Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-04-30
2002-10-01
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C546S275400, C546S296000, C546S297000, C546S298000, C546S256000, C546S193000, C546S194000, C544S364000, C544S238000, C544S333000, C544S405000
Reexamination Certificate
active
06458951
ABSTRACT:
This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3′,5′-monophosphate 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.
In particular, the compounds are of value in the treatment of male erectile dysfunction (MED) and female sexual dysfunction (FSD) 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, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Other conditions which may be mentioned include pre-eclampsia, Kawasaki's syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction.
Particularly preferred conditions include MED and FSD.
Thus the invention provides compounds of formulae (IA) and (IB):
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
3
alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted by one or more substituents selected from C
1
to C
4
alkoxy; halo; CN; CF
3
, OCF
3
or C
1
to C
4
alkyl wherein said C
1
to C
4
alkyl group is optionally substituted by C
1
to C
4
haloalkyl or C
1
to C
4
haloalkoxy either of which is substituted by one or more halo atoms;
R
2
is C
1
to C
6
alkyl;
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
6
cycloalkyl, OH, C
1
to C
4
alkoxy, benzyloxy, NR
5
R
6
, phenyl, furanyl and pyridinyl; C
3
to C
6
cycloalkyl; 1-(C
1
to C
4
alkyl)piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; and 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
;
R
4
is SO
2
NR
7
R
8
;
R
5
and R
6
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
, together with the nitrogen atom to which they are attached, form a 4-R
10
-piperazinyl group optionally substituted with one or two C
1
to C
4
alkyl groups and optionally in the form of its 4-N-oxide;
R
10
is H; C
1
to C
4
alkyl optionally substituted with one or two substituents selected from OH, NR
5
R
6
, CONR
5
R
6
, phenyl optionally substituted with C
1
to C
4
alkoxy, benzodioxolyl and benzodioxanyl; C
3
to C
6
alkenyl; pyridinyl or pyrimidinyl;
and Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C
1
to C
4
alkyl, C
1
to C
4
alkoxy or NHR
15
wherein R
15
is H, C
1
to C
4
alkyl or C
1
to C
4
alkanoyl.
In the above definition, unless otherwise indicated, alkyl, alkoxy and alkenyl groups having three or more carbon atoms, and alkanoyl groups having four or more carbon atoms, may be straight chain or branched chain. The term halo atom includes, Cl, Br, F, and I. Haloalkyl and haloalkoxy are preferably CF
3
and OCF
3
respectively.
The compounds of formulae (IA) and (IB) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formulae (IA) and (IB) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (IA) or (IB) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (IA) or (IB) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.
The compounds of formulae (IA) and (IB) may also exist in tautomeric forms and the invention includes both mixtures thereof and the individual tautomers.
Also included in the invention are radiolabelled derivatives of compounds of formulae (IA) and (IB) which are suitable for biological studies.
The pharmaceutically or veterinarily acceptable salts of the compounds of formulae (IA) and (IB) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Compounds of formulae (IA) and (IB) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts.
A preferred group of compounds of formulae (IA) and (IB) is that wherein R
1
is C
1
to C
2
alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R
2
is C
2
to C
4
alkyl; R
13
is OR
3
or NR
5
R
6
; R
3
is C
1
to C
4
alkyl optionally substituted with one or two substituents selected from cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR
5
R
6
, phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl; cyclobutyl; 1-methylpiperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R
5
and R
6
are each independently selected from H and C
1
to C
2
alkyl optionally substituted with cyclopropyl or methoxy, or, together with the nitrogen atom to which they are attached, form a azetidinyl, pyrrolidinyl or morpholinyl group; R
7
and R
8
, together with the nitrogen atom to which they are attached, form a 4-R
10
-piperazinyl group optionally substituted with one or two methyl groups and optionally in the form of its 4-N-oxide; R
10
is H, C
1
to C
3
alkyl optionally substituted with one or two substituents selected from OH, NR
5
R
6
, CONR
5
R
6
, phenyl optionally substituted with methoxy, benzodioxol-5-yl and benzodioxan-2-yl; allyl; pyridin-2-yl; pyridin-4-yl or pyrimidin-2-yl; and Het is selected from pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypyridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl.
A more preferred group of compounds of formulae (IA) and (IB) is that wherein R
1
is C
1
to C
2
alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R
2
is C
2
to C
4
alkyl; R
13
is OR
3
; R
3
is C
1
to C
4
alkyl optionally monosubstituted with cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl; cyclobutyl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R
7
and R
8
, together with the nitrogen atom to which they are attached, form a 4-R
10
-piperazinyl group optionally in the form of its 4-N-oxide; R
10
is C
1
to C
3
alky
Bunnage Mark Edward
Mathias John Paul
Street Stephen Derek Albert
Wood Anthony
Benson Gregg C.
Berch Mark L.
Jones James T.
Pfizer Inc
Richardson Peter C.
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