Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-14
2004-08-31
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S262000
Reexamination Certificate
active
06784185
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDE5). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
International patent application WO 01/27112 discloses the use of certain pyrazolo[4,3-d]pyrimidinone compounds in the treatment of a variety of conditions and in particular MED.
The present application provides further pyrazolo[4,3-d]pyrimidinone compounds.
DISCLOSURE OF THE INVENTION
According to the present invention, there are provided compounds of general formula I:
or pharmaceutically or veterinarily acceptable salts, solvates, polymorphs or pro-drugs thereof wherein:
A represents C(O) or CH(OH);
X represents O or NR
5
;
R
1
, R
3
, R
4
and R
5
independently represent H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter five groups may all be optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
6
, OC(O)R
6
, C(O)R
6
, C(O)OR
6
, NR
6
C(O)NR
7
R
8
, NR
6
C(O)OR
6
, OC(O)NR
7
R
8
, C(O)NR
9
R
10
, NR
9
R
10
, SO
2
NR
9
R
10
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl wherein said latter five substituent and/or terminal groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
); or when X represents NR
5
then R
3
and R
5
together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, S
2
R
17
;
R
2
represents H, halo, cyano, nitro, OR
6
, OC(O)R
6
, C(O)R
6
, C(O)OR
6
, NR
6
C(O)NR
7
R
8
, NR
6
C(O)OR
6
, C(O)NR
7
R
8
, C(O)NR
9
R
10
, NR
9
R
10
, SO
2
NR
9
R
10
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter five groups may all be optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
6
, OC(O)R
6
, C(O)R
6
, C(O)OR
6
, NR
6
C(O)NR
7
R
8
, NR
6
C(O)OR
6
, OC(O)NR
7
R
8
, C(O)NR
9
R
10
, NR
9
R
10
, SO
2
NR
9
R
10
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl wherein said latter five substituent and/or terminal groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
);
R
6
represents H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
);
R
7
and R
8
independently represent H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
); or R
7
and R
8
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
9
and R
10
independently represent H, C(O)R
6
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
SO
2
NR
15
R
16
, SO
2
R
17
); or R
9
and R
10
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
wherein when R
7
and R
8
, or R
9
and R
10
together with the nitrogen atom to which they are bound form a heterocyclic ring, said heterocyclic ring is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
;
R
11
represents a C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
, SO
2
R
17
;
R represents H or C
1
-C
6
alkyl;
R
13
and R
14
independently represent H or C
1
-C
6
alkyl; or R
13
and R
14
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
15
and R
16
independently represent H, C(O)R
12
, SO
2
R
17
or C
1
-C
6
alkyl; or R
15
and R
16
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
17
represents C
1
-C
6
alkyl;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulpur and mixtures thereof;
with the proviso that when X represents O and R
1
represents H, C
1
-C
3
alkyl optionally substituted with fluoro or C
3
-C
5
cycloalkyl then
R
2
does not represent H, C
1
-C
6
alkyl optionally substituted with one or more fluoro substituents or with C
3
-C
6
cycloalkyl; or
R
3
does not represent C
1
-C
6
alkyl optionally substituted with one or more fluoro substituents or with C
3
-C
6
cycloalkyl; C
3
-C
5
cycloalkyl; C
3
-C
6
alkenyl; or C
3
-C
6
alkynyl; or
R
4
does not represent C
1
-C
4
alkyl optionally substituted with OH, NR
9
R
10
, CN, CONR
9
R
10
, SO
2
NR
9
R
10
or CO
2
R
6
wherein R
6
is H or C
1
-C
4
alkyl and R
9
and R
10
are each independently H or C
1
-C
4
alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-substituted piperizinyl or imidazolyl group wherein said group is optionally substituted with C
1
-C
4
alkyl or OH; C
2
-C
4
alkenyl optionally substitued with CN, CONR
9
R
10
or CO
2
R
6
; C
2
-C
4
alkanoyl optionally substituted with NR
9
R
10
; (C
2
-C
4
)OH optionally substitued with NR
9
R
10
; (C
2
-C
3
)alkoxy(C
1
-C
2
)alkyl optionally substituted with OH or NR
9
R
10
.
which compounds are referred to together hereinafter as “the compounds of the invention”.
The term “aryl”, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl.
The term “Het”, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolin
Allerton Charlotte Moira Norfor
Barber Christopher Gordon
Kemp Mark Ian
Benson Gregg C.
Berch Mark L.
Habte Kahsay
Olson A. Dean
Pfizer Inc.
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