Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-23
2002-11-05
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S184000
Reexamination Certificate
active
06476029
ABSTRACT:
The present invention relates to 7-alkyl- and cycloalkyl-substituted imidazotriazinones, to processes for their preparation and to their use as medicaments, in particular as inhibitors of cGMP-metabolizing phosphodiesterases.
The published specification DE-28 11 780 describes imidazotriazines as bronchodilators having spasmolytic activity and inhibitory activity against phosphodiesterases which metabolize cyclic adenosine monophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III and PDE-IV). An inhibitory action against phosphodiesterases which metabolize cyclic guanosine monophosphate (cGMP-PDEs, nomenclature according to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) PDE-I, PDE-II and PDE-V) has not been described. Compounds having a sulphonamide group in the aryl radical in the 2 position are not claimed. Furthermore, FR 22 13 058, CH-59 46 71, DE-22 55 172, DE-23 64 076 and EP-000 9384 describe imidazotriazinones which do not have a substituted aryl radical in the 2 position and are likewise said to be bronchodilators having cAMP-PDE-inhibitory action.
The compounds according to the invention are potent inhibitors either of one or of more of the phosphodiesterases which metabolize cyclic guanosine 3′,5′-monophosphate (cGMP-PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990) these are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
An increase in the cGMP concentration can lead to beneficial antiaggregatory, antithrombotic, antiprolific, antivasospastic, vasodilative, natriuretic and diuretic effects. It can influence the short- or long-term modulation of muscular and cardiac inotropy, of the pulse and of cardiac conduction (J. C. Stoclet, T. Keravis, N. Komas and C. Lugnier, Exp. Opin. Invest. Drugs (1995), 4 (11), 1081-1100).
The present invention, accordingly, provides 7-alkyl- and cycloalkyl-substituted imidazotriazinones of the general formula (I)
in which
R
1
represents straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
represents straight-chain alkyl having at least 5 carbon atoms or branched alkyl having at least 3 carbon atoms, or represents cycloalkyl having 3 to 10 carbon atoms,
R
3
and R
4
are identical or different and represent hydrogen, or represent straight-chain or branched alkenyl having up to 8 carbon atoms, or represent a straight-chain or branched alkyl chain having up to 10 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of trifluoromethyl, trifluoromethoxy, hydroxyl, halogen carboxyl, benzyloxycarbonyl, straight-chain or branched alkoxy, alkoxycarbonyl and alkylthio having in each case up to 6 carbon atoms and/or by radicals of the formulae —SO
3
H, —(A)
a
—NR
7
R
8
, —O—CO—NR
7′
R
8′
, —S(O)
b
—R
9
, HN═SO—R
9′
, —P(O)(OR
10
)(OR
11
),
in which
a and b are identical or different and represent a number 0 or 1,
A represents a radical CO or SO
2
,
R
7
, R
7′
, R
8
and R
8′
are identical or different and represent hydrogen, or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and/or O, where the ring systems listed above are optionally mono- to trisubstituted by identical or different substituents from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(SO
2
)
c—
NR
12
R
13
,
in which
c represents a number 0 or 1,
R
12
and R
13
are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms,
or
R
7
, R
7′
, R
8
and R
8′
represent straight-chain or branched alkoxy having up to 6 carbon atoms, or represent straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, halogen, aryl having from 6 to 10 carbon atoms, straight-chain or branched alkoxy and alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula —(CO)
d
—NR
14
R
15
,
in which
R
14
and R
15
are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms. and
d represents a number 0 or 1, or
R
7
and R
8
and/or R
7′
and R
8′
together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula —NR
16
,
in which
R
16
represents hydrogen, aryl having 6 to 10 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by hydroxyl,
R
9
and R
9′
are identical or different and represent aryl having 6 to 10 carbon atoms or benzyl, or represent straight-chain or branched alkyl having up to 4 carbon atoms,
R
10
and R
11
are identical or different and represent hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
and/or the alkyl chain listed above under R
3
/R
4
is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 ring heteroatoms from the group consisting of S, N, O or a radical of the formula —NR
17
, where the alkyl chain may optionally also be attached via a ring nitrogen atom,
in which
R
17
represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- to polysubstituted by identical or different substituents from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms,
and where aryl and the heterocycle are optionally mono- to trisubstituted by identical or different substituents from the group consisting of nitro, halogen, —SO
3
H, straight-chain or branched monohydroxy-substituted alkyl, alkylthio or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and/or by a radical of the formula —(SO
2
)
e
—R
18
R
19
,
in which
e represents a number 0 or 1,
R
18
and R
19
are identical or different and represent hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 6 carbon atoms,
and/or
R
3
or R
4
represent radicals of the formulae —NR
20
R
21
or —(O)—E—NR
22
R
23
,
in which
R
20
and R
21
have the meaning of R
18
and R
19
given above and are identical to or different from this meaning, or together with the nitrogen atom form a 5- or 6-membered saturated heterocycle having a further ring heterocycle from the group consisting of S and O or a radical —NR
24
,
in which
R
24
has the meaning of R
16
given above and is identical to or different from this meaning,
E is a straight-chain alkylene group having up to 5 carbon atoms,
R
22
and R
23
have the meaning of R
18
and R
19
given above and are identical to or different from this meaning,
and/or
R
3
or R
4
represent radicals of the formulae
or represent cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represent a 5- to 7-membered partially unsaturated, saturated and unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N, O or a radical of the formula —NR
25
which may optionally also be attached via a ring nitrogen atom,
in which
R
25
has the meaning of R
16
given above and is identical to or different from this meaning, or rep
Bischoff Erwin
Dembowsky Klaus
Es-Sayed Mazen
Haning Helmut
Niewöhner Ulrich
Balasubramanian Venkataraman
Bayer Aktiengesellschaft
Chiu Jerrie L.
Shah Mukund J.
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