Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2003-12-30
Raymond, Richard L. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S234200, C544S118000, C544S262000, C546S293000, C548S364100, C548S372500
Reexamination Certificate
active
06670366
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
International patent application WO 94/28902 discloses the use of certain pyrazolopyrimidinone compounds in the treatment of impotence.
DISCLOSURE OF THE INVENTION
According to a first aspect of the invention there is provided compounds of formulae IA and IB:
wherein
A represents CH or N;
R1 represents Het
1
, Het
1
alkyl, aryl or arylalkyl , all of which are optionally substituted by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
3
independently represent H or lower alkyl, which latter group is optionally substituted and/or terminated by one or more substituents selected from aryl, Het
1
, halo, cyano, nitro, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
4
represents SO
2
NR
12
R
13
;
R
12
and R
13
independently represent H; lower alkyl optionally substituted and/or terminated by one or more substituents selected from aryl, Het
1
, halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10
R
10a
and SO
2
NR
11a
R
11b
; Het
1
; or together with the nitrogen to which they are attached, form Het
2
or structural fragment of formula IIa:
R
14
and R
15
independently represent H, lower alkyl, C(O)R
6
, C(O)OR
7
or C(O)NR
8
R
9
;
Het
1
represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains at least one nitrogen atom and, optionally, one or more further heteroatoms selected from nitrogen, oxygen and sulphur;
Het
2
represents an optionally substituted three- to twelve-membered heterocyclic group, which group contains at least one nitrogen atom and, optionally, one or more further heteroatoms selected from nitrogen, oxygen and sulphur; and
R
5
, R
6
, R
7
, R
8
, R
9
, R
10a
, R
10b
, R
11a
and R
11b
independently represent, at each occurrence when used herein, H or lower alkyl;
or a pharmaceutically, or a veterinarily, acceptable derivative thereof;
provided that when R
2
represents C
1-6
alkyl and:
(a) A represents CH; R
1
represents Het
1
or Het
1
CH
2
(in which both cases Het
1
represents a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C
1-4
alkyl, which alkyl group is optionally substituted with C
1-4
alkoxy, halo or NH
2
), phenyl or benzyl (which latter two groups are optionally substituted with one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halo, CN, CONH
2
, NO
2
, NH
2
and SO
2
NH
2
); and R
3
is C
1-6
alkyl optionally substituted with C
1-4
alkoxy; then R
12
and R
13
do not represent, together with the nitrogen atom to which they are attached, a piperazinyl group, optionally substituted in the 4(N) position with C
1-4
alkyl optionally substituted with OH, C
1-4
alkoxy or CONH
2
; and
(b) A represents N; R
1
represents CH
2
Het
1
(in which Het
1
represents a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C
1-4
alkyl) or benzyl; and R
3
is C
1-4
alkyl (optionally substituted with one or two substituents selected from OH, C
1-4
alkoxy, benzyloxy, NR
5a
R
6a
(where R
5a
and R
6a
are each independently selected from H and C
1-4
alkyl or, together with the nitrogen atom to which they are attached, form a pyrrollidinyl, piperidinyl or morpholinyl group), phenyl, furanyl or pyridinyl), C
3-6
cycloalkyl or 1-(C
1-4
alkyl)piperidinyl; then R
12
and R
13
do not represent, together with the nitrogen atom to which they are attached, a 4-piperazinyl group, optionally substituted with one or two C
1-4
alkyl groups, optionally in the form of its 4-N-oxide, and optionally substituted at the 4(N) position with C
1-4
alkyl optionally substituted with one or two substituents selected from OH, NR
5a
R
6a
, CONR
5a
R
6a
(in which both cases R
5a
and R
6a
are as defined above);
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. Each “aryl” group identified herein is optionally substituted with one or more substituents selected from halo, cyano, nitro, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
, N(H)SO
2
R
11a
and lower alkyl, which latter group is optionally substituted and/or terminated by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
and N(H)SO
2
R
11a
.
The term “Het
1
”, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which may be aromatic in character. Each “Het
1
” group identified herein is optionally substituted with one or more substituents selected from halo, cyano, nitro, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
, N(H)SO
2
R
11a
and lower alkyl, which latter group is optionally substituted and/or terminated by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
and N(H)SO
2
R
11a
. The term “Het
1
” thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl and piperazinyl.
The term “Het
2
”, when used herein, includes three- to twelve-membered, preferably four- to ten-membered, ring systems, which may be aromatic in character. Each “Het
2
” group identified herein is optionally substituted with one or more substituents selected from oxo, ethyleneketal, halo, cyano, nitro, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
, N(H)SO
2
R
11a
and lower alkyl, which latter group is optionally substituted and/or terminated by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
, SO
2
NR
11a
R
11b
and N(H)SO
2
R
11a
. The term thus includes groups such as imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, morpholinyl, tetrahydrothiazinyl, pyrazolyl, imidazopyridinyl and aza- and diaza-cyclo-(C
2
-C
12
)-alkyl groups, such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, aza- or diazacycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, -cycloundecyl and -cyclododecyl.
All Het
1
and Het
2
groups may also be in the form of an N-oxide.
For the avoidance of doubt, when R
12
and R
13
together represent Het
2
, the nitrogen atom to which they are attached is the nitrogen atom that must be present in this ring.
“The term “lower alkyl”, when used herein, includes C1-6 alkyl. Lower alkyl lower alkenyl, lower alkynyl, cyclic lower alkyl, part cyclic/acyclic lower alkyl groups which R
2
, R
3
, R
5
, R
6
, R
7
, R
8
, R
9
, R
10a
, R
10b
, R
11a
, R
11b
, R
12
, R
13
, R
14
an
Bunnage Mark Edward
Mathias John Paul
Street Stephen Derek Albert
Wood Anthony
Benson Gregg C.
Jones James T.
McKenzie Tom
Pfizer Inc
Raymond Richard L.
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