Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-02-08
2002-10-15
Richter, Johann (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S346000
Reexamination Certificate
active
06465465
ABSTRACT:
FIELD OF INVENTION
This invention relates to a therapeutic process for the use of pyrido[3,2-e]-pyrazinones of Formula 1 as active ingredients for the treatment of erectile dysfunction (impotence), new pyrido[3,2-e]pyrazinones, as well as to pharmaceutical compositions containing these compounds.
BACKGROUND
Impotence in a man can be defined as the inability to engage in sexual intercourse because of the absence of an erection and/or because of the failure to ejaculate. One speaks of erectile dysfunction, if the erection, with respect to strength or duration, is insufficient for sexual intercourse.
Erectile disorders affect about 10% of the male population. About 52% of men between the ages of 40 and 70 are affected. Several million men worldwide suffer from this disease (about 7.5 million in Germany alone), which in most cases is due to organic causes and less frequently due to mental causes. Erectile dysfunction is a widespread problem among older men, particularly if other chronic diseases are present, such as a high blood pressure, arteriosclerosis and diabetes.
Although different active ingredients can induce an erection, these act only after an injection directly into the penis (intracavernous, i.c.) or instillation into the urethra (intraurethral). This form of pharmacological therapy has been available for more than 10 years and involves the i.c. injection of vasoactive substances, such as papaverin, phenoxybenzamine, phenotolamine, moxisylyte and prostaglandin El (PGEI). However, the i.c. use of these substances frequently is accompanied by serious side effects such as priapismus, pain or penile fibrosis. PGE, can be used intraurethrally and nitroglycerin and minoxidil transdermally (on the penis). However, this can cause side effect in the man as well as in the partner.
Surgical intervention by implanting a prosthesis is an alternative to pharmacological therapy. However, because of the anticipated late complications (infections, blood circulation disorders), this form of therapy is hardly accepted by patients.
The introduction of sildenafil (Viagra®) by Pfizer in the USA and in Europe was a breakthrough in the treatment of erectile dysfunction. Sildenafil is an orally effective phosphodiesterase 5-inhibitor (PDE5 inhibitor), which does not cause an erection directly, but intensifies the action of nitric oxide (NO), which is released in the penis by sexual stimulation. NO, like its second messenger cGMP, brings about a vascular expansion in the corpus cavernosum (cavernous body), so that more blood, which brings about the erection, can flow in.
Phosphodiesterases (PDE) are an isoenzyme family, to which 10 different isoenzymes can so far be assigned. By hydrolysis, PDE enzymes split cyclic guanosine-3′,5′-monophosphate (cGMP) or cyclic adenosine-3′,5′-monophosphate (cAMP), which occur as ‘second messengers’ in a plurality of cells. The phosphodiesterase 5 (PDE 5) is cGMP-specific and dominates in the tissue of human corpus cavernosum.
The inhibition of the PDE 5 in human corpus cavernosum leads to an increase in the intracellular cGMP level, induced by NO. A relaxation of the smooth musculature of the corpus cavernosum and, consequently, an erection is associated with this.
Inhibitors of PDE 5 accordingly are therapeutic agents, which are suitable in the case of indication of erectile dysfunction.
European patent 0 400 583 relates to imidazoquinoxalines of the formula
wherein A is nitrogen or CH in positions 7 or 8, B and D are nitrogen or CH or a substituted carbon atom and R, R
1
, R
2
are hydrogen or different organic substituents. These compounds are said to have a vasodilating effect.
In addition to various imidazo[1,2-a]-quinoxalinones, D. D. Davey et al. (J. Med. Chem. 34 (1991), 2671-2677) also described two imidazo[1,5-a]-pyrido[3,2-e]pyraxinones of formula
in which, on the one hand R
1
is H, and R
2
is C
2
H
5
, and, on the other, R
1
is 2-methylimidazolo-, and R
2
is CH
3
. Both compounds are PDE 3 inhibitors with a positive inotropic effect.
Patent application No. WO 93/20 077 relates to imidazoquinoxalinones of the formula
wherein A is a 5-membered heterocyclic ring with 2 or 3 nitrogen atoms in the ring, R
1
is NO
2
or CF
3
, and X is a variety of chains, with up to 4 chain elements, some of which contain nitrogen. These compounds are described as glutamate receptor antagonists with psychotropic and anti-ischemic activity.
In German patent application No. 199 02 082, imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones of the formula
are described, which are inhibitors of PDE 5. For these compounds, which in each case are unsubstituted in the 5 position, the use for the treatment of erectile dysfunction is claimed. According to German patent application No. 199 61 302 some of these compounds are dual inhibitors of PDE 3 and PDE 5. For these compounds, the use for different heart and circulatory diseases is also claimed.
In German patent No. 195 10 965, describes pyrido[3,2-e]-pyrazonones of the formula
These also include imidazo[1,5-a]-pyrido[3,2-e]-pyrazinones. Antiasthmatic and antiallergic properties were described for the described group of materials.
REFERENCES:
patent: 5055465 (1991-10-01), Davey
patent: 5166344 (1992-11-01), Davey
patent: 5723463 (1998-03-01), Hofgen et al.
patent: 4228095 (1994-03-01), None
patent: 19510965 (1996-09-01), None
patent: 19728301 (1999-07-01), None
patent: 400583 (1990-12-01), None
patent: 736532 (1996-10-01), None
patent: PCT/JP93/00357 (1993-03-01), None
Terrett et al., Sildenafil (Viagra) a potent and selective, etc., Bioorganic and Medic. Chemistry Ltr. 6, 15, 1819-1824, 1996.
Truss et al., Phosphodiesterase Inhibitors, etc., Drugs of Today, 34, 805-812, 1998.
Polymeropoulos et al., Peptide binding site model for :PDE 4 inhibitors, 18 Quant. Struct. -Act. Relat. (1999) 543-547.
Dent et al., Effects of a selective PDE4 inhibitor D-22888 on human airways, etc., 11 Pulm. Pharmacol. Ther. (1998).
Davey et al., Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity, etc., 34 J. Med. Chem., 1991, 2671-2677.
Egerland Ute
Höfgen Norbert
Kronbach Thomas
Marx Degenhard
Szelenyi Stefan
Arzneimittelwerk Dresden GmbH
Fulbright & Jaworski L.L.P.
Richter Johann
Sackey Ebenezer
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