KR20020015810A - Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence - Google Patents

Abstract

PURPOSE: Provided are a polyethoxylated pyrazolo pyrimidinone derivative, its pharmaceutically acceptable salt, a preparation process thereof and pharmaceutical compositions comprising the same for the treatment of impotence. CONSTITUTION: The polyethoxylated pyrazolo pyrimidinone derivative is represented by the formula(1), wherein R1 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl substituted C1-C6 alkyl, C3-C5 cycloalkyl, C1-C3 perfluoroalkyl; C3-C6 alkenyl; or C1-C3 alkoxy C2-C6 alkyl, where the substituent is linear or branched type; and n is an integer of 2-400.

Description

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

The present invention relates to a novel polyethoxylated pyrazolo [4,3-d] pyrimidin-7-one derivative, a preparation method thereof, and a composition for treating erectile dysfunction comprising the same.

European Patent Application EP 0 463 756 A1, PCT International Publication No. WO 94/28902 and PCT International Publication No. WO 98/49166 include adenosine receptor antagonists and phosphodiesterase (PDE) inhibitors for cardiovascular diseases such as heart failure. And some pyrazolo [4,3-d] pyrimidin-7-ones useful for treating erectile dysfunction. However, these compounds have very low solubility in water (for example, the water solubility of sildenafil citrate [trade name Viagra] is 3.5 mg / ml) and the pharmacokinetic recommended dosage range for a single dose is 25-100 mg. It is known to be quite high.

In addition, the conventional sildenafil citrate, the highest plasma concentration, which shows the efficacy of the drug in terms of absorption and distribution, appears only after 60 minutes after oral administration, and when taken with fatty acids, the absorption rate is decreased by an average of 29%. It is.

Therefore, it is particularly problematic in the treatment of elderly patients who require extremely low doses and special patients such as renal failure and liver failure, pharmacokinetics may cause side effects of blood pressure reduction, and co-administration with nitrate preparations is contraindicated. have.

Accordingly, the present inventors have continued to improve the poor solubility in water, which is the biggest disadvantage of the conventional pyrazolopyrimidinone derivatives mentioned above, and as a result, the pyrazolopyrimidinone derivatives according to the present invention The present invention has been completed by finding that the solubility is large and that the various side effects noted above can be minimized.

More specifically, the present invention relates to a novel polyethoxylated pyrazolopyrimidinone derivative covalently bonded to polyethylene glycol, a neutral polyether having physically and chemically diverse properties, wherein the compound is in the form of a base. Although it has a neutral molecular structure, the solubility in water is much higher than that of conventional cyclic guanosine 3 ', 5'-monophosphatephosphodiesterases (cGMP PDEs), for example sildenafil citrate.

Due to these characteristics, the compound according to the present invention can bring about optimization of drug delivery, and even with the use of low doses, it causes vasoconstriction inhibition, vasodilating activity and ultimately maximizes the desired erectile dysfunction treatment effect. do. In addition, the dosage can be reduced to minimize side effects.

Accordingly, an object of the present invention is to provide a novel polyethoxylated pyrazolo [4,3-d] pyrimidin-7-one derivative, a method for preparing the same, and a pharmaceutical composition for treating erectile dysfunction comprising the same. .

The present invention relates to compounds of formula (1) and pharmaceutically acceptable salts thereof:

[Formula 1]

In the above formula,

R ₁ is hydrogen; C ₁ -C ₆ alkyl; C ₃ ~C ₆ alkyl substituted with C ₁ ~C ₆ by cycloalkyl; C ₃ -C ₅ cycloalkyl; C ₁ -C ₃ perfluoroalkyl; C ₃ -C ₆ alkenyl; C ₃ -C ₆ alkynyl; Or C ₁ -C ₃ alkoxy C ₂ -C ₆ alkyl; Wherein said substituent is present in a straight or branched chain;

n is an integer of 2 to 400.

In the present specification, unless otherwise indicated, substituents having three or more carbon atoms may be present in straight or branched chain.

Preferred groups of compounds of formula 1 are those wherein R ₁ is hydrogen or C ₁ -C ₄ alkyl, eg methyl or ethyl, n is an integer from 2 to 50.

Most preferred groups of compounds of Formula 1 include the following compounds:

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

5- [2-ethoxy-5- (4-ω-methyl polyethyleneglycolyl piperazinylsulfonyl) phenyl] -1-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] -1-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] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo -[4,3-d] -pyrimidin-7-one (n = 11); And

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

The compound of formula 1 may also form pharmaceutically acceptable salts. Pharmaceutically acceptable salts of compounds of formula 1 may be acid addition salts formed with pharmaceutically acceptable acids. Examples thereof include hydrochloride, hydrobromide, sulfate or bisulfate, phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and tartrate salts. The compound of formula 1 may also be a pharmaceutically acceptable metal salt, in particular an alkali metal salt, formed due to the base. Examples thereof include sodium salts and potassium salts.

Separate individual mixtures or single compounds of the compound of Formula 1 are all included in the scope of the present invention. Also included in the scope of the invention are radiolabeled derivatives of compounds of formula 1 suitable for biological studies.

The compound of Formula 1 may be prepared by applying a known cyclization method from the compound of Formula 2. For example, the pyrimidinone ring is refluxed by refluxing the compound of formula 2 at reflux in the presence of a suitable inorganic base such as sodium hydroxide and H ₂ O ₂ in a suitable inert solvent such as ethanol-water mixed solvent The reaction of Formula 1 may be prepared.

Wherein R ₁ and n are as defined above.

In this reaction, the hydrogen peroxide solution is used in 5 to 10 equivalents, preferably 2 to 4 equivalents, based on the compound of formula (2). The inorganic base is used in the amount of 1 to 5 equivalents, preferably 1.1 to 2 equivalents, based on the compound of formula (2). The reaction time is preferably about 5 hours:

The compound of formula (2) used in the reaction is a compound of formula (3), wherein R ₂ is not hydrogen, i.e. a compound of formula (3a), suitable strong base, e.g., hydroxide, in a suitable inert solvent, e. After hydrolysis in the presence of potassium or sodium hydroxide to remove the protecting group of R ₂ ′, the reaction solvent is removed and a suitable condensing agent such as 1,3-dicyclohex in a suitable solvent such as methylenedichloride It can be prepared by reaction with a known compound of formula (4) in the presence of a tertiary amine such as silk carbodiimide (DCC) and a suitable catalyst such as N ', N'-dimethyl-4-aminopyridine.

Compounds of formula (3), in which R ₂ is hydrogen, i.e. compounds of formula (3b), do not require a hydrolysis process to remove protecting groups as described above and are suitable condensing agents, for example in suitable solvents such as , 1,3-dicyclohexylcarbodiimide (DCC) and a suitable catalyst, for example, by reacting with a compound of formula 4 in the presence of tertiary amines such as N ', N'-dimethyl-4-aminopyridine Can be.

In the above formula,

R ₁ and n are as defined above,

R ₂ represents hydrogen, a C ₁ -C ₄ alkyl or sulfonyl group such as p-toluenesulfonyl, C ₁ -C ₄ alkylsulfonyl or C ₆ -C ₁₀ arylsulfonyl.

R ₂ ′ represents a C ₁ -C ₄ alkyl or sulfonyl group, for example p-toluenesulfonyl, C ₁ -C ₄ alkylsulfonyl or C ₆ -C ₁₀ arylsulfonyl,

R ₂ "represents hydrogen.

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

Meanwhile, the compound of Formula 3 is prepared by (a) reacting a compound of Formula 5 with chlorosulfonic acid to prepare a compound of Formula 5a, and reacting it with a compound of Formula 6 to obtain a compound of Formula 3a, or (b) The compound of can be prepared by hydrolysis in the presence of a strong base to remove the R ₂ ′ protecting group to give the compound of formula 3b:

[Formula 3a]

[Formula 3b]

Wherein R ₁ , n, R ₂ ′ and R ₂ ″ are as defined above.

The reaction is carried out in an inert solvent and the acid adducts generated during the reaction are removed. The compound of formula 6 is used in excess of the compound of formula 5, preferably 2.0 to 4.0 equivalents, more preferably 2.0 to 3.0 equivalents.

The compound of formula 6 used in the reaction comprises a reactive leaving group X (where X is halogen, preferably bromine or iodine or sulfonate) to a compound of formula 6a in an inert solvent such as methylenedichloride. After introduction, it can be prepared by heating to reflux with piperazine:

R ₁ O (CH ₂ CH ₂ O) _n CH ₂ CH ₂ -OH

Wherein R ₁ and n are as defined above.

The process for preparing the compound of Formula 1 is shown in Scheme 1 below:

Wherein R ₁ , n, R ₂ ′ and X are as defined above.

Each of the above reaction steps are all conventional, and suitable reagents and conditions for carrying out them can be easily obtained by reference to standard textbooks and the preparations and examples provided later. In addition, the compounds of formula 1 produced in the reaction according to the invention can be converted into salts according to conventional methods known in the art.

The compound according to the present invention exhibits a high relaxation rate for the corpus cavernosum as confirmed in Experimental Example 1 and Experimental Example 2, and can be usefully used as a therapeutic agent for erectile dysfunction because of its high solubility in water. In addition, pyrazolopyrimidinone-based phosphodiesterase (PDE) enzyme inhibitors can be usefully used as a therapeutic agent for angina, hypertension, congestive heart failure, atherosclerosis, and the like. Accordingly, the present invention provides a pharmaceutical composition for treating angina, hypertension, congestive heart failure, atherosclerosis and erectile dysfunction, comprising the compound of formula (1).

The total daily dose to be administered to a patient when administering a compound of the present invention for clinical purposes is in the range of 0.001 to 50 mg per kg of body weight, preferably 0.01 to 50 mg, most preferably 0.1 to 20 mg. However, the specific dosage level for a particular patient may vary depending on the particular compound to be used, the patient's weight, sex, health condition, diet, time of administration of the drug, method of administration, drug mixing and the severity of the disease.

The compounds of the present invention can be administered as oral preparations, injectable preparations or external ointments as desired. Preparations for oral administration include capsules, tablets, pills, powders, and granules. Particularly, capsules and tablets are preferable. The formulations can be prepared by conventional methods. For example, tablets may be prepared by mixing the compound of formula 1 according to the invention with one or more inert diluents such as sucrose, lactose, starch and the like and a carrier such as a lubricant, disintegrant, binder, etc., such as magnesium stearate have. Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, can be prepared using suitable dispersing, wetting or suspending agents according to the known art. Solvents that can be used for this purpose are water, conventional solvents such as sterile fixed oils or suspension media.

The present invention is explained in more detail by the following Preparation Examples, Examples and Experimental Examples, but the scope of the present invention is not limited in any way by these.

Preparation Example 1

Synthesis of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (compound of Formula 4)

Compound 4 is known from EP 0 463 756 A1 from 3-n-propylpyrazole-5-carboxylic acid ethyl ester (prepared by the method of Chem. Pharm. Bull., 1984, 32, 1568). According to the prepared method was prepared as follows.

A mixture of 3-n-propylpyrazole-5-carboxylic acid ethyl ester (24.1 g, 0.132 mol) and dimethyl sulfate (16.8 g, 0.133 mol) was heated to 90 ° C. for 2.5 hours. This mixture was dissolved in methylenedichloride and the solution was washed with sodium carbonate solution. The organic phase was separated, dried over MgSO ₄ and evaporated under reduced pressure to give a solid. Chromatography on silica gel (300 g) eluting with methylene dichloride gave the product (20.4 g, 79%) as a colorless oil. The thus obtained 1-methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester (20.2 g, 0.10 mol) was suspended in 6N aqueous sodium hydroxide solution (50 ml, 0.30 mol) and heated to 80 ° C. for 2 hours. The mixture was diluted with water (50 mL), acidified with concentrated hydrochloric acid (25 mL), and filtered to obtain carboxylic acid (12.3 g, 72%, melting point: 150-154 ° C) as light brown crystals.

The obtained 1-methyl-3-n-propylpyrazole-5-carboxylic acid (12.1 g, 0.072 moles) of fuming sulfuric acid (13 ml) and fuming nitric acid (11 ml) was maintained at a temperature of 60 ° C. or less. To the mixture. The mixture was heated at 60 ° C. for 12 h and after cooling the reaction solution was added dropwise onto ice. The precipitate was filtered to give nitropyrazole (11.5 g, 75%, melting point 124-127 ° C.) as a white solid. The 1-methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid (11.3 g, 0.053 mol) thus obtained was added to thionyl chloride (50 mL) and the resulting mixture was heated to reflux for 3 hours. . The reaction mixture was cooled down and excess thionyl chloride was removed by evaporation under reduced pressure. The oily residue is dissolved in acetone (50 mL) and the solution is carefully added to a mixture of ice (50 g) and concentrated aqueous ammonium hydroxide solution (50 mL), and then the precipitate is filtered and dried to give a solid pyrazolecarboxamide (8.77 g). , 78%, melting point 141-143 ° C).

The obtained 1-methyl-4-nitro-3-n-propylpyrazole-5-carboxamide (3.45 g, 16.2 mmol) and chlorinated tin tin dihydrate (18.4 g, 81 mmol) were suspended in ethanol and mixed Was heated to reflux for 2 hours. The reaction solution was cooled to room temperature, made basic in pH 9 by addition of 2N aqueous sodium hydroxide solution, extracted with methylenedichloride, combined organic extracts, dried over MgSO ₄ , and the solvent was removed under reduced pressure. The residue was triturated with ether to give the title compound (2.77 g, 94%, melting point 98-101 ° C.) as a gray solid.

Preparation Example 2

Synthesis of ω-methyl triethyleneglycocyclyl tosylate

Triethylene glycol mono methyl ether (32.84 g, 0.2 mol), toluene 200 ml, p-toluene sulfonyl chloride (43.85 g, 0.23 mol), and triethylamine (60.7 g, 0.6 mol) were mixed and stirred at room temperature It was. After further reacting the reaction solution for 4 hours, the layers were separated using a large amount of water, dried over MgSO _4, and the solvent was removed under reduced pressure to obtain a liquid title compound (60.4 g, 95%).

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.40 (s, 3H), 3.37 (s, 3H), 3.52 to 3.79 (m, 10H), 4.16 (m, 2H), 7.35 (d, 2H), 7.79 (d, 2H)

Preparation Example 3

Synthesis of ω-Methyl Polyethyleneglycolyl Tosylate (Average Molecular Weight: 504)

Liquid title compound (45 g, 90%) in the same manner as in Preparation Example 2, except that polyethylene glycol methyl ether (average molecular weight: 350) (35 g, 0.1 mol) was used instead of triethylene glycol mono methyl ether. Got.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.39 (s, 3H), 3.35 (s, 3H), 3.51 to 3.80 (m, 27H), 4.14 (m, 2H), 7.33 (d, 2H), 7.76 (d, 2H)

Preparation Example 4

Synthesis of Polyethyleneglycolyl Tosylate (Average Molecular Weight: 554)

Except for using polyethylene glycol (average molecular weight: 400) (40 g, 0.1 mol) instead of triethylene glycol mono methyl ether, the title compound (44 g, 80%) was obtained in the same manner as in Preparation Example 2. .

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.41 (s, 3H), 3.57 to 3.71 (m, 31H), 4.15 (m, 2H), 7.35 (d, 2H), 7.78 (d, 2H)

Preparation Example 5

Synthesis of ω-methyl polyethyleneglycolyl tosylate (average molecular weight: 704)

Liquid title compound (65 g, 92%) in the same manner as in Preparation Example 2, except that polyethylene glycol methyl ether (average molecular weight: 550) (55 g, 0.1 mol) was used instead of triethylene glycol mono methyl ether. Got.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.40 (s, 3H), 3.36 (s, 3H), 3.50 to 3.82 (m, 45H), 4.14 (m, 2H), 7.34 (d, 2H), 7.77 (d, 2H)

Preparation Example 6

Synthesis of ω-Methyl Polyethyleneglycolyl Tosylate (Average Molecular Weight: 2154)

Except for using polyethylene glycol methyl ether (average molecular weight: 2000) (50 g, 0.025 mol) instead of triethylene glycol mono methyl ether, the title compound was obtained in the same manner as in Preparation Example 2 (51 g, 95%). Got.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.42 (s, 3H), 3.39 (s, 3H), 3.50 to 3.83 (m, 177H), 4.18 (m, 2H), 7.35 (d, 2H), 7.80 (d, 2H)

Preparation Example 7

Synthesis of 4-ω-methyl triethyleneglycolyl piperazine

Ω-methyl triethyleneglycolyl tosylate (6.36 g, 0.02 mol) of Preparation Example 2 was dissolved in 15 ml of methylene dichloride, and then piperazine (10 g, 0.12 mol) was added thereto. The reaction solution was heated to reflux for 12 hours, cooled to room temperature, the layers were separated using a large amount of 5% aqueous sodium chloride solution, washed, dried over MgSO _4, and the solvent was removed under reduced pressure to give a liquid as the title compound. (3.25 g, 70%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.55 to 2.61 (m, 6H), 3.42 (s, 3H), 3.53 to 3.70 (m, 14H)

Preparation Example 8

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

The same method as in Preparation Example 7, except that the ω-methyl polyethyleneglycolyl tosylate (average molecular weight: 504) (50 g, 0.1 mol) of Preparation Example 3 was used instead of the ω-methyl triethyleneglycolyl tosylate. The title compound (31 g, 75%) was obtained as a liquid phase.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.53 to 2.62 (m, 6H), 3.43 (s, 3H), 3.51 to 3.69 (m, 31H)

Preparation Example 9

Synthesis of 4-polyethyleneglycolyl piperazine (average molecular weight: 468)

The same procedure as in Preparation Example 7 was conducted except that the polyethyleneglycolyl tosylate (average molecular weight: 554) (55 g, 0.1 mole) of Preparation Example 4 was used instead of ω-methyl triethylene glycolyl tosylate. The title compound (30 g, 65%) was obtained as a liquid.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.56 to 2.63 (m, 6H), 3.51 to 3.73 (m, 35H)

Preparation Example 10

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

The same method as in Preparation Example 7, except that the ω-methyl polyethyleneglycolyl tosylate (average molecular weight: 704) (70 g, 0.1 mol) of Preparation Example 5 was used instead of the ω-methyl triethyleneglycolyl tosylate. The title compound (48 g, 77%) was obtained as a liquid phase.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 2.52 to 2.60 (m, 6H), 3.43 (s, 3H), 3.50 to 3.69 (m, 49H)

Preparation Example 11

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

The same method as in Preparation Example 7, except that the ω-methyl polyethyleneglycolyl tosylate (average molecular weight: 2154) (21 g, 0.01 mol) of Preparation Example 6 was used instead of the ω-methyl triethyleneglycolyl tosylate. The title compound was obtained as a solid (16 g, 78%).

¹ H NMR (300 MHz, CDCl ₃ ):

δ2.50 to 2.63 (m, 6H), 3.41 (s, 3H), 3.53 to 3.75 (m, 181H)

Preparation Example 12

Synthesis of 2-ethoxy-benzoic acid methyl ester

2-ethoxy benzoic acid (20 g, 0.12 mol) and sodium hydrogencarbonate (12.1 g, 0.14 mol) were dissolved in acetone (50 ml). Dimethyl sulfate (22.8 g, 0.18 mol) was slowly added dropwise, then heated to reflux for 10 hours and cooled. Acetone was removed under reduced pressure and diluted with methylenedichloride (100 mL). It was then washed with 10% aqueous sodium hydrogen carbonate solution, dried over MgSO ₄ , filtered and the solvent was removed under reduced pressure. Fractional distillation under reduced pressure (5mmHg) gave a colorless liquid title compound (14.2g, 66%).

¹ H NMR (300 MHz, CDCl ₃ ):

δ 1.45 (t, 3H), 3.90 (s, 3H), 3.96 (s, 3H), 4.12 (q, 2H), 6.94 to 6.98 (m, 2H), 7.40 to 7.44 (t, 1H), 7.76 to 7.79 (d, 1 H)

Molecular weight (M + 1) ⁺ = 181

Preparation Example 13

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

2-Ethoxy-benzoic acid methyl ester (14.1 g, 0.08 mol) was slowly added dropwise to chloro sulfonyl chloride (50 mL) cooled to 0 ° C., followed by stirring at room temperature for 2 hours. The reaction solution was slowly added dropwise to ice water (3 L) and extracted with methylene dichloride. After drying over MgSO ₄ , filtration, and removing the solvent under dark, the solid white title compound (12 g, 55%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 1.52 (t, 3H), 3.93 (s, 3H), 4.24 (q, 2H), 7.12 (d, 1H), 8.07 to 8.11 (dd, 1H), 8.45 (s, 1H)

Molecular weight (M + 1) ⁺ = 279

Example 1

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

5-chlorosulfonyl-2-ethoxy-benzoic acid methyl ester (1.8 g, 0.007 mol) and 4-ω-methyl triethyleneglycolyl piperazine (4.5 g, 0.019 mol) obtained in Preparation Example 7 were obtained by methylenedi. It was dissolved in chloride (35 mL) and stirred at room temperature for 10 hours. Diluted with methylenedichloride (50 mL), washed with 5% aqueous sodium chloride solution, dried over MgSO ₄ , filtered, and the solvent was removed under reduced pressure to give the title compound (2.1 g, 68%) under reduced pressure.

¹ H NMR (300 MHz, CDCl ₃ ):

δ 1.50 (t, 3H), 2.58 (br, 6H), 3.03 (br, 4H), 3.37 (s, 3H), 3.50 to 3.59 (m, 10H), 3.72 (s, 3H), 4.18 (q, 2H), 7.04 (d, 1H), 7.81 (d, 1H), 8.14 (s, 1H)

Molecular weight (M + 1) ⁺ = 475

Examples 2-5

Except for using the compound obtained in Preparation Examples 8 to 11 instead of 4-ω-methyl triethyleneglycolyl piperazine was carried out in the same manner as in Example 1 to obtain a compound of formula 3 shown in Table 1 .

[Formula 3]

Compounds of Examples 2-5 Example Number n R ₁ R ₂ yield(%) Molecular Weight (M + 1) ⁺ [Theoretical] ¹ H-NMR 2 6 CH ₃ CH ₃ 79 651 [650] 1.50 (t, 3H), 2.59 (m, 6H), 3.04 (m, 4H), 3.38 (s, 3H), 3.53 to 3.65 (m, 27H), 3.90 (s, 3H), 4.19 (q, 2H) , 7.05 (d, 1H), 7.81 (d, 1H), 8.14 (s, 1H) 3 8 H CH ₃ 85 725 [724] 1.49 (t, 3H), 2.58 (m, 6H), 3.03 (m, 4H), 3.51-3.62 (m, 31H), 3.88 (s, 3H), 4.18 (q, 2H), 7.03 (d, 1H) , 7.80 (d, 1H), 8.15 (s, 1H) 4 11 CH ₃ CH ₃ 77 871 [870] 1.48 (t, 3H), 2.59 (m, 6H), 3.03 (m, 4H), 3.36 (s, 3H), 3.50 to 3.64 (m, 45H), 3.91 (s, 3H), 4.20 (q, 2H) , 7.07 (d, 1H), 7.80 (d, 1H), 8.13 (s, 1H) 5 44 CH ₃ CH ₃ 80 2323 [2322] 1.51 (t, 3H), 2.61 (m, 6H), 3.02 (m, 4H), 3.37 (s, 3H), 3.49-3.68 (m, 177H), 3.90 (s, 3H), 4.21 (q, 2H) , 7.04 (d, 1H), 7.80 (d, 1H), 8.15 (s, 1H)

Example 6

4- [2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) benzamido] -1-methyl-3-n-propylpyrazole-5-carboxamide synthesis

2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) -benzoic acid methyl ester (1.2 g, 0.004 mole) was dissolved in methanol (50 mL) and sodium hydroxide (0.5 g, 0.013 mol) and water (0.05 ml) were added and stirred for 30 minutes. After adjusting to pH 3-4 with 1N aqueous hydrochloric acid solution, the solvent was removed under reduced pressure. Methylenedichloride (100 ml), dicyclohexylcarbodiimide (0.75 g, 0.004 mol), N ', N'-dimethyl-4-aminopyridine (0.25 g, 0.002 mol) and 4-amino were added to the reaction solution. -1-methyl-3-n-propylpyrazole-5-carboxamide (0.75 g, 0.004 mol) was added and stirred for 1 hour. After filtration, washing with 1N aqueous hydrochloric acid solution, drying, and removing the solvent under reduced pressure. Chromatography with silica gel gave the title compound (2.3 g, 90%) as a white solid.

¹ H NMR (300 MHz, CDCl ₃ ):

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 to 3.62 (m, 10H), 4.06 (s, 3H), 4.40 (q, 2H), 5.92 (br, 1H), 7.18 (d, 1H), 7.62 (br, 1H), 7.88 (d, 1H), 8.58 (s, 1H ), 9.28 (br, 1H)

Molecular weight (M + 1) ⁺ = 625

Examples 7-10

Example 6 except that the compound obtained in Examples 2 to 5 is used instead of 2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) -benzoic acid methyl ester In the same manner to obtain a compound of formula 2 shown in Table 2.

[Formula 2]

Compounds of Examples 7-10 Example Number n R ₁ yield(%) Molecular Weight (M + 1) ⁺ [Theoretical] ¹ H-NMR 7 6 CH ₃ 89 800 [801] 0.95 (t, 3H), 1.60 (t, 3H), 1.62 (m, 2H), 2.54-2.59 (m, 8H), 3.06 (br, 4H), 3.37 (s, 3H), 3.53-3.65 (m, 27H), 4.06 (s, 3H), 5.59 (br, 1H), 7.17 (d, 1H), 7.66 (br, 1H), 7.90 (d, 1H), 8.65 (s, 1H), 9.27 (br, 1H ) 8 8 H 92 875 [874] 0.94 (t, 3H), 1.60 (t, 3H), 1.63 (m, 2H), 2.52-2.59 (m, 8H), 3.07 (br, 4H), 3.52-3.68 (m, 31H), 4.04 (s, 3H), 5.57 (br, 1H), 7.17 (d, 1H), 7.65 (br, 1H), 7.89 (d, 1H), 8.63 (s, 1H), 9.28 (br, 1H) 9 11 CH ₃ 83 1021 [1020] 0.96 (t, 3H), 1.60 (t, 3H), 1.60 (m, 2H), 2.52 to 2.57 (m, 8H), 3.07 (br, 4H), 3.38 (s, 3H), 3.50 to 3.66 (m, 45H), 4.06 (s, 3H), 5.58 (br, 1H), 7.16 (d, 1H), 7.64 (br, 1H), 7.91 (d, 1H), 8.64 (s, 1H), 9.27 (br, 1H ) 10 44 CH ₃ 87 2473 [2472] 0.95 (t, 3H), 1.58 (t, 3H), 1.61 (m, 2H), 2.50 to 2.62 (m, 8H), 3.05 (br, 4H), 3.38 (s, 3H), 3.50 to 3.69 (m, 177H), 4.06 (s, 3H), 5.57 (br, 1H), 7.17 (d, 1H), 7.68 (br, 1H), 7.91 (d, 1H), 8.66 (s, 1H), 9.28 (br, 1H )

Example 11

5- [2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyra Synthesis of zolo- [4,3-d] -pyrimidin-7-one

4- [2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) benzamido] -1-methyl-3-n-propylpyrazole-5-carboxamide ( 1.05 g, 0.002 mole) was dissolved in ethanol (30 mL), sodium hydroxide (0.14 g, 0.003 mole), 30% hydrogen peroxide (0.55 mL) and water (5 mL) were added, and the mixture was heated to reflux for 5 hours. After cooling, the solvent was removed under reduced pressure, neutralized with 2N aqueous hydrochloric acid and extracted with methylene dichloride. After drying over MgSO ₄ , filtration, the solvent was removed under reduced pressure. Chromatography with silica gel gave the solid white title compound (0.92 g, 90%).

¹ H NMR (300 MHz, CDCl ₃ ):

δ1.02 (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 to 3.59 (m, 10H), 4.27 (s, 3H), 4.36 (q, 2H), 7.13 (d, 1H), 7.81 (d, 1H), 8.79 (s, 1H), 10.82 (br, 1H )

Molecular Weight (M + 1) ⁺ = 607

Examples 12-15

Instead of 4- [2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) benzamido] -1-methyl-3-n-propylpyrazole-5-carboxamide Except for using the compound obtained in Examples 7 to 10 was carried out in the same manner as in Example 11 to obtain a compound of formula 1 shown in Table 3.

[Formula 1]

Compounds of Examples 12-15 Example Number n R ₁ yield(%) Molecular Weight (M + 1) ⁺ [Theoretical] ¹ H-NMR 12 6 CH ₃ 73 783 [782] 1.02 (t, 3H), 1.65 (t, 3H), 1.82 (m, 2H), 2.59 (m, 6H), 2.90 (t, 2H), 3.08 (br, 4H), 3.38 (s, 3H), 3.47 -3.72 (m, 27H), 4.28 (s, 3H), 4.38 (q, 2H), 7.15 (d, 1H), 7.82 (d, 1H), 8.82 (s, 1H), 10.82 (br, 1H) 13 8 H 82 857 [856] 1.02 (t, 3H), 1.64 (t, 3H), 1.85 (m, 2H), 2.58 (m, 6H), 2.91 (t, 2H), 3.09 (br, 4H), 3.53-3.71 (m, 31H) , 4.27 (s, 3H), 4.37 (q, 2H), 7.15 (d, 1H), 7.82 (d, 1H), 8.80 (s, 1H), 10.88 (br, 1H) 14 11 CH ₃ 78 1003 [1002] 1.02 (t, 3H), 1.71 (t, 3H), 1.81 (m, 2H), 2.59 (m, 6H), 2.92 (t, 2H), 3.09 (br, 4H), 3.38 (s, 3H), 3.45 -3.74 (m, 45H), 4.23 (s, 3H), 4.35 (q, 2H), 7.12 (d, 1H), 7.81 (d, 1H), 8.82 (s, 1H), 10.82 (br, 1H) 15 44 CH ₃ 71 2455 [2454] 1.02 (t, 3H), 1.65 (t, 3H), 1.85 (m, 2H), 2.61 (m, 6H), 2.93 (t, 2H), 3.10 (br, 4H), 3.38 (s, 3H), 3.40 -3.88 (m, 177H), 4.28 (s, 3H), 4.39 (q, 2H), 7.08 (d, 1H), 7.83 (d, 1H), 8.81 (s, 1H), 10.88 (br, 1H)

The biological activity and solubility in water of the compounds of the present invention were measured in the following experimental examples.

Experimental Example 1: Relaxation test for the corpus cavernosum

The relaxation of penile corpus cavernosum smooth muscle of the compound of formula 1 and the standard control compound sildenafil citrate (trade name: Viagra) was tested on mature New Zealand rabbits and the measurements were compared.

The number of test animals was 7 per test drug group, and the relaxation power of penile corpus cavernosum smooth muscle sections was measured and statistically analyzed, and the relaxation power of the compound of formula 1 and sildenafil citrate was compared at the same concentration. .

1. Experiment Method

Mature male New Zealand white rabbits (2.0-2.5 kg) were prepared. Immediately after injecting air into the rabbit's bilateral vein, the penis was extracted and oxygen-ventilated in a Petri dish containing cooled Krebs's solution. Penile cavernous tissue sections were prepared.

This tissue section was placed in a tissue chamber containing 10 cc Krebs solution (sodium chloride 118.3, potassium chloride 4.7, magnesium sulfate 0.6, potassium hydrogen phosphate 1.2, calcium hypochloride, sodium hydrogencarbonate 25.0 and glucose 11.1 in units of mM / l). Attracted to. After binding both ends of the section with sutures, one end was connected to a metal L-shaped ring and fixed in a tissue container, and the other end was connected to a fixing ring of a tension transducer. 95% oxygen (O ₂ ) and 5% carbon dioxide (CO ₂ ) were ventilated, maintained at pH 7.4 and temperature 37 ° C., and the cavernous sections were incubated for 2 hours with a fresh solution every 20-30 minutes.

The change in tension of the sections shown in the polygraph connected to the tension transducer was measured. The isotonic tension is when the maximum shrinkage tension for the phenylephrine (10 ^-5 M) administered after adding 1 gm tension through the tension sensor at the tip of the tension transducer is less than 10% compared to the previous tension. Considered.

After washing the sections and incubating again, phenylephrine (10 ^-8 ~ 10 ^-3 M) was administered in cumulative concentration to determine the maximum tension at the time of contraction of the sections. The concentration causing EC ₅₀ in the contraction tension curve was determined.

After pretreatment with phenylephrine (10 ^-5 M) to shrink the sections, the compound of formula 1 prepared in sildenafil citrate (10 ^{-8-10 -4} M) and Examples 11-15 (10 ^-8-10 ) ^-4 M) were each administered to determine the relaxation tension of the sections.

The relaxation rate between sildenafil citrate and the compound of formula 1 was statistically analyzed.

2. Experimental Results

The experimental results are shown in Table 1 below.

% Of relaxation rate Concentration (m) ＞ 3 × 10 ^-6 10 ^-5 3 × 10 ^-5 10 ^-4 Sildenafil Citrate 0 0 0 20.6 ± 8.12 ^* Example 11 20.96 ± 13.27 - - - Example 12 - 25.12 ± 5.67 ^** 47.98 ± 13.25 ^** 100 ^** Example 13 5.36 ± 4.44 ^** 13.55 ± 8.23 ^* 28.71 ± 16.12 52.03 ± 26.41 Example 14 10.36 ± 17.50 16.13 ± 20.43 21.63 ± 23.25 27.15 ± 25.10 Example 15 5.96 ± 8.46 ^* 8.82 ± 10.20 ^** 11.65 ± 10.24 ^** 14.87 ± 13.50 ^*

* p <0.05, ** p <0.01

1) Relaxation effect of sildenafil citrate

There was no significant relaxation from 3 x 10 ^-5 M in the relaxation response to the cumulative concentration of sildenafil citrate (10 ^-8 to 10 ^-4 M) of pretreated shrinkage of phenylephrine (10 ^-5 M). The relaxation rate was 20.6 ± 8.12% at 10 ^-4 M (number of individuals = 7).

2) The compound of Formula 1 relaxed the sections proportional to the concentration shrinkage by pretreatment with phenylephrine (10 ^-5 M). Sections were relaxed from 10 ^-5 M and relaxation rates for concentrations were 25.12 ± 5.67%, 47.98% ± 13.25%, and 100% at 10 ^-5 M, 3 × 10 ^-5 M, and 10 ^-4 M, respectively. Relaxed at Maximum relaxation rates at 10 ⁻⁴ M were compared as a reference (100%) (number of individuals = 7).

3) The compound of Formula 1 showed significantly higher relaxation rate than sildenafil citrate at a concentration of 10 ⁻⁵ to 10 ⁻⁴ M (p <0.01).

From the above results, it can be seen that the compound of Formula 1 exhibits an excellent relaxation capacity of 10 times higher than the sildenafil citrate (viagra) and 4-5 times higher at the same concentration of 10 ⁻⁴ M.

Experimental Example 2 Measurement of Solubility in Water

0.1㎖ added to distilled water to a compound of general formula (I) of 10 ^-5 mol was observed whether or not dissolution. 40 µl of the aqueous solution was taken and diluted with 1 ml of acetonitrile, and the remaining aqueous solution was filtered through a filter paper having a pore size of 0.1 µm, and 40 µl was taken and diluted with 1 ml of acetonitrile. The two samples were compared using liquid chromatography to confirm dissolution. If visual observation did not dissolve or when liquid chromatographic peak area showed more than 5% difference, it did not dissolve. Then, 1 ml of distilled water was added to 10 ^-5 moles of the compound of Formula 1, and the above experiment was performed. Repeated.

The dissolution at 10 ⁻¹ mole, the dissolution at 10 ⁻² mole and the dissolution at 10 ⁻³ mole were also confirmed in the same manner as above, and statistical treatment was performed to obtain an approximate solubility value. 2 is shown.

Solubility in water (pH = 6, 24 ° C) compound Solubility (S) (Unit: M) Example 11 S = 10 ^-4 Example 12 S = 10 ^-1 (7.4% w / w: melts) Example 13 S> 1 (> 46% w / w) Example 14 S> 1 (> 50% w / w: soluble) Example 15 S = 0.8 (67% w / w: very soluble)

It can be seen that the solubility of sildenafil citrate is about 20 to 200 times greater compared to 3.5 mg / ml, ie 5.2 × 10 ⁻³ M.

The compounds of the present invention are soluble in water as can be seen in the above experimental examples when compared to inhibitors of common cyclic guanosine 3 ', 5'-monophosphatephosphodiesterases (cGMP PDEs), for example sildenafil citrate. It shows high solubility, and as a result of these characteristic properties, the production rate of cGMP is high, indicating strong vasoconstriction suppression and vasodilating activity, which can ultimately enhance the therapeutic effect of erectile dysfunction. It may also be useful in treating a number of diseases, including angina, hypertension, congestive heart failure, atherosclerosis, reduced vascular patency and peripheral vascular disease.

Claims (10)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1] In the above formula, R ₁ is hydrogen; C ₁ -C ₆ alkyl; C ₃ ~C ₆ alkyl substituted with C ₁ ~C ₆ by cycloalkyl; C ₃ -C ₅ cycloalkyl; C ₁ -C ₃ perfluoroalkyl; C ₃ -C ₆ alkenyl; C ₃ -C ₆ alkynyl; Or C ₁ -C ₃ alkoxy C ₂ -C ₆ alkyl; Wherein said substituent is present in a straight or branched chain; n is an integer of 2 to 400. 2. A compound according to claim ₁ or a pharmaceutically acceptable salt thereof, wherein R ₁ is hydrogen, methyl or ethyl and n is an integer from 2 to 50. The method of claim 2, 5- [2-ethoxy-5- (4-ω-methyl triethyleneglycolyl piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyra Zolo- [4,3-d] -pyrimidin-7-one, 5- [2-ethoxy-5- (4-ω-methyl polyethyleneglycolyl piperazinylsulfonyl) phenyl] -1-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] -1-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] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo -[4,3-d] -pyrimidin-7-one (n = 11), or 5- [2-ethoxy-5- (4-ω-methyl polyethyleneglycolyl piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo -[4,3-d] -pyrimidin-7-one (n = 44); Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating erectile dysfunction comprising an effective amount of a compound according to any one of claims 1 to 3. A pharmaceutical composition for the treatment of angina, hypertension, congestive heart failure and atherosclerosis, comprising an effective amount of a compound according to any one of claims 1 to 3. A method for preparing a compound according to claim 1 by pyrimidinone ring reaction in the presence of an inorganic base and hydrogen peroxide solution: [Formula 2] Wherein R ₁ and n are as defined in claim 1. A compound of formula [Formula 2] Wherein R ₁ and n are as defined in claim 1. a) the compound of formula 3a is hydrolyzed in an inert solvent in the presence of a strong base to remove the protecting group of R ₂ ′, and then reacted with a compound of formula 4 in the presence of tertiary amines as condensing agents and catalysts; b) reacting a compound of formula 3b with a compound of formula 4 in an inert solvent in the presence of tertiary amines as a condensing agent and a catalyst Process for preparing a compound according to claim 7 [Formula 3a] [Formula 3b] [Formula 4] In the above formula, R ₁ and n are as defined in claim 1, R ₂ ′ represents a C ₁ -C ₄ alkyl or sulfonyl group, R ₂ "represents hydrogen. A compound of formula [Formula 3] In the above formula, R ₁ and n are as defined in claim 1, R ₂ represents hydrogen, a C ₁ -C ₄ alkyl or sulfonyl group. (a) reacting a compound of formula 5 with chlorosulfonic acid in an inert solvent to produce a compound of formula 5a, which is reacted with a compound of formula 6 to obtain a compound of formula 3a; (b) hydrolyzing the compound of formula 3a in the presence of a strong base to remove the R ₂ ′ protecting group to obtain a compound of formula 3b Method for preparing a compound according to claim 9 [Formula 5] [Formula 5a] [Formula 6] [Formula 3a] [Formula 3b] In the above formula, R ₁ and n are as defined in claim 1, R ₂ ′ and R ₂ ″ are as defined in claim 8.