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
2001-12-25
Raymond, Richard L. (Department: 1811)
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
06333330
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;
R
1
represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally 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
and SO
2
NR
11a
R
11b
;
R
2
represents C(O)NR
12
R
13
, C(O)OR
12
, NR
12
R
13
N(H)SO
2
R
12
, N(H)SO
2
NR
12
R
13
, N(H)C(O)R
12
, OR
12a
, lower alkyl (which alkyl group is interrupted by one or more of O, S or N(R
12
) and/or substituted or terminated by C(O)NR
12
R
13
, C(O)OR
12
or aryl or Het
1
), cyano, aryl or Het
1
;
R
3
, R
12
and R
13
independently represent H or lower alkyl, which alkyl group is optionally substituted and/or optionally terminated by one or more substituents selected from aryl, Het, halo, cyano, nitro, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR8R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
4
represents SO
2
NR
14
R
15
;
R
14
and R
15
, together with the nitrogen to which they are attached, form Het;
Het 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
1
represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains at least one nitrogen atom or at least one oxygen 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
11a
, R
11b
and R
12a
independently represent, at each occurrence when used herein, H or lower alkyl;
R
10a
and R
10b
, at each occurrence when used herein, either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl; or a pharmaceutically, or a veterinarily, acceptable derivative 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. Each “aryl” group identified herein is optionally substituted with 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
12
.
The terms “Het” and “Het
1
”, when used herein, include four- to twelve-membered, preferably four- to ten-membered, ring systems, which may be wholly or partly aromatic in character. Each “Het/Het
1
” group identified herein is optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl (which alkyl groups may itself be optionally substituted or terminated as defined below), 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
12
. The term 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, benzodioxalyl, pyrazolyl, imidazopyridinyl, furanyl, tetrahydrofuranyl and piperazinyl, e.g. 4-R
16
-piperazinyl, wherein R
16
represents H or lower alkyl, which latter group is optionally substituted or terminated by one or more substituents selected from aryl, Het, 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
and N(H)SO
2
R
12
.
“Het” and “Het
1
” groups may also be in the form of an N-oxide.
Azetidinyl, pyrollidinyl and piperidinyl groups that R
10a
, R
10b
and the nitrogen atom to which they are attached may together represent may also be substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl (which alkyl groups may itself be optionally substituted or terminated as defined below), 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
12
.
For the avoidance of doubt, the nitrogen atom to which R
14
and R
15
are attached is the nitrogen atom that must be present in the relevant Het group.
The term “lower alkyl”, when used herein, includes C
1-6
alkyl. Alkyl groups which R
1
, 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
12a
, R
13
and R
16
may represent, and with which R
1
, NR
10a
R
10b
, aryl, Het and Het
1
may be substituted, may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, be interrupted by oxygen, and/or be substituted by one or more halo atom.
The terms “alkylHet” and “alkylaryl” include C
1-6
alkylHet and C
1-6
alkylaryl. The alkyl groups (e.g. the C
1-6
alkyl groups) of alkylHet and alkylaryl may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, and/or be interrupted by oxygen. When used in this context, the terms “Het” and “aryl” are as defined hereinbefore.
Halo groups, with which R
1
, R
3
, R
12
, R
13
, R
16
, aryl, Het, Het
1
and above-mentioned allyl groups may be substituted or terminated, include fluoro, chloro, bromo and iodo.
The term “pharmaceutically, and veterinary, acceptable derivative” includes salts and solvates. Salts which may be mentioned include: acid addition salts, for example, salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids; base addition salts; metal salts formed with bases, for example, the sodium and potassium salts. Pharmaceutically acceptable derivatives also include C
1
to C
4
alkyl ammonium salts.
Preferred compounds of the invention include those wherein:
R
1
represents H, a linear, branched, cyclic, acyclic and/or part cyclic/acyclic lower alkyl group, alkylHet, or alkylaryl;
R
2
represents a linear or branched, optionally unsaturated lower allyl group (which alkyl group is optionally interrupted by one or more of O, S or N(R
12
)), C(O)NR
12
R
13
, NR
12
R
13
, N(H)C(O)R
12
, OR
12a
, aryl or Het
1
;
R
3
represents linear, branched, cyclic and/or acyclic lower alkyl which is optionally substituted or terminated by one or more substituents selected from Het or OR
5
;
R
12
and R
13
independently represent H, or linear or branched lower alkyl, provided that, in the case where R
2
represents NR
12
R
13
, R
12
and R
13
do not both represent H;
R
14
and R
15
, together with the nitrogen to which they are attached represent 4-R
16
-piperazinyl, in which R
16
is as hereinbefore defined.
More preferred compounds of the invention include those wherein:
R
1
represents H; a linear or part cyclic/acyclic C
1
-C
6
alkyl group; C
1
-C
2
alkylphenyl, the phenyl group of which is optionally substituted by one or more halo atoms; or C
1
-C
3
alkylHet, in which Het represents a six-membered heterocyclic group;
R
2
represents a linear or branched, optionally unsaturated, C
1-6
alkyl group (which alkyl group is optionally interrupted by one or more of O or N(R
12
)), C(O)NR
12
R
13
, NR
12
R
13
, N(H)C(O)R
12
, R
12a
, an optionally substituted phenyl group, or an optionally substituted Het
1
group (e.g. a pyridinyl, benzodioxaz
Bunnage Mark Edward
Mathias John Paul
Maw Graham Nigel
Rawson David James
Street Stephen Derek Albert
Benson Gregg C.
Jones James T.
Liu Hong
Pfizer Inc.
Raymond Richard L.
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