Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-07
2001-02-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S264110, C514S234200, C544S267000, C544S265000, C544S271000, C544S272000, C544S118000
Reexamination Certificate
active
06187780
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to new asymmetrically substituted xanthine derivatives, processes for preparing them and their use as pharmaceutical compositions, particularly as drugs with an adenosine-antagonistic activity.
DESCRIPTION OF THE INVENTION
The new xanthine derivatives have the structure of general formula (I)
in which the dotted line between the nitrogen atoms in general formula (I) indicates the existence of a double bond in one of two possible positions, with the result that the groups R
4
and R
5
cannot both be present at the same time and wherein R
1
cannot simultaneously have the same meaning as R
2
and the groups R
1
, R
2
, R
3
, R
4
and R
5
are defined as follows:
R
1
denotes hydrogen, C
1-6
-alkyl, C
3-6
-alkenyl or C
1-6
-alkynyl;
R
2
denotes a C
1-6
-alkyl, C
3-6
-alkenyl or C
3-6
-alkynyl group substituted by —OR
6
, —SO
2
R
6
, —OCOR
9
, —COOR
9
, —NR
7
R
8
, —OCH
2
CH
2
—NR
7
R
8
, —CONR
7
R
8
, —OCH
2
—CONR
7
R
8
or —OCH
2
CH
2
—CONR
7
R
8
;
R
2
denotes a C
1-6
-alkyl, C
3-6
-alkenyl or C
3-6
-alkynyl group which is substituted by a C-linked 5- or 6-membered heterocyclic ring which may contain 1, 2, 3 or 4 heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be substituted by C
1-4
-alkyl or benzyl;
R
3
denotes C
1-6
-alkyl, which may be substituted by OH, or norbornanyl, norbornenyl, adamantyl or noradamantyl optionally substituted by methyl or OH;
R
4
or R
5
denotes hydrogen, benzyl or benzyl which is mono-, di- or trisubstituted by methoxy;
R
6
denotes hydrogen, C
3-6
-cycloalkyl or C
1-4
-alkyl which may be substituted by —OR
9
or —OCOR
9
;
R
7
denotes hydrogen, —SO
2
R
6
, C
1-4
-alkyl, —COR
9
or —COOR
9
;
R
8
denotes hydrogen, —SO
2
R
6
, C
1-4
-alkyl, —COR
9
or —COOR
9
; or,
R
7
and R
8
together with the nitrogen form a 5- or 6-membered ring which may contain oxygen or nitrogen as a further heteroatom and may optionally be substituted by C
1-4
-alkyl or benzyl; and,
R
9
denotes hydrogen or C
1-4
-alkyl,
optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmaceutically acceptable acid addition salts thereof.
Preferred compounds of general formula (I) are those wherein
R
1
denotes C
1-6
-alkyl, allyl or propargyl;
R
2
denotes a C
1-6
-alkyl, C
3-6
-alkenyl or C
3-6
-alkynyl group which is substituted by —OR
6
, —SO
2
R
6
, —OCOR
9
, —COOR
9
, —NR
7
R
8
, —OCH
2
CH
2
—NR
7
R
8
, —CONR
7
R
8
, —OCH
2
—CONR
7
R
8
or —OCH
2
CH
2
—CONR
7
R
8
;
R
2
denotes a C
1-6
-alkyl, C
3-6
-alkenyl or C
3-6
-alkynyl group substituted by a C-linked 5- or 6-membered heterocyclic ring which may contain 1, 2, 3 or 4 heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be substituted by C
1-4
-alkyl or benzyl;
R
3
denotes C
1-6
-alkyl which may be substituted by OH, or norbomanyl, norbornenyl, adamantyl or noradamantyl optionally substituted by methyl or OH;
R
4
or R
5
denotes hydrogen, benzyl or benzyl which is mono-, di- or trisubstituted by methoxy;
R
6
denotes C
1-4
-alkyl which may be substituted by —OR
9
or —OCOR
9
;
R
7
denotes hydrogen, —SO
2
R
6
, C
1-4
-alkyl, —COR
9
or —COOR
9
;
R
8
denotes hydrogen, —SO
2
R
6
, C
1-4
-alkyl, —COR
9
or —COOR
9
; or,
R
7
and R
8
together with the nitrogen form a 5- or 6-membered ring which may contain oxygen or nitrogen as an additional heteroatom and may optionally be substituted by C
1-3
-alkyl or benzyl; and,
R
9
denotes hydrogen or C
1-4
-alkyl,
optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmaceutically acceptable acid addition salts thereof.
Compounds of general formula (I) which are particularly preferred are those wherein
R
1
denotes C
1-4
-alkyl;
R
2
denotes C
1-4
-alkyl which is substituted by —OR
6
, —SO
2
R
6
, —OCOR
9
, —COOR
9
, —NR
7
R
8
, —OCH
2
CH
2
—NR
7
R
8
, —CONR
7
R
8
, —OCH
2
—CONR
7
R
8
or —OCH
2
CH
2
—CONR
7
R
8
;
R
2
denotes C
1-4
-alkyl which is substituted by a C-linked 5- or 6-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be substituted by C
1-4
-alkyl or benzyl;
R
3
denotes C
1-4
-alkyl which may be substituted by OH or optionally by norbomanyl, norbomenyl, adamantyl or noradamantyl substituted by methyl or OH;
R
4
or R
5
denote hydrogen, benzyl or benzyl which is mono-, di- or trisubstituted by methoxy;
R
6
denotes C
1-4
-alkyl which may be substituted by —OR
9
or —OCOR
9
;
R
7
denotes hydrogen, C
1-4
-alkyl, —COR
9
or —COOR
9
;
R
8
denotes hydrogen, C
1-4
-alkyl, —COR
9
; or —COOR
9
; or,
R
7
and R
8
together with the nitrogen form a 5- or 6-membered ring which may contain oxygen or nitrogen as a further heteroatom and may optionally be substituted by C
1-3
-alkyl or benzyl; and,
R
9
may denote hydrogen or C
1-4
-alkyl,
optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmaceutically acceptable acid addition salts thereof.
Also preferred are compounds of general formula (I) wherein
R
1
denotes C
1-4
-alkyl;
R
2
denotes C
1-4
-alkyl substituted by —OR
6
, —SO
2
R
6
, —OCOR
9
, —COOR
9
, —NR
7
R
8
, —OCH
2
CH
2
—NR
7
R
8
, —CONR
7
R
8
, —OCH
2
—CONR
7
R
8
or —OCH
2
CH
2
—CONR
7
R
8
;
R
2
denotes C
1-4
-alkyl which is substituted by a C-linked 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from the group comprising oxygen, nitrogen or sulphur and may optionally be substituted by C
1-3
-alkyl or benzyl;
R
3
denotes an isobutyl or tert.-butyl group, norbornanyl, norbomenyl, adamantyl or noradamantyl;
R
4
or R
5
denotes hydrogen;
R
6
denotes C
1-4
-alkyl which may be substituted by —OR
9
or —OCOR
9
;
R
7
denotes hydrogen, C
1-4
-alkyl, —COR
9
or —COOR
9
;
R
8
denotes hydrogen, C
1-4
-alkyl, —COR
9
or —COOR
9
; or,
R
7
and R
8
together with the nitrogen form a 5- or 6-membered ring which may contain oxygen or nitrogen as a further heteroatom and may optionally be substituted by C
1-3
-alkyl or benzyl; and,
R
9
denotes hydrogen or C
1-4
-alkyl,
optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmaceutically acceptable acid addition salts thereof.
Also of importance are compounds of general formula (I) wherein
R
1
denotes methyl, ethyl or propyl, preferably propyl;
R
2
denotes a methyl, ethyl, propyl or butyl group substituted by —SO
2
R
6
, —NR
7
R
8
or —CONR
7
R
8
;
R
2
denotes a methyl, ethyl, propyl or butyl group substituted by a C-linked 5- or 6-membered heterocyclic ring which contains one or two heteroatoms selected from the group comprising oxygen, nitrogen or sulphur;
R
3
denotes tert.-butyl, norbornanyl, norbornenyl, or noradamantyl;
R
4
or R
5
denotes hydrogen;
R
6
denotes methyl, ethyl or propyl optionally substituted by —OR
9
or —OCOR
9
;
R
7
denotes hydrogen, methyl, ethyl, propyl or —COR
9
;
R
8
denotes hydrogen, methyl, ethyl, propyl or —COR
9
; or,
R
7
and R
8
together with the nitrogen formn a 5- or 6-membered ring which may contain oxygen or nitrogen as a further heteroatom and may optionally be substituted by methyl or benzyl; and,
R
9
denotes hydrogen, methyl, ethyl or propyl,
optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of the pharmaceutically acceptable acid addition salts thereof.
Also of importance are compounds of general formula (I) wherein
R
1
denotes propyl;
R
2
denotes a methyl, ethyl or propyl group substituted by —SO
2
—CH
2
—CH
2
—OR
9
, —SO
2
—CH
2
—CH
2
—OCOR
9
, —SO
2
—CH
2
—CH
2
—CH
2
—OR
9
, —SO
2
—CH
2
—CH
2
—CH
2
—OCOR
9
, —NR
7
R
8
, —CONR
7
R
8
, pyridyl or pyrimidyl;
R
3
denotes tert.-butyl, norhoranyl, norbomenyl, or noradarmantyl;
R
4
or R
5
denotes hydrogen;
R
7
denotes hydrogen, methyl, ethyl, propyl or —COR
9
;
R
8
denotes hydrogen, methyl, ethyl, propyl or —C
Blech Stefan
Carter Adrian
Gaida Wolfram
Gath Ursula
Hoffmann Matthias
Boehringer Ingelheim Pharma KG
Devlin Mary-Ellen M.
McKenzie Thomas
Raymond Richard L.
Raymond Robert P.
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