WO2002016364A1

WO2002016364A1 - Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence

Info

Publication number: WO2002016364A1
Application number: PCT/KR2000/000951
Authority: WO
Inventors: Bong-Youl Chung; In-Sang Lee; Bong-Jun Park; Young-Keun Kim; Sung-Ji Kim; Seung-Hyun Yoon
Original assignee: LG Life Sciences Ltd; LG Chem Investment Co Ltd
Current assignee: LG Chem Ltd; LG Corp
Priority date: 2000-08-23
Filing date: 2000-08-23
Publication date: 2002-02-28
Anticipated expiration: 2003-02-23
Also published as: AU2000267375A1

Abstract

The present invention relates to polyethoxylated pyrazolopyrimidinone derivatives or pharmaceutically acceptable salts thereof, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence. In addition, the present invention relates to intermediates produced during the above process and the process for preparation thereof.

Description

POLYETHOXYLATED PYRAZOLO PYRIMIDINONE DERIVATIVES,

PROCESS FOR PREPARATION THEREOF AND PHARMACEUTICAL

COMPOSITIONS COMPRISING THE SAME FOR THE TREATMENT OF

IMPOTENCE

TECHNICAL FIELD

The present invention relates to new polyethoxylated pyrazolo[4,3-d]-pyrimidin-7- one derivatives, process for preparation thereof, and pharmaceutical composition comprising the same for the treatment of impotence.

BACKGROUND ART

Some pyrazolo[4,3-d]-pyrimidin-7-one derivatives are disclosed in EP 0 463 756 Al, WO 94/28902 and WO 98/49166 as adenosine receptor antagonists and ρhosphodiesterase(PDE) inhibitors useful in the treatment of cardiovascular diseases such as heart failure and erectile dysfunction. However, since those compounds are sparingly soluble in water (for example, water solubility of sildenafil citrate [commercial brand: Niagra] is 3.5mg/^), a considerably high dose range of from 25 tolOOmg per time has been recommended on a basis of pharmaco-kinetics.

In the aspect of absorption and distribution, the sildenafil citrate is reported to exhibit a maximum plasma concentration no earlier than 60 minutes from oral administration and also to show a decrease of absorption rate in an amount of about 29% average when it is administered together with fatty acid. Therefore, it may cause some problems when used for the aged who require a very small amount of dose and for the special patients who are suffered from kidney or liver failure, etc. It may also cause a side effect of the decrease of blood pressure, and must not be used in a combined treatment with nitrate preparations.

DISCLOSURE OF INVENTION

Thus, the present inventors extensively studied to improve the most serious defect of the aforementioned pyrazolo pyrimidinone derivatives, i.e., low solubility in water. As a result, we have found that the pyrazolo pyrimidinone derivatives according to the present invention have a high water solubility and minimized side effects, and then completed the present invention.

More specifically, the present invention relates to new polyethoxylated pyrazolo pyrimidinone derivatives having a variety of physical and chemical characteristics, wherein the neutral polyether, that is, polyethylene glycol, is combined by a covalent bond. Although the present compounds do not have a basic but a neutral molecular structure, they have a superior water solubility to the existing inhibitors against cyclic guanosine 3',5'-monophosphate phosphodiesterase(cGMP PDEs), for example, sildenafil citrate.

Due to the characteristics as stated above, the compounds of the present invention may effect the optimum drug delivery; result in the inhibition of vasoconstriction as well as vasodilation even with a small dose; and ultimately maximize the desired effect for the treatment of erectile dysfunction. Further, in accordance with the decrease of dose, side effects may be minimized.

Therefore, it is the object of the present invention to provide new polyethoxylated pyrazolo[4,3-d]-pyrimidin-7-one derivatives, process for preparation thereof, and pharmaceutical composition comprising the same for the treatment of impotence.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides compounds of the following formula (1):

in which

Ri represents hydrogen; Cι ~C₆ alkyl; Cι~C₆ alkyl substituted by C₃ ~C₆ cycloalkyl; C₃ ~C₅ cycloalkyl; Ci ~C₃ perfluoroalkyl; C₃ ~C₆ alkenyl; C₃ ~C₆ alkynyl; or Ci ~C₃ alkoxy C₂~C₆ alkyl; wherein the substituents are present in straight-chain or branched type; and n represents an integer of 2 —400, or pharmaceutically acceptable salts thereof.

Unless otherwise indicated in the present specification, the substituents having 3 or more carbon atoms may exist in straight-chain or branched type.

A preferred group of compounds of formula (I) is that wherein Ri represents hydrogen or Ci ~ C₄ alkyl, for example, methyl or ethyl, and n represents an integer of 2 ~ 50. The most preferred individual compounds of the invention include:

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

5-[2-ethoxy-5-(4-polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l-methyl-3- n- propyl- 1 ,6-dihydro-7H-pyrazolo-[4,3 -d]-pyrimidin-7-one(n^:=8);

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

5-[2-ethoxy-5-(4-ω -methyl polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l- methyl-3 -n-propyl- 1 , 6-dihydro-7H-pyrazolo- [4, 3 -d] -pyrimidin-7-one(n=44) .

The compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. Such salt includes pharmaceutically acceptable acid addition salt, for example, hydrochloride, hydrobromide, sulfate or bisulfate, phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate, tartrate, etc. Also, the compound of formula (1) can form a pharmaceutically acceptable metal salt, preferably alkali metal salt such as sodium or potassium salt.

All the individual compounds or mixtures of the compound of formula (1) are included in the scope of the present invention. Further, the compound of formula (1) labeled with radioisotopes, which is appropriate for the biological studies, is included in the scope of the present invention.

The compound of formula (1) may be prepared from a compound of the following formula (2):

in which Ri and n are defined as previously described, according to a known cyclization method. For example, the compound of formula (1) can be prepared by the cyclization of the compound of formula (2) under reflux in a suitable inert solvent, for example, a solvent mixture of ethanol-water in the presence of a suitable inorganic base, for example, sodium hydroxide, and H₂O2 at the reflux temperature to a pyrimidinone ring. In this reaction, hydrogen peroxide is used in an amount of 5 to 10 equivalents, preferably 2 to 4 equivalents with respect to the compound of formula (2). The inorganic base is used in an amount of 1 to 5 equivalents, preferably 1.1 to 2 equivalents with respect to the compound of formula (2). Also, the reaction is carried out for about 5 hours.

The compound of formula (2) used in the above reaction may be prepared by hydrolyzing a compound of the following formula (3a):

in which

Ri and n are defined as previously described, and

R₂' represents Cι-C₄ alkyl or sulfonyl group such as p-toluenesulfonyl, Cι-C alkylsulfonyl or Cδ-Cio arylsulfonyl, which is a compound of the following formula (3) wherein R₂ is not hydrogen:

in which

Ri and n are defined as previously described, and R₂ represents hydrogen, Cι-C₄ alkyl, or sulfonyl group such as p-toluenesulfonyl, Ci-

C₄ alkylsulfonyl or C₆-Cιo arylsulfonyl, in a suitable inert solvent, for example, a solvent mixture of methanol-water in the presence of a suitable strong base, for example, potassium hydroxide or sodium hydroxide to remove the protecting group of R₂', removing the solvent, and then reacting with a known compound of the following formula (4):

in a suitable solvent, for example, methylene dichloride in the presence of a suitable condensing agent, for example, l,3-dicyclohexylcarbodiimide(DCC) and a suitable catalyst, for example, a tertiary amine such as N',N'-dimethyl-4-aminopyridine. A compound of the following formula (3b):

in which

Ri and n are defined as previously described, and R₂" represents hydrogen, which is the compound of formula (3) wherein R₂ is hydrogen, may not have to be subjected to the hydrolysis reaction for removing the protecting group, but directly reacted with the compound of formula (4) in a suitable solvent, for example, methylene dichloride in the presence of a suitable condensing agent, for example, 1,3-dicyclohexylcarbodiimide (DCC) and a suitable catalyst, for example, a tertiary amine such as N',N'-dimethyl-4- aminopyridine, to give the compound of formula (2).

In the above reaction, the compound of formula (4) is preferably used in an amount of about 1 equivalent with respect to the compound of formula (3). The condensing agent, for example, l,3-dicyclohexylcarbodiimide(DCC), is suitably used in an amount of 1.1 to 3.0 equivalents, preferably 1.1 to 2.0 equivalents with respect to the compound of formula (3). The catalyst, for example, N',N'-dimethyl-4-aminopyridine, is suitably used in an amount of 0.1 to 1.0 equivalent, preferably 0.2 to 0.5 equivalent with respect to the compound of formula (3).

While, the compound of formula (3) may be prepared by a process characterized in that

(a) a compound of the following formula (5):

in which R₂' is defined as previously described, is reacted with chlorosulfonic acid to give a compound of the following formula (5 a):

in which R₂' is defined as previously described, and the resulting compound of formula (5a) is reacted with a compound of the following formula (6):

R₁0(CH₂CH₂θ)_πCH₂CH₂— N NH (6) •

in which Ri and n are defined as previously described, to give the compound of formula (3a), or

(b) the compound of formula (3 a) is hydrolyzed in the presence of a strong base to remove the protecting group R2' and to give the compound of formula (3b).

The above reaction is carried out in an inert solvent and the acid addition product which is formed during the reaction is removed. The compound of formula (6) is used in an excess amount, preferably in an amount of 2.0 to 4.0 equivalents, more preferably 2.0 to 3.0 equivalents with respect to the compound of formula (5).

The compound of formula (6) used in the above reaction may be prepared by introducing a reactive leaving group of X (where, X represents halogen, preferably bromine or iodine, or sulfonate) into a compound of the following formula (6a):

R_l0(CH₂CH₂0)_nCH₂CH₂-0H (6a)

in which Ri and n are defined as previously described, in an inert solvent, for example, methylene dichloride, then by heating under reflux with piperazine.

The whole process for preparing the compound of formula (1) may be depicted as in the following reaction scheme 1 :

Reaction Scheme 1

in which Ri, n, R₂' and X are defined as previously described.

All of the reactions as depicted in the above Reaction Scheme 1 are conventional in the art to which the present invention pertains and suitable chemicals and conditions for carrying out the reactions can easily be provided from the textbooks or the following preparations and examples. In addition, the compound of formula (1) produced by the process according to the present invention can easily be converted to a salt form thereof in the conventional manner in this art.

As identified from the following Experiments 1 and 2, since the compound of the present invention exhibits a high relaxation effect for corpus cavernosum penis and a good water solubility, it can be advantageously used for the treatment of erectile dysfunction. Further, the compound of the present invention can be utilized for the treatment of angina, hypertension, congestive heart failure, atherosclerosis, etc. as a pyrazolo pyrimidinone based inhibitor against the enzyme of phosphodiesterase(PDE). Therefore, the present invention also provides a pharmaceutical composition for use in the treatment of angina, hypertension, congestive heart failure, atherosclerosis and erectile dysfunction, which comprises the compound of formula (1).

When the compound according to the present invention is used for clinical purpose, it is administered in an amount ranging from 0.001 to 50mg, preferably from 0.01 to 50mg, most preferably from 0.1 to 20mg per kg of body weight a day. However, the specific administration dosage for the patient can be varied with the specific compound used, body weight, sex, hygienic condition and diet of the subject patient, time and method of administration, mixing ratio of the agent, severity of the disease to be treated, etc.

The compound of the present invention may be administered in the form of oral preparations, injections, or ointments for external use, etc. depending on the purpose. As the oral preparations, capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets can be mentioned. These preparations may be prepared according to the conventional manner. For example, tablets may be prepared by mixing the active compound of formula (1) according to the present invention with at least one carrier selected from a group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricants such as magnesium stearate, disintegrating agent and binding agent. Injections, for example, sterilized aqueous or oily suspension for injection, can be prepared according to the known procedure using suitable dispersing agent, wetting agent, or suspending agent. Solvents which can be used for preparing injections include the conventional solvents or suspending media such as water, sterilized fixing oil, etc.

The present invention will be more specifically explained in the following

Preparations, Examples and Experiments. However, it should be understood that they are intended to illustrate the present invention but not in any manner to limit the scope of the present invention.

Preparation 1

Synthesis of 4-amino-l-methyl-3-n-propylpyrazole-5-carboxamide

[Compound of formula (4)]

The compound of formula (4) was prepared from 3-n-propylpyrazole-5-carboxylic acid ethyl ester (prepared according to the method disclosed in Chem.Pharm.BulL, 1984, 32, 1568) according to the method known in EP 0 463 756 Al as follows.

A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester(24.1g, 0.132mol) and dimethylsulfate(16.8g, 0.133mol) was heated to 90 "C for 2.5 hours. This mixture was dissolved in methylene dichloride and the resulting solution was washed with sodium carbonate solution. The organic layer was separated, dried over MgSO , and evaporated under reduced pressure to give a solid. This solid was subjected to silica gel(300g) chromatography using methylene dichloride as an eluent to give a product(20.4g, 79%) as a colorless oil. l-Methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester(20.2g, O.lOmol) thus obtained was suspended in 6N aqueous sodium hydroxide solution(50m , 0.30mol), heated to 80 ^°C for 2 hours, diluted with water(50m-^β), acidified with cone, hydrochloric acid(25m^), and then filtered to give a carboxylic acid(12.3g, 72%, m.p. 150-154^°C) as a light brown crystal.

l-Methyl-3-n-propylpyrazole-5-carboxylic acid(12.1g, 0.072mol) as obtained above was introduced into a mixture of fuming sulfuric acid(13m^) and fuming nitric acid(llmδ) while maintaining a temperature of 60 ^°C or less. The mixture was heated at 60 ^°C for 12 hours, cooled, and then added dropwise to an ice. The precipitate was filtered to give nitropyrazole(11.5g, 75%, m.p.124-127 ^°C) as a white solid. l-Methyl-4-nitro-3- n-propylpyrazole-5-carboxylic acid(11.3g, 0.053 mol) thus obtained was added to thionyl chloride(50iτK!) and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled and the excess thionyl chloride included therein was removed by evaporation under reduced pressure. The oily residue was dissolved in acetone(50m-2)₃ and the resulting solution was carefully added to a mixture of ice(50g) and cone, aqueous ammonium hydroxide solution(50m^). The precipitate was filtered and dried to give pyrazolecarboxamide(8.77g, 78%), m.p. 141-143 °C) as a solid.

l-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide(3.45g, 16.2mmol) as obtained above and stannous chloride dihydrate(18.4g, Slmmol) were suspended in ethanol and the resulting mixture was heated under reflux for 2 hours. The reaction solution was cooled to room temperature and 2N aqueous sodium hydroxide solution was added thereto to make a basic solution of pH 9 which was then extracted with methylene dichloride. The organic extracts were combined and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was triturated with ether to give the title compound(2.77g, 94%, m.p. 98-101 °C) as a gray solid.

Preparation 2

Synthesis of G) -methyl trimethyleneglycolyl tosylate

Triethyleneglycol mono methyl ether(32.84g, 0.2mol), toluene(200"^), p-toluene sulfonyl chloride(43.85g, 0.23mol), and triethylamine(60.7g, O.όmol) were mixed together and stirred at room temperature. The reaction solution was reacted for further 4 hours. A large quantity of water was added to separate the layer and then dried over MgSO₄. The solvent was removed under reduced pressure to give the title compound(60.4g, 95%) as a liquid.

1H NMR (300 MHz, CDC1₃) : δ 2.40(s, 3H), 3.37(s, 3H), 3.52~3.79(m, 10H), 4.16(m, 2H), 7.35(d, 2H), 7.79(d, 2H)

Preparation 3

Synthesis of ω -methyl polyethyleneglycolyl tosylate(Average molecular weight : 504)

The title compound(45g, 90%) as a liquid was obtained according to the same procedure as Preparation 2 except that polyethyleneglycol methyl ether(Average molecular weight: 350)(35g, O. lmol) was used instead of triethyleneglycol mono methyl ether. 1H NMR (300 MHz, CDC1₃) : δ 2.39(s, 3H), 3.35(s, 3H), 3.51 ~3.80(m, 27H), 4.14(m, 2H), 7.33(d, 2H), 7.76(d,

2H)

Preparation 4

Synthesis of polyethyleneglycolyl tosylate(Average molecular weight : 554)

The title compound(44g, 80%) as a liquid was obtained according to the same procedure as Preparation 2 except that polyethyleneglycol(Average molecular weight: 400)(40g, O.lmol) was used instead of triethyleneglycol mono methyl ether. 1H NMR (300 MHz, CDC1₃) : δ 2.41(s, 3H), 3.57~3.71(m, 31H), 4.15(m, 2H), 7.35(d, 2H), 7.78(d, 2H)

Preparation 5 Synthesis of ω -methyl polyethyleneglycolyl (Average molecular weight : 704)

The title compound(65g, 92%) as a liquid was obtained according to the same procedure as Preparation 2 except that polyethyleneglycol methyl ether( Average molecular weight: 550)(55g, 0. lmol) was used instead of triethyleneglycol mono methyl ether.

1H NMR (300 MHz, CDC1₃) : δ 2.40(s, 3H), 3.36(s, 3H), 3.50~3.82(m, 45H), 4.14(m, 2H), 7.34(d, 2H), 7.77(d, 2H)

Preparation 6

Synthesis of ω -methyl polyethyleneglycolyl tosylate(Average molecular weight : 2154)

The title compound(51g, 95%) as a solid was obtained according to the same procedure as Preparation 2 except that polyethyleneglycol methyl ether(Average molecular weight: 2000)(50g, 0.025mol) was used instead of triethyleneglycol mono methyl ether. 1H NMR (300 MHz, CDC1₃) : δ 2.42(s, 3H), 3.39(s, 3H), 3.50~3.83(m, 177H), 4J8(m, 2H), 7.35(d, 2H), 7.80(d, 2H)

Preparation 7

Synthesis of 4-ω -methyl triethyleneglycolyl piperazine

ω -Methyl triethyleneglycolyl tosylate(6.36g, 0.02mol) prepared in Preparation 2 was dissolved in methylene dichloride(15πn^)₅ and piperazine(10g, 0.12mol) was added thereto. The reaction solution was heated under reflux for 12 hours and cooled to room temperature. A large quantity of 5% aqueous sodium chloride solution was added to separate the layer which was then washed and dried over MgSO₄. The solvent was removed under reduced pressure to give the title compound(3.25g, 70%) as a liquid. 1H NMR (300 MHz, CDC1₃) : δ 2.55 ~2.61(m, 6H), 3.42(s, 3H), 3.53 ~3.70(m, 14H)

Preparation 8

Synthesis of 4-ω -methyl polyethyleneglycolyl piperazine (Average molecular weight : 418)

The title compound(3 Ig, 75%) as a liquid was obtained according to the same procedure as Preparation 7 except that ω -methyl polyethyleneglycolyl tosylate (Average molecular weight: 504)(50g, O.lmol) prepared in Preparation 3 was used instead of 0) - methyl triethyleneglycolyl tosylate.

1H NMR (300 MHz, CDC1₃) : δ 2.53 ~2.62(m, 6H), 3.43(s, 3H), 3.51 ~3.69(m, 31H)

Preparation 9 Synthesis of 4-polyethyleneglycolyl piperazine (Average molecular weight :

468)

The title compound(30g, 65%) as a liquid was obtained according to the same procedure as Preparation 7 except that polyethyleneglycolyl tosylate(Average molecular weight: 554)(55g, O.lmol) prepared in Preparation 4 was used instead of ω -methyl triethyleneglycolyl tosylate.

1H NMR (300 MHz, CDC1₃) : δ 2.56 ~2.63(m, 6H), 3.51 ~3.73(m, 35H)

Preparation 10

Synthesis of 4-ω -methyl polyethyleneglycolyl piperazine (Average molecular weight : 618)

The title compound(48g, 77%) as a liquid was obtained according to the same procedure as Preparation 7 except that ω -methyl polyethyleneglycolyl tosylate (Average molecular weight: 704)(70g, O.lmol) prepared in Preparation 5 was used instead of ω - methyl triethyleneglycolyl tosylate.

1H NMR (300 MHz, CDC1₃) : δ 2.52~2.60(m, 6H), 3.43(s, 3H), 3.50 ~3.69(m, 49H)

Preparation 11

Synthesis of 4-ω -methyl polyethyleneglycolyl piperazine (Average molecular weight : 2068)

The title compound(16g, 78%) as a solid was obtained according to the same procedure as Preparation 7 except that ω -methyl polyethyleneglycolyl tosylate (Average molecular weight: 2154)(21g, O.Olmol) prepared in Preparation 6 was used instead of ω - methyl triethyleneglycolyl tosylate.

1H NMR (300 MHz, CDC1₃) : δ 2.50 ~2.63(m, 6H), 3.41(s, 3H), 3.53 ~3.75(m, 18 IH)

Preparation 12

Synthesis of 2-ethoxy-benzoic acid methyl ester

2-Ethoxybenzoic acid(20g, 0.12mol) and sodium hydrogen carbonate(12.1g,

0.14mol) were dissolved in acetone(50m-2). Dimethylsulfate(22.8g, 0.18mol) was slowly added dropwise thereto, and the resulting mixture was heated under reflux for 10 hours and then cooled. Acetone was removed under reduced pressure and the residue was diluted with methylene dichloride(100m^)₅ washed with 10% aqueous sodium hydrogen carbonate solution, dried over MgSO₄, and filtered. The solvent was removed under reduced pressure and the residue was subjected to fractional distillation under reduced pressure(5mmHg) to give the title compound (14.2g, 66%) as a colorless liquid. 1H NMR (300 MHz, CDC1₃) : δ 1.45(t, 3H), 3.90(s, 3H), 3.96(s, 3H), 4.12(q, 2H), 6.94~6.98(m, 2H), 7.40 ~ 7.44(t, IH), 7.76~7.79(d, IH) Molecular weight(M+l)⁺ = 181

Preparation 13

Synthesis of 5-chlorosulfonyl-2-ethoxy-benzoic acid methyl ester

To chloro sulfonyl chloride(50m^) cooled to 0^°C was slowly added dropwise 2- ethoxy-benzoic acid methyl ester(14.1g, 0.08mol) and the mixture was stirred for 2 hours at room temperature. The reaction solution was slowly added dropwise to ice water(3^ ), which was then extracted with methylene dichloride, dried over MgSO and filtered. The solvent was removed under reduced pressure to give the title compound(12g, 55%) as a white solid.

1H NMR (300 MHz, CDC1₃) : δ 1.52(t, 3H), 3.93(s, 3H), 4.24(q, 2H), 7.12(d, IH), 8.07~8.11(dd, IH), 8.45(s, IH) Molecular weight(M+l)⁺ = 279

Example 1

Synthesis of 2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinyl- sulfonyl)-benzoic acid methyl ester

5-Chlorosulfonyl-2-ethoxy-benzoic acid methyl ester(1.8g, 0.007mol) and 4-ω - methyl triethyleneglycolyl piperazine(4.5g, 0.019mol) prepared in Preparation 7 were dissolved in methylene dichloride(35m ) and stirred for 10 hours at room temperature. The reaction solution was diluted with methylene dichloride(50f^), washed with 5% aqueous sodium chloride solution, dried over MgSO₄, and filtered. The solvent was removed under reduced pressure to give the title compound(2. Ig, 68%) as a liquid. 1H NMR (300 MHz, CDC1₃) : δ 1.50(t, 3H), 2.58(br, 6H), 3.03(br, 4H), 3.37(s, 3H), 3.50~3.59(m, 10H), 3.72(s, 3H), 4J8(q, 2H), 7.04(d, IH), 7.81(d, IH), 8.14(s, IH) Molecular weight(M+l)⁺ = 475 Examples 2 ~ 5

Compounds of formula (3) as described in the following Table 1 were obtained according to the same procedure as Example 1 except that each of the compounds prepared in Preparations 8 to 11 was used instead of 4-ω -methyl triethyleneglycolyl piperazine.

Table 1

Compounds of Examples 2~5

Example 6

Synthesis of 4-[2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinyl- sulfonyI)benzamido]-l-methyl-3-n-propylpyrazole-5-carboxamide

2-Ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinylsulfonyl)-benzoic acid methyl ester(1.2g, 0.004mol) was dissolved in methanol(50m-6), sodium hydroxide(0.5g, 0.013mol) and water(0.05πr !) were added thereto, and the resulting mixture was stirred for 30 minutes. The solution was adjusted to pH 3-4 by lN-aqueous hydrochloric acid solution and the solvent was removed under reduced pressure. To this solution were added methylene dichloride(100m^)₃ dicyclohexyl- carbodiimide(0.75g, 0.004mol), N',N'- dimethyl-4-aminopyridine(0.25g, 0.002mol) and 4-amino-l-methyl-3-n-propylpyrazole-5- carboxamide(0.75g, 0.004 mol), which was then stirred for 1 hour. The reaction solution was filtered, washed with lN-aqueous hydrochloric acid solution, and then dried. The solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography to give the title compound(2.3g, 90%) as a white solid. 1H NMR (300 MHz, CDC1₃) : δ 0.96(t, 3H), 1.59(t, 3H), 1.65(m, 2H), 2.56(m, 8H), 3.04(br, 4H), 3.36(s, 3H), 3.50 ~3.62(m, 10H), 4.06(s, 3H), 4.40(q, 2H), 5.92(br, IH), 7.18(d, IH), 7.62(br, IH), 7.88(d, IH), 8.58(s, IH), 9.28(br, IH) Molecular weight(M+l)⁺ = 625

Examples 7 ~ 10

Compounds of formula (2) as described in the following Table 2 were obtained according to the same procedure as Example 6 except that each of the compounds prepared in Examples 2 to 5 was used instead of 2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinylsulfonyl)-benzoic acid methyl ester.

Table 2

Compounds of Examples 7~ 10

Example 11

Synthesis of 5-[2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinyl- sulfonyl)phenyl]-l-methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7- one

4-[2-Ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinylsulfonyl)benzamido]- l-methyl-3-n-ρropylpyrazole-5-carboxamide(1.05g, 0.002mol) was dissolved in ethanol(30 mi), sodium hydroxide(0.14g, 0.003mol), 30% hydrogen peroxide(0.55m ) and water(5mg) were added thereto, and the mixture was heated under reflux for 5 hours. After cooling, the solvent was removed under reduced pressure and the residue was neutralized by 2N- aqueous hydrochloric acid solution, extracted with methylene dichloride, dried over MgSO₄, and filtered. The solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography to give the title compound(0.92g, 90%) as a white solid. 1H NMR (300 MHz, CDC1₃) : δ 1.02(t, 3H), 1.64(t, 3H), 1.82(m, 2H), 2.59(m, 6H), 2.92(t, 2H), 3.09(br, 4H), 3.34(s, 3H), 3.50~3.59(m, 10H),4.27(s, 3H), 4.36(q, 2H), 7.13(d, IH), 7.81(d, IH), 8.79(s, IH), 10.82(br, IH)

Molecular weight(M+l)⁺ = 607

Examples 12 ~ 15

Compounds of formula (1) as described in the following Table 3 were obtained according to the same procedure as Example 11 except that each of the compounds prepared in Examples 7 to 10 was used instead of 4-[2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinylsulfonyl)benzamido]-l -methyl-3-n-propylpyrazole-5-carbo- xamide.

Table 3

Compounds of Examples 12 — 15

Biological activity and water solubility of the compounds according to the present invention were determined in the following Experiments.

Experiment 1

Relaxation test for corpus cavernosum penis

Relaxation effect of the compound of formula (1) and the standard compound of sildenafil citrate (commercial brand: Niagra) for the smooth muscle of corpus cavernosum penis was determined against mature male rabbit from New Zealand and the results were compared.

The groups including 7 test animals per group were treated with different test compounds group by group. The relaxation effect for the smooth muscle section of corpus cavernosum penis was measured according to the concentration of the test compounds and statistically analyzed. Then, the relaxation effects of the compound of formula (1) and sildenafil citrate at the same concentration were compared.

1. Method

Mature white rabbits(male, 2.0-2.5kg) from New Zealand were prepared. Air was injected into venae ear concha of the rabbit which was to be instantly killed, and the penis was taken out. Connective tissue around the corpus cavernosum penis was removed in a petri dish in which cold Kreb's solution was contained under oxygen gas ventilation under a microscope to prepare a tissue section having a size of 1 x2 8mm of the corpus cavernosum penis.

The resulting tissue section was introduced into an organ chamber in which lOcc of Kreb's solution(sodium chloride 118.3, potassium chloride 4.7, magnesium sulfate 0.6, potassium hydrogen phosphate 1.2, calcium hypochloride 2.5, sodium hydrogen carbonate 25.0 and glucose 11.1 ; each unit is mM/! ) was contained. After both ends of the section were tied together with a suture, one end was bound to a L-shaped metallic ring to be fixed in the organ chamber and the other end was bound to a fixed ring of a tension converter. Mixed gas of 95% oxygen(O₂) and 5% carbon dioxide(CO2) was passed through, and pH 7.4 and a temperature of 37^°C were maintained. The section of corpus cavernosum was culcured for 2 hours during which the medium was replaced with a fresh one at every 20 — 30minutes.

The tension change of the section observed from the polygraphy which was bound to the tension converter was measured. After adding lgm of tension through the tension sensor at the end of the tension converter, 10% or less of tensional difference between the maximum contractile tension against the administered phenylephrine(10^"5 M) and the earlier tension, was regarded as an isotonic tension.

The section was washed and cultivated again and then, phenylephrine(10^"8— 10^" ³M) was added as an accumulated concentration to measure the maximum tension at the time of contraction of the section. In the contractile tension profile, the concentration which induces EC50 was calculated.

After the section was contracted by the pretreatment of phenylephrine(10^"5 M), sildenafil citrate(10^"8 — 10^"4 M) and the compounds of formula (1) prepared in Examples 11 — 15 were administered, respectively, to measure the relaxation tension of the section.

Relaxation rate of sildenafil citrate and the compound of formula (1) was statistically analyzed.

2. Result The experimental results were represented in the following Table 4. Table 4

Comparison of Relaxation rate(%)

^1:p < 0.05, **p < 0.01

1) Relaxation effect of sildenafil citrate

In the relaxation reaction of the section contracted by the pretreatment of phenyl ephrine(10^"5 M) at the accumulated concentration of sildenafil citrate(10^"8~10^"4 M), there were no significant relaxation at the concentration of up to 3 x 10^"5 M and a relaxation rate of 20.6 +8.12% (number of individuals^) at the concentration of 10^"4 M.

2) The section contracted by the pretreatment of phenylephrine(10^" M) was relaxed with the compounds of formula (1) in proportion to the concentration. The section was relaxed from the concentration of 10^"5 M and the relaxation rates versus concentrations were 25.12+5.67%, 47.98+13.25% and 100% at concentrations of 10^"5 M, 3 x 10^"5 M and 10^"4 M, respectively. The relaxation effects were compared based on the maximum relaxation rate (100%) at the concentration of 10^"4 M (number of individuals=7).

3) The compounds of formula (1) show a significantly high relaxation rate (p < 0.01) compared with sildenafil citrate at concentrations of 10^"5 — 10^"4 M.

It can be seen from the above results that the compounds of formula (1) have ten times higher reaction threshold concentration and exhibit four to five times more excellent relaxation effect at the same concentration of 10^"4 M, when compared with sildenafil citrate(Viagra). Experiment 2 Water solubility

OJm-0 of distilled water was added to 10^"5 mol of the compound of formula (1) to observe whether or not the compound is dissolved in water. 40/^ of the aqueous solution was diluted with lm-g of acetonitrile, and the remaining aqueous solution was filtered through a filter having a pore size of 0.1 m. 40/t^β of the filtrate was diluted with lπti! of acetonitrile. Those two kinds of samples were analyzed by liquid chromatography to determine whether or not the compound is dissolved. If the compound is not dissolved when visually observed or 5% or more difference in the peak area of liquid chromatography is appeared, the compound is regarded to have not been dissolved in water, and in this case 1 m-^β of distilled water was added again to 10^"5 mol of the compound of formula (1). Then, the experiment was repeated in the same manner as above.

Whether or not the compounds are dissolved at the concentration of 10-^_lⁱ M, 10^"2 M or 10^"3 M was determined according to the above procedure and statistically analyzed to give an approximate solubility value. The results are shown in the following Table 5.

Table 5

Water solubility(pH=6, 24 °C)

When compared with the solubility of sildenafil citrate of 3.5 mg/m-0, i.e., 5.2x 10^"3 M, it can be seen that the solubility of the compounds of formula (1) is about 20 to 200 times higher than that of sildenafil citrate. INDUSTRIAL APPLICABILITY

As identified in the above experiments, the compounds of the present invention have a high water solubility in comparison with the typical inhibitors against cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDEs), for example, sildenafil citrate. Such a characteristic physical property results in the high production of cGMP, which induces a potent inhibitory activity against vasoconstriction as well as a potent vasodilator activity, and which ultimately gives an excellent therapeutic effect for impotence. The compounds of the present invention also have utilities for the treatment of various diseases including angina, hypertension, congestive heart failure, atherosclerosis, bad circulation condition in blood vessel and diseases in peripheral blood vessel.

Claims

1. A compound of the following formula ( 1 ) :

in which

Ri represents hydrogen; Cι ~ C₆ alkyl; Ct-Gs alkyl substituted by C₃ — C₆ cycloalkyl; C₃ — C₅ cycloalkyl; Ci ~ C₃ perfluoroalkyl; C₃ — C₆ alkenyl; C₃ ~ C₆ alkynyl; or Ci — C₃ alkoxy C₂ - C₆ alkyl; wherein the substituents are present in straight-chain or branched type; and n represents an integer of 2 — 400, or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 wherein Ri represents hydrogen, methyl or ethyl, and n represents an integer of 2 — 50, or pharmaceutically acceptable salts thereof.

3. The compound of claim 2 selected from the group consisting of: 5-[2-ethoxy-5-(4-ω -methyl triethyleneglycolyl piperazinylsulfonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7-one; 5-[2-ethoxy-5-(4-ω -methyl polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7-one (n=^:6); 5-[2-ethoxy-5-(4-polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l-methyl-3-n- propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7-one (n=8); 5-[2-ethoxy-5-(4-ω -methyl polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7-one (n=l 1); 5-[2-ethoxy-5-(4-ω -methyl polyethyleneglycolyl piperazinylsulfonyl)phenyl]-l- methyl-3-n-propyl-l,6-dihydro-7H-pyrazolo-[4,3-d]-pyrimidin-7-one (n=44); and pharmaceutically acceptable salts thereof.

4. A pharmaceutical composition for the treatment of impotence comprising therapeutically effective amount of the compound according to any one of claims 1 to 3.

5. A pharmaceutical composition for the treatment of angina, hypertension, congestive heart failure and atherosclerosis comprising therapeutically effective amount of the compound according to any one of claims 1 to 3.

A process for preparing the compound as defined in claim 1 characterized by a cyclization of a compound of the following formula (2):

in which Ri and n are defined as claim 1, in the presence of an inorganic base and hydrogen peroxide (H₂O₂) to a pyrimidinone ring.

7. A compound of the following formula (2):

in which Ri and n are defined as claim 1.

8. A process for preparing the compound as defined in claim 7 characterized by

(a) hydrolyzing a compound of the following formula (3 a):

in which

Ri and n are defined as claim 1, and

R₂' represents Cι-C₄ alkyl or sulfonyl group, in an inert solvent in the presence of a strong base to remove the protecting group of R2', and then reacting with a compound of the following formula (4):

in the presence of a condensing agent and a catalyst of tertiary amine; or

(b) reacting a compound of the following formula (3b):

in which

Ri and n are defined as claim 1, and R₂" represents hydrogen, with the compound of formula (4) in an inert solvent in the presence of a condensing agent and a catalyst of tertiary amine.

9. A compound of the following formula (3):

in which

Ri and n are defined as claim 1, and

R₂ represents hydrogen, Cι-C₄ alkyl or sulfonyl group.

10. A process for preparing the compound as defined in claim 9 characterized in that

(a) a compound of the following formula (5):

in which R2' is defined as claim 8, is reacted with chlorosulfonic acid in an inert solvent to give a compound of the following formula (5a):

in which R₂' is defined as claim 8, and the resulting compound of formula (5 a) is reacted with a compound of the following formula (6): RιO(CH₂CH₂θ)_nCH₂CH₂— N H (6)

in which Ri and n are defined as claim 1, to give a compound of the following formula (3 a):

in which

Ri and n are defined as claim 1, and R₂' is defined as claim 8, or

(b) the compound of formula (3a) is hydrolyzed in the presence of a strong base to remove the protecting group R2' and to give a compound of the following formula (3 b):

in which

Ri and n are defined as claim 1, and

R2" is defined as claim 8.