BG107077A - Use of pyrido[3,2-e]-pyrazinones as inhibitors of phosphodiesterase 5 for treating erectile dysfunction - Google Patents

Abstract

The invention relates to the use of pyrido[3,2-e]-pyrazinones of formula wherein their substituents have the meanings given in the description. They are used as inhibitors of phosphodieserase 5 for treating erectile dysfunction (impotence). 10 claims

Description

The invention relates to the use of pyrido [3,2-e] -pyrazinones of formula 1 as active compounds for the treatment of erectile dysfunction (impotence) and to pharmaceutical compositions containing these compounds.

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BACKGROUND OF THE INVENTION An impotence in a man can be defined as an inability to engage in sexual relations due to lack of erection and / or lack of ejaculation. The term erectile dysfunction is used if the erection is not adequate for sexual relations in terms of strength or duration.

Erectile disorders affect approximately 10% of the male population. Men between the ages of 40 and 70 are affected, with approximately 52% of them being particularly affected. Worldwide, several million men suffer from this disorder (7.5 million in Germany alone), which in most cases is organically, rarely psychologically, caused.

Erectile dysfunction is a widespread problem among older men, especially if other chronic disorders such as high blood pressure, atherosclerosis and diabetes are present.

Although various active compounds can 'p *' ^w induce an erection, they act only after direct injection into the penis (intra-cavernous, subcutaneous) or insertion into the ureter (intra-ureter). This form of pharmacotherapy has been available for more than 10 years and involves the subcutaneous injection of vasoactive substances such as papaverine, phenoxybenzamine, phentolamine, moxysilitis and prostaglandin Ei (PGE ^. However, subcutaneous administration of these substances is often accompanied by serious side effects, such as priapism (persistent erection), pain or fibrosis of the penis.PGEi can be administered intrareterally as nitroglycerin and minoxidil can be administered transdermally (on the penis), however, side effects can be caused. th as in men, and in partner.

An alternative to pharmacotherapy is surgery by implantation of prostheses. This form of therapy is hardly accepted by patients because of the later complications that can be expected (infections, circulatory disorders).

A breakthrough in erectile dysfunction therapy is an introduction to Pfizer's sildenafil (Viagra®) in the US and Europe. Sildenafil is an inhibitor of orally active phosphodiesterase 5 (PDES5), which does not directly produce an erection but enhances the action of nitric oxide (NO) released in the penis by sexual stimulation. N0, as well as its "second messenger" cGMP, causes vasodilation into the cavernous body (corpus cavernosum) so that blood can invade it in large quantities, leading to an erection.

Phosphodiesterases (PDEs) represent an isoenzyme family that has been able to transcribe 10 different enzymes so far. PDE enzymes cleave cyclic guanosine 3 ', 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'-monophosphate (cAMP), which occurs in cell multiplication as a 'second messenger' by hydrolysis. Phosphodiesterase 5 (PDE 5) is cGMP-specific and dominates the tissue of the human cave body.

Inhibition of PDE 5 in the human cave body leads to an increase in the intracellular level of cGMP induced by NO. In this connection, the smooth muscles of the cave body are relaxed and as a result an erection is achieved.

PDE 5 inhibitors are therefore suitable as therapeutic agents for the indication of erectile dysfunction.

European Patent 0 400 583 relates to imidazokinoxaline of general formula

where A for positions 7 and 8 is a nitrogen atom or CH, B and D are a nitrogen atom or CH or a substituted carbon atom, respectively, and the radicals R, R ¹ , R ² are hydrogen or various organic substituents. The vasodilatory action of these compounds is indicated.

In addition to the various imidazo [1,2-a] quinoxalinones, D.D. Davey et al., (J. Med. Chem. 34 (1991), 26712677) also discloses 2 imidazo [1,5-a] pyrido [3,2-e] pyrazinones of formula

for which, on the one hand, R ¹ = H and R ² = C ² H ⁵ , and on the other hand, R ¹ = 2-methylimidazolo- and R ² = CH 3. Both compounds are characterized as PDE 3 inhibitors having a positive inotropic effect.

Patent application WO 93/20 077 relates to imidazoquinine-oxalinones of general formula

where A is a 5-membered heterocyclic ring having 2 or 3 nitrogen atoms in the ring, R ¹ may be NO ₃ or CF ₃ and X is a different chain, in some cases containing nitrogen having up to 4 members in the chain.

These compounds are described as glutamate receptor antagonists having a psychotropic and anti-ischemic effect,

DE 199 02 082 describes imidazo [1,5-a] pyrido [3,2-e] pyrazinones of the formula

which are inhibitors of PDE 5. For those compounds which are in each case unsubstituted in position 5, protection is required for use as therapeutic agents for the treatment of erectile dysfunction. According to patent application DE 199 61 302, some of these compounds are dual inhibitors of PDE 3 and PDE 5. These compounds also require protection for use as therapeutic agents in various cardiac and circulatory disorders.

In patent DE 195 10 965 pyrido [3,2-e] pyrazinones the protection of compounds of formula

They also include imidazo [1,5-a] pyrido [3,2-e] pyrazinones. The anti-asthmatic and anti-allergic properties of the group of substances for which protection is sought are described.

SUMMARY OF THE INVENTION The invention relates to pyrido [3,2-e] pyrazinones of formula 1

where R ¹ , R ² , R ⁴ may be identical or different and are -C 1-4 alkyl groups which may be branched or straight chain, and

R ³ is -CH ₂ -A.

And it could be in this case

- cyclohexyl group,

- mono- or bicyclic aromatic hydrocarbons having 6 to 10 carbon atoms which may be mono or poly-substituted with -F, -Cl, -Br, -NO ₂ , -OH, -OCH ₃ , or -CN, or mono- or bicyclic heteroaromatic hydrocarbons having 3 to 10 carbon atoms and 1 to 4 heteroatoms, preferably N, S or 0, which may be mono- or polysubstituted by -F, -Cl, -Br, -NO ₂ , -OH , -OCH3, or-CN.

It is an essential part of the invention that the compounds of formula 1 have a nitrogen atom at position 9 as a basic structural prerequisite for use according to the invention as a therapeutic agent for the treatment of erectile dysfunction.

The invention also relates to the physiologically tolerated salts of the compounds of formula 1, which may be prepared by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with organic or inorganic bases or by quaternizing the tertiary amines to preparation of quaternary ammonium salts.

The compounds of formula I according to the invention are known per se by patent DE 195 10 965, which has already been referred to as prior art literature. It characterizes pyrido [3,2-e] pyrazonones as dual inhibitors of PDE 4 and PDE 5, justifying their use as anti-asthmatic and / or anti-allergic agents.

Those compounds of the formula I according to the invention in which A is a cyclohexyl group and R _{1 (} R ₂ and R ₃ have the meaning described are new).

The compounds of the formula I according to the invention are characterized in that their inhibitory effect on PDE 5 is highly emphasized. The essence of this invention is that the compounds of the formula I according to the invention are extremely suitable for use in the treatment of erectile dysfunction, given this principle of action.

A characteristic advantage of the compounds of the invention is that they affect the level of cGMP in human tissues, but not the level of cAMP, at high selectivity. This has been proven for both human heart and penis tissue. When using this selectivity, the risk of cardiovascular side effects can be minimized. With respect to cGMP selectivity, the compounds of the invention exceed the standard therapeutic sildenafil.

The compounds of formula I according to the invention can be administered either systemically, for example, intravenously, intramuscularly, subcutaneously or orally, orally or sublingually. Topical administration, for example by inhalation or intranasal route, is also possible.

Oral administration of 5-200 mg of the compound prior to sexual intercourse is the preferred treatment regimen.

Drugs containing one or more of the compounds of formula I according to the invention, in addition to conventional physiologically acceptable vehicles and / or diluents or excipients, and methods for preparing these drugs are also part of the present invention.

The compounds of formula I according to the invention and the drugs containing the compounds of formula 1 according to the invention can be used both individually and in combination with others.

The invention also provides that the compounds of the invention can be used as veterinary therapeutic agents for the prevention and treatment of erectile dysfunction in male mammals. The dose, route of administration and pharmaceutical dosage form of the compound are selected taking into account the interspecies differences and the needs of veterinary practice.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

The following compounds of formula I, which can be used according to the invention, as active compounds for the treatment of erectile dysfunction, are exemplified:

_R 3

R ⁴ X

She's a yinny -R ¹ -R ² -R ³ R '· Melting point 1 -with ₂ n ₅ -CH3 -CH ₂ SbHz -CH3 136-138 (ethanol) 2 -with ₂ n ₅ -CH3 -CH ₂ -C ₆ H ₅ -CH3 166-167 (acetone) 3 -C ₂ H ₅ -CH3 -sw ₂ -s _s n ₅ -CH3 162-163 (acetone) 4 -C ₂ H ₅ -CH3 -sn ₂ -s ₆ n ₅ -CH3 159-161 (acetone) 5 -C ₂ H ₅ -CH3 -CH ₂ -C ₆ H ₄ (2-F) -CH3 186-187 (ethanol) 6 -C ₂ H ₅ -CH3 -CH ₂ -C ₆ H ₄ (2-CI) -CH3 245-246 (DMF) 7 -C ₂ H ₅ -CH3 -CH ₂ -C ₆ H ₄ (4OCH3) -CH3 156-158 (ethanol) 8 -C ₂ Nb -CH3 -CH ₂ -C ₆ H ₄ (4-F) -CH3 189-191 (DMF) 9 -C ₂ H ₅ -CH3 -CH ₂ -C ₆ H ₄ (2-C1) -CH3 201-202 (DMF) 10 -with ₂ n ₅ -CH3 -CH ₂ -C ₆ H ₄ (2,6-diCI) -CH3 209-212 (toluene) 11 -C ₂ H ₅ -CH3 -CH ₂ -C ₆ H ₄ (2-C1, 6-F) -CH3 197-200 (acetone) 12 -with ₂ n ₅ -CH3 -CH ₂ -C ₆ H ₄ (2,6-di-F) -CH3 177-180 (acetone)

13 -with ₂ n ₅ -CH ₃ -CH ₂ -C ₆ H ₄ (2,3,6tri-F) -CH3 183-185 (acetone) 14 -with ₂ n ₇ -CH ₃ -CH ₂ -C _b H ₄ (2-C1,6 -F) -CH3 159-162 (acetone) 15 -C ₂ H ₇ -CH3 -CH ₂ -C ₆ H ₄ (2,6-cli- F) -CH3 171-172 (acetone) 16 -C ₂ H ₇ -CH3 -CH ₂ -C ₆ H ₄ (2,3,6-tri-F) -CH3 197-199 (acetone) 17 -with ₂ n ₅ -CH3 -CH3 188-190 (ethanol) 18 -C ₂ H ₅ -CH3 -CH3 198-200 (ethanol) 19 -C ₂ H ₅ -CH3 -CH3 237-240 dec. (DMF) 20 -C ₂ H5 -CH3 -CH3 254-256 (ethanol)

The compounds of the invention are potent phosphodiesterase 5 inhibitors. Their therapeutic potential is confirmed in vitro, for example, by enhancing the action of NO on the intracellular levels of cGMP in rat fibroblasts, the selectivity of action on human cAMP and cGMP levels. and the relaxation of the cave body in humans.

Inhibition of phosphodiesterase 5

PDE 5 activity is determined in human platelet enzyme preparations. Human blood is treated with citrate to prevent coagulation. Upon centrifugation of 700 x g for 20 minutes at room temperature, plasma saturated with platelets was separated from erythrocytes and leukocytes. Platelets are lysed by ultrasound and used in the PDE 5 assay.

Phosphodiesterase activity is determined by some modifications according to the method described by Thompson et al. (Thompson, WJ; Appleman, MM, Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv. Cycl. Nucl. Res. 1979 , 10, 69-92).

The reaction mixtures contained 50 mM Tris HCl (pH 7.4), 5 mM MgCI ₂ , the inhibitors at actual concentrations, the enzyme preparation and the following ingredients required for the determination of individual PDE 5 (see below). The reaction C was initiated by the addition of the substrate 0.5 μ ₃ [ ₃ H] -cGMP (approximately 6000 CPM / test). The final volume is 100 ml. The test substances are prepared as stock solutions in DMSO. The concentration of DMSO in the reaction mixture is 1% v / v. At this concentration of DMSO, the activity of PDE 5 is not affected. After initiation of the reaction by the addition of substrate, the samples are incubated at 37 ° C for 30 minutes. The reaction was stopped by heating the test tube to 110 ° C for 2 minutes. Samples remain in ice for another 10 minutes. After the addition of 30 μΙ 5'-nucleotidase (1 mg / ml, from a suspension of snake venom from Crotalus adamanteus), the incubation proceeded at 37 ° C for 10 minutes. Samples were fixed on ice, 400 μΙ Dowex / water / ethanol (1 + 1 + 1) were added and the samples were well stirred and incubated on ice again for 15 minutes. The reaction vessels were centrifuged at 3,000 x g for 20 minutes. 200 μΙ aliquots of the supernatant were transferred directly to scintillation vessels. After the addition of 3 ml of scintillator, the samples were measured in

beta counter. Non-specific enzyme activities in each case were determined in the presence of 100 μΜ ΙΒΜΧ at the time of PDE 5 determination and subtracted from the test values.

For the compounds of the invention, IC ₅₀ values in the range of 10 ' ⁹ to 10' ⁶ M are determined with a view to inhibiting phosphodiesterase 5. For example, the following values are determined for the selected working examples:

An example 1C ₅₀ [μηίοΙ / Ι] 1 0.025 2 .203 5 0,059 7 0.104 8 0.126 9 0,112 10 0,132 11 0.019 12 0,038 13 0.016 14 0.008 15 0.002 16 0,005

Induction of NO production in fibroblasts (in rat)

Rat embryonic fibroblast cells (RFL-6) represent a suitable medium for investigating the effect of NO on the intracellular levels of cGMP (Ishii et al., 1991). The underlying mechanism can also be applied to the smooth muscle of the cavernous blood vessels.

The compounds of the invention potentiate cGMP levels induced by the NO donor 5-nitroso-N-acetyl-O, 1-penicillamine in a concentration-dependent manner.

Therefore, compound 13, for example, at a concentration of 0.10 pmol / l significantly induces an increase in cGMP levels. The efficacy of compound 13 in this case is 1,000 times greater than that achieved with the use of the non-specific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX).

Effect of cAMP and cGMP levels in human tissues

The selectivity of the influence on the cGMP level when compared to the cAMP level by a PDE 5 inhibitor gives an indication of possible side effects of the substances, in particular with regard to the cardiovascular system, sections of the human atrium and the cavernous body of the human being incubated 10 minutes with test compounds at a concentration of 1.0 pmol / l. The preparations were frozen using liquid nitrogen and the resulting levels of cyclic nucleotides were determined.

In both tissue types, the compounds of the invention selectively affect the level of cGMP. For example, the cGMP level is increased by 247% in the atrial tissue of the compound 11 compound, but the cAMP level is only 11%. In human cave tissue, the cGMP level is increased by 214% of compound 11, but the cAMP level is only 80%.

The compounds of the invention are better in view of this selectivity with respect to standard therapeutic sildenafil. In human atrial tissue, the cGMP level is increased by 147% of sildenafil and the cAMP level is simultaneously increased by 240%. In human cave tissue, the cGMP level is increased by only 15% of sildenafil, but the cAMP level is increased by 238%.

Relaxation of a man cave body in vitro

Cave sections of a human body are pre-contracted into an organ bath using norepinephrine. For test compounds, relaxation activity is defined as a function of concentration.

As a function of concentration, the compounds of the invention have a relaxing effect on sections of the cave body pre-contracted using norepinephrine. Therefore, for compound 13, for example, an EC ₅ o value of 0.15 μίτιοΙ / Ι is determined.

t

1. Imidazo [1,5-a] pyrido [3,2-e] -pyrazinones of formula 1

Claims (10)

where R ¹ , R ² , R ⁴ may be identical or different and are -Cl. _4- alkyl groups which may be branched or straight chain, and R ³ is -CH ₂ -A and A is a cyclohexyl group. 2. Use of imidazo [1,5-a] pyrido [3,2-e] -pyrw azinones of formula 1 R ⁴ _X where R ¹ , R ² , R ⁴ may be identical or different and are -C 1-4 alkyl groups which may be branched or straight chain, and R ³ is -CH ₂ -A where Ah - cyclohexyl group, - mono- or bicyclic aromatic hydrocarbons having from 6 to 10 carbon atoms, which may be monoyl substituted with -F, -Cl, -Br, -NO ₂ , -OH, -OCH ₃ , -CH ₃ or -CN, or - mono- or bicyclic heteroaromatic hydrocarbons having from 3 to 10 carbon atoms and from 1 to 4 heteroatoms, preferably N, S or O, - which may be mono- or polysubstituted by -F, -Cl, -Br, -NO ₂ , -OH, -OCH ₃ , or -CN, as therapeutically active compounds for the preparation of drugs for the treatment of erectile dysfunction (impotence ). Use of physiologically tolerable salts of the compounds of formula I according to claim 2, characterized by neutralizing the bases with inorganic or organic acids or neutralizing the acids with inorganic or organic bases or quaternizing the tertiary amines to quaternary ammonium salts, such as quaternary ammonium salts compounds for the preparation of drugs for the treatment of erectile dysfunction (impotence). Compounds of formula 1 according to claims 1 to 3, in particular one of the following compounds: 5-cyclohexyl-1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-8-ethoxy-1-ethyl-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-8-ethoxy-1,3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-5- (2-fluorobenzyl) -8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2-chlorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-5- (4-methoxybenzyl) -3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-5- (4-fluorobenzyl) -8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (4-chlorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2,6-chlorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2-chloro-6-fluorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2,6-difluorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (2,3,6-trifluorobenzyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2-chloro-6-fluorobenzyl) -8-methoxy-3-methyl-1-propylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 5- (2,6-difluorobenzyl) -8-methoxy-3-methyl-1-propylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 8-methoxy-3-methyl-1-propyl-5- (2,3,6, -trifluorobenzyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- [3,5-d and methyl isoxazol-4-yl) methyl] -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (4-pyridylmethyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (4-pyridylmethyl) imidazo- [1,5-a] pyrido [3,2-e] -pyrazinone hydrochloride; 5- [2,6-dichloropyrid-4-yl) -methyl] -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; Medicaments containing one or more compounds according to claims 1 to 4, in addition to conventional physiologically acceptable vehicles and / or diluents or inert diluents. A method for the preparation of a medicament according to claim 5, characterized in that one or more compounds according to claims 1 to 4 are treated to give pharmaceutical compositions or to be presented in a form suitable for therapeutic use using conventional pharmaceutical vehicles and / or diluents or excipients. Use of compounds of general formula I according to claims 1 to 4 and / or pharmaceutical compositions according to claims 5 and 6, alone or in combination with each other or in combination with vehicles and / or diluents or excipients . Use of compounds according to claims 1 to 4 as therapeutically active compounds for the preparation of medicaments for the treatment of erectile dysfunction (impotence) according to claim 5, especially preferably by oral, parenteral, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal or sublingual administration. Use of compounds according to claims 1 to 4 as veterinary therapeutic agents for the prevention and treatment of erectile dysfunction in male mammals. 1. Imidazo [1,5-a] pyrido [3,2-e] -pyrazinones of formula 1 Patent Claims R 3 where R ¹ , R ² , R ⁴ may be identical or different and are -C 1-4 alkyl groups which may be branched or straight chain, and R ³ is -CH ₂ -A and A is a cyclohexyl group. 2. Use of imidazo [1,5-a] pyrido [3,2-e] -pyrazinones of formula 1 R3 A substitution page where R ¹ , R ² , R ⁴ may be identical or different and are -C 1-4 alkyl groups which may be branched or straight chain, and R ³ is -CH ₂ -A where And it is - cyclohexyl group, - mono- or bicyclic aromatic hydrocarbons having from 6 to 10 carbon atoms which may be mono- or polysubstituted by -F, -Cl, -Br, -NO ₂ , -OH, -OCH ₃ , -CH ₃ or - CN, or - mono- or bicyclic heteroaromatic hydrocarbons having from 3 to 10 carbon atoms and from 1 to 4 heteroatoms, preferably N, S or 0, - which may be mono- or polysubstituted by -F, -Cl, -Br, -NO ₂ , -OH, -OCH ₃ , CH ₃ or -CN, as therapeutically active compounds for the preparation of medicaments for the treatment of erectile dysfunction (impotence). Use of physiologically tolerable salts of the compounds of formula I according to claim 2, characterized by neutralizing the bases with inorganic or organic acids or neutralizing the acids with inorganic or organic bases or quaternizing the tertiary amines to quaternary ammonium salts, such as quaternary ammonium salts compounds for the preparation of drugs for the treatment of erectile dysfunction (impotence). Replacement Page Use according to claim 2 or 3, characterized in that the compounds of formula 1 are selected from one of the following compounds: 5-cyclohexyl-1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-8-ethoxy-1-ethyl-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5-benzyl-8-ethoxy-1,3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-5- (2-fluorobenzyl) -8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2-chlorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-5- (4-methoxybenzyl) -3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-5- (4-fluorobenzyl) -8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (4-chlorobenzyl) -1-ethyl 1,8-methoxy-3-methyl and metho azo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2,6-chlorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2-chloro-6-fluorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2,6-difluorobenzyl) -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (2,3,6-trifluorobenzyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; Replacement Page 5- (2-chloro-6-fluorobenzyl) -8-methoxy-3-methyl-1-propylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- (2,6-difluorobenzyl) -8-methoxy-3-methyl-1-propylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 8-methoxy-3-methyl-1-propyl-5- (2,3,6, -trifluorobenzyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5- [3,5-dimethylisoxazol-4-yl) methyl] -1-ethyl-8-methoxy-3methylimidazo [1,5-a] pyrido [3,2-e] pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (4-pyridylmethyl) -imidazo [1,5-a] pyrido [3,2-e] -pyrazinone; 1-ethyl-8-methoxy-3-methyl-5- (4-pyridylmethyl) imidazo [1,5-a] pyrido [3,2-e] pyrazinone; 5 - [(2,6-dichloropyrid-4-yl) -methyl] -1-ethyl-8-methoxy-3-methylimidazo [1,5-a] pyrido [3,2-e] -pyrazinone; Medicaments containing one or more compounds according to claim 1, in addition to conventional physiologically acceptable vehicles and / or diluents or inert vehicles. A method for the preparation of a medicament according to claim 5, characterized in that one or more compounds according to claim 1 are subjected to processing, whereby pharmaceutical compositions are obtained or are presented in a form suitable for therapeutic use in use of conventional pharmaceutical vehicles and / or diluents or excipients. Use of compounds of general formula I according to claims 1 and / or pharmaceutical compositions according to claims 5 and 6, alone or in combination with Replacement page other or in combination with vehicles and / or diluents or excipients. Use of compounds according to any of claims 2 to 4 as therapeutically active compounds for oral, parenteral, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal or sublingual administration. Use of compounds according to any one of claims 2 to 4, 8 as a veterinary drug With therapeutic agents for the prevention and treatment of erectile dysfunction in male mammals. Use of compounds according to any one of claims 2 to 4, 8 or 9, for selectively influencing cGMP levels in the face of treatment for erectile dysfunction.