Ibuprofen-Tyr-Arg-Tyr-Arg and preparation and application thereof

Abstract

The invention discloses a conjugate of Tyr-Arg-Tyr-Arg and ibuprofen, namely, ibuprofen-Tyr-Arg-Tyr-Arg, namely, IBU-YRYR, and a preparation method of the conjugate of Tyr-Arg-Tyr-Arg and ibuprofen. The invention further discloses a preparation method of the IBU-YRYR and an application of the IBU-YRYR. Experiments prove that when the oral dosage of IBU-YRYR is 1 / 100 of the oral dosage of ibuprofen, good analgesic and anti-inflammatory dual activities are shown. According to the characteristics of IBU-YRYR, a known analgesic drug is expanded to a level integrating analgesia and anti-inflammation, potential is provided for selection and application of the analgesic drug in other clinical indications, and a novel candidate molecule is provided for subsequent drug development.

Description

TECHNICAL FIELD

[0001] The present application relates to a compound of Ibuprofen-Tyr-Arg-Tyr-Arg (IBU-YRYR for short), a method for preparing the same, analgesic and anti-inflammatory effects of the same, and thus the present application relates to the use of the same in the preparation of a medicament having both analgesic and anti-inflammatory effects.

[0002] The present application belongs to the field of biological medicine. BACKGROUND

[0003] Ibuprofen reduces prostaglandin synthesis by inhibiting cyclooxygenase and produces analgesic and anti-inflammatory effects. Ibuprofen can also produce antipyretic effects by acting on the hypothalamic thermoregulatory center. In clinical practice, ibuprofen is used to relieve mild and moderate headaches, including migraine, joint pain, dental pain, muscle pain, neuralgia, and dysmenorrhea. In addition, ibuprofen is also used to treat fever caused by common cold or influenza. Ibuprofen shows analgesic effect about 30 minutes after oral administration, and generally can maintain for 6 to 8 hours. Although ibuprofen also has anti-inflammatory effects, it is not used as an anti-inflammatory drug in clinical practice.

[0004] Kyotorphin (Tyr-Arg) and its repeated sequence Tyr-Arg-Tyr-Arg participate in the brain's regulation of pain by releasing enkephalins and inhibiting their degradation, and have endorphin-like analgesic effects. Tyr-Arg and Tyr-Arg-Tyr-Arg do not directly bind to opioid receptors, and have low risk of addiction. Since Tyr-Arg and Tyr-Arg-Tyr-Arg lack the ability to cross the blood-brain barrier, structural modifications of Tyr-Arg and Tyr-Arg-Tyr-Arg are needed to enable them to cross the blood-brain barrier and enhance analgesic effects.

[0005] Based on the above knowledge, the inventors hypothesized that once the conjugate of Tyr-Arg-Tyr-Arg and ibuprofen (Ibuprofen-Tyr-Arg-Tyr-Arg) can cross the blood-brain barrier, not only the analgesic effect of ibuprofen involved in the conjugation can be enhanced, but also the anti-inflammatory effect of ibuprofen can be enhanced. Based on this hypothesis, the present application is proposed. SUMMARY

[0006] The technical problem to be solved by the present application is to provide Ibuprofen-Tyr-Arg-Tyr-Arg and confirm that it has excellent anti-inflammatory and analgesic dual effects. In order to achieve the said purpose, the present application adopts the following technical means.

[0007] The first technical means is to provide Ibuprofen-Tyr-Arg-Tyr-Arg (IBU-YRYR for short) of the following formula

[0008]

[0009] The second technical means is to provide a preparation method of IBU-YRYR, which comprises the following steps.

[0010] 1) Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl is prepared by using a liquid-phase condensation method to synthesize peptides from C-terminal to N-terminal step by step;

[0011] 2) IBU-Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl is prepared by using a liquid-phase condensation method with dicyclohexyl carbodiimide and N-hydroxybenzotriazole as catalysts;

[0012] 3) IBU-Tyr-Arg(Pbf)-Tyr-Arg is obtained by hydrogenolysis of IBU-Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl in methanol under the catalysis of Pd / C;

[0013] 4) IBU-YRYR is obtained by removing Pbf from IBU-Tyr-Arg(Pbf)-Tyr-Arg in water / trifluoroacetic acid / triisopropylsilane.

[0014] The third technical means is to evaluate the analgesic activity and anti-inflammatory activity of IBU-YRYR and the application of IBU-YRYR in the preparation of a medicine with double effects of analgesia and anti-inflammation.

[0015] Compared with the prior art, the beneficial effects of the present application can be described as follows.

[0016] The present application discloses a conjugate of Tyr-Arg-Tyr-Arg and ibuprofen (ibuprofen-Tyr-Arg-Tyr-Arg), namely IBU-YRYR. Experiments prove that IBU-YRYR shows good double activities of analgesia and anti-inflammation when the oral dose of IBU-YRYR is 1 / 100 of the oral dose of ibuprofen. The characteristics of IBU-YRYR expand the known analgesic drugs to the level of integrating analgesia and anti-inflammation, provide potential for the selection and application of analgesic drugs in other clinical indications, and provide a new type of candidate molecule for subsequent drug development. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 Synthetic route of IBU-Tyr-Arg-Tyr-Arg.(i) dicyclohexyl carbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine, tetrahydrofuran; (ii) hydrogen chloride ethyl acetate solution; (iii) hydrogen, palladium / carbon, methanol; (iv) 95% trifluoroacetic acid, 2.5% water, 2.5% triisopropylsilane. DETAILED DESCRIPTION

[0018] To further illustrate the application, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the application and should not be understood as limiting the application.

[0019] Example 1 Preparation of Boc-Tyr-Arg(NO2)-OBzl

[0020] Boc-Tyr (670 mg, 2.40 mmol) was dissolved in 3 mL of anhydrous tetrahydrofuran to give a clear transparent solution. To the resulting solution was added 271 mg (2.00 mmol) of 1-hydroxybenzotriazole (HOBt) and stirred in an ice bath for 10 minutes to give reaction solution A. Dicyclohexylcarbodiimide (DCC) (494 mg, 2.40 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran to give reaction solution B. Reaction solution B was added to reaction solution A and stirred in an ice bath for 30 minutes. Then, a solution of Tos-Arg(NO2)-OBzl (960 mg, 2.00 mmol) in 6 mL of anhydrous tetrahydrofuran was added. The resulting reaction mixture was stirred at room temperature for 6 hours after adjusting the pH value to 9 with N-methylmorpholine (NMM) in an ice bath. TLC (CH2Cl2 / CH3OH = 20 / 1) showed that Tos-Arg(NO2)-OBzl disappeared. The reaction mixture was filtered to remove insoluble materials and the filtrate was concentrated under reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and filtered to remove insoluble materials. The filtrate was washed successively with 5% aqueous sodium bicarbonate solution (40 mL x 3), saturated aqueous sodium chloride solution (40 mL x 3), 5% aqueous potassium bisulfate solution (40 mL x 3), saturated aqueous sodium chloride solution (40 mL x 3), 5% aqueous sodium bicarbonate solution (40 mL x 3), and saturated aqueous sodium chloride solution (40 mL x 3). The collected ethyl acetate solution was dried with anhydrous sodium sulfate for 8 hours, filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure to give a yellow oily substance. The yellow oily substance was purified on a silica gel column (CH2Cl2 / CH3OH = 20 / 1) to give 985 mg of the title compound as a colorless solid with a yield of 86%. ESI-MS (m / z): 595 [M+Na] + ; 1H NMR (300 MHz, DMSO-d6): δ / ppm = 9.15 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 4.3 Hz, 5H), 7.05 (t, J = 9.8 Hz, 2H), 6.85 (m, 1H), 6.64 (d, J = 7.8 Hz, 2H), 5.13 (s, 2H), 4.35 (d, J = 6.5 Hz, 1H), 4.09 (d, J = 14.7 Hz, 1H), 3.16 (s, 2H), 2.80 (dd, J1= 13.8 Hz, J2= 4.1 Hz, 1H), 2.55 (m, 1H), 1.75 (m, 2H), 1.55 (m, 3H), 1.37 (s, 1H), 1.30 (s, 9H).

[0021] Example 2 Preparation of HCl-Tyr-Arg(NO2)-OBzl

[0022] Dissolve 1.15 g (2.00 mmol) of Boc-Tyr-Arg(NO2)-OBzl in 12 mL of anhydrous hydrogen chloride in ethyl acetate with stirring in an ice bath for 3 hours. TLC (CH2Cl2 / CH3OH = 20 / 1) shows that Boc-Tyr-Arg(NO2)-OBzl is gone. Then, the reaction solution is concentrated under reduced pressure, and the residue is dissolved in 20 mL of anhydrous ethyl acetate and concentrated under reduced pressure again. This operation is repeated 3 times to remove the free hydrogen chloride completely. The obtained solid is dispersed in petroleum ether, and the upper solvent is decanted off. The residue is concentrated under reduced pressure to give 966 mg of HCl-Tyr-Arg(NO2)-OBzl as a colorless solid, which is used in the next step without further purification. ESI-MS (m / z): 473 [M+H] + .

[0023] Example 3 Preparation of Boc-Arg(pbf)-Tyr-Arg(NO2)-OBzl

[0024] Using the procedure of Example 1, 1.14 g (2.16 mmol) of Boc-Arg(pbf) and 1.00 g of HCl-Tyr-Arg(NO2)-OBzl give 1.23 g of the title compound as a colorless powder in 64% yield. ESI-MS (m / z): 981 [M+H] + ; 1HNMR (300 MHz, DMSO-d6): δ / ppm = 9.14 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 3.2 Hz, 5H), 6.97 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.6 Hz, 1H), 6.60 (d, J = 8.1 Hz, 2H), 6.40 (s, 2H), 5.12 (s, 2H), 4.49 (s, 1H), 4.31 (q, J = 7.1 Hz, 1H), 3.83 (s, 1H), 3.35 (s, 3H), 2.95 (s, 4H), 2.83 (d, J = 12.2 Hz, 1H), 2.63 (dd, J1= 14.2 Hz, J2= 9.0 Hz, 1H), 2.42 (s, 4H), 2.00 (s, 4H), 1.77 (s, 1H), 1.51 (s, 5H), 1.38 (d, J = 12.8 Hz, 19H), 1.23 (s, 3H).

[0025] Example 4 Preparation of HCl-Arg(pbf)-Tyr-Arg(NO2)-OBzl

[0026] Using the procedure of Example 2, 1.72 g of HCl-Arg(pbf)-Tyr-Arg(NO2)-OBzl was obtained as a yellow powder from 1.960 g (2.00 mmol) of Boc-Arg(pbf)-Tyr-Arg(NO2)-OBzl, which was used in the next step without further purification. ESI-MS (m / z): 881 [M+H] + .

[0027] Example 5 Preparation of Boc-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl

[0028] Using the procedure of Example 1, 830 mg of the title compound was obtained as a colorless solid in 37% yield from 670 mg (2.40 mmol) of Boc-Tyr and 1.76 g of HCl-Arg(pbf)-Tyr-Arg(NO2)-OBzl. ESI-MS (m / z): 1144 [M+Na] + ; 1H NMR (300 MHz, DMSO-d6): δ / ppm = 9.15 (s, 2H), 8.45 (d, J = 7.6 Hz, 1H), 7.95 (m, 2H), 7.85 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 3.9 Hz, 4H), 7.00 (dd, J1= 12.0 Hz, J2= 7.9 Hz, 4H), 6.85 (d, J = 8.2 Hz, 1H), 6.62 (t, J = 6.9 Hz, 4H), 6.39 (s, 1H), 5.11 (s, 2H), 4.46 (s, 1H), 4.31 (d, J = 10.6 Hz, 2H), 4.04 (s, 1H), 3.43 (s, 1H), 3.17 (s, 2H), 2.98 (m, 4H), 2.81 (d, J = 14.9 Hz, 1H), 2.61 (s, 1H), 2.42 (s, 2H), 1.99 (s, 2H), 1.76 (s, 1H), 1.51 (s, 14H), 1.38 (d, J = 10.7 Hz, 7H), 1.26 (d, J = 12.4 Hz, 9H), 1.15 (s, 1H).

[0029] Example 6 Preparation of HCl-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl (7)

[0030] Using the procedure of Example 2, 2.04 g of HCl-Tyr-Arg(pbf)-Tyr-Arg(NO2))-OBzl as a light yellow powder was obtained from 2.28 g (2.00 mmol) of Boc-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl without further purification and was used directly in the next step. ESI-MS (m / z): 837 [M+H] + .

[0031] Example 7 Preparation of IBU-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl (8)

[0032] Using the procedure of Example 1, 966 mg of the title compound as a light yellow powder was obtained from 495 mg (2.40 mmol) of ibuprofen and 2.09 g of HCl-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl in 39% yield. ESI-MS (m / z): 1232 [M+H] + ; 1H NMR (300 MHz, DMSO-d6): δ / ppm = 9.13 (s, 1 H), 8.50 (m, 2 H), 8.05 (m, 1 H), 7.35 (s, 5 H), 7.16 (m, 2 H), 7.02 (d, J = 7.0 Hz, 4 H), 6.82 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 8.0 Hz, 1 H), 6.51 (d, J = 8.2 Hz, 1 H), 5.12 (s, 2 H), 4.36 (m, 4 H), 3.65 (m, 1 H), 3.57 (t, J = 4.8 Hz, 5 H), 3.17 (d, J = 8.2 Hz, 2 H), 2.96 (s, 3 H), 2.43 (d, J = 11.4 Hz, 6 H), 2.31 (s, 5 H), 2.18 (s, 4 H), 2.02 (s, 3 H), 1.82 (m, 3 H), 1.57 (s, 8 H), 1.41 (s, 8 H), 1.26 (d, J = 6.7 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 1 H), 0.84 (d, J = 7.8 Hz, 6 H).

[0033] Example 8 Preparation of IBU-YRYR

[0034] IBU-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl was dissolved in 50 mL of methanol and then 160 mg of palladium on carbon (10% content of product) was added. The resulting suspension was degassed and stirred under hydrogen for 24 hours at room temperature. TLC (CH2Cl2 / CH3OH = 15 / 1) showed that IBU-Tyr-Arg(pbf)-Tyr-Arg(NO2)-OBzl had disappeared. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was evenly dispersed with petroleum ether, left to stand, the upper solvent was decanted off and concentrated under reduced pressure to give 1.35 g of IBU-Tyr-Arg(pbf)-Tyr-Arg as a colourless solid.

[0035] The resulting IBU-Tyr-Arg(pbf)-Tyr-Arg (1.00 g) was mixed with trifluoroacetic acid / water / triisopropylsilane = 38 / 1 / 1 (10 mL) under ice-bath cooling. After stirring for 4 h, TLC (EtOAc / H2O / HAc = 4 / 1 / 1) showed the disappearance of IBU-Tyr-Arg(pbf)-Tyr-Arg. The reaction solution was first evacuated under reduced pressure until no bubbles were generated, and then the remaining solvent was blown dry with nitrogen. The resulting light yellow oil was suspended in diethyl ether, sonicated, centrifuged, and the supernatant was decanted to collect the colorless solid. This operation was repeated three times. The resulting solid was purified on a column of octadecylsilane-bonded silica gel, eluted with a gradient of H2O / CH3OH = 3 / 2 plus 2% formic acid, to give 616 mg of the title compound as a colorless solid, with a yield of 56%. ESI-MS (m / z): 845 [M+H] + ; Mp 122-127 °C; IR (cm -1 ): 3261, 3193, 2959, 2927, 2864, 2689, 2606, 2476, 1651, 1615, 1541, 1514, 1447, 1366, 1229, 1183, 1112, 989, 895, 865, 830, 666, 605, 549, 509, 485, 460; 1 H NMR (300 MHz, DMSO-d6): δ / ppm = 12.55 (s, 1H), 9.19 (s, 2H), 8.31 (d, J = 7.7 Hz, 1H), 8.03 (t, J = 8.0 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 5.6 Hz, 1H), 7.57 (t, J = 5.6 Hz, 1H), 7.01 (m, 6H), 6.84 (m, 2H), 6.62 (m, 2H), 6.53 (m, 2H), 4.51 (s, 1H), 4.38 (q, J = 7.3 Hz, 1H), 4.28 (s, 1H), 4.19 (s, 1H), 3.82 (s, 13H), 3.62 (t, J = 7.1 Hz, 1H), 2.96 (m, 1H), 2.75 (m, 3H), 2.39 (d, J = 7.1 Hz, 2H), 1.79 (dq, J1= 13.8 Hz, J2= 6.8 Hz, 1H), 1.65 (s, 1H), 1.52 (m, 5H), 1.25 (d, J = 6.9 Hz, 3H), 0.85 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ / ppm = 173.94, 173.69, 171.96, 171.56, 158.72, 157.27, 157.23, 156.30, 156.18, 139.51, 139.35, 130.56, 130.47, 129.04, 128.15, 127.86, 127.36, 115.32, 115.19, 54.90, 52.24, 44.76, 44.53, 30.07, 28.63, 25.63, 22.67, 18.20. HPLC purity: 98.6% (methanol / water = 55 / 45).

[0036] Example 1 Evaluation of the analgesic effect of IBU-YRYR

[0037] The analgesic effect of IBU-YRYR was evaluated in the tail-flick model in mice. ICR male mice (body weight 22 ± 3 g) were acclimated for 2 days at 25 °C, then fasted for 24 hours, water deprived for 12 hours, and randomly divided into groups of 12 mice. When the mice were placed in the restrainer of the analgesia meter, the tail was exposed outside the restrainer. To ensure that the mice were stable and to avoid the tail flicking for a long time, the mice were allowed to rest in the restrainer for 1 minute. The tail was marked at a distance of 2-3 cm from the tail tip (this position was at one-third of the tail end from the mouse). The marked position was the point of light perception. The analgesia meter was started and the marked position was irradiated with light. The time taken for the mice to flick their tail was recorded and used as the pain threshold of the mice. The basal pain threshold of the mice was determined first and the time taken for the mice to flick their tail was 3-5 seconds. The pain threshold was measured three times in succession and the difference between each measurement was not more than 1 second. The average value was taken as the basal pain threshold of the mice. The threshold was expressed as the time taken for the mice to flick their tail and the analgesic effect was represented as the % increase in the pain threshold. % increase in the pain threshold = [(pain threshold after administration - basal pain threshold) / basal pain threshold] x 100%.

[0038] The mice were orally administered 5% CMC-Na (blank control, dose 10 mL / kg) or a suspension of ibuprofen and 5% CMC-Na (positive control, dose 252 μmol / kg) or a suspension of YRYR and 5% CMC-Na (coupling component control, dose 252 μmol / kg) or a suspension of IBU-YRYR and 5% CMC-Na (dose 2.52 μmol / kg). The pain threshold of the mice was determined at 6 time points, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes and 180 minutes after oral administration.

[0039] The data in Table 1 show that IBU-YRYR exhibits excellent analgesic effect at 30 minutes, 60 minutes and 90 minutes (p<0.01 compared with 5% CMC-Na and YRYR). The data in Table 1 also show that the analgesic activity of IBU-YRYR is significantly stronger than that of ibuprofen at 30 minutes, 60 minutes and 90 minutes (p<0.01 compared with ibuprofen). IBU-YRYR has outstanding technical effects.

[0040] The data in Table 2 show that IBU-YRYR exhibits excellent analgesic effect at 120 minutes, 150 minutes and 180 minutes (p<0.01 compared with 5% CMC-Na and YRYR). The data in Table 2 also show that the analgesic activity of IBU-YRYR is significantly stronger than that of ibuprofen at 120 minutes, 150 minutes and 180 minutes (p<0.05 compared with ibuprofen). IBU-YRYR has outstanding technical effects.

[0041] Table 1 Effect of IBU-YRYR on the tail-flick time of mice at 30-90 minutes

[0042]

[0043]

[0044] a) p<0.01 compared with 5% CMC-Na and YRYR; b) p<0.05 compared with 5% CMC-Na and YRYR; c) p<0.01 compared with 5% CMC-Na and YRYR, and p<0.05 compared with ibuprofen; d) p<0.01 compared with 5% CMC-Na and YRYR, and p<0.01 compared with ibuprofen; n=12.

[0045] Table 2 Effect of IBU-YRYR on the tail-flick time of mice at 120-180 minutes

[0046]

[0047] a) p<0.01 compared with 5% CMC-Na and YRYR; b) p<0.01 compared with 5% CMC-Na and YRYR, and p<0.05 compared with ibuprofen; n=12.

[0048] Experimental Example 2 Evaluation of the anti-inflammatory effect of IBU-YRYR

[0049] The anti-inflammatory effect of IBU-YRYR was evaluated on the acute inflammation model of mouse ear swelling induced by xylene. ICR male mice (body weight 22±3 g) were rested for 2 days in an environment with a temperature of 25°C, with free access to water and food. Then, the mice were randomly divided into a control group of ibuprofen (oral dose 252 μmol / kg), a control group of YRYR (oral dose 252 μmol / kg), a control group of 5‰ CMC-Na (oral dose 10 mL / kg), and an IBU-YRYR group (oral dose 2.52 μmol / kg). There were 12 mice in each group. After 30 minutes of oral administration, 30 μL of xylene was evenly applied to the left auricle of the mice, and after 2 hours, the mice were anesthetized with ether, sacrificed by cervical dislocation, and the left and right ears were cut off. A 7-mm puncher was used to take circular ear pieces at the same position on both ears, and the weights of the two ears were measured. The difference between the weights of the two ears was taken as the degree of swelling, i.e., the degree of swelling = weight of left ear circle - weight of right ear circle. The degrees of ear swelling of the mice in each group were statistically processed using the Microsoft Word Excel program to obtain the mean and standard deviation. The t value was obtained by comparing between groups.

[0050] The data in Table 3 show that IBU-YRYR exhibits excellent anti-inflammatory activity on the xylene-induced mouse ear swelling model (p<0.01 compared with CMC-Na and YRYR). The data in Table 3 also show that the anti-inflammatory activity of IBU-YRYR is significantly stronger than that of ibuprofen, which has an oral dose that is 100 times that of IBU-YRYR (p<0.05 compared with ibuprofen), and the present application has unexpected technical effects.

[0051] Table 3 Effect of IBU-YRYR on the degree of mouse ear swelling induced by xylene

[0052] Therapeutic agent Oral dose Ear swelling, mean ± SD mg 5% CMC-Na 10 mL / kg 4.78±0.38 YRYR 252 μmol / kg 4.76±0.40 Ibuprofen 252 μmol / kg 3.65 ± 0.31 a ]] IBU-YRYR 2.52 μmol / kg 2.13 ± 0.26 b ]]

[0053] a) p<0.01 compared with 5‰ CMC-Na and YRYR; b) p<0.01 compared with 5‰ CMC-Na and YRYR, and p<0.05 compared with ibuprofen; n=12.

Claims

1. The following formula is ibuprofen-Tyr-Arg-Tyr-Arg.

2. The preparation method of ibuprofen-Tyr-Arg-Tyr-Arg according to claim 1, characterized in that... The method includes the following steps. 1) Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl was prepared by stepwise peptide attachment from the C-terminus to the N-terminus using a liquid-phase condensation synthesis method; 2) Ibuprofen-Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl was synthesized by liquid-phase condensation using dicyclohexylcarbodiimide and N-hydroxybenzotriazole as catalysts; 3) Ibuprofen-Tyr-Arg(Pbf)-Tyr-Arg(NO2)-OBzl in methanol is debenzylated by Pd / C catalysis to give ibuprofen-Tyr-Arg(Pbf)-Tyr-Arg; 4) Ibuprofen-Tyr-Arg(Pbf)-Tyr-Arg is de-Pbfed in water / trifluoroacetic acid / triisopropylsilane to obtain ibuprofen-Tyr-Arg-Tyr-Arg.

3. The use of ibuprofen-Tyr-Arg-Tyr-Arg as described in claim 1 or 2 in the preparation of analgesic and anti-inflammatory drugs.

4. The use of ibuprofen-Tyr-Arg-Tyr-Arg of claim 3 in the preparation of anti-inflammatory drugs.

5. The use of ibuprofen-Tyr-Arg-Tyr-Arg of claim 3 in the preparation of analgesic drugs.

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