Compounds and pharmaceutical compositions containing the same

The present invention relates to novel compounds and pharmaceutical compositions containing the same. The disclosed compounds are useful for treatment of inter alia erectile dysfunction. They are comprised by the general formula (I); ##STR1##

FIELD OF THE INVENTION
 The present invention relates to novel compounds, pharmaceutical
 compositions containing the same as well as a method for treatment of
 erectile dysfunction, wherein said compounds are administered.
 BACKGROUND OF THE INVENTION
 Erectile dysfunction is a disorder which is very common throughout the
 world. The recent introduction of sildenafil (the active ingredient in
 Viagra.RTM.) has improved the possibilities of treating this disorder
 significantly. Sildenafil and compounds closely related thereto are
 disclosed in EP 463 756, EP 702 555 and WO 98/49166 (all to Pfizer Ltd.).
 However, despite the useful therapeutic properties of sildenafil, not all
 patients are successfully treated with this agent. Thus, there is still a
 great need in the art for compounds having improved therapeutic properties
 compared to sildenafil.
 DISCLOSURE OF THE INVENTION
 There are now provided novel compounds with surprisingly improved
 therapeutic efficiency in comparison with the prior art cited above. In
 summary, the present invention relates to a compound having the general
 formula (I):
 ##STR2##
 wherein R.sub.0 -R.sub.6 are independently selected from at least one of a
 group of substituents (a)-(g) consisting of:
 (a) H;
 (b) straight chain, branched or cyclic saturated or unsaturated alkyl or
 hydroxyalkyl having 1-6 carbon atoms;
 (c) O-alkyl, S-alkyl or N-(alkyl), where alkyl is as defined in (b) and n
 is 1 or 2;
 (d) C(O)-alkyl, O--C(O)-alkyl, S--C(O)-alkyl or NH--C(O)-alkyl, where alkyl
 is as defined in (b);
 (e) F, Cl or Br;
 (f) O-aryl;
 (g) NR.sub.8 R.sub.9, wherein R.sub.8 and R.sub.9 independently is H or
 straight chain, branched or cyclic saturated or unsaturated alkyl,
 C(O)-alkyl, hydroxyalkyl or O-alkyl having 1-6 carbons atoms; wherein
 NR.sub.8 R.sub.9 optionally may form a five- or six-membered saturated or
 unsaturated ring;
 wherein X.sub.1 and X.sub.2 are independently selected from a group of
 radicals consisting of:
 --C.sub.m -- independently substituted with the substituents (a)-(g), where
 m is an integer from 1 to 3 and the radical --C.sub.m -- optionally may
 contain a double bond, ketone or thioketone functionality;
 --O--;
 --S--; and
 --NR.sub.10 --, where R.sub.10 is H or straight chain, branched or cyclic
 saturated or unsaturated alkyl,
 C(O)-alkyl, hydroxyalkyl or O-alkyl having 1-6 carbons atoms;
 wherein Y is selected from a group of radicals consisting of:
 --CR.sub.11.dbd.N--; --N.dbd.CR.sub.12 --; --N.dbd.N--;
 --CR.sub.13.dbd.CR.sub.14 --; --CR.sub.15 R.sub.16 CR.sub.17 R.sub.18 --;
 --CR.sub.19 R.sub.20 O--; --OCR.sub.21 R.sub.22 --; --CR.sub.22 R.sub.23
 NR.sub.24 --; --NR.sub.25 CR.sub.26 R.sub.27 -- and
 --NR.sub.28 NR.sub.29 --, where R.sub.11 -R.sub.29 are independently
 selected from the substituents (a)-(g);
 wherein z taken together with the nitrogen atom to which it is attached
 forms a group selected from pyrrolidinyl, piperidinyl, morpholinyl,
 imidazolyl, pyridinyl, pyrrolyl and 4-N-(R.sub.30)-piperazinyl, whereby
 R.sub.30 is selected from the substituents (a)-(g);
 tautomers, solvates and radiolabelled derivatives thereof; and
 pharmaceutically acceptable salts thereof.
 As examples of pharmaceutically acceptable salts mention can be made of
 acid addition salts, e.g. a salt formed by reaction with hydrohalogen
 acids, such as hydrochloric acid, sulphuric acid, phosphoric acid, nitric
 acid, aliphatic, alicyclic, aromatic or heterocyclic sulphonic or
 carboxylic acids, such as formic acid, acetic acid, propionic acid,
 succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid,
 citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid,
 p-hydroxybenzoic acid, embonic acid, methanesulphonic acid,
 ethanesulphonic acid, hydroxyethanesulphonic acid, halogenbensensulphonic
 acid, toluenesulphonic acid and naphtalenesulphonic acid.
 In a preferred embodiment of the present invention, Y is
 --CR.sub.11.dbd.N--. R.sub.11 is preferably an n-propyl group.
 Furthermore, it is preferred that Z taken together with the nitrogen atom
 to which it is attached forms a 4-N-(R.sub.30)-piperazinyl group.
 Preferably, R.sub.30 is a methyl group.
 Moreover, it is preferred that X.sub.1 is --C.sub.m --. Preferably, m is 1.
 Most preferably, X.sub.1 is --CH.sub.2 --.
 It is preferred that X.sub.2 is --O--.
 In a more preferred embodiment of the present invention, R.sub.2 is H.
 In an even more preferred embodiment, R.sub.3 is a methyl group.
 In a still even more preferred embodiment, R.sub.4, R.sub.5 and R.sub.6 are
 all H.
 In the most preferred embodiment of the present invention, said compound is
 5-[2,3-dihydro-5-(4-methylpiperazin-1-ylsulfonyl)-7-benzofuryl]-1-methyl-3
 -propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one, the structure of
 which is depicted hereinbelow. This compound is hereinafter denoted 7a.
 ##STR3##
 Furthermore, the present invention relates to a compound as set forth above
 for use as a pharmaceutical.
 Accordingly, the present invention also relates to a pharmaceutical
 composition comprising a compound as set forth above as active ingredient
 in association with a pharmaceutically acceptable adjuvant, diluent or
 carrier.
 The pharmaceutical composition may be adapted for oral, intravenous,
 topical, intraperitoneal, nasal, buccal, sublingual or subcutaneous
 administration or for administration via the respiratory tract in the form
 of e.g. an aerosol or an air-suspended fine powder. Thus, the composition
 may be in the form of e.g. tablets, capsules, powders, micro-particles,
 granules, syrups, suspensions, solutions, transdermal patches or
 suppositories.
 It should be noted that the composition according to the present invention
 may optionally include two or more of the above outlined compounds.
 In addition, the present invention relates to a method for treatment of
 erectile dysfunction, wherein said method comprises administering to an
 animal, including human, patient of a therapeutically effective amount of
 a compound as outlined above.
 Furthermore, it is also anticipated that the compounds according to the
 present invention have beneficial platelet anti-aggregatory,
 anti-vasospastic and vasodilatory activity. Thus, they should be useful in
 the treatment of a number of disorders, such as angina, hypertension,
 congestive heart failure, peripheral vascular disease, atherosclerosis,
 stroke, bronchitis, asthma, allergic rhinitis and glaucoma.
 The typical dosage of the compounds according to the present invention
 varies within a wide range and will depend on various factors such as the
 individual requirement of each patient and the route of administration.
 The dosage is generally within the range of 0.01-100 mg/kg body weight.
 The general synthetic pathway to formula (I) may be summarized as shown
 below (.DELTA.=heat):
 ##STR4##
 Thus, the present invention also relates to a process for the preparation
 of a compound as set forth above, wherein a compound having the general
 formula (II) is reacted with a compound having the general formula (III),
 optionally in the presence of a solvent, wherein R.sub.0 -R.sub.6 and X-Z
 are as defined above.
 ##STR5##
 The compound (II) is prepared by reacting a compound having the general
 formula (IV) with ClSO.sub.3 H, optionally in the presence of a solvent.
 ##STR6##
 The compound (IV) is prepared by heating a compound having the general
 formula (V) under basic conditions, optionally in the presence of a
 solvent.
 ##STR7##
 The compound (V) is prepared by reacting a compound having the general
 formula (VI) with a compound having the general formula (VII), optionally
 in the presence of a solvent and a base.
 ##STR8##
 As for the selection of e.g. suitable reaction and purification conditions,
 useful guidance is also provided by the following publications, which are
 incorporated herein by reference:
 DeWald, H. A., Nordin, I. C., L'Italien, Y. J., Parcell, R. F., J. Med.
 Chem., 16, 1346-1354 (1973);
 Meyers, A. I., Reuman, M., Gabel., R. A., J. Org. Chem., 46, 783-788
 (1981);
 Hogberg, T., de Paulis, T., Johansson, L., Kumar, Y., Hall,. H., Ogren, S.
 O., J. Med. Chem., 33, 2305-2309 (1990).
 By guidance of known reference literature, the synthesis of the starting
 substances (VI) and (VII) is readily accomplished by a person skilled in
 the art.
 The present invention is further illustrated by the following non-limiting
 experimental part.

PREATION OF THE COMPOUNDS OF THE PRESENT INVENTION
 Instruments used for analysis:
 The melting points (m.p.) were determined on an electrothermal Mel-Temp.
 apparatus. They are uncorrected. .sup.1 H and .sup.13 C NMR spectra were
 recorded on a Bruker-WM 400 or -DPX 300 MHz spectrometer, with
 tetramethylsilane (TMS) as internal reference. Electron impact (EI) mass
 spectra were obtained using a Finnigan 731 spectrometer at 70 eV.
 Elemental analyses were performed at the Microanalytical Laboratory of the
 Chemistry Department, Al-Najah National University, West Bank.
 EXAMPLE 1
 Preparation of Compound 4
 ##STR9##
 Compound 4 was prepared by treating 1 (0.1 mole) with SOCl.sub.2 in a
 conventional manner yielding 2, which was then refluxed with 3 in benzene
 (100 ml) and NEt.sub.3 (30 ml) for 2-3 h. The benzene was distilled off,
 and the solid product 4 was collected, washed with H.sub.2 O, dried and
 recrystallized from a suitable solvent. Yield: 82-93%.
 EXAMPLE 2
 Preparation of Compound 5
 ##STR10##
 Potassium t-butoxide (0.01 mole) was added to a stirred suspension of 4
 (0.01 mole) in t-BuOH (60 ml), and the resulting mixture was refluxed for
 8 h. Water (40 ml) was then added, after which the solution was
 neutralized with diluted HCl (aq; 4%) to pH 7 and cooled. The solid
 product 5 was collected, washed with cold H.sub.2 O and recrystallized
 from a suitable solvent. The yield was 86-95%.
 EXAMPLE 3
 Preparation of Compound 6
 ##STR11##
 Compound 5 (0.006 mole) was added in portions to chlorosulfonic acid (4 ml)
 cooled to 0.degree. C. under stirring. The temperature of the reaction
 mixture was then allowed to rise to 25.degree. C., followed by heating to
 65-70.degree. C. for 1 h. The reaction mixture was subsequently poured
 onto crushed ice (50 g), after which the precipitated solid product 6 was
 collected and used directly in the next reaction step. Yield: 82-91%.
 EXAMPLE 4
 Preparation of Compound 7
 ##STR12##
 Compound 6 (0.005 mole) dissolved in THF (20 ml) was added to a solution of
 1-methylpiperazine (2 ml) in THF (20 ml). The resulting mixture was
 stirred for 1 h at 20-25.degree. C. The THF was distilled off, and the
 residue was treated with cold H.sub.2 O. The resulting white solid product
 7 was collected, washed with H.sub.2 O, drained and recrystallized from a
 suitable solvent. Yield: 80-88%.
 By following the reaction protocol above, the compounds 7a-7l listed in
 Table 1 below were prepared.
 TABLE 1
 Compounds prepared, where X.sub.1 is as
 specified and X.sub.2 is --O-- for all the compounds.
 Compound X.sub.1
 7a CH.sub.2
 7b O
 7c S
 7d NCH.sub.3
 7e NC.sub.2 H.sub.5
 7f NCH(CH.sub.3).sub.2
 7g NC(O)CH.sub.3
 7h NC(O)NHPh
 7i NC(S)NHPh
 7j.sup.i) C.dbd.O
 7k.sup.i) C.dbd.S
 7l.sup.ii) NH
 i) The compounds 7j and 7k were obtained after protection/deprotection of a
 3-keto/thioketo group in the corresponding compounds 2j and 2k.
 ii) Compound 7l was obtained from 7g by selective hydrolysis in 15% HCl for
 20 min with heating.
 EXAMPLE 5
 Detailed Preparation and Physical Properties of 7a and its Precursors
 Preparation of
 4-(2,3-dihydro-7-benzofurylamino)-1-methyl-3-propyl-5-pyrazole-carboxamide
 (4a, i.e. 4 wherein X.sub.1 =CH.sub.2 and X.sub.2 =O):
 A mixture of 2,3-dihydrobenzofuran-7-carboxylic acid (1.5 g, 0.0091 mole)
 and SOCl.sub.2 (8 ml) was refluxed (oil bath) for 3 h. Excess of
 SOCl.sub.2 was removed in vacuo, and the residual acid chloride was
 treated with a solution of compound 1 (1.4 g, 0.0077 mole) in anhydrous
 benzene (25 ml) , followed by addition of NEt.sub.3 (3 ml). The solid
 residue was soaked in cold water (40 ml), and the remaining solid product
 was collected by suction filtration, drained, washed with water
 (2.times.20 ml) and diethyl ether (2.times.10 ml) and dried, thereby
 yielding 4a.
 Product yield=2.3 g (91%);
 M.p.=173-174.degree. C.;
 Elemental analysis=Calculated for C.sub.17 H.sub.20 N.sub.4 O.sub.3
 (MW=328.37). C 62.18, H 6.14, N 17.06%. Found C 61.95, H 6.07, N 17.11%.
 .sup.1 H NMR (CDCl.sub.3): .delta. 0.86 (t, J=7.4 Hz, 3H, CH.sub.2 CH.sub.2
 CH.sub.3), 1.56 (m, 2H, CH.sub.2 CH.sub.2 CH.sub.3), 2.46 (t, J=7.6 Hz,
 2H, CH.sub.2 CH.sub.2 CH.sub.3), 3.27 (t, J=8.5 Hz, 2H, C3'-H), 3.97 (s,
 3H, N--CH.sub.3), 4.73 (t, J=8.5 Hz, 2H, C2'-H), 6.94 (t, J=7.6 Hz, 1H,
 C5'-H), 7.34 (d, J=7.2 Hz, 1H, C4'-H), 6.26, 7.72 (2 br s, 1H each of
 CONH.sub.2), 7.86 (d, J=8.1 Hz, 1H, C6'-H), 8.88 (br s, 1H, NHCO).
 .sup.13 C NMR (CDCl.sub.3): .delta. 13.7 (CH.sub.2 CH.sub.2 CH.sub.3), 22.2
 (CH.sub.2 CH.sub.2 CH.sub.3), 27.5 (CH.sub.2 CH.sub.2 CH.sub.3), 28.9
 (C-3'), 39.1 (N--CH.sub.3), 72.8 (C-2'), 114.5 (C-3), 115.6 (C-7'), 121.4
 (C-5'), 128.0 (C-3'a), 129.35, 129.34 (C-4' and C-6'), 132.1 (C-4), 147.0
 (C-5), 157.9 (C-7'a), 161.7 (NHCO), 165.8 (CONH.sub.2).
 Preparation of
 5-(2,3-dihydro-7-benzofuryl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3
 -d]pyrimidine-7-one (5a)
 Potassium t-butoxide (0.5 g, 0.0045 mole) was added to a stirred suspension
 of compound 4a (1.1 g, 0.0034 mole) in t-butanol (20 ml), and the
 resulting mixture was heated under reflux (oil bath) for 8 h and then
 allowed to cool to room temperature. Water (14 ml) was added, after which
 the solution was neutralized with HCl (aq; 4%; 13 ml) to pH 7, cooled to
 about 5-10.degree. C., collected by suction filtration, washed with cold
 water (2.times.10 ml), crystallized from ethanol and dried, thereby
 yielding 5a.
 Product yield=1.0 g (96%);
 M.p.=176-178.degree. C. (decomposition);
 Elemental analysis=Calculated for C.sub.17 H.sub.18 N.sub.4 O.sub.2
 (MW=310.36) C 65.79, H 5.85, N 18.05%. Found C 65.72, H 5.91, N 17.93%.
 .sup.1 H NMR (CDCl.sub.3): .delta. 0.99 (t, J=7.4 Hz, 3H, CH.sub.2 CH.sub.2
 CH.sub.3), 1.82 (m, 2H, CH.sub.2 CH.sub.2 CH.sub.3), 2.86 (t, J=7.6 Hz,
 2H, CH.sub.2 CH.sub.2 CH.sub.3), 3.22 (t, J=8.1 Hz, 2H, C3'-H), 4.19 (s,
 3H, N--CH.sub.3), 4.73 (t, J=8.1 Hz, 2H, C2'-H), 6.94 (t, J=7.6 Hz, 1H,
 C5'-H), 7.22 (d, J=7.2 Hz, 1H, C4'-H), 8.16 (d, J=8.1 Hz, 1H, C6'-H),
 10.69 (br s, 1H, N6-H).
 .sup.13 C NMR (CDCl.sub.3): .delta. 14.0 (CH.sub.2 CH.sub.2 CH.sub.3), 22.2
 (CH.sub.2 CH.sub.2 CH.sub.3), 27.7 (CH.sub.2 CH.sub.2 CH.sub.3), 28.9
 (C-3'), 38.1 (N--CH.sub.3), 72.6 (C-2'), 114.5 (C-3), 121.6 (C-5'), 124.4
 (C-7'), 127.3, 127.5 (C-4' and C-6'), 128.1 (C-3'a), 138.5 (C-3a), 146.4
 (C-5), 146.7 (C-7a), 154.0 (C-7), 156.8 (C-7'a).
 Preparation of
 5-(2,3-dihydro-5-chlorosulfonyl-7-benzofuryl)-1-methyl-3-propyl-6,7-dihydr
 o-1H-pyrazolo[4,3-d]pyrimidin-7-one (6a)
 Compound 5a (0.95 g, 0.003 mole) was added in portions to chlorosulfonic
 acid (2 ml) cooled to 0.degree. C. (ice-bath) under stirring. The
 resulting yellow solution was then allowed to attain room temperature and
 was subsequently slowly heated to 65-70.degree. C. (oil bath) for 1 h. The
 reaction mixture was then slowly poured onto crushed ice (25 g), whereby a
 white solid precipitated immediately. The white solid was filtered, dried
 and recrystallized from THF/petroleum ether (b.p. 40-60.degree. C.),
 thereby yielding 6a.
 Product yield=1.04 g (84%);
 M.p.=221-222.degree. C.
 No elemental analysis was performed on 6a (C.sub.17 H.sub.17 ClN.sub.4
 O.sub.4 S; MW=408.86).
 [M].sup.+ =408/410 (3:1 ratio; Cl isotopic peaks);
 The crude product 6a (92% yield; m.p. 216-218.degree. C.) can be used
 directly in the next reaction step.
 Preparation of
 5-[2,3-dihydro-5-(4-methylpiperazin-1-ylsulfonyl)-7-benzofuryl]-1-methyl-3
 -propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (7a)
 Compound 6a (1.25 g, 0.003 mole) was dissolved in THF (10 ml) and added to
 a solution of 1-methylpiperazine (1 ml) in THF (10 ml). The resulting
 mixture was stirred at room temperature for 1 h. The THF was then removed
 in vacuo, and the residue was treated with cold water (50 ml). The
 resulting white precipitate was filtered under suction, washed with water
 (2.times.10 ml), drained and recrystallized from 90% ethanol, thereby
 yielding 7a.
 Product yield=1.2 g (83%);
 M.p.=194-195.degree. C.;
 Elemental analysis=Calculated for C.sub.22 H.sub.28 N.sub.6 O.sub.4 S
 (MW=472.57) C 55.92, H 5.97, N 17.78, S 6.79%. Found C 56.00, H 6.09, N
 17.51, S 6.73%.
 .sup.1 H NMR (CDCl.sub.3): .delta. 0.96 (t, J=7.2 Hz, 3H, CH.sub.2 CH.sub.2
 CH.sub.3), 1.79 (m, 2H, CH.sub.2 CH.sub.2 CH.sub.3), 2.20 (s, 3H,
 N4"-CH.sub.3), 2.43 (br s, 4H, C3"-H/C5"-H), 2.85 (t, J=7.2 Hz, 2H,
 CH.sub.2 CH.sub.2 CH.sub.3), 3.01 (br s, 4H, C2"-H/C6"-H), 3.32 (t, J=8.5
 Hz, 2H, C3'-H), 4.17 (s, 3H, N1-CH.sub.3), 4.89 (t, J=8.5 Hz, 2H, C2'-H),
 7.56 (s, 1H, C4'-H), 8.54 (s, 1H, C6'-H), 10.49 (br s, 1H, N6-H).
 .sup.13 C NMR (CDCl.sub.3): .delta. 13.9 (CH.sub.2 CH.sub.2 CH.sub.3), 22.1
 (CH.sub.2 CH.sub.2 CH.sub.3), 27.5 (CH.sub.2 CH.sub.2 CH.sub.3), 28.4
 (C-3'), 38.1 (N--CH.sub.3), 45.6 (N4"-CH.sub.3), 45.9 (C-3"/C-5"), 53.9
 (C-2"/C-6"), 74.0 (C-2'), 114.5 (C-3), 124.4 (C-7'), 126.2 (C-4'), 128.5
 (C-6'), 129.1 (C-5'), 130.2 (C-3'a), 138.1 (C-3a), 145.2 (C-5), 146.7
 (C-7a), 153.6 (C-7), 159.9 (C-7'a).
 Animal Experiments Involving Compound 7a
 The purpose of this study was to compare the biological activity of
 compound 7a with that of sildenafil. In particular, the respective
 ED.sub.50 -value (ED=effective dose), erection episodes and penile
 erection indices of said compounds in the treatment of male rats were
 determined. The penile erection index is an established means of
 determining the erection promoting properties of a substance (see e.g.
 Ang, H. H., Sim, M. K., Pharm. Sci., 3, 117-119 (1997) and references
 cited therein).
 In these experiments, the compounds 7a and sildenafil were administered to
 male rats orally. The doses used for both drugs were 0.0781, 0.1562,
 0.3125 and 0.625 mg/kg body weight. Sildenafil was dissolved in distilled
 water, whereas 7a was dissolved in 1% HCl solution (aq). Control animals
 were administered with the vehicles only, i.e. distilled water or the 1%
 HCl solution. During the experiments, the rats were placed in glass cages
 for observation and had access to food and water. During 2 h after
 administration of the investigated compounds, the penile erection of the
 rats was monitored. It is worth mentioning that no copulation mounting
 behaviour was observed in these experiments.
 The number of rats responding to this experiment protocol was recorded, and
 the ED.sub.50 results are shown in Table 2.
 TABLE 2
 Study of number (#) and percentage response as a function of
 dose for rats subjected to 7a and sildenafil, respectively.
 7a; Sildenafil;
 responding responding
 Dose.sup.i) # Rats rats.sup.ii) rats.sup.iii)
 (mg/kg) tested # % # %
 0.0781 10 3 30 3 30
 0.1562 10 4 40 3 30
 0.3125 10 4 40 5 50
 0.6250 10 8 80 7 70
 .sup.i) No rats responded when distilled water or 1% HCl was administered.
 .sup.ii) Calculated ED.sub.50 = 0.2473 mg/kg body weight;
 .sup.iii) Calculated ED.sub.50 = 0.2843 mg/kg body weight; where the
 ED.sub.50 values are significantly different with a 95% confidence
 interval.
 As is clear from Table 2, the ED.sub.50 value of 7a is lower than that of
 sildenafil. Thus, a lower dose of 7a as compared to sildenafil is required
 in order to elicit an erectile response.
 Furthermore, as for the intensity of the erectile response per se, the
 observed number of erection episodes and calculated penile erection
 indices substantiate that the compound 7a is superior to sildenafil,
 especially at higher doses. The total number of observed erection episodes
 and the calculated penile erection indices are depicted in FIGS. 1 and 2,
 respectively.
 Moreover, according to preliminary toxicity studies in rats, the compound
 7a is tolerated up to a dose of about 35 mg/100 kg body weight without any
 detrimental effects. The compound 7a appears to be completely non-toxic
 and free from undesirable side-effects. Thus, high doses of 7a provide a
 particularly efficient means for treatment of erectile dysfunction.
 In summary, it should be clear from the present disclosure that the
 compounds according to the present invention are versatile new
 pharmaceutically active agents for the treatment of erectile dysfunction.