Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-06
2004-06-29
Berch, Mark L (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S262100, C544S118000, C544S262000, C546S275400, C546S276100
Reexamination Certificate
active
06756373
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).
PRIOR ART
EP-A-0636626 relates to a class of pyrazolo[3,4-d]-pyrimidone compounds and their use as inhibitors of cGMP specific PDE. A series of 6-phenylpyrazolo[3,4-d]pyrimidinones, their synthesis and their cyclic GMP phosphodiesterase inhibitory activity are described in
J. Med. Chem
., 1996, 39, 1635-1644. International patent application WO 96/16657 discloses the use of certain pyrazolo[3,4-d]pyrimidinone compounds (amongst others) in the treatment of MED.
EP-A-0526004 describes certain pyrazolo[4,3-d]pyrimidinone compounds as antianginal agents. International patent application WO 94/28902 discloses the use of certain pyrazolo[3,4-d]pyrimidinone compounds (amongst others) in the treatment of MED.
DISCLOSURE OF THE INVENTION
According to the present invention, there is provided a compound of general formula I:
or a pharmaceutically or veterinarily acceptable salt and/or solvate thereof,
wherein
X represents O or NR
5
R
1
represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
2
represents H, halo, cyano, nitro, OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
, SO
2
NR
14
R
15
, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
3
represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
4
represents H, halo, cyano, nitro, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
, NR
16
Y(O)R
17
, N[Y(O)R
17
]
2
, SOR
18
, SO
2
R
19
, C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
Y represents C or S(O)
A represents lower alkylene
Z represents OR
6
, halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
10
and R
11
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10a
R
11a
, NR
10
R
11
, SO
2
NR
14
R
15
and NR
20
S(O)
2
R
21
or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R
10
and R
11
may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl
R
10a
and R
11a
independently represent R
10
and R
11
as defined above, except that they do not represent groups that include lower alkyl, Het or aryl, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more C(O)NR
10a
R
11a
and/or NR
12
R
13
groups
R
12
and R
13
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR
6
, C(O)OR
9
, C(O)NR
22
R
23
and NR
24
R
25
), one of R
12
or R
13
may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R
12
and R
13
together represent C
3-7
alkylene (which alkylene group is optionally unsaturated, optionally substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR
26
)
R
14
and R
15
independently represent H or lower alkyl or R
14
and R
15
, together with the nitrogen atom to which they are bound, form a heterocyclic ring
R
16
and R
17
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR
6
, C(O)OR
9
, C(O)NR
22
R
23
and NR
24
R
25
) or one of R
16
and R
17
may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl
R
5
, R
6
, R
7
, R
8
, R
9
, R
18
, R
19
, R
20
, R
22
, R
23
, R
24
and R
25
independently represent H or lower alkyl
R
18
and R
19
independently represent lower alkyl
R
21
represents lower alkyl or aryl
R
26
represents H, lower alkyl, aryl, C(O)R
27
or S(O)
2
R
28
R
27
represents H, lower alkyl or aryl
R
28
represents lower alkyl or aryl
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulpfur and mixtures thereof
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, which groups are optionally substituted with one or more substituents selected from aryl (which group may not be substituted by any further aryl groups), lower alkyl, Het, halo, cyano, nitro, OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10a
R
11a
, NR
12a
R
13a
(wherein R
12a
and R
13a
independently represent R
12
and R
13
as hereinbefore defined, except that: (i) they do not represent C(O)Het in which Het is substituted by one or more substituents that include one or more C(O)NR
10a
R
11a
and/or NR
12a
R
13a
groups; or (ii) they do not together represent C
3-7
alkylene interrupted by NR
26
) and SO
2
NR
14
R
15
.
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, sulfor 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. Each “Het” group identified herein is optionally substituted by one or more substituents selected from halo, cyano, nitro, oxo, lower alkyl (which alkyl group may itself be optionally substituted or terminated as defined below), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10a
R
11a
, NR
12a
R
13a
and SO
2
NR
14
R
15
. 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, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms.
“Het” groups may also be in the form of an N-oxide.
The heterocyclic ring that R
14
and R
15
(together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and which ring fo
Allerton Charlotte Moira Norfor
Barber Christopher Gordon
Maw Graham Nigel
Rawson David James
Benson Gregg C.
Berch Mark L
Munchhof Martha G.
Pfizer Inc.
Richardson Peter C.
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