Pyrazolopyrimidinones for the treatment of impotence

Details Pyrazolopyrimidinones for the treatment of impotence Pyrazolopyrimidinones for the treatment of impotence

1996-03-04

2002-10-22

Webman, Edward J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S929000

Reexamination Certificate

active

06469012

ABSTRACT:

This invention relates to the use of a series of pyrazolo[4,3-d]pyrimidin-7-ones for the treatment of impotence.
Impotence can be defined literally as a lack of power, in the male, to copulate and may involve an inability to achieve penile erection or ejaculation, or both. More specifically, erectile impotence or dysfunction may be defined as an inability to obtain or sustain an erection adequate for intercourse. Its prevalence is claimed to be between 2 and 7% of the human male population, increasing with age, up to 50 years, and between 18 and 75% between 55 and 80 years of age. In the USA alone, for example, it has been estimated that there are up to 10 million impotent males, with the majority suffering from problems of organic rather than of psychogenic origin.
Reports of well-controlled clinical trials in man are few and the efficacy of orally administered drugs is low. Although many different drugs have been shown to induce penile erection, they are only effective after direct injection into the penis, e.g. intraurethrally or intracavernosally (i.c.), and are not approved for erectile dysfunction. Current medical treatment is based on the i.c injection of vasoactive substances and good results have been claimed with phenoxybenzamine, phentolamine, papaverine and prostaglandin E
1
, either alone or in combination; however, pain, priapism and fibrosis of the penis are associated with the i.c. administration of some of these agents. Potassium channel openers (KCO) and vasoactive intestinal polypeptide (VIP) have also been shown to be active i.c., but cost and stability issues could limit development of the latter. An alternative to the i.c. route is the use of glyceryl trinitrate (GTN) patches applied to the penis, which has been shown to be effective but produces side-effects in both patient and partner.
As a general alternative to pharmacological intervention, a variety of penile prostheses has been used to assist achievement of an erection. The short term success rate is good, but problems with infection and ischaemia, especially in diabetic men, make this type of treatment a final option rather than first-line therapy.
The compounds of the invention are potent inhibitors of cyclic guanosine 3′,5′-monophosphate phosphodiesterases (cGMP PDEs) in contrast to their inhibition of cyclic adenosine 3′,5′-monophosphate phosphodiesterases (cAMP PDEs). This selective enzyme inhibition leads to elevated cGMP levels which, in turn, provides the basis for the utilities already disclosed for the said compounds in EP-A-0463756 and EP-A-0526004, namely in the treatment of 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).
Unexpectedly, it has now been found that these disclosed compounds are useful in the treatment of erectile dysfunction. Furthermore the compounds may be administered orally, thereby obviating the disadvantages associated with i.c. administration. Thus the present invention concerns the use of a compound of formula (I):
wherein
R
1
is H; C
1
-C
3
alkyl; C
1
-C
3
perfluoroalkyl; or C
3
-C
5
cycloalkyl;
R
2
is H; C
1
-C
6
alkyl optionally substituted with C
3
-C
6
cycloalkyl; C
1
-C
3
perfluoroalkyl; or C
3
-C
6
cycloalkyl;
R
3
is C
1
-C
6
alkyl optionally substituted with C
3
-C
6
cycloalkyl; C
1
-C
6
perfluoroalkyl; C
3
-C
5
cycloalkyl; C
3
-C
6
alkenyl; or C
3
-C
6
alkynyl;
R
4
is C
1
-C
4
alkyl optionally substituted with OH, NR
5
R
6
, CN, CONR
5
R
6
or CO
2
R
7
; C
2
-C
4
alkenyl optionally substituted with CN, CONR
5
R
6
or CO
2
R
7
; C
2
-C
4
alkanoyl optionally substituted with NR
5
R
6
; (hydroxy)C
2
-C
4
alkyl optionally substituted with NR
5
R
6
; (C
2
-C
3
alkoxy)C
1
-C
2
alkyl optionally substituted with OH or NR
5
R
6
; CONR
5
R
6
; CO
2
R
7
; halo; NR
5
R
6
; NHSO
2
NR
5
R
6
; NHSO
2
R
8
; SO
2
NR
9
R
10
; or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl any of which is optionally substituted with methyl;
R
5
and R
6
are each independently H or C
1
-C
4
alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino, 4-N(R
11
)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH;
R
7
is H or C
1
-C
4
alkyl;
R
8
is C
1
-C
3
alkyl optionally substituted with NR
5
R
6
;
R
9
and R
10
together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, morpholino or 4-N(R
12
)-piperazinyl group wherein said group is optionally substituted with C
1
-C
4
alkyl, C
1
-C
3
alkoxy, NR
13
R
14
or CONR
13
R
14
;
R
11
is H; C
1
-C
3
alkyl optionally substituted with phenyl; (hydroxy)C
2
-C
3
alkyl; or C
1
-C
4
alkanoyl;
R
12
is H; C
1
-C
6
alkyl; (C
1
-C
3
alkoxy)C
2
-C
6
alkyl; (hydroxy)C
2
-C
6
alkyl; (R
13
R
14
N)C
2
-C
6
alkyl; (R
13
R
14
NOC)C
1
-C
6
alkyl; CONR
13
R
14
; CSNR
13
R
14
; or C(NH)NR
13
R
14
; and
R
13
and R
14
are each independently H; C
1
-C
4
alkyl; (C
1
-C
3
alkoxy)C
2
-C
4
alkyl; or (hydroxy)C
2
-C
4
alkyl;
or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing either entity, for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.
In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms, alkenyl and alkynyl groups having four or more carbon atoms, alkoxy groups having three carbon atoms and alkanoyl groups having four carbon atoms may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.
The compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as enantiomers or diastereoisomers. Furthermore, certain compounds of formula (I) which contain alkenyl groups may exist as cis-isomers or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The pharmaceutically acceptable salts of the compounds of formula (I) 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 formula (I) can also provide pharmaceutically 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 formula (I) is that wherein R
1
is H, methyl or ethyl; R
2
is C
1
-C
3
alkyl; R
3
is C
2
-C
3
alkyl or allyl; R
4
is C
1
-C
2
alkyl optionally substituted with OH, NR
5
R
6
, CN, CONR
5
R
6
or CO
2
R
7
; acetyl optionally substituted with NR
5
R
6
; hydroxyethyl optionally substituted with NR
5
R
6
; ethoxymethyl optionally substituted with OH or NR
5
R
6
; CH═CHCN; CH═CHCONR
5
R
6
; CH═CHCO
2
R
7
; CONR
5
R
6
; CO
2
H; Br; NR
5
R
6
; NHSO
2
NR
5
R
6
; NHSO
2
R
8
; SO
2
NR
9
R
10
; or pyridyl or imidazolyl either of which is optionally substituted with methyl; R
5
and R
6
are each independently H, methyl or ethyl, or together with the nitrogen atom to which they are attached form a piperidino, morpholino, 4-N(R
11
)-piperazinyl or imidazolyl group wherein said group is optionally substituted with methyl or OH; R
7
is H or t-butyl; R
8
is methyl or CH
2
CH
2
CH
2
NR
5
R
6
; R
9
and R
10
together with the nitrogen atom to which they are attached form a piperidino or 4-N(R
12
)-piperazinyl group wherein said group is optionally substituted with

Affiliated with

Also associated with

Rating

Pyrazolopyrimidinones for the treatment of impotence does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Pyrazolopyrimidinones for the treatment of impotence, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pyrazolopyrimidinones for the treatment of impotence will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2942139