KR100460567B1 - Ibuprofen alkanediol ester and their preparations containg them - Google Patents

Abstract

The present invention relates to a weakly acidic nonsteroidal ibuprofen alkanediol ester represented by the following Chemical Formula 1, which has an anti-inflammatory, analgesic, and antipyretic effect and improves gastrointestinal disorders, especially gastric mucosa, and a pharmaceutical composition containing the same as an active ingredient.

[Formula 1]

Description

Ibuprofen alkanediol ester and their preparations containg them}

The present invention relates to a weakly acidic nonsteroidal ibuprofen alkanediol ester represented by the following Chemical Formula 1, which has an anti-inflammatory, analgesic, and antipyretic effect and improves gastrointestinal disorders, especially gastric mucosa, and a pharmaceutical composition containing the same as an active ingredient.

Inflammation is the body's process for tissue restoration by destroying, inactivating, or removing irritants from invading organisms in a normal and protective response to tissue damage caused by physical trauma, harmful chemicals, or microbial drugs. .

The anti-inflammatory drugs are classified into steroid and nonsteroidal drugs. The non-steroidal anti-inflammatory drugs are classified into non-specific and specific anti-inflammatory drugs according to their action patterns. It can be classified as a drug.

Prostaglandin (PGs), derived from arachidonic acid, is a fatty acid with 20 carbon atoms. Prostaglandins exhibit physiological activity near the point of secretion and secretion throughout the body and are inactivated immediately after showing the required action near the secreted organs, and because of its strong activity, if they remain distributed throughout the body, It will be harmful. In particular, prostaglandin E (PGE) and prostaglandin F (PGF) are secreted during inflammatory reactions to enhance the permeability of capillaries, causing swelling and painful erythema.

Many nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the activity of an enzyme called cyclooxygenase (COX) to reduce the synthesis of prostaglandins, one of the chemical parameters liberated during allergies and inflammatory processes. Action.

Aspirin is the most commonly used aid in the group with this action and is a unique drug that irreversibly inactivates cyclooxygenase. However, aspirin is rapidly deacetylated by esterases present in tissues and blood and hydrolyzed to salicylate and acetic acid. Aspirin at therapeutic doses increases alveola ventilation. That is, the increase in salicylic acid lowers oxidative phosphorylation, thereby increasing CO ₂ and increasing respiration. High doses act directly on the respiratory center of soft water, resulting in overrespiration and respiratory alkalosis.

On the other hand, prostaglandin I ₂ (PGI ₂ ) under normal conditions inhibits the secretion of gastric acid, and prostaglandin E ₂ (PGE ₂ ) and prostaglandin F ₂ α (PGF ₂ α) promote the synthesis of protective mucus in the stomach and small intestine.

The inability to form these prostaglandins by the administration of aspirin results in increased secretion of gastric acid, which lowers the protection of the mucous membranes due to a decrease in mucus synthesis, resulting in epigastric discomfort and pain, nausea, vomiting, ulcers or May cause bleeding.

Recently, the development of weakly acidic nonsteroidal anti-inflammatory drugs has been focused on increasing anti-inflammatory, analgesic and antipyretic effects with the reduction of side effects.

Representatively developed for this purpose, ibuprofen (abbreviated as "IPF"), a propionic acid derivative, is 16-32 times more effective than aspirin and has anti-inflammatory, analgesic and antipyretic effects with less gastrointestinal disorder. Have It is also widely used for the long-term treatment of rheumatoid and osteoarthritis and, in contrast to aspirin, is a reversible inhibitor for cyclooxygenase.

However, like many other nonsteroidal anti-inflammatory drugs, ibuprofen has a higher frequency of gastrointestinal disorders such as indigestion in the gastrointestinal tract by carboxylic acid in its chemical structure compared to other side effects. Central nervous system side effects such as dizziness also occur.

Therefore, the study was carried out on the drug that is expected to improve the main effect with the reduction of side effects through the modification of the chemical structure that can reduce the digestive tract obstruction of ibuprofen.

It is an object of the present invention to provide a ibuprofen alkanediol ester represented by the following formula (1) of a weakly acidic nonsteroidal system having an anti-inflammatory, analgesic and antipyretic effect and an improvement in gastrointestinal disorders, especially gastric mucosa, and a pharmaceutical composition containing the same as an active ingredient. It is.

1 is a graph of the edema inhibitory effect of ibuprofen and its esters.

In the present invention, ibuprofen ethanediol ester (hereinafter, abbreviated as "IE") and ibuprofen butanediol, which significantly reduce gastrointestinal disorders by converting the propionic acid group of ibuprofen, a nonsteroidal anti-inflammatory drug, into two kinds of ester salts. Ibuprofen buthanediol ester (hereinafter abbreviated as "IB") was synthesized.

The following experiments were carried out for the preparation and analysis of physicochemical properties of the present invention, acute toxicity test, analgesic effect test, edema suppression test, gastric mucosal disorder test, pharmacokinetic review by measuring blood concentration, hydrolysis in artificial gastric juice and artificial serous fluid. The experiment was carried out in such a step.

Example 1 Preparation of Ibuprofen Ethane Diol Ester (IE)

After dissolving 20.6 g of ibuprofen (IPF) (III) in 100 mL of benzene, 15 g of thionyl chloride was added dropwise with stirring at 20 ° C., followed by stirring at 65 ° C. for 3 hours. After completion of the reaction, excess thionyl chloride was removed using an evaporator to obtain chlorinated Ibuprofen (II) as an oil phase. To this was added 70 mL of a tetrahydrofuran solution in which 6.2 g of 1,2-ethanediol (1,2-ethanediol) corresponding to a molar ratio of 1: 1 was added, and the reaction was stirred at 40 ° C for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in 50 mL of chloroform, washed three times with dilute hydrochloric acid (10%) and distilled water, dehydrated with anhydrous forget-me-not (Na ₂ SO ₄ ), and concentrated in a water bath at 50 ° C to give a colorless and transparent color. 19.9 g of oily ibuprofen ethanediol ester (IE) (I) was obtained (yield: 74%). This is shown in Scheme 1 below.

IR (KBr, cm ^-1 ): 1725 (C = O), 3500-3200 (alcoholic OH)

¹ H NMR (CDCl ₃ , δ): 2.4 (d, 1H, CH CH ₃ ), 3.3 (s, 1H, -OH),

3.6 (q, 3H, CH CH ₃ ), 4.1 (t, 2H, -COO CH ₂ ), 6.9 ~ 7.2 (m, 4H, phenyl)

Example 2 Preparation of Ibuprofen Butanediol Ester (IB)

In Example 1, except that 9.0g of 1,2-butanediol (1,2-butanediol) was used instead of 6.2g of 1,2-ethanediol, the colorless and transparent oily phase was obtained. 25.7 g of ibuprofen butanediol ester (IB) (I) were obtained (yield: 87%).

IR (KBr, cm ^-1 ): 1730 (C = O), 3500-3200 (alcoholic OH)

¹ H NMR (CDCl ₃ , δ): 2.4 (d, 1H, CH CH ₃ ), 2.8 (s, 1H, -OH),

3.6 (q, 3H, CH CH ₃ ), 4.2 (t, 2H, -COO CH ₂ ), 6.9 ~ 7.2 (m, 4H, phenyl)

When comparing the spectral results of the UV, IR, HPLC, NMR analysis apparatus carried out to confirm the results of the synthesis by the reaction in detail as follows.

By dissolving IPF, IE and IB in methanol, the UV (Ultraviolet) spectra respectively showed the maximum absorption at 262 nm and the absorption form at 250 to 280 nm. I could confirm the note.

In the IR (Infrared) spectrum, the functional group analysis showed that the carboxyl-specific stretching vibration absorption band (C = O) in IPF was found at 1715cm ^-1 , whereas in the synthesized IE and IB, the absorption band of ester group (C = O) each appeared at 1725cm ^-1, 1730cm ^-1.

In IPF, the most characteristic broad OH absorption of carboxylic acid was shown in 3400 ~ 2400cm ^-1 , whereas in synthesized IE and IB, it was lost and absorption by alcoholic OH was shown in 3500 ~ 3200cm ^-1 . The results were confirmed to be successful.

High performance liquid chromatography (HPLC) was performed to separate and purify the synthesized product. The conditions are as follows. The column was ZORVAX ODS C18, the solvent used as the mobil phase was MeOH / H ₂ O (8: 2), the flow rate was 1.0 mL / min, and the detection wavelength was 230 nm. As a result of the test, each retention time showed a single peak at 3.69 minutes for IPF, 7.18 minutes for IE, and 9.48 minutes for IB, thereby confirming that it was a pure single substance with no other substances mixed.

As a result of analysis of NMR (Nuclear Magnetic Resonance) spectrum, four phenyl protons of IPF, IE and IB were identified at δ 6.95 to 7.45, indicating that the mother nucleus was not degraded. The acid proton (-COOH) of IPF in δ12.4 was found to be lost in IE and IB, and both peaks by -COOCH ₂ were observed in δ4.2.

The above experimental results are shown in FIGS. 1 to 7.

Experimental Example 1: Acute Toxicity Experiment

Six mice were used in each group, and each dose of IPF, IE, and IB was injected subcutaneously and intraperitoneally, and a half lethal dose (a dose 50% killing test animals, LD ₅₀ ) was calculated according to the Behren's-kaerber method. In case of subcutaneous administration, IE and IB were 1583.3 mg / kg (1299.9 mg as IPF) and 3416.7 mg / kg (2523.4 mg as IPF), respectively, compared to 683.3 mg / kg of IPF. IE and IB were 487.5 mg / kg (400.2 mg as IPF) and 792.2 mg / kg (588.6 mg as IPF), respectively, 1.2-1.7 times lower than the 346.7 mg / kg of IPF. The results are shown in Table 1.

LD ₅₀ upon subcutaneous and intraperitoneal administration of IPF, IE and IB in mice Subcutaneous administration Intraperitoneal administration Dose, mg / kg No. of died / No. of test dose, mg / kg No. of died / No. of test IPF 2003505006508009501100 0/61/62/63/64/65/66/6 120200280360440520600 0/61/62/63/64/65/66/6 LD ₅₀ 683.3 mg / kg LD ₅₀ 346.7mg / kg IE 1125125013751500162517501875 0/61/63/64/65/65/66/6 250325400475550625700 0/61/61/63/64/65/66/6 LD ₅₀ 1583.3 mg / kg LD ₅₀ 487.5mg / kg IB 2500300035004000450050005500 0/62/62/63/64/65/66/6 2503755006257508751000 0/61/61/62/62/64/66/6 LD ₅₀ 3416.7 mg / kg LD ₅₀ 792.2 mg / kg

Experimental Example 2: Analgesic Effect Experiment

In accordance with Koster's acetic acid method, 6 mice were used in each group, orally administered with a suspension of IPF 100mg / kg, its equivalent IE 121.8mg / kg, and IB 135.4mg / kg in 0.1% Carboxymethyl cellulose (CMC) solution. After 30 minutes, intraperitoneal injection of 0.6% acetic acid-saline soln. 0.1 mL / weight of 10 g was measured, and the number of writhing syndrom occurrences was measured for 20 minutes from 5 minutes. The inhibition rate was 35.6%, IE 46.6%, and IB 51.6%, respectively, 30.9% and 44.9% improvement over IPF, and the results are shown in Table 2.

Inhibitory effect of writhing syndrom on IPF, IE and IB administration in mice Drug Dose (mg / kg) No. of writhing syndrom Inhibition (%) Saline - 33.7 ± 1.10 - IPF 100 21.7 ± 2.33 35.6 IE 121.8 18.0 ± 1.33 46.6 IB 135.4 16.3 ± 1.10 51.6

Experimental Example 3 Edema Inhibition Experiment

According to Van Aman's rat edema test, Wister male rats weighing about 200g were fasted with water only for 24 hours before the experiment, and 6 rats in each group were suspended in 0.1% Na · CMC solution, IPF 50mg / kg, After 30 minutes of oral administration of IE 60.9 mg / kg (50 mg as IPF) and IB 67.7 mg / kg (50 mg as IPF), 1 mL of Carrageenin solution (Sigma-Aldrich) was added 0.1 mL Subcutaneous injection into the sole of the foot.

The volume of the foot was measured immediately after the injection and the volume of the foot was measured for 6 hours every hour to calculate the volume increase rate and edema inhibition rate. In the control group, edema increased by 70% at 3 hours, decreased to 39% after 6 hours, and peaked at 2 hours in the drug-treated group. In the drug group, edema increased by 23.45%, IE 14.28%, and IB 14.14% at 3 hours.

Compared to the control group, edema inhibition rate was 66.5% for IPF, 79.6% for IE, and 79.8% for IB at 3 hours. IE and IB showed similar edema inhibition effects, respectively, about 40% compared to IPF. Showed a high edema suppression effect. Edema inhibition rate is based on the following formula, the experimental results are shown in FIG.

Experimental Example 4: gastric mucosa disorder experiment

Since gastrointestinal disorders of IPF are caused by carboxylic acids, IE and IB replaced with diol esters were tested according to E. Coli method in order to reduce mucosal irritation. That is, six Wister male rats of 180-200 g body weight were fasted for 24 hours, and orally administered with the drugs suspended in each concentration of Table 3 in 0.25% Na · CMC solution, and the stomach was extracted after 6 hours. The incision was made along the surface and visually observed for ulcers and hemorrhagic spots on the inner wall of the stomach.

The degree of obstruction or ulceration on the inner wall is 0: normal, 1: bleeding or mucosal erosion, 2: less than 5 small ulcers (diameter or less than 2 mm long), 3: more than 5 small ulcers or large ulcers (2 mm or more) One, four: Two or more large ulcers were classified into four classes. Considering Grade 2 ulcers, a 50% ulcer development (Stomach Ulcerogenic Dose: SUD ₅₀ ) was calculated at the 95% confidence limit according to the Litchfield & Wilcoxon method from the number and incidence of rats used.

SUD ₅₀ of each drug was 31.3mg / kg for IPF, 58.6mg / kg for IE (48.3mg as IPF), and 73.3mg / kg (54.1mg as IPF) for IB. 1.54 times and 1.73 times lower, respectively. The results are shown in Table 3.

Ulcerative Action on the Stomach of Rats of IPF, IE and IB Compound Dosemg / kg UlcerIncidence SUD ₅₀ mg / kg IPF 5.010.020.040.080.0160.0 0/61/61/63/65/66/6 31.3 (18.3-53.5) IE 10.020.040.080.0160.0320.0 0/62/63/63/65/66/6 58.6 (32.6-105.5) IB 12.525.050.0100.0200.0400.0 0/01/62/64/65/66/6 73.3 (40.1-134.1)

Experimental Example 5: Blood Concentration Experiment

Six New Zealand White male rabbits weighing about 3 kg were used as a group and suspended in 0.1% Na.CMC solution. IPF 100 mg / kg, IE 128.8 mg / kg (100 mg as IPF), IB 135.4 mg / kg ( 100 mg) was orally administered to rabbits fasted for 24 hours. Fasting continued after the drug was administered, but after 4 hours, water was freely consumed. After drug administration, 1.5 mL of blood was collected from the vein at regular intervals, and 0.5 mL of the plasma obtained by centrifugation was immediately taken, deproteinized by adding 1 mL of methanol, shaken for 10 minutes, and centrifuged at 3,000 rpm for 15 minutes. The supernatant was filtered with a 0.45 μm membrane filter, and the filtrate was then diluted with methanol and filtered. The filtrate was used as a sample to determine the blood concentration by HPLC. IPF was determined to be the highest blood concentration (Cmax) after 1.5 hours. The highest blood levels of IPF, IE and IB were comparable, reaching 56.7 ± 18.47 μg / mL, IE reaching 54.3 ± 14.70 μg / mL after 1.33 hours, and IB reaching 58.4 ± 17.27 μg / mL after 1.0 hour. Therefore, the peak blood concentration was similar in time but the value was similar, whereas the blood concentration between 10 minutes and 1 hour in terms of absorption rate was higher than that of IPF by IE and IB. Results obtained for Ka represents the absorption rate, IPF is 2.487hr ^-1, IE is 2.626hr ^-1, IB was the rate of absorption of the IE and IB increases 2.948hr ^-1, Kel showing the excretion rate, IPF is 0.273hr ^-1 , IE for 0.435hr ^-1 , and IB for 0.415hr ^-1 were also faster than for IPF. The biological half-life (t½) was 1.59 hrs for the IE and 1.67 hrs for the IPF compared to 2.54 hrs. The total area under the curve (AUC) after administration of the drugs was about the same for the three drugs. The pharmacokinetic parameters of the above experiments are shown in Table 4.

Pharmacokinetic Parameters of IPF, IE and IB Orally Administered to Rabbits Drug classification Ka (hr ^-1 ) Kel (hr ^-1 ) tmax (hr) IPFIEIB 2.487 ± 0.21492.626 ± 0.38012.948 ± 0.3454 0.273 ± 0.25150.435 ± 0.10010.415 ± 0.0953 1.501.331.00 Drug classification Cmax (μg / mL) AUC (μg / mLhr) t½ (hr) IPFIEIB 56.7 ± 18.4754.3 ± 14.7058.4 ± 17.27 26.9 ± 4.7 128.4 ± 7.6122.1 ± 3.50 2.541.591.67

Ka: Absorption rate constant

Kel: Elimination rate constant

AUC: Area under the plasma concentration- time curve

Experimental Example 6: Hydrolysis Experiment

In order to examine the stability in vivo, 100 mg of each drug was added to each 100mg of artificial intestinal fluid (pharmacopoeia), artificial gastric juice (pharmaceutical), and saturated aqueous solution of pancreatin (USP) to make 100mL, respectively Was taken, and the residual amount of ester was measured by HPLC to obtain the percentage. The results are shown in Table 5.

Residual amount of ester by hydrolysis (%) Artificial gastric juice Artificial serous Pancreatin saturated aqueous solution time IE IB time IE IB time IE IB 1259122448 99.0298.8997.1290.3889.3982.1273.46 97.6897.1995.3892.2891.8173.4061.43 1259122448 99.9999.9799.1199.0898.5998.4597.78 99.6799.6299.5699.4198.7198.4797.92 0.51.02.03.04.0 98.6298.5097.9596.8995.72 99.6099.4699.0597.4996.30

In the present invention, the inventors synthesized ibuprofen ethanediol ester and ibuprofen butanediol ester from ibuprofen and yields of 74% and 87%, respectively.

The synthesized materials were identified using UV, IR, HPLC, and NMR. Acute toxicity test, analgesic effect test, edema suppression test, gastric mucosal obstruction test, pharmacokinetic review through blood concentration measurement, artificial gastric fluid and artificial intestinal fluid As a result of the hydrolysis experiment in, the esters IE and IB significantly inhibited the side effects of acute toxicity and gastric mucosal disorder, and the analgesic effect and edema suppression ability were significantly increased compared to IPF.

The compounds of the present invention can be used as medicaments by mixing pharmaceutically acceptable excipients or adjuvants and formulating them into pharmaceutical preparations which can be administered orally using conventional pharmaceutical methods.

Preparation Example 1 Preparation of Tablet

Ibuprofen ethanediol ester: 10mg

Lactose: 20 mg

Starch: 20mg

Magnesium Stearate: Appropriate

The above ingredients are mixed and compressed into 50 mg tablets according to a conventional method for producing tablets.

Preparation Example 2: Manufacture of capsule

Ibuprofen ethanediol ester: 10mg

Lactose: 20 mg

Starch: 19mg

Talc: 1mg

Magnesium Stearate: Appropriate

The above ingredients are mixed and filled into 50 mg of gelatin capsules according to a conventional method for preparing capsules.

The ibuprofen ethanediol ester and ibuprofen butanediol ester of the present invention significantly reduce side effects in the gastrointestinal tract, reduce edema and analgesic effect by modifying the chemical structure to reduce digestive tract obstruction of ibuprofen, compared to ibuprofen having a carboxylic acid group in the chemical structure. It is effective to significantly improve.

Claims (3)

Ibuprofen alkanediol ester represented by the following formula (1) [Formula 1] As defined in claim 1, the reaction is performed by adding 1,2-ethanediol or 1,2-butanediol dissolved in a tetrahydrofuran solvent to a halogenated ibuprofen of the following Chemical Formula 2, wherein the ibuprofen is halogenated with a halogenating agent in a benzene solvent. To prepare a compound of formula (I). [Formula 2] Pharmaceutical composition containing ibuprofen ethanediol ester or ibuprofen butanediol ester as an active ingredient.