Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2002-03-14

2004-09-21

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S184000

Reexamination Certificate

active

06794387

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
Certain cGMP PDE-inhibiting 2-phenyl substituted imidazotriazinone derivatives are disclosed in international patent applications WO 99/24433, WO 99/67244 and WO 01/646777.
DISCLOSURE OF THE INVENTION
According to the present invention, there are provided compounds of general formula I:
or pharmaceutically or veterinarily acceptable salts, solvates, polymorphs or pro-drugs thereof wherein:
A represents CHOH or C═O;
X represents O or NR
5
;
Y represents CH or N;
R
1
and R
2
independently represent H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl, C
1
-C
6
alkylaryl, halo, cyano, nitro, OR
6
, OC(O)R
6
, C(O)R
6
, C(O)OR
6
, NR
6
C(O)NR
7
R
8
, NR
6
C(O)OR
6
, OC(O)NR
7
R
8
, C(O)NR
9
R
10
, NR
9
R
10
, SO
2
NR
9
R
10
or SO
2
R
11
;
R
3
, R
4
and R
5
independently represent H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl;
or R
3
and R
5
together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
2
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
or SO
2
R
17
;
wherein when R
1
, R
2
, R
3
, R
4
or R
5
is a C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl group, such C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
6
, OC(O)R
6
, C(O)R
6
, C(O)OR
6
, NR
6
C(O)NR
7
R
8
, NR
6
C(O)OR
6
, OC(O)NR
7
R
8
, C(O)NR
9
R
10
, NR
9
R
10
, SO
2
NR
9
R
10
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl;
wherein when R
1
, R
2
, R
3
, R
4
or R
5
is a C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl group which is substituted and/or terminated with one or more substituents selected from: C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl, such substituent groups are optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
or SO
2
R
17
;
R
6
, R
7
and R
8
independently represent H, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl;
or R
7
and R
8
together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
15
R
16
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
or SO
2
R
17
;
R
9
and R
10
independently represent H, C(O)R
6
, SO
2
R
11
, C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl;
or R
9
and R
10
together with the nitrogen atom to which they are bound can form a heterocyclic ring which is optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
or SO
2
R
17
;
R
11
represents C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl;
wherein when R
6
, R
7
, R
8
, R
9
, R
10
or R
11
is a C
1
-C
6
alkyl, Het, C
1
-C
6
or C
1
-C
6
alkylaryl group, such C
1
-C
6
alkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl group may be optionally substituted and/or terminated with one or more substituents selected from: halo, cyano, nitro, OR
12
, OC(O)R
12
, C(O)R
12
, C(O)OR
12
, NR
12
C(O)NR
13
R
14
, NR
12
C(O)OR
12
, OC(O)NR
13
R
14
, C(O)NR
15
R
16
, NR
15
R
16
, SO
2
NR
15
R
16
or SO
2
R
17
;
R
12
, R
13
and R
14
independently represent H or C
1
-C
6
alkyl; or R
13
and R
14
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
15
and R
16
independently represent H, C(O)R
12
, SO
2
R
17
or C
1
-C
6
alkyl or R
15
and R
16
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
17
represents C
1
-C
6
alkyl;
wherein Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof;
with the proviso that when Y is CH and X is O and A is C(O) then R
1
, R
3
and R
4
each do not represent C
1
-C
6
alkyl and R does not represent C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl and
with the further proviso that when Y is CH and X is O and A is CH(OH) then R
1
and R
3
each do not represent C
1
-C
6
alkyl and R does not represent C
1
-C
6
alkyl or C
3
-C
6
cycloalkyl and R
4
is not phenyl or C
1
-C
5
alkyl optionally substituted with up to 2 substituents selected from hydroxy, phenyl, NR
9
R
10
or OC(O)R
6
wherein R
9
and R
10
are H, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkylphenyl or phenyl groups optionally substituted by hydroxy or OR
12
and R
6
is (C
1
-C
6
)alkyl optionally substituted by halogen or OR
12
and wherein OR
12
is O(C
1
-C
6
)alkyl
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.
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, sulfur 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. 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.
Preferred Het groups for use herein are C
5
-C
8
membered ring systems containing at least one N and optionally O, S or mixtures thereof. Highly preferred herein for the Het or alkylHet substitutents on R
1
and/or R
2
are morpholinyl, piperidinyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or azetidinyl groups.
The heterocyclic ring that R
3
and R
5
, R
7
and R
8
, R
9
and R
10
, R
13
and R
14
or R
15
and R
16
(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 forms a stable structure when attached to the remainder of the molecule via the essential nitrogen atom (which, for the avoidance of doubt, is the atom to which R
3
and R
5
, R
7
and R
8
, R
9
and R
10
, R
13
and R
14
or R
15
and R
16
are attached respectively). In this respect, heterocyclic rings that R
3
and R
5
, R
7
and R
8
, R
9
and R
10
, R
13
and R
14
or R
15
and R
16
(together with the nitrogen atom to which they are bound) may represent include four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain at least one nitrogen atom and optionally contain one or m

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