Use of a compound for the manufacture of a medicament for the prevention and / or treatment of pain

Abstract

The application provides use of a compound in preparation of a medicine for preventing and / or treating pain, and belongs to the field of medicine. A structural formula of the compound is shown as formula I. The application proves through animal experiments that in a chronic inflammatory pain model of a mouse induced by complete Freund's adjuvant, the compound can significantly improve a mechanical pain threshold of a model animal, and an analgesic effect of the compound has time dependence and dose dependence. The application provides a brand-new medical application of the compound, and provides a new candidate compound for development of a medicine for treating chronic inflammatory pain. Formula I

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to the use of compound YR-8 in the preparation of medicaments for the prevention and / or treatment of pain, particularly chronic inflammatory pain. Background Technology

[0002] Pain, especially chronic inflammatory pain, is one of the most common and intractable types of chronic pain in clinical practice, widely present in arthritis, post-traumatic inflammation, neuroimmunological diseases, and the repair process of various tissue injuries. The persistent hyperalgesia and spontaneous pain caused by long-term inflammation significantly reduce patients' quality of life, while existing anti-inflammatory and analgesic strategies still suffer from unstable efficacy, significant side effects, and large individual variability. Therefore, identifying key factors and novel peripheral targets for chronic inflammatory pain is of great significance for improving pain control and achieving precise intervention.

[0003] Compound YR-08 is a compound with a known structure (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(4-bromophenyl)sulfonylpiperazine, InChIKey:DPFPJOCTDKDCBB-UHFFFAOYSA-N), but its use in the treatment of pain has not been reported.

[0004] Summary of the Invention The purpose of this invention is to provide a novel pharmaceutical use for compound YR-08, namely its use in the preparation of medicaments for the prevention and / or treatment of chronic inflammatory pain.

[0005] To achieve the above objectives, the present invention provides the following technical solution: This invention provides the use of compounds of Formula I or salts thereof in the preparation of medicaments for the prevention and / or treatment of pain: Formula I Among them, R 1 R 2 R 3 Each is independently selected from halogens; m, n, and o are each independently selected from 0, 1, 2, or 3.

[0006] Furthermore, the structure of the compound is as follows: .

[0007] Furthermore, the pain described is chronic pain.

[0008] Furthermore, the chronic pain is chronic inflammatory pain.

[0009] Furthermore, the chronic pain is chronic inflammatory pain induced entirely by Freund's adjuvant (CFA).

[0010] Furthermore, the drug is a pharmaceutical preparation made by using a compound of Formula I or its salt as the active ingredient, plus pharmaceutically acceptable excipients.

[0011] Furthermore, the pharmaceutical preparation is an oral preparation or an injectable preparation.

[0012] Furthermore, the oral formulation is a tablet, granule, or capsule.

[0013] Furthermore, the injectable preparation is a powder for injection or an injection solution.

[0014] The present invention has achieved the following beneficial effects: 1. Discovery of a novel analgesic use for a known compound (YR-08): This invention is the first to demonstrate through animal experiments that compound YR-08 has a clear and effective analgesic effect in a fully Freund's adjuvant (CFA)-induced chronic inflammatory pain model, opening up a completely new field of pharmaceutical application for this compound.

[0015] 2. Clear analgesic effect with dose-time dependence: This invention demonstrates through examples that compound YR-08, at doses of 5 mg / kg and 10 mg / kg, can significantly reverse mechanosensitive hypersensitivity and increase the mechanosensitive pain threshold in model animals. Its analgesic effect exhibits clear time dependence (peaking 60-90 minutes after administration) and dose dependence (within the tested range of 2.5-10 mg / kg, the 5 mg / kg dose showed the best analgesic effect).

[0016] 3. Possesses good drug development potential: This compound is a small molecule with a well-defined structure. It has shown rapid in vivo onset of action through systemic administration (intraperitoneal injection), which lays a good foundation for its development into analgesic drugs in injection or oral dosage forms.

[0017] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0018] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0019] Figure 1 The analgesic effect of intraperitoneal injection of YR-08. (Statistical symbols:) (This indicates 5 mg / kg vs. solvent; # indicates 5 mg / kg vs. solvent; & indicates 2.5 mg / kg vs. solvent) Detailed Implementation The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products. The technical solution of this invention will be described in detail below through specific embodiments, but the scope of protection of this invention is not limited thereto.

[0020] Example 1: Efficacy verification of compound YR-08 in treating chronic inflammatory pain This embodiment aims to verify the analgesic effect of compound YR-08 on chronic inflammatory pain induced by complete Freund's adjuvant (CFA) in mice.

[0021] 1. Experimental Methods (1) Establishment of experimental animal and chronic inflammatory pain model A mouse model of chronic inflammatory pain was established by injecting complete Freund's adjuvant (CFA) into the left hind paw of mice. Prior to the experiment, mice were acclimatized to the environment, and their mechanical pain threshold was measured as a baseline (the average value was used as the baseline). During modeling, 20 μL of CFA was slowly injected subcutaneously into the paw using a 30-33G needle. After the procedure, mice were placed in individual cages to monitor their activity and the injection site. Pain was then measured 48 hours after CFA injection.

[0022] (2) Drug preparation and administration: Compound YR-08 was dissolved in dimethyl sulfoxide (DMSO) to prepare a storage solution, and an equal volume of Tween 80 was added to aid dissolution. Before injection, the solution was diluted with physiological saline to maintain a final solution of 5% DMSO + 5% Tween 80 + 90% physiological saline. Three dosage groups were established: 2.5 mg / kg, 5 mg / kg, and 10 mg / kg (based on compound YR-08). A control group was also included, receiving only an equal volume of the above solvent. The route of administration was intraperitoneal injection.

[0023] (3) Pain behavioral testing (von Frey test) The von Frey test was used to assess changes in mechanoreparesis in mice. Before each test, mice were placed in a transparent behavioral cage with a mesh bottom for 30–60 minutes to acclimatize. Then, the left hind paw was vertically stimulated from the bottom of the cage using von Frey fibers. The stimulation force range was set to 0.008–2 g, with a moderate force (e.g., 0.4 g) selected as the initial intensity. A rapid withdrawal response was considered positive, and a lower-force fiber was used for the next test; if no response was observed, a higher-force fiber was used. The interval between tests was at least 1 minute, and the intensity of 3 positive responses out of 5 tests was used as the mechanoreparesis threshold. Pain testing was performed on mice immediately after administration, with measurements taken every half hour for up to 150 minutes. The experiment was conducted in a blinded manner, and the tests were repeated at predetermined time points to obtain changes in mechanoreparesis during the development of chronic inflammatory pain.

[0024] 2. Experimental Results The von Frey test was used to assess changes in the mechanical pain threshold of mice after treatment with different doses of YR-08. Figure 1 As shown, YR-08 exhibited a significant time-dependent analgesic effect at different doses. At a dose of 2.5 mg / kg, the mechanical threshold in mice did not increase significantly at any time point after administration, remaining at near-baseline levels (0-0.02 g), suggesting that this dose had no significant effect on mechanical analgesia. In contrast, both the 5 mg / kg and 10 mg / kg groups induced an increase in the mechanical threshold, showing a dose-dependent analgesic trend, with the most significant effect observed in the 5 mg / kg dose group: this group began to show a significant increase (approximately 0.11 g) at 60 min after administration, reached a peak at 90 min (approximately 0.15 g), then gradually decreased to 120 min (approximately 0.04 g) and returned to near-baseline levels at 150 min.

[0025] The 10 mg / kg group also showed an analgesic effect, but the magnitude was lower than that of the 5 mg / kg group. The analgesic threshold reached its peak at 60-90 min (approximately 0.03-0.07 g), gradually decreased after 120 min, and approached the initial level at 150 min. Notably, the 5 mg / kg dose produced the maximum analgesic effect at 90 min, making it the most effective of the three dose groups.

[0026] In summary, the results of this embodiment confirm that compound YR-08, at doses of 5 mg / kg and 10 mg / kg, has a significant therapeutic effect on CFA-induced chronic inflammatory pain in mice, effectively alleviating their mechanical hyperalgesia. This effect is time- and dose-dependent, with the best therapeutic effect observed at a single intraperitoneal injection of 5 mg / kg, and the strongest analgesic effect at approximately 90 minutes.

Claims

1. Use of the following compounds or their salts in the preparation of medicaments for treating chronic inflammatory pain: .

2. The use according to claim 1, characterized in that, The drug is a pharmaceutical preparation made by using the compound or its salt as the active ingredient and adding pharmaceutically acceptable excipients.

3. The use according to claim 2, characterized in that, The pharmaceutical preparation is an oral or injectable preparation.

4. The use according to claim 3, characterized in that, The oral preparation is a tablet, granule, or capsule.

5. The use according to claim 3, characterized in that, The injectable preparation is a powder for injection or an injection solution.

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