5-substituted pyrazolo[4,3-D]pyrimidin-7-ones

Details 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones 5-substituted pyrazolo[4,3-D]pyrimidin-7-ones

1998-10-21

2001-05-22

Raymond, Richard L. (Department: 1609)

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

06235742

ABSTRACT:

The present invention relates to compounds, including inter alia pharmaceutical compositions comprising the same and methods for making the same.
In particular, the present invention relates to compounds that are capable of exhibiting inhibition of a phosphodiesterase (PDE) enzyme.
More in particular, the present invention relates to compounds that are capable of exhibiting at least inhibition of a phosphodiesterase type 1 (PDE1) enzyme—i.e. the compounds are capable of acting as inhibitors of PDE1. Some of these compounds are also capable of exhibiting inhibition of other types of PDE enzymes—such as a phosphodiesterase type 5 (PDE5) enzyme.
By way of background information, EP-A-0201188 discloses certain 5-substituted pyrazolo[4,3-d]pyrimidin-7-ones and suggests their use for the treatment of cardiovascular disorders, such as heart failure or cardiac insufficiency. EP-A-0201188 also suggests the use of those 5-substituted pyrazolo[4,3-d]pyrimidin-7-ones to inhibit PDE.
In particular, Example 1 of EP-A-0201188 discloses the following 5-substituted pyrazolo[4,3-d]pyrimidin-7-one:
For ease of reference this compound will be referred to as the '188 Compound. Like the '188 compound, all of the compounds of EP-A-0201188 have a methyl group attached at the 3 position of the pyrazolo[4,3-d]pyrimidine ring system.
We have found that the '188 compound is at least a weak PDE1 inhibitor.
Furthermore, as there is now a body of evidence associating PDE1 with a number of diseases, e.g. stroke, dementia, memory enhancement, atherosclerosis, urge incontinence, hypertension, angina pectoris, congestive heart failure, myocardial infarction and restenosis, so there is a need to have more potent PDE1 inhibitors.
There is also a need to have more selective PDE inhibitors, in particular PDE1 inhibitors.
The present invention seeks to provide compounds that are useful as PDE1 inhibitors, including pharmaceutical compositions comprising the same and methods for making the same.
According to a first aspect of the present invention there is provided a compound of the formula (I)
wherein
R
a
is C
2
-C
6
alkyl;
R
1
is H or C
1
-C
4
alkyl;
each of R
2
and R
3
is independently selected from H and C
1
-C
4
alkyl, or
R
2
is H or C
1
-C
4
alkyl and R
3
is OH, C
2
-C
4
alkanoyloxy or fluoro, or
R
2
and R
3
when taken together represent C
2
-C
6
alkylene, or
R
2
and R
3
when taken together with the carbon atom to which they are attached represent a carbonyl group;
Ar is either (a)
 wherein each of R
4
, R
5
and R
6
is independently selected from
H,
C
1
-C
4
alkyl,
C
1
-C
4
alkoxy,
C
1
-C
4
alkoxy-Z—,
halo,
halo(C
1
-C
4
)alkyl,
phenoxy, optionally substituted by up to three substitutents each of which substituent is independently selected from halo, C
1
-
4
alkyl, and C
1
-C
4
alkoxy,
nitro,
hydroxy,
hydroxy-Z—,
C
2
-C
4
alkanoyl,
amino,
amino-Z—,
(C
1
-C
4
alkyl)NH,
(C
1
-C
4
alkyl)
2
N—,
(C
1
-C
4
alkyl)NH—Z—
(C
1
-C
4
alkyl)
2
N—Z—,
—COOH,
—Z—COOH,
—COO(C
1
-C
4
alkyl),
—Z—COO(C
1
-C
4
alkyl)
C
1
-C
4
alkanesulphonamido,
C
1
-C
4
alkanesulphonamido-Z—,
halo(C
1
-C
4
)alkanesulphonamido,
halo(C
1
-C
4
)alkanesulphonamido-Z—,
C
1
-C
4
alkanamido,
C
1
-C
4
alkanamido-Z—,
HOOC—Z—NH—,
HOOC—Z—NH—Z—,
(C
1
-C
4
alkyl)OOC—Z—NH—,
(C
1
-C
4
alkyl)OOC—Z—NH—Z—,
C
1
-C
4
alkl-NH—SO
2
—NH—,
C
1
-C
4
alkyl-NH—SO
2
—NH—Z—,
(C
1
-C
4
alkyl)
2
-N—SO
2
—NH—,
(C
1
-C
4
alkyl)
2
-N—SO
2
—NH—Z—,
C
1
-C
4
alkoxy CH═CH—Z—CONH—,
C
1
-C
4
alkoxy CH═CHCONH
C
1
-C
4
alkyl-SO
2
—N(C
1
-C
4
alkyl)-,
C
1
-C
4
alkyl-SO
2
—N(C
1
-C
4
alkyl)-Z—,
(C
1
-C
4
alkyl)NH—Z—SO
2
—NH—,
(C
1
-C
4
alkyl)
2
N—Z—SO
2
—NH—,
(C
1
-C
4
alkyl)NH—Z—SO
2
—NH—Z—,
(C
1
-C
4
alkyl)
2
N—Z—SO
2
—NH—Z—,
benzenesulphonamido, optionally ring substituted by up to three substitutents each of which is independently selected from halo, C
1
-
4
alkyl, and C
1
-C
4
alkoxy,
C
1
-C
4
alkanoyl-N(C
1
-C
4
alkyl)-,
C
1
-C
4
alkanoyl-N(C
1
-C
4
alkyl)-Z—,
C
1
-C
4
alkoxycarbonyl-CH(CH
2
OH)NHSO
2
—,
—SO
3
H,
—SO
2
NH
2
,
H
2
NOC—CH(CH
2
OH)—NHSO
2
—,
HOOC—Z—O—, and
(C
1
-C
4
alkyl)OOC—Z—O—,
or optionally one of R
4
, R
5
and R
6
is a G-Het group and wherein the others of R
4,
R
5
and R
6
are independently selected from the R
4
, R
5
and R
6
subsituents listed above;
Z is C
1
-C
4
alkylene,
G is a direct link, Z, O, —SO
2
NH—, SO
2
, or —Z—N(C
1
-C
4
alkyl)SO
2
—,
Het is a 5- or 6-membered heterocyclic group containing 1, 2, 3 or 4 nitrogen heteroatoms; or 1 or 2 nitrogen heteroatoms and 1 sulphur heteroatom or 1 oxygen heteroatom; or the heterocyclic group is furanyl or thiophenyl; wherein the Het group is saturated or partially or fully unsaturated and optionally substituted by up to 3 substituents, wherein each substituent is independently selected from C
1
-C
4
alkyl, oxo, hydroxy, halo, and halo(C
1
-C
4
) alkyl;
or (b) any one of the following bicyclic groups:
benzodioxolanyl,
benzodioxanyl,
benzimidazolyl,
quinolinyl,
indolyl,
quinazolinyl,
isoquinolinyl,
benzotriazolyl,
benzofuranyl,
benzothiophenyl,
quinoxalinyl, or
phthalizinyl,
wherein said bicyclic Ar groups are linked to the neighbouring —C(R
2
R
3
)— group via the benzo ring portion,
and wherein the heterocyclic portion of said bicyclic Ar group is optionally partially or fully saturated, said group being optionally substituted by one or more of C
1
-C
4
alkyl, halo, hydroxy, oxo, amino, and C
1
-C
4
alkoxy;
or a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable solvate of the compound or the salt.
This and some of the other aspects of the present invention, as well as some preferred embodiments of the present invention, are presented in the accompanying claims.
It will also be appreciated that what is to be claimed includes the following:
(i) a compound of the formula (I) or a pharmaceutically acceptable salt thereof;
(ii) one or more processes for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof;
(iii) novel intermediates for use in any one of those processes;
(iv) a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable diluent, carrier or excipient;
(v) a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament;
(vi) the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of a medicament for the treatment of conditions capable of being treated by the inhibition of PDE enzymes;
(vii) use as in (vi) wherein the medicament is for use as an inhibitor for PDE1;
(viii) a method of treatment of a subject (e.g. a mammal) in need of same, which method comprises administering to the subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt or composition thereof, and wherein the compound, salt or composition produces an inhibitory effect against a PDE; and
(ix) a method as in (viii) wherein the compound, salt or composition produces an inhibitory effect against PDE1.
By way of example, a preferred process according to one embodiment of the present invention for preparing compounds according to the present invention is presented by the following scheme:
wherein each of the groups are as defined above.
By way of further example, a preferred process according to another embodiment of the present invention for preparing compounds according to the present invention is presented by the following scheme:
wherein each of the groups are as defined above, and wherein R
7
is H or C
1-4
alkyl, and wherein X is C
1-4
alkyl, halo(C
1-4
)alkyl, or optionally substituted phenyl.
By way of further example, a preferred process according to another embodiment of the present invention for preparing compounds according to the present invention is presented by the following scheme:
wherein each of the groups are as defined above.
By way of example, a

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