Ibuprofen derivative compound and application thereof

Abstract

The invention discloses an ibuprofen derivative compound and a pharmaceutically acceptable salt thereof. The ibuprofen derivative compound disclosed by the invention can play a role in resisting neuralgia, has an important potential treatment value, and can be used for preparing a medicine for treating neuropathic pain.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and provides a class of ibuprofen-derived compounds, their preparation methods and pharmaceutical uses. These compounds can exert an analgesic effect and can be used to prepare drugs for treating neuropathic pain. Background Art

[0002] Neuropathic pain (NP) is pain caused by damage or diseases of the somatosensory system, which is divided into peripheral neuropathic pain and central neuropathic pain. Peripheral neuropathic pain is more common clinically. A research data from Europe shows that the prevalence of neuropathic pain in the general population is as high as 8.0%. Neuropathic pain is not a single disease, but a syndrome caused by different diseases and damages, manifested as a series of symptoms and signs, which seriously affects the quality of life of patients. Postherpetic neuralgia and diabetic peripheral neuropathy are the two most common types of neuropathic pain. Chronic pain will not only affect the patient's sleep, work and living ability, but also increase the incidence of emotional disorders such as depression and anxiety. Some studies have shown that the quality of life score of patients with postherpetic neuralgia is only 1 / 2 of that of the normal population. There is a lack of therapeutic drugs for neuropathic pain. Currently, calcium channel modulators, antidepressants and local anesthetics are mainly used clinically for treatment. However, due to its relatively complex pathogenesis, the existing treatment methods are not satisfactory, and the pain of a large part of patients has not been fully relieved.

[0003] A class of ibuprofen-derived compounds of the present invention can exert a good analgesic effect in animal neuralgia models and have broad pharmaceutical prospects. Summary of the Invention

[0004] Technical Problem to be Solved: The present invention provides a class of ibuprofen-derived compounds and their preparation methods. The most prominent feature of these compounds is their anti-neuralgia effect, and they can be used to prepare drugs for treating neuropathic pain.

[0005] Technical Solution: A class of ibuprofen-derived compounds represented by formula I or their pharmaceutically acceptable salts, hydrates or solvates:

[0006]

[0007] wherein, R1 is selected from hydrogen or C1-C6 alkyl;

[0008] Preferably, R1 is selected from hydrogen, methyl, ethyl, propyl or isopropyl;

[0009] More preferably, R1 is selected from hydrogen, methyl or ethyl;

[0010] Most preferably, the compounds of formula I include but are not limited to the following specific compound examples:

[0011]

[0012] Compound 1: as shown in S1;

[0013]

[0014] Compound 2: as shown in S2.

[0015] The compounds provided by the present invention also include pharmaceutically acceptable equivalents of the compound or mixtures of two or more thereof.

[0016] Preferably, the compounds provided by the present invention may include one or a mixture of two or more of pharmaceutically acceptable salts, hydrates, and solvates.

[0017] Preferably, the compounds provided by the present invention include acid salts or base salts of the compounds provided by the present invention. The pharmaceutically acceptable salts have the pharmaceutical activity of the compound and meet the requirements both biologically and in practical applications.

[0018] The present invention provides a class of ibuprofen-derived compounds or pharmaceutically acceptable salts thereof for the treatment of neuropathic pain.

[0019] Beneficial effects:

[0020] A class of ibuprofen-derived compounds described in the present application. The most prominent feature of this class of drugs is their anti-neuralgia effect, and they can be used to prepare drugs for the treatment of neuropathic pain. Detailed implementation manners

[0021] The present invention discloses a class of ibuprofen-derived compounds and their uses. Those skilled in the art can draw on the content of this article and appropriately improve the process parameters to achieve. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate alterations and combinations to the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0022] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the following further details the present invention in conjunction with specific embodiments.

[0023] Example 1: Synthesis of Compound S1

[0024]

[0025] Synthesis route:

[0026]

[0027] Synthesis process:

[0028] The first step:

[0029] Take 50 ml of benzyl alcohol, cool it down to 0 - 5 °C, and dropwise add thionyl chloride (6.8 ml, 94.2 mmol). After adding, react at room temperature for 4 h, then cool it down to 0 - 5 °C, add pregabalin (5 g, 31.4 mmol), and react at room temperature for 12 h. After completion, concentrate the system to obtain pregabalin benzyl ester hydrochloride, which can be directly used for the next step without purification.

[0030] ESI-MS: 250.1[M + H] +

[0031] The second step:

[0032] Take the pregabalin benzyl ester hydrochloride from the first step (2 g, 7 mmol), dissolve it clearly with DCM (60 ml), cool it down to 0 - 5 °C, add a DCM (5 ml) solution of chloroformate-1-chloromethyl ester (1.16 g, 9.11 mmol), and then slowly dropwise add a DCM (5 ml) solution of N-methylmorpholine (1.6 g, 16.12 mmol). After adding, react at 5 °C for 3 h. Dilute the system with DCM (120 ml), wash the organic phase with dilute hydrochloric acid 3 times, dry and concentrate to obtain an oily crude product, which can be directly used for the next step without purification.

[0033] The third step:

[0034] Dissolve ibuprofen (0.18 g, 0.87 mmol) with acetone (5 ml), add TEA (0.13 g, 1.3 mmol), stir for 5 min. Take the intermediate from the second step (0.29 g, 0.87 mmol), dissolve it with acetone (5 ml) and add it to the system. Finally, add potassium iodide (72 mg, 0.43 mmol), and react at room temperature for 24 h. After post-treatment, dilute it with EA (100 ml), wash it with dilute hydrochloric acid 3 times and saturated sodium bicarbonate 3 times, dry and concentrate. TLC PE:EA = 1:1, ninhydrin color development. After the crude product is made into sand, purify it by silica gel column chromatography to obtain 0.089 g (yield 20%) of colorless oil.

[0035] ESI-MS: 512.3[M + H] +

[0036] The fourth step:

[0037] Take the pure product from the third step, dissolve it with ethanol (5 ml), add a drop of acetic acid, add 0.1 eq of palladium carbon, and react at room temperature for 8 h under a hydrogen balloon. After post-treatment, filter and concentrate, then purify it by silica gel sand DCM:MeOH system column chromatography to obtain 50 mg of colorless oil (yield 67%).

[0038] ESI-MS: 422.3 [M+H] +

[0039] 1 H NMR (400 MHz, Chloroform-d) δ 7.20 (dd, J=8.1, 2.1 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 6.86–6.76 (m, 2H), 5.04–4.84 (m, 1H), 3.70 (dd, J=14.6, 7.5 Hz, 1H), 3.38–2.98 (m, 2H), 2.46 (dd, J=7.2, 1.6 Hz, 2H), 2.3–2.2 (m, 1H), 1.86 (m, 1H), 1.74–1.60 (m, 1H), 1.54–1.48 (m, 3H), 1.47 (d, J=5.5 Hz, 1H), 1.39 (d, J=5.5 Hz, 1H), 1.18 (ddt, J=11.7, 7.0, 3.2 Hz, 2H), 0.99–0.85 (m, 12H).

[0040] Example 2: Synthesis of Compound S2

[0041]

[0042] Synthesis route:

[0043]

[0044] Synthesis process:

[0045] First step:

[0046] Take 50 ml of benzyl alcohol, cool down to 0 - 5 °C, dropwise add thionyl chloride (6.8 ml, 94.2 mmol). After addition, react at room temperature for 4 h. Then cool down to 0 - 5 °C, add pregabalin (5 g, 31.4 mmol), and react at room temperature for 12 h. After completion, concentrate the system to dryness to obtain pregabalin benzyl ester hydrochloride, which can be directly used in the next step without purification.

[0047] ESI-MS: 250.1 [M+H] +

[0048] Second step:

[0049] Take the first step of pregabalin benzyl ester hydrochloride (2 g, 7 mmol), dissolve it in DCM (60 ml) until clear, cool it down to 0 - 5 °C, add a DCM (5 ml) solution of chloroformic acid 1-chloroethyl ester (1.3 g, 9.11 mmol), and then slowly dropwise add a DCM (5 ml) solution of N-methylmorpholine (1.6 g, 16.12 mmol). After addition, react at 5 °C for 3 h. Dilute the system with DCM (120 ml), wash the organic phase with dilute hydrochloric acid 3 times, dry and concentrate to obtain a crude oil product, which can be directly used in the next step without purification.

[0050] The third step:

[0051] Dissolve ibuprofen (0.18 g, 0.87 mmol) in acetone (5 ml) until clear, add TEA (0.13 g, 1.3 mmol), stir for 5 min. Take the intermediate of the second step (0.31 g, 0.87 mmol), dissolve it in acetone (5 ml) and add it to the system. Finally, add potassium iodide (72 mg, 0.43 mmol), and react at room temperature for 24 h. After work-up, dilute with EA (100 ml), wash with dilute hydrochloric acid 3 times and saturated sodium bicarbonate 3 times, dry and concentrate. TLC PE:EA = 1:1, developed with ninhydrin. After triturating the crude product, purify it by silica gel column chromatography to obtain 0.137 g (yield 30%) of a colorless oil.

[0052] ESI-MS: 526.3[M+H] +

[0053] The fourth step:

[0054] Take the pure product of the third step, dissolve it in ethanol (7 ml), add a drop of acetic acid, add 0.1 eq of palladium on carbon, and react at room temperature for 8 h under a hydrogen balloon. After work-up, filter and concentrate to dryness, and purify it by silica gel trituration DCM:MeOH system column chromatography to obtain 100 mg of a colorless oil (yield 84%).

[0055] ESI-MS: 436.3[M+H] +

[0056] 11H NMR (400 MHz, Chloroform-d) δ 7.20 (dd, J = 8.1, 2.1 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.86–6.76 (m, 1H), 5.04–4.84 (m, 1H), 3.70 (dd, J = 14.6, 7.5 Hz, 1H), 3.38–2.98 (m, 2H), 2.46 (dd, J = 7.2, 1.6 Hz, 2H), 2.41–2.05 (m, 4H), 1.86 (m, 1H), 1.74–1.60 (m, 1H), 1.54–1.48 (m, 3H), 1.47 (d, J = 5.5 Hz, 1H), 1.39 (d, J = 5.5 Hz, 1H), 1.18 (ddt, J = 11.7, 7.0, 3.2 Hz, 2H), 0.99–0.85 (m, 12H).

[0057] Example 3: Study on the Pharmacodynamic Effect of the Compound on Neuropathic Pain

[0058] 1 Materials and Methods

[0059] 1.1 Experimental Animals

[0060] Sprague-Dawley (SD) rats, male, SPF grade, weighing 150 - 200 g.

[0061] 1.2 Tested Drugs

[0062] The control drug pregabalin was from Adamas Reagent, Ltd. The batch number was P1472904.

[0063] 1.3 Experimental Methods

[0064] 1.3.1 Preparation of Neuropathic Pain Animal Model

[0065] The experiment used single ligation of the L5 spinal nerve (SNL) to induce a neuropathic pain model. The animals were anesthetized with 7% chloral hydrate (dose: 420 mg / kg, intraperitoneal injection). The limbs of the rats were fixed in the prone position, and the animals were placed under a dissecting microscope. The back hair was removed, and the area was disinfected by wiping with alcohol. A 2 - 3 cm long incision was made on the right side of the back spine to expose the L4 and L5 spinal nerves. The L5 spinal nerve was gently ligated with 6 - 0 braided thread, and adjacent spinal nerves were avoided from being damaged. The back incision of the experimental animals was sutured in two layers, disinfected with iodophor, and gently placed in the breeding cage for free movement, diet, and water intake.

[0066] 1.3.2 Measurement Method of Mechanical Pain Threshold

[0067] For all experimental animals, a mechanical automatic stinging needle was used to measure the mechanical withdrawal threshold (MWT) of the experimental animals. The experimental animals were placed in a transparent plexiglass box with a wire mesh bottom and allowed to adapt for 30 min. Then, a stinging needle was used to apply a force to the plantar surface of the hind limb of the experimental animal at a constant speed, and the reflex threshold (MWT) when the rat showed a rapid foot withdrawal or foot flicking response was recorded, which was the mechanical pain threshold of the animal.

[0068] 1.3.3 Measurement and calculation of the basic pain threshold of animals

[0069] The basic mechanical pain threshold of each experimental animal was measured for 2 days after modeling, and the basic mechanical pain threshold of the experimental animal was the average of the two measurements.

[0070] 1.4 Animal grouping and experimental process

[0071] The experimental model animals were randomly divided into 6 groups, namely the model control group, the control drug pregabalin group (30 mg / kg), compound S1 group (30 mg / kg), compound S1 group (60 mg / kg), compound S2 group (30 mg / kg), and compound S2 group (60 mg / kg). Pregabalin and compounds S1 and S2 were administered by oral gavage, with 10 animals in each group, and the model control group was given the corresponding blank solvent.

[0072] SD rats with appropriate body weights were selected to prepare the L5-SNL model. At least 7 days after modeling, the postoperative mechanical pain threshold was measured. Animals with a significantly lower pain threshold in the right hind limb compared to the contralateral hind limb after surgery were selected for all subsequent efficacy tests. The experimental model animals were given the corresponding drugs or solvents, and the mechanical pain threshold of the animals was measured at the time points of 0.5 h, 3 h, 6 h, and 8 h after administration.

[0073] 1.5 Data statistics

[0074] The experimental data were expressed as mean ± standard error (Mean±SEM). One-way analysis of variance was used to analyze the differences between groups, and the LSD method was used for pairwise comparison between groups. A P < 0.05 was defined as a significant difference.

[0075] Comparison was performed using the LSD method, and P < 0.05 was defined as a significant difference.

[0076] 2 Results

[0077] The experimental results are shown in Table 1. Compared with the solvent control group, the positive control pregabalin group (30 mg / kg), compound S1 groups (30 mg / kg and 60 mg / kg), and compound S2 groups (30 mg / kg and 60 mg / kg) could significantly increase the mechanical pain threshold of animals at 0.5 h after administration (P = 0.0268, P = 0.0158, P = 0.0020, P = 0.0026, P = 0.0002); the positive control pregabalin group (30 mg / kg), compound S1 groups (30 mg / kg and 60 mg / kg), and compound S2 groups (30 mg / kg and 60 mg / kg) could significantly increase the mechanical pain threshold of animals at 3 h after administration (P < 0.0001, P < 0.0001, P < 0.0001, P < 0.0001, P < 0.0001); the positive control pregabalin group (30 mg / kg), compound S1 groups (30 mg / kg and 60 mg / kg), and compound S2 groups (30 mg / kg and 60 mg / kg) could significantly increase the mechanical pain threshold of animals at 6 h after administration (P < 0.0001, P < 0.0001, P < 0.0001, P < 0.0001, P < 0.0001); the positive control pregabalin group (30 mg / kg), compound S1 groups (30 mg / kg and 60 mg / kg), and compound S2 groups (30 mg / kg and 60 mg / kg) could significantly increase the mechanical pain threshold of animals at 8 h after administration (P = 0.0004, P < 0.0001, P < 0.0001, P < 0.0001, P < 0.0001).

[0078] Table 1 Mechanical pain thresholds of animals in each group (unit: g)

[0079]

[0080] Data are expressed as mean ± standard error, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, compared with the model control group.

[0081] Example 4: PK study after intravenous injection and intragastric administration of compounds to SD rats

[0082] 1 Materials and methods

[0083] 1.1 Experimental animals

[0084] Sprague-Dawley (SD) rats, male, SPF grade, with a body weight of about 220 g

[0085] Source: Zhejiang Vital River Laboratory Animal Technology Co., Ltd. (SPF level).

[0086] 1.2 Test drug

[0087] Compound S2

[0088] 1.3 Dose design

[0089] Group A: 3 rats, i.v. administered 2.00 mg / kg S2

[0090] Group B: 3 rats, i.g. administered 10.0 mg / kg S2

[0091] 1.4 Administration prescription

[0092] i.v.: 5% DMA + 5% Solutol in saline

[0093] i.g.: 0.5% CMC-Na

[0094] 1.5 Administration method

[0095] Animals were fasted (about 12 h) one day before the experiment and allowed free access to food 4 h after dosing; water was not restricted.

[0096] Rats in each group were accurately drawn with the corresponding amount of the administration preparation by syringe and administered via the tail vein or oral gavage. The dosage for each animal was calculated according to the body weight on the day of the experiment.

[0097] 1.6 Blood sample collection

[0098] After the rats were administered the drug, the blood sampling time points were 5, 15, 30 min, 45 min, 1, 2, 4, 6, 8, 10, 24 h after dosing. All the above samples were placed in an EP tube anticoagulated with EDTA-K2 and ice-bathed after collection, centrifuged at 4 °C and 8000 rpm for 5 minutes, and the plasma was transferred to -20 °C for storage and waiting for detection as soon as possible.

[0099] 1.7 Blood drug concentration detection

[0100] The concentrations of S2, pregabalin and ibuprofen in rat plasma were determined by LC-MS / MS analysis method.

[0101] 1.8 Data analysis

[0102] Winnonlin 6.0 software was used to calculate the relevant pharmacokinetic parameters.

[0103] 2 Results

[0104] Table 2. Pharmacokinetic parameters of S2, pregabalin and ibuprofen in SD rats after i.v. 2 mg / kg and i.g. 10 mg / kg S2

[0105]

[0106]

Claims

1. A class of ibuprofen-derived compounds of formula I or pharmaceutically acceptable salts, hydrates or solvates thereof: Wherein, R1 is selected from hydrogen or C1-C6 alkyl.

2. Any compound according to claim 1, characterized in that Wherein, R1 is selected from hydrogen, methyl, ethyl, propyl or isopropyl.

3. Any compound according to claim 1, characterized in that, Wherein, R1 is selected from hydrogen, methyl or ethyl.

4. The compound according to claim 1, wherein The compound is selected from the group consisting of the following compounds or pharmaceutically acceptable salts thereof: Compound 1: as shown in S1; Compound 2: as shown in S2.

5. Use of the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain.

6. A pharmaceutical composition, characterized in that, Comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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