Medicament for preventing and / or treating nausea and vomiting and use thereof

Abstract

The application discloses a medicine for preventing and / or treating nausea and vomiting and application thereof, and belongs to the technical field of medicines. The compound provided by the application can obviously block the combination of substance P and NK-1 receptors, and the blocking effect is better than that of a positive medicine, aprepitant, as verified by experiments. The compound can obviously reduce the times of dry heaves and vomiting of beagles caused by injection of cisplatin, and can be used as a medicine for treating and / or preventing diseases caused by the combination of substance P and NK1R, such as a medicine for preventing and / or treating nausea and vomiting caused by cisplatin chemotherapy or postoperative nausea and vomiting, and has good development prospect and application value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a drug for the prevention and / or treatment of nausea and vomiting and its application. Background Technology

[0002] Neurokinin receptors include neurokinin 1 receptor (NK1R), neurokinin 2 receptor (NK2R), and neurokinin 3 receptor (NK3R). NK1R is found in neurons, brainstem, vascular endothelium, gastrointestinal tract, and urogenital tract cells, with the highest concentration in the brain's vomiting center. Substance P, a regulatory polypeptide of the kinin family, is produced by nerve cells and endocrine cells in the gastrointestinal tract and has the strongest binding affinity to NK1R. Substance P binds to NK1R and acts on calcium ion channels on the cell membrane via inositol trisphosphate, causing membrane depolarization and changes in protein kinase activity, participating in pain and stress signals, and triggering physiological responses such as vomiting, anxiety, and pain. NK-1 receptor antagonists selectively bind to NK-1 receptors in the brain, blocking the effects of substance P, and are used to prevent acute and delayed nausea and vomiting induced by chemotherapy drugs.

[0003] Chemotherapy-induced nausea and vomiting are among the most common toxic reactions during treatment. Many cancer patients experience frequent and prolonged vomiting while undergoing treatment, severely impacting their food and water intake. This, coupled with varying degrees of dehydration and metabolic disturbances, leads to weight loss, further fatigue and weakness. As research into the mechanisms of treatment-induced nausea and vomiting has deepened, various types of antiemetic drugs have been developed. Early drugs primarily targeted dopamine D2 receptors and the vomiting center; later, highly selective targets were developed for 5-HT3 receptors; and in the last two decades, substance P and NK1R have been used as new targets for antiemetic drug development. Currently, commonly used NK1-based antiemetic drugs include aprepitant, lorapeptant, netuppitant, and fosaprepitant; further development of anti-nausea and vomiting drugs with enhanced activity is still needed. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a drug and its application that has excellent blocking effect on the binding of substance P and NK-1 receptor, thereby having excellent preventive and / or therapeutic effects on nausea and vomiting.

[0005] To achieve the above objectives, in a first aspect, the present invention provides the use of a compound of formula I or a salt thereof in the preparation of a medicament for the prevention and / or treatment of nausea and vomiting. Formula I; in, n is selected from any one of 0, 1, and 2, and R a R bEach is independently selected from any one of H and C1-C6 alkyl groups; R1, R2, R3, R4, and R5 are each independently selected from any one of H, F, Cl, Br, I, and C1-C6 alkyl groups; R6, R7, R8, R9, R 10 Each is independently selected from any one of H, F, Cl, Br, and I.

[0006] The compound of Formula I provided by this invention can significantly block the binding of substance P to the NK-1 receptor, and experimental verification shows that its blocking effect is superior to that of the positive control drug aprepitant. It can significantly reduce the frequency of dry heaving and vomiting in beagle dogs caused by cisplatin injection. It can be used as a drug for the treatment and / or prevention of diseases caused by substance P binding to NK1R, such as the preparation of drugs for the prevention and / or treatment of nausea and vomiting caused by cisplatin chemotherapy or postoperative nausea and vomiting. It has good development prospects and application value.

[0007] In a preferred embodiment of the application described in this invention, n is selected from either 1 or 2.

[0008] As a preferred embodiment of the application described in this invention, R a R b Each is independently selected from any one of H and methyl groups.

[0009] In a preferred embodiment of the application described in this invention, any two of R1, R2, R3, R4, and R5 are each independently selected from any one of F, Cl, Br, I, and C1-C6 alkyl groups, and the remaining three are hydrogen.

[0010] Preferably, any two of R1, R2, R3, R4, and R5 are independently selected from either Cl or methyl, and the remaining three are hydrogen.

[0011] As a preferred embodiment of the application described in this invention, R6, R7, R8, R9, R 10 One of them is selected from F, Cl, Br, and I, and the other four are hydrogen.

[0012] Preferably, R6, R7, R8, R9, R 10 One of them is selected from either F or Cl, and the other four are hydrogen.

[0013] The present invention has found that the choice of different functional groups affects the prevention and / or treatment of nausea and vomiting. When R is further selected as a functional group of the above type, the resulting compound has a better therapeutic effect on nausea and vomiting.

[0014] As a preferred embodiment of the application described in this invention, the compound represented by Formula I includes compounds represented by Formulas Ia-Id: Formula Ia, Formula Ib, Formula Ic, FormulaId.

[0015] It should be noted that the compounds represented by formulas Ia-Id are all known compounds disclosed in the prior art. Among them, the CAS number of the compound represented by formula Ia is 899208-52-7 (K788-8587), the CAS number of the compound represented by formula Ib is 901726-67-8 (C530-1072), the CAS number of the compound represented by formula Ic is 902591-63-3 (C530-1075), and the CAS number of the compound represented by formula Id is 902512-88-3 (C530-1864). The inventors of this application have conducted extensive experiments and screenings and found that the compounds represented by formulas Ia-Id have excellent ability to relieve nausea and vomiting after chemotherapy or surgery. Therefore, they can be widely used in the preparation of drugs for the prevention and / or treatment of nausea and vomiting.

[0016] In a preferred embodiment of the application described in this invention, the nausea and vomiting are chemotherapy-induced nausea and vomiting.

[0017] In a preferred embodiment of the application described in this invention, the chemotherapy is cisplatin-based chemotherapy.

[0018] In a preferred embodiment of the application described in this invention, the nausea and vomiting are postoperative nausea and vomiting.

[0019] In a preferred embodiment of the application described in this invention, the salt includes any one of inorganic acid salts and organic acid salts.

[0020] For example, the inorganic acid includes at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid.

[0021] Exemplarily, the organic acids include formic acid, acetic acid, acetoacetic acid, pyruvate, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, bamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethanesulfonic acid, and itacone. At least one of the following: acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheponic acid, glycerophosphate, aspartic acid, and sulfosalicylic acid.

[0022] A second aspect of the present invention provides a pharmaceutical composition for preventing and / or treating nausea and vomiting, characterized in that the pharmaceutical composition comprises a compound of formula I or a salt thereof. Formula I; in, n is selected from any one of 0, 1, and 2, and R a R b Each is independently selected from any one of H and C1-C6 alkyl groups; R1, R2, R3, R4, and R5 are each independently selected from any one of H, F, Cl, Br, I, and C1-C6 alkyl groups; R6, R7, R8, R9, R 10 Each is independently selected from any one of H, F, Cl, Br, and I.

[0023] In a preferred embodiment of the pharmaceutical composition of the present invention, n is selected from any one of 1 and 2.

[0024] As a preferred embodiment of the pharmaceutical composition of the present invention, R a R b Each is independently selected from any one of H and methyl groups.

[0025] In a preferred embodiment of the pharmaceutical composition of the present invention, any two of R1, R2, R3, R4, and R5 are each independently selected from any one of F, Cl, Br, I, and C1-C6 alkyl groups, and the remaining three are hydrogen.

[0026] Preferably, any two of R1, R2, R3, R4, and R5 are independently selected from either Cl or methyl, and the remaining three are hydrogen.

[0027] As a preferred embodiment of the pharmaceutical composition of the present invention, R6, R7, R8, R9, R 10 One of them is selected from F, Cl, Br, and I, and the other four are hydrogen.

[0028] Preferably, R6, R7, R8, R9, R 10 One of them is selected from either F or Cl, and the other four are hydrogen.

[0029] As a preferred embodiment of the pharmaceutical composition of the present invention, the compound represented by Formula I includes the compounds represented by Formulas Ia-Id: Formula Ia, Formula Ib, Formula Ic, FormulaId.

[0030] In a preferred embodiment of the pharmaceutical composition of the present invention, the nausea and vomiting are chemotherapy-induced nausea and vomiting.

[0031] In a preferred embodiment of the pharmaceutical composition of the present invention, the nausea and vomiting are postoperative nausea and vomiting.

[0032] In a preferred embodiment of the pharmaceutical composition of the present invention, the salt includes any one of inorganic acid salts and organic acid salts.

[0033] For example, the inorganic acid includes at least one of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and nitric acid.

[0034] Exemplarily, the organic acids include formic acid, acetic acid, acetoacetic acid, pyruvate, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthylcarboxylic acid, nicotinic acid, bamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, terpentinic acid, 2-hydroxyethanesulfonic acid, and itacone. At least one of the following: acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheponic acid, glycerophosphate, aspartic acid, and sulfosalicylic acid.

[0035] As a preferred embodiment of the pharmaceutical composition of the present invention, the pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

[0036] Preferably, the pharmaceutically acceptable carrier or excipient includes at least one of the following: diluent, filler, binder, disintegrant, lubricant, flow aid, granulator, coating agent, wetting agent, solvent, co-solvent, suspending agent, emulsifier, sweetener, flavoring agent, taste masking agent, colorant, anti-caking agent, humectant, chelating agent, plasticizer, thickener, antioxidant, preservative, stabilizer, surfactant, and buffer. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used for more than one function and for alternative functions, depending on the amount of the excipient present in the formulation and what other components are present in the formulation.

[0037] As a preferred embodiment of the pharmaceutical composition of the present invention, the dosage form of the pharmaceutical composition includes any one of tablets, capsules, granules, powders, suspensions, emulsions, powders, oral liquids, gels, syrups, pills, tinctures, medicated wines, decoctions, lozenges, mixtures, suppositories, injections, inhalers, and sprays.

[0038] Compared with the prior art, the beneficial effects of the present invention are as follows: The compound of Formula I provided by this invention can significantly block the binding of substance P to the NK-1 receptor, and experimental verification shows that its blocking effect is superior to that of the positive control drug aprepitant. It can significantly reduce the frequency of dry heaving and vomiting in beagle dogs caused by cisplatin injection. It can be used as a drug for the treatment and / or prevention of diseases caused by substance P binding to NK1R, such as the preparation of drugs for the prevention and / or treatment of nausea and vomiting caused by cisplatin chemotherapy or postoperative nausea and vomiting. It has good development prospects and application value. Attached Figure Description

[0039] Figure 1 This is a bar chart showing the results of investigating the inhibition of substance P binding to the NK-1 receptor by the compound in Example 1; Figure 2 This is a fluorescence image from Example 1 investigating the inhibition of substance P binding to the NK-1 receptor by the compound. Figure 3 The bar chart shows the results of investigating the inhibitory effect of the compound on vomiting in dogs in Example 2. Detailed Implementation

[0040] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0041] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in the field.

[0042] Example 1 This invention provides an embodiment for establishing a vomiting cell model and evaluating drug efficacy, specifically: 1. Experimental objective: To establish a vomiting cell model targeting the NK1R receptor by stimulating gastric mucosal epithelial cells with histamine and to evaluate the efficacy of the drug.

[0043] 2. Experimental materials: GES-1 gastric mucosal epithelial cells (derived from Lianmai Biotechnology), and compounds as shown in Table 1; Table 1 3. Test methods: 1) Plate the plates at a density of 10,000 / well, using 96-well plates, and incubate for 12 hours in DMEM medium (Sigma) containing 10% fetal bovine serum (Gibco); 2) Add 50 μM stimulant (histamine) and pretreat at 37℃ for 30 min; 3) Group settings: blank control group (0 μM histamine + 0 μM probe for 1 h); probe group (0 μM histamine + 10 μM probe for 1 h), histamine + probe group (50 μM histamine + 10 μM probe for 1 h), experimental compound treatment group (20 μM experimental compound + 10 μM probe for 1 h), positive drug aprepitant group (20 μM aprepitant + 10 μM probe for 1 h), each with three replicates; the probe is the Substance P fluorescent probe (Substance P fluorescent probe is FITC-Substance P, custom-produced by Jier Biochemical (Shanghai) Co., Ltd., with the sequence: FITC-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met). 4) After incubating the drug for 3 hours, remove the culture medium and add 10 μM of Substance P fluorescent probe (the Substance P fluorescent probe is FITC-Substance P, custom-produced by Jier Biochemical (Shanghai) Co., Ltd., with the sequence: FITC-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met), and incubate at 37℃ for 1 hour (in the dark). 5) Wash 3 times with sterile PBS, then fix with paraformaldehyde for 30 min; 6) Wash once with sterile PBS, then stain with Hochest for 5 minutes; 7) Wash once with sterile PBS and perform high content detection.

[0044] 4. Experimental Results: The obtained relative fluorescence intensity bar chart is as follows Figure 1 As shown (** indicates comparison between the experimental compound treatment group and the histamine + probe group, P < 0.01; *** indicates comparison between the experimental compound treatment group and the histamine + probe group, P < 0.001), the fluorescence images are as follows. Figure 2As shown, from Figure 1-2 As can be seen, the compound of the present invention can significantly block the binding of substance P to the NK-1 receptor, and the blocking effect is better than that of the positive drug aprepitant.

[0045] Example 2 This invention provides an embodiment for establishing an animal model of vomiting and evaluating drug efficacy, specifically: 1. Experimental objective: To establish an animal model of vomiting in beagle dogs by induced vomiting through cisplatin injection and to evaluate the efficacy of the drug.

[0046] 2. Experimental materials: 12 healthy beagle dogs aged 12-24 months and weighing 8-12kg (purchased from Hubei Yizhicheng).

[0047] 3. Test methods: 1) Administration: Twelve beagle dogs were randomly divided into three groups: cisplatin + vehicle (solvent) group (n=4), cisplatin + K788-8587 group (n=4, 4 mg / kg), and cisplatin + maropistan group (n=4, 2 mg / kg). Cisplatin was administered three times: 2 hours before, 6 hours after, and 12 hours after cisplatin injection (3 mg / kg). The cisplatin + vehicle group received vehicle (1 wt% CMC-Na aqueous solution) orally each time, the cisplatin + K788-8587 group received K788-8587 orally each time, and the cisplatin + maropistan group received maropistan citrate orally each time.

[0048] 2) Inspection: Use a camera to observe each dog and count the number of times it vomits or gags.

[0049] 4. Experimental Results: like Figure 2 As shown, K788-8587 can significantly reduce the frequency of gagging and vomiting in dogs (* indicates a comparison between the cisplatin + maropistan group and the cisplatin + K788-8587 group and the cisplatin + vehicle group, P<0.05).

[0050] Finally, it should be noted that the above embodiments are used to illustrate the technical solutions of the present invention and not to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. The use of the compound shown in Formula I or a salt thereof in the preparation of medicaments for the prevention and / or treatment of nausea and vomiting. Equation I; in, n is selected from any one of 0, 1, and 2, and R a R b Each is independently selected from any one of H and C1-C6 alkyl groups; R1, R2, R3, R4, and R5 are each independently selected from any one of H, F, Cl, Br, I, and C1-C6 alkyl groups; R6, R7, R8, R9, R 10 Each is independently selected from any one of H, F, Cl, Br, and I.

2. The application according to claim 1, characterized in that, Satisfy at least one of the following: (1) n is selected from either 1 or 2; (2) R a R b Each is independently selected from any one of H and methyl groups; (3) Any two of R1, R2, R3, R4, and R5 are each independently selected from F, Cl, Br, I, and C1-C6 alkyl groups, and the other three are hydrogen; (4) R6, R7, R8, R9, R 10 One of them is selected from F, Cl, Br, and I, and the other four are hydrogen.

3. The application according to claim 2, characterized in that, Satisfy at least one of the following: (1) Any two of R1, R2, R3, R4, and R5 are independently selected from either Cl or methyl, and the other three are hydrogen; (2) R6, R7, R8, R9, R 10 One of them is selected from either F or Cl, and the other four are hydrogen.

4. The application according to claim 3, characterized in that, The compounds represented by Formula I include those represented by Formulas Ia to Id: Formula Ia, Formula Ib, Formula Ic, FormulaId.

5. The application according to claim 1, characterized in that, The nausea and vomiting mentioned are caused by chemotherapy.

6. The application according to claim 5, characterized in that, The chemotherapy used was cisplatin-based chemotherapy.

7. The application according to claim 1, characterized in that, The nausea and vomiting mentioned refers to nausea and vomiting after surgery.

8. The application according to claim 1, characterized in that, The salt includes any one of inorganic acid salts and organic acid salts.

9. A pharmaceutical composition for preventing and / or treating nausea and vomiting, characterized in that, The pharmaceutical composition comprises a compound of formula I or a salt thereof. Equation I; in, n is selected from any one of 0, 1, and 2, and R a R b Each is independently selected from any one of H and C1-C6 alkyl groups; R1, R2, R3, R4, and R5 are each independently selected from any one of H, F, Cl, Br, I, and C1-C6 alkyl groups; R6, R7, R8, R9, R 10 Each is independently selected from any one of H, F, Cl, Br, and I.

10. The pharmaceutical composition according to claim 9, characterized in that, Satisfy at least one of the following: (1) The nausea and vomiting mentioned are caused by chemotherapy; (2) The nausea and vomiting mentioned refers to postoperative nausea and vomiting; (3) The salt includes any one of inorganic acid salts and organic acid salts; (4) The pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

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