Application of medicine for rapidly regulating abnormal sensory status

Abstract

The invention relates to application of a compound in preparation of a medicine for rapidly regulating and controlling abnormal feeling states, and particularly, the abnormal feeling states at least comprise pruritus and can further comprise pain, burning pain or swelling pain, numbness, tightening feeling, dryness, desquamation and other abnormal feelings accompanied by the pruritus. No direct causal relationship exists between the relieving of the abnormal sensory state and the relieving of the inflammatory response, the improvement of the skin lesion or the repair of the tissue. The medicament may be administered by systemic administration or topical administration.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of a class of compounds in the preparation of medicaments for rapidly regulating abnormal sensory states, including one or more of itching, pain, burning or throbbing pain, numbness, tightness, dryness, and peeling. Background Technology

[0002] Abnormal sensations are not a single disease diagnosis, but a clinical symptom, usually manifesting as a combination of various subjective sensory abnormalities and objective signs. Common manifestations include itching, pain, burning pain, throbbing pain, numbness, tightness, dryness, or peeling, and are often accompanied by emotional symptoms such as anxiety and restlessness due to unbearable discomfort. Researchers have historically focused on the mechanisms and treatment strategies of diseases containing individual symptoms such as itching and pain, and have never considered abnormal sensations as an independent treatment target.

[0003] In published research and patents, some literature presents pain or other abnormal sensations as accompanying symptoms or secondary consequences of the disease process. Relief is typically a natural result of disease control, inflammation reduction, or improved tissue condition, rather than an independent target of technological regulation. Clinically, anti-inflammatory and analgesic treatments are the primary approach, and antipruritic or analgesic effects only become apparent after inflammation is controlled. Therefore, the onset of antipruritic and analgesic effects is usually relatively late. Although some studies and patents have reported that certain compounds can reduce scratching behavior shortly after administration, it should be noted that these compounds exhibit high diversity in chemical structure. Compounds with different chemical skeletons, substituent types, and substitution patterns may show significant differences in physicochemical properties, in vivo distribution characteristics, and pharmacological behavior.

[0004] Numerous basic and clinical studies have shown that pruritus and its associated abnormal sensations are not solely caused by local skin lesions, but involve peripheral sensory nerves, the central nervous system, and a complex signal integration process between the two. Related reviews generally agree that itching and pain are not simply opposing sensations, but can transform into or coexist under different conditions, thus forming a complex state of abnormal sensations. Further clinical research has found that in various states of chronic pruritus, even when local skin inflammation is limited or controlled, patients may still experience persistent and significant abnormal sensations such as itching, burning, or stinging, suggesting that central or neuromodulatory factors play an important role in the maintenance and amplification of abnormal sensations.

[0005] Similar phenomena have been observed in neuropathic pruritus, postherpetic neuralgia, and some cases of systemic pruritus, where abnormal sensations often exhibit characteristics of pervasiveness, persistence, or association with central factors such as emotion and sleep. These findings support the understanding that, in certain clinical situations, abnormal sensory states can exist independently of the severity of local skin lesions or inflammatory responses, and are significantly influenced by the nervous system, particularly central nervous system regulatory mechanisms. Therefore, for abnormal sensory states involving nerves or the central nervous system, relying solely on local or anti-inflammatory treatments often fails to achieve rapid and sufficient relief. Systemic or whole-body intervention using drugs that can influence neurosensory regulation processes has clear medical and technological rationale.

[0006] In fact, abnormal sensations can be associated with a variety of skin diseases and systemic diseases. For example, the etiology of chronic pruritus is very broad, including not only primary skin lesions but also cholestasis caused by hepatobiliary diseases, chronic kidney disease, hematological diseases, endocrine / metabolic abnormalities, and malignant tumors. Therefore, systematic differential diagnosis and stratified management are often necessary in clinical practice. In some patients, itching is not isolated but can coexist with abnormal sensations such as pain, burning, stinging, or throbbing, forming a complex abnormal sensory experience (e.g., sensory abnormality / disorder, dysesthesia). Physiological and pathophysiological studies have shown that itching and pain interact and are distinct at the peripheral sensory nerve and central processing levels. Clinically, it can manifest as the coexistence or mutual transformation of itching and pain-related abnormalities, thus suggesting the rationale for "abnormal sensory state" as an independent regulatory object. Furthermore, in systemic pruritus such as cholestasis-related pruritus and uremic pruritus, patients often present with widespread / generalized pruritus, and traditional symptomatic treatments such as antihistamines often have limited efficacy. The clinical and research communities generally adopt a comprehensive treatment strategy centered on systemic medication (such as drugs that affect bile acid circulation or central / peripheral nerve regulation).

[0007] In the clinical management of paresthesia, the choice of route of administration usually depends on the extent of the paresthesia, its pathological origin, and the treatment goal. For paresthesia limited to a specific skin area, local administration can be used to achieve local exposure and reduce systemic exposure; while for widespread, systemic, or medically related paresthesia (such as systemic pruritus or paresthesia related to neurological dysfunction), systemic administration is often required in clinical practice to regulate peripheral sensory nerves, central processing, or systemic pruritus / pain-inducing factors.

[0008] Oral administration, as one of the most common systemic administration methods, has the characteristics of high compliance, suitability for long-term management, and ease of dose adjustment. Multiple reviews and guidelines summarize the common systemic treatment strategies for systemic pruritus, including oral drugs (e.g., oral drug treatment options for pruritus associated with partial cholestasis, oral drugs for neuromodulation in uremic pruritus, etc.), suggesting that the oral systemic drug administration path has clear medical and clinical rationality in the clinical management of systemic or widespread pruritus. For the treatment of chronic pruritus, local or systemic treatment strategies are usually selected in the clinic according to the etiology and severity; when the patient's response to local treatment is insufficient, systemic treatment options such as oral or injection can be considered. For example, in uremic pruritus, oral gabapentin has been confirmed by randomized controlled studies to significantly reduce pruritus scores and improve related sleep and depression symptoms. In pruritus associated with cholestasis, randomized controlled studies have shown that oral drugs (such as opioid receptor antagonists) can significantly improve pruritus scores, with a statistically significant advantage over placebo. Therefore, for widespread or systemic abnormal sensory states, systemic administration, especially oral administration, has clear clinical basis and practical experience. The above medical knowledge further supports that when abnormal sensory states involve systemic or neuroregulatory factors, rapid regulation through systemic administration has predictable technical rationality.

[0009] In the present specification, "systemic pruritus" includes but is not limited to pruritus associated with one or more of the following systemic diseases or states: pruritus associated with cholestasis, pruritus associated with chronic kidney disease (uremic pruritus), pruritus associated with hematological diseases, pruritus associated with endocrine or metabolic abnormalities, pruritus associated with malignant tumors, or chronic pruritus of unknown cause, etc.

[0010] Therefore, the prior art generally follows the following technical logic: by adjusting the inflammatory response, immune status, or abnormality of nerve function, the underlying disease is improved, thereby indirectly reducing the pruritus, pain, or other abnormal sensations perceived by the patient. Under this technical path, abnormal sensations are implicitly regarded as a result of disease improvement, rather than an engineered object that can be regulated independently, directly, and quickly.

[0011] Based on the above understanding, the present application proposes a new technical problem: Can abnormal sensations be quickly regulated without relying on disease cure such as relief of inflammatory response, improvement of skin lesions, or tissue repair? The research on the compound in the prior art does not provide clear teaching or predictable solutions to the above technical problem. SUMMARY

[0012] The purpose of the present application is to provide a new drug use for quickly regulating abnormal sensory states without relying on the relief of inflammatory response, improvement of skin lesions, or tissue repair, thereby overcoming the slow onset and dependence on underlying disease improvement of abnormal sensory state relief in the prior art.

[0013] The object of the present application can be achieved by the following technical solutions: In a first aspect, the present application provides use of a compound selected from the group consisting of Formula A to Formula E in the manufacture of a medicament for fast modulation of abnormal sensory state.

[0014] The medicament comprises at least one compound selected from the group consisting of Formula A to Formula E: A B C D E The term "abnormal sensation" as used herein refers to pruritus, and can further include one or more of pain, burning or swelling pain, numbness, tightness, dryness, peeling, etc. that can occur simultaneously or sequentially with the pruritus.

[0015] The present application has found that the above-mentioned compounds can produce a significant modulation effect on abnormal sensory state in a short time after administration. In some embodiments, the relief of abnormal sensory state can be observed within 5 minutes to 6 hours after administration, preferably within 1 hour after administration. In the present application, 'fast' is used to describe the time characteristics of the relief of abnormal sensory state, and is not limited to a specific molecular mechanism or physiological pathway.

[0016] Further, the relief of abnormal sensory state according to the present application can occur before the relief of inflammatory response, improvement of skin lesion severity, or repair of tissue state, or independently of the above-mentioned pathological changes. In some embodiments, the relief of abnormal sensory state can not have a direct causal relationship with the above-mentioned pathological changes.

[0017] Based on the above understanding, the fast modulation of abnormal sensory state according to the present application is not limited to local skin action mechanism, but can involve modulation processes at the level of peripheral sensory nerves and / or central nerves; however, it should be understood that the technical effect of the present application does not depend on the establishment of any specific neural pathway, receptor or molecular mechanism.

[0018] In the embodiments described in the present specification, the drug can be prepared as a preparation for topical administration (e.g. cream, ointment, gel, spray, solution, emulsion, micro-needle or patch) or a preparation for systemic administration; in some embodiments, the preparation for systemic administration is a preparation for oral administration, such as a tablet, capsule, granule, oral solution, oral suspension, sustained-release or controlled-release preparation, etc. The prescription and preparation of the oral preparation can be achieved by conventional pharmaceutical methods in the art. In some embodiments, the preparation for systemic administration is a preparation for injection, such as an injection solution, nanosuspension for injection, microspheres for injection, implant, liposome, etc. The prescription and preparation of the injection preparation can be achieved by conventional techniques in the art.

[0019] The present application first defines abnormal sensation as a technical object independent of the improvement of underlying diseases. The abnormal sensation includes itch and can further include one or more of pain, burning pain or distending pain, numbness, tightness, dryness, peeling, etc. which are accompanied by the simultaneous or subsequent occurrence of itch and pain, and the subjective perception characteristics, occurrence mechanism and regulatory requirements of which are different from single itch or single pain. In various clinical situations, even if the disease-related inflammatory response or tissue damage has not changed significantly, the patient can still experience significant fluctuations in abnormal sensation.

[0020] Advantages of the present application: (1) It can quickly relieve the abnormal sensation state in a short time and reduce the anxiety caused by skin discomfort.

[0021] (2) The relief is not dependent on the relief of inflammatory response, improvement of skin lesions or tissue repair.

[0022] (3) It is suitable for situations where itch exists alone or itch and other abnormal sensations such as pain coexist.

[0023] (4) It has cross-disease and cross-pathological source migratability.

[0024] (5) It helps to significantly improve the quality of life and compliance of patients. BRIEF DESCRIPTION OF DRAWINGS

[0025] In order to facilitate the understanding of those skilled in the art, the present application will be further described below with reference to the accompanying drawings.

[0026] Figure 1 The change in the number of times of scratching the hind limbs of mice before and after drug intervention in Example 1; Figure 2 The change in the number of times of abnormal behavior of mice before and after drug intervention in Example 1; Figure 3 The change in the thickness of the ears of mice before and after drug intervention in Example 1; Figure 4The changes in inflammation on the back of mice before and after drug intervention in Example 1; Figure 5 The cAMP content in mouse skin tissue after drug intervention in Example 2; Figure 6 The bacterial load of Malassezia on mouse skin after administration in Example 3 (CFU / cm³) 2 ); Figure 7 The change in the number of scratches on the hind limbs of mice before and after drug intervention in Example 5; Figure 8 The change in the number of scratches on the hind limbs of mice within 40 minutes after drug administration in Example 6; Figure 9 The sleep duration of mice after drug administration in Example 6; Figure 10 The change in the number of scratches on the hind limbs of mice within 120 minutes after oral administration in Example 7; Figure 11 The total bilirubin content in mouse serum 120 minutes after oral administration in Example 7; Figures 12-14 The changes in efficacy of the ointment in the subjects of Example 8 within 3 hours after application; Figures 15-18 The changes in efficacy of the ointment in the subjects of Example 10 within 3 hours after application. Detailed Implementation

[0027] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the following detailed description of the specific implementation methods, structures, features and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided.

[0028] Example 1: Results of rapid modulation of abnormal sensations associated with atopic dermatitis Abnormal sensations associated with atopic dermatitis mainly include itching, dryness, tightness, and throbbing pain.

[0029] Compound C was added to a blank moisturizer to form cream C with a concentration of 2%. Cream C was applied to a DNCB-induced atopic dermatitis model to investigate its effect on rapid modulation of related abnormal sensations.

[0030] 1) Establishment of an atopic dermatitis model Eighteen healthy male SPF-grade C57BL / 6 mice, aged 6-8 weeks and weighing 18-22g, were housed separately in SPF-grade animal facilities under standard conditions, with free access to food and water. After acclimatization, the backs of the mice were shaved using an electric razor and depilatory cream, covering an area of ​​approximately 2cm × 2cm.

[0031] On day 1 and day 3, 200 μL of 1% 1-chloro-2,4-dinitrobenzene (hereinafter referred to as DNCB) solution (dissolved in acetone: olive oil = 3:1) was evenly applied to the skin of the depilation area, and 20 μL of 1% DNCB was applied to the right ear to perform the primary sensitization. On day 7, day 9, day 11, day 13, and day 15, 100 μL of 0.5% DNCB solution was applied to the same area to perform repeated stimulation. The success criteria for the model are as follows: 2) Confirmation of the time at which cream C takes effect in regulating abnormal sensations in mice The mice that successfully modeled were randomly divided into 3 groups, each with 6 mice, namely the model group (only DNCB stimulation), the blank group (given emollient), and the cream C group. After grouping, the corresponding treatments were given to each group according to the table below. Within 0-1 hours after treatment, the animals' scratching behavior, as well as abnormal behaviors such as pain and restlessness, were recorded on video, and then the number of scratches and the number of abnormal behaviors were counted, and the severity of the skin lesions and the change in ear thickness were evaluated.

[0032] 3) Test results As shown in Figure 1 , after drug treatment, the number of hind limb scratches in the cream C group decreased significantly within 5 minutes after administration compared to before administration, while the number of hind limb scratches in the model group and the blank group did not change significantly before and after intervention, indicating that cream C can quickly inhibit itching within 5 minutes.

[0033] As shown in Figure 2 , after drug treatment, the number of high-frequency licks, repeated forelimb scratches, and head shaking in the cream C group of mice decreased significantly within 5 minutes, and returned to a calm state that could sleep. In contrast, the number of high-frequency licks, repeated forelimb scratches, and head shaking in the model group and the blank control group did not change significantly. The results show that cream C can quickly relieve abnormal sensations and agitation behavior induced by AD models within 5 minutes after administration.

[0034] The changes in ear thickness and back inflammation within this time window (5 minutes) were also statistically analyzed, and the results are shown in Figure 3 , 4 , which show that the ear thickness and back inflammation in the cream C group did not improve significantly within 5 minutes after administration.

[0035] The above results show that cream C can quickly inhibit abnormal sensations caused by atopic dermatitis within 5 minutes, and this effect does not depend on the improvement of inflammation.

[0036] Example 2 Relationship between the rapid regulation of abnormal sensations by cream C and the concentration of cAMP in skin tissue To further confirm whether the rapid regulation of abnormal sensation by Cream C is related to the inhibition of PDE4 enzyme, the mice in each group in Example 1 were anesthetized with pentobarbital (80 mg / kg, intraperitoneal injection) after 5 min of drug administration and observation of mouse behavior, and then perfused with phosphate buffered saline through the heart. The skin tissue at the E6005 administration site was separated using an 8 mm diameter punch. The skin sample was immediately frozen in liquid nitrogen and stored at -80°C until use. The skin sample was homogenized in the lysis buffer provided by the cAMP enzyme immunoassay kit (GE Healthcare Bio-Sciences Co., Piscataway, NJ, USA) using a Polytron homogenizer (Robert Bosch Tool Corp., Mt. Prospect, IL, USA). After centrifugation of the homogenate at 4°C and 600 g for 5 min, the supernatant was collected and the cAMP content was detected using the cAMP enzyme immunoassay kit. A portion of the supernatant was used to determine the protein concentration using the protein quantification kit (Bio-Rad Laboratories, Inc., Hercules, CA, USA). The concentration of cAMP was finally calculated based on the protein content. The results are shown in Table 1. As shown in Table 1, there was no significant difference in the cAMP content in the skin tissue of mice in different test groups, indicating that the rapid regulation of abnormal sensation by Cream C is not related to the inhibition of PDE4 enzyme. Figure 5

[0037] Example 3 Rapid regulation of abnormal sensation associated with seborrheic dermatitis The abnormal sensation associated with seborrheic dermatitis mainly manifests as itching, tightness and swelling pain, etc.

[0038] The compound of formula D was added to the blank emollient to form Cream D with a concentration of 5%, to confirm the effect of Cream D on the rapid regulation of abnormal sensation associated with seborrheic dermatitis in mice.

[0039] 1) Construction of mouse seborrheic dermatitis model SPF Kunming mice, half male and half female, weighing 18-22 g, 6-8 weeks old; feeding environment: temperature 22-25°C, humidity 50%-60%, 12h light and dark alternation, free feeding and drinking water, adapt to the environment for 3 days before the experiment.

[0040] Mouse pretreatment: one day before the experiment, the mouse back skin was removed with depilatory cream (the depilation area was about 2cm x 2cm), the depilation site was washed with normal saline, and the skin condition was observed after drying. The mice with skin damage, redness and allergy were excluded (to ensure that the skin at the site of action of the external drug and the modeling reagent was intact); ​Sebum induction period (days 1-3): At 9 am every day, use a sterile cotton swab to dip tea seed oil and evenly apply it to the skin of the depilated area on the back of the mouse (the amount applied to each mouse is fixed at 50 μL), gently massage for 10 s after application to ensure that the tea seed oil fully covers the skin; cover with sterile gauze for 30 min after application to prevent the mouse from licking, once a day for 3 consecutive days, to induce increased secretion of sebaceous glands and create an oily microenvironment. Fungal inoculation period (days 4-10): Inoculation operation: Gently wipe the skin of the depilated area on the back of the mouse with 75% ethanol, and then prepare for use after the ethanol has completely evaporated; use a sterile cotton swab to dip 1 x 10 7 CFU / mL of Malassezia liquid (50 μL per mouse), evenly apply it to the skin of the depilated area on the back, gently massage for 30 s to ensure that the liquid fully contacts the skin; cover with sterile gauze for 30 min after application to prevent the mouse from licking the liquid and affecting the colonization effect; Continuous induction: At 9 am every day after inoculation, continue to apply tea seed oil (50 μL per mouse) to maintain an environment rich in sebum and promote the colonization and reproduction of Malassezia, once a day for 7 consecutive days; Modeling success determination (day 10): Observe the skin condition and behavior of the mice on the back every day, and the success criteria are as follows: the skin on the back has obvious erythema and oily scales (the skin surface has a shiny appearance with white / yellowish scales attached), the mice frequently scratch and lick their backs (itching behavior), and some mice have slightly thickened skin; the skin of the blank control group is normal and does not have the above symptoms, and the modeling success rate must be ≥ 90% before entering the drug administration stage.

[0041] 2) Experimental grouping and intervention method After successful modeling, randomly divide the mice into groups, with 6 mice in each group, and start external drug administration 3) Index evaluation Using behavioral observation method, place the mice individually into a transparent observation box after drug administration, immediately start observation and record the itching and pain behavior of the mice within 30 min, and the evaluation indexes are as follows: The results are presented as mean values: Malassezia load detection At 30 min after drug administration, take the skin tissue (about 0.1 g) on the back, homogenize it, and spread it on the surface of Malassezia solid culture medium, incubate at 32°C for 5 days, count the number of colonies (CFU / g tissue), and the results are shown in Figure 6 .

[0042] The above table data shows that the number of scratching times of seborrheic dermatitis mice in the cream D group is reduced by 50% 5 minutes after administration, and the pain is relieved; the number of scratching times of mice is reduced by 75% 15 minutes after administration, and the pain is completely relieved. The overall state of the model group, the blank group and the external anti-viral group has no obvious change before and after intervention. At the same time, combined with the above table data, it can be known that the cream D can quickly regulate the itching and pain state of seborrheic dermatitis mice when the Malassezia is not inhibited. Figure 6 It can be known that the cream D can quickly regulate the itching and pain state of seborrheic dermatitis mice when the Malassezia is not inhibited.

[0043] Example 4: Rapid regulation results of herpes-related abnormal sensation Herpes-related abnormal sensation mainly includes burning pain and itching.

[0044] The compound of formula A is added to the blank emollient to form a cream A with a concentration of 2%, and the effect of the cream A on the rapid regulation of the abnormal sensation of the mouse skin caused by herpes infection is verified.

[0045] 4) Construction of mouse herpes model BALB / c mice, 6-8 weeks old, weighing 18-22 g, were caged and fed in the SPF animal room under standard conditions, and free to eat and drink water. After adapting to the environment, the back of the mouse was shaved with an electric shaver and depilatory cream, with an area of about 2 cm x 2 cm.

[0046] Skin disinfection: when modeling, gently wipe the skin of the mouse back with 75% ethanol, and wait for the ethanol to evaporate completely before use (avoiding ethanol residue to stimulate the skin, affecting the modeling effect and subsequent drug absorption); Virus inoculation: use a sterile needle to lightly scratch the mouse back (scratch length about 1 cm, 3-4 lines, depth to be slightly red and not bleeding), then use a sterile cotton swab to dip 10^6 TCID50 / mL of HSV-1 virus solution (50 μL per mouse), evenly apply it to the scratch, gently massage for 30 s, and make sure the virus solution fully contacts the damaged skin; cover with sterile gauze for 30 min after application to avoid the mouse licking the virus solution, affecting the success rate of modeling; Post-modeling observation: after inoculation, the mice were fed separately, and the general state (spirit, diet, water, weight) and back skin lesion (the appearance time and severity of erythema, blister, erosion, scab) of the mice were observed every day, and the observation was continued for 7 days to confirm the success of the modeling--the success criteria of the modeling: 24-48 h after inoculation, the mouse back appeared obvious erythema, 48-72 h appeared blisters, 72-96 h blisters could be broken, erosion, accompanied by mouse scratching, licking the lesion site (itching performance) and curling, avoiding stimulation (pain performance).

[0047] 5) Experimental grouping and intervention method 24 hours after modeling (i.e. when obvious erythema appears), the animals were randomly divided into groups of 6, and topical medication was started. 6) Indicator Evaluation Behavioral observation was used. After drug administration, mice were placed individually in transparent observation boxes, and their itching, pain, agitation, mental state, and other related behaviors were observed and recorded immediately over 30 minutes. The evaluation indicators are as follows: result: The results showed that in cream A group, the number of scratches in mice infected with herpes zoster virus decreased by 38% 5 minutes after administration and by 88% 20 minutes after administration, with pain scores decreasing to level 1, significantly relieving pain. However, no significant changes were observed in the overall condition of the model group, the control group, and the topical antiviral group before and after intervention.

[0048] Example 5: Results of rapid modulation of abnormal sensations associated with the wound healing period Abnormal sensations associated with the wound healing period mainly include itching, swelling, numbness, and tightness.

[0049] Compound B was added to a blank moisturizer to form cream B with a concentration of 2%, confirming the effect of cream B on rapid regulation of skin-related abnormal sensation in mice during the wound healing period.

[0050] 1) Construction of a skin wound healing model C57BL / 6 mice (8-10 weeks old), half male and half female, weighing 18-22g, 6-8 weeks old, 30 mice in total; housing environment: temperature 22-25℃, humidity 50%-60%, 12h light and dark alternation, free food and water, experiments began after 3 days of acclimatization.

[0051] Mouse pretreatment: After anesthetizing the mice, the hair on their backs was removed using a shaver, and excess hair was removed with depilatory cream to fully expose the skin. The area to be depilated should be 2-3 times larger than the wound site to prevent the growth of surrounding hair from affecting wound healing.

[0052] Wound preparation: After disinfecting the skin on the back, a full-thickness skin excision wound was made in the middle of the back of each group of mice near the tail using a 6mm diameter skin punch. After hemostasis, the wound was not sutured (simulating common clinical open wounds).

[0053] 2) Observe the mice for itching and skin tightness during the healing period. If significant itching occurs, administer the medication immediately.

[0054] 3) Test Results Observation until the 8th day, the mouse wound around the slight redness, a small amount of exudation, mice appear scratching, licking, biting the wound and the surrounding skin, frequent swing body and other abnormal behavior, start dosing, intervention scheme as follows: Statistics after 10 min of giving intervention, the number of mice hind limb scratching changes, the results are as follows: As Figure 7 shown, after drug treatment, the cream B group of mice within 10 minutes, the high frequency of licking, repeated forelimb scratching and head shaking and other abnormal behaviors were significantly reduced, and returned to a quiet state to sleep. In contrast, the high frequency of licking, repeated forelimb scratching and head shaking and other abnormal behaviors of the model group and the blank group had no obvious change. The results showed that cream B could quickly relieve the abnormal feeling state of wound healing within 10 minutes after administration.

[0055] Example 6 Rapid regulation of abnormal feeling state by systemic administration (oral and injection administration) 1) Test method According to the manner of example 1, the mouse atopic dermatitis model was made, and after the modeling was successful, it was randomly divided into 5 groups, 6 in each group, 5 groups were model group, blank group (gavage), compound A group (gavage), blank group (injection), compound C group (injection) respectively. Select formula A, 3% carboxymethyl cellulose sodium solution is suspended and dispersed, compound A group of mice is given gavage at a dose of 5mg / kg, blank group (gavage) is given blank solvent gavage. Compound C is prepared into nanocrystal suspension injection and injected into the right thigh muscle for injection administration, and the blank group (injection) is given blank solvent injection administration, and the model group is not intervened. Immediately after the intervention, the mouse behavior observation and statistics were carried out, and the method was the same as example 1.

[0056] 2) Test results As shown in Figure 8 , after drug treatment, compound A group (gavage) and compound C group (injection) respectively within 15 minutes and 5 minutes after administration, the number of hind limb scratching was significantly reduced compared with before administration, and gradually quiet and sleep, while the model group and the blank group had no significant change in the number of hind limb scratching before and after intervention, and still restless and frequently moving, indicating that compound A and C can quickly inhibit the itching and discomfort caused by atopic dermatitis by systemic administration.

[0057] Continuous observation for 6 hours found that Figure 9 , the mice in compound A gavage group and compound C injection group had no hind limb scratching action for 6 hours, and the sleep time was significantly longer than that of the model group and the blank group. At 6 hours, there was no significant difference in skin inflammation among the three groups of mice.

[0058] Results show that significant relief of the abnormal sensory state, manifested as a decrease in the intensity of the itch and associated pain or discomfort, can be observed within about 5 minutes to 6 hours after systemic administration, before there is any significant improvement in inflammation.

[0059] This example shows that the compound can also achieve rapid modulation of the abnormal sensory state under systemic administration conditions.

[0060] Example 7 Oral administration of systemic itch modulation 1) Establishment of an animal model of systemic itch (cholestatic skin itch) Male C57BL / 6 mice (or other suitable strains) aged 8-10 weeks and weighing 20-25 g are selected, and after one week of adaptive feeding, a one-time gavage of freshly prepared ANIT oil solution (ANIT crystals are dissolved in olive oil or corn oil to prepare the desired concentration) is administered at a dose of 50 mg / kg, and the gavage is repeated for 5 days. After the gavage on the 5th day, the behavior of the mice is recorded for 1 hour using a high-definition video camera, and the hind limb scratching behavior is counted. If the total number of scratches in 30 minutes is greater than 30, the modeling is considered successful, and the animals are randomly divided into 3 groups (model group, blank group, compound C group) with at least 6 animals in each group for subsequent intervention studies. After the grouping is completed, the serum is collected by orbital bleeding, and the total bilirubin is detected.

[0061] 2) Intervention method The compound of formula C is suspended and dispersed in 3% sodium carboxymethyl cellulose solution and is ready for use.

[0062] After the mice are successfully modeled and randomly grouped, the mice are given a gavage of ANIT oil solution on the 6th day. Two hours after the gavage, each group is treated according to the following plan: After the gavage is completed, the behavior of the mice is recorded for 1 hour using a high-definition video camera, and the hind limb scratching behavior is counted. The counting is performed for at least 2 hours, and after 2 hours, the serum is collected by orbital bleeding, and the total bilirubin is detected.

[0063] 3) Test results As shown in Figure 10 After drug treatment, the number of hind limb scratches in the compound C group is significantly reduced within 60 minutes after administration, while the number of hind limb scratches in the model group and the blank group shows no significant change before and after the intervention, indicating that compound C can rapidly inhibit the itch caused by cholestasis within 60 minutes.

[0064] As shown in Figure 11As shown, compared with the change of total bilirubin in the time window, the results showed that the total bilirubin of the cream C group had no significant difference compared with the model group and the blank solvent group at 120 min after administration. The results suggest that the relief of pruritus caused by cholestasis by compound C is not related to the degree of improvement of cholestasis.

[0065] The above results collectively show that the degree of systemic pruritus of the test subject is relieved in a short time after administration, and can be accompanied by a decrease in abnormal sensations such as pain, burning pain or distending pain associated with pruritus. The above-mentioned improvement in sensation can occur without observing a significant improvement in the underlying disease state.

[0066] This example further demonstrates that the compound is suitable for rapid regulation of systemic pruritus and its associated abnormal sensation state by oral systemic administration.

[0067] Example 8 Rapid antipruritic effect in pruritus with distending pain caused by furuncles on the scalp Three adults had single furuncles on the scalp, with a course of 1-2 days. All subjects had obvious pruritus accompanied by distending pain or tenderness, constantly pressing and scratching the swollen and painful area. Cooling oil was used before the application of cream C, and no improvement was observed. An appropriate amount of cream C was evenly applied to the furuncles and surrounding red and swollen skin, and each subject was only administered once. The onset time of pruritus relief was observed; the subjective intensity of pruritus and distending pain was observed; whether there was a scratching impulse or scratching behavior and changes in local redness and swelling were observed. The results showed that within about 5-30 min after administration, pruritus and distending pain were significantly relieved in 3 / 3 subjects, with a subjective evaluation of reduced itching and pain, and no scratching impulse; within 1 h-4 h after administration, there was no discomfort such as pruritus, pain or distending pain, and no scratching behavior; there was no significant difference in local redness and swelling during the above period compared with before administration.

[0068] Example 9 Rapid relief effect of sudden severe pruritus with purulent lesions at night One adult subject had a sudden severe pruritus on the back at night, accompanied by scattered red spots and abscess-like skin lesions, and reported that the itching was intense, with constant scratching of the back, and the more he scratched, the more it itched, making it difficult to sleep. An appropriate amount of cream A containing the compound of the present application was evenly applied to the itchy and lesioned area, and only administered once. About 15 min after administration, the subject's pruritus was significantly relieved and the scratching behavior stopped. Subsequently, the subject fell asleep normally and slept continuously throughout the night without using the drug again, and did not wake up at night due to pruritus or discomfort.

[0069] This example shows that in the case of sudden, severe pruritus accompanied by purulent lesions at night, the topical cream A of the compound of the present application can quickly relieve pruritus and inhibit scratching behavior, significantly improve sleep status, and embody its rapid onset characteristics in the acute pruritus scenario.

[0070] Example 10 Compassionate treatment Compassionate treatment: For some patients with long-term recurrent cases, there is no effective treatment, and in the case of their voluntary, the physician's safety assessment is qualified, and the compassionate treatment is carried out under close observation. Since these cases are only based on safety and clinical research and observation under compassionate treatment, only as research data, for the purpose of evaluating the rapid regulation of abnormal sensation effect of the invention.

[0071] 1. Rapid regulation effect in pruritus with redness caused by atopic dermatitis Subject, male, 32 years old, has had moderate to severe atopic dermatitis since childhood, with recurrent episodes, and when the disease occurs, the skin appears perifollicular papules, i.e. the skin follicle appears normal skin color papules the size of a needle, distributed in patches, accompanied by unbearable itching and dry skin.

[0072] Drug history: 0.05% dexamethasone acetate cream, 0.03% tacrolimus ointment Self-report: When the disease occurs, itching and dry skin often cause sleeplessness and poor mental state. The use of dexamethasone acetate cream only provides temporary and slight relief, while the use of tacrolimus ointment causes skin tingling and difficulty in maintaining the course of treatment.

[0073] Test process: The subject applies cream C to the right arm joint when the disease occurs, records the duration of itching relief, and takes photos before and 10 minutes, 30 minutes, and 3 hours after administration to record the skin condition.

[0074] Results: 5 minutes after administration, the subject's itching at the joint began to subside, and 30 minutes after administration, the itching was completely relieved and lasted for about 3 hours, while the perifollicular papules were only slightly improved at 30 minutes, which is a typical sign of skin immune abnormalities and inflammatory cell infiltration. The results show that before the inflammation is significantly improved, the abnormal sensation state can be observed to be significantly relieved. In the rapid regulation of abnormal skin sensation, the overall effect is better than that of external use of glucocorticoids and tacrolimus ointment, and the effect occurs before the skin symptoms improve.

[0075] 2. Rapid regulation effect in pruritus with pain after ultraviolet exposure Subject, male, 29 years old, after sun exposure on bare skin, within minutes to hours, clear boundary redness, papules, wheals or blisters appear, accompanied by itching, burning or tingling, and the cause is unknown.

[0076] Drug history: calamine lotion, self-reported use of which accelerates skin dryness and cannot relieve skin discomfort.

[0077] Test process: The subject applies cream A to the neck when the disease breaks out, and records the relief and duration of abnormal sensations.

[0078] Results: 10 minutes after administration, the itching at the administration site is quickly relieved, and the burning sensation disappears, lasting until the papules fade.

[0079] 3. Rapid regulatory effect in numbness and pain on the lateral thigh Subject, male, 50 years old, when the lateral thigh is affected, he experiences itching, numbness, tingling, tingling, burning, cooling, and heaviness, with numbness being the most common, but no motor abnormalities or muscle weakness. The symptoms are mild to severe, and the course is 2 years.

[0080] Drug history: none, relieved after rest, usually 6-48 hours.

[0081] Test process: The subject applies cream D to the lateral thigh when the disease breaks out, and records the relief and duration of abnormal sensations.

[0082] Results: 20 minutes after administration, the itching, numbness, tingling, and other abnormal sensations at the administration site are relieved; 30 minutes after administration, the abnormal sensations disappear completely, and the subject successfully overcomes the episode with appropriate rest.

[0083] Cream C has a rapid regulatory effect on itching, pain with numbness, and other abnormal sensations.

[0084] 4. Rapid regulatory effect in itching with tingling caused by cholestasis Subject, female, 45 years old, recently developed itching on the palms and soles, with circadian rhythm, usually aggravated in the evening and at night, and severe tingling sensation.

[0085] Drug history: purchased mometasone furoate cream at the pharmacy, but it did not relieve the skin discomfort.

[0086] Test process: The subject applies cream C to the palms when the disease breaks out, and records the relief and duration of abnormal sensations.

[0087] Results: The episode occurred at night, 10 minutes after administration, the itching with tingling at the administration site was relieved, and the subject could sleep normally. 5 hours later, the subject felt uncomfortable again and went to the hospital for examination, and was finally diagnosed with cholestasis.

[0088] Cream C also has a rapid regulatory effect on pathological skin abnormal sensations, and is superior to external use of glucocorticoids, which are called "skin panacea".

[0089] 5. Rapid regulatory effect in itching with skin dryness caused by diabetes Subject, male, 56 years old, with dry mouth, itchy, dry, flaky and mild swelling on the skin of limbs and back for half a year, went to the hospital for examination and diagnosed as type 2 diabetes a week ago, and the blood sugar was controlled by drugs for a week, but the abnormal skin feeling did not improve, and the itching was persistent and repeated, and the more he scratched, the more he wanted to scratch.

[0090] Drug history: urea cream and mometasone furoate cream for external use, oral loratadine tablets, with poor effect.

[0091] Test process: the subject applied cream E on the back of the hand when the disease was on, and recorded the relief and duration of abnormal feeling.

[0092] Results: 30 min after administration, the abnormal feeling of dryness, swelling and itching at the administration site began to relieve, and there was no more urge to scratch, and the abnormal feeling completely disappeared after 45 min, lasting for 6 h.

[0093] Cream E shows significant rapid regulation effect. This effect does not need to wait for the blood sugar to reach the ideal control state - even in the stage when the blood sugar has not yet been effectively controlled, cream E quickly intervenes and improves the abnormal skin feeling of the patient, helping the patient to relieve discomfort earlier and improve the quality of life. Its rapid regulation feature not only makes up for the long period of blood sugar control, but also provides an efficient solution for early intervention of abnormal skin feeling in diabetic patients.

[0094] The above diseases or pathological states are only examples, and the present application is not limited to the specific cases listed.

[0095] It should be understood that the present application encompasses all pharmaceutically acceptable salts, solvates, prodrugs, etc. of the specific compounds, which can be prepared according to techniques known in the art, and are intended to have the same use as the parent compounds.

[0096] The above is only the preferred embodiment of the present application, and is not intended to limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiment, it is not intended to limit the present application, and any person skilled in the art can make some changes or modifications to the above disclosed technical content to make equivalent embodiments with equivalent changes, without departing from the scope of the technical solution of the present application. Any brief modification, equivalent change and modification of the above embodiments made according to the technical essence of the present application, all still belong to the scope of the technical solution of the present application.

Claims

1. Use of a compound of Formula A to Formula E or a pharmaceutically acceptable salt, isomer, solvate, deuterated compound, or prodrug thereof in the manufacture of a medicament for the rapid modulation of an aberrant sensory state, characterized in that, The medicament comprises at least one compound of Formula A to Formula E: 。 2. Use according to claim 1, characterized in that, The medicament is formulated as a topical or systemic administration formulation.

3. Use according to claim 2, characterized in that, The topical administration formulation is selected from at least one of a cream, an ointment, a paste, a gel, a spray, a solution, an emulsion, a microneedle, and a patch.

4. Use according to claim 2, characterized in that, The systemic administration formulation is an oral or injectable formulation.

5. Use according to claim 1, characterized in that, The relief of the abnormal sensory state occurs from 5 minutes to 6 hours after administration.

6. Use according to claim 1, characterized in that, The relief of the abnormal sensory state occurs before an improvement in the inflammatory signs or the extent of the skin lesions.

7. Use according to claim 1, characterized in that, The abnormal sensory state is associated with at least one of atopic dermatitis, seborrheic dermatitis, contact dermatitis, an allergic reaction, a neurogenic or neuropathic itch.

8. Use according to claim 1, characterized in that, The abnormal sensory state is associated with at least one of shingles or herpes simplex, post-herpetic related paresthesia, a furuncle, a carbuncle, or other bacterial skin infection, a painful variant of atopic dermatitis.

9. Use according to claim 1, characterized in that, The abnormal sensory state is associated with at least one skin state of a wound healing period, a burn recovery period, or a scar-related skin state.

Images