Use of peptide amide compounds for the preparation of a medicament for the treatment of pruritus

Abstract

Use of a compound of formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or a composition thereof, in the manufacture of a medicament for the treatment of pruritus; also relates to a method for treating pruritus, which comprises administering an effective dose of a compound of formula (I) or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or a composition thereof.

Description

Technical Field

[0001] This invention relates to the use of compounds of formula (I) or their stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or cocrystals and combinations thereof in the preparation of medicaments for treating pruritus. Background Technology

[0002] Pruritus, or itching, is a sensation that triggers the urge to scratch. Itching lasting longer than 6 weeks is generally defined as chronic pruritus. The presence of itching not only interferes with a patient's mood, but repeated scratching of the itchy area can also lead to local skin damage and infection, severely hindering a patient's normal life. Based on its origin, pathogenesis, and skin lesions, pruritus can be classified in various ways. Examples include dermatophyte pruritus, systemic pruritus, neurogenic pruritus, and psychiatric pruritus (Hao Fei, Guidelines for the Management of Chronic Pruritus (2018 Edition)).

[0003] Epidemiological data on pruritus is currently limited, and relevant data are lacking in my country. Foreign reports indicate that the incidence of chronic pruritus in adults exceeds 10%, and is as high as 60% in the elderly. The incidence of chronic pruritus varies considerably depending on the disease state. For example, almost 100% of patients with atopic dermatitis and urticaria experience pruritus, approximately 80% in psoriasis patients, 80%-100% in primary biliary cholangitis patients, and approximately 40%-70% in patients with chronic kidney disease (Hao Fei, Guidelines for the Management of Chronic Pruritus (2018 Edition)).

[0004] Although various medications with different mechanisms of action are available for treating chronic pruritus, they often have numerous adverse reactions or only meet the treatment needs of certain types of chronic pruritus. Therefore, there is still a significant unmet clinical need for the treatment of chronic pruritus.

[0005] Treatment of chronic pruritus usually follows this order: removing the cause or treating the underlying disease; using topical moisturizers, oral antihistamines and topical corticosteroids; and systemically applying hormones or non-hormonal anti-inflammatory agents, central nervous system depressants, drugs that antagonize pruritus mediators, and biological agents to target the mechanism of pruritus (Hao Fei, Guidelines for the Management of Chronic Pruritus (2018 Edition)).

[0006] Antihistamines are among the most commonly used systemic antipruritic drugs, but they are typically used for diseases associated with increased mast cell degranulation, such as urticaria, and have no definitive efficacy for some chronic pruritus. European guidelines do not recommend the widespread use of antihistamines for the treatment of nonhistamine-mediated pruritus, such as Alzheimer's disease and psoriasis. For pruritus caused by some systemic diseases, including chronic renal failure, cholestatic liver disease, hematologic disorders, and thyroid diseases, there is also no evidence of the effectiveness of antihistamines (Elke Weisshar, European S2k Guideline on Chronic Pruritus). Systemic corticosteroids are rapidly effective in treating pruritus caused by inflammatory skin diseases, but due to numerous adverse reactions, they can only be used for short periods. Antiepileptic drugs gabapentin and pregabalin are effective for neuropathic pruritus and pruritus in chronic kidney disease. However, a large national cohort analysis based on the US Nephrology Data System showed that their use can lead to a significant increase in the risk of altered mental status, falls, and fractures (Ishida JH, et al. J Am Soc Nephrol. 2018 Jul; 29(7): 1970-1978). Antidepressants can exert their anti-pruritus effects by acting on serotonin and histamine, but adverse reactions to antidepressants are relatively common, such as mental confusion, drowsiness, irritability, dry mouth, worsening of pruritus, atrioventricular block, and even death. Elderly patients should be especially careful. In addition, serotonin reuptake inhibitors (SSRIs) usually have a slow onset of action, taking about 2-3 weeks to take effect (Elke WEISSHAAR, European S2k Guideline on Chronic Pruritus). Immunosuppressants such as cyclosporine, azathioprine, and methotrexate can be used to treat itching caused by inflammatory skin diseases and chronic prurigo. The main adverse reaction is immunosuppression, including leukopenia and liver and kidney damage. Biologics are also rapidly developing; dupilumab is recommended for patients with atopic dermatitis, and omalizumab is recommended for patients with chronic spontaneous urticaria (Elke Weisshaar, European S2k Guideline on Chronic Pruritus).

[0007] In addition, studies have confirmed that endogenous or exogenous endorphins are involved in the occurrence of pruritus, and the application of opioid receptor antagonists or κ receptor agonists can effectively inhibit pruritus. Opioid receptor antagonists include naloxone, naltrexone, etc., but adverse reactions are relatively common, including increased or decreased blood pressure, tachycardia, liver damage, and skin rash. Early κ receptor agonists were mostly non-selective and were mainly used for morphine-induced acute pruritus (Phan, NQ, et al. Acta Derm Venereol, 2012.92(5): p.555-60.). The selective κ receptor agonist nalfuraphenine has been approved in Japan and South Korea for the treatment of pruritus in hemodialysis patients and patients with chronic liver disease. However, nalfuraphenine can enter the central nervous system and has central nervous system-related side effects such as insomnia, drowsiness, dizziness, and constipation. Therefore, developing novel peripherally selective κ receptor agonists, which act only on the periphery and cross the blood-brain barrier less frequently, can maintain their high agonistic activity on κ receptors while avoiding the inherent side effects of traditional centrally selective κ receptor agonists. Summary of the Invention

[0008] This invention provides the use of a compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, cocrystals, or combinations thereof in the preparation of a medicament for treating pruritus, characterized in that an effective dose of the compound of formula (I) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, cocrystals, or combinations thereof administered to mammals is given.

[0009]

[0010] in,

[0011] R1 is selected from

[0012] m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, or 4; m1 and m2 cannot both be 0; m3 and m4 cannot both be 0.

[0013] n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;

[0014] Z is selected from CR z1 R z2 or NR z3 ;

[0015] R z1 R z2 Each group is independently selected from H, F, Cl, Br, I, OH, CF3, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6alkynyl group, -C(=O)-C 1-6 Alkyl group, -(CH2)qC(=O)OC 1-6 Alkyl group, -(CH2)q-NR 1e R 1f , -(CH2)q-COOH, -(CH2)q-CONH2, C 3-8 The alkyl, alkoxy, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, =O, carboxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, and when the heteroatoms are selected from S, they are optionally further S, S=O or S(=O)2;

[0016] R 1e R 1f Each is independently selected from H and C. 1-6 Alkyl, C(=O)OC 1-6 Alkyl group, -C(=O)0-(CH2)qC 3-8 The alkyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 members selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0017] Or, R z1 and R z2 The carbon atom attached thereto forms a 3- to 10-membered nitrogen-containing heterocycle, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, cyano, nitro, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Substituted with alkynyl, C-carbocyclic or 3 to 8-membered heterocyclic groups;

[0018] R 1a R 1b Each is independently selected from F, CF3, NH2, and C. 1-6Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl or 3 to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl or heterocyclic group is optionally further composed of 0 to 5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0019] R z2 Independently selected from H, -C (=O) -C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl, -C(=O)-C 3-8 Carbocyclic group, -C(=O)OC 3-8 Carbocyclic groups, -C(=O)O- (3 to 8 membered heterocyclic groups), -S(=O)pC 1-6 Alkyl group, -S(=O)pC 3-8 Carbocyclic groups, -S(=O)p- (3 to 8 membered heterocyclic groups), -C(=O)NR 1g R 1h -S(=O)p-NR 1i R 1j Or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0020] R 1g R 1h R 1i′ R 1j Each is independently selected from H or C 1-6 alkyl;

[0021] Or, R 1g R 1h The nitrogen atom attached thereto forms a 3- to 10-membered heterocycle, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6Alkyne group or -S(=O)pC 1-6 The heterocyclic group is substituted by an alkyl substituent and contains 1 to 3 heteroatoms selected from N, O or S;

[0022] q is selected from 0, 1, 2, 3, or 4;

[0023] p is selected from 0, 1, or 2;

[0024] a is selected from 0, 1, 2, or 3;

[0025] R 4 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or -(CH2)qC 3-8 The carbocyclic group, wherein the alkyl, alkenyl, alkynyl or carbocyclic group is optionally further composed of 0-5 elements selected from F, Cl, Br, I, OH, CN, CF3, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0026] R 2 R 3 R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl group, -C(=O)OC 1-4 Alkyl group, -C(=O)O-(CH2)qC 3-8 Carbocyclic groups, -C(=O)O-(CH2)q-3 to 8-membered heterocyclic groups or The alkyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0027] b is selected from 0, 1, 2, 3, 4, or 5;

[0028] c is selected from 0, 1, 2, 3, 4 or 5;

[0029] R 5 R 6Each group is independently selected from F, Cl, Br, I, OH, CN, CF3, cyano, nitro, C1-4 alkyl, -OR 5a -C(O)OR 5b -SR 5c -S(O)R 5d -S(O)2R 5e or -NR 5f R 5g ;

[0030] R 5a R 5b R 5c R 5d R 5e R 5f and R 5g Each is independently selected from H or C1-4 alkyl groups;

[0031] Or, R 5f and R 5g The nitrogen atom attached thereto forms a 5- to 6-membered heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms, optionally selected from N, O or S.

[0032] This invention relates to a method for treating pruritus, the method comprising administering to mammals an effective dose of a compound of structural formula (I) or a stereoisomer thereof, a hydrate, a metabolite, a solvate, a pharmaceutically acceptable salt, a cocrystal, or a combination thereof.

[0033]

[0034] in,

[0035] R1 is selected from

[0036] m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, or 4; m1 and m2 cannot both be 0; m3 and m4 cannot both be 0.

[0037] n1 and n2 are each independently selected from 0, 1, 2, 3 or 4;

[0038] Z is selected from CR z1 R z2 or NR z3 ;

[0039] R z1 R z2 Each group is independently selected from H, F, Cl, Br, I, OH, CF3, nitro, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -C(=O)-C 1-6Alkyl group, -(CH2)qC(=O)OC 1-6 Alkyl group, -(CH2)q-NR 1e R 1f , -(CH2)q-COOH, -(CH2)q-CONH2, C 3-8 The alkyl, alkoxy, alkenyl, alkynyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, =O, carboxyl, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S, and when the heteroatoms are selected from S, they are optionally further S, S=O or S(=O)2;

[0040] R 1e R 1f Each is independently selected from H and C. 1-6 Alkyl, C(=O)OC 1-6 Alkyl group, -C(=O)0-(CH2)qC 3-8 The alkyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 members selected from F, Cl, Br, I, OH, CF3, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0041] Or, R z1 and R z2 The carbon atom attached thereto forms a 3- to 10-membered nitrogen-containing heterocycle, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, cyano, nitro, =O, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Substituted with alkynyl, C-carbocyclic or 3 to 8-membered heterocyclic groups;

[0042] R 1a R 1b Each is independently selected from F, CF3, NH2, and C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 Alkynyl or 3 to 8-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl or heterocyclic group is optionally further composed of 0 to 5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0043] R z3 Independently selected from H, -C (=O) -C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl, -C(=O)-C 3-8 Carbocyclic group, -C(=O)OC 3-8 Carbocyclic groups, -C(=O)O- (3 to 8 membered heterocyclic groups), -S(=O)pC 1-6 Alkyl group, -S(=O)pC 3-8 Carbocyclic groups, -S(=O)p- (3 to 8 membered heterocyclic groups), -C(=O)NR 1g R 1h -S(=O)p-NR 1i R 1j Or a 3- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic, or heterocyclic group is optionally further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0044] R 1g R 1h R 1i′ R 1j Each is independently selected from H or C 1-6 alkyl;

[0045] Or, R 1g R 1h The nitrogen atom attached thereto forms a 3- to 10-membered heterocycle, wherein the ring is optionally further selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 Alkyne group or -S(=O)pC1-6 The heterocyclic group is substituted by an alkyl substituent and contains 1 to 3 heteroatoms selected from N, O or S;

[0046] q is selected from 0, 1, 2, 3, or 4;

[0047] p is selected from 0, 1, or 2;

[0048] a is selected from 0, 1, 2, or 3;

[0049] R 4 Independently selected from H and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or -(CH2)qC 3-8 The carbocyclic group, wherein the alkyl, alkenyl, alkynyl or carbocyclic group is optionally further composed of 0-5 elements selected from F, Cl, Br, I, OH, CN, CF3, NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;

[0050] R 2 R 3 R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl group, -C(=O)OC 1-4 Alkyl, -C(=O)O-(CH2)q-C3-8 carbocyclic, -C(=O)O-(CH2)q-3 to 8-membered heterocyclic or The alkyl, carbocyclic, or heterocyclic group may optionally be further composed of 0-5 groups selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 The heterocyclic group is replaced by a carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0051] b is selected from 0, 1, 2, 3, 4, or 5;

[0052] c is selected from 0, 1, 2, 3, 4 or 5;

[0053] R 5 R 6Each group is independently selected from F, Cl, Br, I, OH, CN, CF3, cyano, nitro, C1-4 alkyl, -OR 5a -C(O)OR 5b -SR 5c -S(O)R 5d -S(O)2R 5e or -NR 5f R 5g ;

[0054] R 5a R 5b R 5c R 5d R 5e R 5f and R 5g Each is independently selected from H or C1-4 alkyl groups;

[0055] Or, R 5f and R 5g The nitrogen atom attached thereto forms a 5- to 6-membered heterocycle, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O, or S. This invention relates to some embodiments of the use in medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the compound of formula (I) is selected from formula (II):

[0056]

[0057] in,

[0058] R1 is selected from

[0059] m1, m2, m3, and m4 are each independently selected from 0, 1, or 2; m1 and m2 cannot both be 0; m3 and m4 cannot both be 0.

[0060] n1 and n2 are each independently selected from 0 or 2;

[0061] Z is selected from CR z1 R z2 or NR z3 ;

[0062] R 1a R 1b Independently selected from F, NH2;

[0063] R z1 R z2 Each is independently selected from H, carboxyl group, amino, -CH2NH2 or

[0064] Or R z1 R z2The carbon atom that can be attached to it can form a lactam.

[0065] R z2 Independently selected from H, -C (=O) -C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl, -C(=O)-C 3-6 Carbocyclic group, -C(=O)OC 3-6 Carbocyclic group, -S(=O)pC 1-4 Alkyl group, -S(=O)pC 3-6 Carbocyclic group, -C(=O)NR 1g R 1h -S(=O)p-NR 1i R 1j Or a 3- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic or heterocyclic group is optionally further substituted by 0 to 5 substituents selected from F, Cl, Br, I, OH, CF3, nitro, cyano, amino, methyl, ethyl, methoxy, ethoxy, cyclopropyl or phenyl, wherein the heterocyclic group contains 1 to 3 heteroatoms optionally selected from N, O or S;

[0066] R 1g R 1h R 1i′ R 1j Each is independently selected from H or C 1-4 alkyl;

[0067] Or, R 1g R 1h The nitrogen atom attached thereto forms a 4- to 6-membered heterocycle, wherein the ring is optionally further selected from F, CF3, methyl, methoxy, or -S(=O)pC. 1-4 The heterocyclic group is substituted by an alkyl substituent and contains 1 to 3 heteroatoms selected from N, O or S;

[0068] p is selected from 2;

[0069] R 2 R 3 R 7 R 8 Each is independently selected from H, methyl, or C(=O)O-tert-butyl.

[0070] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the compound of formula (II) is selected from compounds of structural formula (A):

[0071] This invention relates to some embodiments of the use in medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein a compound of structural formula (A) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, eutectics, or combinations thereof are administered to mammals in an effective dose.

[0072] This invention relates to some embodiments of the use in medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein pharmaceutically acceptable salts are selected from propionate, methanesulfonate, acetate, citrate, D-tartrate, benzenesulfonate, phosphate, aspartate, L-tartrate, maleate, fumarate, benzoate, lactate, hydrochloride, formate, hydrobromide, sulfate, nitrate, phosphate, trifluoroacetate, succinate, mandelate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, citrate, glutamate, cinnamate, p-toluenesulfonate, benzenesulfonate, ethanesulfonate, or trifluoromethanesulfonate.

[0073] This invention relates to some embodiments of the use of medicaments for preventing or treating pruritus and methods for treating pruritus, wherein the pruritus is selected from pruritus caused by disease, pruritus caused by drugs, or pruritus related to kidney disease.

[0074] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the pruritus is selected from nephropathy-related pruritus in hemodialysis patients.

[0075] This invention relates to some embodiments of the use of medicaments for preventing or treating pruritus and methods for treating pruritus, wherein the pruritus is selected from hemodialysis skin pruritus.

[0076] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein pruritus caused by disease includes pruritus caused by inflammatory or non-inflammatory skin diseases, peripheral or systemic diseases, etc.

[0077] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, including but not limited to atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, prurigo, and senile dermatitis.

[0078] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, including but not limited to liver disease, kidney disease, autoimmune disease, peripheral neuropathy, etc.

[0079] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, including but not limited to pruritus caused by taking obeticholic acid, antibiotics, angiotensin-converting enzyme inhibitors, xanthine oxidase inhibitors, or morphine.

[0080] This invention relates to some embodiments of the use of medicaments for preventing or treating pruritus and methods for treating pruritus, including liver diseases such as autoimmune liver diseases (e.g., primary biliary cholangitis, primary sclerosing cholangitis, or autoimmune hepatitis), viral hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E), tumors (e.g., hepatocellular carcinoma, cholangiocarcinoma), cirrhosis, alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced hepatitis, cholestasis (e.g., benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy) or jaundice; and kidney diseases including but not limited to chronic kidney disease, uremia, or diabetic nephropathy.

[0081] Autoimmune diseases include, but are not limited to, scleroderma or Sjögren's syndrome;

[0082] Peripheral neuropathy includes, but is not limited to, radial side arm itching, paresthesia, back pain, or small fiber peripheral neuropathy.

[0083] This invention relates to some embodiments of the use of a medicament for the prevention or treatment of pruritus and methods for treating pruritus, wherein an effective dose of a compound of structural formula (A) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, eutectics or combinations thereof is administered to mammals, wherein the amount of said compound, when calculated as a compound of structural formula (A), is 1-1000 μg / day.

[0084] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein, when calculated in terms of the amount of a compound of structural formula (A), the amount of said compound is 1-1000 μg / day, 1-900 μg / day, 1-800 μg / day, 1-700 μg / day, 1-600 μg / day, 1-500 μg / day, 1-400 μg / day, 1-300 μg / day, 1-200 μg / day, 1-100 μg / day, 10-1000 μg / day, 10-900 μg / day, 10-800 μg / day, 10-700 μg / day, 10-600 μg / day, 10-500 μg / day, 10-400 μg / day, etc. μg / day, 10-300μg / day, 10-200μg / day, 10-100μg / day, 20-500μg / day, 20-400μg / day, 20-300μg / day, 20-250μg / day, 20-200μg / day, 20-150μg / day, 30-100μg / day, 30-150μg / day, 30-250μg / day, 30-300μg / day, 30-400μg / day, 40-400μg / day, 50-100μg / day, 50-200μg / day, 50-300μg / day, 50-400μg / day, 50-500μg / day, 50-600μg / day.

[0085] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the amount of said compound, when calculated as a compound of structural formula (A), is 0.05 μg / kg to 0.80 μg / kg, administered by injection.

[0086] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the amount of said compound, when calculated in terms of the compound of structural formula (A), is 0.05 μg / kg, 0.15 μg / kg, 0.30 μg / kg, 0.60 μg / kg, or 0.80 μg / kg, administered by injection.

[0087] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the amount of said compound, when calculated as a compound of structural formula (A), is 2 μg-240 μg / day, administered by injection.

[0088] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods for treating pruritus, wherein the amount of said compound, when calculated in terms of the compound of structural formula (A), is 2 μg-5 μg / day, 6 μg-15 μg / day, 12 μg-30 μg / day, 24 μg-60 μg / day, 32-80 μg / day, 4 μg-10 μg / day, 12 μg-30 μg / day, 24 μg-60 μg / day, 48 μg-120 μg / day, 64-160 μg / day, 6 μg-15 μg / day, 18 μg-45 μg / day, 36 μg-90 μg / day, 72 μg-180 μg / day, 96-240 μg / day, administered by injection.

[0089] In some embodiments of the present invention, the use of the compound of structural formula (A) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, eutectics or combinations thereof is selected from once daily, twice daily, three times daily, once weekly, twice weekly, three times weekly or every other day.

[0090] This invention relates to some embodiments of the use of medicaments for the prevention or treatment of pruritus and methods of treating pruritus, wherein the route of administration of the compound of structural formula (A) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, cocrystals or combinations thereof is selected from oral, injection, infusion, transdermal absorption, sublingual absorption, extragastric and intraperitoneal, rectal, buccal, nasal drops, inhalation, local delivery, subcutaneous, intrafacial, intra-articular, intraperitoneal or intrathecal delivery, preferably oral, injection or nasal spray.

[0091] In some embodiments of the present invention, the use of the compound of structural formula (A) or its stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts, cocrystals or combinations thereof is selected from oral, intravenous, intravenous infusion, arterial, intramuscular, subcutaneous, intra-articular, intraperitoneal, intrathecal or nasal drops, preferably, the route of administration is oral, injection or nasal spray.

[0092] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0093] "Alkyl" refers to a straight-chain and branched monovalent saturated hydrocarbon group, the main chain comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and most preferably 1 to 2 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The alkyl group may optionally be further divided by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR, etc. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by R, where R is a substituent. 19 and R 19a Each group is independently selected from H, hydroxyl, amino, carboxyl, and C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 Alkynyl, 3- to 10-membered carbocyclic, 4- to 10-membered heterocyclic, 3- to 10-membered carbocyclic oxy or 4- to 10-membered heterocyclic oxy, k is selected from 0, 1, 2, 3, 4 or 5, and j is selected from 0, 1 or 2. Alkyl, k, j, R appearing in this document 19 and R 19a Its definition is as described above.

[0094] "alkylene" refers to a straight-chain or branched divalent saturated hydrocarbon group, including -(CH2)v- (v is an integer from 1 to 10). Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene. The alkylene group may optionally be further divided by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, and -SR. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O)jR 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents in the alkylene group are substituted, and when there are two or more substituents in the alkylene group, the substituents can fuse together to form a cyclic structure. The alkylene groups mentioned in this article are defined as described above.

[0095] "Alkoxy" refers to a monovalent group of an O-alkyl group, wherein the alkyl group is as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl-1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 2-methyl-2-butoxy, 3-methyl-2-butoxy, 3-methyl-1-butoxy, and 2-methyl-1-butoxy.

[0096] "Alkenyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain comprises 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms on the main chain. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 4-Hexenyl, 5-Hexenyl, 1-Methyl-1-pentenyl, 2-Methyl-1-pentenyl, 1-Heptenyl, 2-Heptenyl, 3-Heptenyl, 4-Heptenyl, 1-Octenyl, 3-Octenyl, 1-Nonenyl, 3-Nonenyl, 1-Decanyl, 4-Decanyl, 1,3-Butadiene, 1,3-Pentadiene, 1,4-Pentadiene, and 1,4-Hexadiene, etc.; the alkenyl group may optionally be further divided by 0, 1, 2, 3, 4, or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR, etc. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by alkenyl groups. The alkenyl groups appearing in this article are defined as described above.

[0097] "Alynyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octylenyl, 3-nonynyl, and 4-decynyl. The alkynyl group may optionally be further divided by 0, 1, 2, 3, 4, or 5 elements selected from F, Cl, Br, I, =O, hydroxyl, -SR, etc. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by . The ynyl group appearing in this article is defined as described above.

[0098] "Cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. The cycloalkyl group may optionally be further surrounded by 0, 1, 2, 3, 4, or 5 atoms selected from F, Cl, Br, I, =O, hydroxyl, and -SR. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k-C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by the cycloalkyl groups mentioned herein, as defined above.

[0099] "Carbocyclic ring" refers to a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic system. The carbocyclic group can be connected to a bridged ring or a spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, phenyl, or naphthyl. The carbocyclic group may optionally be further composed of 0, 1, 2, 3, 4, or 5 elements selected from F, Cl, Br, I, =O, hydroxyl, and -SR. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19 -OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by the carbon rings mentioned above.

[0100] "Heterocyclic" refers to a saturated or unsaturated aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 10-membered monocyclic ring, a 4- to 12-membered bicyclic ring, or a 10- to 15-membered tricyclic system, and contains 1 to 4 heteroatoms selected from N, O, or S, preferably a 3- to 8-membered heterocyclic group. The N and S selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms, and can be connected to bridged rings or spirocyclic rings. Non-limiting examples include epoxyethyl, epoxypropyl, azirropropyl, oxacyclobutyl, azirrobutyl, thiohexacyclobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexacycloyl, azirroheptyl, oxacycloheptyl, thiohexacycloheptyl, oxacyclohexacycloyl, diazacyclohexacycloyl, thioazacyclohexacycloyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thiooxane, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophene, tetrahydropyranyl. Tetrahydrothiaranyl, tetrahydropyrrolidinyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-anyl, 4H-anyl, dioxacyclohexyl, 1,3-dioxacyclopentyl, pyrazolinyl, dithiamoleyl, dithiaphenyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclohexyl, 3-azabicyclohepyl, azabicyclohexyl, 3H-indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclooctyl, azabicyclononyl, oxatricyclododecyl, azaadamantyl, and oxaspirohepyl. The heterocyclic group may optionally be further surrounded by 0, 1, 2, 3, 4 or 5 groups selected from F, Cl, Br, I, =O, hydroxyl, -SR. 19 nitro, cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Carbocyclic groups, 3- to 8-membered heterocyclic groups, -(CH2) k -C(=O)-R 19 -(CH2) k -C(=O)-OR 19 -(CH2) k -C(=O)-NR 19 R 19a -(CH2) k -S(=O) j -R 19-OC(=O)-OR 19 Or -NR 19 R 19a The substituents are replaced by the heterocycles mentioned above.

[0101] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0102] "Pharmaceutical composition" means one or more of the compounds described herein or their physiologically / pharmaceutical acceptable salts or stereoisomers, solvates, pharmaceutically acceptable salts or eutectics, and mixtures with other components, wherein the other components include physiologically / pharmaceutical acceptable carriers and excipients.

[0103] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0104] "Effective dose" refers to the amount of a compound that elicits a physiological or medical response in an tissue, system, or subject. This amount is sought, including the amount of a compound, when administered to a subject, sufficient to prevent the occurrence of one or more symptoms of the treated disease or condition or condition, or to alleviate them to some extent.

[0105] "Solvates" refer to the compounds of this invention or their salts, which also include stoichiometric or non-stoichiometric solvents bound by intermolecular non-covalent forces. When the solvent is water, it is a hydrate. Attached Figure Description

[0106] Figure 1 For compound 1 pair The inhibition rate of Compound 48 / 80-induced scratching behavior in mice.

[0107] Figure 2 For compound 1 pair ED50 of the inhibition rate of Compound 48 / 80-induced scratching behavior in mice 50 Fitted curve.

[0108] Figure 3 for The inhibition rate of compound 1 on 5-hydroxytryptamine hydrochloride-induced scratching behavior in rats.

[0109] Figure 4 for The ED50 of compound 1 on the inhibition rate of 5-hydroxytryptamine hydrochloride-induced scratching behavior in rats 50 Fitted curve.

[0110] Figure 5 For nasal administrationCompound 1's inhibitory effect on Compound 48 / 80-induced scratching behavior in mice

[0111] Figure 6 Compound 1 for nasal administration ED50 of the inhibition rate of Compound 48 / 80-induced scratching behavior in mice 50 Fitted curve. Detailed Implementation

[0112] The technical solution of the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0113] Synthesis Example:

[0114] Compound 1: (2R)-N-[(1R)-1-(2-acetyl-2,7-diazaspiro[3.5]nonane-7-carbonyl)-5-amino-pentyl]-2-[[(2R)-2-[[(2R)-2-amino-3-phenyl-propionyl]amino]-3-phenylpropionyl]amino]-4-methyl-pentanamide (CAS No.: 2269511-95-5) was prepared according to the method described in WO2019015644.

[0115]

[0116] Biological test cases

[0117] Test Example 1: Study on the antipruritic effect of compound 1 in a Compound 48 / 80-induced mouse pruritus model

[0118] Male ICR mice obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. were randomly divided into groups and intravenously administered different doses of Compound 1 or physiological saline. Fifteen minutes later, 50 μg of Compound 48 / 80 (Sigma, Cat#: C2313) was subcutaneously injected into the neck and back of the mice. The number of scratches by the mice within 30 minutes after injection was immediately recorded. The obtained data were processed according to the formula [(scratching count in the solvent control group - scratching count in the drug treatment group) / scratching count in the solvent control group × 100] to calculate the scratching inhibition rate. Statistical analysis was performed using Graphpad Prism 8 software, and the efficacy (ED) was fitted. 50 value.

[0119] The results are as follows Figure 1 and Figure 2 As shown, compound 1 dose-dependently inhibited Compound 48 / 80-induced scratching behavior in mice, with an effective antipruritic dose and ED50. 50The values ​​were 0.03 and 0.09 mg / kg, respectively. Therefore, compound 1 exhibited significant pharmacological activity in the Compound 48 / 80-induced mouse pruritus model.

[0120] Test Example 2: Study on the antipruritic effect of a single dose of compound 1 in a rat pruritus model induced by 5-hydroxytryptamine hydrochloride.

[0121] Male SD rats obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. were randomly divided into groups and administered different doses of Compound 1 or physiological saline intravenously. Fifteen minutes later, 10 μL of 2% serotonin hydrochloride (Sigma) was injected intradermally into the neck and back of the rats. The number of scratches by the rats within 60 minutes after injection was immediately recorded. The obtained data were processed according to the formula [(scratching count in the solvent control group - scratching count in the drug treatment group) / scratching count in the solvent control group × 100] to calculate the scratching inhibition rate. Statistical analysis was performed using Graphpad Prism 8 software, and the efficacy (ED) was fitted. 50 value.

[0122] The results are as follows Figure 3 and Figure 4 As shown, compound 1 dose-dependently inhibited 5-hydroxytryptamine hydrochloride-induced scratching behavior in rats, with an antipruritic effect at the effective dose and an efficacy ED50-90%. 50 The values ​​were all 0.03 mg / kg. Therefore, compound 1 exhibited significant pharmacological activity in a 5-hydroxytryptamine hydrochloride-induced rat pruritus model.

[0123] Test Example 3: Study on the antipruritic effect of compound 1 administered nasally in a Compound 48 / 80-induced mouse pruritus model

[0124] Male ICR mice obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd. were randomly divided into groups and administered different doses of Compound 1 or physiological saline intranasally. Fifteen minutes later, 50 μg of Compound 48 / 80 (Sigma, Cat#: C2313) was subcutaneously injected into the neck and back of the mice. The number of scratches by the mice within 30 minutes after injection was immediately recorded. The obtained data were processed using the formula [(scratching count in the solvent control group - scratching count in the drug treatment group) / scratching count in the solvent control group × 100] to calculate the scratching inhibition rate. Statistical analysis was performed using Graphpad Prism 8 software, and the efficacy (ED) was fitted. 50 value.

[0125] The results are as follows Figure 5 and Figure 6 As shown, compound 1 dose-dependently inhibited Compound 48 / 80-induced scratching behavior in mice, with an effective antipruritic dose and ED50. 50The values ​​were 0.3 and 2.72 mg / kg, respectively. Therefore, in the Compound 48 / 80-induced mouse pruritus model, nasal administration of compound 1 showed significant pharmacological activity. Test Example 4: Clinical Trial

[0126] Example 4-1: A multicenter, randomized, double-blind, placebo-controlled phase II clinical study on the safety, pharmacokinetics, and efficacy in hemodialysis subjects.

[0127] For compound 1, a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial was conducted to evaluate the safety, pharmacokinetics, and efficacy of compound 1 injection in hemodialysis subjects. This study was conducted in two phases.

[0128] Phase I is a dose-escalation, randomized, double-blind, placebo-controlled study involving multiple intravenous administrations over one week in hemodialysis subjects. The study plans to enroll 40 subjects undergoing hemodialysis, with four dose groups: 0.05 μg / kg, 0.15 μg / kg, 0.30 μg / kg, and 0.80 μg / kg. Each dose group will have 10 subjects enrolled (including 2 subjects in the placebo group). Each dose group will be administered three times, on days 1, 3, and 5.

[0129] Phase II is a randomized, double-blind, placebo-controlled study involving 12 weeks of administration to hemodialysis patients with moderate or severe pruritus. Based on the results of Phase I, two doses, 0.3 μg / kg and 0.6 μg / kg, were selected for Phase II, with placebo as the control. The study planned to enroll 90 hemodialysis patients with moderate or severe pruritus, who were randomly assigned in a 1:1:1 ratio to the three groups mentioned above, with 30 patients planned for each group. Patients received either compound 1 injection or placebo.

[0130] In Phase I, all groups showed a decrease in NRS scores and Skindex-16 total scores after treatment. In Phase II, all groups showed a decrease in NRS scores and the percentage decrease increased over time. All groups also showed a decrease in Skindex-16 total scores and scores on each dimension, as well as in the 5-D scale, after treatment compared to baseline.

[0131] Efficacy results showed that in maintenance hemodialysis patients, compound 1 administered multiple times a week for 12 consecutive weeks effectively reduced pruritus symptoms and improved various aspects of quality of life. The improvement was more significant in the 0.30 μg / kg group than in the placebo group, and the efficacy was well maintained after discontinuation. Safety results showed that compound 1 had a good overall safety profile in maintenance hemodialysis patients at doses ranging from 0.05 to 0.80 μg / kg, with no serious adverse events related to the study drug and no significant withdrawal tendency after discontinuation.

[0132] Test Example 4-2: A multicenter, randomized, double-blind, placebo-controlled phase III clinical trial assessing the efficacy and safety of chronic kidney disease-related pruritus in maintenance hemodialysis patients.

[0133] For compound 1, a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial was conducted to evaluate the efficacy and safety of compound 1 injection in patients undergoing maintenance hemodialysis for chronic kidney disease-related pruritus.

[0134] This study included a double-blind period and an open-label period. The double-blind period consisted of a double-blind screening period (4 weeks, including a 1-week induction period) and a double-blind treatment period (12 weeks). Subjects who met the inclusion criteria were randomly assigned in a 1:1 ratio to the experimental group (0.3 μg / kg) and the control group (placebo). The open-label period consisted of an open screening period (2 weeks; screening of subjects who directly entered the open-label period after completing the double-blind period was conducted during the double-blind period), an open-label treatment period (52 weeks), and a follow-up period (1 week). Subjects who had completed the double-blind period and met the protocol requirements, or other subjects who met the inclusion and exclusion criteria for the open-label period, could voluntarily enter the open-label period study, and all subjects received compound 1 at 0.3 μg / kg. During the double-blind treatment period, subjects were given either compound 1 injection or placebo, three times a week, on D1 (the date of the first administration of the investigational drug in the week was defined as D1), D3 (+2), and D5 (+2) after dialysis, for 12 consecutive weeks. During the open-label treatment period, all subjects received compound 1 injection three times a week for 52 consecutive weeks. The study planned to enroll approximately 544 patients, with approximately 272 in the experimental group and 272 in the control group.

[0135] During the double-blind period, the most severe pruritus intensity was assessed daily (WI-NRS) from the first dose until the end of the double-blind treatment period. Quality of life assessments (Skindex-16 scale, 5-D pruritus scale) were performed on the day of the first dose (defined as D1) and on the first visit at weeks 5, 9, 11, and 13 post-treatment. During the open treatment period, the 5-D pruritus scale was used to assess quality of life on the first dialysis day at weeks 1, 5, 9, 13, 17, 25, 37, and 53 of the open treatment period.

[0136] Test Example 4-3: A multicenter, randomized, double-blind, placebo-controlled phase II clinical trial to assess the efficacy, safety, and pharmacokinetics of liver disease patients with pruritus.

[0137] For compound 1, a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial was conducted to evaluate the efficacy, safety, and pharmacokinetics of compound 1 injection in subjects with hepatic pruritus.

[0138] This is a multicenter, randomized, double-blind, placebo-controlled study. Approximately 90 subjects with liver disease experiencing moderate to severe pruritus were planned for enrollment. Two dosage groups were established: 0.3 μg / kg and 0.6 μg / kg, along with a placebo control group. Subjects were randomly assigned to these three groups in a 1:1:1 ratio, with approximately 30 subjects planned for each group. Subjects received the medication twice daily, for a duration of 7–28 days. During the study, subjects completed the WI-NRS scale daily, morning and evening, to assess the intensity of pruritus. The Skindex-16 scale was used to assess quality of life on the first day of each week.

Claims

1. The use of a compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of pruritus, characterized in that... The pruritus is chronic kidney disease-related pruritus in patients undergoing maintenance hemodialysis, and is administered via intravenous injection to mammals at an effective dose of a compound of formula (A) or a pharmaceutically acceptable salt thereof. 。 2. The use according to claim 1, wherein when the amount is calculated as a compound of structural formula (A), the amount of said compound is 1-1000 μg / day.

3. The use according to claim 2, wherein the interval for administration of the compound of structural formula (A) or a pharmaceutically acceptable salt thereof is selected from once daily, twice daily, three times daily, once weekly, twice weekly, three times weekly, or every other day.

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