WO2023202102A1 - Use of sesquiterpenoid compound in inhibiting trpa1 channel activity - Google Patents

Use of sesquiterpenoid compound in inhibiting trpa1 channel activity Download PDF

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WO2023202102A1
WO2023202102A1 PCT/CN2022/138608 CN2022138608W WO2023202102A1 WO 2023202102 A1 WO2023202102 A1 WO 2023202102A1 CN 2022138608 W CN2022138608 W CN 2022138608W WO 2023202102 A1 WO2023202102 A1 WO 2023202102A1
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pain
compound
diseases
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王树
刘荆婧
贺冬梅
陈飞裕
张文杰
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广州医科大学
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Definitions

  • the present invention relates to the field of biomedicine technology, and in particular to an antagonist of the transient receptor potential (TRP) ion channel family. Specifically, the present invention relates to the application of sesquiterpenoids in inhibiting the activity of the TRPAl channel.
  • TRP transient receptor potential
  • TRP channels are a type of ion channel widely present in mammals. This family is divided into seven subfamilies, namely TRPC, TRPV, TRPM, TRPN, TRPML, TRPA and TRPP. TRP channels are all six-transmembrane proteins, with both their N-terminal and C-terminal ends inside the cell. The fifth and sixth transmembrane domains together form a non-selective cation channel. These channels usually serve as receptors for a variety of chemical and physical stimuli and can be regulated by many factors, including temperature, osmotic pressure, pH, mechanical force, as well as some endogenous and exogenous ligands and intracellular signaling molecules.
  • the TRPA1 channel is a member of the transient receptor potential channel family. It has at least 14 ankyrin repeat sequences at its N-terminus. It is also called ankyrin-like protein with transmembrane domain protein 1 (ANKTM1) and is widely distributed in lactation.
  • ANKTM1 transmembrane domain protein 1
  • the former mainly include sensory neurons of the peripheral nervous system such as trigeminal ganglia, dorsal root ganglia and vagus ganglia, while the latter include vascular endothelial cells, pancreatic islet cells, cardiomyocytes, inner ear hair cells, Hepatocytes, gastrointestinal mucosa, pancreatic cells, renal epithelial cells, prostate epithelial cells, breast cells, B lymphocytes, T lymphocytes, lung fibroblasts, melanocytes, dental pulp fibroblasts, mast cells and enterochromaffin cells and keratinocytes, etc.
  • the peripheral nervous system such as trigeminal ganglia, dorsal root ganglia and vagus ganglia
  • the latter include vascular endothelial cells, pancreatic islet cells, cardiomyocytes, inner ear hair cells, Hepatocytes, gastrointestinal mucosa, pancreatic cells, renal epithelial cells, prostate epithelial cells, breast cells, B lymph
  • the TRPA1 channel is a ligand-dependent non-selective cation conduction channel. It undergoes structural changes by binding to specific ligands. The channel opens and cations such as calcium ions, sodium ions, and potassium ions flow into the cell, which affects the cell membrane. The regulation of electric potential is of great significance to maintaining the normal physiological functions of the body.
  • This channel is generally considered to be a sensor of various senses (pain, cold, mechanical, itching, vision, smell, hearing, etc.) in humans and other mammals, and also serves as a stimulus to elicit protective responses (tears, airway resistance, and coughing). ) sensor, and studies over the past few years have found that this receptor is also involved in inflammation and immune responses.
  • TRPA1 channels In addition to physiological functions, TRPA1 channels also play an important role in pathological processes in various systems of humans and animals, including pain and inflammation, pruritus, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiac diseases, etc. Various pathological processes such as vascular diseases and skin diseases.
  • TRPA1 channels Activation of TRPA1 channels plays an important role in the generation and enhancement of pain. This channel is widely involved in nociceptive pain, neuropathic pain, cancer pain, dysfunctional pain, migraine, trigeminal neuralgia, inflammatory pain, and chronic pain. Wait for the occurrence and development of various types of pain. Activation of TRPA1 plays a major role in the rapid onset and maintenance of inflammation. Many endogenous TRPA1 agonists are produced during inflammation. Activation of TRPA1 can lead to vasodilation, a major symptom of inflammatory tissue. At the same time, activation of TRPA1 in epidermal keratinocytes enhanced the expression of known pro-inflammatory cytokines, which are key factors in skin inflammation.
  • TRPA1 Such as inflammation caused by atopic dermatitis, allergic dermatitis, otitis media, acne, acne, rosacea and other diseases. Itch is associated with TRPA1 activation, including histamine-dependent and histamine-independent itch. Literature suggests that activation of TRPA1 is closely related to pruritus caused by contact dermatitis, atopic dermatitis (AD), allergic dermatitis, and lymphoma. TRPA1 is widely distributed in the gastrointestinal cell network and is believed to be involved in gastrointestinal inflammation (such as idiopathic inflammatory bowel disease, IBD) and its pain response mechanism.
  • IBD idiopathic inflammatory bowel disease
  • TRPA1 may be a target for the treatment of stress visceral hyperalgesia in irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • TRPA1 antagonists or deletion of the TRPA1 gene can reduce pancreatic inflammation, while inflammatory mediators that activate TRPA1 can increase pancreatic inflammation and pain.
  • TRPA1 not only plays an important role in normal airway function, but is particularly important in respiratory diseases characterized by allergies, such as asthma, rhinitis, chronic obstructive pulmonary disease (COPD), bronchitis, and chronic cough.
  • TRPA1 channels are abundant in the cells of the lower urinary tract of animals, so TRPA1 is considered to have a regulatory effect on the urinary system.
  • TRPA1 may play an important role in the regulation of bladder contraction, and TRPA1 antagonists can reduce overactive bladder (OAB) symptoms and reduce the micturition reflex.
  • OAB overactive bladder
  • TRPA1 substance P and CGRP were co-expressed in bladder nerve terminals, suggesting that TRPA1 plays an important role in inflammatory cystitis.
  • Peripheral diabetic neuropathy (PDN) is a complication of diabetes, and TRPA1 activation at nerve fiber terminals may be a mechanism leading to this complication.
  • TRPA1-mediated mechanism is involved in the occurrence and development of diabetic cardiomyopathy. People are still learning more about the function and role of the TRPA1 channel, and the latest research has found that its antagonists have antidepressant and anxiolytic effects.
  • TRPA1 channels can be activated by many chemical or physical factors, including electrophilic agonists, non-electrophilic agonists, natural compounds, calcium ions, metal ions, pH, hot and cold stimuli, light, polyphosphates, and phosphorylation modifications wait.
  • electrophilic agonists Non-electrophilic agonists
  • non-electrophilic agonists natural compounds
  • calcium ions calcium ions
  • metal ions calcium ions
  • pH hot and cold stimuli
  • light polyphosphates
  • phosphorylation modifications wait.
  • Classic antagonists include HC-030031, GRC17536, A-967079, ALGX-2513, ALGX-2541, ALGX-2563, ALGX-2561, ALGX-2542, etc.
  • TRPA1 plays an important role in pain, inflammation, and potential indications for many other acquired diseases. Many TRPA1 agonists have been shown to cause pain, irritation, inflammation, and worsen disease symptoms in humans and animals. It is expected that TRPA1 antagonists may be used in As they play a therapeutic role in related diseases, the market demand for TRPA1 antagonists will also steadily increase. Although research on TRPA1 channel-related diseases has made great progress in the past decade, many TRPA1 agonists have been discovered, but there are only a few antagonists, and only 5 have entered clinical trials, and almost none will be used in clinical trials. Preclinical results translate into clinical practice, and research on these antagonists is currently at a standstill. There are currently few new treatments available to patients, and older drugs have considerable side effects and incomplete efficacy. For these reasons, patients are often undertreated and there is a clear need for new, safer and more effective TRPA1 antagonists.
  • the object of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an application of sesquiterpenoids in inhibiting the activity of TRPA1 channels.
  • the first object of the present invention is to provide the use of a compound, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, which is characterized in that it is used for the preparation of medicines or Preparations, the drugs or preparations are used for: (a) inhibiting the activity of TRPAl channels; (b) treating diseases related to TRPAl channels;
  • Sesquiterpenes are a type of terpene composed of three isoprene units, and their molecular formula is usually C 15 H 24 . Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical changes such as oxidation or rearrangement produce related sesquiterpenes. Sesquiterpenes occur naturally in plants and insects and are signaling chemicals such as defense agents or pheromones. Plants, fungi and animals produce a range of different sesquiterpenes that can effectively modulate the activity of TRPA1 channels in response to external stimuli.
  • the compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.
  • the R1, R10 and R15 are selected from CH 3 ;
  • R2 is selected from -OH
  • R3 is selected from COOH;
  • the diseases include at least one of pain, inflammation, itching, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiovascular diseases, and skin diseases. kind.
  • the pain includes chronic pain, neuropathic pain, acute pain, inflammatory pain, post-herpetic pain, neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy , nerve damage, rheumatoid arthritis pain, osteoarthritis pain, back pain, lumbago, cancer pain, toothache, headache, migraine, trigeminal neuralgia, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica , at least one of pelvic allergy, pelvic pain, menstrual pain, visceral pain, and postoperative pain; the inflammation includes burns or osteoarthritis; the neurological disease includes neurological disorders induced by anticancer agents;
  • the gastrointestinal disease includes at least one of functional gastrointestinal disease, reflux esophagitis, ulcer, inflammatory bowel disease, vomiting, and pancreatitis; the functional gastrointestinal disease includes swallowing disorder, irritable bowel syndrome and functional abdominal pain syndrome; the urinary system diseases include at least one of overactive bladder,
  • the diseases include chronic pain, neuropathic pain, acute pain, asthma, chronic obstructive pulmonary disease, functional gastrointestinal disease, reflux esophagitis, inflammatory bowel disease, pruritus, anticancer agent-induced at least one of the neurological disorders.
  • the medicine contains 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% of the compound of formula (I), or its optical isomer or its The racemate, or its solvate, or its pharmaceutically acceptable salt, based on the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which includes compounds as used in the above applications and other drugs that can inhibit the activity of TRPAl channels.
  • Other drugs that can inhibit the activity of TRPA1 channels include HC-030031, A-967079, AP-18, PF-04745637, Chembridge-5861528, etc.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all substances that are compatible with the administration of the drug, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and Other substances and compounds. Except to the extent that a conventional media or agent is incompatible with the active compound, its use in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • Useful carriers for preparing compositions thereof may be solid, liquid or gaseous; thus, the compositions may be in the form of tablets, pills, capsules, suppositories, powders, enteric-coated or otherwise protected formulations (e.g. combined with in the form of ion exchange resin or packaged in lipoprotein vesicles), sustained-release preparations, solutions, suspensions, elixirs, aerosols, etc.
  • the carrier may be selected from different oils, including petroleum, animal oils, vegetable oils or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, especially (when isotonic with blood) for injectable solutions.
  • formulations for intravenous administration include sterile aqueous solutions of the active ingredient, which are prepared by dissolving the solid active ingredient in water to produce an aqueous solution, and rendering the solution sterile.
  • suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, chlorine Sodium chloride, anhydrous skim milk, glycerin, propylene glycol, water, ethanol, etc.
  • compositions will contain an effective amount of the active compound, together with a suitable carrier to prepare a suitable dosage form for appropriate administration to the recipient.
  • the compounds of the invention may be administered in any suitable manner, such as oral (eg, buccal), topical, sublingual, rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and intrathecal Extramembranous and intranasal and, if necessary for local treatment, intralesional administration.
  • Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.
  • the present invention has the following beneficial effects:
  • the medicine of the present invention includes specific sesquiterpene compounds, which can significantly inhibit the activity of TRPAl channel.
  • the compound of formula (I) has a good inhibitory effect on TRPA1 channels and can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders), itching, and skin diseases (acne, pimples) related to TRPA1 targets. ), urinary tract disorders, inflammatory bowel disease, etc.
  • Figure 1 is a diagram showing compound A’s inhibition of TRPA1 current activated by AITC in hTRPA1-HEK293;
  • Figure 2 is a concentration-response curve generated by the TRPA1 agonist AITC and compound A in hTRPA1-HEK293;
  • Figure 3 is a diagram showing the influence of each group in Example 2 on the mechanical pain threshold of CFA-induced model group mice;
  • Figure 4 is a graph showing the results of scratching times in 1 hour for each group in the SADBE-induced mouse chronic itch model in Example 3;
  • Figure 5 is a graph showing the results of the number of coughs of each group in the rat variant asthma model in Example 4.
  • the present invention relates to patch clamp technology, which is a technology that records the ion current of ion channels to reflect the activities of single (or multiple) ion channel molecules on the cell membrane.
  • patch clamp technology is a technology that records the ion current of ion channels to reflect the activities of single (or multiple) ion channel molecules on the cell membrane.
  • Whole-cell patch clamp technology was used to verify whether compound A plays an antagonistic role in TRPA1 channel.
  • the structure of compound A is:
  • HEK293 cells purchased from Invitrogen.
  • cell culture medium DMEM Gibco BRL, Invitrogen
  • penicillin/streptomycin 5 ⁇ 10 6 IU/L, Gibco
  • 10% fetal calf serum Hyclone, Logan UT, USA
  • 12-well cell culture plate, 24-well cell culture plate and 3.5cm cell culture dish Corning
  • LipoD293 in vitro DNA transfection reagent (1ml, SignaGen)
  • NaCl 500g, Sigma
  • MgCl 500g, Sigma
  • EGTA 500g, Sigma
  • HEPES (1g, Macklin
  • AITC (1g, Sigma).
  • HEK293 cells were cultured in DMED cell culture medium containing 0.05g/L streptomycin, 0.05g/L penicillin, and 10% fetal calf serum, and placed in a constant temperature incubator at 37°C, 5% CO2, and saturated humidity. nourish.
  • 2.2 Cell transfection Use LipoD293 in vitro DNA transfection reagent to transiently transfect hTRA1 channel and EGFP plasmid into HEK293 cells. After 24 hours, observe the transfection efficiency and cell status under a 10X fluorescence microscope. If both are acceptable, resuspend the cells and transfer them to a 3.5cm cell culture dish and use them within 48 hours.
  • compound A can inhibit the TRPA1 current activated by AITC in hTRPA1-HEK293.
  • the half inhibitory concentration is 4.242 ⁇ M.
  • Each point represents the mean ⁇ S.E.M., n>10 cells.
  • Preparation of compound A solution Use DMSO with a concentration of 30% as a solvent to prepare a compound A solution with a concentration of 1 mg/ml, then dilute it with physiological saline to a concentration of 100umol/L and store it in a 4°C refrigerator for later use.
  • HC-030031 solution Use DMSO with a concentration of 30% as a solvent to prepare a HC-030031 solution with a concentration of 10 mg/ml, then dilute it with physiological saline to a solution with a concentration of 300 ⁇ mol/L and store it in a 4°C refrigerator for later use.
  • Preparation of CFA solution and Tween-80 solution After uniformly mixing 20ul of Tween-80 and 180ul of physiological saline, add 800ul of CFA, mix evenly on a vortex mixer to form a CFA solution, and place it at 4°C Store in the refrigerator for later use; mix 20ul of Tween-80 and 980ul of physiological saline evenly, prepare a Tween-80 solution, and store it in a 4°C refrigerator for later use.
  • mice Twelve C57BL/6J mice, 6-8 weeks old, male, weighing 20-25g, were randomly divided into four groups.
  • Normal group CFA group, CFA+Compound A group (100umol/L), CFA+HC-030031 (300umol/L) positive control group.
  • CFA group CFA+Compound A group (100umol/L)
  • CFA+HC-030031 300umol/L positive control group.
  • mice's spontaneous activity decreased, and there was obvious redness and swelling in the right hind foot compared with the left hind foot, which was different from normal. Compared with the group, the activity behavior was significantly reduced, indicating that the modeling was successful.
  • the normal group and CFA model group were gavaged with double-distilled water, and the CFA+ administration group was gavaged with the above concentrations of Compound A and HC-03003150ul respectively, and the mechanical stimulation pain threshold was measured.
  • mice C57BL/6J mice 6-8 weeks old, male 20-25g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008.
  • Animal breeding environment temperature (24+2)°C, relative humidity 50% to 70%, and 12h:12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
  • mice After 1 week of adaptive feeding, 18 mice were selected and divided into blank group, model control group, dexamethasone group and compound A low (1mg/kg), medium (5mg/kg) and high dose (10mg/kg) using random number table method. kg) groups, 3 animals in each group. Two days before the experiment, the hair on the back of the mouse's neck was shaved, with an area of approximately 2cmx3cm. Except for the blank group, other groups applied 20 ⁇ L of 0.5% SADBE acetone topically to the shaved abdominal skin of mice for sensitization once a day for three consecutive days.
  • mice After 5 days, 20 ⁇ L of 0.5% SADBE in acetone was topically applied to the shaved neck skin of mice once a day for three consecutive days. One day later, the low, medium and dose groups of Compound A were applied to the back skin of mice once a day by subcutaneous injection for 3 consecutive days. The mice in the control group were injected subcutaneously with physiological saline at the same time and frequency as those in the drug administration group. On the 15th day, a video recorder was used to observe and record the itch behavioral changes of the mice.
  • mice The severity of itch between groups was observed through the behavioral scratching count of mice.
  • Compound A the mice were placed in a transparent observation cage and filmed for 90 minutes in a quiet environment without people. The video was played back to record the behavioral tickling number of the mice.
  • a tickling event is when the mouse raises its hind paws to scratch the shaved area once or multiple times in a row. The tickling event ends when the mouse's hind paws fall to the ground or retract its paws and pause.
  • a rat variant asthma model was first constructed, and then Compound A was used to treat the mice and its efficacy was observed.
  • Animals SD rats 6-8 weeks old, male 200-250g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008.
  • Animal breeding environment temperature (24+2)°C, relative humidity 50% to 70%, and 12h: 12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
  • A02AI ultrasonic nebulizer Shanghai Yuyue Medical Equipment Co., Ltd.
  • the rats were randomly divided into three groups (blank group, model control group, and compound A group), with 6 rats in each group.
  • On the first day 2 mg of ovalbumin (OVA) and 100 mg AI(OH) 3 were intraperitoneally injected. After 3 weeks, 0.01 mg OVA and 100 mg AI(OH) 3 were intraperitoneally injected again.
  • the blank group was injected with normal saline.
  • the model control group and Compound A group began to use 1% OVA for aerosol challenge, and the normal control group used physiological saline once every other day for a total of 7 times.
  • Administration began on the day of atomization.
  • Compound A (0.6 mg/kg) was administered to the administration group 30 minutes before atomization.
  • the model control group and the normal control group were administered the same amount of drinking water once a day, a total of 14 times.
  • the rats in each group were placed in the atomization box and inhaled atomized 10-4 mol/L capsaicin solution for 60 seconds, and the number of coughs of each rat within 2 minutes was recorded.
  • the compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.

Abstract

The present invention relates to the technical field of biomedicine, it has been found in the present invention that a compound shown in formula I, or an optical isomer or racemate thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof can be used to prepare a medicament or preparation, and the medicament or preparation is used for: (a) inhibiting the activity of a TRPA1 channel; and (b) treating diseases related to the TRPA1 channel. It has been shown in experiments that the compound represented by formula (I) has a good inhibitory effect on the TRPA1 channel, and the compound represented by formula (I) of the present invention can be used for the treatment of pain, inflammation, respiratory disorders (such as breathing disorders), itching, skin disorders (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.

Description

倍半萜类化合物在抑制TRPA1通道的活性中的应用Application of sesquiterpenoids in inhibiting the activity of TRPA1 channels 技术领域Technical field
本发明涉及生物医药技术领域，尤其是涉及一种瞬时受体电位(TRP)离子通道家族的拮抗剂，具体地，本发明涉及倍半萜类化合物在抑制TRPA1通道的活性中的应用。The present invention relates to the field of biomedicine technology, and in particular to an antagonist of the transient receptor potential (TRP) ion channel family. Specifically, the present invention relates to the application of sesquiterpenoids in inhibiting the activity of the TRPAl channel.
背景技术Background technique
瞬时受体电位(TRP)通道是广泛存在于哺乳动物中的离子通道类型。该家族一共划分为7个亚家族，即TRPC、TRPV、TRPM、TRPN、TRPML、TRPA和TRPP。TRP通道均为六次跨膜蛋白，其N末端和C末端均在胞内,由第五和第六跨膜结构域共同构成非选择性阳离子孔道。这些通道通常作为多种化学和物理刺激的感受器，可被许多种因素调节,包括温度、渗透压、pH值、机械力,以及一些内、外源性配体和细胞内信号分子。Transient receptor potential (TRP) channels are a type of ion channel widely present in mammals. This family is divided into seven subfamilies, namely TRPC, TRPV, TRPM, TRPN, TRPML, TRPA and TRPP. TRP channels are all six-transmembrane proteins, with both their N-terminal and C-terminal ends inside the cell. The fifth and sixth transmembrane domains together form a non-selective cation channel. These channels usually serve as receptors for a variety of chemical and physical stimuli and can be regulated by many factors, including temperature, osmotic pressure, pH, mechanical force, as well as some endogenous and exogenous ligands and intracellular signaling molecules.
TRPA1通道是瞬时受体电位通道家族的成员，因其N端至少存在14个锚蛋白重复序列，也被称为带有跨膜结构域蛋白1的锚蛋白样蛋白(ANKTM1)，广泛分布于哺乳动物的神经和非神经细胞中，前者主要包括三叉神经节、背根神经节和迷走神经节等外周神经***的感觉神经元，后者包括如血管内皮细胞、胰岛细胞、心肌细胞、内耳毛细胞、肝细胞、胃肠粘膜、胰腺细胞、肾上皮细胞、***上皮细胞、乳腺细胞、B淋巴细胞、T淋巴细胞、肺成纤维细胞、黑色素细胞、牙髓成纤维细胞、肥大细胞和肠嗜铬细胞和角质细胞等。The TRPA1 channel is a member of the transient receptor potential channel family. It has at least 14 ankyrin repeat sequences at its N-terminus. It is also called ankyrin-like protein with transmembrane domain protein 1 (ANKTM1) and is widely distributed in lactation. Among the nerve and non-nerve cells of animals, the former mainly include sensory neurons of the peripheral nervous system such as trigeminal ganglia, dorsal root ganglia and vagus ganglia, while the latter include vascular endothelial cells, pancreatic islet cells, cardiomyocytes, inner ear hair cells, Hepatocytes, gastrointestinal mucosa, pancreatic cells, renal epithelial cells, prostate epithelial cells, breast cells, B lymphocytes, T lymphocytes, lung fibroblasts, melanocytes, dental pulp fibroblasts, mast cells and enterochromaffin cells and keratinocytes, etc.
TRPA1通道是配体依赖性的非选择性阳离子传导通道，通过结合特异性的配体而发生结构变化，由此通道打开，钙离子、钠离子、钾离子等阳离子流入胞内，对细胞的膜电位加以调节，对维持机体的正常生理功能有重要意义。该通道通常被认为是人类和其他哺乳动物各种感觉(疼痛、寒冷、机械、瘙痒、 视觉、嗅觉、听觉等)的传感器，同时也作为刺激物引起保护性反应(眼泪、气道阻力和咳嗽)的传感器，几年来的研究发现，该受体还参与炎症和免疫反应。除外生理功能，TRPA1通道还在人和动物各个***的病理过程中发挥重要作用，参与了包括疼痛和炎症、瘙痒、神经疾病、胃肠道疾病、糖尿病、肥胖、泌尿***疾病、呼吸道疾病、心血管疾病、皮肤疾病等多种病理过程。The TRPA1 channel is a ligand-dependent non-selective cation conduction channel. It undergoes structural changes by binding to specific ligands. The channel opens and cations such as calcium ions, sodium ions, and potassium ions flow into the cell, which affects the cell membrane. The regulation of electric potential is of great significance to maintaining the normal physiological functions of the body. This channel is generally considered to be a sensor of various senses (pain, cold, mechanical, itching, vision, smell, hearing, etc.) in humans and other mammals, and also serves as a stimulus to elicit protective responses (tears, airway resistance, and coughing). ) sensor, and studies over the past few years have found that this receptor is also involved in inflammation and immune responses. In addition to physiological functions, TRPA1 channels also play an important role in pathological processes in various systems of humans and animals, including pain and inflammation, pruritus, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiac diseases, etc. Various pathological processes such as vascular diseases and skin diseases.
TRPA1通道的激活在疼痛的产生和增强中起重要作用，该通道广泛参与到伤害感受性疼痛、神经病理性疼痛、癌症性疼痛、功能失调性疼痛、偏头痛、三叉神经痛、炎症性疼痛、慢性疼痛等各类疼痛的发生发展中。TRPA1的激活在炎症的快速发生和维持中起主要作用。在炎症过程中会产生许多内源性TRPA1激动剂。TRPA1的激活可以导致血管舒张，这是炎症组织的一个主要症状。同时，表皮角化细胞中TRPA1的激活增强了已知的促炎细胞因子的表达，这是皮肤炎症的关键因素。如特应性皮炎、变应性皮炎、中耳炎、粉刺、痤疮、酒糟鼻等疾病导致的炎症。瘙痒与TRPA1激活有关，包括组胺依赖性和非组胺依赖性的瘙痒。有文献提示TRPA1的激活与接触性皮炎、特应性皮炎(AD)、变应性皮炎和淋巴瘤导致的瘙痒密切相关。TRPA1广泛分布于胃肠道细胞网络，被认为参与了胃肠道炎症(如特发性炎症性肠病，IBD)及其疼痛反应机制。有研究显示，TRPA1可能是治疗肠易激综合征(IBS)应激性内脏痛觉过敏的靶点。至于常见的胰腺炎，有实验发现TRPA1拮抗剂或TRPA1基因的缺失可减轻胰腺炎症，而激活TRPA1的炎症介质会增加胰腺炎症和疼痛。TRPA1不仅在正常气道功能中发挥着重要作用，而且在以过敏为特征的呼吸***疾病中尤为重要，如哮喘、鼻炎、慢性阻塞性肺病(COPD)、支气管炎和慢性咳嗽。TRPA1通道大量存在于动物下尿路细胞中，因此TRPA1被认为对泌尿***有调节作用。实验表明TRPA1可能在膀胱收缩调节中发挥重要作用，TRPA1拮抗剂可减轻膀胱过度活动症(OAB)症状并降低排尿反射。另外，有研究人员发现TRPA1、P物质和CGRP在膀胱神经末梢共表达，提示TRPA1在炎症性膀胱 炎中起重要作用。周围性糖尿病神经病变(PDN)是糖尿病的并发症，神经纤维末端的TRPA1激活可能是导致该并发症的一种机制。另外，有研究提示TRPA1介导的机制参与了糖尿病性心肌病的发生发展。人们还在不断深入了解TRPA1通道的功能和作用，最新研究发现其拮抗剂具有抗抑郁和抗焦虑作用。Activation of TRPA1 channels plays an important role in the generation and enhancement of pain. This channel is widely involved in nociceptive pain, neuropathic pain, cancer pain, dysfunctional pain, migraine, trigeminal neuralgia, inflammatory pain, and chronic pain. Wait for the occurrence and development of various types of pain. Activation of TRPA1 plays a major role in the rapid onset and maintenance of inflammation. Many endogenous TRPA1 agonists are produced during inflammation. Activation of TRPA1 can lead to vasodilation, a major symptom of inflammatory tissue. At the same time, activation of TRPA1 in epidermal keratinocytes enhanced the expression of known pro-inflammatory cytokines, which are key factors in skin inflammation. Such as inflammation caused by atopic dermatitis, allergic dermatitis, otitis media, acne, acne, rosacea and other diseases. Itch is associated with TRPA1 activation, including histamine-dependent and histamine-independent itch. Literature suggests that activation of TRPA1 is closely related to pruritus caused by contact dermatitis, atopic dermatitis (AD), allergic dermatitis, and lymphoma. TRPA1 is widely distributed in the gastrointestinal cell network and is believed to be involved in gastrointestinal inflammation (such as idiopathic inflammatory bowel disease, IBD) and its pain response mechanism. Studies have shown that TRPA1 may be a target for the treatment of stress visceral hyperalgesia in irritable bowel syndrome (IBS). As for common pancreatitis, experiments have found that TRPA1 antagonists or deletion of the TRPA1 gene can reduce pancreatic inflammation, while inflammatory mediators that activate TRPA1 can increase pancreatic inflammation and pain. TRPA1 not only plays an important role in normal airway function, but is particularly important in respiratory diseases characterized by allergies, such as asthma, rhinitis, chronic obstructive pulmonary disease (COPD), bronchitis, and chronic cough. TRPA1 channels are abundant in the cells of the lower urinary tract of animals, so TRPA1 is considered to have a regulatory effect on the urinary system. Experiments have shown that TRPA1 may play an important role in the regulation of bladder contraction, and TRPA1 antagonists can reduce overactive bladder (OAB) symptoms and reduce the micturition reflex. In addition, some researchers found that TRPA1, substance P and CGRP were co-expressed in bladder nerve terminals, suggesting that TRPA1 plays an important role in inflammatory cystitis. Peripheral diabetic neuropathy (PDN) is a complication of diabetes, and TRPA1 activation at nerve fiber terminals may be a mechanism leading to this complication. In addition, some studies have suggested that the TRPA1-mediated mechanism is involved in the occurrence and development of diabetic cardiomyopathy. People are still learning more about the function and role of the TRPA1 channel, and the latest research has found that its antagonists have antidepressant and anxiolytic effects.
TRPA1通道可以被许多化学或物理因素激活，包括亲电性激动剂、非亲电性激动剂、天然化合物、钙离子、金属离子、PH、冷热刺激、光照、多聚磷酸盐、磷酸化修饰等。而TRPA1通道的拮抗剂种类则少了很多，经典的拮抗剂包括HC-030031、GRC17536、A-967079、ALGX-2513、ALGX-2541、ALGX-2563、ALGX-2561、ALGX-2542等。TRPA1 channels can be activated by many chemical or physical factors, including electrophilic agonists, non-electrophilic agonists, natural compounds, calcium ions, metal ions, pH, hot and cold stimuli, light, polyphosphates, and phosphorylation modifications wait. There are many fewer types of antagonists for the TRPA1 channel. Classic antagonists include HC-030031, GRC17536, A-967079, ALGX-2513, ALGX-2541, ALGX-2563, ALGX-2561, ALGX-2542, etc.
TRPA1在疼痛、炎症和许多其他获得性疾病的潜在适应症中发挥重要作用，已经证实许多TRPA1激动剂能在人和动物中引起疼痛、刺激、炎症并加重疾病症状，可以预期TRPA1拮抗剂可能在相关疾病中发挥治疗作用，因此市场对TRPA1拮抗剂的需求也将稳步增加。虽然在过去的十年中，TRPA1通道相关的疾病的研究取得了巨大的进展，发现了许多TRPA1的激动剂，但是其拮抗剂只有少数几种，进入临床实验的仅仅只有5种，几乎没有将临床前的结果转化为临床实践，而且目前关于这些拮抗剂的研究全部陷入了停滞状态。当下很少有新的治疗药物提供给患者，旧的药物有相当大的副作用和不完全的疗效。由于这些原因，患者往往得不到充分治疗，显然需要新的、更安全和更有效的TRPA1拮抗剂。TRPA1 plays an important role in pain, inflammation, and potential indications for many other acquired diseases. Many TRPA1 agonists have been shown to cause pain, irritation, inflammation, and worsen disease symptoms in humans and animals. It is expected that TRPA1 antagonists may be used in As they play a therapeutic role in related diseases, the market demand for TRPA1 antagonists will also steadily increase. Although research on TRPA1 channel-related diseases has made great progress in the past decade, many TRPA1 agonists have been discovered, but there are only a few antagonists, and only 5 have entered clinical trials, and almost none will be used in clinical trials. Preclinical results translate into clinical practice, and research on these antagonists is currently at a standstill. There are currently few new treatments available to patients, and older drugs have considerable side effects and incomplete efficacy. For these reasons, patients are often undertreated and there is a clear need for new, safer and more effective TRPA1 antagonists.
发明内容Contents of the invention
本发明的目的在于克服上述现有技术的不足之处而提供一种倍半萜类化合物在抑制TRPA1通道的活性中的应用。The object of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an application of sesquiterpenoids in inhibiting the activity of TRPA1 channels.
为实现上述目的，本发明采取的技术方案为：In order to achieve the above objects, the technical solutions adopted by the present invention are:
第一目的，本发明提供了一种化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐的用途，其特征在于，用于制备药物 或制剂，所述药物或制剂用于：(a)抑制TRPA1通道的活性；(b)治疗与TRPA1通道相关的疾病；The first object of the present invention is to provide the use of a compound, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, which is characterized in that it is used for the preparation of medicines or Preparations, the drugs or preparations are used for: (a) inhibiting the activity of TRPAl channels; (b) treating diseases related to TRPAl channels;
所述化合物的结构如式I所示：The structure of the compound is shown in Formula I:
Figure PCTCN2022138608-appb-000001
Figure PCTCN2022138608-appb-000001
R1-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 R1-R17 is selected from at least one of the following group: hydrogen, oxo (=O), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 ring Alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkoxy, or substituted or unsubstituted 5-8 membered heterocycle, the heterocycle containing 1-3 heteroatoms selected from N, O, S.
倍半萜是由三个异戊二烯单元组成的一类萜，分子式通常为C 15H 24。像单萜一样，倍半萜可能是无环或含有环，包括许多独特的组合。生物化学的变化，如氧化或重排产生相关的倍半萜。倍半萜天然存在于植物和昆虫中，是一种信号化学物质，如防御剂或信息素。植物、真菌和动物产生了一系列不同的倍半萜，可以有效调节TRPA1通道的活性，从而对外界刺激做出反应。 Sesquiterpenes are a type of terpene composed of three isoprene units, and their molecular formula is usually C 15 H 24 . Like monoterpenes, sesquiterpenes may be acyclic or contain rings, including many unique combinations. Biochemical changes such as oxidation or rearrangement produce related sesquiterpenes. Sesquiterpenes occur naturally in plants and insects and are signaling chemicals such as defense agents or pheromones. Plants, fungi and animals produce a range of different sesquiterpenes that can effectively modulate the activity of TRPA1 channels in response to external stimuli.
本发明人经过广泛而深入地研究，首次意外地发现了一类结构如式(I)所示化合物(倍半萜)可以显著地抑制TRPA1的活性。实验表明，所述的式(I)化合物对TRPA1通道有较好的抑制效果，本发明的式(I)化合物可用于治疗与TRPA1靶点相关的疼痛、炎症、呼吸道疾病(如呼吸障碍)、瘙痒、皮肤病(痤疮、粉刺)、尿路障碍、炎症性肠病等。After extensive and in-depth research, the inventor unexpectedly discovered for the first time that a type of compound (sesquiterpene) with a structure such as formula (I) can significantly inhibit the activity of TRPA1. Experiments show that the compound of formula (I) has a good inhibitory effect on the TRPA1 channel. The compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.
作为本发明所述用途的优选实施方式，所述R1、R10和R15选自CH 3；R2～ R9、R11～R14及R16～R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 As a preferred embodiment of the use of the present invention, the R1, R10 and R15 are selected from CH 3 ; R2 ~ R9, R11 ~ R14 and R16 ~ R17 are selected from at least one of the following groups: hydrogen, oxo (=O ), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or Unsubstituted C 3 -C 8 cycloalkoxy group, or substituted or unsubstituted 5-8 membered heterocyclic ring, the heterocyclic ring contains 1-3 heteroatoms selected from N, O, and S.
所述R2选自-OH，R1、R3-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 The R2 is selected from -OH, and R1 and R3-R17 are selected from at least one of the following groups: hydrogen, oxo (=O), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkoxy, or substituted or unsubstituted 5- 8-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S.
所述R3选自COOH；R1-2、R4-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 The R3 is selected from COOH; R1-2 and R4-R17 are selected from at least one of the following groups: hydrogen, oxo (=O), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, Substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkoxy, or substituted or unsubstituted 5 -8-membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S.
更优选地，所述R4可选自-NO 2；所述R5可选自-NH 2；R6可选自-X(卤素)；所述R7可选自-CN；所述R8可选自-SH；所述R9可选自-C＝C；所述R11可选自-C＝O；所述R12可选自-CHO；所述R13可选自-SO 3H；所述R14可选自-C 6H 6。 More preferably, the R4 can be selected from -NO 2 ; the R5 can be selected from -NH 2 ; R6 can be selected from -X (halogen); the R7 can be selected from -CN; the R8 can be selected from - SH; the R9 can be selected from -C=C; the R11 can be selected from -C=O; the R12 can be selected from -CHO; the R13 can be selected from -SO 3 H; the R14 can be selected from -C 6 H 6 .
作为本发明所述用途的优选实施方式，所述化合物的结构如式II所示：As a preferred embodiment of the use of the present invention, the structure of the compound is shown in formula II:
Figure PCTCN2022138608-appb-000002
Figure PCTCN2022138608-appb-000002
作为本发明所述用途的优选实施方式，所述疾病包括疼痛、炎症、瘙痒、神经疾病、胃肠道疾病、糖尿病、肥胖、泌尿***疾病、呼吸道疾病、心血管疾病、皮肤疾病中的至少一种。As a preferred embodiment of the use of the present invention, the diseases include at least one of pain, inflammation, itching, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiovascular diseases, and skin diseases. kind.
作为本发明所述用途的优选实施方式，所述疼痛包括慢性疼痛、神经性疼痛、急性疼痛、炎症性疼痛、带状疱疹后疼痛、神经病变、神经痛、糖尿病性神经病变、HIV相关神经病变、神经损伤、类风湿关节炎痛、骨关节炎痛、背痛、腰痛、癌性疼痛、牙痛、头痛、偏头痛、三叉神经痛、腕管综合征、纤维肌痛症、神经炎、坐骨神经痛、骨盘过敏症、骨盘痛、月经痛、内脏痛、术后疼痛中的至少一种；所述炎症包括烧伤或骨关节炎；所述神经疾病包括由抗癌剂诱发的神经障碍；所述胃肠道疾病包括功能性胃肠病、反流性食管炎、溃疡、炎症性肠病、呕吐、胰腺炎中的至少一种；所述功能性胃肠病包括咽下障害、肠易激综合征、功能性腹痛综合征中的至少一种；所述泌尿***疾病包括膀胱过度活动症、排尿异常、膀胱炎中的至少一种；所述呼吸道疾病包括哮喘、打喷嚏、慢性咳嗽、慢性阻塞性肺疾病、支气管收缩、过敏性鼻炎中的至少一种；所述皮肤疾病包括特应性皮炎、变应性皮炎、瘙痒症、粉刺、痤疮、酒糟鼻中的至少一种。As a preferred embodiment of the use of the present invention, the pain includes chronic pain, neuropathic pain, acute pain, inflammatory pain, post-herpetic pain, neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy , nerve damage, rheumatoid arthritis pain, osteoarthritis pain, back pain, lumbago, cancer pain, toothache, headache, migraine, trigeminal neuralgia, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica , at least one of pelvic allergy, pelvic pain, menstrual pain, visceral pain, and postoperative pain; the inflammation includes burns or osteoarthritis; the neurological disease includes neurological disorders induced by anticancer agents; The gastrointestinal disease includes at least one of functional gastrointestinal disease, reflux esophagitis, ulcer, inflammatory bowel disease, vomiting, and pancreatitis; the functional gastrointestinal disease includes swallowing disorder, irritable bowel syndrome and functional abdominal pain syndrome; the urinary system diseases include at least one of overactive bladder, abnormal urination, and cystitis; the respiratory diseases include asthma, sneezing, chronic cough, chronic At least one of obstructive pulmonary disease, bronchoconstriction, and allergic rhinitis; the skin disease includes at least one of atopic dermatitis, allergic dermatitis, pruritus, acne, acne, and rosacea.
更优选地，所述疾病包括慢性疼痛、神经性疼痛、急性疼痛、哮喘、慢性阻塞性肺疾病、功能性胃肠病、反流性食管炎、炎症性肠病、瘙痒症、抗癌剂诱发的神经障碍中的至少一种。More preferably, the diseases include chronic pain, neuropathic pain, acute pain, asthma, chronic obstructive pulmonary disease, functional gastrointestinal disease, reflux esophagitis, inflammatory bowel disease, pruritus, anticancer agent-induced at least one of the neurological disorders.
作为本发明所述用途的优选实施方式，所述药物中含有0.001-99wt％，优选为0.1-90wt％，更优选为1-80wt％的式(I)化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐，按组合物的总重量计。As a preferred embodiment of the use of the present invention, the medicine contains 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% of the compound of formula (I), or its optical isomer or its The racemate, or its solvate, or its pharmaceutically acceptable salt, based on the total weight of the composition.
第二目的，本发明提供了一种药物组合物，所述药物组合物包括如上述应用中的化合物和其他能抑制TRPA1通道的活性的药物。其他能抑制TRPA1通道的活性的药物如HC-030031、A-967079、AP-18、PF-04745637、Chembridge-5861528等。For a second purpose, the present invention provides a pharmaceutical composition, which includes compounds as used in the above applications and other drugs that can inhibit the activity of TRPAl channels. Other drugs that can inhibit the activity of TRPA1 channels include HC-030031, A-967079, AP-18, PF-04745637, Chembridge-5861528, etc.
作为本发明所述药物组合物的优选实施方式，所述药物组合物还包括药物上可接受的载体。As a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
术语“药物上可接受的载体”包括与药物施用相容的任意和所有物质，包括溶剂、分散介质、包衣、抗细菌和抗真菌剂、等渗和吸收延缓剂和与药物施用相容的其它物质和化合物。除非到了某一常规介质或试剂与活性化合物不相容的程度，否则考虑其在本发明组合物中的用途。补充的活性化合物也可以整合入组合物。The term "pharmaceutically acceptable carrier" includes any and all substances that are compatible with the administration of the drug, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and Other substances and compounds. Except to the extent that a conventional media or agent is incompatible with the active compound, its use in the compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
用于制备其组合物的有用的载体可以是固体，液体或气体；因此，所述组合物可以采用片剂、丸剂、胶囊、栓剂、粉末剂、肠包衣的或其它保护的制剂(例如结合于离子交换树脂或包装在脂蛋白泡囊中)、缓释制剂、溶液、混悬剂、酏剂、气溶胶等的形式。所述载体可以选自不同油，包括石油、动物油、植物油或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。水、盐水、含水葡萄糖和二元醇是优选的液体载体，特别是(当与血液等渗时)用于可注射溶液。例如，用于静脉施用的制剂包括活性成分的无菌水溶液，其通过将固体活性成分溶解于水来产生水溶液，并使得所述溶液无菌来制备。合适的药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、滑石、明胶、麦芽、大米、面粉、白垩、硅石、硬脂酸镁、硬脂酸钠、甘油单硬脂酸酯、氯化钠、无水脱脂乳、甘油、丙二醇、水、乙醇等。组合物可以加入常规药物添加剂比如防腐剂、稳定剂、湿润剂或乳化剂、用于调节渗透压的盐、缓冲剂等。合适的药物载体。在任何情况中，这种组合物将含有与合适的载体一起的有效量活性化合物，以制备适当剂型用于适当施用于接受者。Useful carriers for preparing compositions thereof may be solid, liquid or gaseous; thus, the compositions may be in the form of tablets, pills, capsules, suppositories, powders, enteric-coated or otherwise protected formulations (e.g. combined with in the form of ion exchange resin or packaged in lipoprotein vesicles), sustained-release preparations, solutions, suspensions, elixirs, aerosols, etc. The carrier may be selected from different oils, including petroleum, animal oils, vegetable oils or oils of synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, especially (when isotonic with blood) for injectable solutions. For example, formulations for intravenous administration include sterile aqueous solutions of the active ingredient, which are prepared by dissolving the solid active ingredient in water to produce an aqueous solution, and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glyceryl monostearate, chlorine Sodium chloride, anhydrous skim milk, glycerin, propylene glycol, water, ethanol, etc. Conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure, buffers, etc. may be added to the composition. Suitable pharmaceutical carriers. In any event, such compositions will contain an effective amount of the active compound, together with a suitable carrier to prepare a suitable dosage form for appropriate administration to the recipient.
本发明的化合物可以以任何合适的方式施用，例如口服(例如，颊)、局部、舌下、直肠、***、经皮、肠胃外、皮下、腹膜内、肺内、皮内、鞘内以及硬膜外和鼻内、并且、如果需要用于局部治疗、病灶内的施用。肠胃外注入包括肌肉内、静脉内、动脉内、腹膜内、脑内、眼内、病灶内或皮下施用。The compounds of the invention may be administered in any suitable manner, such as oral (eg, buccal), topical, sublingual, rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and intrathecal Extramembranous and intranasal and, if necessary for local treatment, intralesional administration. Parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional, or subcutaneous administration.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明药物包括特定的倍半萜化合物，对于可以显著地抑制TRPA1通道的活性。实验表明，所述的式(I)化合物对TRPA1通道有较好的抑制效果，可用于治疗与TRPA1靶点相关的疼痛、炎症、呼吸道疾病(如呼吸障碍)、瘙痒、皮肤病(痤疮、粉刺)、尿路障碍、炎症性肠病等。The medicine of the present invention includes specific sesquiterpene compounds, which can significantly inhibit the activity of TRPAl channel. Experiments have shown that the compound of formula (I) has a good inhibitory effect on TRPA1 channels and can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders), itching, and skin diseases (acne, pimples) related to TRPA1 targets. ), urinary tract disorders, inflammatory bowel disease, etc.
附图说明Description of the drawings
图1为化合物A抑制hTRPA1-HEK293中由AITC激活的TRPA1电流图；Figure 1 is a diagram showing compound A’s inhibition of TRPA1 current activated by AITC in hTRPA1-HEK293;
图2为hTRPA1-HEK293中，TRPA1激动剂AITC和化合物A产生的浓度-响应曲线图；Figure 2 is a concentration-response curve generated by the TRPA1 agonist AITC and compound A in hTRPA1-HEK293;
图3为实施例2各组对CFA诱导的模型组小鼠机械痛阈值的影响图；Figure 3 is a diagram showing the influence of each group in Example 2 on the mechanical pain threshold of CFA-induced model group mice;
图4为实施例3各组对SADBE诱导的小鼠慢性瘙痒模型在1h内挠痒次数的结果图；Figure 4 is a graph showing the results of scratching times in 1 hour for each group in the SADBE-induced mouse chronic itch model in Example 3;
图5为实施例4各组对大鼠变异性哮喘模型的咳嗽次数的结果图。Figure 5 is a graph showing the results of the number of coughs of each group in the rat variant asthma model in Example 4.
具体实施方式Detailed ways
为更好的说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。In order to better explain the purpose, technical solutions and advantages of the present invention, the present invention will be further described below with reference to the drawings and specific embodiments.
在以下实施例中，所使用的实验方法如无特殊说明，均为常规方法，所用的材料、试剂等，如无特殊说明，均可从商业途径得到。In the following examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used can be obtained from commercial sources unless otherwise specified.
实施例1Example 1
本发明涉及到膜片钳技术，该技术是一种以记录离子通道的离子电流来反映细胞膜上单个的(或多个的)离子通道分子活动的技术。利用全细胞膜片钳技术验证化合物A是否在TRPA1通道中起拮抗作用。化合物A的结构为：The present invention relates to patch clamp technology, which is a technology that records the ion current of ion channels to reflect the activities of single (or multiple) ion channel molecules on the cell membrane. Whole-cell patch clamp technology was used to verify whether compound A plays an antagonistic role in TRPA1 channel. The structure of compound A is:
Figure PCTCN2022138608-appb-000003
Figure PCTCN2022138608-appb-000003
1.材料1.Materials
1.1细胞系：HEK293细胞(购自Invitrogen)。1.1 Cell line: HEK293 cells (purchased from Invitrogen).
1.2药物：化合物A，CAS No.5986-55-0，规格：10mg，品牌：Sigma。1.2 Drug: Compound A, CAS No.5986-55-0, Specification: 10mg, Brand: Sigma.
1.3试剂及耗材：细胞培养基DMEM(Gibco BRL，Invitrogen)；5g/L青霉素/链霉素(5×10 6IU/L，Gibco)；10％胎小牛血清(Hyclone，Logan UT，USA)；12孔细胞培养板、24孔细胞培养板及3.5cm细胞培养皿(Corning)；LipoD293体外DNA转染试剂(1ml,SignaGen)；NaCl(500g,Sigma)；MgCl(500g，Sigma)；EGTA(500g,Sigma)；HEPES(1g,Macklin)；AITC(1g，Sigma)。 1.3 Reagents and consumables: cell culture medium DMEM (Gibco BRL, Invitrogen); 5g/L penicillin/streptomycin (5×10 6 IU/L, Gibco); 10% fetal calf serum (Hyclone, Logan UT, USA) ; 12-well cell culture plate, 24-well cell culture plate and 3.5cm cell culture dish (Corning); LipoD293 in vitro DNA transfection reagent (1ml, SignaGen); NaCl (500g, Sigma); MgCl (500g, Sigma); EGTA ( 500g, Sigma); HEPES (1g, Macklin); AITC (1g, Sigma).
1.4仪器：超净工作台，青岛海尔医用低温科技有限公司；CO 2培养箱，新加坡ESCO公司；倒置显微镜，日本Nikon公司；微电极拉制仪(P-1000)，美国Sutter公司；抛光仪，美国WPI公司；放大器(MultiClamp 700B)，美国Sutter公司；数字转换器(Digidata11550B)，美国Sutter公司；微操仪(MP-225)，美国Sutter公司。 1.4 Instruments: ultra-clean workbench, Qingdao Haier Medical Cryogenic Technology Co., Ltd.; CO2 incubator, Singapore ESCO Company; inverted microscope, Japan Nikon Company; microelectrode drawing instrument (P-1000), US Sutter Company; polishing instrument, WPI Company of the United States; amplifier (MultiClamp 700B), Sutter Company of the United States; digital converter (Digidata11550B), Sutter Company of the United States; microcontroller (MP-225), Sutter Company of the United States.
2.试验方法2.Test method
2.1细胞培养：HEK293细胞培养于含0.05g/L链霉素、0.05g/L青霉素、10％胎牛血清的DMED细胞培养基中，置37℃、5％CO2及饱和湿度的恒温孵育箱中培养。2.1 Cell culture: HEK293 cells were cultured in DMED cell culture medium containing 0.05g/L streptomycin, 0.05g/L penicillin, and 10% fetal calf serum, and placed in a constant temperature incubator at 37°C, 5% CO2, and saturated humidity. nourish.
2.2细胞转染；使用LipoD293体外DNA转染试剂瞬时转染hTRA1通道和EGFP质粒到HEK293细胞中。24h后，在荧光显微镜10X观察转染效率及细胞状态，如若皆可，即可将细胞重悬后传至3.5cm的细胞培养皿中，并在48小时内使用。2.2 Cell transfection: Use LipoD293 in vitro DNA transfection reagent to transiently transfect hTRA1 channel and EGFP plasmid into HEK293 cells. After 24 hours, observe the transfection efficiency and cell status under a 10X fluorescence microscope. If both are acceptable, resuspend the cells and transfer them to a 3.5cm cell culture dish and use them within 48 hours.
2.3配制电极内液：145mM Nacl、10mM Hepes、2mM MgCl 2、2mM EGTA PH7.3。 2.3 Prepare the electrode internal solution: 145mM Nacl, 10mM Hepes, 2mM MgCl 2 , 2mM EGTA PH7.3.
配制电极外液：145mM Nacl、10mM Hepes、2mM MgCl 2、PH 7.3。 Prepare the electrode external solution: 145mM Nacl, 10mM Hepes, 2mM MgCl 2 , pH 7.3.
2.4全细胞记录2.4 Whole cell recording
所有实验均在室温下进行(～22℃)。制作玻璃微电极并热抛光至2～3MΩ用于全细胞膜片钳记录，在表达hTRPA1的HEK293细胞(即hTRPA1-HEK293)中，通过500ms的电压斜坡，从-100到+100mV的连续性电压刺激，频率为0.5Hz，钳制电位为0mV，用AITC诱导TRPA1通道电流，并用化合物A抑制电流。电流用MultiClamp 700B进行放大，并用Digidata1550B(分子器件)进行数字化。电流在2kHz处进行低通滤波，并在10kHz处进行采样。采用PCLAMP软件(分子器件)进行数据采集和分析。实验前立即制备含化合物A的测试溶液，并在5min内使用。All experiments were performed at room temperature (~22°C). Glass microelectrodes were made and heat-polished to 2 to 3 MΩ for whole-cell patch clamp recording. In HEK293 cells expressing hTRPA1 (i.e., hTRPA1-HEK293), continuous voltage stimulation from -100 to +100 mV was performed through a 500 ms voltage ramp. , the frequency is 0.5Hz, the clamping potential is 0mV, AITC is used to induce TRPA1 channel current, and compound A is used to inhibit the current. The current was amplified with a MultiClamp 700B and digitized with a Digidata 1550B (Molecular Devices). The current is low-pass filtered at 2kHz and sampled at 10kHz. Data acquisition and analysis were performed using PCLAMP software (Molecular Devices). Prepare the test solution containing compound A immediately before the experiment and use it within 5 minutes.
3、实验结果3. Experimental results
如图1，化合物A能抑制hTRPA1-HEK293中由AITC激活的TRPA1电流。As shown in Figure 1, compound A can inhibit the TRPA1 current activated by AITC in hTRPA1-HEK293.
如图2，hTRPA1-HEK293中，TRPA1激动剂AITC和化合物A产生的浓度-响应曲线。半数抑制浓度为4.242μM。每个点代表平均±S.E.M.，n>10个细胞。As shown in Figure 2, the concentration-response curve generated by the TRPA1 agonist AITC and compound A in hTRPA1-HEK293. The half inhibitory concentration is 4.242μM. Each point represents the mean ±S.E.M., n>10 cells.
实施例2Example 2
先构建CFA炎性疼痛小鼠模型，然后使用化合物A治疗其小鼠，观察其疗效。First, a mouse model of CFA inflammatory pain was constructed, and then Compound A was used to treat the mice to observe its efficacy.
1、实验材料1. Experimental materials
1.1动物：C57BL/6J小鼠6-8周，雄性20-25g，由北京华阜康生物科技股份有限公司提供，实验动物生产许可证号：SCXK(京)2019-0008。1.1 Animals: C57BL/6J mice 6-8 weeks old, male 20-25g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008.
1.2药物：化合物A，CAS No.5986-55-0，规格：10mg，品牌：Sigma；HC-030031，CASNo.349085-38-7，规格：10mg，品牌：Sigma；完全弗氏佐剂(CFA)，规格：10mL，品牌：Sigma；吐温-80，规格500mL，品牌：Sigma；生理盐水，石家庄四药有限公司；二甲基亚砜(DMSO)，规格：500ml，品牌：Sigma。1.2 Drugs: Compound A, CAS No. 5986-55-0, Specification: 10 mg, Brand: Sigma; HC-030031, CAS No. 349085-38-7, Specification: 10 mg, Brand: Sigma; Complete Freund's Adjuvant (CFA ), specification: 10mL, brand: Sigma; Tween-80, specification: 500mL, brand: Sigma; physiological saline, Shijiazhuang No. 4 Medicine Co., Ltd.; Dimethyl sulfoxide (DMSO), specification: 500ml, brand: Sigma.
1.3仪器：微量注射器，品牌：Hamilton Bonaduz AG；Von Frey纤毛机械刺激针，品牌：North Coast；测试平台，支架尺寸48*34*39cm，笼子尺寸 40*23*15cm，上海玉研科学仪器有限公司。1.3 Instruments: Microsyringe, brand: Hamilton Bonaduz AG; Von Frey cilia mechanical stimulation needle, brand: North Coast; test platform, bracket size 48*34*39cm, cage size 40*23*15cm, Shanghai Yuyan Scientific Instrument Co., Ltd. .
实验步骤Experimental steps
2.1药物制备及溶液配制2.1 Drug preparation and solution preparation
化合物A溶液的配制：以浓度为30％的DMSO作为溶剂配制浓度为1mg/ml的化合物A溶液，然后用生理盐水稀释成浓度为100umol/L的溶液并放置4℃冰箱保存备用。Preparation of compound A solution: Use DMSO with a concentration of 30% as a solvent to prepare a compound A solution with a concentration of 1 mg/ml, then dilute it with physiological saline to a concentration of 100umol/L and store it in a 4°C refrigerator for later use.
HC-030031溶液的配制：以浓度为30％的DMSO作为溶剂配制浓度为10mg/ml的HC-030031溶液，然后用生理盐水稀释成浓度为300μmol/L的溶液并放置4℃冰箱保存备用。Preparation of HC-030031 solution: Use DMSO with a concentration of 30% as a solvent to prepare a HC-030031 solution with a concentration of 10 mg/ml, then dilute it with physiological saline to a solution with a concentration of 300 μmol/L and store it in a 4°C refrigerator for later use.
CFA溶液及吐温-80溶液的配制：将20ul吐温-80与180ul的生理盐水均匀混合后，加入800ul的CFA，置于涡旋混合器上混合均匀配置成CFA溶液，并放置在4℃冰箱保存备用；将20ul吐温-80与980ul的生理盐水混合均匀后，配置成吐温-80溶液，并放置在4℃冰箱保存备用。Preparation of CFA solution and Tween-80 solution: After uniformly mixing 20ul of Tween-80 and 180ul of physiological saline, add 800ul of CFA, mix evenly on a vortex mixer to form a CFA solution, and place it at 4°C Store in the refrigerator for later use; mix 20ul of Tween-80 and 980ul of physiological saline evenly, prepare a Tween-80 solution, and store it in a 4°C refrigerator for later use.
2.2造模及分组给药2.2 Modeling and group administration
取C57BL/6J小鼠12只，6-8周，雄性，体重20-25g，随机分为四组。正常组，CFA组，CFA+化合物A组(100umol/L)，CFA+HC-030031(300umol/L)阳性对照组。取25ul微量注射器给CFA组和CFA+给药组小鼠右后足底皮下缓慢注射20ul上述配制的CFA溶液，小鼠自主活动量减少，右后足与左后足比较出现明显的红肿，与正常组比较其活动行为明显减少，说明造模成功。30min后，正常组和CFA模型组灌胃双蒸水，CFA+给药组分别灌胃上述浓度的化合物A及HC-03003150ul，并进行机械刺激痛阈测定。Twelve C57BL/6J mice, 6-8 weeks old, male, weighing 20-25g, were randomly divided into four groups. Normal group, CFA group, CFA+Compound A group (100umol/L), CFA+HC-030031 (300umol/L) positive control group. Take a 25ul microsyringe and slowly subcutaneously inject 20ul of the above-prepared CFA solution into the right hind foot of the mice in the CFA group and CFA+ administration group. The mice's spontaneous activity decreased, and there was obvious redness and swelling in the right hind foot compared with the left hind foot, which was different from normal. Compared with the group, the activity behavior was significantly reduced, indicating that the modeling was successful. After 30 minutes, the normal group and CFA model group were gavaged with double-distilled water, and the CFA+ administration group was gavaged with the above concentrations of Compound A and HC-03003150ul respectively, and the mechanical stimulation pain threshold was measured.
2.3机械刺激痛阈值测定2.3 Determination of mechanical stimulation pain threshold
将实验小鼠置于测试平台上，盖上透明的有分格的有机玻璃罩，先让小鼠适应20min，等小鼠安静下来及其探究活动明显减少或者消失后，用0.04～2g范围内的Von-Frey机械刺激针垂直刺激小鼠右后足底中部，使其成90° 弯曲并维持6s，观察小鼠足趾的反应情况，若小鼠在刺激时间内出现迅速的缩足、弹腿、舔足活动则记为阳性反应，若没有此类反应则记为阴性；该方法按照Dixon的up-down法测定及分析，机械刺激痛阈值分别在CFA注射前1h、注射后1h、2h测定。Place the experimental mouse on the test platform and cover it with a transparent plexiglass cover. Let the mouse adapt for 20 minutes. After the mouse calms down and its exploratory activities are significantly reduced or disappears, use a 0.04-2g range of The Von-Frey mechanical stimulation needle vertically stimulates the middle part of the mouse's right rear foot, bending it at 90° and maintains it for 6 seconds. Observe the reaction of the mouse's toes. If the mouse rapidly shrinks or bounces its feet during the stimulation time, Leg and foot licking activities were recorded as positive reactions, and if there were no such reactions, they were recorded as negative; this method was measured and analyzed according to Dixon's up-down method, and the mechanical stimulation pain thresholds were 1 hour before, 1 hour, and 2 hours after CFA injection. Determination.
3.实验结果3.Experimental results
如图3，CFA诱导的模型组小鼠机械痛阈值均显著降低，实验组及阳性对照组均能逆转。As shown in Figure 3, the mechanical pain threshold of mice in the CFA-induced model group was significantly reduced, and it was reversed in both the experimental group and the positive control group.
采用SPSS17.0统计软件进行统计学分析，t检验得P＜0.05，差异有统计学意义。通过上述实验说明，采用本发明所述方法可以缓解CFA炎性疼痛。SPSS17.0 statistical software was used for statistical analysis. The t test showed P＜0.05, and the difference was statistically significant. It is demonstrated through the above experiments that CFA inflammatory pain can be relieved by using the method of the present invention.
实施例3Example 3
先构建SADBE诱导小鼠慢性瘙痒模型，然后使用化合物A治疗其小鼠，观察其疗效。First, a SADBE-induced chronic itch model in mice was constructed, and then Compound A was used to treat the mice to observe its efficacy.
1.1动物：C57BL/6J小鼠6-8周，雄性20-25g，由北京华阜康生物科技股份有限公司提供，实验动物生产许可证号：SCXK(京)2019-0008。动物饲养环境:温度(24+2)℃，相对湿度50％～70％，采用12h:12h昼夜间断照明。SPF级饲料和纯化水饲养，适应性饲养1周，各组小鼠分笼饲养。1.1 Animals: C57BL/6J mice 6-8 weeks old, male 20-25g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008. Animal breeding environment: temperature (24+2)°C, relative humidity 50% to 70%, and 12h:12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
1.2药物：化合物A，CAS No.5986-55-0，规格：10mg，品牌：Sigma；SADBE(J&KScientific公司，批号：481805，含量：98％)；***磷酸钠注射液(湖北天药药业股份有限公司，批号：H42020019)；生理盐水，石家庄四药有限公司。1.2 Drugs: Compound A, CAS No.5986-55-0, specification: 10 mg, brand: Sigma; SADBE (J&KS Scientific Company, batch number: 481805, content: 98%); dexamethasone sodium phosphate injection (Hubei Tianyaoyao Industry Co., Ltd., batch number: H42020019); physiological saline, Shijiazhuang No. 4 Medicine Co., Ltd.
1.3仪器：微量注射器，品牌：Hamilton Bonaduz AG；录像相机；透明观察笼。1.3 Instruments: microsyringe, brand: Hamilton Bonaduz AG; video camera; transparent observation cage.
2实验步骤：2 Experimental steps:
2.1SADBE诱导小鼠慢性瘙痒模型建立：2.1 Establishment of SADBE-induced chronic itch model in mice:
选取18只小鼠适应性饲养1周后随机数字表法分为空白组、模型对照组、 ***组及化合物A低(1mg/kg)、中(5mg/kg)、高剂量(10mg/kg)组，每组3只。实验前2天剃光小鼠颈背部发,面积约为2cmx3cm。除空白组外，其他组将20μL 0.5％SADBE的丙酮局部应用于小鼠已剃毛腹部皮肤，连续三天每天一次进行敏化。5天后，连续三天每天一次将20μL0.5％SADBE的丙酮局部应用于小鼠已剃毛颈部皮肤。1天后，化合物A低、中、剂量组通过皮下注射方式每天一次应用于小鼠背部皮肤连续用药3天。对照组小鼠皮下注射生理盐水，时间和频率与给药组相同。在第15天采用录像机观察并记录小鼠的瘙痒行为学变化。After 1 week of adaptive feeding, 18 mice were selected and divided into blank group, model control group, dexamethasone group and compound A low (1mg/kg), medium (5mg/kg) and high dose (10mg/kg) using random number table method. kg) groups, 3 animals in each group. Two days before the experiment, the hair on the back of the mouse's neck was shaved, with an area of approximately 2cmx3cm. Except for the blank group, other groups applied 20 μL of 0.5% SADBE acetone topically to the shaved abdominal skin of mice for sensitization once a day for three consecutive days. After 5 days, 20 μL of 0.5% SADBE in acetone was topically applied to the shaved neck skin of mice once a day for three consecutive days. One day later, the low, medium and dose groups of Compound A were applied to the back skin of mice once a day by subcutaneous injection for 3 consecutive days. The mice in the control group were injected subcutaneously with physiological saline at the same time and frequency as those in the drug administration group. On the 15th day, a video recorder was used to observe and record the itch behavioral changes of the mice.
2.2检测指标和方法：2.2 Detection indicators and methods:
小鼠挠痒的行为学观察：Behavioral observations on tickling in mice:
通过小鼠行为学挠痒数观察各组之间的瘙痒严重程度。小鼠皮下注射化合物A后立刻将小鼠放入透明观察笼，在无人安静的环境中拍摄90min，回放录像记录小鼠行为学挠痒数。1次挠痒为小鼠后爪抬起抓挠剃毛部位1次或连续多次抓挠，小鼠后爪落地或缩爪停顿为本次挠痒结束。The severity of itch between groups was observed through the behavioral scratching count of mice. Immediately after the mice were subcutaneously injected with Compound A, the mice were placed in a transparent observation cage and filmed for 90 minutes in a quiet environment without people. The video was played back to record the behavioral tickling number of the mice. A tickling event is when the mouse raises its hind paws to scratch the shaved area once or multiple times in a row. The tickling event ends when the mouse's hind paws fall to the ground or retract its paws and pause.
3.实验结果：3.Experimental results:
SADBE诱导小鼠慢性瘙痒模型挠痒行为学观察Observation on scratching behavior in SADBE-induced chronic itch model in mice
为了观察化合物A对小鼠挠痒行为的影响，以小鼠抬起后爪抓挠颈部剃毛部位皮肤次数作为判断瘙痒严重程度的标准统计由SADBE诱导小鼠慢性瘙痒行为学模型的结果。与空白组比较模型组挠痒次数显著增多(P<0.001)。与模型组比较，化合物A低、中、高剂量组小鼠挠痒次数显著减少(P<0.001)，***组比模型对照组小鼠挠痒次数显著性减少(P<0.01)，化合物A剂量组药效强于***组组具有统计学差异(P<0.05)，见图4。In order to observe the effect of Compound A on the scratching behavior of mice, the number of times the mice raised their hind paws to scratch the skin of the shaved neck area was used as a standard to judge the severity of itch. The results of the chronic itch behavioral model of mice induced by SADBE were calculated. Compared with the blank group, the number of scratches in the model group was significantly increased (P<0.001). Compared with the model group, the number of times mice scratched in the low, medium and high dose groups of Compound A was significantly reduced (P<0.001). The number of times mice in the dexamethasone group were scratched was significantly reduced (P<0.01) compared with the model control group. The drug effect of dose A group was stronger than that of dexamethasone group, with statistical difference (P<0.05), see Figure 4.
实施例4Example 4
先构建大鼠变异性哮喘模型，然后使用化合物A治疗其小鼠，观察其疗效。A rat variant asthma model was first constructed, and then Compound A was used to treat the mice and its efficacy was observed.
1.1动物：SD大鼠6-8周，雄性200-250g，由北京华阜康生物科技股份有限公司提供，实验动物生产许可证号：SCXK(京)2019-0008。动物饲养环境:温度(24+2)℃，相对湿度50％～70％，采用12h：12h昼夜间断照明。SPF级饲料和纯化水饲养，适应性饲养1周，各组小鼠分笼饲养。1.1 Animals: SD rats 6-8 weeks old, male 200-250g, provided by Beijing Huafukang Biotechnology Co., Ltd., experimental animal production license number: SCXK (Beijing) 2019-0008. Animal breeding environment: temperature (24+2)°C, relative humidity 50% to 70%, and 12h: 12h day and night lighting. They were fed with SPF grade feed and purified water, and were adaptively fed for 1 week. The mice in each group were housed in separate cages.
1.2药物：化合物A，CAS No.5986-55-0，规格：10mg，品牌：Sigma；卵清白蛋白(卵蛋白，OVA)：品牌：Sigma，CAS No.9006-59-1，规格：1g；辣椒素:品牌：Sigma，CAS No.456-42-9，规格：1g。1.2 Drugs: Compound A, CAS No.5986-55-0, Specification: 10mg, Brand: Sigma; Ovalbumin (oval protein, OVA): Brand: Sigma, CAS No.9006-59-1, Specification: 1g; Capsaicin: Brand: Sigma, CAS No.456-42-9, specification: 1g.
1.3仪器：1.3 Instruments:
A02AI超声波雾化器：上海鱼跃医疗设备有限公司。A02AI ultrasonic nebulizer: Shanghai Yuyue Medical Equipment Co., Ltd.
2实验步骤：2 Experimental steps:
2.1模型的制备及分组给药：2.1 Preparation of model and group administration:
大鼠随机分成三组(空白组、模型对照组、化合物A组)，每组6只。第1日腹腔注射2mg卵蛋白(OVA)和100mg AI(OH) 3，3周后再次腹腔注射0.01mg OVA及100mg AI(OH) 3，空白组注射等生理盐水。3周后模型对照组和化合物A组开始用1％OVA进行雾化攻击，正常对照组用生理盐水，隔日一次，共7次。雾化当天开始给药，在雾化前30min给药组进行化合物A(0.6mg/kg)灌胃给药，模型对照组与正常对照组灌胃等量饮用水，一天一次，共14次。 The rats were randomly divided into three groups (blank group, model control group, and compound A group), with 6 rats in each group. On the first day, 2 mg of ovalbumin (OVA) and 100 mg AI(OH) 3 were intraperitoneally injected. After 3 weeks, 0.01 mg OVA and 100 mg AI(OH) 3 were intraperitoneally injected again. The blank group was injected with normal saline. After 3 weeks, the model control group and Compound A group began to use 1% OVA for aerosol challenge, and the normal control group used physiological saline once every other day for a total of 7 times. Administration began on the day of atomization. Compound A (0.6 mg/kg) was administered to the administration group 30 minutes before atomization. The model control group and the normal control group were administered the same amount of drinking water once a day, a total of 14 times.
2.2辣椒素引咳实验：2.2 Capsaicin-induced cough experiment:
最后一次给药24h后，各组大鼠置于雾化箱内，雾化吸入10-4mol/L辣椒素溶液60s，记录2min内各大鼠的咳嗽次数。24 hours after the last administration, the rats in each group were placed in the atomization box and inhaled atomized 10-4 mol/L capsaicin solution for 60 seconds, and the number of coughs of each rat within 2 minutes was recorded.
3.实验结果：3.Experimental results:
辣椒素引咳实验：Capsaicin-induced cough experiment:
与正常对照组比较，模型对照组咳嗽次数显著增多(P<0.01)；与模型对照组比较，给药组的咳嗽次数显著减少(P<0.05)，说明模型对照组对辣椒素的刺激更加敏感(见图5)。Compared with the normal control group, the number of coughs in the model control group was significantly increased (P<0.01); compared with the model control group, the number of coughs in the medication group was significantly reduced (P<0.05), indicating that the model control group is more sensitive to the stimulation of capsaicin. (See Figure 5).
本发明人经过广泛而深入地研究，首次意外地发现了一类结构如式(I)所示化合物(倍半萜)可以显著地抑制TRPA1的活性。实验表明，所述的式(I)化合物对TRPA1通道有较好的抑制效果，本发明的式(I)化合物可用于治疗与TRPA1靶点相关的疼痛、炎症、呼吸道疾病(如呼吸障碍)、瘙痒、皮肤病(痤疮、粉刺)、尿路障碍、炎症性肠病等。After extensive and in-depth research, the inventor unexpectedly discovered for the first time that a type of compound (sesquiterpene) with a structure such as formula (I) can significantly inhibit the activity of TRPA1. Experiments show that the compound of formula (I) has a good inhibitory effect on the TRPA1 channel. The compound of formula (I) of the present invention can be used to treat pain, inflammation, respiratory diseases (such as respiratory disorders) related to the TRPA1 target, Itching, skin diseases (acne, pimples), urinary tract disorders, inflammatory bowel disease, etc.
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that The technical solution of the present invention may be modified or equivalently substituted without departing from the essence and scope of the technical solution of the present invention.

Claims (10)

  1. 一种化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐的用途，其特征在于，用于制备药物或制剂，所述药物或制剂用于：(a)抑制TRPA1通道的活性；(b)治疗与TRPA1通道相关的疾病；The use of a compound, or its optical isomer or its racemate, or its solvate, or its pharmaceutically acceptable salt, characterized in that it is used to prepare a drug or preparation, and the drug or preparation is used For: (a) inhibiting the activity of TRPA1 channels; (b) treating diseases related to TRPA1 channels;
    所述化合物的结构如式I所示：The structure of the compound is shown in formula I:
    Figure PCTCN2022138608-appb-100001
    Figure PCTCN2022138608-appb-100001
    R1-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 R1-R17 is selected from at least one of the following group: hydrogen, oxo (=O), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 ring Alkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 cycloalkoxy, or substituted or unsubstituted 5-8 membered heterocycle, the heterocycle containing 1-3 heteroatoms selected from N, O, S.
  2. 如权利要求1所述的用途，其特征在于，所述R1、R10和R15选自CH 3；R2～R9、R11～R14及R16～R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 The use as claimed in claim 1, characterized in that, R1, R10 and R15 are selected from CH3 ; R2~R9, R11~R14 and R16~R17 are selected from at least one of the following groups: hydrogen, oxo ( =O), halogen, -OH, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, Substituted or unsubstituted C 3 -C 8 cycloalkoxy group, or substituted or unsubstituted 5-8 membered heterocyclic ring, the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S.
  3. 如权利要求1所述的用途，其特征在于，所述R2选自-OH，R1、R3-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未 取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 The use according to claim 1, characterized in that, R2 is selected from -OH, R1, R3-R17 are selected from at least one of the following group: hydrogen, oxo (=O), halogen, -OH, substituted Or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8 Cycloalkoxy group, or a substituted or unsubstituted 5-8 membered heterocyclic ring, the heterocyclic ring contains 1-3 heteroatoms selected from N, O, and S.
  4. 如权利要求1所述的用途，其特征在于，所述R3选自COOH；R1-2、R4-R17选自下组中至少一种：氢、氧代(＝O)、卤素、-OH、取代或未取代的C 1-C 8烷基、取代或未取代的C 3-C 8环烷基、取代或未取代的C 1-C 8烷氧基、取代或未取代的C 3-C 8环烷氧基、或取代或未取代的5-8元杂环，所述杂环含有1-3个选自N、O、S的杂原子。 The use according to claim 1, characterized in that, the R3 is selected from COOH; R1-2, R4-R17 are selected from at least one of the following group: hydrogen, oxo (=O), halogen, -OH, Substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 1 -C 8 alkoxy, substituted or unsubstituted C 3 -C 8- cycloalkoxy group, or a substituted or unsubstituted 5-8 membered heterocyclic ring, the heterocyclic ring contains 1-3 heteroatoms selected from N, O, and S.
  5. 如权利要求1所述的用途，其特征在于，所述化合物的结构如式II所示：The use according to claim 1, characterized in that the structure of the compound is shown in formula II:
    Figure PCTCN2022138608-appb-100002
    Figure PCTCN2022138608-appb-100002
  6. 如权利要求1所述的用途，其特征在于，所述疾病包括疼痛、炎症、瘙痒、神经疾病、胃肠道疾病、糖尿病、肥胖、泌尿***疾病、呼吸道疾病、心血管疾病、皮肤疾病中的至少一种。The use according to claim 1, wherein the diseases include pain, inflammation, pruritus, neurological diseases, gastrointestinal diseases, diabetes, obesity, urinary system diseases, respiratory diseases, cardiovascular diseases, and skin diseases. At least one.
  7. 如权利要求6所述的用途，其特征在于，所述疼痛包括慢性疼痛、神经性疼痛、急性疼痛、炎症性疼痛、带状疱疹后疼痛、神经病变、神经痛、糖尿病性神经病变、HIV相关神经病变、神经损伤、类风湿关节炎痛、骨关节炎痛、背痛、腰痛、癌性疼痛、牙痛、头痛、偏头痛、三叉神经痛、腕管综合征、纤维肌痛症、神经炎、坐骨神经痛、骨盘过敏症、骨盘痛、月经痛、内脏痛、术后疼痛中的至少一种；所述炎症包括烧伤或骨关节炎；所述神经疾病包括由抗癌剂诱发的神经障碍；所述胃肠道疾病包括功能性胃肠病、反流性食管炎、溃疡、炎症性肠病、呕吐、胰腺炎中的至少一种；所述功能性 胃肠病包括咽下障害、肠易激综合征、功能性腹痛综合征中的至少一种；所述泌尿***疾病包括膀胱过度活动症、排尿异常、膀胱炎中的至少一种；所述呼吸道疾病包括哮喘、打喷嚏、慢性咳嗽、慢性阻塞性肺疾病、支气管收缩、过敏性鼻炎中的至少一种；所述皮肤疾病包括特应性皮炎、变应性皮炎、瘙痒症、粉刺、痤疮、酒糟鼻中的至少一种。The use of claim 6, wherein the pain includes chronic pain, neuropathic pain, acute pain, inflammatory pain, post-herpetic pain, neuropathy, neuralgia, diabetic neuropathy, HIV-related Neuropathy, nerve damage, rheumatoid arthritis pain, osteoarthritis pain, back pain, lumbago, cancer pain, toothache, headache, migraine, trigeminal neuralgia, carpal tunnel syndrome, fibromyalgia, neuritis, At least one of sciatica, pelvic hypersensitivity, pelvic pain, menstrual pain, visceral pain, and postoperative pain; the inflammation includes burns or osteoarthritis; the neurological disease includes neurological disorders induced by anticancer agents ; The gastrointestinal disease includes at least one of functional gastrointestinal disease, reflux esophagitis, ulcer, inflammatory bowel disease, vomiting, and pancreatitis; the functional gastrointestinal disease includes swallowing disorder, intestinal At least one of irritable syndrome and functional abdominal pain syndrome; the urinary system disease includes at least one of overactive bladder, abnormal urination, and cystitis; the respiratory disease includes asthma, sneezing, and chronic cough , chronic obstructive pulmonary disease, at least one of bronchoconstriction, and allergic rhinitis; the skin disease includes at least one of atopic dermatitis, allergic dermatitis, pruritus, acne, acne, and rosacea.
  8. 如权利要求1所述的用途，其特征在于，所述药物中含有0.001-99wt％，优选为0.1-90wt％，更优选为1-80wt％的式(I)化合物、或其光学异构体或其外消旋体、或其溶剂化物、或其药学上可接受的盐，按组合物的总重量计。The use according to claim 1, characterized in that the medicine contains 0.001-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% of the compound of formula (I), or its optical isomer Or its racemate, or its solvate, or its pharmaceutically acceptable salt, based on the total weight of the composition.
  9. 一种药物组合物，其特征在于，所述药物组合物包括如权利要求1-5任一项所述应用中的化合物和其他能抑制TRPA1通道的活性的药物。A pharmaceutical composition, characterized in that the pharmaceutical composition includes the compound used in any one of claims 1-5 and other drugs that can inhibit the activity of the TRPAl channel.
  10. 如权利要求9所述的药物组合物，其特征在于，所述药物组合物还包括药物上可接受的载体。The pharmaceutical composition of claim 9, further comprising a pharmaceutically acceptable carrier.
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