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
2002-06-18
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S262000, C544S118000, C544S061000, C514S234500, C514S228500
Reexamination Certificate
active
06407114
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 phosphodiesterase (cGMP PDEs). The compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).
PRIOR ART
International patent application WO 93/07149 discloses certain pyrazolo[3,4-d]pyrimidinone compounds as antianginal agents. International patent application WO 96/16657 discloses the use of these compounds (amongst others) in the treatment of MED.
DISCLOSURE OF THE INVENTION
According to the invention there is provided compounds of formulae IA and IB:
wherein
A represents CH or N;
R
1
and R
2
independently represent 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
3
represents H or lower alkyl, which latter 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)NR
8
R
9
and 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
, 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, sulphur and oxygen; 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 the compound is not:
6-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one; or
3-methyl-6-[5-(morpholinosulphonyl)-2-n-propoxyphenyl]-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one;
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, lower alkyl, 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
11a
.
The term “Het”, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which may be wholly or partly aromatic in character. Each “Het” group identified herein is optionally substituted by one or more substituents selected from halo, cyano, nitro, lower alkyl (which alkyl group may itself be optionally substituted or terminated a defined below for R
14
), OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
and NR
10a
R
10b
, SO
2
NR
11a
R
11b
and N(H)SO
2
R
11a
. 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, pyrazolyl imidazopyridinyl and piperazinyl, e.g. 4-R
14
-piperazinyl, wherein R
14
represents H or lower alkyl, which alkyl 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
11a
.
“Het” groups may also be in the form of an N-oxide.
For the avoidance of doubt, the nitrogen atom to which R
12
and R
13
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
and R
14
may represent, and with which R
1
, R
2
and Het 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
2
, R
3
, R
14
, aryl, Het and above-mentioned alkyl groups may be substituted or terminated include fluoro, chloro, bromo and iodo.
Pharmaceutically, and veterinarily, acceptable derivatives 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, when the compound is a compound of formula IA, in which R
1
represents C
1-6
alkyl, R
2
represents H, methyl or ethyl, R
3
represents C
2-4
alkyl and A represents CH, then R
12
and R
13
, together with the nitrogen to which they are attached, do not form a pyrrolidinyl, piperidinyl, morpholinyl, 1-imidazoyl or a 4-R
14
-piperazinyl (in which R
14
represents H, C
1-3
alkyl or hydroxyC
2-3
alkyl) group, which heterocyclic groups are optionally substituted by one or two C
1-4
alkyl groups.
Further preferred compounds of the invention include those wherein, when A represents CH, R
2
does not represent lower alkyl or H.
Further preferred compounds of the invention include those wherein, when A represents N, R
1
represents lower alkyl and R
2
represents lower alkyl, Het, alkylHet, aryl or alkylaryl.
Preferred compounds of the invention include those wherein:
R
1
represents linear, branched, cyclic, or acyclic, lower alkyl, Het or alkylHet;
R
2
represents linear or branched, cyclic, acyclic, or part-cyclic, lower alkyl (which alkyl group is optionally terminated by OH), alkylHet or alkylaryl (the alkyl group of both of which is optionally interrupted by an O atom), aryl or Het;
R
3
represents linear or branched lower alkyl, optionally terminated by OR
5
, where R
5
represents H or methyl;
R
12
and R
13
together with the nitrogen atom to which they are attached, represent 4-R
14
-piperazinyl, in which R
14
is as hereinbefore defined.
More preferred compounds of the invention include those wherein:
R
1
represents linear or cyclic C
2-5
alkyl, Het or C
1-3
alkylHet, in which both latter cases, Het represents a six-membered aromatic ring containing one or two nitrogen atoms;
R
2
represents linear or branched, cyclic, acyclic or part-cyclic C
1-4
alkyl (which alkyl group is optionally terminated by OH), C
1-3
alkylHet (in which Het represents a six-membered heterocyclic group containing one or two nitrogen atoms), C
1-3
alkylaryl (the alkyl group of which is optionally interrupted by an O atom), aryl or Het (in which Het represents a six-membered heterocyclic group containing one or two nitrogen atoms);
R
3
represents linear or branched C
1-4
alkyl, optionally terminated by OR
5
, where R
5
represents H or methyl;
R
12
and R
13
, together with the nitrogen atom to which they are attached, represent 4-R
14
-piperazinyl, in which R
14
represents lower alkyl, optionally terminated by OH.
Bunnage Mark Edward
Mathias John Paul
Street Stephen Derek Albert
Wood Anthony
Balasubramanian Venkataraman
Benson Gregg C.
Jones James T.
Pfizer Inc.
Richardson Peter C.
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