Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

2000-10-06

2004-01-13

Berch, Mark E (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S118000, C544S262000, C544S357000, C546S275400, C514S258100, C548S372500, C548S374100, C548S371700

Reexamination Certificate

active

06677335

ABSTRACT:

This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3′,5′-monophosphater phosphodiesterases (cGMP PDEs). More notably, the compounds of the invention are potent and selective inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (cGMP PDE5) and have utility therefore in a variety of therapeutic areas.
The compounds of the invention 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 labor, 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 characterized 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, hemorrhoids, hypoxic vasoconstriction as well as the stabilization of blood pressure during haemodialysis.
Particularly preferred conditions include MED and FSD.
PCT application PCT/IB99/00519 relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs).
Thus the present invention provides compounds of the formula (I):
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein
R
1
is C
1
to C
6
alkyl or C
3
to C
6
alkenyl, C
3
to C
6
cycloalkyl or C
4
to C
6
cycloalkenyl wherein said alkyl group may be branched or straight chain and wherein
when R
1
is C
1
to C
3
alkyl said alkyl group is substituted by;
and wherein when R
1
is C
4
to C
6
alkyl, C
3
to C
6
alkenyl or C
3
to C6 cycloalkyl said alkyl, alkenyl or cycloalkyl group is optionally substituted by;
one or more substituents selected from:
hydroxy;
C
1
to C
4
alkoxy;
C
3
to C
6
cycloalkyl;
phenyl substituted with one or more substitutents selected from C
1
to C
3
alkyl, C
1
to C
4
alkoxy, C
1
to C
4
haloalkyl, C
1
to C
4
haloalkoxy, halo, CN, NO
2
, NHR
11
, NHCOR
12
, NHSO
2
R
12
, SO
2
R
12
, SO
2
NHR
11
, COR
11
or CO
2
R
11
wherein said haloalkyl and haloalkoxy groups contain one or more halo atoms;
NR
7
R
3
, CONR
7
R
8
or NR
7
COR
11
wherein R
7
and R
8
are each independently selected from H, C
1
to C
4
alkyl, C
3
to C
4
alkenyl, CO
2
R
9
or SO
2
R
9
and wherein said alkyl or alkenyl groups are optionally substituted by C
1
to C
4
haloalkyl or C
1
to C
4
haloalkoxy;
Het
1
;
Het
2
or Het
3
;
or R
1
is Het
4
or phenyl wherein said phenyl group is optionally substituted by one or more substituents selected from C
1
to C
4
alkyl, C
3
to C
4
alkenyl, C
1
to C
4
alkoxy, halo, CN, CF
3
, OCF
3
, NO
2
, NHR
11
, NHCOR
12
, NHSO
2
R
12
, SO
2
R
12
, SO
2
NHR
11
, COR
11
, CO
2
R
11
;
R
2
is C
1
to C
6
alkyl, C
3
to C
6
alkenyl or (CH
2
)n(C
3
to C
6
cycloalkyl) wherein n is 0, 1 or 2;
R
13
is OR
3
or NR
5
R
6
;
R
3
is C
1
to C
6
alkyl optionally substituted with one or two substituents selected from C
3
to C
5
cycloalkyl, hydroxy, C
1
to C
4
alkoxy, benzyloxy, NR
5
R
6
, phenyl, Het
1
, Het
2
, Het
3
or Het
4
wherein the C
1
to C
6
alkyl and C
1
to C
4
alkoxy groups may optionally be terminated by a haloalkyl group such as CF
3
and wherein the C
3
-C
5
cycloalkyl group may optionally be substituted by C
1
-C
4
alkyl, hydroxy or halo;
C
3
to C
6
cycloalkyl; Het
1
, Het
2
, Het
3
or Het
4
;
R
4
is a piperazin-1-ylsulphonyl group having a substituent R
10
at the 4-position of the piperazinyl group wherein said piperazinyl group is optionally substituted with one or two C
1
to C
4
alkyl groups and is optionally in the form of its 4-N-oxide;
R
5
and R
8
are each independently selected from H and C
1
to C
4
alkyl optionally substituted with C
3
to C
5
cycloalkyl or C
1
to C
4
alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;
R
7
and R
8
are each independently selected from H, C
1
to C
4
alkyl, C
3
to C
4
alkenyl, CO
2
R
9
or SO
2
R
9
;
R
9
is C
1
to C
4
alkyl optionally substituted with C
1
to C
4
haloalkyl, C
1
to C
4
haloalkoxy or phenyl wherein said phenyl group is optionally substituted by one or more substituents selected from C
1
to C
4
alkyl optionally substituted by C
1
to C
4
haloalkyl or C
1
to C
4
haloalkoxy, C
1
to C
4
alkoxy, halo, CN, NO
2
, NHR
11
, NHCOR
12
, NHSO
2
R
12
, SO
2
R
12
, SO
2
NHR
11
, COR
11
or CO
2
R
11
;
R
10
is H; C
1
to C
4
alkyl optionally substituted with one or two substituents selected from hydroxy, NR
5
R
6
, CONR
5
R
6
, phenyl optionally substituted with C
1
to C
4
alkyl or C
1
to C
4
alkoxy; C
3
to C
6
alkenyl or Het
4
;
R
11
is H, C
1
to C
4
alkyl, C
3
to C
4
alkenyl, CO(C
1
to C
4
alkyl) or C
1
to C
4
haloalkyl;
R
12
is C
1
to C
4
alkyl, C
3
to C
4
alkenyl, C
1
to C
4
haloalkyl or C
1
to C
4
haloalkoxy;
Het
1
is an N-linked 4-, 5- or 6-membered nitrogen-containing heterocyclic group optionally containing one or more further heteroatoms selected from S, N or O;
Het
2
is a C-linked 5-membered heterocyclic group containing an O, S or N heteroatom optionally containing one or more heteroatoms selected from N, O or S;
Het
3
is a C-linked 6-membered heterocyclic group containing an O or S heteroatom optionally containing one or more heteroatoms selected from O, S or N or Het
3
is a C-linked 6-membered heterocyclic group containing three N heteroatoms;
Het4 is a C-linked 4-, 5- or 6-membered heterocyclic group containing one, two or three heteroatoms selected from S, O or N; and
wherein any of said heterocyclic groups Het
1
, Het
2
, Het
3
or Het
4
may be saturated, partially unsaturated or aromatic and wherein any of said heterocyclic groups may be optionally substituted with one or more substituents selected from C
1
to C
4
alkyl, C
3
to C
4
alkenyl, C
1
to C
4
alkoxy, halo, CF
3
, CO
2
R
11
, COR
11
, SO
2
R
12
, NHR
11
or NHCOR
12
and/or wherein any of said heterocyclic groups is benzo-fused;
with the provisos that (a) when R
1
is C
1
to C
3
alkyl then Het
1
is not morpholinyl or piperidinyl and (b) when R
1
is C
1
to C
3
alkyl substituted by phenyl then said phenyl group is not substituted by C
1
to C
4
alkoxy, halo, CN, CF
3
, OCF
3
or C

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