Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2002-03-06

2004-12-14

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S247000, C514S252120, C514S257000, C514S252130, C514S252140, C514S253010, C544S245000, C544S251000, C544S252000, C544S358000, C544S360000

Reexamination Certificate

active

06831074

ABSTRACT:

This invention relates to fused pyrazolo[4,3-d] pyrimidin-7-ones and pyrazolo [3,4-d] pyrimidin-4-ones and purinones which inhibit cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds are potent and selective inhibitors of the type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterases and have utility therefore in a variety of therapeutic areas.
The present compounds are of value for the curative or prophylactic treatment of mammalian sexual disorders. In particular, the compounds are of value in the treatment of mammalian sexual dysfunctions such as male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction (FSOD) as well as sexual dysfunction due to spinal cord injury or selective serotonin re-uptake inhibitor (SSRI) induced sexual dysfunction but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, nitrate induced tolerance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, diseases and conditions of the eye such as glaucoma, optic neuropathy, macular degeneration, elevated intra-occular pressure, retinal or arterial occulsion and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Further medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated, and for which treatment with compounds of the present invention may be useful, include pre-eclampsia, Kawasaki's syndrome, nitrate tolerance, multiple sclerosis, diabetic nephropathy, neuropathy including autonomic and peripheral neuropathy and in particular diabetic neuropathy and symptoms thereof (e.g. gastroparesis), peripheral diabetic neuropathy, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure, haemorrhoids, hypoxic vasoconstriction, hypoxic vasoconstriction, diabetes, type 2 diabetes mellitus, the insulin resistance syndrome, insulin resistance, impaired glucose tolerance, as well as the stabilisation of blood pressure during haemodialysis.
Particularly preferred conditions include MED and FSD.
The prior art discloses a number of fused structures which are useful during the treatment of a number of disorders. For example, WO 94/15937 discloses the use of imidazopyrazinone derivatives as agonists/antagonists for GABA receptors. WO 99/02528 teaches the use of fused triazoles in anti-allergy/anti-inflammatory preparations. WO 98/14431 teaches the use of quinazolinyl piperazine derivatives for use in the treatment of arterial sclerosis and/or cancer. European Patent No 0 431 943 discloses the use of nitrogen containing fused spirocycles in the treatment of arrhythmia. European Patent No 0 623 620 teaches the use of pyrrolo pyrazine derivatives having activity on 5-HT3 receptors.
The present invention provides a compound of formula (I):
where Q is a group of formula:
wherein
A represents SO
2
, C(O) or CH(OH);
V represents O or NR
5
;
W represents CHR, CH
2
, —(CH
2
)
m
—CH(R)—, —C(O)—N(R
a
)—, —(CH
2
)
m
—O—, —(CH
2
)
m
—N(R
a
)—, —(CH
2
)
m
C(O)NH— or —(CH
2
)
m
NHC(O)—;
X represents CH or N;
m equals 1, 2 or 3;
n equals 1, 2, 3, 4 or 5 with the proviso that the ring containing W contains 5, 6, 7 or 8 atoms only;
R is hydrogen; halo; cyano; nitro; C
1
to C
6
alkyl; C
3
to C
6
cycloalkyl; C
2
to C
6
alkenyl; C
1
to C
6
alkylhet; C
1
to C
6
alkylaryl; aryl; het; OR
b
; OC(O)R
b
; C(O)R
b
;
C(O)OR
b
; NR
b
C(O)NR
c
R
d
; NR
b
C(O)OR
b
; OC(O)NR
c
R
d
; C(O)NR
c
R
d
; NR
c
R
d
; SO
2
NR
c
R
d
;
R
a
represents hydrogen, C
1
to C
6
alkyl; C
3
to C
6
cycloalkyl; C
2
to C
6
alkenyl; C
1
to C
6
alkylhet; C
1
to C
6
alkylaryl; aryl; het; C(O)OR
b
; C(O)R
b
; SO
2
NR
c
R
d
; or SO
2
R
b
;
wherein R
b
, R
c
and R
d
independently represent hydrogen or C
1
to C
6
alkyl or C
3
to C
6
cycloalkyl or C
2
to C
6
alkenyl optionally substituted by halo; or R
c
and R
d
together with the nitrogen atom to which they are attached form a heterocyclic ring;
R
1
and R
2
are bonded to a carbon atom in the ring and independently represent hydrogen; halo; cyano; nitro; C
1
to C
6
alkyl; C
3
to C
6
cycloalkyl; C
2
to C
6
alkenyl; C
1
to C
6
alkylhet; C
1
to C
6
alkylaryl; aryl; het; OR
b
; OC(O)R
b
; C(O)R
b
; C(O)OR
b
; NR
b
C(O)NR
c
R
d
; NR
b
C(O)OR
b
; OC(O)NR
c
R
d
; C(O)NR
e
R
f
; NR
e
R
f
; SO
2
NR
e
R
f
; or SO
2
R
b
;
wherein when R
1
or R
2
is C
1
to C
6
alkyl; C
3
to C
6
cycloalkyl; C
2
to C
6
alkenyl; C
1
to C
6
alkylhet; C
1
to C
6
alkylaryl; aryl; or het each such group may be optionally substituted and/or terminated with one or more substituents selected from the group comprising: halo; cyano; nitro; OR
b
; OC(O)R
b
; C(O)R
b
; C(O)OR
b
; NR
b
C(O)NR
c
R
d
; NR
b
C(O)OR
b
; OC(O)NR
c
R
d
; C(O)NR
e
R
f
; NR
e
R
f
; SO
2
NR
e
R
f
; or SO
2
R
b
;
wherein R
e
and R
f
independently represent H, C(O)R
12
, SO
2
R
17
or C
1
-C
6
alkyl; or R
e
and R
f
together with the nitrogen atom to which they are bound can form a heterocyclic ring;
R
3
, R
4
and R
5
independently represent H, C
1
-C
6
alkyl, C
3
to C
6
cycloalkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter six groups may all 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, C
3
to C
6
cycloalkyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl wherein said latter six substituent and/or terminal groups are all 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
, S0
2
NR
15
R
16
, SO
2
R
17
); 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
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
, SO
2
R
17
; with the proviso that when A represents SO
2
, R
4
does not represent hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkylhet, C
1
-C
6
alkylaryl, aryl or a C-linked Het;
R
6
represents H, C
1
-C
6
alkyl, C
3
to C
6
cycloalkyl, C
2
-C
6
alkenyl, Het, C
1
-C
6
alkylHet, aryl or C
1
-C
6
alkylaryl (which latter seven groups are all 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
, SO
2
R
17
);
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 (which latter five groups are all 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
, SO
2
R
17
); or R
7
and R
8
together with the nitrogen atom

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