KR20080003602A - Fumarate of pyrrolopyrimidinone derivative and process for preparing it - Google Patents

Abstract

A fumarate of pyrrolopyrimidinone derivative is provided to prevent and treat diseases associated with PDE5(phosphodiesterase 5) by inhibiting the enzyme activity, and improve stability of the compound by inhibiting hygroscopicity and corrosion properties and enhancing stability against heat and light. A PDE5 inhibitor, fumarate of pyrrolopyrimidinone derivative represented by the formula(1) is a crystalline acid addition salt prepared by solubilizing fumaric acid represented by the formula(3) in a solvent selected from water, acetone, methanol, ethanol, isopropanol and acetonitrile, slowly adding pyrrolopyrimidinone derivative represented by the formula(2) into the fumaric acid solution, stirring the mixture at room temperature for 1 hour, removing the solvent through concentration under reduced pressure, filtering the prepared solid, washing the filtered solid with solvent, and drying the washed solid at 50 deg.C under vacuum condition.

Description

Fumarate salt of pyrrolopyrimidinone derivatives and preparation method thereof {Fumarate of Pyrrolopyrimidinone Derivative and process for preparing it}

The present invention relates to a fumarate salt of a pyrrolopyrimidinone derivative represented by the following Chemical Formula 1 having an excellent effect of inhibiting PDE-5 activity, and a preparation method thereof, and more particularly to a pyrrolopyrimidinone derivative and a fumaric acid. It is a crystalline acid addition salt prepared by reacting), has no hygroscopicity, has long-term storage stability, light stability, thermal stability, and is suitable for formulating formulations. (Pulmonary arterial hypertension), Chronic Obstructive Pulmonary Disease, Benign Prostatic Hypertrophy, and Fumarate salts of pyrrolopyrimidinone derivatives represented by the following general formula (1) as effective treatment and prevention of lower urinary tract symptoms: It relates to a manufacturing method thereof.

[Formula 1]

Korean Patent No. 358083 discloses a pyrrolopyrimidinone derivative having a novel structure, an intermediate compound used in the preparation and preparation thereof, and a compound thereof having an excellent effect of inhibiting PDE-5 activity, thereby leading to erectile dysfunction and pulmonary arterial hypertension. ), Chronic obstructive pulmonary disease, Benign Prostatic Hypertrophy, lower urinary tract symptomatic treatment and prevention, pharmaceutical compositions and therapeutic agents are also disclosed.

Among the pyrrolopyrimidinone derivatives disclosed in Korean Patent No. 358083, 5-ethyl-2- {5- [4- (2-hydroxyethyl) piperazin-1-ylsulfonyl]- 2-n-propoxyphenyl} -7-n-propyll-3,5-dihydro-4H-pyrrolo [3,2-d] pyrimidin-4-one (hereinafter abbreviated as "SK-3530") PDE-5 has good selectivity for drug efficacy and other PDEs, and is selected as an optimal drug candidate through preclinical studies and may be in clinical trials as an erectile dysfunction treatment drug.

SK-3530 has been studied in the form of dihydrochloride salt represented by the formula (3) in preclinical and clinical.

SK-3530 dihydrochloride salt represented by the formula (3) is excellent in solubility, and there is no difficulty in stabilizing the formulation, but as a raw material itself has some problems to be solved.

First, the SK-3530 dihydrochloride salt is hygroscopic, and when the moisture content in the air is high, it easily absorbs and discolors. In addition, due to this hygroscopicity, a stable form may be obtained by simultaneously meeting anhydrous solvent conditions and dry atmospheric conditions in the manufacturing process.

Second, SK-3530 dihydrochloride should be stored at low temperature, not at room temperature, because the stability of the raw material itself is not sufficiently secured. SK-3530 dihydrochloride was not particularly stable against heat and light, resulting in a variety of flexible substances when exposed to heat and light.

Third, SK-3530 dihydrochloride salts are corrosive, and punching was observed during tableting. This is due to the fact that SK-3530 dihydrochloride is not a stable form of crystalline acid addition salt or hydrate, but an amorphous substance, in which one molecule of hydrochloric acid, which forms a weak ionic bond, is released from severe conditions That means you can.

As mentioned above, SK-3530 dihydrochloride can secure sufficient stability in formulation, but there is a problem in the physical properties and stability of the raw material itself, which requires additional technology and additional costs.

Accordingly, the present inventors can solve all of the above problems when manufactured with fumarate instead of hydrochloride after various efforts to solve the problems of the raw material itself despite the pharmacological other advantages of SK-3530 dihydrochloride. It was found that crystalline acid addition salts suitable for formulation formulation were formed.

Accordingly, the present inventors were able to secure sufficient stability against temperature, moisture, and light by reacting the free base of SK-3530 with fumaric acid, and also maintained excellent drug efficacy and effective blood concentration when administered as a drug. The present invention was completed by preparing a fumarate salt, a novel crystalline acid addition salt of SK-3530, which satisfies all the conditions required as a pharmaceutically acceptable salt of.

Accordingly, it is an object of the present invention to provide a SK-3530 fumarate salt that satisfies all the physicochemical conditions required as pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for preparing SK-3530 fumarate salt by reacting SK-3530 free base group with fumaric acid.

In addition, the present invention is erectile dysfunction, pulmonary hypertension (Pulmonary arterial hypertension), chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease), prostatic hypertrophy (Benign Prostatic Hypertrophy), lower urinary tract symptoms containing SK-3530 fumarate salt as an active ingredient It is another object to provide a pharmaceutical composition for treatment and prophylaxis.

The present invention has no hygroscopicity, is excellent in stability and efficacy, and exhibits the highest blood concentration at a physiologically useful time period, so that erectile dysfunction, pulmonary arterial hypertension, chronic obstructive pulmonary disease, and prostatic hyperplasia (Benign) Prostatic Hypertrophy), a fumarate salt of pyrrolopyrimidinone derivative represented by the following formula (1) which is effective for the treatment and prevention of lower urinary tract symptoms.

[Formula 1]

On the other hand, the present invention includes a method for preparing the SK-3530 fumarate salt represented by the formula (1), the preparation method is shown in the following Scheme 1, SK-3530 free base represented by the following formula (2) and the following formula It consists of making by making the fumaric acid represented by 3 react.

When subdividing the production method of the present invention represented by the reaction scheme 1 for each process,

Dissolving or suspending fumaric acid to prepare a fumaric acid-containing reaction solution;

Preparing a mixture of the fumaric acid-containing reaction solution and SK-3530 free base; And

Filtering, washing and drying the solid obtained by stirring the mixture to form a crystalline acid addition salt.

In the method for preparing the crystalline acid addition salt of SK-3530 according to the present invention, in preparing a mixture of SK-3530 free base and fumaric acid, fumaric acid may be added and mixed with SK-3530 freebase, or SK-3530 to fumaric acid. Free base can also be added and mixed.

The manufacturing method according to the present invention will be described in detail for each manufacturing step as follows.

In the process of preparing the fumaric acid-containing reaction solution of the first step, it is important to control the concentration of fumaric acid in the reaction solution. In order to promote crystallization efficiently, it is preferable to adjust the concentration of fumaric acid in the range of 1 to 30% by weight.

In the process of preparing the mixture of SK-3530 free base and fumaric acid in the second step, it is preferable to use 0.5 to 3.0 equivalents of fumaric acid with respect to SK-3530. In preparing the mixture, fumaric acid may be added to the SK-3530 free base, or SK-3530 free base may be added to the fumaric acid. In this case, SK-3530 free base may be added in a solid state or dissolved in a suitable reaction solvent. More specifically illustrating the second step, the mixture may be prepared by adding and mixing the SK-3530 free base solution in the solid state or the SK-3530 free base solution dissolved in a suitable solvent to the fumaric acid-containing reaction solution. As another method, a mixture may be prepared by adding and mixing a fumaric acid-containing reaction solution to a SK-3530 free base in a solid state or a SK-3530 free base solution dissolved in a suitable solvent.

In the first and second steps described above, water or a conventional organic solvent is used as the reaction solvent, and particularly preferably, water or an organic solvent selected from acetone, methanol, ethanol, isopropanol and acetonitrile is used alone or in combination. will be.

The third step is the formation of the crystalline acid addition salt, the reaction is carried out in the temperature range of -30 to 50 ℃.

SK-3530 fumarate salt represented by the formula (1) according to the present invention satisfies all of the following physical and chemical conditions to be provided as a pharmaceutically acceptable salt. That is, all five of the following physical and chemical conditions are satisfied. (1) Low hygroscopicity (2) Proper solubility should be secured (3) Low adhesion of tablets (4) Excellent stability (5) Ease of mass production should be secured.

Therefore, the present invention includes a pharmaceutical composition for treating erectile dysfunction containing SK-3530 fumarate salt represented by Formula 1 as an active ingredient.

The pharmaceutical composition according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. That is, it can be formulated into various formulations for oral and parenteral administration, which are prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are commonly used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules and the like. Such solid preparations are prepared by mixing the active compound with at least one excipient such as starch, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspending agents, solvents, emulsions, syrups, and the like, and various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The dosage of the pharmaceutical composition according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient. The effective dose of SK-3530 fumarate salt represented by Formula 1 is 10.0 to 200.0 mg based on SK-3530 free base. Preferably it is 20-150 mg.

The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.

Example 1 Preparation of SK-3530 Fumarate Salt

1.44 g of fumaric acid was dissolved in 100 ml of acetone and the reaction solution was stirred at room temperature. 6.0 g of SK-3530 free base was slowly added to the fumaric acid reaction solution. The mixture was stirred at room temperature for 1 hour, and then 50 mL of acetone was removed by concentration under reduced pressure. The resulting solid was filtered, washed with 20 mL of ether and dried in vacuum at 50 ° C. to give 6.92 g of the title compound as a white crystal (yield). 94.7%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm) 11.69 (s, 1H), 7.88 (d, 1H), 7.79 (dd, 1H), 7.37 (d, 1H), 7.30 (s, 1H) , 6.62 (s, 2H), 4.37 (q, 2H), 4.12 (t, 2H), 3.43 (t, 2H), 2.90 (m, 4H), 2.59-2.48 (m, 6H), 2.40 (t, 2H ), 1.75-1.59 (m, 4H), 1.35 (t, 3H), 0.96 (t, 3H), 0.92 (t, 3H)

Example 2: Preparation of SK-3530 Fumarate Salt

1.44 g of fumaric acid was dissolved in 100 ml of acetone and the reaction solution was stirred at room temperature. 8.0 g of SK-3530 free base was dissolved in 100 ml of acetone, and then slowly added to the fumaric acid reaction solution. The mixture was stirred at room temperature for 1 hour, and then the resulting solid was filtered, washed with 20 ml of acetone and dried in vacuo at 50 ° C. to obtain the title compound as white crystals.

Example 3: Preparation of SK-3530 Fumarate Salt

80 mg of SK-3530 free base was suspended in 1 ml of acetone, and the reaction solution was stirred at room temperature. 14.4 mg of fumaric acid was dissolved in a mixed solvent of 1 ml of acetone and 2 ml of water, and then slowly added to the SK-3530 free base reaction solution. The mixture was stirred at rt for 30 min, then 12 ml of water was added and further stirred for 30 min. The resulting solid was filtered, washed with 10 ml of water and dried in vacuo at 50 ° C. to give the title compound as white crystals.

Example 4: Formulation of SK-3530 Fumarate Salt-Containing Tablets

Anhydrous calcium hydrogen phosphate (315 g) and microcrystalline cellulose (525 g, 90 μm) were combined and transferred to a drum. SK-3530 fumarate salt (70 g) and microcrystalline cellulose (187.5 g, 50 μm) were combined and passed through the screen into a drum containing the powder mixture. The screen used in the previous step was washed with microcrystalline cellulose (525 g, 90 μm). Anhydrous calcium hydrogen phosphate (315 g) was added to the mixture and the entire mixture was blended for 10 minutes. Sodium starch glycolate (40 g) was then added to the mixture and blended for 6 minutes. Finally, magnesium stearate (20 g) was added and the resulting mixture was blended for 3 minutes. The powder mixture was then compressed into tablets by conventional methods.

Example 5: Formulation of SK-3530 Fumarate Salt-Containing Capsule

Microcrystalline cellulose (525 g, 90 μm) and dry corn starch were premixed, then SK-3530 fumarate salt (70 g) was mixed with a portion of the premix and sieved. The remaining premix was added and mixed for 10 minutes, then sieved and further mixed for 5 minutes. And the capsule of appropriate size was made to manufacture the capsule.

Example 6: Formulation of SK-3530 Fumarate Salt-Containing Injection

Sodium chloride was dissolved in sterile water for injection and propylene glycol was mixed with this solution. SK-3530 fumarate salt was added, and when dissolved, additional sterile water for injection was added to prepare a solution of the desired concentration. This solution was filtered through a sterile filter and filled into sterile ampoules used as injection containers.

Experimental Example 1: Stability Test

This experimental example is an experimental example for confirming the storage stability of the SK-3530 fumarate salt.

1) Moisture and air stability test

In order to process the drug into a specific formulation, sufficient stability needs to be ensured, e.g., when it is formulated into tablets or capsules, atmospheric stability will be particularly required, and when formulated into injections, the stability against water (water) is particularly May be required.

The following Table 1 is at 25 ℃ temperature and 75% humidity conditions, the following Table 2 is at 40 ℃ temperature and 60% humidity conditions, the following Table 3 is at 50 ℃ temperature and 75% humidity conditions, respectively SK-3530 dihydrochloride ( 2HCl) and SK-3530 fumarate were stored, and after 1 and 3 weeks, the content of total analog was measured by liquid chromatography.

SK-3530 salt % Of lead substance at 25 ° C and 75% humidity Early 1 week 3 weeks SK-3530 dihydrochloride 0.20 0.24 0.31 SK-3530 fumarate salt 0.02 0.02 0.03

SK-3530 salt % Of lead substance at 40 ℃ and 60% humidity Early 1 week 3 weeks SK-3530 dihydrochloride 0.20 0.24 0.38 SK-3530 fumarate salt 0.02 0.02 0.05

SK-3530 salt % Of lead substance at 50 ℃ and 75% humidity Early 1 week 3 weeks SK-3530 dihydrochloride 0.20 0.27 0.42 SK-3530 fumarate salt 0.02 0.02 0.05

2) Light stability check experiment

Table 4 and Table 5 show the results of the light stability comparison experiment, the total amount of ultraviolet light (UV) is 200 W · h / ㎡, the total amount of visible light (visible light) is 1080 klux / m ² h. Each salt was stored in a Petri dish and the storage conditions were 25 ° C temperature and 60% humidity conditions.

SK-3530 salt Content of Leading Material (%) Early Ultraviolet (UV) Visible light SK-3530 dihydrochloride 0.20 5.92 1.37 SK-3530 fumarate salt 0.02 0.08 0.07

SK-3530 salt Change of color Early Ultraviolet (UV) Visible light SK-3530 dihydrochloride White Brown yellow SK-3530 fumarate salt White Pale yellow White

3) thermal stability test

Table 6 and Table 7 show the results of the thermal stability comparison experiment. Each salt was placed in a petri dish and placed in a dryer at 105 ° C. to visually observe the results after 3 and 48 hours.

SK-3530 salt Content of Leading Material (%) Early 3 hours 48 hours SK-3530 dihydrochloride 0.20 3.06 14.37 SK-3530 fumarate salt 0.02 0.11 0.61

SK-3530 salt Change of color Early 3 hours 48 hours SK-3530 dihydrochloride White White yellow SK-3530 fumarate salt White White White

As shown in Tables 1 to 7, it was confirmed that the SK-3530 fumarate salt is much better than the conventional SK-3530 dihydrochloride salt, and the light stability and thermal stability against UV and visible light.

As described above, SK-3530 fumarate salt according to the present invention is a crystalline acid addition salt suitable for the manufacture of pharmaceutical formulations, so it has an excellent effect of inhibiting PDE-5 activity, erectile dysfunction, pulmonary arterial hypertension, chronic It may be usefully used as a pharmaceutical composition for treating and preventing Chronic Obstructive Pulmonary Disease, Benign Prostatic Hypertrophy, and Lower Urinary Tract Symptoms.

Claims (12)

Fumarate salt of pyrrolopyrimidinone derivatives, characterized by the following formula (1): [Formula 1]

A method for preparing a fumarate salt of a pyrrolopyrimidinone derivative represented by the following formula (1), which is prepared by reacting a pyrrolopyrimidinone derivative represented by the following formula (2) with a fumaric acid represented by the following formula (3):

The method of claim 2, Preparing a fumaric acid-containing reaction solution by dissolving or suspending fumaric acid represented by Chemical Formula 3; Preparing a mixture of the pyrrolopyrimidinone derivative represented by Formula 2 and the fumaric acid-containing reaction solution; And Filtering, washing and drying the solid obtained by stirring the mixture to form a crystalline acid addition salt; Manufacturing method characterized in that comprises a. The method of claim 2 or 3, wherein the concentration of fumaric acid in the reaction solution is 1 to 30% by weight. The solvent according to claim 2 or 3, wherein the solvent for dissolving or suspending fumaric acid represented by the formula (3) is a single solvent or a mixed solvent selected from the group consisting of water, acetone, methanol, ethanol, isopropanol and acetonitrile. Manufacturing method. The method according to claim 2 or 3, wherein the fumaric acid represented by Chemical Formula 3 is used in the range of 0.5 to 3.0 equivalents based on the pyrrolopyrimidinone derivative represented by Chemical Formula 2. The method of claim 2 or 3, wherein the reaction is carried out at a temperature range of -30 to 50 ℃. The method according to claim 2 or 3, wherein the pyrrolopyrimidinone derivative represented by Chemical Formula 2 is used in a solid state or in a solution dissolved in a solvent. The solvent for dissolving the pyrrolopyrimidinone derivative represented by Chemical Formula 2 is a single solvent or a mixed solvent selected from the group consisting of water, acetone, methanol, ethanol, isopropanol and acetonitrile. Manufacturing method. A pharmaceutical composition for treating erectile dysfunction comprising a fumarate salt of a pyrrolopyrimidinone derivative represented by Formula 1 as an active ingredient: [Formula 1]

Pulmonary arterial hypertension, Chronic Obstructive Pulmonary Disease, Benign Prostatic Hypertrophy, and Lower Urinary Tract Pharmaceutical compositions for the treatment of symptoms: [Formula 1]

The pharmaceutical composition according to claim 10 or 11, formulated as a tablet, capsule or injection.