Method of synthesizing pyrazole-/4,3-d/ pyrimidinone-7 derivatives

The present invention relates to a process for the production of new pyrazolo [4,3d] pyrimidonone-7 derivatives which are potent and selective 3 ', 5'-cyclic guanosine monophosphate (cGMP PDE) phosphodiesterase inhibitors, applicable in many areas of therapy, including the treatment of various cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.

The compounds of the present invention show the selectivity of inhibiting cGMP PDE instead of 3 ', 5'-cyclic adenosine monophosphate phosphodiesterase (cAMP PDE) and, as a result of this selective PDE inhibition, there are elevated levels of cGMP, which in turn may increase the beneficial anti-sticking activity blood, against vasoconstriction and vasodilation, as well as enhancing the effects of endothelial-derived relaxation factor (EDRF) and nitro vasodilating factors. Thus, these compounds are applicable to the treatment of many disorders, including persistent unstable and variant (Prinzmetal) angina pectoris, hypertension, congestive heart failure, atherosclerosis, conditions of decreased patency of blood vessels, e.g. in coronary artery disease through intact skin (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, allergic rhinitis and glaucoma.

European Patent Application EP-A-0 201 188 discloses certain pyrazolo [4,3-d] pyrimidinones-7 as adenosine receptor antagonists and PDE inhibitors useful in the treatment of cardiovascular disorders such as heart failure or heart failure. However, these compounds are neither particularly potent PDE inhibitors nor have they been found to be selective cGMP PDE inhibitors.

The compounds of the present invention have formula 1 in which R¹ is hydrogen, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl, r2 is hydrogen, C1-C6 alkyl optionally substituted with OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl, R³ means C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 perfluoroalkyl or R⁴ taken together with the nitrogen atom to which it is attached, it forms a pyrrolidinyl, piperidine, morpholine group or a group of 4- (R&) piperazinyl, distinguishes hydrogen, C1-C4 alkyl, C1-C3 alkoxy, group of formula NR⁷R⁸, R⁶ is hydrogen, C1-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, group of formula (r7r⁸N) C2-C6 alki1, (R7r⁸NCO) C1-C6; alkyl, CONR^sr8 CSNR⁷R^s or C (NH) NR⁷R⁸, R7 and R8 are each independently hydrogen, C1-C4 alkyl, (C1-C3 alkoxy) C2-C4 alkyl or hydroxy C2-C4 alkyl and may be in the form of pharmacologically acceptable salts.

In the above definitions, unless otherwise stated, alkyl or perfluoroalkyl groups having three or more carbon atoms may have a straight or branched chain. In addition, alkenyl or alkynyl groups having four or more carbon atoms, or alkoxy groups having three carbon atoms may be straight or branched.

The compounds of formula I may contain one or several centimeters of asymmetry, and therefore they may exist as enantiomers or diastereomers. The process of the invention includes both the preparation of mixtures and individual individual isomers.

Compounds of formula I may also exist in tautomeric forms and the invention includes the preparation of both mixtures and separate, individual tautomers.

The pharmacologically acceptable salts of the compounds of formula I which contain a basic center are acid addition salts formed with pharmacologically acceptable acids. Examples include the hydrochloride, hydrobromic, sulfate or bisulfate, phosphate or phosphate, acetate, citrate, fumarate, gluconate, amber and tartrate salts. Compounds of formula I may also give pharmacologically acceptable metal salts, especially alkali metal salts, with bases. Examples include sodium and potassium salts.

A preferred group of compounds of formula 1 are those in which R 1 is a hydrogen atom, a methyl or ethyl group, r 2 is a C 1 -C 3 alkyl group optionally substituted with an oH or methoxy group, r 3 is a C 2 -C 3 alkyl or allyl group, r 4 taken together with the atom the nitrogen to which it is attached completes the piperidine or 4-N- group (R⁶) piperazinyl, R⁵ is hydrogen, a group of formula NR^rR⁸ or COnR7r8, r6 is hydrogen, C1-C3 alkyl or hydroxy C2-C3 alkyl, group of formula CONR⁷r8, CSNRkIuó C (NH) NR7r8, and each of R7 and R⁸ is independently hydrogen or methyl.

A particularly preferred group of compounds of formula 1 are those in which R1 is a methyl group, R2 is allyl means an n-propyl group, r3 is an ethyl, n-propyl or allyl group, R4 taken together with the nitrogen atom to which it is attached, creates a group

4- N- (R6) -piperazinyl, R⁵ is hydrogen and R⁶ represents a hydrogen atom, a C 1 -C 3 alkyl or 2-hydroxyethyl group.

Particularly preferred individual compounds produced according to the invention are: 5- [2-allyloxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7, melting point 151-153 ° C, 5- [2-ethoxy5- (piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7, melting point 194 -196 ° C, 5- [2-ethoxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone- 7, melting point 187-188 ° C, 5- [2-ethoxy-5- [4- (2-propyl) piperazinylsulphonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7 mp 209-212 ° C, 5- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazinylsulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] -pyrimidinone-7, melting point 194-196 ° C, 1-methyl-5 [5-piperazinylsulfonyl] -2-n-propoxyphenyl] -3-n-propyl-1,6-dihydro-7H pyrazo [4,3-d] p-irimidinone-7, melting point 185-186 ° C, and 5- {5- [4- (2-hydroxyethyl) piperazinylsulfonyl] -2-n-propoxyphenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d ] pyrimidine-7, melting point 158-159 ° C.

166 490

The method for preparing compounds of formula 1 consists in subjecting compounds of formula 2 in which R1 R² and R³ have the meaning given above, Y is a halogen atom, preferably a chlorine atom, reaction with a compound of formula 3 in which R4 and R5 are as defined above.

This reaction is usually carried out at room temperature, preferably in the presence of a solvent, for example an alkanol containing one to three carbon atoms, using an excess of the compound of formula 3 to remove the acid by-product (HI).

Compounds of formula 2 are prepared from compounds of formula 4 in which R1 r2 and R³ have the meaning given above by using known methods to introduce the SO group₂Y, wherein Y is as defined above, to an aromatic ring, for example, if Y is a chlorine atom, by treatment with chlorosulfonic acid at or near 0 ° C.

If r3 is a group susceptible to removal under chlorosulfonylation conditions, for example allyl, then this group may be introduced in the final phase of the synthesis. Thus, phenol of formula 4 in which R³ is hydrogen, and R1 and r2 have the meanings given above which can be obtained by unblocking the 0-allyl analog possible via Pd⁰as illustrated in the example, chlorosulfonation to a compound of formula II wherein Y is chloro, r3 is hydrogen, and R1 and R2 are as defined above. The latter is then reacted with the appropriate amine of formula 3 to obtain a compound of formula 1 in which r3 is hydrogen and R1, r2, r4 and r5 are as defined above, which is finally 0-allylated to give the compound of formula 1 in which R¹, r3, r4 and R⁵ have the meanings given for formula 1. Allylation may be carried out under standard conditions using a suitable alkyl halide, for example allyl bromide, in the presence of a base such as potassium carbonate in a suitable solvent, e.g. butanone-2, at the boiling point of the reaction mixture under reflux condenser. Alternatively, the alkylation can be carried out under conventional Mitsunobu reaction conditions.

For other compounds of formula 4 that may not be compatible with the conditions of the chlorosulfonylation reaction, e.g. where R 2 is a hydroxy C 1 -C 6 alkyl group, the hydroxyl group may be protected by an acyl group such as acetyl or benzoyl. The protected group is then removed in the final synthesis step under standard alkaline hydrolysis conditions to give compounds of formula 1 in which r2 is a hydroxy C1-C6 alkyl group and R1 R '\ r4, R5 are as defined for formula 1. The latter compounds can also be obtained accidentally as by-products by chlorosulfonylation of the corresponding anologists, i.e. compounds of formula 4 in which R2 is a (C1-C3 alkoxy) C-C6 alkyl group, followed by reaction of the crude product with the appropriate amine of formula 3, which illustrated in example XVI.

Compounds of formula 4 are prepared from compounds of formula 5 in which R1 R2 and R2 are as defined above, by using known cyclization methods for the pyrimidine ring in its formation. Thus, for example, cyclization can be carried out by treating the compound of formula 5 with a base, such as sodium hydroxide or potassium carbonate, optionally in the presence of hydrogen peroxide, in an ethanol-water environment at reflux for 2-40 hours. Under these conditions, the corresponding nitrile compound of formula 6 can also be used as a precursor for the compound of formula 4 in which R1 r2 and r3 are as defined above.

In an alternative cyclization process, compounds of formula 4 can be obtained by treating a compound of formula 5 with polyphosphoric acid at or near 140 ° C for 6-18 hours.

Compounds of formula 5 and formula 6 can be obtained from compounds of formula 7 and formula 8, respectively, in which formulas R1 and R2 have the meanings given above, by reaction with a compound of formula 9 in which R³ and Y have the above meanings.

The reaction is usually carried out using an excess of the compound of formula 9 in the presence of an excess of an aliphatic tertiary amine, such as triethylamine, acting as an absorber for the acid by-product (HY), optionally in the presence of a catalyst such as

166 490 dimethylaminopyridine, in an inert solvent such as dichloromethane at 0 ° C to 25 ° C for 2-6 hours.

Amines of formula 3, aminopyrazoles of formulas 7 and 8, and acyl halides of formula 9, unless they are commercially available, are prepared by known synthetic methods according to literature regulations from readily available starting materials using known procedures, reagents and reaction conditions .

All of the above reactions are fully known and the appropriate reagents and conditions for carrying them out can be easily determined by reference to known textbooks and examples below. Alternatives and variations will also be apparent to those skilled in the art of making all compounds represented by Formula 1.

The biological activities of the compounds of the present invention were determined by the following test methods.

Phosphodiesterase activity.

The affinity of the compound for cGMP and cAMP PDE was assessed by determining their IC 50 (inhibitor concentration necessary for 50% inhibition of enzyme activity). PDE enzymes are isolated from the platelets of rabbits and kidneys of rats, in fact in a way taken from WJ Thompson et al. (Biochem., 1971, 10,311). Calcium / calmodine independent cGMPPDE (Ca / CAM) and cAMP PDE inhibited cGMP PDE enzymes were obtained from rabbit platelets, while from the four major PDE enzymes in rat kidneys, Ca / CAM dependent cGMP PDEE (fraction I) was isolated. The tests were performed using a modification of the WJ Thompson and MM Appleman bath method (Biochem., 1979, 18.5228). The results obtained from these studies show that the compounds of the invention are potent and selective inhibitors of both cGMP PDEs.

Anti-platelet activity.

It is evaluated by determining the ability of compounds to inhibit platelet activating factor (PAF) induced in vitro platelets, and to enhance the in vitro anti-platelet aggregation effect of guanylate cyclase activators such as nitroprusside and EDRF. Washed plates were prepared essentially by the method of JF Mustard et al. (Methods in Enzymol., 1989, 169.3) and agglomeration was assessed using known turbidimetric techniques described by GVR Born, J. Physiol. (Lond), 1962, 162, 67P.

Antihypertensive activity.

It was evaluated by intravenous or oral administration of compound to rats with essential hypertension. Blood pressure was recorded through a cannula implanted in the carotid artery of non-asleep or asleep animals.

For administration to humans for therapeutic or prophylactic purposes in cases of angina, hypertension or congestive heart failure, oral doses of the compounds will usually be in the range of 4-800 mg per day for the average adult patient (70 kg). Thus, for a typical adult patient, individual tablets or capsules contain from 2-400 mg of active compound in a suitable acceptable vehicle or carrier for administration in single or multiple doses, once or several times a day. Dosages for intravenous, buccal or sublingual administration will usually be in the range of 1-400 mg per single dose, as needed. In practice, the physician will determine the current dosage regimen that will be most appropriate for a single patient and will vary with age, body weight, and response from the individual patient. The above dosages are exemplary of the average case, but there may be individual circumstances in which dosing may deviate from the limits given.

For human use, the compounds of Formula 1 may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally, buccal or sublingually, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. These compounds can also be injected parenterally, for example intravenously,

16 (6490 intramuscularly, subcutaneously or intrathecally. For parenteral administration, they are best used in the form of sterile aqueous solutions that may contain other substances, for example, enough salt or glucose to make the solution isotonic with blood.

Thus, the pharmaceutical composition contains a compound of formula I or a pharmacologically acceptable salt thereof and is intended for use in medicine, especially for the treatment of angina, hypertension or congestive heart failure in humans.

The compound of formula 1 is used for the preparation of medicaments for the treatment of permanent, unstable and variant (Prinzmetal) angina pectoris, hypertension, congestive vascular disease, chronic angina, bronchitis, allergic asthma, allergic rhinitis and glaucoma.

The preparation of compounds of the invention will now be illustrated in more detail by reference to the following experimental examples. Compound purity was routinely monitored by thin layer chromatography (TLC) using Merck Kieselgel 60 F 254 plates. Nuclear magnetic resonance spectra were recorded using a Nicolet GE-300 spectrometer and in all cases consistent with the proposed structure.

Example I. 5- [2-Ethoxy -5- (4-carbamoylpiperidinylsulfonyl) phenyl] -1-methyl3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinon-7.

4-Carbamoylpiperidine (703 mg, 5.50 mmol) was added to the mixed suspension of 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4, 3-d] pyrimidine on-7 (750 mg, 1.80 mmol) in ethanol (50 mL) at room temperature. The resulting mixture was stirred for 4 days before removing the solvent by evaporation in vacuo. The residue was dissolved in a 9: 1 mixture of dichloromethane and methanol (100 mL) and the solution was washed with saturated aqueous sodium carbonate solution (100 mL). The aqueous phase was extracted further with dichloromethane-methanol mixtures (3 x 100 mL) and all organic fractions were combined, dried (MgSO4) and evaporated in vacuo to give a solid. Crystallization from a methanol-dimethylformamide mixture gave the title sulfonamide as a cream solid (446 mg, 49%), mp 274-276 ° C.

Found: C 55.36; H, 6.01; N 16.65.

Calcd for C 23 H 29 N 6 O: C 55.08; H 5.83; N 16.75%.

Examples II-VII The following compounds of formula 10 listed in Table 1 were prepared as in Example 1 using the appropriate amine. In formulas 10,14 and 15 appearing in table 1 the abbreviation Me means methyl group, and in formula 16 also appearing in table 1 the abbreviation Pr means propyl group.

Table 1

<td rowspan="2">Number example</td><td rowspan="2">Formula 11</td><td rowspan="2">% performance</td><td rowspan="2">Temperature m.p.</td><td colspan="3">Analysis% (theoretical values ​​in parentheses)</td>

<td>C</td><td>H</td><td>N</td>

<td>II</td><td>formula 12</td><td> 51</td><td> 161-162</td><td> 54,82</td><td> 6,13</td><td> 17,95</td>

<td></td><td></td><td></td><td></td><td> (54,77</td><td> 6,13</td><td> 18,25)</td>

<td>III</td><td>formula 13</td><td> 79</td><td> 194-196</td><td> 54,63</td><td> 6,47</td><td> 16,50</td>

<td></td><td></td><td></td><td></td><td> (54,75</td><td> 6,39</td><td> 16,65)</td>

<td>IV</td><td>formula 14</td><td> 88</td><td> 187-189</td><td> 55,61</td><td> 6,23</td><td> 17,74</td>

<td></td><td></td><td></td><td></td><td> (55,68</td><td> 6,37</td><td> 17,71)</td>

<td>V</td><td>formula 15</td><td> 21</td><td> 187-188</td><td> 57,48</td><td> 6,74</td><td> 16,47</td>

<td></td><td></td><td></td><td></td><td> (57,35</td><td> 6,82</td><td> 16,72)</td>

<td>VI</td><td>formula 16</td><td> 74</td><td> 209-212</td><td> 57,64</td><td> 6,66</td><td> 16,81)</td>

<td></td><td></td><td></td><td></td><td> (57,35</td><td> 6,82</td><td> 16,72)</td>

<td>VII</td><td>model 17</td><td> 18</td><td> 229-230</td><td> 51,25</td><td> 5,56</td><td> 18,92</td>

<td></td><td></td><td></td><td></td><td> (50,85</td><td> 5,63</td><td> 18,87)</td>

166 490

Example VIII. 5- {2-Ethoxy-5- [4- (methylamidino) piperazinylsulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-nuhydride 7.

5- {2-Ethoxy-5- [4-methylthioimidoyl) piperazinylsulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 (0, 5 g, 0.75 mmol) was added to a 33% solution of methylamine in ethanol (20 mL) and the mixture was stirred 18 hours at room temperature. The solution was evaporated in vacuo and the residue was triturated with ether. Chromatography of the obtained solid on silica gel (10 g) using methanol in dichloromethane with an elution gradient (0-4%) followed by trituration of the crude product with ether gave a light brown powder. Crystallization from ethyl acetate - methanol gave the title compound as colorless crystals (112 mg, 23%), melting point 253-255 ° C

Found: C 42.90; H, 5.09; N, 17.41

Calculated for C 23 H 32 N 8 O 4 S; HJ C 42.86; H 5.16; N 17.39%

Example IX. 1-Methyl-5- [5- (piperazinylsulfonyl) -2-n-propoxyphenyl] -3-n-propyl-1,6 dihydro-7H-pyrazolo [4,3-d] pyrimidinon-7.

This sunfonamide was obtained from piperazine and 5- (5-chlorosulfonyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 and using further the procedure of Example 1, a white solid (70%) was obtained, melting point 185-186 ° C.

Found: C 56.17 H 6.38; N 17.65.

Calcd for C22H30N6O4S: C 55.67; H, 6.37; N 17.71%

Example X. 5- {5- [4- (2-Hydroxyethyl) piperazinylsulfonyl] -2-n-propoxyphenyl} -1-methyl-3-n-propyl-1,6-dihydro-YH-pyrazoI [4, 3-d] piry mids non-7.

This sunfonamide was obtained from N-2-hydroxyethyl) piperazine and 5- (5-chlorosulfonyl) -2-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidinone-7 and using the further procedure of Example 1, the product being obtained as colorless needles (66%), melting point 158-159 ° C.

Found: C 55.83; H, 6.58; N, 16.13.

Calculated for C24H34N6O5S: C 55.58; H, 6.61; N 16.20%.

Example XI. 5- (2-AIliloksy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7.

Allyl bromide (0.02 m1, 0.00023 mol) was added to the mixed suspension of 5- [2 [hydroxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H - pyrazolo [4.3d] pyrimidinone-7 (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and this mixture was heated at reflux for 8 hours. condenser. After cooling, the reaction mixture was evaporated in vacuo and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3 x 20 mL), the combined extracts were dried (Na2SO4) and after filtration, evaporated in vacuo to give an oil. Column chromatography on silica gel (2 g) using methanol in dichloromethane with an elution gradient (0-3%) followed by evaporation in vacuo of the appropriate fractions gave a semi-solid which was dissolved in acetone. Evaporation of the resulting solution in vacuo gave the title compound (0.011 g, 10%), melting point 151-153 ° C. Rf 0.5 (silica, dichloromethane, methanol, 95: 5), m / e 487 (m + 1).

Examples XII - XIV. The following compounds of formula 18 in which the abbreviation Me is a methyl group are summarized in table 2 obtained from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1,3-dimethyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidinone-7 and the corresponding amine, following Example 1. In formula 14 in Table 2 the abbreviation Me means methyl.

166 490

Table 2

<td rowspan="2">Number example</td><td rowspan="2">Formula 11</td><td rowspan="2">% performance</td><td rowspan="2">Temperature m.p.</td><td colspan="3">Analysis% (theoretical values ​​in parentheses)</td>

<td>C</td><td>H</td><td>N</td>

<td>XII</td><td>formula 14</td><td> 68</td><td> 225-226</td><td> 53,88</td><td> 5,81</td><td> 18,42</td>

<td></td><td></td><td></td><td></td><td> (53,79</td><td> 5,87</td><td> 18,81)</td>

<td>XIII</td><td>formula 12</td><td> 68</td><td> 240-242</td><td> 53,07</td><td> 5,77</td><td> 19,27</td>

<td></td><td></td><td></td><td></td><td> (52,76</td><td> 5,59</td><td> 19,43)</td>

<td>XIV</td><td>formula 13</td><td> 62</td><td> 228-229</td><td> 53,23</td><td> 5,87</td><td> 17,72</td>

<td></td><td></td><td></td><td></td><td> (52,93</td><td> 5,92</td><td> 17,63)</td>

Example XV 5- [2-Ethoxy-5- (4-methylpiperazinylsulfonyl) phenyl] -3-n-propylo1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7.

The title compound was prepared from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 according to the procedure of Example I to obtain as a white solid (70%), melting point 236-239 ° C.

Found: C 54.84; H, 6.27; N18,10.

Calcd for C21H28N6O4S: C 54.76; H, 6.13; N 18.25%.

Example XVI. 3-Methoxymethyl-1-methyl-5- [5- (4-methylpiperazinylsulfonyl) -2-ethoxyphenyl] -1,6-dihydro-7H-pyrazolo [4,3-d] 7-one.

5- (2-Ethoxyphenyl) -3-methoxymethyl-1-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 (470 mg, 1.50 mmol) was dissolved in chlorosulfonic acid ( 3 ml) at 0 ° C. The solution was stirred 2 hours at room temperature, then carefully added to ice-water (50 mL). The resulting solution was neutralized with saturated sodium carbonate solution, then extracted with a 20: 1 mixture of dichloromethane and methanol (2 x 50 mL). The combined organic extracts were evaporated in vacuo and the residue dissolved in ethanol (55 ml) and the solution treated with N-methylpiperazine (450 mg, 4.5 mmol). After 1 hour at room temperature, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of dichloromethane, methanol and aqueous ammonium hydroxide (90: 10: 1 by volume). A solution of the crude product with ethyl acetate gave the title compound as a white solid (49 mg, 7%), melting point 198-199 ° C.

Found: C 52.94; H, 6.04; N 17.67.

Calcd for C21H28N6O5S: C 52.93; H 5.92; N 17.64%.

Also isolated following chromatography and crystallization from a mixture of ethyl acetate and methanol 3-hydroxymethyl-1-methyl-5- [5- (4-methylpiperazinylsulfonyl) -2-ethoxyphenyl] -1,6-dihydro-7H-pyrazolo [4.3 -d] pyrimidinone-7 as a white solid (51 mg, 7%), melting point 209-210 ° C.

Found: C 51.94; H 5.77; N, 18.05.

Calcd for C20H26N6O5S: C 51.94; H 5.67; N 18.17%

Example XVII. 5- (2-Ethoxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7.

The title sulfonamide was prepared from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-ethyl-3-npropyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 and N-methylpiperazine according to the procedure for Example 1 and the product was obtained as a colorless solid (43%), m.p. 160-162 ° C.

Found: C 57.24; H, 6.17; N 16.83.

Calcd for C23H32N6O4S: C 56.54; H 6.60; N, 17.20%.

Rf 0.35 (silica, dichloromethane, methanol, 9: 1).

Example XVIII. 5- {2-Ethoxy-5- [4- (2- (2-hydroxyethyl) piperazinylsulfonyl] phenyl} -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7.

166 490

The title sulfonamide was prepared from 5- (chlorosulfonyl-2-ethoxyphenyl) -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidinone-7 and N- (2-hydroxyethyl) ) piperazine according to the procedure of Example 1 and was obtained as a colorless solid (88%), m.p. 191-193 ° C.

Found: C 55.74; H, 6.55; N, 15.78.

Calculated for C24H 34N 60 5S: C 55.58; H, 6.61; N 16.20%

<img file="PL166490B1_D0001.tif" />

Formula 1

<img file="PL166490B1_D0002.tif" />

<img file="PL166490B1_D0003.tif" />

Formula 3

166 490

<img file="PL166490B1_D0004.tif" />

<img file="PL166490B1_D0005.tif" />

<img file="PL166490B1_D0006.tif" />

OR³

<img file="PL166490B1_D0007.tif" />

<img file="PL166490B1_D0008.tif" />

Formula 10

166 490 NJ⁶ ñjvih °^H

Formula 11 Formula 12 Formula 13 tCjJMe f t ^ y-NMe₂ γ ^ ~ Ν * Pr

Pattern 14 Pattern 15 Pattern 16 n ~ ncsnh₂

<img file="PL166490B1_D0009.tif" />

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