 8 -alkenyl or
C
2 8 -alkynyl group which may optionally be substituted, by -CN, -CH 2
NR
8
R
9
-OH
(polysubstitution also possible)
-OR'
0 -NR 8
R
9
NHCOR'
0
-NHCONR
8
R
9
-NHCOOR'
0 halogen, -OCOR' 0 -OCO-pyridyl,
-OCH
2 COOH-, -OCH 2 COOR1 0 -S0 2 R S-R 7 -NHCONH-phenyl,
-OCH
2
-CONR
8
R
9
-OCH
2
CH
2
OH,
-S0 2
-CH
2
-CH
2 -0-COR1 0
-OCH
2
-CH
2
-NRBR
9
-SO
2
-CH
2 -dCH 2 -OH, -CONHSO 2
R"
0
CH
2
CONHSO
2
R'
0
-OCH
2
CH
2
OR'
0 -COOH, -COOR' 0
-CONR
8
R
9 -CHO, -SRl'
SOR'
0 -S S 2 R1 0
SO
3 H, SO 2
NROR
9 OCH 2
CH
2
OCOR'
0 ~-CH=NOH,
-CH=NOR'
0 -COR", -CH(OH)R"1, CH (OR' 0 2
-CH=CH-R'
2
OCONR
8
R
9 optionally monoor poly-substituted, preferably mono-methylsubstituted, i, 3-dioxolane or 1, 3-dioxane; R 2 denotes phenyl-C..
6 -alkyl, preferably phenyl- Cl,-alkyl, phenyl -C 2 6 -alkeny. or phenyl-
C
2 6 -alkynyl, wherein the phenyl ring is optionally substituted either directly or via a Cl,.-alkylene bridge by one or more, preferably one, of the groups 3 -alkyl, -CN, -NR 8 R9, -NO 2 -OH, -OR' 0 O, -CH 2 -NH-S0 2
-R'
0
-NHCOR
0
-NHCONR
8
R
9 halogen,
-OCOR
0 -OCO-pyridyl,
-OCH
2
COOH,
-OCH
2 COOR1 0
-CH
2
OCOR'
0 O, -S0 2 R 7
-OCH
2 -CONRR9,
OCH
2
CH
2 OH, OCH 2
H-NR
8 R9, CONHSO 2
R
0
-OCH
2
CH
2
OR
0 -COOH, -COOR 0 -CF 3 1 cyclopropyl,
-CONROR
9
-CH
2 OH, -CH 2 0R 0 -CHO, -SR' 0
-SOR
0
SO
2 R1 0
SO
3 H, SO 2
NR
8
R
9 -0C1 2
CH
2
OCOR'
0
CH=NOH,
-CH=NOR'
0 -COR", -CH(OH)R",
-CH(OR'
0 2
-NHCOOR'
0
-CH
2
CONHSO
2
R'
0
-CH=CH-R'
2
OCONR
6 R9,
-CH
2 -O-CONROR9,
-CH
2
-CH
2
-O-CONR
8
R
9 optionally mono- or poly- preferably mono-methylsubstituted 1, 3-dioxolane or 1, 3-dioxane; R 2denotes
C
3 7 -cycloalkyl-C,- 6 -alkyl,
C
3 -,-cycloalkyl-C 2 6 ,-alkenyl,
C
3 cycloalkyl-
C
2 alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a
C,-
4 -alkylene bridge by one or more, preferably one, of the groups -CN, NR 8
R
9 -OH, -OR' 0
O,
-NRGR
9
-NHCOR
0
-NHCONR
8
R
9 halogen,
-OCOR
0 OCO-pyridyl,
-OCH
2 COOH, OCH 2
COOR
0
CH
2
OCOR
0 S0 2 R 7
OCH
2
-CONROR
9
OCH
2
CH
2 OH, OCH 2
-CH
2
-NR
8
R
9
-OCH
2
CH
2
OR'
0 -COOH, -COOR' 0 -CONReR 9
-CH
2
OH,
-CH
2 0R1 0 I -CHO, -SR' 0
-SOR'
0
-SO
2
R'
0
-SO
3
HI
SO
2 NR"R', -00H 2
-CH
2 OCOR1 0 CH=NOH,
CH=NOR
0 -COR"1, -OH (OH) -CONHSO 2 R1 0 -OCH (OR' 0 2
-NHCOOR'
0 OH=CH-R 1' 2
OCONR
8
R
9
OH
2
CONRBR
9
_CH
2
H
2 -O-CONRaR 9 methyl -substituted 1,3dioxolane or 1,3-dioxane; R 2 denotes a group of the formula A-Cl-c-alkyl,
A-CONH-C,.
6 -alkyl,
A-CONH-C
2 6 -alkenyl,
A-CONH-C
2 6 -alkynyl, A-NH-CO-C,.-alkyl, A-NH- CO-C 2 6 -alkenyl,
A-NH-CO-C
2 6 -alkynyl,
A-C
2 6 -alkenylene,
A-C
2 6 -alkynylene or wherein A is a C- or Nlinked 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, C,.
4 -alkyl, halogen, -OR", -ON, -NO 2
-NH
2
-CH
2
NR
8
R
9 -OH, a ketal, ethyleneketal, -OOOH, -SO 3 H, -COOR 0
-CONOR
9 -COR"1, -S02-R1 0 or -CONR 8
R
9 R 2 denotes C 3 7 -cycloalkyl, preferably cyclopentyl or cyclohexyl, which may optionally be substituted by -OH, -OR'1 0
OCOR'
0 or -OCO-pyridyl; 2 denotes phenyl which is optionally substituted by -OH, halogen, -OR' 0 O,-alkyl, preferably
-OH
3
-NH
2 -00011, -S0 3 H, -COOR' 0
-OCH-
2 COOR1 0
-ON
or -OCH 2
CONR
8
R
9 2 denotes a norbornane, norbornene,
C
3 dicycloalkylmethyl, preferably R 2 R' or -R 5 dicyclopropylmethyl, adamantane or noradamatane group optionally substituted by C 1 4 -alkyl, preferably methyl; denotes -CH=CII-phenyl in which the phenyl ring is mono- or polysubstituted by methoxy, hydroxy or halogen; is a 3 .3.0]-bicyclooctane, preferably a -bicyclooctan-2.yl; is a C-linked piperidine or furan; is an amine of general formula
NROR
9 denotes hydrogen, an optionally branched
C
1 alkyl, C2-,-alkenyl or C 2 8 -alkynyl group which is substituted by -CN, -CH 2
NR
8
R
9
-OH
(polysubstitution also possible)
-OR"
0 -N4ROR 9
-NHCR
10 -NHCONRaR- 9 halogen,
OCOR'
0 -OCO-pyridyl,
-OCH
2 COOH,
-OCH
2
COOR'
0 -S0 2
R,
S-R 7 -NHCONH-phenyl,
-OCH
2
-CONR
8
R
9
OCH
2
CH
2
OH,
-SO
2
-CH
2
-CH
2
-O-COR"
0
-OCH
2
-CH
2
-NR
5
R
9 -S0 2
-C!H
2
-CH
2 -OH, -CONHSO 2
R'
0
-CH
2 CONHS0 2
R'
0
-OCH
2
CH
2
OR'
0 -COOH,
-COOR'
0
-CONR
8
R
9 -CHO,
-SR'
0 SOR1 0
SO
2 R1 0
SO
3 H, SO 2
NR
8
R
9
-OCR
2
-CH
2
OCOR'
0 -CH=NOH,
-CH=NOR'
0 -COR"1, -CH(OH)R"1, -CH(0R 1 0 2 -CH=CtI-R 1 2
-OCONR
8 R9, optionally monoor poly-, preferably mono-methyl-substituted l,3-dioxolane or 1,3-dioxane; Ror R 5 denotes phenyl-C,- 6 -alkyl, preferably phenyl- C,-,-alkyl, phenyl-C 2 6 -alkenyl or phenyl-
C
25 6-alicynyl, wherein the phenyl ring is optionally substituted either directly or via a
C.
4 -alkylene bridge by one or more, preferably one of the groups,
C,.
3 -alkyl, -MR, -NRBR 9
-NO
2 R"or R' -OH, -OR' 0
-CH
2 -NH-S0 2 -R'1 0 -NHCOR3- 0
-NHCONROR
9 halogen,
-OCOR
0 -OCO-pyridyl,
-OCH
2
COOH,
-OCH
2 COOR1 0
-CH
2 OCOR1 0 -S0 2 R 7
-OCH
2
-CONR
8
R
9
-OCH
2
CH
2 OH, -OCH 2
-CH
2
-NR
8
R
9 -CON{SO 2
-OCH
2
CH
2
OR'-
0 -COOH, -COOR' 0 -CF 3 1 cyclopropyl, -CONROR9, -CH 2 OH, -CH 2 0R1 0 -CHO, -SR' 0
-SOR'
0
-SO
2
R'
0
-SO
3 H, -SO 2
NR
8
R
9
-OCH
2
-CH
2 OCOR3- 0
-CH=NOH,
-CH=NOR'
0 -COR"1, -CH(OH)R",
-CH(OR'
0 2
-NHCOOR'
0
-CH
2
CONHSO
2
R'
0 -CH=CH-R 1 2
-OCONROR
9
CH
2
-O-CONR
8
R
9
-CH
2
-CH
2
-O-CONR
8
R
9 optionally mono- or poly-, preferably mono-methylsubstituted 1, 3-dioxolane or 1, 3-dioxane; denotes an optionally substituted
C
3 cycloalkyl group; denotes C 3 7 -cycloalkyl-C,- 6 -alkyl,
C
3 7 -cycloalkyl-C 2 6 -alkenyl, C 3 7 -cycloalkyl-
C
2 alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a C,--alkylene bridge by -CN, -NROR 9
-OH,
-OR'
0
-NR
8
R
9
-NHCOR
0
-NHCONR
8
R
9 halogen,
-OCOR'
0 -OCO-pyridyl,
-OCH
2 000H, -OCH 2 COOR1 0
-CH
2
OCOR'
0 -S0 2 R 7
-OCH
2
-CONROR
9
-OCH
2
CH
2
OH,
2 -NR8R 9
OCH
2
CH
2
OR
0 COOH, COOR' 0
-CONR
8
R
9
-CH
2 OH, -CH 2 0R1 0 -CHO, -SR' 0
-SOR'
0
SO
2 R1 0
SO
3 H, SO 2
NR
8
R
9
OCH
2
-CH
2 OCOR1 0
CH=NOH,
-CH=NOR'
0 -COR"1, -CH(OH)R",
-CONHSO
2
R'
0
-CH(OR'
0 2
-NHCOOR'
0 -CH=CH-R 1 2
-OCONR
3
R
9
-CH
2
-O-CONR
8
R
9
-CH
2
-CH
2
-O-CONROR
9 optionally mono- or poly-, preferably mono-methylsubstituted 1, 3-dioxolane or 1, 3-dioxane; R'or R' R4or R 5 denotes a group of the formula
A-C..
6 -alkyl, A-CONH-C,._,,-alkyl,
A-CONH-C
2 -15-alkenyl,
A-CONH-C
2 6 -alkynyl,
A-NH-CO-C..
6 -alkyl, A-NH-CO-C 2 6 -alkenyl,
A-NH-CO-C
2 6 -alkynyl,
A-C
2 alkenyl or
A-C
2 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, preferably monosubstituted, by C, 4 alkyl, halogen,
-OR
10 -CN, -NO 2
-NH
2
-CH
2
NR
8
R
9 -OH, a ketal, ethyleneketal, -COOH,
-SO
3 H, -COOR 0
-CONR
8
R
9 -COR", -S0 2 -R1 0 or -CONR 8
R
9 R 6 denotes hydrogen, a 8 -alkyl,
C
2 alkenyl or
C
2 8 -alkynyl group which is substituted by -CN,
-CH
2
NROR
9 -OH (polysubstitution also possible),
-OR'
0
-NRBR
9
-NHCOR
0
-NHCONROR
9
-NHCOOR
0 halogen,
-OCOR
0 1 -OCO-pyridyl,
-OCH
2
COOH,
-OCH
2
COOR
0
-SO
2 R 7, -S-R 7 -NHCONH-phenyl,
-OCH
2
-CONR
8
R
9
-OCH
2
CH
2 OH, SO 2
-CH
2
-CH
2 COR1 0
-OCH
2
-CH
2
-NR
8
R
9 -S0 2
-CH
2
_CH
2 -OH, -C0NHS0 2 R1 0
CH
2
CONHSO
2
R'
0
OCH
2
CH
2
OR'
0 COOH, COOR' 0
-CONR
8
R
9 -CHO, -SR' 0
-SOR'
0
-SO
2 R1 0
-SO
3
H,
SO
2 NR8R 9
OCH
2
-CH
2 OCOR1 0 CH=NOH, CH=NOR' 0 -COR"1, -CH(OH)R1",
-CH(OR'
0 2
-CH=CH-R'
2 -OCONR8R 9 optionally mono- or poly-, preferably mono-methyl-substituted i, 3-dioxolane or 1,3dioxane; R 6 denotes phenyl-C,-,-alkyl, preferably phenyl- Cl,.
4 -alkyl, phenyl-C 26 -alkenyl or phenyl-
C
2 6 -alkynyl, wherein the phenyl ring is optionally substituted either directly or via a
C
2 alkylene bridge by one or more of the groups, 3 -alkyl, -EN, -NR 8
R
9
-NO
2 -OH, -OR 10
-CH
2 -NH-S0 2
-R'
0
-NHCOR'
0
-NHCONR
8
R
9 halogen,
-OCOR'
0 -OCO-pyridyl,
-OCH
2 COOH, -OCH 2 COOR1 0
-CH
2 OCOR1 0 -S0 2 R 7
-OCH
2
-CONR
8
R
9
-OCH
2
CH
2 0H,
OCH
2
-CH
2
-NR
8
R
9
CONHSO
2
R'
0
OCH
2
CH
2
OR'
0 O, COOR,
-COOR'
0
-CF
3 1 cyclopropyl,
-CONR
8
R
9 -CH 2 0H-,
-CH
2 0R' 0 -CHO, -SR' 0
-SOR'
0
-SO
2 R1 0
-SO
3
H,
SO
2
NR
8
R
9
OCH
2
-CH
2
OCOR'
0 CH=NOH, CH=NOR' 0 -COR", -CH(OH)R", -CH(OR' 0 2
-NHCOOR'
0
CH
2 00NHSO 2
R
0 CH=CH R1 2
OCONROR
9
-CH
2
-O-CONR
6
R
9
-CH
2
-CH
2
-O-CONR
8
R
9 -CO-R1 0 -CO-C,.-alkyl-NRR 9 optionally mono- or poly-, preferably mono-methyl-substituted 1, 3-dioxolane or 1,3-dioxane; R 6denotes C 3 7 -cycloalkyl-c,.-alkyl,
C
3 cycloalkyl-C 2 6 ,-alkenyl, C 3 7 cycloalkyl-
C
2 6 -alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a
CI-
4 -alkylene bridge by one or more, preferably one, of the groups -GN, NR 8
R
9 -OH, -OR 0
-NR
8
R
9
-NHCOR'
0
-NHCONR
8
R
9 halogen, -OCOR' 0 -OCO-pyridyl, -OCH 2 COOH, -OCH 2
COOR
0
-CH
2 OCOR1 0 S0 2 R 7
-OCH
2
-CONR
8
R
9
OCH
2
CH
2 OII, _OCH 2
-CH.
2
-NR
8
R
9
OCH
2
CH
2 COOH, COOR' 0
CONR
8
R
9 -CH 2 0H,
-CH
2 0R' 0 -CHO, -SR' 0 -S0R 1 0
_SO
2
R'
0 -SoyH, S0 2
NR
8
R-
9
OCH
2
-CH
2
OCOR'
0 CH=NOH, CH=NOR' 0 -COR", -CH(OH)R",
-CONHSO
2
R'
0
-CH(OR'
0 2
-NHCOOR'
0 -CH=CH-R'1 2
-OCONR
8
R
9
-CH
2
-O-CONR
8
R
9
-CH
2
-CH
2
-O-CONR
8
R
9 methyl -substituted 1,3dioxolane or 1,3-dioxane;
R
6 denotes a group of the formula A-Ci,.-alkyl, A-CON{-C,-,-alkyl,
A-CONH-C
2 6 -alkenyl, A-CONH-C 2 6 -alkynyl, A-NH-CO-C,-,-alkyl,
A-NH-CO-C
26 ,-alkenyl,
A-NH-CO-C
2 6 -alkynyl, A-C 2 alkenyl or
A-C
2 alkynyl or A-, wherein A is a C- or N-linked 6- or 7membered heterocyclic group 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, C_.
4 -alkyl, halogen, -OR 0 -CN, -NO 2
-NH
2
-CH
2
NRR
9 -OH, a ketal, ethyleneketal, -COOH, -SO 3 H, -COOR 1
-CONRR
9
-COR
1 1 -S0 2
-R
1 0 or -CONR'R 9
R
6 denotes -CHO, -COOR1 0
-CONR'R
9
R
6 denotes C 3 cycloalkyl, preferably cyclopentyl or cyclohexyl, optionally substituted by =0, -OH, -OR 0
OCOR
1 0 or -OCO-pyridyl;
R
6 denotes phenyl optionally substituted by -OH, halogen, -OR' 1
C,.
4 -alkyl, preferably
-CH
3
-NH,,
-COOH, -S03H, -COOR1 0
-OCH
2
COOR
1 0 -CN or
-OCH
2
CONRR
9
R
6 denotes a norbonane, norbornene, C 3 .,-dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane group optionally substituted by C,_ 4 -alkyl, preferably methyl;
R
6 denotes -CH=CH-phenyl, wherein the phenyl ring may be mono- or polysubstituted by methoxy, hydroxy or halogen; R' denotes a [3.3.0]-bicyclooctane, preferably a [3.3.0]-bicyclooctan-2-yl;
R
6 denotes a C-linked piperidine or furan;
R
7 denotes C, 4 4-alkyl which is optionally substituted by -OH, -OCOR 10 -OCO-pyridyl,
-NH,,
-NR'R
9 or -NHCOR 10 preferably
-CH
2
-CH,-OH,
-CH,-CH,OCORo, -CH,-CH2-CH2-OH or -CHCH 2
CH
2
COCOR
1 0 Re denotes hydrogen, an optionally substituted
C
3 6 -cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to carbon atoms, preferably a C 1 _4-alkyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C 1 _--alkoxy, preferably C 1 _--alkoxy, or -(CH 2
-NHCOOR
i0 where m 1, 2, 3 or 4; R' denotes a 6- or 7-membered heterocyclic group which is C-linked directly or via a
C,_
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, Ci.
4 -alkyl, halogen, -OR 10 -CN, -NO 2
-NH
2 -OH, -COOH, -S03H or -COOR 0
R
8 denotes a bicyclic heterocyclic group C-linked directly or via a C 1 4 -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, C.
4 -alkyl, halogen, -OR 10 -CN, -NO 2
-NH
2 -OH, -COOH, -SO3H or -COOR1 0
R
9 denotes hydrogen, an optionally substituted
C
3 6 -cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to carbon atoms, preferably a C,, 4 -alkyl group, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C1,.-alkoxy, preferably
C,.
4 -alkoxy, or -(CH 2
),-NHCOOR
0 wherein m is 1, 2, 3 or 4, preferably hydrogen;
R
9 denotes a 6- or 7-membered heterocyclic group which is C-linked directly or via a
C,.
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, C,_--alkyl, halogen,
-OR
1 0 -CN, -NO, -NH 2 -OH, -COOH,
-SO
3 H or -COOR' 0
R
9 denotes a bicyclic heterocyclic group C-linked directly or via a C,_.-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, C,.
4 -alkyl, halogen, -OR 10 -CN, -NO -OH, -COOH, -SO 3 H or -COOR 1 0 or R' and R 9 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 C,..-alkyl group, preferably methyl, or may carry one of the following groups:
-(CH
2 )n-phenyl,
-(CH
2
),-NH
2 a ketal preferably
-O-CH
2
-CH
2
(CH
2 )nNH-C,_ 4 -alkyl,
(CH
2 8 -alkyl) 2
(CH,{),,-NHCOOR
0 (n 1, 2, 3, 4) halogen,
-OR
10 -CN, -NO 2 -N2' -CH 2
NR
8
R
9 -OH, -COON, -S0 3 H, -COOR 10 -CONR 8
R
9 -S0 2
-R
10
R
10 denotes hydrogen, c,,-alkyl,
C
2 4 -alkenyl,
C
2 4 -alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH 3 R" ~denotes
C
1 4 -alkyl, C 2 -1-alkenyl,
C
2 4 -alkynyl, optionally substituted phenyl, optionally substituted benzyl, C 36 ,-cycloalkyl; R 12 denotes -COOR' 0
-CH
2
OR'
0
-CONR
8
R
9 hydrogen,
C,-
3 -alkyl, optionally substituted phenyl or
CH
2
NR
8
R
9 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) 0 R 0 R4I- I R 4 N N 2I R NIa R 6/N(1b) R N N R 0 R 0 N N N-R2 R (Ic) R (Id) wherein R or R 3 denotes hydrogen, C 14 -alkyl or benzyl;
R
2 denotes hydrogen, C,-_-alkyl, preferably
C
1 I,-alkyl;
R
2 denotes phenyl which is optionally substituted by halogen, preferably fluorine or chlorine,
C
1 -4-alkyl, C 1 4 -alkyloxy, hydroxy or NRR 9
R
2 denotes phenyl-C 1 _--alkyl, preferably benzyl, phenyl-C2-6-alkenyl or phenyl-C 26 -alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, C 1 _4-alkyl, C_4-alkyloxy, hydroxy or
NR"R
9
R
2 denotes an optionally substituted amine, preferably NR 8
R
9
R
2 denotes a 5- or 6-membered heterocyclic group which is optionally C- or N-linked either directly or via a C 1 4 -alkylene bridge, containing one or more heteroatoms selected from the group comprising nitrogen or oxygen and optionally substituted by benzyl or C 1 _4-alkyl;
R
2 denotes a C 3 6 -cycloalkyl which may optionally be substituted by hydroxy, C 4 -alkyl or
C
14 -alkyloxy; RA denotes norbornane, norbornene, adamantane or noradamantane optionally substituted by
C
1 4 -alkyl, preferably methyl; Ror R' denotes hydrogen, C 1 8 -alkyl, phenyl-Cl.- alkyl, preferably benzyl, phenyl-c 2 6 -alkenyl or phenyl- C,-,-alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably chlorine or fluorine, hydroxy, Cl- 4 -alkyl, C3 1 4 -alkyloxy or NR 8
R
9
R
6 denotes hydrogen, C 1 6 ,-alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy,
C,
1 4 -alkyloxy, NR8R 9 phenyloxy, -0-phenyl-
C
1 4 -alkyloxy, benzyloxy, -0-benzyl-0- C3.
4 -alkyloxy, -0C0-C.- 4 -alkyl, -OCO-phenyl, -0C0-benzyl, -OCO-pyridyl, -0-C 2 4 -alkylene, -C0- Cl 14 -alkyl, -CHO0, =NOH, -00011, -COO-CI- 4 -alkyl, -COO-phenyl, -COO-benzyl, -CONROR 9 -NHCO-Cl--alkyl, -NHCO-phenyl,
-CO-C,-
4 -alkyl-NR 8
R
9
-SO
2 0H, -S0 2 -Cl- 4 -alkyl or -S0 2 -phenyl; R 6 denotes phenyl which may optionally be substituted by halogen, preferably chlorine or fluorine, hydroxy, C 1 4 -alkyl, Cl.
4 -alkyloxy, benzyloxy, phenyloxy, NR 8
R
9 -OCO-Cl.
4 -alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -0-C 2 4 -alkylene, -CO-C.
4 -alkyl, -C 1 4 -alkyl-N1 2 -Cl- 4 -alkyl-OH, -C 14 -alkyl=NOH, -COOH,
-COO-C
1 4 -alkyl, -COC-phenyl, -C00-benzyl,
CONROR
9 -CO-Cl- 4 -alkyl-NH 2
-SO
2 0H, -S0 2 -Cj_,-alkyl or -S0 2 -phenyl; R6 denotes phenyl-C-.
4 -alkyl, preferably benzyl, phenyl-C 26 -alkenyl or phenyl-C 2 6 -alkynyl, wherein the phenyl. ring may be optionally substituted by halogen, preferably chlorine or fluorine, hydroxy, C,-,-alkyl,
C
1 alkoxy, benzyloxy, phenyloxy, -NRaR 9
-OCO-C-.
4 -alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl,
-O-C
2 4 -aJlkylene,
-CO-C.
4 -alkyl, -C 1 alkyl-NR 8
R
9
-C
1 4 -alkyl-OH, -C 1 4 -alkyl=NOH,
-COOH,
-COO-C
1 4 -alkyl, -COO-phenyl, -COO-benzyl, -CONROR9,
-CO-C.-
4 -alkyl-NH 2
-SO
2 0H, -S0 2 -Cl.
4 -alkyl or -S0 2 -phenyl; R 6denotes a 5- or 6-membered heterocyclic group optionally C- or N-linked either directly or via a C 1 4 -alkylene bridge, which contains one, two or three heteroatoms selected from nitrogen or oxygen and is optionally mono- or polysubstituted by benzyl or CI.
4 -alkyl;
R
6 denotes a C 3 cycloalkyl or C 3 6 -cycloalkyl-
C
1 4 -alkyl group which may optionally be substituted by hydroxy, C 1 4 -alkyl or
C
1 4 -alkyloxy;
R
6 denotes norbornyl, norbornenyl, adamantyl or noradamantyl optionally substituted by
C
1 4 -alkyl, preferably methyl; 6 denotes -CHO, -COOH, -COO-C 1 4 -alkyl, COO-phenyl, COO -benzyl or CONR8R 9 6 denotes an amine of general formula NR 8
R
9 R denotes hydrogen, a branched or unbranched
CI-
4 -alkyl group; Re denotes a C-linked 5- or 6-membered heterocyclic group which cont-ains one, two or three heteroatoms selected from the group comprising nitrogen, oxygen and sulphur and is optionally substituted by benzyl, C 1 _4-alkyl, C 1 _4-alkyloxy, halogen, -CN, -OH or =0;
R
9 denotes hydrogen, a branched or unbranched
C
1 _4-alkyl group;
R
9 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, C, 4 -alkyl, C 14 -alkyloxy, halogen, -CN, -NH 2 -OH or =0; or
R
8 and R 9 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 C 1 _4-alkyl group, preferably methyl, or by a -(CH 2 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.
Also preferred are compounds of general formulae (Ia) and (Ib) O R 0 4 1 4 RN N RR 2 2 N N NN N R (la)
R
6 (Ib) wherein R or R 3 denotes hydrogen,
C,.
4 -alkyl, preferably
C-.
3 -alkyl and benzyl; R2 denotes hydrogen,
C
1 ,-alkyl, preferably
C
14 -alkyl;
R
2 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydrocyclohexane;
R
2 denotes a morpholine group optionally substituted by C 1 4 -alkyl, preferably methyl, a piperidinyl group, a piperazinyl group optionally substituted by benzyl or C_ 4 -alkyl, preferably methyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furyl;
R
2 denotes a phenyl group optionally substituted by CI-4-alkyl, halogen or hydroxy;
R
2 denotes a phenyl-C_4-alkyl, preferably benzyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine,
C
1 4 -alkyl,
C
1 4 -alkyloxy, hydroxy or
NR
8
R
9 R2 denotes an amine of general formula
NR'R
9 R2 denotes a norbornenyl, norbornyl, adamantyl or noradamantyl optionally substituted by
C
1 -4-alkyl, preferably methyl;
R
4 denotes hydrogen,
C.
7 ,-alkyl, preferably C,-s-alkyl, phenyl-C 1 -3-alkyl, preferably benzyl, wherein the phenyl ring may be substituted by halogen, preferably chlorine or fluorine, hydroxy, C 1 alkyl, C 1 4 -alkyloxy or NR 8
R
9 R 6 denotes hydrogen, C 1 alkyl, preferably
C
1 4 -alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy, =O,
C
1 4 -alkylo'xy, NR 8 R9, phenyloxy, -O-phenyl-o-
C-
4 -alkyloxy, benzyloxy, -O-benzyl-O-C..
4 -alkyloxy, -OCO-C..
4 -alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -0-
C
2 4 -alkylene, -CO-Cl.
4 -alkyl, -CHO, =NOH, -COOH,
-COO-C..
4 -alkyl; -COO-phenyl, -COO-benzyl,
-CONR
8
R
9
-NHCO-C..
4 -alkyl, -NIICO-phenyl,
-CO-C,.
4 -alkyl-NR 8
R
9
-SO
2 -S0 2
-C
1 4 -alkyl or -S0 2 -phenyl; R6 denotes phenyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, C 1 4 -alkyl, C 1 4 -alkyloxy or
NR
8
R
9 R6 denotes phenyl-C 1 3 -alkyl, preferably benzyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, C 1 4 -alkyl, C 1 4 -alkyloxy, benzyloxy, phenyloxy, NR 8
R
9 -OCO-Cl.
4 -alkyl, '-OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C 2 4 -alkylene,
-CO-C
1 4 -alkyl, -C 1 4 -alkyl-NR 8
R
9 4 -alkyl-OH,
-C
1 4 -alkyl=NOH, -COOH, -COO-CI- 4 -alkyl, -COO-phenyl, -COO-benzyl, -CQNR 8
R
9
-CO-C
1 4 -alkyl-NR 8
R
9 -S0 2 0H1, -S0 2 4 -alkyl or -S0 2 -phenyl; RG denotes a cyclopentyl, cyclohexyl, cyclohexyl-
C,-
3 -alkyl, preferably cyclohexylmethyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydroxycyclohexane linked via a single bond or via a C 1 alkylene chain; RG denotes a furan, tetrahydrofuran, a-pyran, y-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 C 1 alkylene chain; R6 denotes -CHO, -COOH, -COO-C,.
4 -alkyl; -COO-phenyl, -COO-benzyl,
-CO-NH-C
1 4 ,-alkyl, -CO-N (Cl.
4 -alkyl) 2 or -CO-NH-phenyl; R6 denotes an amine of general formula NR 8
R
9 R 8 denotes hydrogen, a branched or unbranched Cl-,-alkyl group;
R
8 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, C 1 4 -alkyl,
C
1 alkyloxy, NO 2
NH
2 or OH; R9 denotes hydrogen, a branched or unbranched
C,.
4 -alkyl group; 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, C, 4 -alkyl,
C
1 4 -alkyloxy, NO 2
NH
2
OH,
or
R
8 and R 9 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 C 14 -alkyl group, preferably methyl, or by a -(CH 2 )1-4-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) 0 R N
NN
N N
N
N R R (Ib) wherein
R
2 denotes hydrogen, C 14 -alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted by fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4-benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR'R', cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;
R
3 denotes hydrogen,
C
1 3 -alkyl or benzyl;
R
4 denotes hydrogen,
C
1 _s-alkyl or benzyl;
R
6 denotes hydrogen, C-.-alkyl, preferably methyl, which may optionally be substituted by OH, chlorine, bromine,
C_
4 -alkyloxy or NRR 9
-CHO,
-COOH, -COO-Cl_ 4 -alkyl, preferably
-COOCH
3 phenyl, phenyl-C.
3 -alkyl optionally substituted by fluorine or benzyloxy, preferably benzyl, phenyloxy-C-.3-alkyl optionally substituted by methoxy, preferably phenyloxymethyl, benzyloxy-C 1 3 -alkyl optionally substituted by methoxy, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or N-morpholinomethyl;
R
8 denotes hydrogen,
C
1 _4-alkyl or pyridyl;
R
9 denotes hydrogen,
C
1 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.
Other preferred compounds are those of general formula (Ia) O Ri
^VN
N N N
NR
R (la) wherein R1 denotes hydrogen,
C
1 .3-alkyl or benzyl;
R
2 denotes hydrogen,
C
1 4 -alkyl, phenyl, benzyl, wherein the phenyl ring is optionally fluorinesubstituted, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4 -benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl,
NRR
9 cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl;
R
4 denotes hydrogen,
C
1 _s-alkyl or benzyl;
R
6 denotes hydrogen, Cl-4-alkyl, preferably methyl, which may optionally be substituted by OH, chlorine, bromine, C 1 -4-alkyloxy or NRR 9
-CHO,
-COOH, -COO-C_ 4 -alkyl, preferably
-COOCH
3 phenyl, phenyl-C,.
3 -alkyl optionally substituted by fluorine or benzyloxy, preferably benzyl, phenyloxy-C 1 3 -alkyl optionally substituted by methoxy, preferably phenyloxymethyl, benzyloxy-
C_
3 -alkyl, optionally substituted by methoxy, preferably benzyloxymethyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolylmethyl or Nmorpholinomethyl; denotes hydrogen,
C,-
4 -alkyl or pyridyl; R' may denote hydrogen,
C,
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.
Also of interest are compounds of general formula (Ic) 9 R N N R2 R-N N N R (c) wherein
R
I denotes hydrogen or C 1 3 -alkyl;
R
2 denotes hydrogen,
C-_
4 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;
R
5 denotes C 1 ,_-alkyl, preferably
C
1 _4-alkyl, most preferably methyl, ethyl or tert.-butyl;
R
6 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) N" N N R 1 R 2 R N<N N
R
a (Id) wherein
R
1 denotes hydrogen or C 1 3 -alkyl;
R
2 denotes hydrogen, C 1 4 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl;
R
s denotes C, _-alkyl, preferably C,_4-alkyl, most preferably methyl, ethyl or tert.-butyl;
R
6 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) 0 RN% N I
R
2
N
N N R
N
R
6 (lb) wherein
R
2 denotes hydrogen, methyl, ethyl, n-propyl, ipropyl, n-butyl, tert.-butyl, phenyl, benzyl, 4fluorobenzyl, pyridyl, N-piperidinyl, Nmorpholinyl, N-piperazinyl, 4-benzylpiperazinyl, 2-furyl, 3-tetrahydrofuranyl, 4tetrahydropyranyl, -NMe 2 cyclopentyl, cyclohexyl, adamantan- l-yl, noradamantan- 3-yl, norbornan-2-yl or 5-norbornen-2-yl; R3 denotes hydrogen, methyl, ethyl, n-propyl or benzyl; R 4 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, 3pyridylmethyl, 4 -pyridylmethyl, cyclohexylmethyl, phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl) -NH-CH 2 PhCO-O-CH 2 pyridyl-CO-O-CH 2 Ph-O-CH 2 (4-MeO-Ph) -0-CH 2 (4-Meo-Ph) -CH 2
-O-CH-
2 (4-Ph-CH 2 4-F-Ph-C 2 3,4-F-Ph-CH 2 -COOH, -COOMe, -CH 2 -OI, -CH 2 -OMe, -CH 2 OEt or
-CH
2 -NMe 2 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) 0
R
N N I
>R
K
wherein R1 denotes hydrogen, methyl, ethyl, n-propyl or benzyl; R 2 denotes hydrogen, methyl, ethyl, n-propyl, ipropyl, n-butyl, tert.-butyl, phenyl, benzyl, 4fluorobenzyl, pyridyl, N-piperidinyl, Nmorpholinyl, N-piperazinyl, 4 -benzylpiperazinyl, 2-furyl, 3-tetrahydrofuranyl, 4tetrahydropyranyl, -NMe 2 J, cyclopentyl, cyclohexyl, adamantan- 1-yl, noradamantan- 3-yl, norbornan-2-yl or 5-norbornen-2-yl; R'denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl; R 6 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert. -butyl, phenyl, benzyl, cyclopentyl, 2-furyl, 2-pyridylmethyl, 3pyridylmethyl, 4 -pyridylmethyl, cyclohexylmethyl, phenylethyl, N-anorpholinomethyl, N-pyrrolylmethyl, (3-pyridyl) -NH-CH 2 PhCO-O-CH 2 pyridyl-CO-O-CH 2 I Ph-a-OCH 2 (4-MeO-Ph) 0oCH 2 (4-Meo-Ph) -CH 2 -0-CH 2
I
2 -0-Ph) -OH 2 4-F-Ph-OH 2 3,4-F-Ph-OH 2
-,I
-COOH, -COOMe, -OH 2 -OH, -0H 2 -OMe, -OH 2 OEt or
-CH
2 -NMe 2 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)
N'N
R (Ib 0) R 2 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, -NMe 2 cyclopentyl, cyclohexyl, adamantan-i-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; 3 denotes hydrogen; 4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl; 6 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-morpholinomet hyl, N-pyrrolylmethyl, (3-pyridyl)
-NH-CH
2 Ph-COO-CH 2 3-pyridyl-COO-C 2 Ph-O-CI 2 (4- Meo-Ph)-O-CH- 2 (4-Meo-Ph)-C 2
-O-CH
2 4-F-Ph-CH 2 3,4F-Ph-11 2 -C11 2 -OH, -C11 2 -OMe,
-CH
2 -OEt, -CH 2 NMe 2 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.
Also of particular interest are compouh'ds of general formula (Ia) N N
N
-NN
RIa where in R' denotes hydrogen; R 2 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, -N~e 2 cyclopentyl, cyclohexyl, adamantan-l-yl, noradamatan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R 4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl;
R
6 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-CH 2 Ph-COO-C1 2 3-pyridyl-COO-CrI 2 I Ph-O-CH 2 1 (4- MeO-Ph) -O-CH 2 I (4-MeO-Ph)-C1 2 -o-CH2- 4-F-Ph-CH 2 3,4-F-Ph-CH- 2
-CH
2 -OH, -C11 2 -OMe,
-CH
2 -OEt, -C1 2 N~e 2 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.
In addition, the invention relates to a new category of compounds which contain basic structures of general formulae (Ia) to (Id).
NN N~ N N N 0 0 (Ia) (Ib) 0 a 0 NN
N
N N (Ic) (Id) Preferred compounds are derivatives of general formula 0 N N N N N
H
which have a substituent in positions 2, 4 and 7.
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, tartaric acid or maleic acid. Moreover, mixtures of these acids may be used.
The alkyl groups 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 S(including those which are components of other groups) may, for example, carry one or more of the following substituents: halogen, hydroxy, mercapto, C 1 _--alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, -CHO, -COOH, -COO-C 1 s-alkyl, -S-C 1 6 -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 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, C,.
6 -alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, -CHO, -COOH, -COO-C 1 alkyl, -S-C 1 _--alkyl.
The term alkynyl groups (including those which are components of other groups) refers to alkynyl groups having 2 to 10 carbon atoms provided that they have at 1 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, C 1 alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, -CHO, -COOH, -COO-Cl.
6 -alkyl, -S-C 1 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 C 1 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 carbon atoms which, unless otherwise specified, may carry one or more of the following substituents, for example: C 1 alkyl, C 1 6 -alkyloxy, halogen, hydroxy, mercapto, amino, alkylamino, dialkylamino, CF 3 cyano, nitro, -CHO, -COOH, -COO-C_, 6 -alkyl, -S-Cl- 6 -alkyl. The preferred aryl group is phenyl.
Examples of N-linked cyclic groups of general formula NR'R' are as follows: pyrrole, pyrroline, pyrrolidine, 2methylpyrrolidine, 3-methylpyrrolidine, piperidine, piperazine, N-methylpiperazine, N-ethylpiperazine, N-(npropyl)-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 C,--alkyl, preferably methyl, or may be substituted as in the definitions.
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, y-butyrolactone, a-pyran, y-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, 4 oxadiazole and pyrazolidine, whilst the heterocycle may be substituted as in the definitions.
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 A, A 2 and A 3 receptors.
In the CNS, adenosine develops inhibitory effects predominantly by activating A 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.
A, antagonists cancel out the inhibitory effects of adenosine and promote neuronal transmission and neuronal activity.
A, 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, motorcoordination 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 A receptor antagonists promote neuronal transmission by increased provision of neurotransmitters, they increase the excitability of 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 A, receptors.
Another indication for centrally acting adenosine A, antagonists is depression. The therapeutic success of antidepressant substances appears to be connected to the regulation of A, receptors. A, antagonists may lead to the regulation of adenosine A 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-D 2 receptors.
A
2 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 A receptors appears to be involved.
Selective A 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 A 1 receptors in the lungs may lead to bronchoconstriction. Selective adenosine Al antagonists relax the smooth muscle of the trachea, cause bronchodilation and may thus be useful as antiasthmatic agents.
By activating
A
2 receptors, adenosine may also lead, under certain circumstances, to respiratory depression and stoppage of breathing. A, 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 A 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 A, receptor antagonists are able to prevent damage to the heart and lungs caused by ischaemia and subsequent reperfusion. Consequently, adenosine 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 A, receptors causes vasoconstriction of afferent arterioles and, consequently, a fall in renal blood flow and glomerular filtration.
A,
antagonists act as powerful potassium-saving diuretics on the kidneys and can thus be used for kidney protection and for the treatment of oedema, renal insufficiency and acute renal failure.
Because of the adenosine antagonism on the heart and the diuretic activity, A 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 A 3 -adenosine receptor. A 3 antagonists inhibit the degranulation of mast cells caused by activation of the A 3 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 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 A, 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 suffering from cystic fibrosis (mucovicidosis).
The A, receptor binding values obtained have been determined analogously with Ensinger et al. in "Cloning and functional characterisation of human A, adenosine receptor Biochemical and Biophysical Communications, Vo.187, No. 2, 919-926, 1992" and are assembled in Table The A 3 receptor binding values assembled in Table 21 were determined analogously to Salvatore et al. "Molecular cloning and characterization of the human A 3 -adenosine receptor" (Proc. Natl. Acad. Sci. USA 90, 10365-10369, 1993).
The new compounds of general formula (Ia) to (Id) may be 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 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, preferably between 1 and 50, most preferably between 5 and 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 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.
The compounds according to the invention may be prepared by the following methods. In order to synthesise the two isomers 0 R 0 R 4 R 2 R 4R 2 N IN N N N
R
R (la) R (Ib) of general formula (Ia) and wherein the substituents are as hereinbefore defined, the following procedure is used.
In a first step, aminoguanidine is reacted with a carboxylic acid derivative of general formula to obtain a triazole of general formula (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.
N
R
6 -COOH
N,
N, or Step 1 R 6
NH
'N N 6 N N R -CNN
NH
NH
2 (3) Diagram 1: Then, in a second step, the triazole of general formula is reacted with alkylcyanoacetate in a cyclising reaction under alkaline conditions to obtain a triazolopyrimidine of general formula (Diagram 2).
=N
R _N H St 2NH N NHN'
R
6 (4) Diagram 2: The base may be an alkali or alkaline earth metal alkoxide, e.g. of methanol, ethanol, isopropanol, secor 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 hydroxides may be used as bases. The hydrides of sodium, lithium, potassium, magnesium and calcium are preferred. Suitable inert solvents 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 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, acetic acid or inorganic acids such as hydrochloric or sulphuric acid.
In a third step, the groups R 4 and R 5 are introduced into the triazolopyrimidine of general formula and the compounds of general formulae and (12) are obtained (Diagram 3).
0 0 0 4 10 HNSp
R
N i tep3 N
N
N N NH, N N NH2 2 N 'N
\=N
R R R (12) Diagram 3: For this, a compound of general formula 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 considered are the alkoxides of the alkali and alkaline earth metals already mentioned in step 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 R' and R 5 given hereinbefore. The reaction mixture is stirred at ambient temperature for 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 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 and (12) are obtained by chromatographic purification of the residue (Diagram 3).
By nitrosing a compound of general formula a compound of general formula is obtained in the fourth step (Diagram 4).
0 0 4 4 RN R Step
NO
NNP
N
R R (6) Diagram 4: According to the invention, there are two alternative processes which may be used.
Step 4, alternative A: A compound of general formula is dissolved or suspended in a polar solvent, the polar solvent possibly consisting 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 0 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).
Step 4, alternative B: A compound of general formula is mixed with an aqueous acid, the acid being an organic acid, formic acid, acetic acid, propionic acid, preferably acetic acid or an 1 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 most preferably 70 0 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 most preferably 10 0 C. The product is filtered, the residue is washed and dried in vacuo.
In the fifth step the nitroso compound is reduced to form a diamine derivative of general formula (Diagram 0 0 Rl N NO Step R N NH 2 N N
NH
2 N N NH 2 >N N R
R
6 (7) Diagram The following alternative methods may be used for this purpose.
Step 5. alternative A: The nitroso compound 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 35 used. Moreover, the nitroso group may be catalytically hydrogenated using transition metal catalysts based on palladium, platinum, nickel or rhodium or by transfer 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 1000C, preferably 50 to 900C, most preferably 60 to 80 0
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 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 by weight sodium hydroxide solution by neutralising and then filtered off as a free base.
Step 5, alternative
B:
The nitroso compound 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 preferably 1.5 to 3 hours. The product precipitated is isolated by filtering.
In the sixth step, the isomeric compounds are prepared from the diamines of general formula (Diagram 6).
0 0 0 R NNH R NHCOR 2 N NH 2 1 Step 6 NH N NH NHCOR 1 0 NN NH, N 2 NNHCOR 2
R
6
R
6
R
6 Diagram 6: For this, the amino compound of general formula 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 minutes, most preferably 25 to 45 minutes, the mixture is cooled to 0 to 15 0 C, preferably 5 to 10 0 C and combined with a carboxylic acid derivative wherein the group R 2 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 activated. This may be done, for example, by reacting with chloroformic acid esters, carbonyldiimidazole, carbodiimides, such as dicyclohexylcarbodiimide, EDAC, or benzotriazoles, such as HOBt (l-hydroxy-l-H-benzotriazole) 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 0 C, preferably 7 to 0 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 off, washed and optionally purified by recrystallisation or chromatography, preferably column chromatography.
In the seventh step, a compound of general formula or is cyclised to form the compound of general formula in accordance with methods A to C (Diagram 7).
0 R J L -1NHCOR 2 N Step 7,
N
2 Method A N (8) 0 0
H
RN
NH
2
I
oN
I
N NH Method B N N N
N
0 Rik N NQ Step 7, N 9N NH, Method C
R
67 (6) Diagram 7: Step 7, Method A: A compound of general formula 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 carried out with inorganic acid chlorides such as thionyl chloride, phosphorusoxychloride or phosphorus pentachloride and with polyphosphoric acid.
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 cyclisation.
Step 7. Method B: In another process it is possible to prepare the compound wherein R 2 is hydrogen starting from the diamine To do this, 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 to 250 0 C, preferably 100 to 225 0 C, most preferably 180 200 0 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 may be obtained directly from the nitroso compound of general formula if R 2 denotes a group NR'R 9 wherein R 8 and R 9 are as hereinbefore defined. To a solution of the desired N-formylamine in diglyme, phosphorusoxychloride is added at -10 to +20 0 C, preferably -5 to most preferably o0C. Then the mixture is stirred in an ice bath and the nitroso compound 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 0 C, preferably to 100 0 C, most preferably 70 to 80 0 C and then added to ice 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 (Diagram 8).
4 N N O H N 7 N N N Step 8 (la) N N 0 N N N I 3
NR
R (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 is filtered off and optionally purified 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) 0 0 R NN N N N kR
/R>-RR
2 RRN N R- N N R (d) 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 to obtain (6) described hereinbefore (cf. Diagram 4, Step 4).
0 0 o o
NO
N step 4 Rs'-N N NH, Rse-- N NH2 R N (12) N (1 3 2 Diagram 9: This may be converted in accordance with the method of Step 5 (cf. Diagram 5) into a compound of general formula (14) (Diagram N NO NH2 2 I Step R N N NH 2 R N N
NH
2 R (13) R (14) Diagram In accordance with the alternative methods described hereinbefore for reacting compound to obtain compound (cf. Diagram 6, Step 6) the compounds of general formula (14) may be converted into the compounds of general formula (15) (Diagram 11).
Step 6
NH
2
NHCOR
2 (14) Diagram 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).
-NHCOR
2
NH
2 (14) (16)
NH
2 (13) Method Diagram 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).
0 R N
-N
Step2 S -S R (Ic) R N N N 0 N (16) N N R
R
'N N N N
R
N \3 Diagram 13: Id) By introducing suitably substituted groups R 1
R
2
R
3
R,
R
5 or R 6 the imidazotriazolopyrimidinones (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 R 6 of the compounds (Ib) which may arise according to the invention.
The reactions outlined by way of example in Diagram 14 lead to reactive imidazotriazolopyrimidinones which may be used as starting compounds for further structural variations (esterifications, alkylations, substitutions etc.). According to the invention, all the groups R 1
R
2
R
3
R
4
R
5 or R 6 may be functionalised. These modifications are not restricted to compounds of general formula (Ib) but may also be transferred to the imidazotriazolopyrimidinones of general formulae (Ia), (Ic) and Diagram 14 serves as an explanation by way of example of possible structural variations of the imidazotriazolopyrimidinones (Ic) and (Id), without restricting the invention to the reaction sequences shown.
0 4 N 'N N (lb) NN
R
Oxidation Rr: MeO-C- 0 CHAylf- N [Halogenation
R
4
N
R2
IR
2 N N N
R
3 N R 3 -CH2AIkyl-, X-R' -CH2Alkyl-, Oxidation Oxidation X: Halogen,
N
\^R
2
N
k3
H
0 -Alkyl-, -Alkyl-, Diagram 14: The present invention is explained more fully by means of descriptions of synthesis of imidazotriazolopyrimidinones given by way of example. These Examples serve as an illustration without restricting the invention to their scope.
SteR 1: SYnthOMIR of 5-gubptituted 3 -amino-1,2,4-.triazoles 16 N.NI- I The unsubstituted 3-amino-i, 2,4-triazole is commercially obtainable, the 5-substituted 3-amino-i, 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 R 6 -COOH and nitriles R'-CN -are commercially obtainable or may be prepared by methods known from the literature.
Table 1:- No. R6Yield M commercially obtainable 1.2. -Methyl 76 145-148 1.3. -Ethyl 75 152 1.4. -n-Propyl 62 140-1 43 -i-Propyl 67 103-104 1.6. -n-Butyl 62 118 1.7. -tButyl 39 130-131 1.8. B3enzyl- 70 167-169 1.9. Cyctopentyl- 64 168-172 1.10. 2-Furyl- (Hemisufate) 76 207-208 1.11. Phenyt- 68 185-186 1.12. Cyclohexylmethyl- 51 186-188 1.13. 2-Phenylthytl- 53 139-140 1.14. (4-MeO-Ph)-O-CH 2 41 1. 15 (4-MeO-Ph)-CH 2
-O-CH
2 54 153 1.16. (4-Ph-CH 2 0-Ph)-CH 2 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-7-amino-1.2 4derivatives (4) f
NH
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 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 this process the following Table 2: compounds were.prepared: No R6 Yield Mp 2.1. -H 73 >370 2.2. -Methyl 76 >300 2.3. -Ethyl 81 >300 2.4. -n-Propyl 80 290 (Decomp.) -i-Propyl 81 294 (Decomp.) 2.6. -n-Butyl 77 256 2.7. -t-Butyl 78 >300 2.8. Benzyl- 82 300 (Decomp.) 2.9. Cyclopentvi- 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-CH 2 68 302 2.15. (4-MeO-Ph)-CH 2
-O-CH
2 89 245-- 2.16. (4-PhCH 2 O-Ph)-CH 2 96 296-298 No R6Yield Mp (OC) 2.17. 4-Fluorbenzyl- 79 300-302 2.18. 3,4-Difluorbenzyl- 62 290-292 L2.19. 1 3-Pyridylmethyl- 82 ->300 I I Sterp 3: Synthesis of the alkylated triazolopyrimidine derivatives and (12): 0 4 RN
N
N N NI11 2 RN N11 2 R R 6 (12) General method: 66 mMol of the relevant 7 -amino-1,2,4-triazolo[1,5-a]pyrimidin-5-one 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 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 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 and optionally (12) are isolated by chromatographic purification of the residue. The alkyl halides required R'-X (wherein R'
R
4
R
S
are commercially obtainable or may be prepared by methods known from the literature.
Using this method the following substances were prepared: Table 3: r No. R6R 5 Yield Mp (OC) 3.1 -H -Methyl -80 31 0(Decomp.) 3.2 -H -n-Propyl -58 184 -186 3.3 -H -n-PropyI 18 183 3.4 -Methyl -n-Propyl 61 228 -Ethyl -n-P ropyl 65 194 3.6 -n-Propyl -n-Propyl 69 170 3.7 -i-Propyl -n-Propy 50 138 3.8 -Buty -n-Propyl 62 167 3.9 -t-Butyl -n-Propyl 64 164 -165 3.10 2-Furyl- -n-Propyl 45 260 -262 3.11 Cyclopentyl -n-ProPyl 64 148- 150 3.12 Cyclopetyl- n-Propyl 22 173 3.131 Benzyl- -n-Propyl 60 208 3.14 Benzyl- -Methyl 52 296 3.15 Benzyl- -Ethyl 58 213 3.161 Bienzyl A-rpl- 29 232 3.17 Benzyl- -nBtl- 55 175 3.18 Benzyl- -Pentyl 63 188 3.19, Benzyl- Bnv 51 180-181 3.20 Phenyt- -n-PTRop 30 270 -271 3.21 Cyclohexleh- 67210-212 3.22 1 2-Phenyl yl- -Ethyl 29 173-1 74 3.23 (4-MeO-Ph)-O-CH 2 -Ethyl 58 177-180 3.24 (4-MeO-Ph)-CH 2
-O-CH
2 -Ethyl 100* 3.25 1(4-PhCH 2 -O-Ph)-CH 2 -Ehy 63 240-242 3.26 4-Fluorobenzyl- -Ethyl 53 3.27 3,4-Difluorobenzyl- -Ethyl -61 228 3.281 3-Pyridylmethyl- -Ethyl 4186-188 Isomer separation in following step Step 4: Synthesis of the nitroso compounds and (13) O0 0 R N
R
(13) General methods (alternative A): mMol of 7-amino-l,2,4-triazolo[l,5-a]pyrimidin-5-one or (12) are dissolved or suspended in 10-30 ml of anhydrous dimethylformamide and the mixture is cooled to 0 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.
The following substances were prepared by this method: Table 4a: No. R 6
R
4 R5 Yield Mp 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.) -Ethyl -n-Propyl 94 190 4.6 -n-Propyl -n-Propyl -96 206 (Decomp.
4.7 -1-Propyl -n-Propyl -72 210
JP~P.)
4.8 -n-Buty! -n-Propyl -95 196 (eoP.) 4.9 -t-Butyl -n-Propyt 93 200 4.10 2-Furyl- -n-Proovl 85 261 4.11 Cyclopentyl- -n-Propyl 97 224 4.12 Cyclopentyl- -H 89 225 (Deco2p.
4.13 Benzyl- -H 97 238 (Dcp 4.14 Benzyl- -n-Propyl 95 208- No.
R
4 Yield
(O
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 APe22ofl2 4.20 Benzyl- Benzyl- 96 236 4.21 Phenyl- -n-Propyl 92 257 -258 (Decomp.) 4.22 -H -n-Propyl 63 206 (Deomp) 4.23 Cyclopentyl- -n-Propyl 74 146 4.24 Cyclohexylmethyl- -Ethyl -83 208-209 4.25 2-Phenylethyl- -Ethyl -90 200-201 4.26 (4-MeO-Ph)-O-CH 2 -Ethyl 93 214-216 4.27 (4-MeO-Ph)-CH2-O-CH 2 -Ethyl 56 156-158 4.28 (4-PhCH 2 -O-Ph)-CH 2 -Ethyl 97 201 (Decomp.) 4.29 4-Fluorobenzyl- -Ethyl 89 241-242 4.30 3,4-Difluorobenzyl- -Ethyl 97 234-236 4.31 3-Pyridylmethyl- -Ethyl 44 229 General method (alternative B): mMol of 7-amino-1,2,4-triazolo[1,5-a]pyrimidin-5-one or (12) are suspended in 80 to 100 ml of glacial acetic acid. The mixture is heated to 70 0 C, mixed with a solution of 20 mMol of sodium nitrite in 2-4 ml of H 2 0 and stirred-for 0.5-2 hours at 70 0 C, then for a further 0.5-2 hours at 10 0 C. The product is filtered off, washed and dried in vacuo. Using this process the following compounds were prepared: Table 4b: No. R6 R 4
R
5 Yield(%) Mp (oC) 4.32 Benzyl- -H 65 236 (Decomp.) Step 5: Synthesis of the diamines and (14): 4 0 0 R4"N NY N H 2 N2 NH2 RN N NH 2 1 1 ^N
=-N
R
6
R
(14) General method (alternative A): 12.7 mMol of the nitroso compound or (13) are suspended in 86 ml of HO with stirring and 4.9 g (2.9 mMol) of Na 2
S
2 04 are added. The suspension is heated to 80 0 C and within 30 minutes 15 ml of 50% H2SO, are added.
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 free base precipitated is filtered off.
General method (alternative B): 11.5 mMol of nitroso compound 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 0 C until the nitroso compound has substantially dissolved, a solution of 6.1 g (34.7 mMol) of Na 2
S
2 0 4 in 57 ml of H 2 0 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 Na 2
S
2 O, 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 Table No. R6R 5 Alter- Yield Salt formn Melting point in naive in o 5.1 -H -H -A 73 Hemnisuffate >300 5.2 -H -Methyl -A 65 -267 (Decomp.) 5.3 -H -n-Propyl -A 65 185-188 5.4 -Methyl -n-Propyl A 70 174 -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 Hem isulfate 224 5.11 Cyclopentyl- -n-Propyl A 48 He-misulfate 195-197 5.12 2-Furyl- -n-Propyl B 75 -204-205 5.13 Benzyl -i-Propyl A 8 Hemnisuffate 223 5.14 Benzyl- -n-Propyl A 62 Hemnisulfate 217 5.15 Benzyl- -Methyl B 91 -248 No. R6R 5 Alter- Yield Salt form Melting point native in inO 5.16 Benzyl- -Ethyl B 95 -175 5.17 Benzyl- -n-Butyl A 48 Hem isulfate 203-205 5.18 Benzyl- -n-Pentyl B 92 -146 5.19 Benzyl- -H A 47 Hemnisulfate 218-220 5.20 Benzyl- Benzyl- -B 80 -273 5.21 Phenyl- -n-Propyl -A 79 Hemisulfate 260 5.22 -H -n-Propyl A 81 222-224 5.23 Cyclopentyl- -n-Propyl A 86 175 5.24 Cyclohexylmethyl- -Ethyl -B 94 158-160 5.25 2-Phenylethyl- -Ethyl -B 94 204-205 5.26 (4-MeO-Ph)-O-CH 2 -Ethyl -B 86 154-156 5.27 (4-MeO-Ph)-CH 2
-O-CH
2 -Ethyl -B 88 133-139 5.28 (4-PhCH 2 -O-Ph)-CH 2 -Ethyl -B 84 155 5.29 4-Fluorobenzyl- -Ethyl -B 88 202-205 5.30 3,4-Difluorobenzyl- -Ethyl -B 95 209-212 5.30_ 3-Pyridylmethyl- -Ethyl -B 82 1 79-180 Step 6: Synthesis of amides and 0 4 2 RN NHCOR2 N NHCOR 2 N N NH 2 RN
NNH
2 R N R N 0 0 RN F2
NH
2 N N NHCOR' RS N NHCOR' R'NN
NOR
R R 6 (8) General method (alternative A): 30 mMol of diamino compound or (14) are suspended in 165 ml of anhydrous dimethylformamide and mixed with mMol (or in the case of hemisulphates 78 mMol) of 4dimethylaminopyridine. The mixture is stirred for minutes at ambient temperature, cooled to 5 10 0 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 0 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.
84 Using this method the compounds of formulae and described in Table 6a were prepared, inter alia: Table 6a: No. RR4RR2Yield in Melting point in 6.1 -H -H Cyclopentyl- 86 284 (Decomp.) 6.2 -H -Methyl -Benzyl- 35 306 6.3 -H -n-Pro I Benzl- 65 178 6.4 -H -n-Propyl -Cyclopentyl- 95 192 -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- -n7Propyl -Ethyl 76 205 6.15 Cyclopentyl- -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 L6.22 Benzyl- -Ethyl -4-Tetrahydropyranyl- 65 237 No. R 6 R4R 2Yield in Melting point in 6.23 Benzyl- -Ethyl 2-Pyridyl- 63 223 6.24 Benzyl- -Ethyl 4-Pyridyl- 55 6.25 Benzyl- -n-Propyl -Ethyl 61 183 6.26 Benzyl- -n-Propyl -n-Propyl 62 166 6.27 Benzyl- -Methyl Cyclopentyl- 88 205-208 6.28 Benzyl- -Ethyl -Cyclopentyl- 90 188-189 6.29 Benzyl- -n-Propyl -Cyclopentyl- 77 170 6.30 Benzyl- -n-Butyl -Cyclopentyl- 60 163 6.31 1Benzyl- -n-Pentyl -Cyclopentyl- 67 162 6.32 Phenyl- -n-Propyl Ethyl 47 165-166 6.33 Phenyl- -n-Propyl -Cyclopentyl- 68 >300 6.34 -H -n-PropyI Cyclopentyl- 69 248 6.35 Benzyl- -Ethyl 2-Pyridyl- 40 223 6.36 Benzyl- -Ethyl 4-Pyridyl- 55 6.37 Benzyl- -Ethyl 3-Pyridyl- 88 206 6.38 Benzyl- -Ethyl____ Cy clohexy- 86 186-1 87 6.39 Benzyl- n-Butyl- -H 84 231-232 6.40 Benzyl- -H Phenyl- 72 276-279 6.41 Benzyl- -H 2-Furyl- 69 305-307 6.42 3-Pyridylmethyl- -Ethyl Cyclopentyl- 73 163-165 6.43 3-Pyridylmethyl-. -Ethyl -Ethyl 71 186-187 6.44 2-Furyl- -n-Propyl 2-Furyl- 81 228 No. RR4RR2Yield in Melting point in 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)- 0CH2- -Ethyl -Ethyl 93 160-164 6.52 (4-MeO-Ph)- OCH 2 -Ethyl Cyclopentyl- 76 176-1 78 6.53 (4-MeO-Ph)-CH2-O-CH2- -Ethyl -Cyclopentyl- 91 133-136 6.54 (4..PhCH 2 O..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 -IV 6.59 4-Fluorobenzyl- -Ethyl -91 6.60m 3,4-Difluorobenzyl- -Ethyl -Cyclopentyl- 100 222-224 6.61 3,4-Difiuorobenzyl- -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 or (14) are suspended with 7.3 mol of the corresponding 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 0 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 and described in Table 6b were prepared: Table 6b: No. R 6
R
4
R
5
R
2 Yield in 6.64 4-fluorobenzyl- Ethyl- 26 Step 7: Reactions of cyclisation to obtain the imidazotriazolopyrimidinones and (16) O H H N 2 N N Rt Rs-- N "R2 N N N
R"N
R
6
R'
(16) General method (Method A, alternative A): 14.4 mMol of or (15) are suspended in 75.5 ml of HO and 37.8 ml of ethanol and refluxed with 17.4 ml of 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 89 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.
'1 Table 7a: No. RR4RR2Yield in Melting point in OC 7.1 -H -H -Cygiopentyl- 80 >360 -7.2 -H -Methyl Benzyl- 35 306 -7.3 -H -n-PropyI Benzyl- 68 222-223 7.4 -H -n-Propyl Cyclopentyl- 59 250 -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- 49 300 (Decomp.) 7.10 -n-Propyl -n-Propyl 4-Fluorbenzyl- 65 221 7.11 -i-Propyl -n-Propyl Cyclopentyl- 62 260-261 7.12 -n-Butyl -n-PropyI Cyclopentyl- 72 246 7.13 -t-Butyl -n-Propyl Cyclopentyl- 64 310 7.14 Cyclopentyl- -n-Propyl -Ethyl 85 245-248 7.15 Cyclopentyl- -n-Propyl -Methyl 56 248-250 7.16 Cyclopentyl- -n-Propyl Benzyl- 70 233 7.17 2-Furyl- -n-Propyl Cyclopentyl- 61 >300(Decomp.) 7.18 2-Furyl- -n-Propyl -Ethyl 44 >300(Decomp.) 7.19 Benzyl- -H Cyclopintyl- 40 270 (Decomp.) 7.20 Benzyl- Benzy Cyclopentyl- 13 270 7.21 Benzyl- -Ethyl -3-Tetrahydrofuranyl- 60 227 T if, 1 No. RR4RR2Yield in Melting point in OC 7.22 Benzyl- -Ethyl 4-Tetrahydropyranyl- 64 237 7.23 Benzyl- -Ethyl 2 4 'yridlyl- 21 287 7.24 Benzyl- -Ethyl m 4-Pyridyl- 8 346 7.25 Benzyl- -n-Propyl -Ethyl 57 223 7.26 Benzyl- -n-PToyl -n-Propyl 53 202 7.27 Benzyl- -Methyl C yclopentyl- 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-Penty Ccopenty-5 3-3 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- 24260 7.36 Benzyl- -Ethyl 3-Pyridyl- 11 33 1-332 7.37 Benzyl- -Ethyl Cyclohexyl- 74 260-262 7.38 3-Pyridylmethyl- -Ethyl Cylopentyl- 60 26 1-263 7.39 3-Pyddylmethyl- -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 7.42 Cyclohexylmethyl- -Ethyl -Ethyl 73 230-2S2 7.43 Cyclohexylmethyl- -Ethyl -Cyclopentyl- 62 273-274
I
No. RR4RR2Yield in Melting point in OC 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)-OCH- 2 -Ethyl -Ethyl 47 225 7.49 (4-MeO-Ph)-OCH 2 -Ethyl Cyclopentyl- 20 234-236 7.50 (4-MeO-Ph)-CH 2
-O-CH
2 -Ethyl Cyclopentyl- 70 182 7.51 (4-PhCH 2 O-Ph)-CH 2 -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- 60 264-266 7.57 3,4-Difiuorobenzyl- -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 or (15) are stirred in 10-15 ml pf tetrahydrofuran and 25-35 ml of H 2 0 with 46 mMol of lithium hydroxide monohydrate at 45-650 for 14 days. Then 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.
The compounds of general formula described in Table 7b were prepared by this method.
Table 7b: No. R 6
R
4
R
2 Yield Mp (OC) 7.62 Cyclohexylmethyl- Ethyl- 10 246-248 7.63 Cyclohexylmethyl- Ethyl- 3 258-260(Decomp.) General method (Method B): 10.1 mMol of or (14) are stirred into 34 ml of formamide for 1.5 hours at 200 0 C. The remaining formamide 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.
Using this process, the compounds and (16) listed in Table 7c were prepared: No. R6R 5 R 2 Yield Mp C~C) 7.64 -Ethyl -n-Propyl -H 84 >300 7.6 Cylopentyl- -H -H 53 215 7.66 Cyclopentyl- -Methyl -H 1 7 >300 7.67 3-Pyridylmethyl- -Ethyl -H 58 328-330 7.68 Cyclopentyl- _-n-Propyl -H 58 287 (Decomp.) 7.69 2-Furyl- -n-Protpyl -H 74 >300 (Decomp.) 7.70 Bezl -Methyl -H 9 >300 7.71 Benzyl- -n-Propyl -H 75 >300 7.72 Benzyl- -i-PrOpyl -H 90 >300 7.73 Benzyl- -n-Butyl -H 75 >300 7.74 Benzyl- -H -H 63 >300 7.75 Phenyl- -n-Propyl -H 75 295-296 _____Decomp.
7.76 Cyclopentyl- n- -H 35 202-203 Propy I 7.77 3-Pyridylmethyl- -Ethyl -H 58 328-330 7.78 Cyclohexy lmethyl- -Ethyl -H 87 328-330 7.79, 2-Phenylethyl- -Ethyl -H 84 1 273 General method (Method At 0 0 C, 0. 66 ml (7.2 inMol) of phosphorusoxychloride are added to a solution of 6.8 rnMol of the desired Nformylamine in 6 ml of diglyme. The mixture is stirred for 30 minutes in an ice bath and then 4.8 mMol of nitroso compound or (13) are added. The mixture is stirred at 0 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 described in Table 7d were prepared: Table 7d: No. R 6
R
4 R2 Yield 7.80 Benzyl- -n-Propyl N-Morpholinyl- 21 7.81 Benzyl- -n-Propyl 4 -Benzyl-l-piperazinyl- 21 7.82 Benzyl- -n-Propyl Dimethylamino- 9 7.83 Benzyl- -n-Propyl N-Piperidinyl- 22 Mp (C) 298 266-268 272-274 294-297 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 imidazo[4,5-e]-[1,2,4]triazolo[l,5-a]pyrimidinunsubstituted in the 4-position with R 4 H] or (16) with R 5 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 precipitated is filtered off and purified by chromatography. If required, the dialkylation products (Ia) and (Ib) may be isolated.
The following compounds were prepared using this method: Table No._ R6 R4R52 8.11 Benzyl- -~Methyl J -H -8.2 Cyclopentvi- -Methyl -Methyl T -H I -Methyl I 8.4 8.6 8.7 8.8 8.9 8.10 8.11
-H
-H
-H
-H
Benzyl- Benzyl- -Ethyl -n-P ropyl- -n-Butyl -t-Butyl -Ethyl -Ethyl
I
Cyclopentyl- -Cyclopentyl- Cyclopentyl- Cyclopentyl- Cyclopentyl- -t-Butyl Phenyl- Yield 9 7 44 57 52 45 10 24 24 4 9I >300 7 >300 44 285 57 249-253 52 255 45 243 10 190-191 24 243-244 24 343-345_ 4 1435
I
-H
-H
-n-Butyl Cyclopentyli t 1
I
Cyclopentyl- Moreover, the following compounds (Ia) and (Tb) could be obtained by this method: 4
R
1
N
'N
R 4
IN
N
(la) (11) Table 8b: No R6R 1or RR2Yield MVp 0
C)
8.12 Benzyl- -Ethyl -Ethyl -H 4 >300 8.13 -H -Methyl -:Methyl Cyclopentyl- 4 206 8.14 ,Cyclopentyl- -n-Propyl -n-Propyl -H 10 146 8.15 Cyclopentyl- -n-Propyl -n-Propyl -H 5 151 8.16 Benzyl- Ethyl -Ethyl I2-Furyl- 16 1187-1891 General method (alternative B): 20.4 mMol of imidazo[4,5-e]-[1,2,4]triazolo[l,5-a]unsubstituted in the 4-position with
R
4 H] or (16) with R 5 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 0 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 CH 2 Cl 2
/CH
3 OH 9:1 and the extract is evaporated down. The isomeric alkylation products and (16) are isolated by chromatography on silica gel with
CH
2 C1 2
/CH
3 OH 95:5 (Table 8c). The following compounds were prepared using this method.
Table 8c: No. R 6 R4 R 5 R2 Yield Mp (oC) 8.17 -H -t-Butyl Cyclopentyl- 10 190-191 8.18 -H -t-Butyl Cyclopentyl- 5 149-150 General method (alternative C): 0.05 Mol of starting compound 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.
Table 8d: No.
R1 or R3 Yield 170' 8.191 (4-MeO-Ph)-CH 2
-O-CH
2 Ethyl- Benzyl- Cyclopentyl- 85 8.201 (4-PhCH 2 O-Ph)-CH 2 Ethyvl- Benzyl- Cyclopentyl- 166 Ye MID (OC) 127-128 1f38-1401 IX. Functionalisation of the imidazotriazolopyrimidinones of general formula IX.a. Deblockincr of imidazotriazolopvrimidinones (LaY/ib) with protected hydroxvl functions- General diagram of synthesis taking as example the compounds of general (formula Ib): 0 N R2 P RKIIN N2 R'aN N
IHO
DDQ: 2, 3-Dichloro-5, G-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: Table 9: No. RR4
R
1 or R2Yield Mp (OC) 9. O-H-
R
3
M%~
9. j HO-H2- Ethyl Benzyl- C.Ycoentyl- 97 204-207 IXb. Dbckin rofimiotrazoiaoorimir..nn T= I /(TI-0 with protected amine functions in t-he s-r ,4-ri General diagram of synthesis taking as example the compounds of general formula (Ib): u 0 R N N
N
NN
NH
I-N N 6N
NH
N
N
R
6
R
0.83 mMol of a 7-(4-N-benzyl-l-piperazinyl)imidazo[4,5-e]- [1,2,4]triazolo[1,5-a]pyrimidin-5-one are taken up in ml of glacial acetic acid and hydrogenated at 60 0 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 CH 3 OH, the solid product is filtered off, washed and dried. Using this method the following was obtained: Table No. R 6 R4 R 1 or R2 Yield Salt form Mp
R
3 10.1 Benzyl- n-Propyl- H- 1-Piperazinyl- 53 Acetate 2( IX.c. Cleaving of protective amine groups from the imidazotriazolopyrimidinone core structure: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 RN N R
N
R H
N
N N N Cat. N N 3-N-benzylated imidazotriazolopyrimidinones of general formula are dissolved in methanol or absolute glacial acetic acid and hydrogenated under a hydrogen atmosphere bar) at 25-80°C with the help of a palladium catalyst Pd/C) over a period of 2.5-40 hours. The catalyst 100 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.
Table 11: 11.2 11.3 11.41 Methoxymethyl- Ethoxymethyl- Hydroxymethyl- Benzoyloxvmethi- _Ethyl- Ethyl- Ethyl- CyR2etl Cyclopentyl- Cyclopentyl- Cyclopentyl- Salt form Yield 27 Mp (00) 246-248 224-225 305-307 Ethyl-
I
I
238-239 No.
R
6 R4 R2 Salt form Yield Mp 11.5 Dimethylaminomethyl- Ethyl- Cyclopentyl- Methanesulfonate 29 224- 225 11.6 N-Morpholinyl-methyl- Ethyl- Cyclopentyl- Methanesulfonate 47 184 11.7 Phenoxymethyl- Ethyl- Cyclopentyl- 40 229 IX.d. Alkylation of hydroxy-substituted imidazotriazolopyrimidinone: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 N N N N N N alkylhalide N N N N R N R HO R 3 mMol of hydroxyalkyl- or hydroxyaryl-substituted imidazotriazolopyrimidinones of general formula (Ia), (Ic) or (Id) are dissolved in 30 ml of anhydrous dimethylformamide, mixed with 3.6 mMol of sodium hydride 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: 102 Table 12: No.
R
6
R
4
R
1 or R2 Yield Mp (oC)
R
3 12.1 Methoxymethyl- Ethyl- Benzyl- Cyclopentyl- 37 116-118 12.2 Ethoxymethyl- Ethyl- Benzyl- Cyclopentl- 36 120-123 IX.e. Acylation of hydroxy-substituted imidazotriazolopyrimidinones: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 R N R N -R pyridine i 2
C
N N N carboxylic acid N N N chloride N R 3 HO-/ R 6 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
R
1 or R2 Yield
R
3 12.1 0 Ethyl- Benzyl- Cyclopentyl- 73 0- CHI_ 12.2 Ethyl- Benzyl- Cyclopentyl- 93 N CH.- 103 IX.f. Halogrenation of hvdroxv-substituted imidazotriazolopyrimidinones: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 4IN N halogenating R N
N
P2means N 3 NF-t 3 N N N 3 H-1O
R
The hydroxylated imidazotriazolopyrimidinones are converted into the corresponding halides in the usual way with halogenating reagents such as SOC 2 SOBr 2 POCd 3 in inert solvents in the presence of bases NEt,).
The following compounds were prepared analogously: Table 14: No. R6R 1or R2Yield Mp (00)1
R
3
M%
14.1 Br-CH 2 Ethyl- Benzyl- Jo do entyI- 66 188-189 IX.q. Nucleophilic substitution in halogen-substituted imidazotriazolopyrimidinones: General diagram of synthesis taking as example the compounds of general formula (Ib): 4 0alcohol 4 0 N orin
N
I ~N I>i amin N N P~aseN N N 3 1 XX: chlorine, bromine, R iodine 104 Using generally known standard procedures, halogensubstituted imidazotriazolopyrimidinone derivatives may be converted into the corresponding amines and alkyloxy/aryloxy compounds by reacting with nucleophiles 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 analogously: Table No.
R
6
R
4
R
1 or R2 Yield Mp (oC)
R
3 15.1 (CH 3 2
N-CH
2 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 imidazotriazolopyrimidinones: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 4 4 N N R NR R Using generally known standard procedures (e.g.
Tetrahedron Letters 1979, 5, 399-402) hydroxy-substituted imidazotriazolopyrimidinone derivatives may be converted into imidazotriazolopyrimidinones with functionalities of a higher oxidation state aldehydes, carboxylic acids). The following compounds were prepared analogously: 105 Table 16: No. R6 R4 R1 or R3 Yiel 16.1 -CHO Ethyl- Benzyl- Cyclopentyl- 48 16.2 -COOH Ethyl- Benzyl- Cyclopentyl- 38 Id o) Mp (oC) 153-154 157-158 IX.i. Derivatisation of imidazotriazolopyrimidinone carboxylic acids: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 N-N R3
N
HO- R6 0 Using methods known from the literature, imidazotriazolopyrimidinone carboxylic acids may be converted into a plurality of carboxylic acid derivatives halides, anhydrides, amides, ester, etc.). The following general method may be used to prepare the corresponding imidazotriazolopyrimidinone-methyl carboxylates: 0.003 mol of imidazotriazolopyrimidinone carboxylic acid are suspended in a 1 molar solution of SOC1, (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: Table 17: N o R 6 R 4 R or R2 Yield Mp (oC)
R
3 17.1 -COOCH 3 Ethyl- Benzyl- Cyclopentvl- 71 155-157 106 IX.k. Reductive amination of imidazotriazol yimidnon aldehydes: General diagram of synthesis taking as example the compounds of general formula (Ib): 0 0 R4 N N R
N
Using generally known standard procedures, imidazotriazolopyrimidinone aldehydes may be converted into the corresponding amines by reaction with primary or secondary amines and subseent reduction or hydrogenation
N
3 or H 2
R
0 Using generally known standard procedures, imidazotriazolopyrimidinone 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: IA~l"i]; 107 Table 19 summarises the compounds of general formula prepared analogously to the processes described hereinbefore: O
R
R N N
R
d
(I'
Table 19: ~i~j 108 Example
-R
1 or Melting No -3-R 2 -4-R 5
-R
6 point in Chemical Name
C
6 -H -Ethyl -n-Propyl 223 2 -Benzyl-7-ethyl-4-n-propyl-imidazo.
,241tdazolof1,5-alpYdimidjn-5-one 7 H -n-Propyl -n-Propyl k- )202 2 -BenzyI-4,7-di-n-propyl-imidazo[4,5-e..
ii [1241triazolofl,5-alpyrmidin-5-one 8 H -Q-Methyl 265-267 2 -BenzyI-7-c.ycopenty-4-methyI.imidzo 14,5-0141 ,24]Mrazolo[1 9 -H -<)-Ethyl 242 2 -Benzyl-7-copentyl4ethylimidazo.
,2,4ltrazolo[i -H *n-Propyl 234-235 2 -Benzy-7-cylopenyI4n-propyJ.-imdzo -Fl 1 4 azolofI 5-a 11 H -c n-Butyl -238-240 2 -BenzylIA-n-buty-7-cylopentyJ.imidzo 1[4,5-el-[1 ,2,4ltriazolo[1 12 -11 -270 2 ,4-DibenzyI-7-cyclopentyl-imidazo 12 ,2,4ltriazo ol 13 H P opy -29 2-BenzyI-4-n-propyl-7-(N-morpholino)- .2,4jtnazolo[1 14 -H -n-Propyl -266-268 2 -Benzyl-7-(4-benzylpiperazino)-4n-propyl.
,2,4jtriazolofl one -H -N -n-Propyl -260 2 -BenzyI4-n-propy!7-(l pIpera4InyI)imidazO_ I I 1[4,5-el-f1 2,4 tdazolo 1,5-a 109 Example -RI or Melting No. -3-2-4-5-6Point in Chemical Name 16 -H -Ethyl 3237 2 -BenzyIA4-ethyl-7-(3-tetrahydrofuryl)-imidazo- ,2,4]triazolorl 17 -H -4 Ethyl -227 2 -Benzyl-4-ethyl-7-(4-tetrahydropyranyl).
imidazo[4,5-e]-[1 ,2,4]triazolo[1 one 18 -H
-<J-R
4 or -R 5 -H 270 2-Benzyl-7-cyclopentyl-imidazo[4,5e..
Decomp.- fi ,2,41triazolofl 19 -H -H
-R
4 or -H J215 2-Cyclopenty-imidazo4,..eI[1,2,4] trazolo[I -H -H -Methyl 3 300 2 -Cyclopentyl-4-methyl-imidazo[4,&e..
[1,2,4]trjazolofi 21 -H -H -n-Propyl 287 2 -Cyclopentyl-4-n-propyl-imidazo45ep- Decomp. [1 ,2,4]triazolo[1 22 -H
-CH
3 -nPropyl J248-250 2 -Cyclopentyl-4n-propyl-7-methylimidazo- ,2,41triazolo[l ,5-alpyrimid 23 -H -Ethyl -n-Propyl -QJ245-248 2 -Cyclopentyl-7-ethylA4-n-propyl-imidazo- ,,4triazoo1 24 -H -n-Propyl -J1233 7 -Benzy-2-cyclopentyl-4-n-propy..imidazo.
-Pntyl- 14,5-el-[I ,2,4ltriazolofl -H -ci -n-etl--F 231-236 2 -BenzyI- 7 -cyclopenty-4-n-pentylimidazo-.
4 5-el-fl ,2,4ltriazolofl 130 Example -R 1 or Melting No. -R 3
-R
2 -4R5R6poin in Chemical Name 26 -H
-CH
3 H 306 7-Benzyl-4-methyl-imidazo[4,5-e][1,2,4] triazolo I 5-a 27 -H -n-Propyl H 222-223 7 -BenzyI-4-n-propy-imidazo4,5-eI12,4]triazololi 28 -H
R
4 or -R 5 -H 360 7-Cyclopentyl-imidazo[4,5-e.f1 triazolori 29 -H -Methyl H 285 7 -Cyclopentyl-4-methyl-imidazo[4,5-eJ4[1 2,41triazolo[I -H -Ethyl H 249-253 7-Cyclopentyl-4-ethyl-imidazo45-el..[1,2,41tilazolo I 5-a 31 -H J -n-Propyl H 250 7 IIf.2.4]-tazoofl,5-alpyrimidin-5-one 32 -H -Ethyl
-COOCH
3 270-271 2-Carboxymethyl-7-cyclopentyl4ethylimidazo[4,5-e]-[1 ,2,4]triazolo(I one 33 -H -n-Propyl
H
3 262-264 7 -Cyclopenty-2-methyI4npropyimidzo I [4,5-e -[1,2,4]triazolo I 5-a 34 -H -H -n-Propyl Ethyl 300 2-EthyI-4-n-propy-imidazo-[4,5-e]{[1,2,4]- I trazolofI -H J -n-Propyl Ethyl 253 7 -Cyclopentyl-2-ethyIA4-n-propyl-imidazo- 1,2,4]triazolo[I 5-a jil Example
-R
1 or Melting No. -3-2-4-5-R 6 point in Chemical Name OC 36 -H KIJ -n-Propyl -n-Propyl 256 7 -Cyclopenty-2,4-di-n-propyl-imidazo.
I 1,2,41triazolori 5-a 37 -H -'3J -n-Propyl -i-Propyl 260-261 7 -CyclopentyI.2-i-propyl-4-n-propyI..imidazo- 1 4,5-elfl ,2,4]triazolofI 38 -H -n-Propyl -n-Butyl 246 2 -fl-ButyI-7-cyclopenty-4-n-propyI-imidazo.
24]triazolofl 39 -H 1J -n-Propyl 310 2 -t-ButyI-7-c-ycopentylI4n-propy..imidazoi -H y -n-Propyl -n-Propyl 300 2 4 -Di-n-propy-7-pheny-imidazo45-e[1 Decomp. triazotofI 5-a -F -n-Propyl -n-Propyl 221 2 4 -Di-n-propyl-7-(p-fluorbenzyl)-imidazo- 1 2,4]tnazolo I 5-alrim 42 -H -Ethyl -n-Propyl -Ethyl 229 2 7 -Diethyl-4-n-propyl-imidazo[45e]{[1,2,41triazolo I 5-a 43 -H -H -n-Propyl 295-296 2 -PhenyI-4-n-propyl-imidazo[4,5sej.1,2,4p Decomp. tdazolo[I 44 -H -Ethyl -n-Propyl 300 7-Ethyl-2-phenyl-4n.propyl-imidazo- Decomp. ,241tdazojo[1 -H .(7J -n-Propyl 300 7 -CyclopentyI-2-phenyI-4n..propyl-imidazo- DeCOMP. ,f4,5-e]-H ,2,41triazolo[1 112 Example
-R
1 or Melting No. -3-2-4-5-6point in Chemical Name 46 H -nProyl >300 2 -(2-FuryI)-4-n-propyl-imidazo) Decomp 14,5-el-fl ,2,4ltriazolof 47 -H -Ethyl -n-Propyl 300 7 -Ethyl-(-y)n.rplmdz 0 Decomp. tnazolo[1 5-a 48 -H (3-n-Propyl 300 7 -CyclopentyI2(2-Iy)-4-n-propyI.imidzo 0 Decomp. .[4,5-el-fl ,2,41triazoloFI 49 -n-Propyl -H
-R
4 or -R 5 -H 271-273 2 -Cyclopent6-n-propy-imidazo.
,2,4JRiazolofl -H -H
-R
4 or -R 5 -H -H 300 Imidazo[4,5-eJ-[1,2,41triazolo[1,5-apyrmidn-5-.
one 51 -H -EJ Ehyl H 260 7 -Cyclopentyl-3-ethyl-imidazo[4,5-e].[1 triazolofi 52 -H -c7 nPoy H217-220 7 -Cyclopentyl-3-n-propyl-imidazo- 145-el-fl ,2,4ltriazolofl 53 -CH 3 -Cn 3 H 206 7 -Cyclopentyl-4,8-cjimethyl-imidazo.
,2,4ltriazolo[ 1,5-alpyrimidin-5-one 54 Ethl H -thy 300 2 -Benzyi-4,8-diethy-imidazo- 45-el-fl,2.41trazolo[1,5-alpydmidin-5-one -H -H n-Propyl i202-203 2 -Cyclopentyl-3-n-propyl.imidazo.
-F1 2,41triazolo[I 5-a 113 Example -R 1 or Melting No. -R 3 -2-4-5R6Point in Chemical Name
OC
56 -n-Propyl -H -n-Propyl -<Qj146 2 -Cyclopentyl-46-di-n-propy-imidazo- 1 2,4 tnazolo I 57 -n-Propyl -H -n-Propyl 151 2 -Cyclopenty-4,8.in-propyljimidazo- 1,2,4 trazolo I 5-a 58 -H i-n-Butyl -H 243 7 -Cyclopentyl-4-n-butyl-imidazo- [4,5-elf1 ,2A4lriazolo[1 59 -H -Ethyl 287 2 -BenzyI-4-ethyl-7-(2-pyridyl)limidazo.
,2,4ltriazolo[l -H N-Ethyl -346 2 -BenzyI-4-ethyI-7-(4-pyndy)imidazo- 12 4 tdazolof I 61 -H 149-1 50 7 -CyclopentyI-3-tert.-butyl-imidazo- ,2,4ltnazolo1 62 -H 190-191 7 -CyclopentyI-4-tert.-butyl-imidazo- 1 24 triazolofI 63 -H >-Ethyl 331-332 2 -Benzy-4-ethy-7-(3-pyridy)-imidazo- [4,5-el-fl,2,4]triazolof 64 -H -n-Propyl -385-387 2 7 -Di-(2-furyl)-4-n-propyl-imidazo.
_14,5-el-[1 .2,4]triazolofl -H -N(CH 3 2 -n-Propyl 272-274 2 -BenzyI-7-dimethylamino-4-npropyl.
imidazo[4,5-eJ-[1I,2,4]triazolofl one a 114 Example -R 1 or Melting No. -3-R 2 -4R5R6point in Chemical Name OC 66 -H -Ethyl \_77 260-262 2 -Benzyl-7-cyclohexyl-4-ethyl-imidazo- 1 2,4 triazolo I 5-a 67 -H ND-n-Propyl 294-297 2 -Benzyl-7-(N-pipeidiny)-4-n-propy-iImidazo- ,2,4ltriazolofl 68 -H -Ethyl 243-244 2 -BenzyI-7-tert.-butyl-4-ethyl-imidazo.
,2,4ltriazolofl 69 -H -K Ethyl \-~343-345 2-BenzyI-4-ethy!-7-pheny-imidazo- ,2,4ltriazoloflI,5-alpyrimidin-5-one -H Ethyl 261-263 7 -Cyclopentyl-4-ethy12-(3pyridylmethyl)imidazo[4,5-e]-[1 ,2,4]triazolo[1 one 71 -H -Ethyl -Ethyl >225-227 4 7 -Diethyl-2(3-pyridylmethyl)-imidazo- I I N 14,5-e -[1,2,41triazolofI 5-a 72 -Ethyl I -Ehy-o--63 187-189 2 -Benzyl-4,6-diethyl-7.(2-furyl)-imidazo.
[459-A]-[l 92,Altraof 1 5a 73 -H -H -Ethyl 3:2:8:--328330 4-Ethyl-2-(3-pyridylmethyl)-imidazo- 4 s;-el-ri l t'izlf ,5a 74 H H -thl 328-330 2-Cyclohexylmethyl-4.ethyl.imidazo- ,2,4ltriazolofl -H -Ethyl -Ethyl 230-232 2-CyclohlexylmlethylA47-diethyl imidazo- ,2,.4ltrazolofl 1"s Example -R 1 or Melting No. -R 3
-R
2 -4-R 5
-R
6 point in Chemical Name C 76 -H J-Ethyl O 273-274 2-Cyclohexyfmethyl-7-cyclopentyl-4-ethyl- ,2,4]triazolo1 77 -H -H -Ethyl 273 4-Ethyl-2-(phenylethyl)-imidazo- ,2,4ltnazolofl 78 -H -Ethyl -Ethyl -~282-283 4,7-Diethyl-2-(phenylethyl)-imidazo- ,2,4ltiiazolof 79 -H -Ethyl ~Y 292-294 7-Cyclopentyl-4-ethyl-2-(phenylethyl)-imidazo- -H -n-Propyl -(I289-290 2-Cyclopentyl-4-n-propyl-7-(3-tetrahydro-furany)- ,2,4triazolo[ 82 -H -Ehl -Ethryl 306-308OCH 222,7-Dicoeth yl-2- 4-hn-phenyloxy-methyl imzf4,5-e-[1 ,2,4]triazolo[1 83 -H j-Ethyl OCH, 234-236 7-Cyclopentyl-4-ethyl-2-(4-methoxy-phenyloxymethyl)-imidazo[4,5-e]-[1 ,2,4Jtriazolotl pyrimidin-6-one 84 j-Ethyl 127-128 8-Benzyl-7-cyciopentylA4-ethyl-2-(4-methoxy- OCH3benzyloxy-methyl)-imidazo4,5-e]-1 triazolo[l im 116 Example -R 1 or Melting No. -3-2-4-5-6point in Chemical Name -H -Ethyl OCH 182 7-Cyclopentyl-4-ethyl-2-(4-methoxy-benzyloxymethyl)-imidaza[4,5-e]f1 ,2,4]triazolo[1 86 Ethyl 0 138-140 8-Benzyi-7-cyclopenty-4-etl-2-(4-benzyloxy.
benzyl)-imidazo[4,5-e]-11,2,4]-triazolo[1 87 -H j-Ethyl 0251 7-Cyclopentyl-4-ethyi-2-(4-benzyloxy-benzyl)imidazo[4,5-e]-[1,2,4trazalo1 88 -H -J-Ethyl -F 252-254 7-Cyclopenty--ethyl-2-(4-fluoro-benzy)imidazo[4,5-e4[1 2,4]triazolo1 89 -H -Ethyl F 262-264 7-tert.-ButyJ-4-ethyl-2-(4-fluoro-benzyl)-imidazo- ,2,4]triazolo1 -Ethyl 2 04-207 8 -Benzyl-7-cyciopentyi.4-ethy;2-hydroxymethylimidazo[4,5-e-[1 ,2,4]triazolof 91 -H -c J-Ethyl OH305-307 7 -CyclopentyI-4-ethyl-2-hydroxymethyl-imidazo- ,2,4]triazoo[1 92 -H -Ethyl V-K7- F 337-339 7-(Adamantan--yI)-4-ethy-2-(4-fluoro-benzy)- I imidazo[4,5-el-[i ,24]triazolo[l i
PT
11'. 7 Example -R 1 or Melting No. -3-R 2 -4-R 5 -6point in Chemical Name 93 -H -Ethyl 246-248 1 2 -Cyciohexymethy!A4-ethy[7(5norbomen- 2(S)-yI)-imidazo[4,5-e]-[1 ,2,4]triazolo[1 94 -H -Ethyl 258-260 2 y-Ethyl -""OCHA 120-123 8-BenzyI-7-cyclopentyl..4-ethyl.2.
ethyloxymethyl-imidazo[4,5-e]-[1 ,2,4]triazolo- (I ,5-alpyrid 96 -H j-Ethyl
OC
2
H
5 224-22 5 7 -Cyclopentyl-4-ethyi-2-ethyloxymethy- ,2,4]triazolo[I -Ethylone 97 Ety 7 -Cyclopentyi-4ethyl-2-(benzoyloxy-methyl)- ,2,4]triazolo[1 98 -H J-Ethyl .0 u 238-239 7 -Cyclopentyl-4-ethyl-2-(benzoyloxy-methyl)midazo(4,5-e]-[1 ,2,4]triazolo(1 99 ij-Ethyl 116-118 8 -Benzy-7-cycopentyi4ethy-2-methyloxymethylimidazo[4,5-e]1 2,41-triazolorl. 100 -H -Ethyl
"OCH
3 246-248 7 -cyclopentyl-4-ethyl-2-methyloxymethyl.
I I Iimidazo[4,5-e-[1 ,2,4ltriazoio1 ,5-alpyrimidin-5-one I 118 Example
-R
1 or Melting No. -R 3 -R 4-5-6point in Chemical Name O~~C 101 -H -Ethyl F 325-32 7 4 -EthyI- 2 -(4-fluoro-benzyl)-7.(noradamantan..a.
,2,4]triazolo[l 102 -Ethyl N NC 3 8-BenzyI-7-.clopentylA-ethy..2- CH3 (dimethylamnino-methy)-imidzo- 4 5r- e 1,2,4 tnazolo 1 5-a 103 -H -3-Ethyl
'CH
3 224-225a 7 -CyCdopentyJ4-ethyl-2-(dimethylamino.metl) 3 kniazo[ss-e-f ,24ltrazolorl ,5-a1pyrfmicin-5-one- 104 -Eth l F 264-266 7 -Cycopenty ethy 2-(34 ifiuor -nzy).
F Imldazo[4,5-ej-f1 ,24jtazoIo4l 105-H-EhF 315-317 4-EthyI-2-(3,4-difiuor-benzy).7 (noradamnantan-3-y)-imnidazo- ,2,4ltrzazolofl 106 -3-Ethyl N NO\ 8-Benzyl-7-cyclopentylk4-ethy-2(N.
morpholino-methyl)-imidazo- [4 5-e -1 ,2,ltriaowW1 ,5ar 107 -H -Ethyl VN 0 184a 7 -CyclopentyI-4-ethyl-2-(N-morpholino-methyl)- .2,4]triazolo[l one 108 -H -Ethyl ~320-322 2 -Benzyl-4-ethyl-7-(noradamantan-3yl)- ,2,4]triazolo[l J one 119 Example -R 1 or Melting No. -3-2-4-R 5 -6point in Chemical Name 0C 109 -H -Ethyl -330-332 4-Ethyl-7-(noradamantan-3-y)-2-(3-pyridyl- ,2,4]-triazolo[1 0 8-Benzyl-7-cyclopentyl-4-ethyl-2-(3- -pyridylcarbonyloxy-methy)-imidazor4,5-eI-[1 ,2,4]triazolo[1 111 -Ethyl COOH 157-158 8-Benzy-2-carboxy-7-cyclopentyl.4ethylimidazo[4,5-e]-[1 ,2,4]triazolo[1 one 112 -{J-Ethyl
COOCH
3 155-157 8 -BenzyI-2-carboxymethyl-7-cyclopentyl4ethyl- 2,4]triazolo 1 5-a 113 ~-Ethyl CHO 153-154 8 -Benzyi-7-cyclopentyl;4ethyl2-formylimidazo.
1,2,4 triazolo 1 5-a prim 114 -'j-Ethyl
CH
2 -Br 153-154 8-Benzyl-7-bromomethyl-7-cyclopenty-4-ethylimidazo[4,5-e-[1 ,2,4]triazolof I 115 -QJ-Ethyl -NJ137-138 8-Benzyl-7-cyclopentyl-4-ethyl-2-(N-pyro.
Iylmethyl)-imidazo[4,5-e-[1 ,2,4]triazolo[1 116 Ethyl N 8-Benzyl-7-cyclopentyl-4-ethyl-2-(3-pyridyl- H [1,2,41triazolo[1,5-a Methanesu Iphonate 120 The structures of the examples of compounds (Ia) to (Id) synthesised hereinbefore were confirmed by NMRspectroscopy.
NMR-spectroscopic data of selected compounds: Example (3) 1 H-NMR (DMSO-d6): 8 14.10 (1H1, s, broad, NH); 8.24 (1H1, s, H2); 7..35-7.14 (5H1, m, Aryl-H); 4.12 (2H, t, J 7.5 Hz; N H 2
CH
2
CH
3 4.09 (2H, s, -CH 2 -Phenyl); 1.73 (2H1, m, N-CH 2
CH
2
CH
3 0.89 (3H, t, J 7.5 Hz, N-CH 2
CH
2
C{
3 Example (4) 1 H-NMR (DMSO-d6): 8 =13.28 (1H, s, broad, NH); 8.24 (1H, s, H2); 7.35-7.14 (5H, m, Aryl-H); 4.15 (2H, t, J= Hz, N-CH 2
CH
2
CH
2
CH
3 1.68 (2H, m, N-CH 2
CH
2
CH
2
CH
3 1.32 (2H, m, N-CH 2
CH
2
CH
2
CH
3 0.90 (31, t, J 7.5 Hz, N-
CH
2
CH
2
CH
2
CH
3 Example 1 H-NMR (DMSO-d6): 813.22 (111, s, broad, NH); 8.25 (1H1, s, 112); 7.35-7.14 (5H1, m, Aryl-H);5.33 (1H, m, CH- Isopropyl); 4.09 (2H1, s, -CH 2 -Phenyl); 1.55 (611, d, J =7.0 Hz, (CH3) 2 -Isopropyl).
Example (6) 1 H-NMR (DMSO-d6): 8 =13.66 (1H, s, broad, NH); 7.34- 7.14 (511, m, Aryl-H); 4.11 (2H, t, J 7.5 Hz, N-CH 2 C11 2
CH
3 4.07 (211, s, CH2- Phenyl); 2.79 (2H, qu, J 7.5 Hz, -CH 2
CH
3 1.71 (211, m, N-
CH
2
CH
2
CH
3 1.29 (3H, t, J 7.5 Hz, -CH 2 -gH 3 0.90 (3H, t, J Hz, N-CH 2
CH
2
CH
3 Example (7) 121 1H-NMR (DMSO-d6): 8 13.70 (1H, s, broad, NH); 7.43- 7.14 (5H, m, Aryl-H); 4.09 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 4.07 (2H, S, -CH 2 Phenyl); 2.75 (2H, t, J 7.5 Hz, -CH 2
CH
2
CH
3 1.74 (4H, m, N-
CH
2
CH
2
CH
3
-CHCH
2
CU
3 0.92 (6H, m, N-CH 2
CH
2
CH
3
CH
2
CH
2
CH
3 Example (8) 1 H-NMR (DMSO-d6): 8 7.34-7.12 (5H, m, Aryl-); 4.07 (2H, s, CH 2 -Phenyl); 3.55 (3H, a, N-CH 3 3.23 m, CH-Cyclopentyl); 2.14- 1.52 (8H, m, CH2-Cyclopenty).
Example (9) 1 H-NMR (DMSO-d6): 8 13.68 (11, s, broad, NH); 7.40- 7.14 (5H, m, Aryl-H); 4.19 (2H, qu, J 7.5 Hz, N-CH 2
CH
3 4.09 (2H, a, CH 2 Aryl); 3.24 (1H, m, CH-Cyclopentyl); 2.26-1.50 (8H, m, CH2-Cyclopentyl); 1.26 (3H, t, J 7.5 Hz, N-CH 2
CH
3 Example 1 H-NMR (DMSO-d6): 8 13.65 (1H, a, broad, NH); 7.38- 7.14 (5H, m, Ary1-H); 4.11 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 4.08 (2H, a, Phenyl-CH 2 3..23 (1H, m, CH-Cyclopentyl); 2.14-1.49 H, m, CH2-Cyclopentyl;
N-CH
2
CH
2
CH
3 0.89 (3H, t, J Hz,
N-CH
2
CH
2
CH
3 Example (11) 1H-NMR (DMSO-d6): 8= 13.85 (11, a, broad, NH); 7.62- 7.33 (5H, m, Aryl-H); 4.34 (2H, t, J 7.5 Hz, N-OH 2 4.28 (2H, a, CH 2 -Phenyl); 3.43 (1H, m, CH-Cyclopentyl); 2.33-1.38 (12H, m, CH2- Cyclopentyl; N-CH2.Qj 2 Qi-CH 3 1.10 (3H, t, J 7.5 Hz, N-(CH 2 3
-CH
3 Example (12) 122 1 H-NMR (DMSO-d6): 8 12.58 (11, s, broad, NH); 7.52- 7.14 (10 H, m, Aryl-H); 5.52 (2H, s, N-CH 2 Aryl); 4.18 (2H, s, -CH 2 -Aryl); 3.31 (1H, m, CH-Cyclopentyl); 2.21-1.50 (8H, m, CH 2 -Cyclopentyl).
Example (13) 1 H-NMR (DMSO-d6): 8= 7.14 (5H, m, Aryl-H); 4.08 (2H, t, J 7.5 Hz, Phenyl); 3.69; 3.59 (8H,
CH
2
.CH
2
CH
3 0.88 (3H, t, Example (14) 1 H-NMR (DMSO-d6):8= 7.14 (10 H, m, Aryl-H); 4. 08 (2H, t, J 7.5 Hz, Phenyl) 3.57; 2.46 (8H,
N-CH
2 -Phenyl); 1.70 (2H, 0.88 (3H, t, J 7.5 Hz, 12.38 (1H, s, broad, NH); 7.34-
N-CH
2
CH
2
CH
3 4.6 (2H, s, -CH 2 in, morpholin-H); 1.70 (2H, in, N- J 7.5 Hz, N-CH 2
CH
2
CH
3 12.26 (lH, s, broad, NH); 7.38-
N.CH
2
CH
2
CH
3 4.06 (2H, s, CH 2 M, -CH2-Piperaz.); 3.52 (2H, s, in, N-CH 2
CH
2
CH
3
N-CH
2
CH
2
CH
3 Example 1 H-NMR (DMSO-d6): 8 =7.40-7.14 (5H, mn, Aryl-H); 4.76 (3H, s, broad, NH, NH 2 4.08 (2H, t, J 7.5 Hz; N-CH 2
CH
2
-CH
3 4.06 (2H, s, -CH 2 Phenyl); 3.48; 2.79 (8H, 2mn, CH2-Piper.); 1.90 (3H, s,
CH
3 COOH) 1. 70 (2H, in, N-CH 2
CH
2
-CH
3 0. 88 O3H, t, J Hz,
N-CH
2
CH
2
-CH
3 Example (16) 1 H-NMR (DMSQ-d6)8 13.82 (1H, s, broad, NH); 7.34- 7.14 (5H, m, Aryl-H); 4.19 (2H, qu, J 7.0 Hz, N-CH 2
CH
3 4.08 (2H, s, -CH2- Phenyl); 3.93; 3.43 (4H, 2mn, 2 CH 2 3.09 (1H, mn, -CH- THP); 2.00-1.68 (4H, m, 2-CH 2 -THP); 1.25 O3H, t, J Hz, N-CH 2
CH
3 Example (17) 123 1H-NMR (DMSO-d6): 8 13.84 (1H, s, broad, NH); 7.34- 7.14 (5H, Aryl-H); 4.18 (2H, qu, J 7.0 Hz, N-CH 2
CH
3 4.08 (2H, s 1
-CH
2 Phenyl); 4.08-3.74 (4H, i, 2 CH2-O-3THF); 3.62 (1H, m, CH- 3 THF); 2.29 (21, m, CH 2 3 THF); 1.25 (3H, t, J 7.0 Hz, N CH 2
CH
3 Example (18) IH-NMR (DMSOd6): 13.64; 12.76 (21, 2s, broad, 2NH); 7.35-7.14 (5H, m, Aryl-H); 4.02 (2H, s, -CH2- Phenyl); 3.23 (1H, m, CH-Cyclopentyl); 2.14-1.50 (8H, m, CH 2-Cclopenty).
Example (19) 1H-NMR (DMSO-d6): 13.42; 13.20 (2H, 2s, broad, 2 NH); 8.24 (1H, s, 12); 3.20 (11, m, CH-Cyclopentyl); 2.17-1.50 (1H, m, CH 2 Cyclopentyl).
Example 1 H-NMR (DMSO-d6): S= 13.86 (11, S, broad, NH); 8.22 (11, s, 12); 3.58 s, N-CH 3 3.23 (11, m, CH- Cyclopentyl); 2.14-1.52 (8H, m, CH2-cylcopentyl).
Example (21) 1 H-NMR (DMSO-d6): S 14.04 (1H, s, broad, NH); 8.24 (1H, s, H2); 4.13 (21, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.21 (1H, m, CH-Cyclopentyl); 2.14-1.52 (10 H, m, CH2- Cyclopentyl;
N-CH
2
CH
2
CH
3 0.90 (3H, t, J 7.5 Hz, N- C1 2
CH
2
CH
3 Example (22) 1 H-NMR (DMSO-d6): S 13.68 (1H, s, broad, NH); 4.12 (2H, t, J 7.5 Hz, N-CH 2
-CH
2
CH
3 );3 2 0 (111, m, CH- Cyclopropyl); 2.45 s, -CH 3 2.12-1.52 (10 H, m, CH 2 Cyclopentyl); 0.89 (3H, t, J 7.5 Hz, N-CH 2
-CH
2
CH
3 Example (23) 124 1 H-NMR (DMSO-d6): 8 13.64 (1H, a, broad, NH); 4.12 (2H, t, J 7.5 Hz, N-CH2-CH 2
CH
3 );320 (1H, m, CH- Cyclopentyl); 2.80 (2H, qu, J 7.5 Hz, -CH 2
-CH
3 2.13-1.52 (10 H, m, CH2-Cyclopentyl;
N-CH
2
-C
2 CH 3 1.29 (3H, t, J 7.5 Hz, -CH 2
-CH
3 0.90 (3H, t, j 7.5 Hz,
N-CH
2
-CH
2 CH3).
Example (24) 1 H-NMR (DMSO-d6): 8 13.88 (1H, s, broad, NH); 7.35- 7.14 (5H, m, Aryl-H); 4.13 (2H, a, -CIi 2 -Phenyl); 4.11 (2H, t, J 7.5 Hz, N- 91 2
CH
2
CH
3 3.19 (11, m, CH-Cyclopentyl); 2.09-1.52 (1=H, m, CH 2 -Cyclopentyl;
N-CH
2
CH
2
CH
3 0.89 (3H, t, J 7.5 Hz, N-CH 2
CHCF
3 Example 1 H-NMR (DMSO-d6): 13.60 (1H, a, broad, NH); 7.43- 7.14 (5H, m, Aryl-H); 4.36 (21, t, J 7.5 Hz, N-CH 2
(CH
2 3
-CH
3 4.19 (2H, a, 2H 2 -Phenyl); 3.40 (1H, m, CH-Cyclopentyl); 2.31-1.24 (14H, m, CH2-Cyclopentyl;
N-CH
2
(CH
2 3
-CH
3 0.89 (31, m, N-(CH 2 4 -C11 3 Example (26) 1 H-NMR (DMSO-d6) 8= 13.85 (11, s, broad, NH); 8.16 (1H, a, H6); 7.35-7.14 (51, m, Aryl-H); 4.15 (2H, s, -CH 2 Phenyl); 3.59 (3H, s, N-CU 3 Example (27) 1H-NMR (DMSO-d6): 8 14.02 (11, s, broad, NH); 8.19 (1H, s, 16); 7.35-7.14 (5H, m, Aryl-H); 4.18 (2H, s, -CH2- Phenyl); 4.15 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 1.75 (2H, i, N-CH 2 C11 2
CH
3 0.93 (31, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 Example (28) 1 H-NMR (DMSO-d6): 8= 13.50, 12.92 (2H, 2s, broad, 2NH); 8.10 (11, a, 16); 125 3.24 (1H1, m, 011-Cyclopentyl); 2.17-1.52 (8H, m, CH 2 Cyclopentyl).
Example (29) 1HNM (DMSQ-d6): 8 13.70 (1H, s, broad, NH); 8.18 (1H1, s, H6); 3.59 (3H, s, C-OH 3 3.25 (1H, m, CH- Cyclopentyl); 2.15-1.52 (8H, m, CH2-Cyclopentyl).
Example 1 H-NMR (DMSO-d6): 8 13.70 (1H1, s, broad, NH); 8.20 (1H, s, H6) 4. 25 (2H, qu, J 7. 0 Hz, N- -C 2
H
3 3.2 7 (1H1, m, 011-Cyclopentyl); 2.21-1.52 (8H1, m, Cl! 2 Cyclopentyl); 1.29 (3H, t, J =7.0 Hz, N-CH 2
-CH
3 Example (31) IH-NMR (DMSO-d6): S= 13.74 (1H1, s, broad, NH); 8.18 (1H, s, 116); 4.14 (2H, t, J 7.5 Hz, N-CH 2
-CH
2
CH
3 3.25 (1H, m, CH-Cyclopentyl); 2.15-1.54 (10 H, m, 0112- Cyclopentyl; N-CH 2
-CH
2
CH
3 0.90 (3H, t, J 7.5 Hz, N-
CH
2
-CH
2
CH
3 Example (33) 1 H-NMR (DMSO-dG): 8 13.62 (1H, s, broad, NH); 4.11 (211, t, J 7.5 Hz, N-CH 2 C11 2
CH
3 3.23 (1H, in, OH- Cyclopentyl);. 2.37 (3H, s, -CH 3 2.14-1.50 (10 H, in, 0112- Cyclopentyl, N-CH 2
CH
2
CH
3 0.90 (31, t, J =7.5 Hz, N-
CH
2
CH
2
CH
3 Example (34) 1 H-NVR (DMSO-d6): S= 8.22 (1H1, s, Hz); 4.13 (2H1, t, J Hz, N-OH 2
CH
2
CH
3 2.75 (2H1, qu, J 7.5 Hz, -CH 2
CH
3 1.74 (211, in, N-
CH
2
CH
2
CH
3 1.29 (311, t, J =7.5 Hz, CH 2 -0H 3 0.92 (3H, t, J 7.5 Hz, N-CH 2
OH
2
CH
3 Example 126 1H-NMR (DMSO-d6): 6 13.62 (1H, s, broad, NH); 4.12 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.25 (1H, m, CH- Cyclopentyl); 2.74 (2H, qu, J 7.5 Hz, -CH 2
CH
3 2.17-1.51 (10 H, m, CH 2 -Cyclopentyl;
N-CH
2
CH
2
CH
3 1.29 (3H, t, J 7.5 Hz, -CH 2
CH
3 0.90 t, J 7.5 Hz, N-
CH
2
CH
2
CH
3 Example (36) 1 H-NMR (DMSO-dE): 6= 13.58 (1H, s, broad, NH); 4.12 (21, t, J 7.5 Hz, N-CH 2 C1 2
CH
3 3.24 (1H, m, CH- Cyclopentyl);2.69 (21, t, J 7.5 Hz, -CH 2
CH
2
CH
3 2.15-1.50 (12, m, CH 2 -Cyclopentyl;
(CH
2
CH
2
CH
3 2 0.95; 0.90 (61, 2t, J 7.5 Hz, (CH 2
CH
2
CH
3 2 Example (37) 1 H-NMR (DMSO-d6): 6= 13.62 (11, s, broad, NH); 4.13 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.24 (11, m, CH- Cyclopentyl); 3.05 (1H, m, CH-Isoprop.); 2.14-1.50 (10 H, m, CH 2 -Cyclopentyl;
N-CH
2
CH
2
CH
3 1.32 (6H, d, J 7.5 Hz, CH 3 -Isoprop.); 0.90 (3H, t, J Hz,
CH
2
CH
2
CH
3 Example (38) 1 H-NMR (DMSO-d6): 6= 13.62 (11, s, broad, NH); 4.12 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.24 (1H, n, Cyclopentyl-H); 2.70 (21, t, J 7.5 Hz, CH 2
-CH
2
CH
2
CH
3 2.15-1.26 (14H, m, CH 2 -Cyclopentyl;
N-CH
2
CH
2
-CH
3 C1 2 gHZCH 2
CH
3 0.90 (61, n, N-CH 2
CH
2
CH
3
(-CH
2 3
-CH
3 Example (39) 1 H-NMR (CDC1 3 6 4.36 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.40 (1H, m, CH -Cyclopentyl); 2.32-1.63 (10 H, m, CH 2 Cyclopentyl;
N-CH
2
CH
2
CH
3 1.46 (91, s, C(CH 3 3 1.02 (3H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 Example 1 H-NMR (DMSO-d6): 6 14.28 (1H, s, broad, NH); 8.26- 7.45 (51, m, Aryl-H);
M
127 4.14 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 2.71 (2H, t, J= Hz, -CH 2
CH
2
CH
3 1.76 (4H, m, (-CH 2
CH
2
CH
3 2 0.98; 0.93 (6H, 2t,
CH
2
CH
2
CH
3 2 Example (41) 1 H-NMR (DMSO-d6): 6= 7.44-7.05 (4H, mn, Aryl-H); 4.13 (2H, s, CH 2 -Phenyl); 4.11 (2H, t, J 7.5 Hz, N-CH 2
CH
2
-CH
3 2.68 (2H, t, J 7.5 Hz, -CH 2
CH
2
-C{
3 1. 74 (4H, m, (-CH 2
CH
2
-CH
3 2 0.-95; 0.-89 (6H, 2t, J Hz, (CH 2
CH
2
-QH
3 2 Exampl e (42) 1 H-NMR (DMSO-d6): 6= 13.64 (1H, s, broad, NH); 4.12 (2H, t, J =7.5 Hz; N-CH 2
CH
2
CH
3 2.76 (4H, in, (CH 2
CH
3 2 1.73 (2H, mNCH 2
CH
2
CH
3 2.29 (6H, m,(CH 2 -gIH 3 2 0.90 (3H, t, J 7.5 Hz, N-
CH
2
CH
2
CH
3 Example (43) 1 H-NMR (DMSO-d6): 6= 14.19 (1H, s, broad, NH); 8.31 (1H1, s, H2); 8.16-7.38 (5H, mn, Aryl-H); 4.21 (2H, t, J 7.5 Hz, N- -HC2H) 1.83 (2H, m, N-CH 2
CH
2
CH
3 0.98 O3H, t, J 7.5 Hz, N-
CH
2
CH
2
CH
3 Example (44) 1 H-NMR (DMSO-d6): 8 13.78 (111, s, broad, NH); 8.19- 7.43 (5H1, mn, Aryl-H); 4.21 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 2.83 (2H, qu, J= Hz, -CH 2
CH
3 1.81 (2H, mn, N..CH 2
CH
2
CH
3 1.33 (3H, t, j 7.5 Hz,
CH
2
CH
3 0.95 (3H, t, J 7.5 Hz, -N-CH 2
CH
2
CH
3 Example 128 1H-NMR (DMSO-d6): 8 13.70 (1H, s, broad, NHl); 8.19- 7.38 (5H, mn, Aryl-H); 4.21 (2H, t, J =7.5 Hz, N-CH 2
CH
2
CH
3 3.28 (1H, mn, CH- Cyclopentyl); 2.19-1.50 (10 H, mn, CH2-Cyclopentyl;
N-CH
2
CH
2 CH); 0.94 (3H, t, J 7.5 Hz, N-CH 2
CH
2
CI
3 Example (46) 1H-NMR (DMSO-d6): 6 8.26 (1Hi, s, Hz); 7.84; 7.10; 6.69 (3H, 3m, Furyl-H); 4.10 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 1.81 (2H, in, N-
CHCH
2
CH
3 0.98 (3H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 Example (47) 1 H-NMR (DMSO-d6): 13.56 (1H, s, broad, NH); 7.70; 6.91; 6.50 (3H, 3m, Furyl-H); 4.00 (2H, t, J 7.5 Hz, N- CHi 2
CH
2
CH
3 2.66 (2H, qu, J 7.5 Hz, -CH 2
CH
3 1.61 (2H, mn, N-CH 2
CH
2
-CH
3 1.14 (3H, L, J =7.5 Hz, N-
CH
2
CH
2
CH
3 0.77 (3H, t, J 7.5 Hz, -CH 2
CH
3 Example (48) 1 H-NMR (DMSO-d6): 6= 13.84 (1Hi, s, broad, NH); 8.00; 7.18; 6.78 (3H, 3m, Furan-H); 4.26 (2H, L, J 7.5 Hz, N-
CH
2
CH
2
CH
3 3.37 (1H, mn, CH-Cyclopentyl); 2.28-1.62 (10 H, mn, CH2-Cyclopentyl;
N-CH
2
H
2
CH);
1.04 (3H, L, J 7.5 Hz; N-CH 2
CH
2
C{
3 Example (49) 1 H-NMR (DMSO-d6): 6= 12.84 (1H, s, broad, NH); 8.26 (1H, s, H2); 4.32 (2H, L, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.18 (1H, mn, CH- Cyclopentyl); 2.09-1.52 (10 H,rn, CH2-CycJlopentyl;
N-CHCH
2
CH
3 0.83 (3H, L, J 7.5 Hz, N-CH 2
CII
2
CH
3 129 Example IH-NMR (DMSO-d6): 8 112); 13.35 (211, s, broad).
8.28 (111, s, H6) 8.15 (1H, S,.
Example (51) 1 H-NMR (DMSO-d6): 813.74 (111, s, broad, NH); 8.34 (111, s, H6); 4.63 (2H, qu, J =7.5 Hz, N-CH 2
CH
3 3.33 (11, mn, CHI- Cyclopentyl); 2.24-1.57 (8H1, m, CH2-Cyclopentyl) 1.47 (3H1, t, J Hz,
N-CH
2
CH
3 Example (52) 1 11-NMR (DMSO-d6): 8 13.72 (111, s, broad, NH); 8.34 (111, s, 116); 4.53 (2H1, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.34 (11, mn, CH- Cyclopentyl); 2.20-1.57 (811, mn, CH2-Cyclopentyl); 1.87 (2H1, mn, N-
CH
2
CH
2
CH
3 1.06 (3H, t, J 7.5 Hz, N-CH 2
CH
2
C{
3 Example (53) 1H.-Ivfl (DMSO-d6). 8 8.19 (11, s, H16); 4.00 (311, s, N-
H)
3.58 (311, s, N-CH 3 3.42 (111, mn, CH-Cyclopentyl); 2.18- 1.57 (811, mn, CH 2 -Cyclopentyl).
Example 1 H-NMR (DMSO-d6): 8 14.12 (1H, s, broad, NH); 8.44 (11, s, Hz); 4.53 (211, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.28 (1H1, mn, CH- Cyclopentyl); 2.17-1.55 (811, mn, C12-Cyclopentyl); 1.87 (2H, mn, N-
CH
2 9H 2
CH
3 1.05 (311, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 130 Example (56) 1 H-NMR (DMSO-d6): 8.28 (11, s, H2); 4.36 (2H1, t,T J 7.5 Hz, N-CH 2
CH-
2 C1{ 3 4.12 (2H, t, J 7.5 Hz, N-CH 2
CH
2
CH
3 3.21 (1H, m, CH- Cyclopentyl).
2.12-1.57 (12H, m, CH2-Cyclopentyl;
(N-CH
2 C1c1 3 2 0.92; 0.87 (6H, 2t, J 7.5 Hz, (N-CII 2 dl 2
CH
3 2 Example (57) 1H-NMR (DMSO-d6): 6= 8.02 (1H, s, H2); 4.45 (2H1, t, J 7.5 Hz, N-.CH 2
CH
2
CH
3 4.14 (2H1, t, J 7.5 Hz, N-C 2 C11 2
CH
3 3.24 (111, M, CH- Cyclopentyl) 2.14-1.57 (1211, m, CH2-Cyclopentyl;
(N-CH
2 C2H 2
CH)
2 0.93; 0.89 (611, 2t, J 7.5 Hz, (N-CH 2
CH
2
CH
3 2 131 The following Table contains KA, (human) and KA, (rat) receptor binding values.
Table Example KiA 1 KiA 2 No.: [nM] [nM] 7 8,1 158 8 1,9 363 9 1,4 422 1,7 730 11 8,3 345 13 5,2 82 10,3 1231 81,5 3292 36 5,8 731 37 6,4 307 38 6,4 532 39 6,0 539 48 11,4 4455 The following Table contains KiA (human) receptor binding values.
Table 21: Example KiA3 No. [nM] 3 4,7 4 2,3 6 2 12 19 3,8 23 2 26 38 22 3 68 78 5,3 82 132 The compounds of general formula 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 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.
133 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 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 134 the magnesium stearate are screened and mixed together.
The mixture is compressed into tablets of suitable shapp and size.
B) Tablets er Per Talet Active substance Corn starch Lactose Microcrystalline cellulose Polyvinylpyrrolidone Sodium carboxymethyl starch Magnesium stearate mg 190 mg mg 35 mg mg 23 mg 2 mg 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 size.
Coated tablets Active substance Corn starch Lactose Polyvinylpyrrolidone Magnesium stearate per coated tablet mg 41.5 mg mg 3 mg 0.5 mq 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 0 C and the granules are then
I
135 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) Capsules per capsule Active substance 50 mg Corn starch 268.5 mg Magnesium stearate 1.5 mq 320 mq 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.
136 Ampoule solution Active substance Sodium chloride Water for injections 50 mg 50 mg 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 Solid fat 50 mg 1650 mq 1700 mg The hard fat is melted. At 40 0 C the ground active substance is homogeneously dispersed therein. It is cooled to 38 0 C and poured into slightly chilled suppository moulds.
Oral Suspension Active substance Hydroxyethylcellulose Sorbic acid Sorbitol Glycerol Flavouring Water ad 50 mg 50 mg 5 mg 600 mg 200 mg 15 mg 5 ml Distilled water is heated to 700C. Hydroxyethylcellulose is dissolved therein with stirring. After the addition of 137 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.
Claims (13)
1. Imidazotriazolopyrimidinones of general formula (I) 0 R NR;N N R' R- N- N Rwherein wherein R or R or R 3 denotes hydrogen, an optionally substituted C 1 1 -alkyl, C2- 10 -alkenyl or C2- 10 -alkynyl, an optionally substituted C 3 8 -cycloalkyl, an optionally substituted C 4 ,_-cycloalkenyl or an optionally substituted C, 6 _-cycloalkynyl; R 3 denotes an optionally substituted C 6 _-aryl-C1- 6 alkyl, C 6 10 -aryl-C2-6-alkenyl, C 6 10 -aryl- C 2 -,-alkynyl, an optionally substituted C 6 0 -aryl or an optionally substituted heteroaryl, an optionally substituted
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; R 1 or R 3 denotes an optionally substituted Ciio-alkyloxycarbonyl, an optionally substituted C 2 10 -alkenyloxycarbonyl, an optionally substituted C2- 10 -alkynyloxycarbonyl, an optionally substituted C 38 -cycloalkyloxy- carbonyl, an optionally substituted C 6 _o 0 -aryloxycarbonyl, an optionally substituted Cs- 10 -aryl-CI- 6 -alkyloxycarbonyl, A-O-CO- wherein A denotes an optionally substituted 6- or 7- membered heterocyclic group which contains as 139 R 1 or R' R 1 or R 3 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, is an optionally substituted C 1 _--alkyl- sulphonyl, C 2 C 2 1 O-alkynylsulphonyl, an optionally substituted C 3 _,-cycloalkylsulphonyl, an optionally substituted C_-,,-arylsulphonyl, an optionally substituted C,_,o-aryl-C-,-alkylsulphonyl, a group A-SO 2 wherein A is as hereinbefore defined and is linked via a carbon atom of the ring; denotes an optionally substituted Cl-lo-alkylcarbonyl, an optionally substituted C 2 10 -alkenylcarbonyl, an optionally substituted C 2 10 -alkynylcarbonyl, an optionally substituted C 3 8 -cycloalkylcarbonyl, an optionally substituted Co 10 -arylcarbonyl, an optionally substituted C 6 .io-aryl-C_,-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined; R' or R 3 denotes a group of general formula H R O wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C 3 .,-cycloalkyl group, a branched or unbranched C-, 0 o-alkyl, preferably C,. 4 -alkyl, C 2 0 -alkenyl or C 2 10 -alkynyl group which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino; 140 R 2 denotes hydrogen, hydroxy, amino, halogen, nitro, CF 3 COOH, mercapto, Ci..-alkylmercapto,. an optionally substituted 1 -alkyl, an optionally substituted C 2 0 alkenyl, an optionally substituted C 2 10 alkynyl, an optionally substituted C 3 cycloalkyl, an optionally substituted cycloalkanone, an optionally substituted 8 -cycloalkenyl, an optionally substituted C. 8 cycloalkynyl, an optionally substituted C 6 -10 -aryl, an optionally substituted C 6 10 -aryl-Cl- 6 -alkyl, C 6 10 -aryl- C 2 6 -alkenyl, C 6 -1 0 -aryl-C 2 1-alkynyl, C. 8 cycloalkyl -C 1 alkyl, cycloalkyl C 2 alkenyl, or C 3 cycloalky1-C 2 6 .alkynyl; R 2dntsan optionally substituted 6- or7- 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 C,-,,-alkyl, C 2 6 -alkenyl or C 2 alkynyl bridge; R 2 denotes an optionally substituted C 1 1 -a lkylsulphonyl, C 2 1 0 -alkenylsulphonyl or C 2 1 0 -alkynylsulphonyl, an optionally substituted C 3 8 -cycloalkylsulphonyl, an optionally substituted C 6 10 -arylsulphonyl, an optionally substituted heteroarylsulphonyl or an optionally substituted C..-oarylc- 6 ;alkylsulphonyl; R denotes an optionally substituted Cl-.i-alkylsulphonylox,~ C 2 i-alkenylsulphonyloxy or C 2 1 0 -alkynylsulphonyloxy, an optionally substituted C 3 acycloalkylsulphonyloxy, an optionally substituted C 6 10 -arylsuiphonyloxy, an optionally substituted C 6 1 0 -aryl-c 1 6 alkylsuiphonyloxy or an optionally substituted heteroarylsulphonyl 5 y R 2 denotes an optionally substituted Ci.-,0alkyl sulphonyl amino, C 2 .i-alkenylsulphonyl amino or C 2 -1 0 alkynyl sulphonyl amino, an optionally substituted C 3 cycloalkyl- suiphonylamino, an optionally substituted C 6 10 -arylsulphonylamino, an optionally substituted Cc1 rl-C- aklslhnlaio or an optionally substituted heteroarylsulphonyl amino; R 2 denotes an optionally substituted C 1 1 0 ,-alkylaminocarbonyl, C,. 10 -dialkyl amino carbonyl, C1.oalkyl-C 2 10 alkenylaminocarbonyl, C 2 .i-alkenylaminocarbonyl, C 2 10 -dialkenyl amino carbonyl, C 2 i-alkynylaminocarbonyl or C 1 .l 0 -alkyl -C 2 .i-alkynylaminocarbonyl, an optionally substituted C 3 cycloalkyl aminocarbonyl, an optionally substituted C,-.,-arylaminocarbonyl, an optionally substituted C 6 o-arylC 1 6 ,-alkylaminocarbonyl, or an optionally substituted heteroarylamino- carbonyl; R 2 denotes an optionally substituted Cl-.iO-alkyloxycarbonylamino, C 2 10 -alkenyloxy- carbonylamino or C 2 10 -alkynyloxycarbonyl amino, an optionally substituted C 3 cycloalkyloxy- carbonylamino, an optionally substituted CG 610 -aryloxycarbonylamino, an optionally substituted C6..l- arylC-c 6 al kyloxycarbonyl amino or an optionally substituted heteroaryloxy- carbonyl amino; 142 R' denotes an optionally substituted Ci..x-alkylaminocarbonyloxy, C 2 i-alkenylamino- carbonyloxy or C.21-a~lkynyamnocarbonyloxy, an optionally substituted C,-O-cycloalkylamino. carbonyloxy, an optionally substituted C 610 ,-arylaminocarbonyloxy, an optionally substituted C 6 10 -aryl -C,--alkylaminocarbonyloxy or an optionally substituted heteroarylamino. carbonyloxy; R 2 denotes an optionally substituted C 1 1 0 alkyl-N- amidino, C 2 -i-alkenyl-N-amidino or C 2 10 -alkynyl- N-amidino, an optionally substituted C 3 cycloalkyl-N..amidino, an optionally substituted C 6 1 -aryl-N-amidino, an optionally substituted C.l-aryl-Cl 6 ,-alkyl.4N.amidino or an optionally substituted heteroaryl -N-arnidino; R 2 denotes an optionally substituted 1 0 alkyloxy, C 210 -alkenyloxy or C 210 -alkynyloxy, an optionally substituted C 3 cycloalkyloxy, an optionally substituted C 6 1 -aryloxy, an optionally substituted C 6 -1o-aryl-Cl- 6 -alkyloxy or an optionally substituted heteroaryloxy; R 2denotes an optionally substituted Ci..i-alkyloxycarbonyl, C 2 0 -alkenyloxycarbonyl or C 2 i-alkynyloxycarbonyl, an optionally substituted C 3 cycloalkyloxycarbonyl, an optionally substituted C 6 .i-aryloxycarbonyl, an optionally substituted C 6 .io,-aryl-Cq. 6 -alkyloxy- carbonyl or an optionally substituted heteroaryloxycarbonyl; R 2 denotes an optionally substituted C3.i-alkylcarbonyloxy, C 2 -i-alkenylcarbonyloxy or C 2 -1-alkynylcarbonyloxy, an optionally substituted C 3 cycloalkylcarbonyloxy, an 143 optionally substituted C 610 -arylcarbonyloxr, an optionally substituted C aryl-C 1 6 -alkyl- carbonyloxy or an optionally substituted heteroarylcarbonyloxy; R2 denotes an optionally substituted Cl-.. 1 -alkylthio, C 2 10 -alkenylthio or C 2 1 -alkynylthio, an optionally substituted C 3 .e-cycloalkylthio, an optionally substituted C 6 10 -arylthio, an optionally substituted C 6 10 -aryl-C- 6 -alkylthio or an optionally substituted heteroarylthio; R 2 denotes an optionally substituted amine, pref erably NR 8 R'; R 2 denotes an optionally substituted group of the formula 2 0 0 C R 2 denotes an optionally substituted group of the formula (CH 2 12 (CH 2 12 (CH 2 1 2 -w/ "I;Y 144 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;' denotes an optionally substituted group of the formula R 2 I IY- (C H2)0,1,2 GJZACy R or Rs 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; denotes a hydrogen atom, an optionally substituted C 1 10 -alkyl, C2- 10 -alkenyl or C 210 -alkynyl, an optionally substituted C 3 cycloalkyl, an optionally substituted C 4 cycloalkenyl or an optionally substituted C, cycloalkynyl, an optionally substituted Cc- 10 -aryl-C.,-alkyl, CG_ 10 -aryl-C 2 alkenyl, C 6 0 o-aryl-C 2 .,-alkynyl, an optionally substituted C 6 0 -aryl or an optionally substituted heteroaryl; denotes an optionally substituted 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; R 4 or R 5 145 R 4 or R 5 denotes an optionally substituted C 1 .,,-alkyloxycarbonyl, an optionally substituted Ca 2 ,m-alkenyloxycarbonyl, an optionally substituted C2-_ 1 -alkynyloxycarbonyl, an optionally substituted C 3 ._-cycloalkyloxy- carbonyl, an optionally substituted C 610 -aryl- Ci-g-alkyloxycarbonyl, an optionally substituted C 10 -aryloxycarbonyl; R 4 or R 5 denotes A-O-CO- wherein A denotes an optionally substituted 6- or 7-membered heterocyclic group which contains as heteroatoms one or more atoms selected from the group comprising nitrogen, oxygen or sulphur; R 4 or R s R 4 or R 5 denotes an optionally substituted C-.i 0 -alkylsulphonyl, C2- 0 -alkenylsulphonyl, C 2 0 -alkynylsulphonyl, an optionally substituted C 3 ,--cycloalkylsulphonyl, an optionally substituted C,_ 10 -arylsulphonyl, a group A-SO 2 wherein A is as hereinbefore defined and is linked via a carbon atom of the ring; denotes an optionally substituted C, -alkylcarbonyl, an optionally substituted C 2 1 -alkenylcarbonyl, an optionally substituted C 2 1 0 -alkynylcarbonyl, an optionally substituted C 3 -_-cycloalkylcarbonyl, an optionally substituted C_ 10 -arylcarbonyl, an optionally substituted C,_,-aryl-C_,-alkylcarbonyl, a group A-CO- wherein A is as hereinbefore defined; R 4 or R 5 denotes a group of general formula H N R 0 146 wherein R denotes hydrogen, phenyl, substituted phenyl, an optionally substituted benzyl, an optionally substituted C 3 _,-cycloalkyl group, a branched or unbranched C, 1 ,,-alkyl, preferably C 14 -alkyl, C 2 10 -alkenyl or C 2 10 -alkynyl group, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, amino or substituted amino; R 6 denotes hydrogen, hydroxy, -CHO, amino, halogen, nitro, CF3, COOH, mercapto, C 1 _,-alkylmercapto, an optionally substituted C-,,o-alkyl, an optionally substituted C 2 0 -alkenyl, an optionally substituted C 2 0 ,0-alkynyl, an optionally substituted C3_ 8 -cycloalkyl, an optionally substituted Cs_--cycloalkanone, an optionally substituted C 4 8 -cycloalkenyl, an optionally substituted C 6 cycloalkynyl, an optionally substituted C 6 10 -aryl, an optionally substituted C, 1 -aryl-C 1 alkyl, C. 10 o-aryl- C 2 -,-alkenyl, C,_ 0 -aryl-C 2 ,_-alkynyl, an optionally substituted C 3 ._-cycloalkyl-C,- 6 alkyl, C 3 cycloalkyl-C2-6-alkenyl or C 3 ._-cycloalkyl- C 2 ,.-alkynyl; R 6 denotes an optionally substituted 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 Cl. 6 -alkyl, C 26 -alkenyl or C,2,- alkynyl bridge; R 6 denotes an optionally substituted C 1 -o,-alkylsulphonyl, C2-o 0 -alkenylsulphonyl or C2- 10 -alkynylsulphonyl, an optionally substituted I 147 C 3 -8-cycloalkylsulphonyl, an optionally substituted C 6 1 -arylsulphonyl, an optionally substituted C61-O-aryl-Cl- 6 .alkylsulphonyl or an' optionally substituted heteroarylsuiphonyl; R 6 denotes an optionally substituted C,- 1 ,-alkylsulphonyloxy, C 2 ,.iO-alkenylsulphonyloxy or C, 2 -O-alkynylsulphonyloxy, an optionally substituted C 3 cycloalkylsulphonylox,~ an optionally substituted C 6 1 O-arylsulphonyoy an optionally substituted C 6 10 -aryl-Cl- 6 -alkyl. suiphonyloxy or an optionally substituted heteroaryl suiphonyloxy; R 6 denotes an optionally substituted C, 10 -alkyl sulphonyl amino, C,-,-alkenylsulphonyl amino or C,1 0 -alkynyl sulphonyl amino, an optionally substituted C 3 scycloalkylsulphonyl. amino, an optionally substituted C 6 ,,-aryl sulphonyl amino, an optionally substituted C6-1-aryl-Cli 6 -alkylsulphonylamino or an optionally substituted heteroarylsulphonyl- amino; R 6 denotes an optionally substituted Cl-. 1 -alkyl- aminocarbonyl, C, 10 dial kylaminocarbonyl, C1.iO-alkylC 2 1 0 -alkenylaminocarbonyl, C 2 i-alkenylaminocarbonyl, C 2 10 -dialkenylamino- carbonyl, C 2 -1i-alkynylaminocarbonyl or Cl,-ly-2,-lyyaioabnl an optionally substituted C-.-cycloalkylamino- carbonyl, an optionally substituted C 6 10 -arylaminocarbonyl, an optionally substituted C6-10-aryl-C,- 6 -alkylaminocarbonyl or an optionally substituted heteroarylamino- carbonyl; 148 R 6 denotes an optionally substituted c,_ 10 alkyl aminocarbonyl amino, C, 1 alkenyl aminocarbonyl amino or C, 1 alkynyl aminocarbonyl amino, an optionally substituted C--cyc olkloalkloarbnlamna optionally substituted C,-,,,-arylaminocarbonyl amino, an optionally substituted C 6 10 -aryl- C1.-6al1kylaminocarbonyl amino or an optionally substituted heteroarylaminocarbonylamino; R 6 denotes an optionally substituted alkyloxycarbonyl amino, C2 al kenyloxycarbonyl amino or C2 1- alkynyloxycarbonyl amino, an optionally substituted C3-, -cycloalkyloxycarbonyl amino, an optionally substituted C,-,,-aryloxycarbonyl amino, an optionally substituted C 6 10 -aryl- 6 alkyloxycarbonylamino or an optionally substituted heteroaryloxycarbonylamjno; R 6 denotes an optionally substituted Cl- 0 alkylaminocarbonyloxy, 2-10alkenylaminocarbonyloxy or C 2 Ilalkynyaminocarbonylox,~ an optionally substituted C3.-cycloalkylaminocarbonyloxy an optionally substituted CG. 10 -arylamino- carbonyloxy, an optionally substituted C6.1oarylC 1 6 -,alkylaminocarbofloxy or an optionally substituted heteroarylamino. carbonyloxy; R 6 denotes an optionally substituted 1 -alkyl-N- amidino, C 2 1 0 -alkenyl..Namidino or C 2 10 -alkynyl- N-amidino, an optionally substituted C3-.-cycloalkyl.N.amidino, an optionally substituted C 6 -1-aryl-N-amidino, an optionally substituted C6-1-aryl-CI- 6 -alkyl.N..amjijfl or an optionally substituted heteroaryl -N-amidino; 149 RD denotes an optionally substituted C 1 10 -alkyloxy, C,-,-alkenyloxy or C,.O-alkynyloxcy, an optionally substituted C,-.-cycloalkyloxy, an optionally substituted C 6 10 -aryloxy, an optionally substituted C 6 i-aryl-C 16 ,-alkyloy or an optionally substituted heteroaryloxy; R 6dntsan optionally substituted Ci..iO-alkylcarbonyl, an optionally substituted C 2 i-alkenylcarbonyl, an optionally substituted C 2 i-alkynylcarbonyl, an optionally substituted C-.-cycloalkylcarbonyl, an optionally substituted C 6 10 -arylcarbonyl, an optionally substituted Cs-1-aryl-Ci 6 -Galkylcarbony1; R6 denotes a group A-Ca- wherein A is as hereinbefore defined; R6 denotes an optionally substituted C,-io-alkyloxycarbonyl, C 2 -1o-alkenyloxycarbonyl or C 2 -i-alkynyloxycarbonyl, an optionally substituted C 3 cycloalkyloxycarbonyl, an optionally substituted C 6 1 0 -aryloxycarbonyl, an optionally substituted C 6 1 0 -aryl -C 1 6 alkyloxycarbonyl or an optionally substituted heteroaryloxycarbonyl; R 6denotes an optionally substituted Cl-lo-alkylcarbonyloxy C,- 1 0 -alkenylcarbonyloxy or C,-iO-alkynylcarbonyloxy an optionally substituted C 3 cycloalkylcarbonyloxy, an optionally substituted C 6 i-arylcarbonyloxy, an optionally substituted C 6 i-aryl-C 16 ,alkyl. carbonyloxy or an optionally substituted heteroarylcarbonyloxy; 150 R' denotes an optionally substituted C 1 1 0 alkylthio, C 2 1 -alkenylthio or C 210 -alkynylthio, an optionally substituted C,.-cycloalkylthio, an optionally substituted C 6 1 -arylthio, an optionally substituted C.ioarylC 1 6 -,alkylthio or an optionally substituted heteroarylthio. R 6 denotes an optionally substituted Cllo,.-alkylcarbonylox-Calkyl, C2.loalkenylcarbonyloxyZ....Calkyl or C2-.1-a lkynylcarbonylox ,.alkyl, an optionally substituted C3.-8cycloalkylcarbonyloxyCalkyl an optionally substituted. 0 -arylcarbonyloxy. C 1 alkyl, C6-..1-arylCl 6 alkylcarbonyloxy C 1 alkyl or heteroarylcarbonylox.C-,alkyl; R 6 denotes an optionally substituted group of the formula H) wherein n=1, 2, 3 or 4, where B denotes a C 6 10 -aryl or a single bond; R 6 denotes an optionally substituted amine, pref erably NR 8 R 9 R 6 denotes an optionally substituted group of the formula 151 R 6 denotes an optionally substituted group of the formula (CH 2 )1, 2 (CH 2 )1, 2 (CH 2 )1,2 <CH 2 1 CH -Y (CH2)1, 2 (CH2)1,2 Y -y C,-C 6 -Alkyl C,-C6-Alkyl 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; R 6 is an optionally substituted group of the formula 152 Y r-" 2 0,1,2 (CHZ)0.1.2 N H 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; R 8 denotes hydrogen, an optionally substituted C 3 .,-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to 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 C,._-alkyloxy, preferably C,_,-alkyloxy, or -(CH 2 )-NHCOOR' 1 wherein m 1, 2, 3 or 4; R 8 denotes a 6- or 7-membered heterocyclic group which is carbon linked directly or via a C,. 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, C,_4-alkyl, halogen, -OR 10 -CN, -NO 2 -NH 2 -OH, -COOH, -S03H or -COOR 10 R 8 denotes a bicyclic heterocyclic group which is C-linked directly or via a C,. 4 -alkyl chain and which contains one or more heteroatoms selected from the group comprising nitrogen, oxygen or 153 sulphur and is optionally mono- or polysubstituted, preferably monosubstituted, by benzyl, optionally substituted benzyl, C,. 4 -alkyl, halogen, -OR 10 -CN, -NO 2 -NH 2 -OH, -COOH, -SO 3 H, -COOR 10 R 9 denotes hydrogen, an optionally substituted C 3 6 -cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to preferably 1 to 4 carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino, preferably C,1 4 -alkoxy, or -(CH 2 ),-NHCOOR wherein m equals 1, 2, 3 or 4; R 9 denotes a 6- or 7-membered heterocyclic group which is carbon linked directly or via a C,_ 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, -OR 10 -CN, -NO NH 2 -OH, -COOH, -S03H or -COOR 1 0 R 9 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, C,1 4 -alkyl, halogen, -OR 1 0 -CN, -OH, -COOH, -SO 3 H, -COOR 0 or R 8 and R 9 together with the nitrogen atom form a saturated or unsaturated 5- or 6-membered ring 154 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 -(CH,)n-phenyl, -(CH 2 a ketal preferably -O-CH2-CH 2 -(CH 2 NH-C., 4 -alkyl, -(CH 2 n-N(C,_,-alkyl) 2, -(CH 2 )n-NHCOOR 1 0 (n 2, 3, halogen, -OR 10 -CN, -NO 2 -CH 2 NR 8 R 9 -OH, -COOH, -S03H, -COOR 10 -CONRR 9 -SO,-R 10 R 0 denotes hydrogen, C,_-alkyl, C 2 4 -alkenyl, C 24 -alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by OCH 3 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) 0 R 0 N R R2 (Ib) 155 o R 0 1 R..NANN N N N NA R 6 R(1c) RJ a wherein R1 or R 3 denotes hydrogen, C,- 4 -alkyl or benzyl; R 2denotes hydrogen, a C,- 8 -alkyl, C-. 8 -alkenyl or C 28 -alkynyl group which may optionally be substituted, by -CN, -CH 2 NR 8 R 9 -OR (polysubstitution also possible), -NqR 8 R 9 -NHCOR' 0 -NHCONR 8 R 9 NHCOOR' 0 halogen, -OCOR' 0 -OCO-pyridyl, -OCH 2 COOHI- -OCH 2 COOR1 0 -SO 2 R -S-R 7 _-NHCONH-phenyl, -OCR 2 -CONR 8 R 9 -OCII 2 CH 2 OR, -S0 2 -CH 2 -CH1 2 -0OCOR10, -OCH 2 -CH 2 -NRR 9 -SO 2 CH 2 -CH 2 -OH, CONHSO 2 R 0 CH 2 CONHS 2 R1 0 -OCR 2 CH 2 OR 0 -COOR-, -COOR 0 -CONRR 9 -CHO, -SR' 0 O, -SOR' 0 -SO 2 R' 0 -SO 3 H, SO 2 NR"R 9 -OCH 2 -CH 2 OCOR' 0 -CH=NOR, -CH=NOR' 0 -COR"1, -CH(OHI)R"1, -CH(OR' 0 2 -CH=CH-R' 2 OCONR 8 R 9 optionally mono- or poly-substituted, preferably mono-methyl- substituted i, 3-dioxolane or 1, 3-dioxane; R 2 denotes phenyl-C,-,-alkyl, phenyl-C,-,-alkenyl or pheny1-C 26 -alkynyl, wherein the phenyl ring is optionally substituted either directly or via a Cj_-alkylene bridge by one or more, of the group C 1 3 -alkyl, -CN, -NR 8 R 9 -NO 2 -OH, -OR' 0 -CR 2 -NR-S0 2 -R' 0 O -NHCOR' 0 O, -NIICONR 8 R 9 halogen, -OCOR' 0 -OCO-pyridyl, -OCR 2 COOR, -OCR 2 COOR' 0 CH 2 OCOR' 0 S0 2 R 7 OCR 2 -CONR 8 R 9 OCHCR 2 O0i, OCR 2 -CR 2 -NR 8 R 9 CONHS 2 R 0 OCR 2 CH 2 OR' 0 COOR, -COOR' 0 -CF 3 cyclopropyl, -CONR 8 R 9 -CH 2 OR, -CH 2 0R 10 CR0, -SR' 0 -SOR' 0 -SOR' 0 O, -S0 3 H, 156 SO 2 NROR 9 00H 2 OH 2 0C0R]L, CI=NOH, CH=NOR 1 0 -COR' 1 -OH (OH) R 11 -OH (OR 10 2 -NHCOOR 10 -CH 2 CONHSO 2 R' 0 -OH=OH-R' OCONR 8 R9, -CH 2 -O-CONR8R9, -CH 2 -CH 2 -O-CONRR9, optionally mono- or poly-methyl-substituted 1, 3 -dioxolane or l,3-dioxane; R 2 ~denotes C3- 7 -cycloalkyl...O6alkyl, C3-7-cycloalkyl-C 2 6 .alkenyl, C 3 7 -cycloalkyl. C 2 6 -alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a Cl-,-alkylene bridge by one or more, of the groups -ON, -NROR 9 -OH, -OR 10 -NaR 9 -NHOOR 10 -NHCONROR9, halogen, -000R 10 -OCO-pyridyl, -OCH 2 000H, -OCH 2 000R' 0 -OH 2 000R1 0 -S0 2 R 7 -OCH 2 -CONR 6 R9, -OCH 2 CH 2 0H, -00H 2 O 2 -NR 8 R 9 -00H 2 01{ 2 0R' 0 -COOH, -C00R 10 -CONRR9, -OH 2 OH, -0H 2 0R 1 0 -CHO0, -SR' 0 -S0R 10 SO 2 R1O, -SO 3 H, SO 2 NR8R 9 -0OCH 2 H 2 000R1 0 CH=NOH, CH=N0R 1 0 -COR' 1 -OH (OH) R 1 -CONHSO 2 R' 0 -CH (OR 10 2 NHCOOR 10 CH=CH-R 1 2 -OOONROR 9 -C012-0- CONR 0 R 9 -CH 2 -0H 2 -O-CONROR 9 methyl -substituted 1,3- dioxolane or l,3-dioxane; R 2 denotes a group of the formula A-0 1 alkyl, A-OONH-0 1 6 ,-alkyl, A-CONH-C 26 ,-alkenyl, A-OONH-O 26 ,-alkynyl, A-N{-O-C3, 6 -alkyl, A-NH-OO-O 2 6 -alkenyl, A-NH-OO-O 2 6 ,-alkynyl, A-0 2 6 -alkenylene, A-O 2 6 -alkynylene or wherein A is a 0- or N- linked 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, C 1 4 -alkyl, halogen, -OR 10 -ON, -NO 2 _N21 -CH 2 NRBR 9 -OH, a ketal, ethyleneketal, 157 -COOH, -SO 3 H, -COOR' 0 -CON 8 R 9 -COR"1, -S0 2 -R1 0 or CONROR 9 denotes c 3 7 -cycloalkyl, which may optionally be substituted by -OH, -O10 -OCOR' 0 or -OCO-pyridyl; denotes phenyl which is optionally substituted by -OH, halogen, Cl,-alkyl, -NH 2 COOH, -SO 3 H, COOR 0 -OCH 2 COOR1 0 -CN or -OCH 2 CONROR9; denotes a norbornane, norbornene, C 3 6 -dicycloalkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamatane group optionally substituted by CI- 4 -alkyl; denotes -CH=CH-phenyl in which the phenyl ring is mono- or polysubstituted by methoxy, hydroxy or halogen; is a [3.3.01-bicyclooctane; is a C-linked piperidine or furan; is an amine of general formula NR 8 R 9 R"or R denotes hydrogen, an optionally branched Cj, 8 alkyl, C 2 6 -alkenyl or C 2 alkynyl group which is substituted by -CN, -CH 2 NR 6 R 9 -OH (polysubstitution also possible) -OR' 0 -NRBR 9 -NHCOR' 0 -NHCONR 8 R 9 halogen, -OCOR' 0 OCO -pyridyl, -OCH 2 COOII, -OCH 2 COOR1 0 S0 2 R, S-R 7 -NHCONH-phenyl, -OCH 2 -CONROR 9 OCH 2 CH 2 OH, -SO 2 _CH 2 -CH 2 -O-COR1 0 -OCH 2 -CH 2 -NR 8 R9, -SO 2 _-CH 2 _-CH 2 -OH, CONHSO 2 R' 0 CH 2 CONHSO 2 R' 0 -OCH 2 CH 2 OR' 0 -COOH, -COOR' 0 -CONRBR 9 -CHO, -SR' 0 -S I0 -S50 2 R1 0 SO 3 H, SO 2 NR'R 9 OCH 2 -C2CR 158 -CH=NOH, -CH-N0R 0 -COR 11 -CH(OH)R 1 -CH(0R 0 2 -CH=CH-R 2 -OCONR 8 R 9 optionally mono- or poly-, methyl-substituted l, 3 -dioxolane or' 1,3 -dioxane; Ror R' denotes phenyl-C 1 6 -alkyl, phenyl-C 2 6 -alkenyl or phenyl-C 26 -alkynyl, wherein the phenyl ring is optionally substituted either directly or via a C 1 4 -alkylene bridge by one or more, preferably one of the groups, -C 1 3 -alkyl, -CN, -NR 8 R 9 -NO 2 -OH1, -O10 -CH 2 NH-S0 2 -R' 0 -NHCOR' 0 O, -NHCONR 8 R 9 halogen, -0C0R 10 -OCO-pyridyl, -OCH 2 COOH, OCH 2 COOR' 0 CH 2 OCOR 10 S0 2 R 7 0C11 2 CONR 8 R 9 OCH 2 CH 2 OH, -OCH 2 -CH 2 -NR 8 R 9 CONHSO 2 R' 0 -OCH 2 CH 2 OR' 0 -COOH, -C00R 1 0 -CF 3 1 cyclopropyl, -CONROR9, -CH 2 OH, -CH 2 OR' 0 -CHO, -S10 -S0R 10 _SO 2 R" 0 -S03H, -SO 2 NROR 9 -OCH 2 -CH 2 OCOR 10 -CH=NOH, -CH=N0R 10 -C0R 11 -CH (OH) R 1 -CE (OR 10 2 -NHCOOR 10 -CH 2 CONHSO 2 R 10 -CH=CH-R 1 2 -OCONR 8 R 9 -CH 2 -O-CONR 8 R 9 -C11 2 -CH 2 -O-CONR 8 R 9 optionally mono- or poly-, methyl-substituted l,3-dioxolane or 1,3-dioxane; R4or R 5 R4or R' denotes an optionally substituted C 37 -cycloalkyl group; denotes C 3 7 -cycloalkylC 16 ,alkyl, C3,cycloalkylC 26 alkenyl, C 3 7 -cycloalkyl- C,-,-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a Cl-,-alkylene bridge by -CN, -NR 8 R 9 -OH, -OR' 0 -NR8R 9 -NHCOR' 0 -NHCONR 8 R 9 halogen, -OCOR 0 -OCO-pyridyl, -OCH 2 COOH, -OCH 2 COOR1 0 CHOCOR' 0 S0 2 R 7 OCH 2 -CONROR 9 OCH 2 CH 2 OH, -0C11 2 -CH 2 -NR 8 R 9 -OCH 2 CH 2 OR' 0 -COOH, -COOR' 0 -CONROR 9 -CH 2 OH, -CH 2 OR' 0 -CHO, -S10 -S0R 10 SO 2 R' 0 SO 3 H, SO 2 NR 8 R9, OCH 2 -CH 2 000R 0 CH=NOH, -CH=NOR' 0 -COR"1, -CH (OH) -CONHS0 2 R' 0 159 -CH'02 -NHCOOR' 0 -CH=CH-R 1 2 OCONR 8 R 9 -CH 2 -O-CONR 8 R 9 -CH 2 -CH 2 -O-CONR 8 R 9 optionally mono- or poiy-, methyl -substituted 1,3-dioxol~ane or 1,3-dioxane; Ror R 5 denotes a group of the formula A-Cl- 6 -alkyl, A-CONH-C,-,-alkyl, A-CONH-C 2 6 -alkenyl, A-CONH-C 26 -alkynyl, A-NH-CO-C,. 6 alkyl, A-NH-CO-C 2 6 -alkenyl, A-NH-CO-C 2 6 -alkynyl, A-C 2 6 -alkenyl or A-C 2 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 C 1 4 -alkyl, halogen, -OR' 0 -CN, -NO 2 -NH 2 -CH 2 NR 8 R 9 -OH, a ketal, ethyleneketal, -COOH, -SO 3 H, -COOR' 0 -CONROR', -COR", -S0 2 -R1 0 or -CONR 8 R9; R6 denotes hydrogen, a Cl-.-alkyl, C-. 8 -alkenyl or C 2 alkynyl group which is substituted by -CN, -CH 2 NR 8 R 9 -OH (polysubstitution also possible), -OR' 0 -NR 8 R 9 -NHCOR' 0 -NHCONR 8 R 9 -NHCOOR 0 halogen, -OCOR 0 -OCO-pyridyl, -OCH 2 COOH, -OOH 2 COOR' 0 S0 2 R 7 S-R 7 -NHCONH-phenyl, -OCH 2 -CONR 8 R 9 -OCH 2 CH 2 OH, -S0 2 -CH 2 -CH 2 -O-COR' 0 -OCH 2 -CH 2 -NR 8 R 9 -S0 2 -CH 2 -CH 2 -OH, -CONHSO 2 R' 0 CH 2 CONHSO 2 R' 0 OCH 2 CH 2 OR' 0 COOH, COOR' 0 -CONR 8 R 9 -CHO, -SR' 0 -SOR' 0 -S0 2 -SO 3 H, 50 2 NR 8 R 9 OCH 2 -CH 2 OCOR' 0 CH=NOH, CH=NOR' 0 O, -COR", -CH (OH) -CHi(OR' 0 2 -CH=CH-R' 2 -OCONR 8 R 9 optionally mono- or poly-, methyl- substituted 1,3-dioxolane or 1,3-dioxane; R6 denotes phenyl-C,- 6 -alkyl, phenyl-C 2 6 -alkenyl or phenyl-C 2 6 ,-alkynyl, wherein the phenyl ring is optionally substituted either directly or via a 160 C,-,-alkylene bridge by one or more of the groups, C,. 3 -alkyl, -ON, NR 8 R 9 -NO 2 -OH, -OR' 0 -CH 2 -NH-S0 2 -R1 0 -NHCOR' 0 -NHCONR 8 R 9 halogen, -OCOR' 0 -OCOpyridyl, -ocH 2 C00H, OCH 2 CO0R' 0 CH 2 000R1 0 S0 2 R 7 OCH 2 -CONqR 8 R 9 OCH 2 CH 2 OH, OCH 2 -MO 2 -NRBR 9 OONHSO 2 R1 0 -OCH 2 CH 2 OR' 0 COOH, -COOR' 0 -CF 3 Cyclopropyl, -CONR 6 R 9 -CH 2 OH, -CH 2 0R' 0 -CHO, -SR' 0 -SOR' 0 -SO 2 R1 0 -S 3 H, SO 2 NR 8 R 9 OCH 2 -CH 2 0C0R1 0 CH=NOH, CH=NOR' 0 -C0R 1 1 -OH (OH) -CH (OR' 0 2 -NHCOOR' 0 CH 2 CONHSO 2 R' 0 CH= OH-R R, -OCONRBR 9 CH 2 -0-CONROR 9 -CH 2 -CH 2 -O-CONR 8 R9, -CO-R1 0 -CO-C1- 4 -alkyl-NR 8 R 9 optionally mono- or poymty-usiue l, 3 -dioxolane or 1,3- dioxane; R 6 denotes C3..7-cycloalkylC,,alkyl, C3-7cycloalkylCalkel or C 3 7 -cycloalkyl. C 2 6 ,-alkynyl, wherein the cycloalkyl group is optionally substituted either directly or via a O,..-alkylene bridge by one or more of the groups -ON, -NROR 9 -OH, -OR' 0 -NTR 8 R 9 -NHCOR' 0 -NHCONR 8 R 9 halogen, -OCOR' 0 -OCO-pyridyl, OCH 2 C00H, OCH 2 C00R1 0 OH 2 0C0R1 0 S0 2 R -OCH 2 -CONR 8 R 9 -OCH 2 CH 2 OI{, -OCH.-CH 2 -NROR 9 -OCH 2 CH 2 OR' 0 -COOH, -COOR' 0 -CONR 8 R 9 -CH 2 OH, -CH 2 0R1 0 -CHO, -SR' 0 -SOR' 0 -SO 2 R' 0 -SO 3 H, SO 2 NR 8 R 9 OCH 2 -CH 2 000R' 0 CH=NOH, OH=NOR' 0 -COR"1, -OH (OH) -CONHSO 2 R' 0 -OH (OR' 0 2 -NHOOOR' 0 -CH=CH-R 1 2 OCONR 8 R 9 -CH 2 -O-CONR 8 R 9 -CH 2 -OH 2 -0-CONR8R9 or methyl -substituted i, 3- dioxolane or l,3-dioxane; R 6 denotes a group of the formula A-C,-,-alkyl, A-CONH-C,. 6 -alkyl, A-CONH-C 2 6 -alkenyll A-CONH-C 2 6 -alkynyl, A-NH-CO-,.-,.alkyl, A-NHCO-C 2 6 1alkenyl, 161 A-NCo-c 2 6 -alkynyl, A-C 2 alkenyl or A-C 2 6 -alkynyl or A-, wherein A is a C- or N-linked 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, C 4 -alkyl, halogen, -OR' 0 -CN, -NO 2 -NH 2 CH 2 NR 8 R 9 -OH, a ketal, ethyleneketal, -COOH, -S0 3 H, -COOR' 0 -CONROR 9 -COR", -S0 2 -R1 0 or -CONR 8 R 9 6 denotes -CHO, -COOR' 0 -CONRBR 9 R 6 denotes C 3 7 -cycloalkyl optionally substituted by -OH, -OR' 0 -OCOR 0 or -OCO-pyridyl; 6 denotes phenyl optionally substituted by -OH, halogen, -OR' 0 Cl,.-alkyl, preferably -CH 3 -Nl 2 -COOH, -SO 3 HI -COOR 0 -OCH 2 COOR1 0 -CN or -OCH 2 CONROR 9 6 denotes a norbonane, norbornene, C 3 dicyclo- alkylmethyl, preferably dicyclopropylmethyl, adamantane or noradamantane group optionally substituted by C,. 4 -alkyl; 6 denotes -CH=CH-phenyl, wherein the phenyl ring may be mono- or polysubstituted by methoxy, hydroxy or halogen; denotes a [3.3.0]-bicyclooctane; 6 denotes a C-linked piperidine or furan; 7 denotes C,.-alkyl which is optionally substituted by -OH, -OCOR' 0 -OCO-pyridyl, -NH,, 162 -NRR' 9 or -NHCOR' 1 preferably -CH,-CH 2 -OH, -CHCH 2 OCOR' 1 -CH,-CH,-CH 2 OH or -CH-CH 2 CH2OCOR 10 R8 denotes hydrogen, an optionally substituted C3-.-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, substituted amino or C 1 ,_-alkoxy, preferably C, alkoxy, or -(CH 2 ),-NHCOOR"0 where m 1, 2, 3 or 4; R 8 denotes a 6- or 7 -membered heterocyclic group which is C-linked directly or via a C 1 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, C 1 _4-alkyl, halogen, -OR O -CN, -NO -OH, -COOH, -S03H or -COOR 1 0 R8 denotes a bicyclic heterocyclic group C-linked directly or via a C,. 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, C,. 4 -alkyl, halogen, -OR 10 -CN, -NO -NH 2 -OH, -COOH, -SO3H or -COOR 10 R 9 denotes hydrogen, an optionally substituted C 3 -,-cycloalkyl group, a branched or unbranched alkyl, alkenyl or alkynyl group having up to carbon atoms, which may optionally be substituted by hydroxy, phenyl, substituted phenyl, benzyl, substituted benzyl, amino, 163 substituted amino or C._--alkoxy, preferably C,._-alkoxy, or -(CH 2 )m-NHCOOR 0 wherein m is 1, 2, 3 or 4; R 9 denotes a 6- or 7-membered heterocyclic group which is C-linked directly or via a C,_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, C,- 4 -alkyl, halogen, -OR 10 -CN, -NO 2 -NH 2 -OH, -COOH, -S03H or -COOR 10 R 9 denotes a bicyclic heterocyclic group C-linked directly or via a C._ 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, C 1 _4-alkyl, halogen, -OR 10 -CN, -NO 2 -NH 2 -OH, -COOH, -S03H or -COOR 1 0 or R' and R 9 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 Cl 4 alkyl group, or may carry one of the following groups: -(CH 2 )n-phenyl, -(CH 2 )n-NH 2 a ketal preferably -O-CH2-CH 2 (CH 2 NH-C1_ 4 -alkyl, -(CH 2 -N(C,.--alkyl) 2 -(CH 2 )n-NHCOOR' 0 (n 1, 2, 3, halogen, -OR 1 0 -CN, -NO 2 -NH 2 -CH 2 NR 8 R 9 164 -OH, -COOH, -S0 3 H1, -COOR' 0 -CONR 8 R 9 -S0 2 R1 0 denotes hydrogen, C 1 alkyl, C 2 alkenyl, C 24 -alkynyl, a benzyl or phenyl group which is optionally mono- or polysubstituted by 0C1 3 R" denotes C 1 4 -alkyl, C 2 4 -alkenyl, C 2 4 -alkyyl, optionally substituted phenyl, optionally substituted benzyl or C 36 ,-cycloalkyl; R 12 denotes -COOR' 0 -CH 2 0R 1 0 -CONR 8 R 9 hydrogen, C 1 3 -alkyl, optionally substituted phenyl or CH 2 NR 8 R 9 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) RI% N N 2 N. N 2 N N N N' ,N N -1 Re (a R (I N b) 0 RI 0 Ni N N N R I i I k R I)Re (Pd) wherein R 1 or R 3 o denotes hydrogen, Cl-,-alkyl or benzyl; 165 R denotes hydrogen, C,.,-alkyl, preferably C,_,-alkyl; R 2 denotes phenyl which is optionally substituted by halogen, C 1 -4-alkyl, C 1 4 -alkyloxy, hydroxy or NReR 9 R 2 denotes phenyl-C, 1 _-alkyl, phenyl-C2-,-alkenyl or phenyl-C2-_-alkynyl, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, C,. 4 -alkyl, C,.,-alkyloxy, hydroxy or NROR 9 R 2 denotes an amine of formula NR 8 R 9 R 2 denotes a 5- or 6-membered heterocyclic group which is optionally C- or N-linked either directly or via a C 1 4 -alkylene bridge, containing one or more heteroatoms selected from the group comprising nitrogen or oxygen and optionally substituted by benzyl or C-_ 4 -alkyl; R 2 denotes a C 36 -cycloalkyl which may optionally be substituted by hydroxy, C 1 4 -alkyl or C, alkyloxy; R 2 denotes norbornane, norbornene, adamantane or noradamantane optionally substituted by C,_ 4 -alkyl; R 4 or R 5 denotes hydrogen, C 1 .,-alkyl, phenyl-C 1 ,-alkyl, phenyl-C2-_-alkenyl or phenyl- C 2 .,-alkynyl, wherein the phenyl ring is optionally substituted by halogen, hydroxy, C _4-alkyl, C1-.-alkyloxy or NR 8 R 9 166 R* denotes hydrogen, C 1 alkyl, wherein the alkyl chain may be substituted by halogen, hydroxy, C 1 4 -alkyloxy, NR'R 9 phenyloxy, -O-phenyl2' C 1 4 -alkyloxy, benzyloxy, -O-benzyl -0- C 1 4 -alkyloxy, -OCO-C, 1 4 -alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, 4 -alkylene, -CO- C 1 4 -alkyl, -CHO, =,NOH, -COOH, -COO-C.. 4 -alkyl, -COO-phenyl, -COO-benzyl, -CONR 8 R 9 -NHCO-C.. 4 -alkyl, -NHCO-phenyl, -CO-C 1 4 -akyl-N 8 R9, -SO 2 0H, -S0 2 -Cl-.-alkyl or -S0 2 -phenyl; R 6 denotes phenyl which may optionally be substituted by halogen, hydroxy, C 1 4 -alkyl, C 1 4 -alkyloxy, benzyloxy, phenyloxy, -NR 8 R 9 -OCO- C 1 4 -alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -0-C 2 4 alkylene, -CO-C 1 4 -alkyl, -C 1 4 -alkyl-N1 2 -C 1 4 -alkyl-OH, -C 1 4 -alkyl=NOH, -COOH, -COO-Cl- 4 -alkyl, -COO-phenyl, -COO-benzyl, CONRR 9 CO -C 4 -alkyl.NH21 -SO 2 0H, -S0 2 4 -alkyl or -S0 2 -phenyl; R6 denotes phenyl-c, 1 4 -alkyl, phenyl-C 2 6 -alkenyl or phenyl-C 26 ,-alkynyl, wherein the phenyl ring may optionally substituted by halogen, hydroxy, C 1 4 -alkyl, C 1 4 -alkoxy, benzyloxy, phenyloxy, *-NR. 8 R 9 -OCO-C.. 4 -alkyl, -OCO-phenyl, -OCO-benzyl, -OCO-pyridyl, -O-C 2 4 -alkylene, -CO-C. 4 -alkyl, -COOl!, -COO-C 1 4 -alkyl, -COO-phenyl, -COO-benzyl, -CONRR 9 -CO-C 1 4 -alkyl-NH 2 -SO 2 0H, -SO 2 -C 1 4 -alkyl or -S0 2 -phenyl; R 6 denotes a 5- or 6-membered heterocyclic group optionally C- or N-linked either directly or via a C 1 4 -alkylene bridge, which contains one, two or three heteroatoins selected from nitrogen or s 167 oxygen and is optionally mono- or polysubstituted by benzyl or C 1 ,.-alkyl; R 6 denotes a C 3 ,_-cycloalkyl or C 3 _-cycloalkyl- C 1 ,-alkyl group which may optionally be substituted by hydroxy, C_. 4 -alkyl or Ci. 4 -alkyloxy; R 6 denotes norbornyl, norbornenyl, adamantyl or noradamantyl optionally substituted by C 1 _,-alkyl; R 6 denotes -CHO, -COOH, -COO-C,_ 4 -alkyl, -COO-phenyl, -COO-benzyl or -CONR'R 9 R 6 denotes an amine of general formula NR 8 R 9 R' denotes hydrogen, a branched or unbranched C,- 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, C 1 4 -alkyl, C 4 ,-alkyloxy, halogen, -CN, -NO, -NH 2 -OH or =0; R 9 denotes hydrogen, a branched or unbranched C,. 4 -alkyl group; R 9 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, Cl. 4 -alkyl, C 1 4 -alkyloxy, halogen, -CN, -NO 2 -OH or =0; or 168 R" and R 9 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 C, 4 ,-alkyl group, preferably methyl, or by a -(CH 2 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) 0 RNR RR R N N N N"N N 1 R R (1a) R (Ib) wherein R or R 3 denotes hydrogen, C,-4-alkyl or benzyl; R2 denotes hydrogen or C 1 alkyl, R 2 denotes cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, hydroxycyclopentane or hydrocyclohexane; R 2 denotes a morpholine group optionally substituted by C, 4 -alkyl, a piperidinyl group, a piperazinyl group optionally substituted by benzyl or C 1 _4-alkyl, pyridyl, tetrahydrofuranyl, tetrahydropyranyl or furyl; M 169 R 2 denotes a phenyl. group optionally substituted by C,-,-alkyl, halogen or hydroxy; R 2 denotes a phenyl-C,-. 4 -alky1, wherein the phenyl ring is optionally substituted by halogen, preferably fluorine or chlorine, C 1 -alkyl, C,- 4 -alkyloxy, hydroxy or NR 8 R 9 R 2 denotes an amine of general formula NR 8 R 9 R 2 enots anorbornenyl, norbornyl, adamantyl or noradamantyl optionally substituted by C,-,-alkyl; R 4 denotes hydrogen, C 1 alkyl, phenyl-C,-,-alkyl, preferably benzyl, wherein the phenyl ring may be substituted by halogen, hydroxy, C 1 4 -alkyl, C 1 4 -alkyloxy or NR 8 R 9 R 6 denotes hydrogen, C 1 al1kyl wherein the alkyl chain may be substituted by halogen, hydroxy, C 1 4 -alkyloxy, NR 8 R 9 phenyloxy, -0-phenyl-o- C 1 4 -alkyloxy, benzyloxy, -O-benzyl-o-C 1 4 .alkyloxy, -OCO-C 1 4 -alkyl, -OCO-phenyl, -OCO-pyridyl, -OCO-benzyl, -0- C,- 4 -alkylene, -CO-C 1 4 alkyl, -CHO, =NOH, -COOH, -COO-C 14 -alkyl; -COO-phenyl, -COO-benzyl, -CONR 8 R 9 -NI{CO-C 1 4 -alkyl, -NHCO-phenyl, -CO-c- 4 alkyl-NR 8 R 9 -SO 2 0H. -S0 2 -C- 4 -alkyl or -SO.-phenyl; R 6 denotes phenyl, wherein the phenyl ring may be substituted by halogen, hydroxy, C 1 4 -alkyl, C 1 alkyloxy or NR 8 R 9 R 6 denotes phenyl-c 1 3 -alkyl, wherein the phenyl ring may be substituted by halogen, preferably fluorine or chlorine, hydroxy, Cl-.-alkyl, 170 CI- 4 -alkyloxy, benzyloxy, phenyloxy, -NR 8 R 9 oco- C,_-alkyl, -OCO-phenyl, -OCO--benzyl, -OCO-pyridyl, 4 -alkylene, -Co-C 4 alkyl, -C 1 4 ,-alkyl-NR 8 R 9 -C 1 4 -alkyl.0H, -c 1 4 -alkyl=NOH, -COOH, -COO-C 1 alkyl, -COO--phenyl, -COO-benzyl, -CONR 8 R 9 -CO-C 1 4 -alkyl -NR 8 R 9 -SO 2 OHI -S0 2 -Cl-.-alkyl or -S0 2 phenyl; R 6 denotes a cyclopentyl, cyclohexyl, cyclohexyl- Cj_ 3 -alkyl, preferably Cyclohexylmethyl, cyclopentanone, Cyclohexanone, hydroxycyclopentane or hydroxycycJlohexane linked via a single bond or via a CI. 4 -alkylene chain; R 6 denotes a furan, tetrahydrofuran, c-pyran, y-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 C 1 4 -alkylene chain; R 6 denotes -CHO, -COOH, -COO-C 1 4 -alkyl; -COO-phenyl, -COO-benzyl, -CO-NH-C 14 alkyl, -CO-N(Cl 1 4 -alkyl) 2 or -CO-NI{-phenyl; R6 denotes an amine of general formula NR 8 R 9 Ra denotes hydrogen, a branched or unbranched Cj_ 4 -alkyl group; R 8 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, C 1 4 -alkyl, C 1 4 -alkyloxy, -NO 2 -NH, or -OH; R 9 denotes hydrogen, a branched or unbranched C 1 _4-alkyl group; R 9 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, C_. 4 -alkyl, C 1 4 -alkyloxy, -NO 2 -NH 2 -OH, or R" and R 9 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 C_1--alkyl group, or by a -(CH 2 )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. Compounds of general formula (Ib) 0 4 R N- N N R NR N R N (Ib) 172 where in R 2 denotes hydrogen, c 1 4 -alkyl, phenyl, benzyl, wherein the phenyl ring is optionally substituted by fluorine, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4 -benzylpiperazinyl, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR 8 R 9 cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl; R 3 denotes hydrogen, C 1 3 -alkyl or benzyl; R 4 denotes hydrogen, C 1 alkyl or benzyl; R 6 denotes hydrogen, C 1 alkyl, which may optionally be substituted by OH, chlorine, bromine, C 1 4 -alkyloxy or NR 8 -CHO, -COON, -COO-C 1 4 -alkyl, phenyl, phenyl-C 1 3 alkyl optionally substituted by fluorine or benzyloxy, optionally methoxy-substituted phenyloxy-Cl 1 3 -alkyl, optionally methoxy- substituted benzyloxy-Cl 1 3alkyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N-pyrrolyl methyl or N-morpholinomethyl; R 8 denotes hydrogen, C 1 4 -alkyl or pyridyl; R 9 denotes hydrogen, C 14 -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) 173 N N N N N R" where in R1 denotes hydrogen, C 13 -alkyl or benzyl; *R eoe hydrogen, C 1 ,-alkyl, phenyl, benzyl, -wherein the phenyl ring is optionally fluorine- substituted, pyridyl, piperidinyl, morpholinyl, piperazinyl, 4 -benzylpiperazinyi, furyl, tetrahydrofuranyl, tetrahydropyranyl, NR 8 R 9 cyclopentyl, cyclohexyl, adamantyl, noradamantyl, norbornyl or norbornenyl; 4 denotes hydrogen, C.- 5 -alkyl or benzyl; *R denotes hydrogen, C- 4 alkyl, which may optionally be substituted by OH, chlorine, bromine, C 1 4 -alkyloxy or NR 8 R 9 -CHO, -COOH, -COO-Cl- 4 -alkyl, phenyl, phenyl-C 1 3 -alkyl optionally substituted by fluorine or benzyloxy, optionally methoxy-substituted phenyloxy-C 1 3 -alkyl, optionally methoxy- substituted benzyloxy- Cl- 3 -alkyl, benzyloxybenzyl, benzoyloxymethyl, pyridylcarbonyloxymethyl, cyclopentyl, furyl, cyclohexylmethyl, pyridylmethyl, N- pyrrolylmethyl or N-morpholinomethyl; R8 denotes hydrogen, C 14 -alkyl or pyridyl; may denote hydrogen, Cl- 4 -alkyl or pyridyl, 174 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) O R i N N R-N N -R 2 R (Ic) wherein- R1 denotes hydrogen or C, 1 3 -alkyl; R 2 denotes hydrogen, C, 1 ,-alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl; R s denotes C 1 6 -alkyl; R 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) 0 Ns N I I\ R2 R N N Ra I (id) 175 wherein R denotes hydrogen or C 1 3 -alkyl; R 2 denotes hydrogen, C 14 -alkyl, cyclopentyl, cyclopentanone, hydroxycyclopentane, furan or benzyl; Rs denotes C 1 ,_-alkyl; R 6 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) 0 R IN N NN N >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, 2-furyl, 3 -tetrahydrofuranyl, 4- tetrahydropyranyl, -NMe 2 cyclopentyl, cyclohexyl, adamantan-1-yl, noradamantan-3-yl, norbornan-2-yl or 5-norbornen-2-yl; R 3 denotes hydrogen, methyl, ethyl, n-propyl or benzyl; 176 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, n-pentyl or benzyl; R 6 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-C! 2 Ph-CO-O-CH 2 pyridyl-CO--C1 2 Ph-a-C! 2 (4-MeO-Ph)-O-Cl 2 4 -MeO-Ph)-Cl 2 -OCH2 (4-Ph-l! 2 Ph)-C 2 4-F--Ph-C! 2 3,4-F-ph-c! 2 -COO!, -COOMe, -CH 2 -CI{ 2 -OMe, -CH 2 OEt or -Cl! 2 -NMe 2 optionally in the form of the racemates, the enantiomers, the diastereomers and mixtures thereof and optionally the pharmacologically acceptable acid addition salts thereof. Compounds of general formula (Ia) 0 R N RISIIN N 2 R (isR wherein R1 denotes hydrogen, methyl, ethyl, n-propyl or benzyl; R 2 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- 177 tetrahydropyranyl, -N~e 2 cyclopentyl, cyclohexyl, adamantan-l-yl, noradamantan-3.y1, norbornan-2-yl or 5-norbornen-2-yl; R 4 denotes hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert. -butyl, n-pentyl or benzyl; R 6 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-CH 2 Ph-CO-O-CH 2 I pyridyl-CO-o-CH,-, Ph-O-C1 2 (4-MeO-Ph) -O-CH 2 (4-MeO--Ph) -CH 2 -O-C- 2 (4-Ph-CH 2 Ph) -CH 2 4-F--Ph-cH 2 3, 4-F-Ph-CH 2 -COOH, -COOMe, -CH 2 -OI -CH 2 -OMe, -CH 2 OEt or -C11 2 -NMe 2 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) 0 RN N N N N R (Ib) where in R 2 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- 178 piperazinyl, 3 -tetrahydrofuranyl, 4 -tetrahydro. pyranyl, -NMe 2 cyclopentyl, cyclohexyl, t adamantan-1.yl, noradamatan-3 -yl, norbornan-2.yl or 5-norbornen-2-yl; R 3 denotes hydrogen; R 4 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, cyclohexyl- methyl, 2 -phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl) -NH-CH 2 -1 Ph-COO-CH 2 3-pyridyl-COO-C 2 Ph-O-C2- (4- MeO-Ph) -0-CH-I 4 -MeO-Ph)-C 2 0-CH2, 4-F-Ph-CH 2 3,4-F-Ph-cH 2 -CH- 2 -CI{ 2 -OMe, -CH- 2 -OEt, -Cl- 2 -NMe 2 -COOMe or -COCH, 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) 4 1~ RN N N 2 RR wherein R' denotes hydrogen; R 2 denotes hydrogen, ethyl, n-propyl, i-propyl, n-butyl, tert.-butyl, phenyl, benzyl, 2-pyridyl, 179 3 -pyridyl, 4-pyridyl, N-piperidinyl, N-morpholinyl, N-piperazinyl, 4-benzyl- piperazinyl, 3 -tetrahydrofuranyl, 4-tetrahydro- pyranyl, -NMe 2 cyclopentyl, cyclohexyl, adamantan-l-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, cyclohexyl- methyl, 2 -phenylethyl, N-morpholinomethyl, N-pyrrolylmethyl, (3-pyridyl)-NH-CH 2 Ph-COO-CH 2 3 -pyridyl-COO-CH,-, Ph-O-CH 2 (4- MeO-Ph)-O-CH,-, (4-MeO-Ph)-CH2-0-CH,-, 4-F-Ph-CH,-, 3,4-F-Ph-CH 2 -CH 2 -OH, -CH,-OMe, -CH 2 -OEt, -CH 2 -NMe 2 -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 adenosine- antagonistic activity. 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. I 180
16. Process for preparing imidazotriazolopyrimidinone derivatives of general formula (I) 0 R N. N R 6 (I) wherein R 1 R, R 3 R 4 Rs and R 6 are defined as in claims 1 to 12, characterised in that a) a compound of general formula (9) R6 (9) or a tautomer thereof, wherein R 2 R 4 and R 6 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 R 3 wherein R' and R 3 are as hereinbefore defined and X denotes a leaving group, or b) a compound of general formula (16) 181 0 N N R..N N N N R 6 (16) or a tautomer thereof, wherein R 2 R s and R 6 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 R 1 -X or R 3 wherein R 1 and R 3 are as hereinbefore defined and X denotes a leaving group, or c) for R 4 =R 1 a compound of general formula 0 R N N N N R 6 or a tautomer thereof, wherein R 2 and R 6 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 R 1 -X or R -X to form the monoalkylated compounds or directly to form the dialkylated compounds wherein R' and R 3 are as hereinbefore defined and X denotes a leaving group.
17. Process for preparing imidazotriazolopyrimidinone derivatives of general formula (9) 0 H 4 'NN 182 or-the tautomers thereof, wherein R 2 R 4 and R 6 are defined as in claims 1 to 12, characterised in that a) a compound of general formulae 0 0 R ,N NHCOR 2 RN YNH 2 N NH 2 N N NHCOR 2 R or R wherein R 2 R 4 and R 6 are as hereinbefore defined, is cyclised under basic, acidic or dehydrating conditions to obtain the tricyclic imidazotriazolopyrimidinone derivatives of general formula or b) for R 2 a diamine of general formula 0 RN NH, N' N NH N>= R6 wherein R 4 and R 6 are as hereinbefore defined, is converted by thermal reaction with formamide into imidazotriazolopyrimidinone derivatives of general formula or c) for R 2 =NRR 9 wherein R 8 and R 9 are as hereinbefore defined, a nitroso compound of general formula 0 R NO 183 wherein R 4 and R 6 ate as hereinbefore defined, is reacted under dehydrating conditions with N-formylamines to obtain imidazotriazolopyrimidinone derivatives of general formula
18. Process for preparing imidazotriazolopyrimidinone derivatives of general formula (16) 0 I R N R (16) or the tautomers thereof, wherein R 2 R 5 and R 6 are defined as in claims 1 to 12, characterised in that a) a compound of general formula 0 0 N NHCOR 2 N NH 2 N N NH2 R-N N NHCOR 2 or R R6~ N N wherein R 2 R 5 and R 6 are as hereinbefore defined, is cyclised under basic, acidic or dehydrating conditions to obtain the tricyclic imidazotriazolopyrimidinone derivatives of general formula or b) for R 2 a diamine of general formula 0 N NH 2 5 RN Re 184 wherein R 5 and R' are as hereinbefore defined, is converted by thermal reaction with formamide into imidazotriazolopyrimidinone derivatives of general formula or c) for R2=NR'R' wherein R' and R 9 as hereinbefore defined, a nitroso compound of general formula O N NO R-N N NH2 R wherein R 5 and R' are as hereinbefore defined, is reacted with N-formylamines under dehydrating conditions to obtain imidazotriazolopyrimidinone derivatives of general formula (16).
19. A triazolopurine compound having the following characteristics: 'H-NMR (DMSO-d6) 6 13.62 (1H, s, broad, NH) 4.11 (2H, t, J =7.5 Hz, N- .I.CH 2 CH) 3.23 (1H, m, CH-Cylclopentyl) 2.37 (3H, s, -CH 3 2.14-1.50 H, m, CH 2 -Cyclopentyl, N-CH.i 2 CH 3 0.90 (3H, t, J 7.5 Hz, N-CHCH 2 CH 3 and m.p. 262-264°C. Triazolopurines of general formula pharmaceutical preparations containing same and processes for their preparation substantially as hereinbefore described with reference to the Examples. DATED this 19th day of February 1999 BOEHRINGER INGELHEIM INTERNATIONAL GMBH By its Patent Attorneys DAVIES COLLISON CAVE I
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19629378A DE19629378A1 (en) | 1996-07-20 | 1996-07-20 | New triazolopurines, process for their preparation and their use as medicaments |
| DE19629378 | 1996-07-20 | ||
| AU36955/97A AU3695597A (en) | 1996-07-20 | 1997-07-17 | New triazolopurines, method of preparing them and their use as drugs |
| US9058798P | 1998-06-25 | 1998-06-25 | |
| CA002242097A CA2242097C (en) | 1996-07-20 | 1998-06-26 | Imidazotriazolopyrimidines, process for preparing them and their use as pharmaceutical compositions |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU36955/97A Division AU3695597A (en) | 1996-07-20 | 1997-07-17 | New triazolopurines, method of preparing them and their use as drugs |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU1741899A true AU1741899A (en) | 1999-06-17 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU17418/99A Abandoned AU1741899A (en) | 1996-07-20 | 1999-02-19 | New imidazotriazolopyrimidinones, processes for preparing them and their use as pharmaceutical compositions |
Country Status (1)
| Country | Link |
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| AU (1) | AU1741899A (en) |
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1999
- 1999-02-19 AU AU17418/99A patent/AU1741899A/en not_active Abandoned
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