Methods of using dihydropteridinones

Bauer, Eckhart ;   et al.

Patent Application Summary

U.S. patent application number 10/756623 was filed with the patent office on 2004-07-29 for methods of using dihydropteridinones. This patent application is currently assigned to Boehringer Ingelheim Pharma Gmbh & Co. KG. Invention is credited to Bauer, Eckhart, Breitfelder, Steffen, Eickmeier, Christian, Grauert, Matthias, Hoffmann, Matthias, Lehmann-Lintz, Thorsten, Phol, Gerald, Quant, Jens, Redemann, Norbert, Schnapp, Gisela, Steegmaier, Martin.

Application Number20040147524 10/756623
Document ID /
Family ID31498915
Filed Date2004-07-29

United States Patent Application 20040147524
Kind Code A1
Bauer, Eckhart ;   et al. July 29, 2004

Methods of using dihydropteridinones

Abstract

Disclosed are dihydropteridinones of the formula (I): 1 wherein the groups X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.7 have the meanings given in the claims and specification, the isomers thereof, processes and intermediates for preparing these dihydropteridinones as well as the use thereof as pharmaceutical compositions.


Inventors: Bauer, Eckhart; (Biberach, DE) ; Breitfelder, Steffen; (Assmannshardt, DE) ; Eickmeier, Christian; (Mittelbiberach, DE) ; Grauert, Matthias; (Biberach, DE) ; Hoffmann, Matthias; (Mittelbiberach, DE) ; Lehmann-Lintz, Thorsten; (Ochsenhausen, DE) ; Phol, Gerald; (Biberach, DE) ; Quant, Jens; (Guntramsdorf, AU) ; Redemann, Norbert; (Biberach, DE) ; Schnapp, Gisela; (Biberach-Rindenmoos, DE) ; Steegmaier, Martin; (Wien, AT)
Correspondence Address:
    BOEHRINGER INGELHEIM CORPORATION
    900 RIDGEBURY ROAD
    P. O. BOX 368
    RIDGEFIELD
    CT
    06877
    US
Assignee: Boehringer Ingelheim Pharma Gmbh & Co. KG
Binger Strasse 173
Ingelheim
DE
55216

Family ID: 31498915
Appl. No.: 10/756623
Filed: January 13, 2004

Related U.S. Patent Documents

Application Number Filing Date Patent Number
10756623 Jan 13, 2004
10226710 Aug 23, 2002
60332681 Nov 14, 2001

Current U.S. Class: 514/251
Current CPC Class: C07D 487/04 20130101; C07D 475/00 20130101
Class at Publication: 514/251
International Class: A61K 031/525

Foreign Application Data

Date Code Application Number
Sep 4, 2001 DE 101 43 272.0

Claims



1. A method of treating a disease or condition chosen from cancer, infections, inflammatory and autoimmune diseases said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I), 1368wherein R.sup.1 denotes a group selected from among hydrogen, NH.sub.2, XH, halogen and a C.sub.1-C.sub.3-alkyl group optionally substituted by one or more halogen atoms, R.sup.2 denotes a group selected from among hydrogen, CHO, XH, --X--C.sub.1-C.sub.2-alkyl and an optionally substituted C.sub.1-C.sub.3-alkyl group, R.sup.3, R.sup.4 are identical or different and denote a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkyny- l, aryl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-heterocyc- loalkyl, --X-aryl, --X-heteroaryl, --X-cycloalkyl, --X-heterocycloalkyl, --NR.sup.8-aryl, --NR.sup.8-heteroaryl, --NR.sup.8-cycloalkyl,- and --NR.sup.8-heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR.sup.8, CON(R.sup.8).sub.2, COR.sup.8 and XR.sup.8, or R.sup.3 and R.sup.4 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms, R.sup.5 denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl and --C.sub.3-C.sub.6-cycloalkyl , or R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms, R.sup.6 denotes optionally substituted aryl or heteroaryl, R.sup.7 denotes hydrogen or --CO--X--C.sub.1-C.sub.4-alkyl, and X in each case independently of one another denotes O or S, and R.sup.8 in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl and phenyl, or the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

2. A method of treating a disease or condition chosen from HIV, Kaposi's sarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis, conditions related to wound healing, bacterial, fungal and/or parasitic infections, leukaemias, lymphoma, solid tumours, psoriasis, bone diseases and cardiovascular disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) 1369wherein R.sup.1 denotes a group selected from among hydrogen, NH.sub.2, XH, halogen and a C.sub.1-C.sub.3-alkyl group optionally substituted by one or more halogen atoms, R.sup.2 denotes a group selected from among hydrogen, CHO, XH, --X--C.sub.1-C.sub.2-alkyl and an optionally substituted C.sub.1-C.sub.3-alkyl group, R.sup.3, R.sup.4 are identical or different and denote a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-heterocycloalkyl, --X-aryl, --X-heteroaryl, --X-cycloalkyl, --X-heterocycloalkyl, --NR.sup.8-aryl, --NR.sup.8-heteroaryl, --NR.sup.8-cycloalkyl,- and --NR.sup.8-heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR.sup.8, CON(R.sup.8).sub.2, COR.sup.8 and XR.sup.8, or R.sup.3 and R.sup.4 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms, R.sup.5 denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl and --C.sub.3-C.sub.6-cycloalkyl , or R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms, R.sup.6 denotes optionally substituted aryl or heteroaryl, R.sup.7 denotes hydrogen or --CO--X--C.sub.1-C.sub.4-alkyl, and X in each case independently of one another denotes O or S, and R.sup.8 in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl and phenyl, or the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

3. The methods according to claims 1 or 2 wherein for the formula (I) R.sup.1 denotes hydrogen, R.sup.2 denotes a group selected from among a CHO, OH, and CH.sub.3 group, R.sup.3, R.sup.4 are identical or different and denote a group selected from among hydrogen, optionally substituted C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl, or R.sup.3 and R.sup.4 together denote a C.sub.2-C.sub.5-alkyl bridge, R.sup.5 denotes a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, C.sub.3-C.sub.6-cycloalkyl and C.sub.3-C.sub.6-cycloalkenyl, or R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms, and R.sup.7 denotes hydrogen.

4. The methods according to claim 3, wherein for the formula (I) R.sup.6 denotes a group of general formula 1370wherein n denotes 1, 2, 3 or 4, R.sup.9 denotes a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, --CONH--C.sub.1-C.sub.10-alkylene, --O-aryl, --O-heteroaryl, --O-cycloalkyl, --O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among --O--C.sub.1-C.sub.6-alky- l-Q.sup.1, --CONR.sup.8--C.sub.1-C.sub.10-alkyl-Q.sup.1, --CONR.sup.8--C.sub.2-C.sub.10-alkenyl-Q.sup.1, --CONR.sup.8--Q.sup.2, halogen, OH, --SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8).sub.2, --COR.sup.8, --COOR.sup.8, --N(R.sup.8).sub.2, --NHCOR.sup.8, CONR.sup.8OC.sub.1-C.sub- .10 alkylQ.sup.1 and CONR.sup.8OQ.sup.2, Q.sup.1 denotes hydrogen, --NHCOR.sup.8, or a group selected from among an optionally substituted --NH-aryl, --NH-heteroaryl, aryl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl- and heterocycloalkyl group, Q.sup.2 denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, C.sub.3-C.sub.8-heterocycloalkyl, C.sub.3-C.sub.8-cycloalkyl- and C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.8-cycloalkyl group, R.sup.10 is identical or different and denotes a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl , C.sub.2-C.sub.6-alkenyl and C.sub.2-C.sub.6-alkynyl, --O--C.sub.1-C.sub.6-alkyl, --O--C.sub.2-C.sub.6-alkenyl, --O--C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl, or a group selected from among hydrogen, --CONH.sub.2, --COOR.sup.8, --OCON(R.sup.8).sub.2, --N(R.sup.8).sub.2, --NHCOR.sup.8, --NHCON(R.sup.8).sub.2, --NO.sub.2 and halogen, or adjacent groups R.sup.9 and R.sup.10 together denote a bridge of the formula 1371Y denotes O, S or NR.sup.11, m denotes 0, 1 or 2 R.sup.11 denotes hydrogen or C.sub.1-C.sub.2-alkyl, and R.sup.12 denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, --C.sub.1-C.sub.3-alkyl-phenyl, --C.sub.1-C.sub.3-alkyl-pyridyl, --C.sub.1-C.sub.3-alkyl-pyrazinyl, --C.sub.1-C.sub.3-alkyl-pyrimidinyl and --C.sub.1-C.sub.3-alkyl-pyridazin- yl, and R.sup.13 denotes C.sub.1-C.sub.6-alkyl.

5. The methods according to claim 4, wherein for the formula (I) R.sup.1 denotes hydrogen, R.sup.2 denotes CH.sub.3, and R.sup.7 denotes hydrogen.

6. A method of treating a disease or condition chosen from cancer, infections, inflammatory and autoimmune diseases said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (II), 1372wherein R.sup.1-R.sup.5 and X have the meanings given in claim 1.

7. A method of treating a disease or condition chosen from HIV, Kaposi's sarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis, conditions related to wound healing, bacterial, fungal and/or parasitic infections, leukaemias, lymphoma, solid tumours, psoriasis, bone diseases and cardiovascular disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (II), 1373wherein R.sup.1-R.sup.5 and X have the meanings given in claim 1.
Description



APPLICATION DATA

[0001] This application is a continuation of U.S. application Ser. No. 10/226,710 filed Aug. 23, 2002 which claims benefit to DE 101 43 272.0 filed Sep. 4, 2001 and U.S. provisional application No. 60/332681 filed Nov. 14, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to new dihydropteridinones of general formula (I) 2

[0003] wherein the groups X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 have the meanings given in the claims and specification, the isomers thereof, processes for preparing these dihydropteridinones and the use thereof as pharmaceutical compositions.

BACKGROUND TO THE INVENTION

[0004] Pteridinone derivatives are known from the prior art as active substances with an antiproliferative activity. WO 01/019825 describes the use of pteridinone derivatives for the treatment of neoplastic and viral diseases. The resistance of many types of tumours calls for the development of new pharmaceutical compositions for combating tumours.

[0005] The aim of the present invention is to prepare new compounds with an antiinflammatory and antiproliferative activity.

DETAILED DESCRIPTION OF THE INVENTION

[0006] Surprisingly it has been found that compounds of general formula (I) wherein the groups X and R.sup.1 to R.sup.7 have the meanings given hereinafter act as inhibitors of specific cell cycle kinases. Thus, the compounds according to the invention may be used for example to treat diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.

[0007] The present invention therefore relates to compounds of general formula (I) 3

[0008] wherein

[0009] R.sup.1 denotes a group selected from among hydrogen, NH.sub.2, XH, halogen and a C.sub.1-C.sub.3-alkyl group optionally substituted by one or more halogen atoms,

[0010] R.sup.2 denotes a group selected from among hydrogen, CHO, XH, --X--C.sub.1-C.sub.2-alkyl and an optionally substituted C.sub.1-C.sub.3-alkyl group,

[0011] R.sup.3, R.sup.4 which may be identical or different denote a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl, C.sub.3-C.sub.8-heterocycloalkyl, --X-aryl, --X-heteroaryl, --X-cycloalkyl, --X-heterocycloalkyl, --NR.sup.8-aryl, --NR.sup.8-heteroaryl, --NR.sup.8-cycloalkyl and --NR.sup.8-heterocycloal- kyl, or a group selected from among hydrogen, halogen, COXR.sup.8, CON(R.sup.8).sub.2, COR.sup.8 and XR.sup.8, or

[0012] R.sup.3 and R.sup.4 together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,

[0013] R.sup.5 denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkynyl, aryl, heteroaryl and --C.sub.3-C.sub.6-cycloalk- yl, or

[0014] R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms,

[0015] R.sup.6 denotes optionally substituted aryl or heteroaryl,

[0016] R.sup.7 denotes hydrogen or --CO--X--C.sub.1-C.sub.4-alkyl, and

[0017] X in each case independently of one another denotes O or S,

[0018] R.sup.8 in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl and phenyl,

[0019] optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0020] Preferred compounds of formula (I) are those wherein

[0021] X and R.sup.6 have the meaning indicated, and

[0022] R.sup.1 denotes hydrogen,

[0023] R.sup.2 denotes a group selected from among a CHO, OH, and CH.sub.3 group,

[0024] R.sup.3, R.sup.4 which may be identical or different denote a group selected from among hydrogen, optionally substituted C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.7-cycloalkyl, or

[0025] R.sup.3 and R.sup.4 together denote a C.sub.2-C.sub.5-alkyl bridge,

[0026] R.sup.5 denotes a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl, C.sub.2-C.sub.10-alkyny- l, C.sub.3-C.sub.6-cycloalkyl and C.sub.3-C.sub.6-cycloalkenyl, or

[0027] R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms, and

[0028] R.sup.7 denotes hydrogen,

[0029] optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0030] Particularly preferred compounds of formula (I) are those wherein

[0031] R.sup.1-R.sup.5, R.sup.7, R.sup.8 and X have the meaning indicated, and

[0032] R.sup.6 denotes a group of general formula 4

[0033] wherein

[0034] n denotes 1, 2, 3 or 4,

[0035] R.sup.9 denotes a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, --CONH--C.sub.1-C.sub.10-alkylene, --O-aryl, --O-heteroaryl, --O-cycloalkyl, --O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among --O--C.sub.1-C.sub.6-alky- l-Q.sup.1, --CONR.sup.8--C.sub.1-C.sub.10-alkyl-Q.sup.1, --CONR.sup.8--C.sub.2-C.sub.10-alkenyl-Q.sup.1, --CONR.sup.8--Q.sup.2, halogen, OH, --SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8).sub.2, --COR.sup.8,--COOR.sup.8, --N(R.sup.8).sub.2, --NHCOR.sup.8, CONR.sup.8OC.sub.1-C.sub.10 alkylQ.sup.1 and CONR.sup.8OQ.sup.2,

[0036] Q.sup.1 denotes hydrogen, --NHCOR.sup.8, or a group selected from among an optionally substituted --NH-aryl, --NH-heteroaryl, aryl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl- and heterocycloalkyl group,

[0037] Q.sup.2 denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, C.sub.3-C.sub.8-heterocycloalkyl- , C.sub.3-C.sub.8-cycloalkyl- and C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.8-cy- cloalkyl group,

[0038] R.sup.10 which may be identical or different denotes a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl , C.sub.2-C.sub.6-alkenyl and C.sub.2-C.sub.6-alkynyl, --O--C.sub.1-C.sub.6-alkyl, --O--C.sub.2-C.sub.6-alkenyl, --O--C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl, or a group selected from among hydrogen, --CONH.sub.2, --COOR.sup.8, --OCON(R.sup.8).sub.2, --N(R.sup.8).sub.2, --NHCOR.sup.8, --NHCON(R.sup.8).sub.2, --NO.sub.2 and halogen, or

[0039] adjacent groups R.sup.9 and R.sup.10 together denote a bridge of general formula 5

[0040] Y denotes O, S or NR.sup.11,

[0041] m denotes 0, 1 or 2

[0042] R.sup.11 denotes hydrogen or C.sub.1-C.sub.2-alkyl, and

[0043] R.sup.12 denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, --C.sub.1-C.sub.3-alkyl-phenyl, --C.sub.1-C.sub.3-alkyl-pyridyl, --C.sub.1-C.sub.3-alkyl-pyrazinyl, --C.sub.1-C.sub.3-alkyl-pyrimidinyl and --C.sub.1-C.sub.3-alkyl-pyridazinyl, p1 R.sup.13 denotes C.sub.1-C.sub.6-alkyl,

[0044] optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0045] Particularly preferred are compounds of formula (I) wherein

[0046] R.sup.3--R.sup.6, R.sup.8 and X have the meaning indicated, and

[0047] R.sup.1 denotes hydrogen,

[0048] R.sup.2 denotes CH.sub.3, and

[0049] R.sup.7 denotes hydrogen,

[0050] optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

[0051] The invention further relates to compounds of formula (I), wherein X and R.sup.1-R.sup.7 have the meanings indicated, for use as pharmaceutical compositions.

[0052] Of particular importance according to the invention are compounds of formula (I), wherein X and R.sup.1-R.sup.7 have the meaning indicated, for use as pharmaceutical compositions with an antiproliferative activity.

[0053] The invention also relates to the use of a compound of formula (I), wherein X and R.sup.1-R.sup.7 have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.

[0054] The invention also relates to a method of treating and/or preventing cancer, infections, inflammatory and autoimmune diseases, characterised in that a patient is given an effective amount of a compound of formula (I), wherein X and R.sup.1-R.sup.7 have the meanings indicated.

[0055] The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), wherein X and R.sup.1-R.sup.7 have the meanings indicated, or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.

[0056] The invention also relates to a process for preparing a compound of general formula (I), 6

[0057] wherein

[0058] R.sup.1-R.sup.7 and X are as hereinbefore defined, characterised in that a compound of general formula (II) 7

[0059] wherein

[0060] R.sup.1-R.sup.5 and X are as hereinbefore defined and L is a leaving group, is reacted with an optionally substituted compound of general formula (III) 8

[0061] wherein

[0062] R.sup.6 and R.sup.7 are as hereinbefore defined.

[0063] The invention also relates to a compound of formula (II), 9

[0064] wherein

[0065] R.sup.1-R.sup.5 and X are as hereinbefore defined. Compounds of formula (II) are important intermediate products for preparing the compounds of formula (I) according to the invention.

[0066] The invention also relates to a process for preparing a compound of general formula (I), 10

[0067] wherein

[0068] R.sup.6 denotes a group of general formula, 11

[0069] R.sup.9 denotes an optionally substituted group --CONH--C.sub.1-C.sub.10-alkylene or a group selected from among --CONR.sup.8--C.sub.1-C.sub.10-alkyl-Q.sup.1, --CONR.sup.8--C.sub.2-C.sub- .10-alkenyl-Q.sup.1, --CONR.sup.8--Q.sup.2 and --COOR.sup.8, and

[0070] R.sup.1-R.sup.5, R.sup.7, R.sup.10, n and X are as hereinbefore defined, characterised in that a compound of general formula (IA) 12

[0071] wherein

[0072] R.sup.1 to R.sup.5, R.sup.7 and R.sup.10 are as hereinbefore defined, and

[0073] L denotes a leaving group,

[0074] is reacted with a primary or secondary amine to form the corresponding amide or is reacted with an alcohol to form the corresponding ester.

[0075] The term alkyl groups, including alkyl groups which are a part of other groups, denotes branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as, for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Unless otherwise stated, the abovementioned terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include all the possible isomeric forms. For example, the term propyl includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc.

[0076] In the abovementioned alkyl groups one or more hydrogen atoms may optionally be replaced by other groups. For example these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkyl group may optionally also be replaced.

[0077] Similarly, in the abovementioned alkyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced for example by an optionally substituted group selected from among CN, OCOCH.sub.3, aryl, preferably phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.

[0078] The term alkyl bridge, unless otherwise stated, denotes branched and unbranched alkyl groups with 2 to 5 carbon atoms, for example propylene, isopropylene, n-butylene, iso-butyl, sec. butyl and tert.-butyl etc. bridges. Propylene and butylene bridges are particularly preferred. In the alkyl bridges mentioned 1 to 2 C-atoms may optionally be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur.

[0079] The term alkenyl groups (including those which are a part of other groups) denotes branched and unbranched alkylene groups with 2 to 10 carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbon atoms, provided that they have at least one double bond. Examples include: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwise stated, the abovementioned terms propenyl, butenyl, etc also include all the possible isomeric forms. For example, the term butylene includes n-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1.1-dimethylethenyl, 1.2-dimethylethenyl etc.

[0080] In the abovementioned alkenyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkenyl group may optionally also be replaced.

[0081] The term alkynyl groups (including those which are a part of other groups) denotes branched and unbranched alkynyl groups with 2 to 10 carbon atoms, provided that they have at least one triple bond, for example ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferably ethynyl or propynyl.

[0082] In the abovementioned alkynyl groups, unless otherwise stated, one or more hydrogen atoms may optionally be replaced by other groups. For example, these alkyl groups may be substituted by the halogen atoms fluorine, chlorine, bromine or iodine. The substituents fluorine and chlorine are preferred. The substituent chlorine is particularly preferred. All the hydrogen atoms of the alkynyl group may optionally also be replaced.

[0083] The term aryl denotes an aromatic ring system with 6 to 14 carbon atoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unless otherwise stated, may carry one or more of the following substituents, for example: OH, NO.sub.2, CN, --OCHF.sub.2, --OCF.sub.3, --NH.sub.2, halogen, for example fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, C.sub.1-C.sub.10-alkyl, preferably C.sub.1-C.sub.5-alkyl, preferably C.sub.1-C.sub.3-alkyl, most preferably methyl or ethyl, --O--C.sub.1-C.sub.3-alkyl, preferably --O-methyl or --O-ethyl, --N-methyl-tetrahydro-oxazinyl, --COOH, --COO--C.sub.1-C.sub.4-alkyl, preferably --COOCH.sub.2CH.sub.3, --COO--C(CH.sub.3).sub.3 or --COOCH.sub.3, --CONH.sub.2, --CONH--C.sub.1-C.sub.10-alkyl, while this alkyl may optionally be further substituted, optionally substituted --CONH--C.sub.3-C.sub.6-cyclo- alkyl, preferably optionally substituted --CONH-cyclopentyl, optionally substituted --CONH-heterocycloalkyl, preferably piperidinyl, pyrrolidinyl or piperazinyl, optionally substituted --CONH-heteroaryl, preferably optionally substituted --CONH-pyridyl, optionally substituted --CONH-aryl, preferably optionally substituted --CONH-phenyl, --CONMeC.sub.1-C.sub.3-alkyl, while this alkyl may optionally be further substituted, preferably --CONMeCH.sub.2-pyridyl, benzimidazole or a group of formula 13

[0084] Examples of 5-10-membered mono- or bicyclic heteroaryl rings wherein up to three C-atoms may be replaced by one or more heteroatoms selected from among oxygen, nitrogen or sulphur include furan, thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole, thiazole, thiadiazole and oxadiazole, while each of the abovementioned heterocycles may optionally also be annellated onto a benzene ring, preferably benzimidazole, and unless otherwise stated these heterocycles may for example carry one or more of the following substituents: OH, NO.sub.2, CN, --OCHF.sub.2, --OCF.sub.3, --NH.sub.2, halogen, preferably fluorine or chlorine, C.sub.1-C.sub.10-alkyl, preferably C.sub.1-C.sub.5-alkyl, preferably C.sub.1-C.sub.3-alkyl, most preferably methyl or ethyl, --O--C.sub.1-C.sub.3-alkyl, preferably --O-methyl or --O-ethyl, -methyl-N-tetrahydro-oxazinyl, --COOH, --COO--C.sub.1-C.sub.4-alkyl, preferably --COO--C(CH.sub.3).sub.3 or --COOCH.sub.3, --CONH.sub.2, optionally substituted phenyl, optionally substituted heteroaryl, preferably optionally substituted pyridyl or pyrazinyl, --CONH--C.sub.1-C.sub.10-alkyl, while this alkyl may itself optionally be substituted, optionally substituted --CONH--C.sub.3-C.sub.6-cycloalkyl, preferably optionally substituted --CONH-cyclopentyl, optionally substituted --CONH-heteroaryl, preferably optionally substituted --CONH-pyridyl, optionally substituted --CONH-aryl, preferably optionally substituted --CONH-phenyl, --CONMeC.sub.1-C.sub.3-alkyl, while this alkyl may itself optionally be substituted, preferably --CONMeCH.sub.2-pyridyl, benzimidazole or a group of formula 14

[0085] The term cycloalkyl groups denotes, for example, saturated or unsaturated cycloalkyl groups with 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl, cyclopentyl or cyclohexyl, while each of the abovementioned cycloalkyl groups may optionally also carry one or more substituents, preferably .dbd.O, or may be annellated to a benzene ring.

[0086] ".dbd.O" denotes an oxygen atom linked via a double bond.

[0087] The term heterocycloalkyl groups, unless otherwise described in the definitions, may denote 5-, 6- or 7-membered, saturated or unsaturated heterocycles, which may contain nitrogen, oxygen or sulphur as heteroatoms, for example tetrahydrofuran, tetrahydrofuranon, .gamma.-butyrolactone, .alpha.-pyran, .gamma.-pyran, dioxolane, tetrahydropyran, dioxane, dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazine, tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, while the heterocycle may optionally be substituted.

[0088] Generally, the term halogen denotes fluorine, chlorine, bromine or iodine.

[0089] The leaving group L denotes either identical or different leaving groups such as for example chlorine, bromine, iodine, methanesulphonyl, trifluoromethanesulphonyl or p-toluenesulphonyl, preferably chlorine.

[0090] The compounds according to the invention may be present in the form of the individual optical isomers, mixtures of the individual enantiomers, diastereomers or racemates, in the form of the tautomers and also in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids--such as for example acid addition salts with hydrohalic acids, for example hydrochloric or hydrobromic acid, or organic acids, such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

[0091] The substituent R.sup.1 may denote a group selected from among hydrogen, NH.sub.2, XH, preferably OH, halogen, preferably fluorine or chlorine and a C.sub.1-C.sub.3-alkyl group optionally substituted by one or more, preferably one, two or three halogen atoms, preferably fluorine or chlorine, preferably methyl or ethyl. Most preferably, the substituent R.sup.1 is hydrogen .

[0092] The substituent R.sup.2 may denote a group selected from among hydrogen, CHO, XH, preferably OH, --X--C.sub.1-C.sub.2-alkyl, preferably --O--CH.sub.3 or --O--CH.sub.2CH.sub.3, and an optionally substituted C.sub.1-C.sub.3-alkyl group, while the alkyl group preferably consists of 1 to 2 carbon atoms, particularly preferably a carbon atom and may optionally be substituted, preferably by halogen atoms, most preferably by fluorine atoms. In particular, the substituent R.sup.2 denotes methyl.

[0093] The substituents R.sup.3 and R.sup.4 may be identical or different and may represent a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, preferably C.sub.1-C.sub.6-alkyl, preferably C.sub.1-C.sub.4-alkyl, most preferably methyl, ethyl or propyl, particularly preferably methyl or ethyl, C.sub.2-C.sub.10-alkenyl, preferably ethenyl or propenyl, preferably ethenyl, C.sub.2-C.sub.10-alkynyl, preferably ethynyl or propynyl, aryl, preferably optionally substituted phenyl, heteroaryl, C.sub.3-C.sub.8-cycloalkyl, preferably cyclopropyl and cyclobutyl, C.sub.3-C.sub.8-heterocycloalkyl, --X-aryl, --X-heteroaryl, --X-cycloalkyl, --X-heterocycloalkyl, --NR.sup.8-aryl, --NR.sup.8-heteroaryl, --NR.sup.8-cycloalkyl and --NR.sup.8-heterocycloal- kyl, or

[0094] a group selected from among hydrogen, halogen, COXR.sup.8, CON(R.sup.8).sub.2, COR.sup.8 and XR.sup.8, preferably hydrogen, or

[0095] the groups R.sup.3 and R.sup.4 may together denote a 2- to 5-membered alkyl bridge, preferably an ethylene, propylene or butylene bridge , while the propylene or butylene bridge may contain 1 to 2 heteroatoms, preferably oxygen, nitrogen or sulphur, most preferably an ethylene bridge.

[0096] Most preferably, the substituent R.sup.3 denotes methyl or ethyl. The substituent R.sup.4 most preferably denotes hydrogen or methyl. Particularly preferred are compounds wherein R.sup.3 and R.sup.4 represent methyl.

[0097] All the groups mentioned in the definition of R.sup.3 and R.sup.4 may optionally be substituted.

[0098] The group R.sup.5 may contain hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.10-alkyl, for example C.sub.1-C.sub.6-alkyl-aryl or C.sub.1-C.sub.6-alkyl-heteroaryl, preferably C.sub.1-C.sub.6-alkyl, most preferably C.sub.1-C.sub.5-alkyl, particularly preferably propyl, butyl, pentyl, hexyl, --CH.sub.2-cyclohexyl, (CH.sub.2).sub.1-2cyclopropyl or (CH.sub.2).sub.4--OCOCH.sub.3, C.sub.2-C.sub.10-alkenyl, preferably propenyl, butenyl, pentenyl or hexenyl, preferably propenyl or hexenyl, C.sub.2-C.sub.10-alkynyl, preferably propynyl, butynyl or pentynyl, preferably propynyl, aryl, preferably phenyl, heteroaryl, --C.sub.3-C.sub.6-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and -C.sub.3-C.sub.6-cycloalkenyl, preferably cyclohexenyl or cyclopentenyl, or the substituents R.sup.3 and R.sup.5 or R.sup.4 and R.sup.5 together denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may contain 1 to 2 heteroatoms, preferably oxygen, sulphur or nitrogen.

[0099] All the groups mentioned in the definition of R.sup.5 may optionally be substituted.

[0100] The substituent R.sup.6 may denote optionally substituted aryl, or heteroaryl, preferably aryl, preferably phenyl.

[0101] Most preferably, the substituent R.sup.6 denotes a phenyl group, which may be substituted by one of the groups R.sup.9 and R.sup.10 described hereinafter, while the phenyl ring may carry one of the groups R.sup.9, preferably in the para position, and one, two, three or four, preferably one or two, of the groups R.sup.10, preferably in the ortho or meta position.

[0102] The substituent R.sup.7 may denote hydrogen or --CO--X--C.sub.1-C.sub.4-alkyl, preferably hydrogen.

[0103] X denotes, in each case independently of one another, O or S, preferably O.

[0104] The groups R.sup.8 mentioned in the definitions of the substituents R.sup.3 and R.sup.4 represent, independently of one another in each case, hydrogen or a group selected from among optionally substituted C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl, C.sub.2-C.sub.4-alkynyl and phenyl, preferably hydrogen or C.sub.1-C.sub.2-alkyl.

[0105] The substituent R.sup.9 may represent a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl, preferably C.sub.1-C.sub.4-alkyl, preferably methyl, ethyl or propyl, most preferably methyl, C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl, --CONH--C.sub.1-C.sub.10-alkylene, preferably --CONH--C.sub.1-C.sub.3-alk- ylene, preferably --CONH--C.sub.1-C.sub.2-alkylene, --O-aryl, preferably O--C.sub.6-C.sub.10-aryl, most preferably O-phenyl, --O-heteroaryl, --O-cycloalkyl, preferably O--C.sub.3-C.sub.6-cycloalkyl, most preferably O-cyclopropyl, --O-heterocycloalkyl, aryl, preferably C.sub.6-C.sub.10-aryl, most preferably phenyl, heteroaryl, cycloalkyl, preferably C.sub.3-C.sub.6-cycloalkyl, most preferably cyclopropyl, and heterocycloalkyl, or a group selected from among --O--C.sub.1-C.sub.6-alk- yl-Q.sup.1, --CONR.sup.8--C.sub.1-C.sub.10-alkyl-Q.sup.1, --CONR.sup.8--C.sub.1-C.sub.10-alkenyl-Q.sup.1, --CONR.sup.8Q.sup.2, halogen, for example fluorine, chlorine, bromine or iodine, OH, --SO.sub.2R.sup.8, --SO.sub.2N(R.sup.8).sub.2, --COR.sup.8,--COOR.sup.8, --N(R.sup.8).sub.2, --NHCOR.sup.8, CONR.sup.8OC.sub.1-C.sub.10-alkylQ.sup- .1 and CONR.sup.8OQ.sup.2, where Q.sup.1 and Q.sup.2 are as hereinbefore defined.

[0106] Preferably, R.sup.9 denotes one of the following groups --CONH--C.sub.1-C.sub.10-alkyl, preferably --CONH--C.sub.1-C.sub.3-alkyl, most preferably --CONH--C.sub.1-C.sub.2-alkyl, while this alkyl may itself optionally be substituted, by CN, optionally substituted aryl, preferably optionally substituted phenyl, heteroaryl, preferably thienyl, thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group, preferably methylamine, benzylamine, phenylamine or heteroarylamine, saturated or unsaturated bicyclic ring systems, preferably benzimidazolyl and cycloalkyl, preferably cyclohexyl. Moreover R.sup.9 preferably denotes --CONH-heteroaryl, preferably --CONH-pyridyl, --CONH--C.sub.3-C.sub.10-cycloalkyl, preferably --CONH-cyclopropyl --CONH-cyclobutyl or --CONH-cyclopentyl, most preferably --CONH-cyclopropyl; --CONH--C.sub.3-C.sub.10-heterocycloalkyl, --CONH--C.sub.6-C.sub.10-aryl, preferably --CONH-phenyl, COO--C.sub.1-C.sub.3-alkyl, most preferably COOCH.sub.3, COOH, halogen, preferably F or chlorine, OH or a group of formula 15

[0107] All the groups mentioned in the definition of R.sup.9 may optionally be substituted, preferably by one or more of the groups selected from among OH, OCH.sub.3, Cl, F, CH.sub.3, COOH, CONHCH.sub.2Ph and CONHCH.sub.2-pyrazinyl-CH.sub.3.

[0108] The substituent R.sup.10 may be identical or different in each case and may denote a group selected from among optionally substituted C.sub.1-C.sub.6-alkyl , preferably C.sub.1-C.sub.3-alkyl, C.sub.2-C.sub.6-alkenyl, preferably C.sub.2-C.sub.3-alkenyl and C.sub.2-C.sub.6-alkynyl, preferably C.sub.2-C.sub.3-alkynyl, --O--C.sub.1-C.sub.6-alkyl, preferably --O--C.sub.1-C.sub.3-alkyl, --O--C.sub.2-C.sub.6-alkenyl, --O--C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl, or a group selected from among hydrogen, --CONH.sub.2, --COOR.sup.8, --OCON(R.sup.8).sub.2, --N(R.sup.8).sub.2, --NHCOR.sup.8, --NHCON(R.sup.8).sub.2, --NO.sub.2 and halogen, for example fluorine, chlorine, bromine or iodine.

[0109] Preferably, the substituent R.sup.10 denotes hydrogen, methyl, methoxy, fluorine or chlorine, most preferably hydrogen or methoxy, particularly preferably methoxy.

[0110] Adjacent groups R.sup.9 and R.sup.10 may together denote a bridge of general formula 16

[0111] wherein

[0112] Y denotes O, S or NR.sup.11, preferably NR.sup.11,

[0113] m denotes 0, 1 or 2, preferably 1,

[0114] R.sup.11 denotes hydrogen or C.sub.1-C.sub.2-alkyl, preferably hydrogen or methyl, most preferably hydrogen,

[0115] R.sup.12 denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, --C.sub.1-C.sub.3-alkyl-phenyl, --C.sub.1-C.sub.3-alkyl-pyridyl, --C.sub.1-C.sub.3-alkyl-pyrazinyl, --C.sub.1-C.sub.3-alkyl-pyrimidinyl and -C.sub.1-C.sub.3-alkyl-pyridazinyl, preferably phenyl, pyridyl and pyrazinyl, and

[0116] R.sup.13 denotes C.sub.1-C.sub.6-alkyl, preferably methyl or ethyl.

[0117] The compounds according to the invention may be prepared by synthesis methods A and B described hereinafter, while the substituents of general formulae (A1) to (A6) have the meanings given hereinbefore. These methods are to be understood as illustrations of the invention without restricting it to their subject matter.

[0118] Method A

[0119] Step 1A

[0120] A compound of formula (A1) is reacted with a compound of formula (A2) to obtain a compound of formula (A3) (Diagram 1A). This reaction may be carried out according to WO 0043369 or WO 0043372. Compound (A1) is commercially obtainable, for example, from City Chemical LLC, 139 Allings Crossing Road, West Haven, Conn., 06516, USA. Compound (A2) may be prepared by procedures known from the literature: (a) F. Effenberger, U. Burkhart, J. Willfahrt Liebigs Ann. Chem. 1986, 314-333; b) T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F. E. Dutton, B. H. Byung Tetrahedron Lett. 1998, 30, 5313-5316; e) J. M. Ranajuhi, M. M. Joullie Synth. Commun. 1996, 26, 1379-1384.). 17

[0121] In Step 1A, 1 equivalent of the compound (A1) and 1 to 1.5 equivalents, preferably 1.1 equivalents of a base, preferably potassium carbonate, potassium hydrogen carbonate, sodium carbonate or sodium hydrogen carbonate, calcium carbonate, most preferably potassium carbonate, are stirred in a diluent, for example acetone, aqueous acetone, tetrahydrofuran, diethylether or dioxane, preferably acetone or diethylether, most preferably acetone.

[0122] At a temperature of 0 to 15.degree. C., preferably 5 to 10.degree. C., 1 equivalent of an amino acid of formula (A2), dissolved in an organic solvent, for example acetone, tetrahydrofuran, diethylether or dioxane, preferably acetone, is added dropwise.

[0123] The reaction mixture is heated to a temperature of 18.degree. C. to 30.degree. C., preferably about 22.degree. C., with stirring and then stirred for a further 10 to 24 hours, preferably about 12 hours. Then the diluent is distilled off, the residue is combined with water and the mixture is extracted two to three times with an organic solvent, such as diethylether or ethyl acetate, preferably ethyl acetate. The combined organic extracts are dried and the solvent is distilled off. The residue (compound A3) may be used in Step 2 without any prior purification.

[0124] Step 2A

[0125] The compound obtained in Step 1A (A3) is reduced at the nitro group and cyclised to form the compound of formula (A4) (Diagram 2A). 18

[0126] In Step 2A, 1 equivalent of the nitro compound (A3) is dissolved in an acid, preferably glacial acetic acid, formic acid or hydrochloric acid, preferably glacial acetic acid, and heated to 50 to 70.degree. C., preferably about 60.degree. C. Then a reducing agent, for example zinc, tin or iron, preferably iron filings, is added to complete the exothermic reaction and the mixture is stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to 125.degree. C., preferably at about 117.degree. C. After cooling to ambient temperature the iron salt is filtered off and the solvent is distilled off. The residue is taken up in a solvent or mixture of solvents, for example ethyl acetate or dichloromethane/methanol 9/1 and semisaturated NaCl solution, and filtered through kieselgur, for example. The organic phase is dried and evaporated down. The residue (compound (A4)) may be purified by chromatography or by crystallisation or used as the crude product in Step 3A of the synthesis.

[0127] Step 3A

[0128] The compound obtained in Step 2A (A4) may be reacted by electrophilic substitution as shown in Diagram 3A to obtain the compound of formula (A5). 19

[0129] In Step 3A 1 equivalent of the amide of formula (A4) is dissolved in an organic solvent, for example dimethylformamide or dimethylacetamide, preferably dimethylacetamide, and cooled to about -5 to 5.degree. C., preferably 0.degree. C. Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3 equivalents of alkyl halide, for example methyl iodide, are added. The reaction mixture is stirred for 0.1-3 hours, preferably about 1 hour, at about 0 to 10.degree. C., preferably at about 5.degree. C., and may optionally be left to stand for a further 12 hours at this temperature. The reaction mixture is evaporated down and extracted with water and an organic solvent, preferably dichloromethane or ethyl acetate. The organic phases are evaporated down. The residue (compound (A5)) may be purified by chromatography, preferably over silica gel.

[0130] Step 4A

[0131] The amination of the compound (A5) obtained in Step 3A to yield the compound of formula (A7) (Diagram 4A) may be carried out using the methods known from the literature of variants 4.1 A (a) M. P. V. Boarland, J. F. W. McOmie J. Chem. Soc. 1951, 1218-1221; b) F. H. S. Curd, F. C. Rose J. Chem. Soc. 1946, 343-348., 4.2 A (a) Banks J. Am. Chem. Soc. 1944, 66,1131 b) Ghosh and Dolly J. Indian Chem. Soc. 1981, 58, 512-513. 20

[0132] For example, in variant 4.1 A, 1 equivalent of the compound (A5) and 1 to 3 equivalents, preferably about 2 equivalents of the compound (A6) are heated without a solvent or in an organic solvent such as for example sulpholane, dimethylformamide, dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulphoxide or dioxane, preferably sulpholane, for 0.1 to 4 hours, preferably 1 hour, at 100 to 220.degree. C., preferably at about 160.degree. C. After cooling, the product (A7) is crystallised by the addition of organic solvents or mixtures of solvents, e.g. diethylether/methanol, ethyl acetate, methylene chloride, or diethylether, preferably diethylether/methanol 9/1, or purified by chromatography.

[0133] For example, in variant 4.2 A, 1 equivalent of the compound (A5) and 1 to 3 equivalents of the compound (A6) are stirred with acid, for example 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol, for example ethanol, propanol, butanol, preferably ethanol, at reflux temperature for 1 to 48 hours, preferably about 5 hours.

[0134] The product precipitated (A7) is filtered off and optionally washed with water, dried and crystallised from a suitable organic solvent.

[0135] If R.sup.6 denotes an optionally substituted benzimidazole, the preparation of the compounds (A6) using methods known from the literature may be carried out as shown in the following diagram, for example: 21

[0136] Accordingly, for example, 33 mmol of the compound (Z1), 49 mmol of the compound (Z2) and 49 mmol of 1-ethoxycarbonyl-2-ethoxydihydroquinolin- e (EEDQ) are stirred into 50 ml of an organic solvent, preferably dimethylformamide, at about 100 to 130.degree. C., preferably at about 115.degree. C., 1 to 4 hours, preferably about 3 hours. Then the cooled reaction solution is added to 50 to 400 ml, preferably about 200 ml of a water/ethyl acetate mixture (mixing ratio about 1:1). The crystals formed (Z3) are suction filtered and washed.

[0137] Then 4.2 mmol of the compound (Z3) are stirred with 12.5 mmol of tin(II)chloride and 30 mmol of potassium carbonate in about 50 ml of an organic diluent, preferably ethyl acetate, at about 22.degree. C. for 4 to 48 hours, preferably about 24 hours. After the addition of 22 g of kieselgur the mixture is extracted with an organic diluent or mixture of diluents, preferably with a mixture of dichloromethane/methanol (9:1), the combined extracts are evaporated down and the precipitate formed (Z4) or the crystals produced (Z4) is or are isolated.

[0138] Step 5A

[0139] If R.sup.9 denotes --CONR.sup.8--C.sub.1-C.sub.10-alkyl-Q.sup.1, --CONH--C.sub.1-C.sub.5-alkylene or --CONR.sup.8--Q.sup.2, wherein the substituents have the meanings given hereinbefore, the compounds according to the invention may be prepared using methods known from the literature, for example as shown in Diagram 5A.

[0140] The compound (A7') obtained in Step 4A may be reacted either by saponification and subsequent amination to obtain the amide of general formula (A10) (Diagram (5A) variant 5.1 A), or by saponification, with subsequent conversion into the acid chloride (A9) and subsequent amination (Diagram (5A) variant 5.2A). 22

[0141] Variant 5.1 A:

[0142] In variant 5.1 A, for example, 20 mmol of the ester (A7') are heated in about 100 ml of a base, preferably 1N sodium hydroxide solution or lithium hydroxide solution and about 500 ml of an alcohol, for example with ethanol, dioxane or methanol, preferably methanol, until the ester is completely reacted. Then the alcohol is distilled off. The residue is taken up in about 200 ml of water and acidified while cooling with acid, for example hydrochloric acid, preferably with 2 N hydrochloric acid. The product (A8) is filtered off and dried.

[0143] For example, about 0.5 mmol of the compound (A8) are dissolved with about 0.5 mmol of O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and about 1.4 mmol of diisopropylethylamine (DIPEA) in about 5 ml of an organic diluent, for example tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethylacetamide, preferably dimethylformamide. After the addition of about 0.75 mmol of an amine which forms the substituent R.sup.9, the reaction mixture is stirred for 0.1 to 24 hours, preferably about 12 hours at 20.degree. C. to 100.degree. C. The product of formula (A10) is obtained for example by crystallisation or chromatographic purification.

[0144] Variant 5.2 A:

[0145] In variant 5.2 A about 1 mmol of the acid (A8) for example is suspended in about 2.7 ml of thionyl chloride. The mixture is heated to 40.degree. C. to 80.degree. C., preferably about 50.degree. C., and at constant temperature 2 to 10 drops, preferably about 3 drops of dimethylformamide are added to the reaction mixture with stirring. Then stirring is continued at 90.degree. C. until the reaction is complete. Excess thionyl chloride is distilled off. About 1 mmol of the acid chloride formed (A9) are dissolved in about 30 ml of an organic diluent, for example dichloromethane. After the addition of an amine which forms the substituent R.sup.9 the mixture is stirred at about 22.degree. C. The precipitate formed is filtered off and washed with water. The residue remaining is washed with an organic diluent, for example methanol. The mother liquor is purified, for example by chromatography, and evaporated down. The product (A10) remains.

[0146] Method B

[0147] Alternatively to the methods described above, after Step 1A first the compound (A3) may be aminated and then the product (B1) may be cyclised to yield the compound (B2), as shown in Diagram B. Further substitution of the compound (B2) to yield the compound (A7) may be carried out for example as in Step 3A. 23

[0148] The new compounds of general formula (I) may be synthesised analogously to the following examples of synthesis. These Examples are, however, intended only as examples of procedures to illustrate the invention further, without restricting the invention to their subject matter.

EXAMPLE 63 AND EXAMPLE 109

[0149] In order to synthesise the compounds 63 and 109, first an intermediate compound 4 24

[0150] is prepared as described hereinafter.

[0151] 38.9 ml (0.263 mol) of ethyl 2-bromobutyrate and 36.4 g (0.263 mol) of potassium carbonate were placed in 350 ml of ethyl acetate, and then 46.7 ml (0.402 mol) of isoamylamine, dissolved in 70 ml of ethyl acetate, were rapidly added dropwise. The mixture was refluxed for 20 h. The salt formed was filtered off, the filtrate was concentrated by evaporation, combined with 50 ml of toluene and again evaporated to dryness.

[0152] Yield: 54.3 g of a compound 1 (red oil)

[0153] 54.3 g of compound 1, dissolved in 400 ml acetone, and 30.7 g (0.222 mol) of potassium carbonate were cooled to 8.degree. C. with stirring, combined with a solution of 43.1 g (0.222 mol) of 2,4-dichloro-5-nitropyrimidine in 250 ml acetone and then stirred for 24 h at RT.

[0154] The suspension formed was concentrated by evaporation, the residue was extracted with water and ethyl acetate, the organic phase was washed with water and NaCl solution, dried over MgSO.sub.4 and evaporated to dryness.

[0155] Yield: 87.3 g of a compound 2 (brown oil)

[0156] 44.1 g of compound 2 were dissolved in 800 ml glacial acetic acid and heated to 65.degree. C. and 36 g of iron filings were added batchwise. Then the mixture was stirred for 3 h at 70.degree. C., the precipitate was filtered off and the filtrate was concentrated by evaporation.

[0157] The residue was applied to silica gel in dichloromethane/methanol 90:10, concentrated by evaporation and purified by column chromatography (eluant: ethyl acetate/cyclohexane 1:1).

[0158] The residue was precipitated from ethyl acetate/petroleum ether.

[0159] Yield: 16.1 g of a compound 3 (beige powder)

[0160] 16.1 g of compound 3 were dissolved in 75 ml of dimethylacetamide and cooled to 5.degree. C. under a nitrogen atmosphere with stirring. Then 2.51 g (0.063 mol) of NaH, 60% dispersion in mineral oil, was added, whereupon the temperature temporarily rose to 16.degree. C. After 30 minutes 3.94 ml (0.063 mol) of methyl iodide, dissolved in 75 ml dimethylacetamide, were added, and the mixture was stirred for 24 h at 22.degree. C.

[0161] The solvent was concentrated by evaporation, combined with 200 ml of water and the precipitate formed was suction filtered, then extracted by stirring with petroleum ether.

[0162] Yield: 15.1 g of a compound 4 (yellow powder)

[0163] .sup.1H-NMR (250 MHz):=7.80 (1H, s), 4.35 (m, 1H), 3.92 (m, 1H), 3.22 (s, 3H), 3.14 (m, 1H), 1.81 (m, 2H), 1.60-1.40 (m, 3H), 0.90 (m, 6H), 0.70 (t, 3H).

SYNTHESIS OF EXAMPLE 63

[0164] 2.5 g of compound 4, 1.43 g of 4-amino-3-methoxybenzoic acid, 1.25 mL of conc. hydrochloric acid, 150 mL of dist. water and 37.5 mL of ethanol were refluxed for 10 h. The precipitate was filtered off, washed with water and extracted by stirring in methanol. Then the precipitate was recrystallised using petroleum ether and ether.

[0165] Yield: 1.6 g of a compound 5 (white powder)

[0166] 0.2 g of compound 5, 5 mL of benzylamine, 0.16 g of TBTU, 0.17 g of DIPEA were dissolved in 2 ml of dimethylformamide (DMF) and stirred for 48 h at ambient temperature. Then the reaction mixture was taken up in methylene chloride, washed with water and the organic phase was evaporated down. When petroleum ether/ethyl acetate 9:1 was added the product was precipitated in the form of light beige crystals.

[0167] Yield: 0.18 g. Melting point: 178.degree. C.

SYNTHESIS OF EXAMPLE 109

[0168] 5 g of 2 amino-5-nitroaniline, 6.03 g of 4-pyridylcarboxylic acid, 12.1 g of EEDQ are dissolved in 50 mL of DMF and stirred at 115.degree. C. for 1.75 h, then the DMF is distilled off in vacuo and the reaction mixture is then heated to 180.degree. C. for 1 h. The residue is taken up in 30 mL of DMF and combined with 200 mL of water and 100 mL of ethyl acetate. The crystal slurry obtained is filtered off and washed with water, ethyl acetate and ether.

[0169] Yield: 5.8 g of a compound 6

[0170] 2 g of the compound 6 is combined with 0.2 g of 5% Pd/C in 30 mL of ethanol and hydrogenated in the presence of hydrogen. It is then evaporated down and crystallised from ethanol and toluene.

[0171] Yield: 1.75 g of white powder of a compound 7.

[0172] 0.2 g of the compound 5, 0.28 g of the compound 7, 0.001 g of sodium-tert. butoxide, 2.5 mL of ethyleneglycol dimethylether, 0.006 g of palladium(II) acetate and 0.22 g of 2-(di-tert.-butylphospino)biphenyl are dissolved in 1.5 mL of N-methylpyrrolidone (NMP). Then the mixture is heated to 160.degree. C. for 0.5 h. The reaction mixture is then purified over 20 g of silica gel and the product is crystallised from ether, ethyl acetate and petroleum ether.

[0173] Yield: 0.04 g of yellow crystals. Melting point: 180.degree. C.

EXAMPLE 218, 58 AND 4

[0174] In order to synthesise the compounds 218, 58 and 4, first an intermediate compound 11 25

[0175] is prepared as described hereinafter.

[0176] 55.8 g of DL-alanine methyl ester.times.HCl were dissolved in 500 ml of methanol, then 76.1 ml of 30% sodium methoxide solution was added and the salt was filtered off. 37.8 g of trimethylacetaldehyde were added to the filtrate, then it was left to stand for 22 h. Then 9.5 g of 10% Pd/C was added and the mixture was hydrogenated for 3.1 h at 0.5 bar and 20.degree. C. The reaction mixture was suction filtered through kieselgur and concentrated by evaporation. The residue was taken up in diethylether, the salts were filtered through kieselgur and the filtrate was concentrated by evaporation.

[0177] Yield: 55.8 g of a compound 8 (clear liquid)

[0178] 48.5 g of 2,4-dichloro-5-nitropyrimidine were placed in 400 ml of diethylether, 41.0 g of potassium hydrogen carbonate in 400 ml of water were added, and the mixture was cooled to -5.degree. C. 43.3 g of compound 8 were dissolved in 400 ml of diethylether and added dropwise at -5.degree. C. The mixture was stirred for 1 h at -5.degree. C. and for 2 h at 0.degree. C., then heated to ambient temperature and the reaction mixture was left to stand for 24 h.

[0179] The organic phase was separated off, dried over MgSO.sub.4 and evaporated to dryness.

[0180] Yield: 79.2 g of a compound 9 (yellow resin)

[0181] 79.0 g of compound 9 were dissolved in 1000 ml of glacial acetic acid and heated to 70.degree. C. After the removal of the heat source 52 g of iron was added batchwise. The temperature rose to about 110.degree. C. and the mixture was stirred for 1 h at this temperature. The suspension was filtered while hot and the filtrate was concentrated by evaporation.

[0182] The residue was taken up in ethyl acetate and combined with 150 ml of conc. HCl, the organic phase was separated off and the aqueous phase extracted several times with dichloromethane. The combined organic phases were concentrated by evaporation, applied to silica gel and purified by column chromatography (eluant: petroleum ether/ethyl acetate 1:1).

[0183] As the isolated substance was still highly contaminated, it was again purified over silica gel. The desired compound crystallised out, the crystals were suction filtered. The mother liquor was concentrated by evaporation and recrystallised from ethyl acetate/diethylether.

[0184] Yield: 17.63 g of a compound 10

[0185] 7.6 g of the compound 10 and 6.4 ml of methyl iodide were placed in 75 ml of dimethylacetamide (DMA) and cooled to -15.degree. C. 1.25 g of NaH, 60% dispersion in mineral oil, was added batchwise, and stirred for 30 min. at -10.degree. to -5.degree. C. Then 150 ml of ice water were added, the crystals were suction filtered and washed with water and petroleum ether. The crystals were taken up in dichloromethane, filtered through kieselgur and the filtrate was evaporated to dryness. It was recrystallised from petroleum ether.

[0186] Yield: 6.3 g of compound 11 (beige crystals) .sup.1H-NMR (250 MHz):=7.73 (1H, s), 4.35 (d, 1H), 4.25 (m, 1H), 3.35 (s, 3H), 2.55 (d, 1H), 1.31 (d, 3H), 0.95 (s, 9H).

SYNTHESIS OF EXAMPLE 218

[0187] 0.2 g of compound 11, 3,5-difluoro-4-hydroxyaniline and 0.75 mL of sulpholane were heated to 130.degree. C. for 15 min, to 140.degree. C. for 15 min and to 170.degree. C. for 10 min. Then the mixture was combined with ether, the supernatant solution was decanted off and the residue was crystallised from methanol/ether and recrystallised again from methanol.

[0188] Yield: 0.15 g of white crystals. Melting point:>250.degree. C.

SYNTHESIS OF EXAMPLE 4

[0189] 6.3 g of compound 11 were dissolved in 25 mL of sulpholane at 100.degree. C., then combined with 4.0 g of ethyl 4-aminobenzoate and heated to 170.degree. C. for 1 h. Then the mixture was combined with 50 mL of ether. After crystallisation started, a further 50 mL of ether and 50 mL of methanol were added. The crystals were recrystallised from methanol.

[0190] Yield: 6.6 g of a compound 12 (yellowish crystals), melting point: from 65.degree. C. decomposition sets in

[0191] 3.55 g of compound 12 were suspended in 250 mL of methanol and at 60.degree. C. combined with 25 mL of 4N sodium hydroxide solution. After 6 h, 15 mL of glacial acetic acid were added, the resulting crystals were filtered off and washed with methanol/ether.

[0192] Yield: 1.2 g of a compound 13 (white crystals)

[0193] 1.5 g of compound 13 were dissolved in 7.5 mL of thionyl chloride and heated to 80.degree. C. for 1 h. Then the thionyl chloride was eliminated by distillation, the residue was stirred with ether, the crystals were suction filtered and washed with ether.

[0194] Yield: 1.7 g of a compound 14 (yellow crystals)

[0195] 0.18 g of 3-aminopyridine were dissolved in 10 mL of tetrahydrofuran (THF) and combined with 0.4 mL of triethylamine. Then 0.22 g of compound 14 were added and the mixture was stirred for 16 h at ambient temperature. The mixture was evaporated to dryness, taken up in ethyl acetate, extracted with water, evaporated down again and the product was crystallised from ethyl acetate.

[0196] Yield: 0.07 g (beige crystals), Melting point: 215-216.degree. C.

SYNTHESIS OF EXAMPLE 58

[0197] 0.05 g of compound 13 were suspended in 10 mL of dichloromethane, then combined with 0.15 mL of DIPEA and 0.05 g of TBTU. The solution was then stirred for 30 min and combined with 0.01 mL of 4-picolylamine. After 18 h the mixture was combined with 20 mL of water, the organic phase was separated off and the product was purified by silica gel chromatography, then recrystallised from ethyl acetate/petroleum ether.

[0198] Yield: 0.044 g (white crystals), Melting point: 238-240.degree. C.

EXAMPLES 65 AND 125

[0199] In order to synthesise the compounds 65 and 125, first an intermediate compound 18 26

[0200] is prepared as described hereinafter.

[0201] 28.3 g of isobutylamine, 36 g of ethyl R,S-2-bromopropionate and 28 g of potassium carbonate were refluxed in 150 ml of ethyl acetate for 6 h. After cooling the salt was suction filtered, the mother liquor was concentrated by evaporation.

[0202] The residue was combined with 100 ml of toluene and evaporated to dryness.

[0203] Yield: 37.2 g of a compound 15 (yellow oil)

[0204] 38.4 g of 2,4-dichloro-5-nitropyrimidine were placed in 300 ml of diethylether, 30 g of potassium hydrogen carbonate in 300 ml of water were added and the mixture was cooled to 0.degree. C. 37.0 g of compound 15 were dissolved in 300 ml of diethylether and added dropwise at 0.degree.-3.degree. C. After 3 h the phases were separated, the organic phase was dried and evaporated to dryness.

[0205] Yield: 71.6 g of a compound 16

[0206] 40.0 g of compound 16 were dissolved in 300 ml of glacial acetic acid and heated to 70.degree. C. After removal of the heat source, 30 g of iron was added batchwise. The temperature rose to 110.degree. C. The reaction mixture was cooled to 90.degree. C. and stirred for 20 min. at this temperature. Then it was filtered while hot and the filtrate was concentrated by evaporation. The residue was stirred with 300 ml of water and 300 ml of dichloromethane and filtered through kieselgur. The phases were separated. The organic phase was washed with water, dried over MgSO.sub.4 and evaporated to dryness. It was extracted from petroleum ether.

[0207] Yield: 26.7 g of a compound 17

[0208] 15.0 g of compound 17 were placed in 100 ml of DMA, 4.13 ml of methyl iodide were added and the mixture was cooled to 5.degree. C. 2.60 g of NaH were added batchwise as a 60% dispersion in mineral oil. The temperature rose to 13.degree. C. After 30 min. 300 ml of ice water were added, the crystals precipitated were suction filtered and washed with petroleum ether.

[0209] Yield: 13.9 g of a compound 18 .sup.1H-NMR (250 MHz):=7.95 (1H, s), 4.30 (m, 1H), 3.95 (m, 1H), 3.24 (s, 3H), 2.95 (m, 1H), 2.05 (m, 1H), 1.30 (d, 3H), 0.96 (d, 3H), 0.92 (d, 3H).

SYNTHESIS OF EXAMPLE 65

[0210] 2.1 g of compound 18 were combined with ethyl 4-aminobenzoate in 10 mL sulpholane and stirred for 2 h at 160.degree. C. Then ether was added and the crystals precipitated were washed with ether:

[0211] Yield: 3.0 g of a compound 19

[0212] 3 g of the compound 19 were combined with 200 mL of methanol and 25 mL of 4N NaOH and stirred for 4 h at 60.degree. C. Then glacial acetic acid was added, the crystals precipitated were filtered off and washed with ether.

[0213] Yield: 2.3 g of a compound 20 (white crystals)

[0214] 0.1 g of compound 20 were suspended in 3 mL of dichloromethane and 3 mL of DMF, and then combined with 0.13 g of DIPEA, 0.095 g of TBTU and 0.045 g of hydroxybenzotriazole (HOBt). Then the solution was stirred for 30 min and combined with 0.035 g of N-methyl-3-picolylamine. After 0.5 h the mixture was combined with water and 1 g of potassium carbonate, the aqueous phase was extracted twice with 50 mL of ethyl acetate and the product was purified by silica gel chromatography and then recrystallised from ethanol/acetone.

[0215] Yield: 0.08 g

SYNTHESIS OF EXAMPLE 125

[0216] 3.7 g of compound 20, 3.8 g of TBTU, 1.6 g of HOBt, 5 mL of DIPEA were dissolved in 40 mL of DMF and stirred for 4 h at ambient temperature. The mixture was evaporated down, taken up in 200 mL of ethyl acetate and extracted twice with 5 mL of 5% potassium carbonate solution. The organic phase was evaporated down, the crystals precipitated were filtered off and washed with ethyl acetate and ether.

[0217] Yield: 1.65 g of a compound 21 (yellowish crystals)

[0218] 0.486 g of compound 21 were refluxed with 0.33 g of 1,2-phenylenediamine in 10 mL of toluene for 0.5 h, then the mixture was evaporated down. The residue was combined with 100 mL ethyl acetate, the organic phase was extracted twice with water. The organic phase was evaporated down, the crystals precipitated were suction filtered and washed with a little ethyl acetate.

[0219] Yield: 0.25 g of a compound 22 (white crystals)

[0220] 0.22 g of compound 22 were stirred into 20 g of polyphosphoric acid for 0.5 h at 150.degree. C., then the mixture was poured onto ice and ammonia was added. It was then extracted twice with 100 mL of ethyl acetate, the organic phase was washed with water and evaporated down. The precipitated product (crystals) was suction filtered and washed with ethyl acetate and ether.

[0221] Yield: 0.115 g of yellowish crystals, Melting point: 287.degree. C. (decomposition)

EXAMPLE 171

[0222] In order to synthesise compound 171 first an intermediate compound 27 [sic] 27

[0223] 34.4 g of N-isopentyl-benzylamine, 36.2 g of ethyl 2-bromo-propionate and 42.0 g of potassium carbonate were placed in 250 ml of DMF and stirred for 3 h at 110.degree. C. After cooling the inorganic salts were filtered off, the filtrate was concentrated by evaporation. The residue was extracted with water and diethylether, the organic phase was washed with water, dried and evaporated to dryness.

[0224] Yield: 55.5 g of a compound 23

[0225] 55.5 g of compound 23 were placed in 600 ml of ethanol, and hydrogenated with 20 ml of 32% HCl and 6 g of 10% Pd/C at 20.degree. C. under 5 bar for 20 min. Then it was filtered through kieselgur and concentrated by evaporation. The residue was combined with 400 ml of diethylether, the precipitate was suction filtered and washed with diethylether.

[0226] Yield: 23.5 g of a compound 24, melting point 105.degree. C.

[0227] 23.5 g of compound 24 were dissolved in 200 ml of water and combined with 20.0 g (0.103 mol) of 2,4-dichloro-5-nitropyrimidine in 400 ml of diethylether. After the reaction mixture had been cooled to -10.degree. C., 50.0 g (0.499 mol) of potassium carbonate were added batchwise. The mixture was stirred at -5.degree. C. for 1 h and at 0.degree. C. for 1 h, then heated to ambient temperature. The aqueous phase was separated off, the organic phase was washed with water, dried and evaporated to dryness.

[0228] Yield: 36.9 9 of a compound 25

[0229] 20.0 g of the compound 25 were dissolved in 280 ml of glacial acetic acid and heated to 70.degree. C. After removal of the heat source 17 g of iron were added. The temperature rose to 100.degree. C., then the mixture was stirred for 30 min. at this temperature.

[0230] It was then filtered while hot and the filtrate was concentrated by evaporation. The residue was combined with 300 ml of dichloromethane and 30 ml of 32% HCl, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with water and aqueous ammonia solution, dried and evaporated to dryness. The residue was extracted with diethylether.

[0231] Yield: 10.5 g of a compound 26, melting point: 182.degree.-185.degree. C.

[0232] 2.7 g of the compound 26 and 2.5 ml of methyl iodide were placed in 27 ml of DMA and cooled to -10.degree. C. 0.45 g of NaH, 60% dispersion in mineral oil, was added and stirred for 30 min. at -5.degree. C. Then 10 g of ice and 5 ml of 2N HCl were added and the mixture was concentrated by evaporation. The residue was extracted with ethyl acetate and water, the organic phase was dried, evaporated to dryness and filtered through silica gel.

[0233] Yield: 3.0 g of compound 27 (oil) .sup.1H-NMR (250 MHz):=7.67 (1H, s), 4.32-4.07 (m, 2H), 3.32 (s, 3H), 3.08 (m, 1H), 1.70-1.50 (m, 3H), 1.42 (d, 3H), 0.95 (m, 6H).

SYNTHESIS OF EXAMPLE 171

[0234] 0.28 g of compound 27, 0.9 mL of sulpholane and 0.22 g of p-aminobenzoic acid-benzylamide were stirred for 0.5 h at 170.degree. C., then the mixture was combined with ether and the crystals were filtered off. The product was recrystallised from ethanol.

[0235] Yield: 0,15 g, melting point: 228-240.degree. C. (yellowish crystals)

[0236] The compounds of formula (I) listed in Table 1 are obtained analogously to the process described above.

[0237] The abbreviations X.sub.2, X.sub.3, X.sub.4, X.sub.5 and X.sub.6 used in Table 1 in each case denote a link to a position in the general formula shown under Table 1 instead of the corresponding groups R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6.

1TABLE 1 28 config. mp. Ex. R.sup.2 R.sup.3 R.sup.4 R.sup.3 or R.sup.4 R.sup.5 R.sup.6 [.degree. C.] 1 29 H H rac. 30 31 2 32 33 H rac. 34 35 208 3 36 37 H rac. 38 39 241 4 40 41 H rac. 42 43 5 44 45 H rac. 46 47 175 6 48 49 H R 50 51 190 7 52 53 H rac. 54 55 8 56 57 H rac. 58 59 200 9 60 61 H rac. 62 63 168 10 64 65 H rac. 66 67 190 11 68 69 H rac. 70 71 12 72 73 H rac. 74 75 13 76 77 H rac. 78 79 145 14 80 81 H rac. 82 83 15 84 85 H rac. 86 87 55 16 88 89 H rac. 90 91 250 17 92 93 H rac. 94 95 204 18 96 97 H rac. 98 99 19 100 101 H rac. 102 103 20 104 105 H R 106 107 221 21 108 109 H rac. 110 111 172 22 112 113 H rac. 114 115 221 23 116 117 H rac. 118 119 24 120 121 H rac. 122 123 210 25 124 125 H R 126 127 213 26 128 129 H rac. 130 131 188 27 132 133 H rac. 134 135 28 136 137 H S 138 139 29 140 141 H rac. 142 143 178 30 144 145 H R 146 147 175 31 148 149 H rac. 150 151 32 152 153 H rac. 154 155 221 33 156 157 H R 158 159 124 34 160 161 H rac. 162 163 136 35 164 165 H rac. 166 167 162 36 168 169 H rac. 170 171 169 37 172 173 H rac. 174 175 219 38 176 177 H rac. 178 179 179 39 180 181 H rac. 182 183 211 40 184 185 H rac. 186 187 41 188 189 H rac. 190 191 42 192 193 H R 194 195 100 43 196 197 H rac. 198 199 175 44 200 201 H rac. 202 203 203 45 204 205 H rac. 206 207 165 46 208 209 H rac. 210 211 47 212 213 H rac. 214 215 48 216 217 H rac. 218 219 49 220 221 H rac. 222 223 50 224 225 H rac. 226 227 212 51 228 229 H S 230 231 52 232 233 H rac. 234 235 53 236 237 H rac. 238 239 54 240 241 H rac. 242 243 55 244 245 H rac. 246 247 191 56 248 249 H rac. 250 251 158 57 252 253 H rac. 254 255 230 58 256 257 H rac. 258 259 59 260 261 H R 262 263 125 60 264 H H rac. 265 266 250 61 267 268 H rac. 269 270 62 271 272 H rac. 273 274 169 63 275 276 H rac. 277 278 178 64 279 280 H rac. 281 282 65 283 284 H rac. 285 286 66 287 288 H R 289 290 225 67 291 292 H rac. 293 294 68 295 296 H rac. 297 298 69 299 300 H rac. 301 302 70 303 304 H rac. 305 306 71 307 308 H rac. 309 310 72 311 312 H rac. 313 314 73 315 316 H rac. 317 318 74 319 320 321 322 167 75 323 324 H rac. 325 326 76 327 328 H rac. 329 330 246 77 331 332 H rac. 333 334 78 335 336 H rac. 337 338 172 79 339 340 H rac. 341 342 170 80 343 344 345 rac. 346 347 222 81 348 349 H rac. 350 351 187 82 352 353 H rac. 354 355 215 83 356 357 358 359 199 84 360 361 362 rac. 363 364 127 85 365 366 H rac. 367 368 86 369 370 H rac. 371 372 169 87 373 374 H rac. 375 376 250 88 377 378 H rac. 379 380 233 89 381 382 H rac. 383 384 160 90 385 386 H rac. 387 388 154 91 389 390 H rac. 391 392 92 393 394 H rac. 395 396 93 397 398 H rac. 399 400 94 401 402 H R 403 404 95 405 406 H rac. 407 408 150 96 409 410 411 rac. 412 413 300 97 414 415 H rac. 416 417 243 98 418 419 H rac. 420 421 209 99 422 423 H rac. 424 425 182 100 426 427 H rac. 428 429 101 430 431 H R 432 433 232 102 434 435 H rac. 436 437 103 438 439 H rac. 440 441 104 442 443 H rac. 444 445 146 105 446 447 H rac. 448 449 209 106 450 451 H rac. 452 453 286 107 454 455 H rac. 456 457 108 458 459 H R 460 461 202 109 462 463 H rac. 464 465 180 110 466 467 H rac. 468 469 111 470 471 H rac. 472 473 250 112 474 475 H rac. 476 477 113 478 479 H rac. 480 481 114 482 X.sub.3--CH.sub.3 483 484 485 237 115 486 487 H rac. 488 489 135 116 490 491 H rac. 492 493 117 494 495 H rac. 496 497 118 498 499 H rac. 500 501 119 502 503 H rac. 504 505 213 120 506 507 H rac. 508 509 198 121 510 511 H rac. 512 513 122 514 515 H rac. 516 517 123 518 519 H rac. 520 521 124 522 523 H rac. 524 525 125 526 527 H rac. 528 529 287 126 530 531 H rac. 532 533 127 534 535 H rac. 536 537 128 538 539 H rac. 540 541 129 542 543 H rac. 544 545 247 130 546 547 H rac. 548 549 131 550 X.sub.3--CH.sub.3 551 552 553 281 132 554 555 H rac. 556 557 133 558 559 H rac. 560 561 134 562 563 H rac. 564 565 208 135 566 567 H rac. 568 569 136 570 571 H R 572 573 192 137 574 575 H rac. 576 577 212 138 578 579 H rac. 580 581 139 582 583 H rac. 584 585 140 586 587 H rac. 588 589 148 141 590 591 H rac. 592 593 142 594 595 H rac. 596 597 143 598 599 H rac. 600 601 186 144 602 603 604 605 199 145 606 607 H rac. 608 609 214 146 610 611 H rac. 612 613 155 147 614 615 H rac. 616 617 148 618 619 H rac. 620 621 149 622 623 H rac. 624 625 245 150 626 627 H rac. 628 629 151 630 631 H rac. 632 633 152 634 635 H rac. 636 637 153 638 639 H rac. 640 641 154 642 643 H rac. 644 645 155 646 647 H rac. 648 649 156 650 651 H rac. 652 653 265 157 654 655 H rac. 656 657 192 158 658 659 H rac. 660 661 222 159 662 663 H rac. 664 665 221 160 666 667 668 669 670 298 161 671 672 H rac. 673 674 181 162 675 676 H S 677 678 163 679 680 681 682 172 164 683 684 H rac. 685 686 227 165 687 688 H rac. 689 690 258 166 691 X.sub.3--CH.sub.3 692 693 694 266 167 695 696 H rac. 697 698 168 699 700 701 rac. 702 703 159 169 704 705 706 707 250 170 708 709 H rac. 710 711 213 171 712 713 H rac. 714 715 228 172 716 717 H rac. 718 719 181 173 720 721 H rac. 722 723 182 174 724 725 H rac. 726 727 175 728 729 H rac. 730 731 197 176 732 733 H rac. 734 735 177 736 737 H rac. 738 739 216 178 740 741 H rac. 742 743 200 179 744 745 H rac. 746 747 197 180 748 749 750 rac. 751 752 143 181 753 754 755 756 234 182 757 758 H rac. 759 760 183 761 762 H rac. 763 764 169 184 765 766 H rac. 767 768 185 769 770 H rac. 771 772 198 186 773 774 775 776 202 187 777 778 H rac. 779 780 200 188 781 782 H rac. 783 784 189 785 786 H rac. 787 788 198 190 789 790 791 792 196 191 793 X.sub.3--CH.sub.3 794 795 796 253 192 797 798 H rac. 799 800 193 801 802 H rac. 803 804 201 194 805 806 H rac. 807 808 250 195 809 810 H rac. 811 812 198 196 813 814 H rac. 815 816 245 197 817 818 H rac. 819 820 198 821 822 H rac. 823 824 199 825 826 H rac. 827 828 200 829 X.sub.3--CH.sub.3 830 831 832 198 201 833 H H rac. 834 835 202 836 837 H rac. 838 839 203 840 841 H rac. 842 843 198 204 844 845 H rac. 846 847 205 848 849 H rac. 850 851 206 852 853 H rac. 854 855 207 856 857 H rac. 858 859 184 208 860 861 H rac. 862 863 253 209 864 865 H rac. 866 867 240 210 868 869 H rac. 870 871 211 872 X.sub.3--CH.sub.3 873 874 875 266 212 876 877 H rac. 878 879 213 880 881 H rac. 882 883 214 884 885 H rac. 886 887 215 888 889 H rac. 890 891 232 216 892 893 H rac. 894 895 217 896 897 H rac. 898 899 218 900 901 H rac. 902 903 >250 219 904 905 H rac. 906 907 260 (Zers.) 220 908 909 H R 910 911 190 221 912 913 H R 914 915 228 222 916 917 H R 918 919 223 920 921 H R 922 923 243 224 924 925 H R 926 927 258 225 928 929 H R 930 931 226 932 933 H R 934 935 227 936 937 H R 938 939 241 228 940 941 H R 942 943 229 944 945 H R 946 947 300 230 948 949 H R 950 951 200 231 952 953 H R 954 955 232 232 956 957 H R 958 959 149 234 960 961 H R 962 963 197 235 964 965 H R 966 967 226 236 968 969 H R 970 971 182 237 972 973 H R 974 975 238 976 977 H R 978 979 239 980 981 H R 982 983 240 984 985 H R 986 987 241 988 989 H R 990 991 194 242 992 993 H R 994 995 200 243 996 997 H R 998 999 156 244 1000 1001 H R 1002 1003 195 245 1004 1005 H R 1006 1007 147 246 1008 1009 H R 1010 1011 247 1012 1013 H R 1014 1015 85 248 1016 1017 H R 1018 1019 249 1020 1021 H R 1022 1023 250 1024 1025 H R 1026 1027 158 251 1028 1029 H R 1030 1031 188 252 1032 1033 H R 1034 1035 245 253 1036 1037 H R 1038 1039 254 1040 1041 H R 1042 1043 128 255 1044 1045 H R 1046 1047 256 1048 1049 H R 1050 1051 181 257 1052 1053 H R 1054 1055 217 258 1056 1057 H R 1058 1059 259 1060 1061 H R 1062 1063 260 1064 1065 H R 1066 1067 261 1068 1069 H R 1070 1071 230 262 1072 1073 H R 1074 1075 193 263 1076 1077 H R 1078 1079 264 1080 1081 H R 1082 1083 152 265 1084 1085 H R 1086 1087 207 266 1088 1089 H R 1090 1091 229 267 1092 1093 H R 1094 1095 268 1096 1097 H R 1098 1099 183 269 1100 1101 H R 1102 1103 270 1104 1105 H R 1106 1107 161 271 1108 1109 H R 1110 1111 282 272 1112 1113 H R 1114 1115 157 273 1116 1117 H R 1118 1119 129 274 1120 1121 H R 1122 1123 164 275 1124 1125 H R 1126 1127 219 276 1128 1129 H R 1130 1131 277 1132 1133 H R 1134 1135 200 278 1136 1137 H R 1138 1139 200 279 1140 1141 H R 1142 1143 280 1144 1145 H R 1146 1147 281 1148 1149 H R 1150 1151 282 1152 1153 H R 1154 1155 283 1156 1157 H R 1158 1159 277 284 1160 1161 H R 1162 1163 197 285 1164 1165 H R 1166 1167 286 1168 1169 H R 1170 1171 182 287 1172 1173 H R 1174 1175 288 1176 1177 H R 1178 1179 163 289 1180 1181 H R 1182 1183 212 290 1184 1185 H R 1186 1187 291 1188 1189 H R 1190 1191 292 1192 1193 H R 1194 1195 293 1196 1197 H R 1198 1199 200 294 1200 1201 H R 1202 1203 144 295 1204 1205 H R 1206 1207 221 296 1208 1209 H R 1210 1211 150 297 1212 1213 H R 1214 1215 298 1216 1217 H R 1218 1219 163 299 1220 1221 H R 1222 1223 300 1224 1225 H R 1226 1227 98 301 1228 1229 H R 1230 1231 302 1232 1233 H R 1234 1235 303 1236 1237 H R 1238 1239 304 1240 1241 H R 1242 1243 305 1244 1245 H R 1246 1247 306 1248 1249 H R 1250 1251 307 1252 1253 H R 1254 1255 179 308 1256 1257 H R 1258 1259 174 309 1260 1261 H R 1262 1263 231 310 1264 1265 H R 1266 1267 311 1268 1269 H R 1270 1271 312 1272 1273 H R 1274 1275 313 1276 1277 H R 1278 1279 314 1280 1281 H R 1282 1283 69 315 1284 1285 H R 1286 1287 200 316 1288 1289 H R 1290 1291 210 317 1292 1293 H R 1294 1295 131 318 1296 1297 H R 1298 1299 319 1300 1301 H R 1302 1303 145 320 1304 1305 H R 1306 1307 321 1308 1309 H R 1310 1311 322 1312 1313 H R 1314 1315 149 323 1316 1317 H R 1318 1319 324 1320 1321 H R 1322 1323 325 1324 1325 H R 1326 1327 326 1328 1329 H R 1330 1331 327 1332 1333 H R 1334 1335 328 1336 1337 H R 1338 1339 176 329 1340 1341 H R 1342 1343 330 1344 1345 H R 1346 1347 331 1348 1349 H R 1350 1351 332 1352 1353 H R 1354 1355 333 1356 1357 H R 1358 1359 334 1360 X.sub.3--CH.sub.3 1361 1362 1363 250 335 1364 X.sub.3--CH.sub.3 1365 1366 1367 236 In the preceding Table the abbreviations X1 to X6 in the groups specified denote the bond which links the particular group to the corresponding group R1 to R6.

[0238] As has been found, the compounds of general formula (I) are characterised by their wide range of applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific cell cycle kinases, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also the proliferation of other cells, such as endothelial cells, for example, plays a part.

[0239] As could be demonstrated by FACS analysis, the inhibition of proliferation brought about by the compounds according to the invention is mediated by the arrest of the cells, particularly at the G2/M phase of the cell cycle. The cells arrest, independently of the cells used, for a specific length of time in this phase of the cell cycle before programmed cell death is initiated. An arrest in the G2/M phase of the cell cycle is triggered, for example, by the inhibition of specific cell cycle kinases. Studies in model organisms such as Schizosaccharomyces pombe or Xenopus, or investigations in human cells have shown that the transition from the G2 phase to mitosis is regulated by the CDK1/cyclin B kinase (Nurse, 1990). This kinase, which is also known as the "mitosis promoting factor" (MPF), phosphorylates and thereby regulates a number of proteins, such as e.g. nuclear lamins, kinesin-like motor proteins, condensins and Golgi matrix proteins, which play an important part in the breakdown of the nuclear envelope, in centrosome separation, the formation of the mitotic spindle apparatus, chromosome condensation and the breakdown of the Golgi apparatus (Nigg. E., 2001). A murine cell line with a temperature-sensitive CDK1 kinase mutant shows a rapid breakdown of the CDK1 kinase and a subsequent arrest in the G2/M phase after a temperature increase (Th'ng et al., 1990). The treatment of human tumour cells with inhibitors against CDK1/cyclin B such as e.g. butyrolactone also leads to an arrest in the G2/M phase and subsequent apoptosis (Nishio, et al. 1996). Another kinase which is involved in the G2 and mitosis phase is polo-like kinase 1 (Plk1), which is responsible for the maturation of the centrosomes, for the activation of the phosphatase Cdc25C, as well as for the activation of the anaphase promoting complex (Glover et al., 1998, Qian, et al., 2001). The injection of Plk1 antibodies leads to a G2 arrest in untransformed cells whereas tumour cells arrest in the mitosis phase (Lane and Nigg, 1996). In addition, the protein kinase aurora B has been described as having an essential function during entry into mitosis. Aurora B phosphorylates histone H3 at Ser11 and thereby initiates chromosome condensation (Hsu, J. Y. et al., 2000). A specific cell cycle arrest in the G2/M phase may, however, also be triggered e.g. by the inhibition of specific phosphatases such as e.g. Cdc25C (Russell and Nurse, 1986). Yeasts with a defective cdc25 gene arrest in the G2 phase, while overexpression of cdc25 leads to early entry into the mitosis phase (Russell and Nurse, 1987). However, an arrest in the G2/M phase can also be triggered by the inhibition of certain motor proteins, so-capped kinesins such as e.g. Eg5 (Mayer et al., 1999), or by agents which stabilise or destabilise microtubules (e.g. colchicin, taxol, etoposide, vinblastin, vincristin) (Schiff and Horwitz, 1980).

[0240] In view of their biological properties the compounds of general formula I according to the invention, their isomers and their physiologically acceptable salts are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation.

[0241] Such diseases include, for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphoma and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from damage to their DNA caused by radiation, UV treatment and/or cytostatic treatment (Davis et al., 2001).

[0242] The new compounds may be used for the prevention, short-term or long-term treatment of the abovementioned diseases, also in combination with other active substances used for the same indications, e.g. cytostatics.

[0243] The activity of the compounds according to the invention was determined in the cytotoxicity test on cultivated human tumour cells and/or in a FACS analysis, for example on HeLaS3 cells. In both test methods, the compounds exhibited a good to very good activity, i.e. for example an EC.sub.50 value in the HeLaS3 cytotoxicity test of less than 5 .mu.mol, generally less than 1 .mu.mol.

[0244] Measurement of Cytotoxicity on Cultivated Human Tumour Cells

[0245] To measure the cytotoxicity on cultivated human tumour cells, cells of the cervical cancer tumour cell line HeLaS3 (obtained from American Type Culture Collection (ATCC)) in Ham's F12 Medium (Life Technologies) and 10% foetal calf serum (Life Technologies) were cultivated and harvested in the logarithmic growth phase. Then the HeLaS3 cells were placed in 96-well plates (Costar) at a density of 1000 cells per well and incubated overnight in an incubator (at 37.degree. C. and 5% CO.sub.2), while on each plate 6 wells were filled only with medium (3 wells as a control of the medium, 3 wells for incubation with reduced AlamarBlue). The active substances were added to the cells in various concentrations (dissolved in DMSO; final concentration: 1%) (in each case as a triple measurement). After 72 hours' incubation, 20 .mu.l of AlamarBlue (AccuMed International) were added to each well, and the cells were incubated for a further 7 hours. As a control, 20 .mu.l of reduced Alamar Blue (AlamarBlue reagent which had been autoclaved for 30 min) were added to 3 wells. After 7 h incubation the colour change of the AlamarBlue reagent in the individual wells was determined in a Perkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission 590 nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity was calculated as a percentage of the control (HeLa S3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (IC.sup.50) was obtained. The values were calculated from the average of three individual measurements, correcting for the control value (medium control).

[0246] FACS Analysis

[0247] Propidium iodide (PI) binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the percentage of cells in the G1, S and G2/M phase of the cell cycle on the basis of the cell DNA content. Cells in the G0 and G1 phase have a diploid DNA content (2N), whereas cells in G2 or mitosis have a 4N DNA content. For PI staining, 0.4 million HeLaS3 cells were seeded, for example, on a 75 cm.sup.2 cell culture flask, and after 24 h either 1% DMSO was added as control or the substance was added in various concentrations (in 1% DMSO). The cells were incubated for 24 h with the substance or with DMSO, before the cells were washed with 2.times.PBS and detached with trypsin/EDTA. The cells were centrifuged (1000 rpm, 5 min, 4.degree. C.), and the cell pellet was washed 2.times. with PBS, before the cells were resuspended in 0.1 ml of PBS. Then the cells were fixed with 80% ethanol for 16 hours at 4.degree. C. or alternatively for 2 hours at -20.degree. C. The fixed cells (10.sup.6 cells) were centrifuged (1000 rpm, 5 min, 4.degree. C.), washed with PBS and then centrifuged again. The cell pellet was resuspended in 2 ml of Triton X-100 in 0.25% PBS, and incubated for 5 min on ice, before 5 ml of PBS were added and the mixture was centrifuged again. The cell pellet was resuspended in 350 .mu.l of PI stain solution (0.1 mg/ml of Raze A, 10 .mu.g/ml of presidium iodide in 1.times.PBS). The cells were incubated for 20 min in the dark with the stain buffer before being transferred into sample measuring vessels for the FACS scan. The DNA measurement was carried out in a Becton Dickinson FACS Analyzer, with an argon laser (500 mW, emission 488 nm), and the DNA Cell Quest Program (BD). The logarithmic PI fluorescence was determined with a band-pass filter (BP 585/42). The cell populations in the individual phases of the cell cycle were quantified with the ModFit LT program of Becton Dickinson.

[0248] The compounds of general formula (I) may be used on their own or combined with other active substances according to the invention, optionally also in conjunction with other pharmacologically active substances. Suitable preparations include for example tablets, capsules, suppositories, solutions, particularly solutions for injection (s.c., i.v., i.m.) and infusion, syrups, emulsions or dispersible powders. The amount of pharmaceutically active compound in each case should be in the range from 0.1-90 wt. %, preferably 0.5-50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage range given below. The doses specified may, if necessary, be given several times a day.

[0249] Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as 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 delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.

[0250] Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.

[0251] Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

[0252] Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifiers and/or dispersants, while if water is used as the diluent organic solvents may optionally be used as solubilisers or auxiliary solvents, and transferred into injection vials or ampoules or infusion bottles.

[0253] Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.

[0254] Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.

[0255] Suitable excipients may be, for example, water, pharmaceutically acceptable organic solvents, such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolin, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silica and silicates), sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

[0256] The preparations are administered in the usual way, preferably by oral or transdermal route, particularly preferably by oral route. When administered orally the tablets may, of course, contain additives, such as e.g. sodium citrate, calcium carbonate and dicalcium phosphate together with various additives, such as starch, preferably potato starch, gelatine and the like, in addition to the abovementioned carriers. Lubricants such as magnesium stearate, sodium laurylsulphate and talc may also be used to form tablets. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the abovementioned excipients.

[0257] For parenteral use, solutions of the active substances may be prepared using suitable liquid carrier materials.

[0258] The dosage for intravenous use is 1-1000 mg per hour, preferably between 5-500 mg per hour.

[0259] However, it may optionally be necessary to deviate from the amounts specified, depending on the body weight or method of administration, the individual response to the medication, the nature of the formulation used and the time or interval over which it is administered. Thus, in some cases, it may be sufficient to use less than the minimum quantity specified above, while in other cases the upper limit specified will have to be exceeded. When large amounts are administered it may be advisable to spread them over the day in a number of single doses.

[0260] The formulation examples that follow illustrate the present invention without restricting its scope:

Examples of Pharmaceutical Formulations

[0261]

2 A) Tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg 500 mg

[0262] The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.

3 B) Tablets per tablet active substance 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

[0263] The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.

4 C) Ampoule solution active substance 50 mg sodium chloride 50 mg water for inj. 5 ml

[0264] The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

* * * * *


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