Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-29
2004-04-20
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S241000, C514S258100
Reexamination Certificate
active
06723719
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).
WO-A-94/28902 and WO-A-96/16644 relate to the use of various series of cGMP PDE inhibitors for the treatment of MED including, within the latter, the compounds disclosed in EP-A-020188 which are also adenosine receptor antagonists and reported to be useful in the treatment of cardiovascular disorders as well as the compounds disclosed in EP-A-0352960 which have bronchodilator, vasodilator and anti-allergic properties.
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 substituted with C
3
to C
6
cycloalkyl, CONR
5
R
6
or a N-linked heterocyclic group selected from pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, piperidinyl, morpholinyl and 4-R
9
-piperazinyl; (CH
2
)
n
Het or (CH
2
)
n
Ar;
R
2
is C
1
to C
6
alkyl;
R
3
is C
1
to C
6
alkyl optionally substituted with C
1
-C
4
alkoxy;
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
1
to C
4
alkoxy, or, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, piperidinyl, morpholinyl or 4-R
9
-piperazinyl group;
R
7
and R
8
, together with the nitrogen atom to which they are attached, form a 4-R
10
-piperazinyl group;
R
9
is C
1
to C
4
alkyl;,
R
10
is H or C
1
to C
4
alkyl optionally substituted with OH, C
1
to C
4
alkoxy or CONH
2
;
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 from one to four heteroatoms selected from nitrogen, oxygen and sulphur, wherein either of said heterocyclic groups is optionally substituted with one or two substituents selected from C
1
to C
4
alkyl optionally substituted with C
1
to C
4
alkoxy, C
1
to C
4
alkoxy, halo and NH
2
,
Ar is phenyl optionally substituted with one or two substituents selected from C
1
to C
4
alkyl, C
1
to C
4
alkoxy, halo, CN, CONH
2
, NO
2
, NH
2
, NHSO
2
(C
1
to C
4
alkyl) and SO
2
NH
2
;
and n is 0 or 1.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.
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 organo-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 salt is the citrate.
A preferred group of compounds of formulae (IA) and (IB) is that wherein R
1
is C
1
to C
2
alkyl substituted with C
3
to C
5
cycloalkyl, CONR
5
R
6
or a N-linked heterocyclic group selected from pyrazolyl, triazolyl, morpholinyl and 4-R
9
-piperazinyl; (CH
2
)
n
Het or (CH
2
)
n
Ar; R
5
is H and R
6
is C
1
to C
4
alkyl optionally substituted with C
1
to C
4
alkoxy or R
5
and R
6
, together with the nitrogen atom to which they are attached, form a morpholinyl group; Het is selected from pyridinyl, 1-oxidopyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, isoxazolyl, triazolyl, triazolyl and oxadiazolyl, any of which is optionally substituted with one or two substituents selected from CH
3
, CH
2
CH
2
OCH
3
, OCH
3
and NH
2
; and R
2
, R
3
, R
4
, R
9
, Ar and n are as previously defined.
A more preferred group of compounds of formulae (IA) and (IB) is that wherein R
1
is C
1
to C
2
alkyl substituted with cyclobutyl, CONR
5
R
6
, pyrazol-1-yl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, morpholin-4-yl or 4-methylpiperazin-1-yl; pyrimidin-2-yl; CH
2
Het or (CH
2
)
n
Ar; R
2
is C
1
to C
3
alkyl; R
3
is C
1
to C
3
alkyl optionally substituted with C
1
to C
2
alkoxy; R
5
is H and R
6
is C
1
to C
2
alkyl optionally substituted with C
1
to C
2
alkoxy or R
5
and R
6
, together with the nitrogen atom to which they are attached, form a morpholin-4-yl group; R
10
is C
1
to C
2
alkyl optionally monosubstituted with OH, OCH
3
or CONH
2
; Het is selected from pyridin-2-yl, 1-oxidopyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, 3-methoxypyridin-2-yl, 6-aminopyridin-2-yl, 1-methylimidazol-2-yl, 3,5-dimethylisoxazol-4-yl, 2-methylthiazol-4-yl, 1-methyl-1,2,4-triazol-5-yl, 1-(2-methoxyethyl)-1,2,4-triazol-5-yl, 4-methyl-1,2,4-triazol-3-yl, 3-methyl-1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl; Ar is selected from phenyl, 4-chlorophenyl, 4-bromophenyl, 2-cyanophenyl, 2-carbamoylphenyl, 4-carbamoylphenyl, 2-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 4-aminophenyl, 2-methanesulphonamidophenyl, 4-methanesulphonamidophenyl, 4-ethanesulphonamidophenyl, 4-(prop-2-ylsulphonamido)phenyl and 4-sulphamoylphenyl; and n is as previously defined.
A particularly preferred group of compounds of formulae (IA) and (IB) is that wherein R
1
is cyclobutylmethyl, morpholin-4-ylcarbonylmethyl, 2-(morpholin-4-yl)ethyl, pyrimidin-2-yl, CH
2
Het or (CH
2
)
n
Ar; R
2
is CH
2
CH
3
or CH
2
CH
2
CH
3
; R
3
is CH
2
CH
3
, CH
2
CH
2
CH
3
or CH
2
CH
2
OCH
3
; R
10
is CH
3
, CH
2
CH
3
or CH
2
CH
2
OH; Het is selected from
Bunnage Mark Edward
Mathias John Paul
Street Stephen Derek Albert
Wood Anthony
Balasubramanian Venkataraman
Benson Gregg C.
Jones James T.
Pfizer Inc
Richardson Peter C.
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