Dihydropteridinones, processes for preparing them and their...

Details Dihydropteridinones, processes for preparing them and their... Dihydropteridinones, processes for preparing them and their...

2002-08-23

2004-10-19

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S257000

Reexamination Certificate

active

06806272

ABSTRACT:

APPLICATION DATA
This application 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
The present invention relates to new dihydropteridinones of general formula (I)
wherein the groups X, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and R
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 OF THE INVENTION
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.
The aim of the present invention is to prepare new compounds with an antiinflammatory and antiproliferative activity.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly it has been found that compounds of general formula (I) wherein the groups X and R
1
to R
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.
The present invention therefore relates to compounds of general formula (I)
wherein
R
1
denotes a group selected from among hydrogen, NH
2
, XH, halogen and a C
1
-C
3
-alkyl group optionally substituted by one or more halogen atoms,
R
2
denotes a group selected from among hydrogen, CHO, XH, —X—C
1
-C
2
-alkyl and an optionally substituted C
1
-C
3
-alkyl group,
R
3
, R
4
which may be identical or different denote a group selected from among optionally substituted C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, aryl, heteroaryl, C
3
-C
8
-cycloalkyl, C
3
-C
8
-heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR
8
-aryl, —NR
8
-heteroaryl, —NR
8
-cycloalkyl and —NR
8
-heterocycloalkyl, or a group selected from among hydrogen, halogen, COXR
8
, CON(R
8
)
2
, COR
8
and XR
8
, or
R
3
and R
4
together denote a 2- to 5-membered alkyl bridge which may contain 1 to 2 heteroatoms,
R
5
denotes hydrogen or a group selected from among optionally substituted C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, aryl, heteroaryl and —C
3
-C
6
-cycloalkyl, or
R
3
and R
5
or R
4
and R
5
together denote a saturated or unsaturated C
3
-C
4
-alkyl bridge which may contain 1 to 2 heteroatoms,
R
6
denotes optionally substituted aryl or heteroaryl,
R
7
denotes hydrogen or —CO—X—C
1
-C
4
-alkyl, and
X in each case independently of one another denotes O or S,
R
8
in each case independently of one another denotes hydrogen or a group selected from among optionally substituted C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
2
-C
4
-alkynyl and phenyl,
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.
Preferred compounds of formula (I) are those wherein
X and R
6
have the meaning indicated, and
R
1
denotes hydrogen,
R
2
denotes a group selected from among a CHO, OH, and CH
3
group,
R
3
, R
4
which may be identical or different denote a group selected from among hydrogen, optionally substituted C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, C
3
-C
7
-cycloalkyl, or
R
3
and R
4
together denote a C
2
-C
5
-alkyl bridge,
R
5
denotes a group selected from among optionally substituted C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, C
3
-C
6
-cycloalkyl and C
3
-C
6
-cycloalkenyl, or
R
3
and R
5
or R
4
and R
5
together denote a saturated or unsaturated C
3
-C
4
-alkyl bridge which may contain 1 to 2 heteroatoms, and
R
7
denotes hydrogen,
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.
Particularly preferred compounds of formula (I) are those wherein
R
1
-R
5
, R
7
, R
8
and X have the meaning indicated, and
R
6
denotes a group of general formula
wherein
n denotes 1, 2, 3 or 4,
R
9
denotes a group selected from among optionally substituted C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, —CONH—C
1
-C
10
-alkylene, —O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl or a group selected from among —O—C
1
-C
6
-alkyl-Q
1
, —CONR
8
—C
1
-C
10
-alkyl-Q
1
, —CONR
8
—C
2
-C
10
-alkenyl-Q
1
, —CONR
8
—Q
2
, halogen, OH, —SO
2
R
8
, —SO
2
N(R
8
)
2
, —COR
8
, —COOR
8
, —N(R
8
)
2
, —NHCOR
8
, CONR
8
OC
1
-C
10
alkylQ
1
and CONR
8
OQ
2
,
Q
1
denotes hydrogen, —NHCOR
8
, or a group selected from among an optionally substituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl, C
3
-C
8
-cycloalkyl-and heterocycloalkyl group,
Q
2
denotes hydrogen or a group selected from among an optionally substituted aryl, heteroaryl, C
3
-C
8
-heterocycloalkyl, C
3
-C
8
-cycloalkyl- and C
1
-C
4
-alkyl-C
3
-C
8
-cycloalkyl group,
R
10
which may be identical or different denotes a group selected from among optionally substituted C
1
-C
6
-alkyl , C
2
-C
6
-alkenyl and C
2
-C
6
-alkynyl, —O—C
1
-C
6
-alkyl, —O—C
2
-C
6
-alkenyl, —O—C
2
-C
6
-alkynyl, C
3
-C
6
-heterocycloalkyl and C
3
-C
6
-cycloalkyl, or a group selected from among hydrogen, —CONH
2
, —COOR
8
, —OCON(R
8
)
2
, —N(R
8
)
2
, —NHCOR
8
, —NHCON(R
8
)
2
, —NO
2
and halogen, or
adjacent groups R
9
and R
10
together denote a bridge of general formula
Y denotes O, S or NR
11
,
m denotes 0, 1 or 2
R
11
denotes hydrogen or C
1
-C
2
-alkyl, and
R
12
denotes hydrogen or a group selected from among optionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, —C
1
-C
3
-alkyl-phenyl, —C
1
-C
3
-alkyl-pyridyl, —C
1
-C
3
-alkyl-pyrazinyl, —C
1
-C
3
-alkyl-pyrimidinyl and —C
1
-C
3
-alkyl-pyridazinyl,
R
13
denotes C
1
-C
6
-alkyl,
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.
Particularly preferred are compounds of formula (I) wherein
R
3
-R
6
, R
8
and X have the meaning indicated, and
R
1
denotes hydrogen,
R
2
denotes CH
3
, and
R
7
denotes hydrogen,
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.
The invention further relates to compounds of formula (I), wherein X and R
1
-R
7
have the meanings indicated, for use as pharmaceutical compositions.
Of particular importance according to the invention are compounds of formula (I), wherein X and R
1
-R
7
have the meaning indicated, for use as pharmaceutical compositions with an antiproliferative activity.
The invention also relates to the use of a compound of formula (I), wherein X and R
1
-R
7
have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
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
1
-R
7
have the meanings indicated.
The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), wherein X and R
1
-R
7
have the meanings indicated, or the physiologically acceptable salts thereof, optionally combined with conventional excipients and/or carriers.
The invention also relates to a process for preparing a compound of general formula (I),
wherein
R
1
-R
7
and X are as hereinbefore defined, characterised in that a

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