HU211646A9 - Pyrazolopyrimidinone antianginal agents - Google Patents

Description

The present invention relates to a series of pyrazolo [4,3-d] pyrimidin-7-ones which are potent and selective cyclic guanosine 3 ', 5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors useful in a variety of medical applications, including various cardiovascular diseases. such as angina, hypertension, heart failure and atherosclerosis.

The compounds of the present invention exhibit greater selectivity in inhibiting cGMP PDEs than cyclic adenosine 3 ', 5'-monophosphate phosphodiesterases (cAMP PDE), and this selective PDE inhibition results in an increase in cGMP levels and is useful in thrombocytes. It exhibits anti-vasoplastic and vasodilatory effects, and enhances endothelial-derived relaxing factor (EDRF) and nitro vasodilators. Thus, the compounds are useful in the treatment of a variety of disorders, including stable and unstable and variable (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, decreased vascular occlusion, e.g. , bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma and bowel movement disorders, such as hypersensitive bowel syndrome (IBS).

European Patent Application 0 201 188 discloses certain pyrazolo [4,3-d] pyrimidin-7-ones as adenosine receptor antagonists and PDE inhibitors which are cardiovascular disorders, e.g. can be used to treat heart failure or heart failure. However, these compounds are not particularly potent PDE inhibitors, nor are they selective cGMP PDE inhibitors.

Summary of the Invention.

The compounds of the present invention and pharmaceutically acceptable salts thereof are represented by formula (I) wherein R ¹ is hydrogen, C 1-3 alkyl, C 3-5 cycloalkyl, or C 1-3 perfluoroalkyl,

R ² is hydrogen, C 1-6 alkyl optionally substituted with hydroxy, C 13 alkoxy, C 3-6 cycloalkyl, or C 1-3 perfluoroalkyl,

R ³ is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, C 1-6 perfluoroalkyl, or (C 36 cycloalkyl) -1-6 carbon atoms alkyl group,

R ⁴ together with the nitrogen atom to which it is attached may form a pyrrolidinyl, piperidino, morpholino, or 4-N- (R ⁶ ) -piperazinyl group,

R ⁵ is hydrogen, C 1-4 alkyl, C 1-3 alkoxy, NR ⁷ R ⁸ or CONR ⁷ R ⁸ .

R ⁶ is hydrogen, (C 1 -C 6) alkyl, (C 13 -alkoxy) -2 (C 6) alkyl, hydroxy (C 2 -C 6) alkyl, (R ⁷ R ⁸ N) C 2 -C 6 alkyl, ( R ⁷ R ⁸ NCO) -C 1-6 alkyl, CONR ⁷ R ⁸ , CSNR ⁷ R ⁸ or C (NH) NR ⁷ R ⁸ ,

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, C 14 alkyl, C 1 -C 3 alkoxy-C 2 -C 4 alkyl, and hydroxy C 2 -C 4 alkyl.

Unless otherwise indicated, alkyl or perfluoroalkyl groups in the above definition may contain three or more carbon atoms and may be straight or branched. In addition, C4-C4 alkenyl or alkynyl groups or C3-alkoxy groups may be straight or branched.

The compounds of formula (I) have one or more asymmetric centers and thus may exist as enantiomers or diastereomers. The invention includes both mixtures and individual isomers.

The compounds of formula (I) also exist in their tautomeric forms and the present invention also encompasses these mixtures and tautomers separately.

The invention also includes radiolabelled compounds of formula (I) for biological studies.

Pharmaceutically acceptable salts of the compounds of formula (I) with a basic center may form acid addition salts with pharmaceutically acceptable acids. These include hydrochloride, hydrobromide, sulfate or hydrogen sulfate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactal, maleate, succinate and tartrate salts. The compounds of formula I may also form pharmaceutically acceptable metal salts, in particular alkali metal salts with bases. These include the sodium and potassium salts.

A preferred group of compounds of formula I wherein R ¹ is hydrogen, methyl or ethyl; R ² is C 1 -C 3 alkyl optionally substituted with hydroxy or methoxy, R ³ is C 2 -C 3 alkyl or allyl, R ⁴ is taken together with the nitrogen to which it is attached, piperidino or 4-N- (R ⁶ ) forms a piperazinyl group; R ⁵ is hydrogen, NR ⁷ R ⁸ or CONR ⁷ R ⁸ ; R ⁶ is hydrogen, C 1-3 alkyl, hydroxy (C 2-3 alkyl), CONR ⁷ R ⁸ , CSNR ⁷ R ⁸ or C (NH) NR ⁷ R ⁸ ; and ^R7 and ^R8 are independently hydrogen or methyl.

A particularly preferred group of compounds of formula I wherein R ^{1 is} methyl, R ^{2 is} n-propyl, R ^{3 is} ethyl, n-propyl or allyl and R ^{4 is taken} together with the nitrogen to which it is attached,

Forms a 4-N- (R ⁶ ) piperazinyl group; R ⁵ is hydrogen, R ⁶ is hydrogen, C 1-3 alkyl, or 2-hydroxyethyl.

The following compounds of the invention are particularly preferred:

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5- [2-allyloxy-5- (4-methylpiperazinyl) phenyl] -lmetil-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d) pyrimidine 7-one;

5- [2-ethoxy-5- (piperazinyl) phenyl] -l-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one;

5- [2-Ethoxy-5- (4-methyl-piperazinylsulfonyl) -phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -you;

5- {2-Ethoxy-5- [4- (2-propyl) -piperazinylsulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidin-7-one;

5- {2-Ethoxy-5- [4- (2-hydroxyethyl) piperazinylsulfonyl] phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d ] pyrimidin-7-one;

l-methyl-5- [5- (piperazinylsulfonyl) -2-n-propoxyphenyl] -3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; and

5- {5- [4- (2-Hydroxyethyl) piperazinylsulfonyl] -2-n-propoxyphenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one.

DETAILED DESCRIPTION OF THE INVENTION.

Compounds of formula (I) may be prepared by reacting a compound of formula (II) wherein R ¹ R ² , R ³ are as defined above and Y is a halogen atom, preferably chlorine, with a compound of formula III wherein R ⁴ and R ⁵ are as defined above.

The reaction is generally carried out at room temperature, preferably in the presence of a solvent such as a C 1-3 alkanol, and the acid by-product HY is bound with an excess of the compound of formula III.

Compounds of formula (II) may be prepared from compounds of formula (IV) wherein R ¹ , R ² , R ³ are as defined above by introducing a SO ₂ Y group wherein Y is as defined above into the aromatic ring. known methods, for example, Y is chlorine, and reacting chlorosulfonic acid at or near 0 ° C.

If R ^{3 is} a group that is prone to cleavage under chlorine sulfonylation conditions, such as an allyl group, then this group may be introduced into the molecule in the final step of the synthesis. Thus, the phenol of formula (IV), wherein R ³ is hydrogen, R ¹ and R ² are as defined above and which may be prepared by the palladium cleavage of the Ο-allyl analogue according to Example 25, is (II). ) of the compound of formula is obtained wherein Y is Cl, R ³ is hydrogen and R ¹ and R ² are as defined above. The resulting compound of formula (II) is then reacted with the corresponding amine of formula (III) to give a compound of formula (I) wherein R ³ is hydrogen, R ¹ , R ² , R ⁴ and R ⁵ are as defined above. and finally O-alkylating to give a compound of formula (I) wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for compound (I). Alkylation can be carried out under known conditions with a suitable alkyl halide such as allyl bromide in the presence of a base such as potassium carbonate in a solvent such as 2-butanone at the reflux temperature of the reaction mixture. Alkylation can be carried out under known Mitsunobu reaction conditions.

For other compounds of Formula IV that are incompatible with the chlorosulfonylation reaction conditions, for example, when R ^{2 is} hydroxy-C 1-6 alkyl, the hydroxy group may be protected with an acyl group such as acetyl or benzoyl. The protecting group is then removed in the final synthesis step under basic basic hydrolysis conditions to give compounds of formula I wherein R ^{2 is} hydroxy-C 1-6 alkyl, R ¹ , R ³ , R ⁴ and R ⁵ are as defined above. The latter compounds can also be obtained as by-products by the corresponding alkoxy analogs chlorosulfonylated, i.e., compounds of formula IV wherein R ² is C 1-3 alkoxy (C 1-6 alkyl) and the crude product is the desired ( Reaction with the amine of formula III as in Example 48.

Compounds of formula (IV) may be prepared from compounds of formula (V): wherein R ¹ , R ² , R ³ are as defined above using known cyclization processes for pyrimidinone ring formation. For example, cyclization of a compound of formula (V) may be accomplished by treating the latter with a base such as sodium hydroxide or potassium carbonate, optionally in the presence of hydrogen peroxide, in ethanol-water at reflux for 2-40 hours. Under these conditions, a similar nitrile of formula (VI) may also be used as a precursor of a compound of formula (IV) wherein R ¹ , R ² , R ³ are as defined above.

In another cyclization process, compounds of formula IV can be prepared by treating a compound of formula V with polyphosphoric acid at or near 140 ° C for 618 hours.

Compounds of formula (V) and (VI) may be prepared from compounds of formula (VII) and (VIII) wherein R * and R ² are as defined above by reacting the latter with a compound of formula (IX) wherein R ³ and Y has the meaning given above.

The reaction is usually carried out in excess of the compound of formula IX, in excess of an aliphatic tertiary amine such as triethylamine, to bind the acidic by-product HY, optionally in the presence of a catalyst such as 4-dimethylaminopyridine. in a solvent such as dichloromethane at 0-25 ° C for 2-6 hours.

The amines of formula (III), the aminopyrazoles of formulas (VII) and (VIII) and the acyl halides of formula (IX), if not commercially available, can be prepared by known synthetic procedures from readily available starting materials in the literature, standard reagents. and reaction conditions.

Certain compounds of formula I wherein R ⁴ together with the nitrogen to which it is attached form a 4-N (R ⁶ ) piperazinyl group and R ⁶ is as defined above with the exception of the corresponding 4-N-unsubstituted piperazine analogue can be produced directly, ie

A9 of a compound of formula (I) wherein R ^{6 is} hydrogen and is synthesized according to known methods.

The above reactions are completely conventional and the reagents and reaction conditions used can be found in the textbooks. It will be apparent to those skilled in the art that the foregoing may be departed from and that the compounds of formula (I) will still be obtained.

The biological activity of the compounds was determined by the following test methods.

Phosphodiesterase effect

Affinity for AcGMP and cAMP PDEs is estimated by determining their IC ₅₀ values (the concentration of inhibitor required to inhibit 50% of the enzyme activity). PDE enzymes were isolated from rabbit platelets and from rat kidney essentially according to WJ Thompson et al. (Biochem. 1971, 0.311). Calcium, calmodulin (Ca / CAM) -dependent cGMP PDE and cGMP-inhibited cAMP PDE enzymes were prepared from rabbit platelets, while four major PD enzymes of rat kidney and Ca / CAMp-dependent cGMP PDE (fraction I) were isolated. Experiments are carried out by modifying the so-called batch method [WJ Thompson et al. M. Appleman (Biochem. 1979, 18, 5228). The test results show that the compounds of the invention are potent and selective cGMP PDE inhibitors.

Platelet anti-aggregation effect

This property is estimated by determining the ability of the compound to inhibit platelet aggregation induced by platelet activating factor (PAF) in vitro and to enhance the antiplatelet effect of platelet in vitro on guanylate cyclase such as nitroprusside and EDRF. . Washed platelets are prepared essentially as described in J. F. Mustard et al., Methods in Enzymol. 169, 3, 1989, and aggregation is determined by standard turbodimetric techniques in G. V. R. Born, J. Physiol. (Lond), 1962, 162, page 67.

Antihypertensive effect

This is determined after intravenous or oral administration of the compounds, with spontaneous hypertension in rats. Blood pressure is recorded using either a cannula implanted into the carotid artery of conscious or stunned animals.

For therapeutic and prophylactic purposes, angina hypertension in patients with congestive heart failure is usually 4-800 mg / day for a 70 kg average adult patient. Thus, in a typical adult patient, the tablets or capsules will contain from 2 to 400 mg of the active ingredient, in the presence of a suitable pharmaceutically acceptable medium or carrier, for single or multiple daily or multiple daily administration. Dosages for intravenous buccal sublingual administration are usually in the range of 1400 mg / dose, and in practice, the dosage ranges that are most advantageous for each patient in terms of age, weight and response are determined by the physician. The above doses correspond to the average case, but there may be individual cases where higher or lower dose ranges are to be mentioned.

For human use, the compounds of formula (I) may be administered alone or generally in admixture with pharmaceutically acceptable carriers, which carriers are selected according to the route of administration and medical practice. For example, they may be administered orally, buccally, sublingually in the form of tablets containing excipients, and these excipients may be in the form of starch or lactose or capsules or ovules, alone or in admixture with other excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. The compounds may be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronally. For parenteral administration, the best form of administration is a sterile aqueous solution which may contain other substances, for example, enough salt or glucose to make the solution isotonic with the blood.

The present invention also provides pharmaceutical compositions comprising the compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient, in particular for the treatment of angina, hypertension and congestive heart failure in human patients.

The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament, wherein the diseases to be treated are stable or unstable variant (Prinzmetal) angina, hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, e.g. post-PTCA, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or disorders of the intestinal motility such as IBS.

Further details on the preparation of the compounds are illustrated by the following examples. The purity of the compounds is routinely monitored by Merck Kieselgel 60-254 plates with TLC. 'H-Nuclear Magnetic Resonance Spectra were recorded on a Nicolet QE 300 spectrometer and in each case corresponded to the corresponding proposed structure.

/. Example 1-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester

Chem. Pharm., 24.1 g, 0.132 mol. Bull., 1984, 32, 1568, and a mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester and 16.8 g (0.133 mol) of dimethyl sulfate were heated to 90 ° C for 2.5 hours. The mixture was dissolved in dichloromethane and the solution was washed with sodium carbonate solution. The organic phase was removed, dried over magnesium sulfate and evaporated in vacuo to give a solid. Chromatography on silica gel (300 g), eluting with dichloromethane gave the product as a colorless oil (20.4 g, 79%). Rf = 0.8 (silica, dichloromethane, methanol, acetic acid = 80: 20: 1).

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Example 2 1-Methyl-3-n-propyl-pyrazole-5-carboxylic acid

20.2g 0.10 mol of 1-methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester are suspended in 50 ml of 0.30 mol of 6N aqueous sodium hydroxide solution. The mixture was heated to 80 ° C for 2 hours, then diluted with water (50 mL) and acidified with concentrated hydrochloric acid (25 mL). Filtration gave the title carboxylic acid as light brown crystals (12.3 g, 71%).

Melting point: 150-154 ° C

Elemental Analysis for C ₈ H | ₂ N ₂ O ₂ calculated: Calc:% C = 57.13, H% = 7.19, N% = 16.66;

Found: C, 56.99; H, 7.25; N, 16.90.

Example 3

I-Methyl-4-mixture of anhydrous cupric-3-n-propylindol-5-carboxylic acid

1-Methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 mol) was added portionwise to a mixture of 13 ml of oleum and 11 ml of fuming nitric acid and the temperature was kept below 60 ° C. After the addition was complete, the mixture was heated at 60 ° C overnight, then cooled to room temperature and poured onto ice. The precipitate was filtered to give nitro-pyrazole as a white solid

11.5 g in 75% yield.

124-127 ° C

Analysis calculated for C ₈ HHN ₃ O _4: Calc: C% = 45.57, H% = 5.20, N% = 19.71; Found: C, 45.43; H, 5.22; N, 19.42.

Example 4

I-Methyl-4-nitro-3-n-propyl-pyrazole-5-carboxamide

1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) was added to thionyl chloride (50 ml) and the resulting mixture was heated to reflux for 3 hours. The mixture was cooled and the excess thionyl chloride evaporated in vacuo. The oily residue is dissolved in 50 ml of acetone and the solution is carefully added to a mixture of 50 g of ice and 50 ml of concentrated aqueous ammonium hydroxide solution. Filtration of the precipitate gave the pyrazole carboxamide as a pale yellow solid (8.77 g, 78%).

Melting point: 141-143 ° C.

Analysis calculated for C ₈ H ₁₂ N ₄ O ₃ : C, 45.28; H, 5.70; N, 26.40;

Found: C, 45.22; H, 5.71; N, 26.12.

Example 5

4-Amino-l-methyl-3-n-propyl-pyrazole-5-carboxamide

1-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and tin chloride dihydrate (18.4 g, 81 mmol) were suspended in ethanol and heated to reflux. hours. The resulting solution was cooled to room temperature, basified to pH 9 by the addition of 2N aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 150 mL). The organic extract was combined, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to give the aminopyrazole as an off-white solid (2.77 g, 94%).

Melting point: 98-101 ° C.

Elemental Analysis for C ₈ H | Calc'd for C ₄ NH ₄ 4N NO: C, 52.73; H, 7.74; N, 30.75; Found: C, 52.84; H, 7.81; N, 30.38.

Example 6

4- (2-Ethoxy-benzamido) -1-methyl-3-n-propyl-pyrazole-5-carboxamide

A solution of 6.1 g (33 mmol) of 2-ethoxybenzoyl chloride in 50 ml of dichloromethane was added 3 g, 16.4 mmol of 4-amino-methyl-3-n-propylpyrazole-5-carboxamide, 0.02 g, 0.164 4-dimethylaminopyridine (3.00 g) and triethylamine (3.34 g, 33 mmol) in dichloromethane (50 mL) at 0 ° C. The resulting mixture was allowed to warm to room temperature and stirred for a further 2 hours. The solvent was evaporated in vacuo, the residue was dissolved in dichloromethane: methanol (19: 1, 250 mL), washed with 1N hydrochloric acid (100 mL), dried over magnesium sulfate and evaporated in vacuo. The crude material was chromatographed on silica gel (200 g) eluting with dichloromethane: methanol (97: 3) to give a pink solid which was crystallized from ethyl acetate / hexane to give 2.2 g of pyrazole-5-carboxamide (40%). as a solid, m.p. 153-155 ° C.

Analysis calculated for C ₁₇ H ₂₂ N ₄ O _3: Calc: C% = 61.80, H% = 6.71, N% = 16.96;

Found: C, 61.66; H, 6.77; N, 16.95.

Example 7

5- (2-Ethoxyphenyl) -1-methyl-3-n-propyl], 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

4- (2-Ethoxybenzamido) -1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added in portions to 54 g (1.35 mol) of sodium hydroxide and 224 ml of 30% hydrogen peroxide in 2000 ml of water. Ethanol (700 mL) was added and the resulting mixture was heated to reflux for 2.5 h, cooled and finally concentrated in vacuo. The resulting solid was treated with 380 mL of 2N hydrochloric acid under external cooling and extracted with dichloromethane (1 x 700 mL and 3 x 200 mL). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3 x 400 mL) and brine (300 mL), dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on 1000 g of silica gel eluting with methanol in dichloromethane (0-1% gradient), triturated with 300 ml of ether to give 152.2 g, 72% of a colorless solid.

Melting point: 143-146 ° C.

Analysis calculated for C ₄ H ₂₀ O ₄ N ₂ O: Calculated: C% = 65.36, H% = 6.45, N% = 17.94; Found: C, 65.56; H, 6.44; N, 18.14.

Example 8

5- (5-Chlorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-pmyl] -6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one 10 g, 32.1 mmol of 5- (2-ethoxyphenyl) -1-methyl-3-npropyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

A9 was added portionwise to 20 mL of chlorosulfonic acid at 0 ° C under nitrogen. After stirring overnight, the solution was carefully added to 150 mL of ice water and the aqueous mixture was extracted with dichloromethane: methanol (9: 1, 4 x 100 mL). The combined extracts were dried over sodium sulfate, concentrated in vacuo and the desired sulfonyl chloride was obtained as a white solid (12.8 g, 97%). Melting point: 179-181 ° C.

Analysis calculated for C ₁₇ H ₁₉ ClN ₄ O ₄ S: C, 49.70; H, 4.66; N, 13.64. Found: C, 50.07; H, 4.71; N, 13.29.

Example 9

5- [2-Ethoxy-5- (4-karbainoil-piperidinyl) phenyl] -] - methyl-3-n-propyl -], 6-dihydro-7H-pyrazolo [4,3-d] pyrimidine -7-one

4-Carbamoylpiperidine (703 mg, 5.50 mmol) is added to 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro (750 mg, 1.80 mmol). Of 7H-pyrazolo [4,3-d] pyrimidin-7-one in 50 ml of ethanol at room temperature. The resulting mixture was stirred for 4 days and then the solvent was evaporated in vacuo. The residue was dissolved in dichloromethane / methanol (9: 1, 100 mL) and washed with saturated aqueous sodium carbonate (100 mL). The aqueous phase was further extracted with dichloromethane / methanol (3 x 100 mL) and all the organic fractions were combined, dried over magnesium sulfate and evaporated in vacuo to give a solid.

Crystallization from methanol / dimethylformamide gave the title sulfonamide as an off-white solid (446 mg, 49%), mp 247-276 ° C.

Analysis for C ₂₃ H29N ₆ O ₅ S Calcd: Calculated: C% = 55.08, H% = 5.83, N% = 16.75; Found: C, 55.36; H, 6.01; N, 16.65.

10-14. Example

The following compounds were prepared by the method of Example 9 using the appropriate amine.

Compounds of formula IA

Example number Yield% Mp (° C) Analysis% (calculated values in parentheses) C H N 10th / - \ _ / NH 51 161-162 54.82 6.13 17.95 (54.77 6.13 18,25) 11th 79 194-196 54.63 6.47 16,50 (54.75 6.39 16.65) 12th \ __ V 88 187-189 55.61 6.23 17.74 (55.68 6.37 17.71) 13th N ^-NMc ₂ 21 187-188 57.48 6.74 16.47 (57.35 6.82 16.72) 14th _ ^ ITR 74 209-212 57.64 6.66 16.81 (57.35 6.82 16.72) 15th / NCSNH, \ _z ² 18 229-230 51.25 5.56 18.92 (50.85 5.63 18,87)

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Example 16

5- {2-Ethoxy-5- [4- (methylthio imidoyl) piperazinylsulphonyl] -fenilf -] - methyl-3-n-propylindol-l, 6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one hydroiodide

0.78 g, 1.5 mmol of 5- [2-ethoxy-5- (4-thiocarbamoyl-piperazinylsulfonyl) -phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole A mixture of [4,3-d] pyrimidin-7-one, 426 mg, 3 mmol of methyl iodide and 20 ml of methanol was stirred at reflux for 2 hours and then allowed to cool. The resulting white solid was filtered and crystallized from ethyl acetate-methanol to give 0.70 g (71%) of a colorless crystal.

Melting point: 227-228 ° C

Analysis calculated for C ₂₃ H _3I N ₄ O ₇ S ₂ -pyrrole O: Calculated: C% = 41.75, H% = 4.88, N% = 14.82; Found: C, 41.43; H, 4.79; N, 14.42.

Example 17

5- {2-Ethoxy-5- [4- (methyl-amidino) -piperazylsulfonyl] -phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3- d] pyrimidin-7-one hydroiodide

0.5 g, 0.75 mmol of 5- {2-Ethoxy-5- [4- (methylthio-imidazoyl) -piperazinylsulfonyl] -phenyl} -1-methyl-3-n-propyl, 6-dihydro 7H-pyrazolo [4,3-d] pyrimidin-7-one hydroiodide was added to 20 ml of a 33% solution of methylamine in ethanol and the mixture was stirred at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was triturated with ether. The resulting solid was chromatographed on silica gel (10 g), eluting with a gradient of 0-4% methanol in dichloromethane, and the crude product was triturated with ether to give a light brown powder. Crystallization from ethyl acetate / methanol gave the title compound as colorless crystals (112 mg, 23%). Melting point: 253-255 ° C.

Analysis calculated for C ₂₃ H ₃₂ N _g O ₄ SHJ: C, 42.86; H, 5.16; N, 17.39; Found: C, 42.90; H, 5.09; N, 17.41.

Example 18 1-Methyl-4- (2-n-propoxybenzofunido) -3-n-propylpyrazole-5-carboxamide

The amide was prepared from 2-n-propoxybenzoyl chloride according to the procedure of Example 6 to give 63% as a pink solid, m.p. 148-149 ° C.

Analysis calculated for C _Ig H ₂₄ N ₄ O _3: Calc: C% = 62.77, H% = 7.02, N% = 16.27;

Found: C, 62.97; H, 7.00; N, 16.29.

Example 19 1-Methyl-5- (2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

1-Methyl-4- (2-n-propoxybenzamido) -3-n-propylpyrazole-5-carboxamide (0.34 g, 0.99 mmol) was added to 1 mL of 30% hydrogen peroxide solution, Potassium carbonate (54 g, 3.92 mmol) in water (10 mL) and ethanol (5 mL). The mixture was heated under reflux for 38 hours and then concentrated in vacuo. The residue was suspended in water (20 mL), acidified with 2N hydrochloric acid and extracted with dichloromethane (3 x 20 mL). The extracts were combined, dried over sodium sulfate and concentrated in vacuo. The residue obtained is chromatographed on silica gel (6 g), eluting with a gradient of 0.0-1.0% methanol: dichloromethane. Trituration with ether gave the desired product as a white solid (0.19 g, 59%). Melting point: 111-114 ° C.

Elemental analysis aC | _g, calculated as H ₂₂ N ₄ O _2: Calc: C% = 66.23, H% 6.80, N% = 17.17; Found: C, 66.26; H, 6.92; N, 17.15.

Example 20

5- (5-chlorosulfonyl-2-n-propoxy-phenyl) -l-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-pyrimidin-7-one

This sulfonyl chloride was prepared from 5- (2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one. Example 8 gave a white solid in 92% yield.

Elemental analysis for _{C] 8} H ₄ O ₄ S ₂ iC1N Calcd: Calculated: C% = 50.88, H% = 4.98, N% = 13.19;

Found: C, 51.26; H, 5.02; N, 12.90.

Example 27] -Methyl-5- [5- (piperazinylsulfonyl) -2-n-propoxyphenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -you

The sulfonamide is from piperazine and 5- (5-chlorosulfonyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 of Example 9 and is obtained in 70% yield as a white solid.

Melting point: 185-186 ° C.

Analysis calculated for C ₂₂ H ₃₀ N ₆ O ₄ S: C, 55.67; H, 6.37; N, 17.71.

Found: C, 56.17; H, 6.38; N, 17.65.

Example 22

5- {5- [4- (2-Hydroxyethyl) piperazinylsulfonyl] -2-naphthoxyphenyl}] - methyl-3-n-propyl-1,6-dihydm-7H-pyrazolo [4,3- d-pyrimidin-7-one

The sulfonamide was prepared from N- (2-hydroxyethyl) piperazine and 5- (5-chlorosulfonyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-. pyrazolo [4,3-d] pyrimidin-7-one was prepared as in Example 9 and obtained as colorless needles in 66% yield.

Melting point: 158-159 ° C

Analysis: Calculated for C ₂₄ H ₃₄ N ₆ O ₅ S: C, 55.58; H, 6.61; N, 16.20; Found: C, 55.83; H, 6.58; N, 16.13.

Example 23

4- (2-Allyloxybenzamido) -1-methyl-3-n-propylpyrazole-5-carboxamide

A solution of 2-allyloxybenzoyl chloride (3.93 g, 0.02 mol) in dichloromethane (20 ml) was added dropwise (3.64 g, 0.02 mol).

Of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide in 50 ml of pyridine, and the resulting mixture was stirred at room temperature overnight in a dry atmosphere.

EN 211 6-6 Stir at A9. The solvent was evaporated in vacuo and the residue partitioned between dichloromethane (50 mL) and saturated aqueous sodium carbonate (50 mL). The organic layer was separated and the aqueous layer was extracted extensively with additional dichloromethane. The combined organic solutions were washed with 2M hydrochloric acid (3 x 30 mL) and brine (1 x 30 mL) and dried over sodium sulfate. After filtration and concentration of the filtrate in vacuo, the crude product is crystallized from ethyl acetate to give 4.525 g (66%) of the title compound. 132-134 ° C.

Analysis calculated for C ₁₈ H ₂₂ N ₄ O ₃ : C, 63.14; H, 6.48; N, 16.36.

Found: C, 63.49; H, 6.42; N, 16.33.

Example 24

5- (2-Allyloxyphenyl) -N-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

1.2 g (0.0035 mol) of 4- (2-allyloxybenzamido) -1-methyl-3-n-propylpyrazole-5-carboxamide, 0.70 g, 0.018 mol of sodium hydroxide, 34 ml of water and 8 ml the ethanol mixture was refluxed for 5 hours. After cooling, the solution was extracted extensively with ethyl acetate, and the combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and the solvent evaporated in vacuo to give a crude product which was crystallized from ethyl acetate / hexane. 0.476 g (37%) of the title compound are obtained.

Melting point: 116-119 ° C

Elemental analysis of C | Calculated for C ₈ H ₂₀ N ₄ O ₂ : C, 66.65; H, 6.21; N, 17.27;

Found: C, 67.00; H, 6.21; N, 17.23.

Example 25

5- (2-Hydroxy-phenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

0.25 g, 0.0008 mol of 5- (2-allyloxyphenyl) -1-methyl-3-npropyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one A mixture of 0.145 g, 0.0015 moles of phenol, 0.131 g, 0.0015 moles of piperidine and 0.046 g, 0.00004 moles of tetrakis (triphenylphosphine) palladium (O) in 5 ml of absolute ethanol is heated at reflux overnight under nitrogen stream. The mixture was allowed to cool, the solvent was evaporated in vacuo, and the residue was dissolved in ethyl acetate (40 mL). The solution was washed with water (3 x 10 mL), 1M hydrochloric acid (3 x 10 mL) and brine (1 x 10 mL). After drying over sodium sulfate, filtration, the filtrate was concentrated in vacuo to give the crude product. The title phenol (0.021 g, 10%) was obtained after trituration with diethyl ether and crystallization from ethyl acetate / pentane.

Melting point: 233-238 ° C

Elemental Analysis for C ₁₅ H | ₆ N ₄ O ₂ calculated: Calc: C% 63.36, H% = 5.67, N% = 19.71;

Found: C, 63.17; H, 5.65; N, 19.52.

Example 26

5- (5-Chlorosulfonyl-2-hydroxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one 0.239 g, 0.00084 mol of 5- (2-hydroxyphenyl) -1-methyl-3n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one are added in portions to 3 ml of stirred chlorine. sulfuric acid under nitrogen and cooled to 0 ° C. The resulting deep red solution was stirred at room temperature for 18 hours. The reaction mixture was carefully added dropwise to a mixture of ice and water to give a brown solid. The latter mixture was extracted with dichloromethane (3 x 30 mL) and the combined extracts were dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo to give 0.24 g (75%) of a brown solid. This is used in the next step without further purification.

Rf = 0.3 (silica, dichloromethane, methanol: 95: 5).

Example 27

5- [2-Hydroxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine 7-one

0.235 g (0.0006 mol) of 5- (5-chlorosulfonyl-2-hydroxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 and 0.5 ml of 0.0045 molar solution of N-methylpiperazine in 40 ml of ethanol are stirred for 18 hours at room temperature. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate (40 mL) and water (40 mL). The fine precipitate was filtered off, washed with water and then with ethyl acetate, and crystallized from a mixture of ethyl acetate and dimethylformamide. 0.26 g (49%) of the title compound is obtained as an off-white powder.

Melting point: 283-284 ° C

Analysis calculated for C ₂₀ H ₂₆ N ₆ O ₄ S: C, 53.80; H, 5.87; N, 18.82; Found: C, 53.53; H, 5.89; N, 18.40.

Example 28

5- [2-Allyloxy-5- (4-methyl-piperazinylsulfonyl) -phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3-d] pyrimidine-7- you

Allyl bromide (0.02 mL, 0.00023 mol) was added to 0.103 g. 0.00023 mole of 5- [2-hydroxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4,3- d) Pyrimidin-7-one and 0.032 g, 0.00023 mol of potassium carbonate in 10 ml of 2-butanol and the mixture was heated under reflux for 8 hours. After cooling, the reaction mixture is concentrated in vacuo and the residue is suspended in 20 ml of water. The aqueous slurry was extracted with ethyl acetate (3 x 20 mL), and the combined extracts were dried over sodium sulfate and, after filtration, concentrated in vacuo to an oil. Purify by column chromatography on silica gel (2 g) eluting with a gradient of 0-3% methanol in dichloromethane. The appropriate fractions were evaporated in vacuo to give a semi-solid which was dissolved in acetone and evaporated in vacuo to give 0.011 g. 10% of the title compound are obtained, m.p. 151-153 ° C.

R f = 0.5 (silica, dichloromethane: methanol = 95: 5), m / e 487 (M ⁺ +1).

HU 211 646 A9

Example 29

4- (2-Ethoxybenzamido) -1,3-dimethylpyrazole-5-carboxamide

The amide is prepared from 4-amino-1,3-dimethylpyrazole-5-carboxamide (prepared as described in J. Med. Chem. 1987, 30, 91). Example 6 gave 81% of an off-white solid, mp 178-181 ° C.

Elemental Analysis for _C15 H | N4O _grams per ₃ O: Calculated: C% = 59.59, H% = 6.00, N = 18.53%

Found: C, 59.89; H, 6.05; N, 18.44.

Example 30

5- (2-Ethoxyphenyl) -1,3-dimethyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

4- (2-Ethoxybenzamido) -1,3-dimethylpyrazole-5-carboxamide (1.6 g, 5.29 mmol) was added to 50 g of polyphosphoric acid and the mixture heated to 140 ° C for 6 hours. The solution was cooled, poured into ice water (100 mL), basified with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (3 x 100 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane: methanol (97: 3). The crude product was crystallized from aqueous ethanol to give the title compound as a colorless solid.

Melting point: 201-204 ° C.

Analysis calculated for C ₁₅ H ₁₆ N ₄ O ₇ : C, 63.36; H, 5.67; N, 19.71 Found: C, 63.43; H, 5.57. , N% = 19.35

Example 31

5- (5-Chlorosulfonyl-2-ethoxyphenyl) -1,3-dimethyl-1,6-dihydro-7H-pyrazolol4,3-dipyrimidin-7-one

This sulfonyl chloride was prepared according to Example 8, 5- (2-Ethoxyphenyl) -1,3-dimethyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one. and yields a white solid in quantitative yield.

Rf 0.3 (silica: ether).

Use without further purification.

32-34. Example

The following compounds were prepared from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1,3-dimethyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; from the corresponding amine as in Example 9.

Compounds of formula (IB)

Example number Yield% Mp (° C) Analysis% (calculated value in parentheses) C H N 32nd / WH <; V_ / 68 225-226 53.88 5.81 18.42 (53.79 5.87 18.82) 33rd / NMe 68 240-242 53.07 5.77 19,27 (52.76 5.59 19.43) 34th 62 228-229 53.23 5.87 17.72 (52.93 5.92 17.63)

Example 35

4-Nitro-3-n-propyl-pyrazole-5-carboxylic acid

Chem. Pharm. Bull. 3-n-propylpyrazole-5-carboxylic acid (1984, 32, 1568) was nitrated as in Example 3 to give the title compound as a colorless solid in 75% yield. Melting point: 169-173 ° C.

Elemental analysis calculated for C ₇ H ₉ N ₃ O ₄ :

Calculated: C, 42.21; H, 4.55; N, 21.10; Found: C, 42.35; H, 4.56; N, 21.07.

Example 36

4-Nitro-3-n-propyl-pyrazole-5-carboxamide

A mixture of 7.8 g (39.2 mmol) of 4-nitro-3-n-propylpyrazole-5-carboxylic acid and 35 ml of thionyl chloride was heated at reflux for 3 hours. The solvent was evaporated in vacuo and the solid residue was added portionwise to 40 mL of aqueous ammonium hydroxide at 0 ° C. The mixture was then diluted with water (60 mL) and extracted with dichloromethane: methanol (9: 1, 3 x 100 mL). The organic fractions were combined, dried over magnesium sulfate, concentrated in vacuo and the residue crystallized from ethanol to give 1 g (13%) of a colorless solid carboxamide.

Analysis calculated for C ₇ H ₁₀ N ₄ O ₃ : C, 42.42; H, 5.09; N, 28.27;

Found: C, 42.35; H, 5.01; N, 28.38.

Example 37

4-Amino-3-n-propylpyrazole-5-carboxamide A solution of 4-nitro-3-n-propylpyrazole-5-carboxamide (198 mg, 1.0 mmol) in methanol (5 mL) was added dropwise to sodium (113 mg, 2.97 mmol). borohydride, 5 mg of 10% palladium 9

EN 211 646 A9 dilim for a mixture of charcoal catalyst and 3 ml water. The mixture was stirred at room temperature for 3 hours, filtered and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate / methanol to give the title compound as an off-white solid (61 mg, 36%).

Melting point: 196-201 "C.

Rf = 0.4 (silica, dichloromethane, methanol, ammonium hydroxide 90: 10: 1)

Analysis calculated for C7 H12 N4 O: C, 49.98; H, 7.19; N, 33.31;

Found: C, 48.96; H, 6.98; N, 32.08.

Example 38

4- (2-Ethoxybenzamido) -3-n-propylpyrazole-5-carboxamide

The title amide was obtained as in Example 6 from 4-amino-3n-propylpyrazole-5-carboxamide in 64% yield as a white solid.

M.p. 209-211 ° C.

Elemental analysis of C | Calculated for C ₆ H ₂₀ N ₄ O ₃ : C, 60.74; H, 6.37; N, 17.71; Found: C, 60.73; H, 6.41; N, 17.80.

Example 39

5- (2-Ethoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

The title compound was obtained as in Example 30 from 16 (16%) of 4- (2-ethoxybenzamido) -3-n-propylpyrazole-5-carboxamide as a white solid.

Melting point: 199-201 ° C.

Analysis calculated for C ₆ H ₄ O ₂ N _Ig O: Calculated: C% = 64.41, H% = 6.08, N% = 18.78;

Found: C, 64.44; H, 6.19; N, 18.44.

Example 40

5- (5-Chlorosulfonyl-2-ethoxyphenyl) -3-n-propyl-1,6-dihydm-7H-pyrazolo [4,3-d] pyrimidin-7-one The title sulfonyl chloride - (2-Ethoxyphenyl) 3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7one was prepared as in Example 8 in 78% yield as a white solid. form.

Rf = 0.25 (silica, ether).

Use without further purification.

Example 41

5- [2-Ethoxy-5- (4-methylpiperazinyl) sulfonyl-phenyl] -3-n-propyl-1,6-dihydno-7H-pyrazolo [4,3-d] pyrimidin-7-one sulfonamide was prepared from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one according to Example 9, and 70% white solid, m.p. 236-239 ° C.

Analysis for C ₂₁ H ₂₈ N ₆ O ₄ S Calcd: Calculated: C% = 54.76, H% = 6.13, N% = 18.25;

Found: C, 54.84; H, 6.27; N, 18.10.

Example 42

3-Bromomethyl-5-chloro-l-methyl-4-nitro-pyrazole

N, N-bromosuccinimide (10.7 g, 60 mmol) was added (8.78 g). To a solution of 5-chloro-1,3-dimethyl-4-nitro-pyrazole (50.0 mmol) in carbon tetrachloride (100 mL) was heated under reflux while irradiated with 150 W of Wolframos lamp for 3 days. During the reaction, 6 x 50 mg of benzoyl peroxide are added at intervals. The solvent was evaporated in vacuo and the residue chromatographed on silica gel eluting with dichloromethane: hexane (1: 1) to give the bromide as an white solid (8 g, 63%), m.p. 80-82 ° C.

Elemental analysis for C ₅ H ₅ BrClN ₃ O ₂ Calculated: C, 23.60; H, 1.98; N, 16.51.

Found: C, 23.95; H, 2.05; N, 16.31.

Example 43

5-Chloro-3-methoxycarbonyl-l-methyl-4-methyl-pyrazol anhydrous cupric chloride

A solution of 3-bromomethyl-5-chloro-1-methyl-4-nitropyrazole (5.0 g, 19.6 mmol) in methanol (50 mL) was treated with silver nitrate (5.75 g, 33.8 mmol) and the mixture was stirred for 2 hours. heat under reflux. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL) and the aqueous layer was extracted with additional ethyl acetate (50 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo. Chromatography on silica gel, eluting with dichloromethane: methanol (97: 3), afforded the title pyrazole as a white solid (1.6 g, 40%).

Melting point: 59-63 ° C

Analysis calculated for C ₆ H _g ClN ₃ O ₃ : C, 35.05; H, 3.92; N, 20.44.

Found: C, 34.65; H, 3.83; N, 20.05.

Example 44

5-Cyano-3-methoxymethyl-l-methyl-4-nitro-pyrazole

5-Chloro-3-methoxymethyl-1-methyl-4-nitro-pyrazole (205 mg, 1 mmol), potassium cyanide (130 mg, 2 mmol) and 18-crown-6 (10 mg) in 2 mL of acetone were heated under reflux overnight. . The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo to give a residue which was chromatographed on silica gel, eluting with 1: 1 ethyl acetate: pentane. The crude product was triturated with ether to give 38 mg (19%) of a yellow solid, mp 48-50 ° C.

Analysis calculated for C ₇ H _g N ₄ O ₃ : C, 42.86; H, 4.11; N, 28.56;

Found: C, 42.89; H, 4.15; N, 28.78.

Example 45

4-Amwo-5-cyano-3-methoxymethyl-1-methylpyrazole

The title compound was prepared as in Example 5 from 5-cyano-3-methoxymethyl-1-methyl-4-nitro-pyrazole to give 68% of an off-white solid, m.p. 82-84 ° C.

Elemental Analysis for C ₇ H | N ₀ being ₄ O Calc:% C = 50.59, H% = 6.07, N% = 33.72;

Found: C, 50.81; H, 6.13. N, 33.94.

IO

HU 211 646 A9

Example 46

5-Cyano-4- (2-ethoxybenzamido) -3-methoxymethyl-J-methpyrazole

The title compound was prepared as in Example 6 from 4-amino-5-cyano-3-methoxymethyl-1-methylpyrazole and was obtained in 61% yield as an off-white solid.

Melting point: 103-105 ° C.

Analysis calculated for C ₁₆ H ₈ N ₄ O ₃ Calcd: C% = 61.13, H% = 5.77, N% = 17.83;

Found: C, 61.21; H, 5.98; N, 17.80.

Example 47

5- (2-Ethoxyphenyl) -3-methoxymethyl-1-methyl-1,6-dihydm-7H-pyrazolo [4,3-d] pyrimidin-7-one The title compound was prepared according to Example 7. of 5-cyano-4- (2-ethoxybenzamido) -3-methoxymethyl-1-methylpyrazole by in situ formation of the 5-primary amide derivative to give a white solid (38%). The 161Cs are.

Elemental analysis of C | ₆ H ₎ Calculated for _g N ₄ O ₃ : Calculated: C, 61.13; H, 5.77; N, 17.83;

Found: C, 61.35; H, 5.75; N, 17.98.

Example 48

3-Methoxy-methyl -] - methyl-5- [5- (4-methyl-piperazinylsulfonyl) -2-ethoxyphenyl] -l, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7- you

5- (2-Ethoxyphenyl) -3-methoxymethyl-1-methyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one (470 mg, 1.50 mmol) in 3 mL of chloro- dissolved in sulfonic acid at 0 ° C. The solution was stirred for 2 hours at room temperature and then carefully added to 50 ml of ice water. The resulting solution was neutralized with saturated sodium carbonate solution and extracted with 2 x 50 mL dichloromethane: methanol (20: 1). The combined organic extracts were concentrated in vacuo and the residue was dissolved in ethanol (5 mL) and 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 90: 10: 1 by volume dichloromethane: methanol: aqueous ammonium hydroxide. Trituration of the crude product with ethyl acetate gave 49 mg (7%) of the title compound as a white solid.

Melting point: 198-199'C.

Elemental analysis: Calculated: C, 52.93; H, 5.92; N, 17.64. Found: C, 52.94; H, 6.04; N, 17.67.

After chromatography and crystallization from ethyl acetate / methanol, 3-hydroxymethyl-1-methyl-5- [5- (4-methylpiperazinylsulfonyl) -2-ethoxyphenyl] -1,6-dihydro- is isolated. 7H-pyrazolo [4,3-d] pyrimidin-7-one was also obtained as a white solid (51 mg, 7%).

Melting point: 209-210 ° C.

Analysis calculated for C ₂₀ H ₂₆ N ₆ O ₅ S: C, 51.94; H, 5.67; N, 18.17; Found: C, 51.94; H, 5.77; N, 18.05.

Example 49

J-ethyl-3-n-propylester pyrazole-5-carboxylic acid ethyl ester

This pyrazole was prepared from 3-n-propylpyrazole-5-carboxylic acid ethyl ester and diethyl sulfate as in Example 1 as a colorless oil in 72% yield.

Rf = 0.5 (silica; ethyl acetate / hexane 1: 1).

Example 50

I-Ethyl-3-rt-propyl-pyrazole-5-carboxylic acid

This carboxylic acid was obtained from 1-ethyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester according to Example 2 as a pale brown solid in 89% yield.

Melting point: 73-77 ° C.

Analysis calculated for C _{9 H] 4} N ₂ O _2: Calc: C% = 59.32, H% = 7.74, N% = 15.37; Found: C, 58.62; H, 7.69; N, 15.23.

Example 57 1-Ethyl-4-nitro-3-n-pmylpyrazole-5-carboxylic acid

The title compound was obtained from 1-ethyl-3-n-propylpyrazole-5-carboxylic acid as a colorless solid in Example 3 in 96% yield.

Melting point: 120-123 ° C.

Elemental Analysis for C ₉ H | Per ₃ N ₃ O _4: Calc: C% = 47.57, H% = 5.77, N% = 18.49; Found: C, 47.61; H, 5.81; N, 18.54.

Example 52

1-Ethyl-4-nitro-3-n-propyl-pyrazole-5-carboxamide

The title amide was obtained from 1-ethyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid in Example 4 as an off-white solid in 86% yield.

Melting point: 119-120'C.

Analysis calculated aC _I4 H ₉ N ₃ O _4: Calc: C% = 47.78, H% = 6.24, N% = 24.77;

Found: C, 47.38; H, 6.18; N, 24.34.

Example 53

4-amino -] - ethyl-3-n-propyl-pyrazole-5-carboxamide

The title compound was obtained from 1-ethyl-4-nitro-3-n-propylpyrazole-5-carboxamide in 100% yield as an white solid as in Example 5.

Melting point: 93-97 ° C.

Elemental analysis aC ₉ H | N ₆ O ₄ calculated: Calc:% C = 55.08, H% = 8.22, N% = 28.55;

Found: C, 55.17; H, 8.34; N, 28.93.

Example 54

4- (2-Ethoxybenzamido) -1-ethyl-3-n-propylpyrazole-52-carboxamide

The title amide was obtained from 4-amino-1-ethyl-3-n-propylpyrazole-5-carboxamide and 2-ethoxybenzoyl chloride as in Example 6 in 73% yield as a solid colorless solid.

Melting point: 139-141 ° C.

Analysis calculated for _{C) 8} H ₂₄ N ₄ O _3: Calc: C% = 62.77, H% = 7.02, N% = 16.27;

Found: C, 63.03; H, 7.15; N, 16.50.

ll

Example 55

5- (2-Ethoxyphenyl) -1-ethyl-3-n-propyl-N, 6-dihydro-7H-pyrazolol 4,3-d] pyrimidin-7-one The title compound is 4- (2-ethoxybenzamide). ) -ethyl-3-n-propylpyrazolo-5-carboxamide as in Example 7 as a colorless solid in 46% yield.

Melting point: 112-114 ° C.

Analysis calculated for C ₂ H 2 N _{4 Ig} O2 Calc:% C = 66.23, H% = 6.79, N% = 17.17;

Found: C, 66.59; H, 6.85; N, 17.26.

Example 56

5- (5-Chlorosulfonyl-2-ethoxyphenyl) -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one

The title compound was obtained from 5- (2-ethoxyphenyl) -1-ethyl-3n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one as described in Example 8. and in 86% yield as a methylene chloride solvate. Melting point: 170-172 ° C.

Elemental analysis calculated for C, _g H ₂ , CIN ₄ O ₄ S 1/6 CH ₂ Cl ₂ :

Calculated: C, 49.70; H, 4.90; N, 12.77 Found: C, 49.82; H, 4.84; N, 12.77.

Example 57

5- [2-Ethoxy-5- (4-methylpiperazinyl) phenyl] ethyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7 -you

The title sulfonamide was 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one- and N-methylpiperazine as in Example 9 in 43% yield as a colorless solid.

Melting point: 160-162 ° C.

Analysis for C ₂₃ H ₃₂ N ₆ O ₄ S Calcd: Calculated: C% = 56.54, H% = 6.60, N% = 17.20;

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

Rf 0.35 (silica; dichloromethane: methanol = 9: 1).

Example 58

5- {2-Ethoxy-5- [4- (2-hydroxy-ethyl) -piperazinylsulfonyl] -phenyl} -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazole [4, 3-d] pyrimidin-7-one

The title sulfonamide was prepared from 5- (5-chlorosulfonyl-2-ethoxyphenyl) -1-ethyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one and Obtained from N- (2-hydroxyethyl) piperazine according to Example 9 as a colorless solid in 88% yield.

Melting point: 191-193 ° C.

Elemental analysis calculated for C ₂₄ H ₃₄ N ₆ O ₅ S: Calculated:

C, 55.58; H, 6.61; N, 16.20;

Found:

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

Claims (8)

CLAIMS 1. Pyrazolo-pyrimidinones of formula (I) wherein R ¹ is hydrogen, C 1-3 alkyl, C 3-5 cycloalkyl, or C 1-3 perfluoroalkyl, R ² is hydrogen, C 1-6 alkyl optionally substituted with hydroxy, C 13 alkoxy, C 3-6 cycloalkyl, or C 1-3 perfluoroalkyl, R ³ is C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 3-7 cycloalkyl, C 1-6 perfluoroalkyl, or (C 36 cycloalkyl) -1-6 carbon atoms alkyl, R ⁴ together with the nitrogen atom to which it is attached may form a 4-N- (R ⁶ ) -piperazinyl group, R ⁵ is hydrogen, C 1-4 alkyl, C 1-3 alkoxy, NR ⁷ R ⁸ or CONR ⁷ R ⁸ , R ⁶ is hydrogen, (C 1 -C 6) alkyl, (C 13 -alkoxy) -2 (C 6) alkyl, hydroxy (C 2 -C 6) alkyl, (R ⁷ R ⁸ N) C 2 -C 6 alkyl, ( R ⁷ R ^{8 is} NCO) -1-10 alkyl, CONR ⁷ R ⁸ , CSNR ⁷ R ⁸ or C (NH) NR ⁷ R ⁸ ; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen, C 14 alkyl, C 1 -C 3 alkoxy-C 2 -C 4 alkyl, and hydroxy (C 2 -C 4 alkyl) and pharmaceutically acceptable salts thereof. A compound according to claim 1, wherein R ¹ is hydrogen, methyl or ethyl, R ² is C 1 -C 3 alkyl optionally substituted with hydroxy or methoxy, R ^{3 is C} 2 -C ³ alkyl or allyl, R ⁵ is hydrogen, NR ⁷ R ⁸ or CONR ⁷ R ⁸ ; R ⁶ is hydrogen, (C 1 -C 3) alkyl or hydroxy (C 2 -C 3) alkyl, CONR ⁷ R ⁸ or CSNR ⁷ R ⁸ or C (NH) NR ⁷ R ⁸ ; and ^R7 and ^R8 are independently hydrogen or methyl. The compound of claim 2, wherein R * is methyl, R ² is n-propyl; R ³ is ethyl, n-propyl or allyl; R ⁵ is hydrogen; R ⁶ is hydrogen, C 1-3 alkyl, or 2-hydroxyethyl. The compound of claim 3, which may be 5- [2-allyloxy-5- (4-methyl-piperazinyl-sulphonyl) phenyl] -lmetil-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidine 7-one; 5- [2-ethoxy-5- (piperazinyl) phenyl] -l-methyl-3-n-propyl-l, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-ethoxy-5- (4-methylpiperazinyl) phenyl] -lmetil-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7- you; 5- {2-Ethoxy-5- [4- (2-propyl) -piperazinylsulfonyl] -phenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidin-7-one; 5- {2-ethoxy-5- [4- (2-hydroxyethyl) piperazinylsulphonyl] 12 I A9 phenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3d] pyrimidin-7-one; l-methyl-5- [5- (piperazinylsulfonyl) -2-n-propoxyphenyl] -3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; and 5- {5- [4- (2-Hydroxyethyl) piperazinylsulfonyl] -2-n-propoxyphenyl} -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] -pyrimidin-7-one and pharmaceutically acceptable salts thereof. Pharmaceutical compositions, characterized in that a compound according to any one of claims 1-4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 together with pharmaceutically acceptable carriers or diluents. 6. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 4, in particular for angina, hypertension, heart failure or atherosclerosis 5 treatment. The pharmaceutical composition according to claim 5 for the treatment of angina, hypertension, heart failure or atherosclerosis. 8. A method of treating angina, hypertension, heart failure, or atherosclerosis in a human, comprising administering to said subject an effective amount of a compound of any one of claims 1-4. or a pharmaceutically acceptable salt thereof The pharmaceutical composition of claim 5 is administered.