WO2018103624A1 - 一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途 - Google Patents

一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途 Download PDF

Info

Publication number
WO2018103624A1
WO2018103624A1 PCT/CN2017/114571 CN2017114571W WO2018103624A1 WO 2018103624 A1 WO2018103624 A1 WO 2018103624A1 CN 2017114571 W CN2017114571 W CN 2017114571W WO 2018103624 A1 WO2018103624 A1 WO 2018103624A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor agonist
formula
opioid receptor
compound
farnesoid
Prior art date
Application number
PCT/CN2017/114571
Other languages
English (en)
French (fr)
Inventor
孙飘扬
桂雨舟
杨昌永
张连山
黄晓星
Original Assignee
江苏恒瑞医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to CN201780016809.5A priority Critical patent/CN108883185B/zh
Publication of WO2018103624A1 publication Critical patent/WO2018103624A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the use of a kappa opioid receptor agonist for the manufacture of a medicament for treating pruritus caused by a farnesoid X receptor agonist.
  • Obeticholic acid (OCA, INT-747) is a farnesol X-receptor agonist developed by Intersec Pharmaceuticals, licensed by the University of Perugia, Italy. It is a 7 ⁇ configuration for the treatment of portal veins. High blood pressure, primary biliary cirrhosis, bile acid diarrhea, nonalcoholic fatty liver disease, in January 2014, non-alcoholic fatty liver disease completed Phase III clinical practice in the United States.
  • oleic acid The most common side effects of oleic acid include severe itching of the skin, fatigue, abdominal pain and discomfort, joint pain, oropharyngeal pain, dizziness, and constipation.
  • the incidence of pruritus was 69% in the 10 mg group, and 23% in the 10 mg group in the 10 mg group.
  • the incidence of severe pruritus was 19%.
  • the proportion of severe pruritus in the OCA 25 mg group was 23%. Reducing the amount of oleic acid can alleviate the symptoms of itching, but it also reduces the therapeutic effect.
  • the commonly used antipruritic drugs in the clinic are mainly antihistamines, mainly loratadine (10mg) and cetirizine (10mg). These drugs mainly inhibit the action of histamine by inhibiting H1 or H2 receptors and achieve antipruritic effects.
  • glucocorticoids such as dexamethasone, also have an antipruritic effect.
  • Opioid receptors play an important role in the induction and inhibition of pruritus.
  • opioids have three receptors: ⁇ (MOR), ⁇ (KOR), and ⁇ (DOR).
  • Opioids herein, morphine, codeine
  • Systemic application of mu receptor agonists induces scratching, but ⁇ receptor agonists and ⁇ receptor agonists inhibit scratching.
  • CN1214634A discloses a class of kappa opioid receptor agonists, including Nalfurafine, which is approved by the Japanese PMDA for the treatment of urinary pruritus (2009) and pruritus caused by chronic liver disease ( Year 2014).
  • WO2008057608 discloses a ⁇ opioid receptor agonist having the structural formula shown by formula (I)
  • CN105168228A discloses a composition of oleic acid and berberine, which claims to alleviate the side effects of oleic acid, but the principle is to increase the efficacy of oleic acid by combination, thereby reducing Aube The amount of bile acid used to reduce side effects.
  • the present invention provides a use of a medicament selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid for the preparation of a medicament for treating pruritus caused by a farnesoid X receptor agonist.
  • a medicament selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid
  • the antihistamines may be selected from the group consisting of loratadine and cetirizine
  • the glucocorticoid may be selected from the group consisting of dexamethasone.
  • the invention provides the use of a ⁇ opioid receptor agonist for the manufacture of a medicament for treating pruritus caused by a farnesoid X receptor agonist.
  • the farnesoid X receptor agonist of the present invention is selected from the group consisting of coffee alcohol, chenodeoxycholic acid, oleic acid, tropifexor, GS-9674, LMB-763, EDP-305, EYP-001, cryptochinone-D , fexaramine, TC-100, BAR-704, M-480, M-450, M-780, M-790, MET-409, RDX-023, INV-33, NTX-023-1, EP-024297, GNF-5120, AKN-083, GSK-8062, GSK-2324, GSK-7230, GSK-7681, GSK-6826, GSK-3088, GSK-4997, GSK-3543, GSK-5327, GSK-3237, GSK- 2034, GSK-8359, INT-767, Px-103, AGN-29, AGN-31, SR-45023A, LY-2562175 or a pharmaceutical
  • the farnesoid X receptor agonist is oleic acid or a pharmaceutically acceptable salt thereof.
  • the kappa opioid receptor agonist is selected from the group consisting of nalufuraphine, a compound of formula (I), a compound of formula (II) and a compound of formula (III), or a pharmaceutically acceptable salt thereof .
  • the ⁇ opioid receptor agonist is used in an amount of from 1 to 1000 ⁇ g, preferably from 1 to 100 ⁇ g; and when the ⁇ opioid receptor agonist is nalfural, the dosage is more preferred 1-10 ⁇ g; when the ⁇ opioid receptor agonist is a compound of the formula (1), the formula (II) or the formula (III), the dose is more preferably 30-90 ⁇ g.
  • the specific administration dose may be 1 ⁇ g, 2.5 ⁇ g, 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g, 100 ⁇ g, 110 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g.
  • the ⁇ opioid receptor agonist is used in an amount of 0.01 to 100 ⁇ g/kg, preferably 0.01 to 20 ⁇ g/kg, and when the ⁇ opioid receptor agonist is nalfororin,
  • the dosage is more preferably 0.01-1 ⁇ g/kg;
  • the ⁇ opioid receptor agonist is a compound of the formula (1), the formula (II) or the formula (III)
  • the dose is more preferably 0.5 to 5 ⁇ g/kg.
  • the specific administration dose may be 0.01 ⁇ g/kg, 0.02 ⁇ g/kg, 0.03 ⁇ g/kg, 0.04 ⁇ g/kg, 0.06 ⁇ g/kg, 0.08 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 1.5 ⁇ g/kg, 2 ⁇ g/kg, 2.5 ⁇ g/kg, 3 ⁇ g/kg, 3.5 ⁇ g/kg, 4 ⁇ g/kg, 4.5 ⁇ g/kg, 5 ⁇ g/kg, 6 ⁇ g/kg, 7 ⁇ g/kg, 8 ⁇ g/kg, 9 ⁇ g/ Kg, 10 ⁇ g/kg, 15 ⁇ g/kg, 20 ⁇ g/kg, 25 ⁇ g/kg, 30 ⁇ g/kg, 40 ⁇ g/kg, 50 ⁇ g/kg, 60 ⁇ g/kg, 70 ⁇ g/kg or 80 ⁇ g/kg.
  • the ⁇ opioid receptor agonist is recommended to be administered three times a day, twice a day, once a day, once every two days, three times a week, twice a week or one week.
  • the ⁇ opioid receptor agonist is a compound of formula (I), preferably administered three times a week; when the ⁇ opioid receptor agonist is of formula (1), formula (II) or formula (III) In the case of a compound, it is preferably administered once a day.
  • the present invention also provides a method of treating pruritus caused by a farnesoid X receptor agonist using a drug selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid.
  • the invention provides a method of treating a pruritus caused by a farnesoid X receptor agonist with a ⁇ opioid receptor agonist.
  • the type of administration, the dose to be administered, and the method of administration of the method are as described above.
  • Another aspect of the present invention provides a pharmaceutical composition selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid in combination with a farnesoid X receptor agonist for the treatment of portal hypertension and cholestatic liver disease.
  • a pharmaceutical composition selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid in combination with a farnesoid X receptor agonist for the treatment of portal hypertension and cholestatic liver disease.
  • the antihistamines may be selected from the group consisting of loratadine and cetirizine
  • the glucocorticoid may be selected from the group consisting of dexamethasone.
  • the present invention provides a farnesoid X receptor agonist in combination with a kappa opioid receptor agonist for the treatment of portal hypertension, cholestasis liver disease, primary biliary cirrhosis, bile acid diarrhea or non-alcoholic Use in drugs for fatty liver.
  • the farnesoid X receptor agonist of the present invention is selected from the group consisting of coffee alcohol, chenodeoxycholic acid, oleic acid, tropifexor, GS-9674, LMB-763, EDP-305, EYP-001, cryptochinone-D , fexaramine, TC-100, BAR-704, M-480, M-450, M-780, M-790, MET-409, RDX-023, INV-33, NTX-023-1, EP-024297, GNF -5120, AKN-083, GSK-8062, GSK-2324, GSK-7230, GSK-7681, GSK-6826, GSK-3088, GSK-4997, GSK-3543, GSK-5327, GSK-3237, GSK-2034 , GSK-8359, INT-767, Px-103, AGN-29, AGN-31, SR-45023A, LY-2562175 or a
  • the farnesoid X receptor agonist is oleic acid or a pharmaceutically acceptable salt thereof
  • the kappa opioid receptor agonist is selected from the group consisting of nalufuraphine, a compound of formula (I), a compound of formula (II), and a compound of formula (III), or a pharmaceutically acceptable thereof salt.
  • the kappa opioid receptor agonist and the farnesoid X receptor agonist are used in a weight ratio of 1:100,000 to 1:1000, preferably 1:50,000 to 1:2000, more preferably 1:12000 to 1:3000, the specific weight ratio can be 1:80000, 1:40000, 1:20000, 1:16000, 1:12000, 1:10000, 1:8000, 1:5000, 1:3000, 1 : 2000 or 1:1000.
  • the ⁇ opioid receptor agonist is used in an amount of from 1 to 1000 ⁇ g, preferably from 1 to 100 ⁇ g; when the ⁇ opioid receptor agonist is nalfural, the dosage is more Preferably 1-10 ⁇ g when the ⁇ opioid receptor is stimulated
  • the emollient is a compound of the formula (1), the formula (II) or the formula (III)
  • the dose is more preferably 30-90 ⁇ g; the specific dose may be 1 ⁇ g, 2.5 ⁇ g, 5 ⁇ g, 10 ⁇ g, 15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g, 100 ⁇ g, 110 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 160 ⁇ g, 170 ⁇ g, 180
  • the ⁇ opioid receptor agonist is used in an amount of 0.01 to 100 ⁇ g/kg, preferably 0.01 to 20 ⁇ g/kg, and when the ⁇ opioid receptor agonist is nalfurop,
  • the dose to be administered is more preferably 0.01 to 1 ⁇ g/kg; when the ⁇ opioid receptor agonist is a compound of the formula (1), the formula (II) or the formula (III), the dose is more preferably 0.5 to 5 ⁇ g/kg.
  • the specific administration dose may be 0.01 ⁇ g/kg, 0.02 ⁇ g/kg, 0.03 ⁇ g/kg, 0.04 ⁇ g/kg, 0.06 ⁇ g/kg, 0.08 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 1.5 ⁇ g/kg, 2 ⁇ g/kg, 2.5 ⁇ g/kg, 3 ⁇ g/kg, 3.5 ⁇ g/kg, 4 ⁇ g/kg, 4.5 ⁇ g/kg, 5 ⁇ g/kg, 6 ⁇ g/kg, 7 ⁇ g/kg, 8 ⁇ g/kg, 9 ⁇ g/ Kg, 10 ⁇ g/kg, 15 ⁇ g/kg, 20 ⁇ g/kg, 25 ⁇ g/kg, 30 ⁇ g/kg, 40 ⁇ g/kg, 50 ⁇ g/kg, 60 ⁇ g/kg, 70 ⁇ g/kg or 80 ⁇ g/kg.
  • the farnesoid X receptor agonist is used in an amount of from
  • the present invention also provides a method for treating portal hypertension, cholestatic liver disease, primary bile using a drug selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid in combination with a farnesoid X receptor agonist.
  • a drug selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid in combination with a farnesoid X receptor agonist.
  • the present invention provides a farnesoid X receptor agonist in combination with a ⁇ opioid receptor agonist for the treatment of portal hypertension, cholestasis liver disease, primary biliary cirrhosis, bile acid diarrhea or nonalcoholic fatty liver disease Methods.
  • the type of the drug, the dose to be administered, and the mode of administration of the method are as described above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any one or more selected from the group consisting of a kappa opioid receptor agonist, an antihistamine, and a glucocorticoid, and a farnesoid X receptor An agonist, as well as a pharmaceutically acceptable carrier.
  • the antihistamines may be selected from the group consisting of loratadine and cetirizine
  • the glucocorticoid may be selected from the group consisting of dexamethasone.
  • the pharmaceutical composition comprises a kappa opioid receptor agonist and a farnesoid X receptor agonist, and a pharmaceutically acceptable carrier.
  • the farnesoid X receptor agonist of the present invention is selected from the group consisting of coffee alcohol, chenodeoxycholic acid, oleic acid, tropifexor, GS-9674, LMB-763, EDP-305, EYP-001, cryptochinone-D , fexaramine, TC-100, BAR-704, M-480, M-450, M-780, M-790, MET-409, RDX-023, INV-33, NTX-023-1, EP-024297, GNF -5120, AKN-083, GSK-8062, GSK-2324, GSK-7230, GSK-7681, GSK-6826, GSK-3088, GSK-4997, GSK-3543, GSK-5327, GSK-3237, GSK-2034 , GSK-8359, INT-767, Px-103, AGN-29, AGN-31, SR-45023A, LY-2562175 or a
  • the farnesoid X receptor agonist is oleic acid or a pharmaceutically acceptable salt thereof.
  • the kappa opioid receptor agonist is selected from the group consisting of nalufuraphine, a compound of formula (I), a compound of formula (II) and a compound of formula (III), or a pharmaceutically acceptable salt thereof.
  • the term “combination” or “combination” is a mode of administration, which includes various conditions in which two drugs are administered sequentially or simultaneously, and the term “simultaneously” as used herein refers to the same administration cycle.
  • the farnesoid X receptor agonist and the kappa opioid receptor agonist are administered, for example, within 2 days, or within 1 day.
  • the so-called “sequential" administration includes the administration of a farnesoid X receptor agonist and a kappa opioid receptor agonist, respectively, in different administration cycles.
  • These modes of administration all belong to the combination administration described in the present invention.
  • the combination of the invention is administered simultaneously.
  • both the farnesoid X receptor agonist and the kappa opioid receptor agonist are administered once daily.
  • the pruritus caused by the farnesoid X receptor agonist of the present invention comprises: (1) the patient has symptoms of pruritus before the use of the farnesol X receptor agonist, and itching after the use of the farnesoid X receptor agonist Symptoms worsened; (2) The patient did not have pruritus before using the farnesol X receptor agonist, and itching symptoms occurred after the farnesoid X receptor agonist.
  • the kappa opioid receptor agonist, antihistamine drug, glucocorticoid, farnesoid X receptor agonist or pharmaceutical composition thereof of the present invention may be administered by any suitable means such as oral administration or gastrointestinal administration.
  • parenteral administration method may be an intravenous, intraperitoneal, subcutaneous or intramuscular route using a dosage form such as an injection or a powder injection.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the crude product 1b (0.9 g, 2.5 mmol) was dissolved in 20 mL of methanol, and then a solution of <RTIgt; The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated.
  • the crude product 5f (60 mg, 0.066 mmol) was dissolved in dichloromethane (2 mL), and 1 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced vacuo.
  • Example 2 Therapeutic effect of ⁇ opioid receptor agonists on pruritus caused by oleic acid
  • Nafuralin solution An appropriate amount of nalfural hydrochloride was weighed and prepared into a dosing solution of 0.004 mg/mL with sodium chloride injection.
  • loratadine solution weigh the appropriate amount of loratadine, sodium chloride injection to prepare 1mg / mL of the drug solution.
  • SPF-class ICR mice male and female, weighing 20g-26g, were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., license number: SCXK (Shanghai) 2013-0016, certificate number: 20130016000547.
  • mice were randomly divided into negative control group, model control group (0 mg/kg), loratadine (10 mg/kg) group, nalfural (0.04 mg/kg) group, and compound of formula (III) was low.
  • the dose (0.03 mg/kg) group, the compound of formula (III) (0.3 mg/kg) group, the compound of formula (III) high dose (1.0 mg/kg) group, 10 mice each, male and female.
  • Loratadine was administered orally in mice 120 min before modeling.
  • the nanofuraine hydrochloride solution was administered subcutaneously 20 minutes before the modeling.
  • Each concentration of the compound of the formula (III) is administered intravenously immediately after the mouse is modeled.
  • a pruritus model was established by subcutaneous injection of 100 ⁇ g of oleic acid in the neck of mice.
  • the negative control was subcutaneously injected with ultrapure water at the same site.
  • the number of times the mouse was scratched after the ear was counted within 30 minutes after administration (one time after continuous uninterrupted grasping of the ear).
  • the homogeneity test of variance was performed for each dose group and the vehicle control group. If the variance was homogeneous (P ⁇ 0.05), one-way analysis of variance was performed, and there was a significant difference (P ⁇ 0.05). Dunnett test was performed between each dose group and the vehicle control group; otherwise, the test was completed. If the variance is not uniform (P ⁇ 0.05), a nonparametric test (Kruskal-Wallis H test, ie KW H test) is performed. If the KW H test is statistically different (P ⁇ 0.05), between the dose groups and the control group. Do the Mann-Whitney U test; otherwise the test ends.
  • the negative control also showed a certain scratching reaction after injection of the same volume of normal saline, which was presumed to be the stress response after subcutaneous injection.
  • the mice in the model group were injected subcutaneously with oleic acid 100 ⁇ g/ Only afterwards, the mice showed obvious reaction to the site of administration of the ear, and the number of scratches was significantly increased compared with the negative control group (P ⁇ 0.001); 0.03-1 mg/kg peripherally selective ⁇ opioid receptor agonist (III)
  • the compound significantly reduced the number of scratches in a dose-dependent manner (P ⁇ 0.05-0.001); 0.4 mg/kg of the centrally selective ⁇ opioid receptor agonist in the narfural group did not show a scratching reaction; and the model group Compared with the 10 mg/kg antihistamine loratadine group, the number of scratching was decreased (P ⁇ 0.05), but the number of scratching was significantly higher than that of 0.1 and 1 mg/kg of the compound of formula (III) (P ⁇ 0.05- 0.01) and
  • the ⁇ opioid receptor agonist compound of formula (III) and nalfural have significant inhibitory effects on pruritus caused by oleic acid, 0.1, 1 mg/kg of compound (III) and 0.4 mg/kg of compound (III).
  • the antipruritic effect of furanoside is stronger than that of the 10 mg/kg antihistamine loratadine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途。本发明还涉及一种法尼醇X受体激动剂联合κ阿片受体激动剂在制备治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的药物中的用途。

Description

一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途 技术领域
本发明涉及一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途。
背景技术
奥贝胆酸(Obeticholic acid,OCA,INT-747)是英特赛普特医药品公司获意大利佩鲁贾大学许可开发的法尼醇X受体激动剂，为7α构型，用于治疗门静脉高压、原发性胆汁性肝硬化、胆汁酸腹泻、非酒精性脂肪肝，2014年1月非酒精性脂肪肝在美国完成3期临床。美国FDA于5月27日加速批准了Ocaliva(奥贝胆酸)联合熊去氧胆酸(UDCA)用于治疗UDCA应答不充分的原发性胆汁性胆管炎(PBC)成人患者，或作为单药治疗用于不能耐受UDCA的成人患者。
奥贝胆酸最常见副作用包括皮肤严重瘙痒、疲乏、腹痛和不适、关节痛、口咽部疼痛、头晕以及便秘等。在PBC适应症的III临床实验中，10mg组瘙痒的发生率为69％，而严重瘙痒的发生率在10mg组为23％，在OCA爬坡组中，严重瘙痒的发生率为19％。针对NASH适应症的临床II期试验中，OCA 25mg组发生严重瘙痒的比例为23％。降低奥贝胆酸的用量可以减轻瘙痒症状，但是同时也使得治疗效果降低。
目前，临床常用的止痒的药物主要是抗组胺类药物，主要有氯雷他定(10mg)和西替利嗪(10mg)等。这类药物主要通过抑制H1或者H2受体，抑制组胺的作用，达到止痒的效果。另外，糖皮质激素，例如地塞米松，也具有止痒的作用。
阿片类受体在诱发和抑制瘙痒的过程中都具有重要的作用。在灵长类，阿片类药物有3种受体：μ(MOR)、κ(KOR)、δ(DOR)。阿片类药物(海洛因、吗啡、可待因)可以引发瘙痒。全身应用μ受体激动剂诱发挠抓动作，但是κ受体激动剂和δ受体激动剂却能抑制挠抓。
CN1214634A公开了一类κ阿片受体激动剂，其中包括如下式所示的纳呋拉啡(Nalfurafine)，该化合物被日本PMDA批准用于治疗尿毒性瘙痒(2009年)和慢性肝病引起的瘙痒(2014年)。
Figure PCTCN2017114571-appb-000001
WO2008057608公开了一种κ阿片受体激动剂，结构式如式(I)所示
Figure PCTCN2017114571-appb-000002
申请人的在先申请CN107098871A和PCT/CN2017/087328分别得到了不同的κ阿片受体激动剂，结构式分别如式(II)和式(III)所示，
Figure PCTCN2017114571-appb-000003
但是上述文献均未公开κ阿片受体激动剂与法尼醇X受体激动剂联合使用，更未公开用于减轻法尼醇X受体激动剂引起的瘙痒。
CN105168228A公开了一种奥贝胆酸和小檗碱的组合物，其声称可以减轻奥贝胆酸的副作用，但是其原理是在于通过联用增加了奥贝胆酸的药效，从而降低奥贝胆酸的用量来减轻副作用。
发明内容
本发明本发明一方面提供了一种选自κ阿片受体激动剂、抗组胺类药物和糖皮质激素的药物在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途。其中，抗组胺类药物可以选自氯雷他定和西替利嗪，糖皮质激素可以选自地塞米松。
优选地，本发明提供了κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途。
本发明所述的法尼醇X受体激动剂选自咖啡醇、鹅去氧胆酸、奥贝胆酸、tropifexor、GS-9674、LMB-763、EDP-305、EYP-001、cryptochinone-D、fexaramine、TC-100、BAR-704、M-480、M-450、M-780、M-790、MET-409、RDX-023、INV-33、NTX-023-1、EP-024297、 GNF-5120、AKN-083、GSK-8062、GSK-2324、GSK-7230、GSK-7681、GSK-6826、GSK-3088、GSK-4997、GSK-3543、GSK-5327、GSK-3237、GSK-2034、GSK-8359、INT-767、Px-103、AGN-29、AGN-31、SR-45023A、LY-2562175或上述任一化合物的可药用盐。
在优选的实施方案中，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐。
在优选的实施方案中，所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐。
Figure PCTCN2017114571-appb-000004
在优选的实施方案中，其中所述的κ阿片受体激动剂的用量为1-1000μg，优选1-100μg；当所述κ阿片受体激动剂为纳呋拉啡时，给药剂量更优选1-10μg；当所述κ阿片受体激动剂为式(1)、式(II)或式(III)化合物时，给药剂量更优选30-90μg。具体给药剂量可为1μg、2.5μg、5μg、10μg、15μg、20μg、25μg、30μg、35μg、40μg、50μg、60μg、70μg、80μg、90μg、100μg、110μg、120μg、125μg、130μg、135μg、140μg、145μg、150μg、160μg、170μg、180μg、190μg、200μg、250μg、300μg、350μg、400μg、450μg、500μg、600μg、700μg、800μg或900μg。
在优选的实施方案中，其中所述的κ阿片受体激动剂的用量为0.01-100μg/kg，优选0.01-20μg/kg，当所述κ阿片受体激动剂为纳呋拉啡时，给药剂量更优选0.01-1μg/kg；当 所述κ阿片受体激动剂为式(1)、式(II)或式(III)化合物时，给药剂量更优选0.5-5μg/kg。具体给药剂量可为0.01μg/kg、0.02μg/kg、0.03μg/kg、0.04μg/kg、0.06μg/kg、0.08μg/kg、0.1μg/kg、0.5μg/kg、1μg/kg、1.5μg/kg、2μg/kg、2.5μg/kg、3μg/kg、3.5μg/kg、4μg/kg、4.5μg/kg、5μg/kg、6μg/kg、7μg/kg、8μg/kg、9μg/kg、10μg/kg、15μg/kg、20μg/kg、25μg/kg、30μg/kg、40μg/kg、50μg/kg、60μg/kg、70μg/kg或80μg/kg。
在优选的实施例方案中，κ阿片受体激动剂推荐一天给药三次、一天给药两次、一天给药一次、两天给药一次、一周给药三次、一周给药两次或一周给药一次；当所述κ阿片受体激动剂为式(I)化合物时，优选一周给药三次；当所述κ阿片受体激动剂为式(1)、式(II)或式(III)化合物时，优选一天给药一次。
本发明还提供了一种使用选自κ阿片受体激动剂、抗组胺类药物和糖皮质激素的药物治疗法尼醇X受体激动剂引起的瘙痒的方法。
优选的，本发明提供了一种κ阿片受体激动剂治疗法尼醇X受体激动剂引起的瘙痒的方法。
所述方法的用药种类、给药剂量、给药方法等同前文所述。
本发明另一方面提供了提供了一种选自κ阿片受体激动剂、抗组胺类药物和糖皮质激素的药物联合法尼醇X受体激动剂在制备治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的药物中的用途。其中，抗组胺类药物可以选自氯雷他定和西替利嗪，糖皮质激素可以选自地塞米松。
优选的，本发明提供了一种法尼醇X受体激动剂联合κ阿片受体激动剂在制备治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的药物中的用途。
本发明所述的法尼醇X受体激动剂选自咖啡醇、鹅去氧胆酸、奥贝胆酸、tropifexor、GS-9674、LMB-763、EDP-305、EYP-001、cryptochinone-D、fexaramine、TC-100、BAR-704、M-480、M-450、M-780、M-790、MET-409、RDX-023、INV-33、NTX-023-1、EP-024297、GNF-5120、AKN-083、GSK-8062、GSK-2324、GSK-7230、GSK-7681、GSK-6826、GSK-3088、GSK-4997、GSK-3543、GSK-5327、GSK-3237、GSK-2034、GSK-8359、INT-767、Px-103、AGN-29、AGN-31、SR-45023A、LY-2562175或上述任一化合物的可药用盐。
在优选的实施方案中，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐
在优选的实施方案中，其中所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐。
在联合使用时，优选的实施方案中，κ阿片受体激动剂和法尼醇X受体激动剂的用量重量比为1：100000至1：1000，优选1：50000至1：2000，更优选1：12000至1：3000，具体重量比可为1：80000、1：40000、1：20000、1：16000、1：12000、1：10000、1：8000、1:5000、1:3000、1:2000或1:1000。
在本发明的一个实施例中，所述的κ阿片受体激动剂的用量为1-1000μg，优选1-100μg；当所述κ阿片受体激动剂为纳呋拉啡时，给药剂量更优选1-10μg，当所述κ阿片受体激 动剂为式(1)、式(II)或式(III)化合物时，给药剂量更优选30-90μg；具体给药剂量可为1μg、2.5μg、5μg、10μg、15μg、20μg、25μg、30μg、35μg、40μg、50μg、60μg、70μg、80μg、90μg、100μg、110μg、120μg、125μg、130μg、135μg、140μg、145μg、150μg、160μg、170μg、180μg、190μg、200μg、250μg、300μg、350μg、400μg、450μg、500μg、600μg、700μg、800μg或900μg。
在本发明的一个实施例中，所述的κ阿片受体激动剂的用量为0.01-100μg/kg，优选0.01-20μg/kg，当所述κ阿片受体激动剂为纳呋拉啡时，给药剂量更优选0.01-1μg/kg；当所述κ阿片受体激动剂为式(1)、式(II)或式(III)化合物时，给药剂量更优选0.5-5μg/kg。具体给药剂量可为0.01μg/kg、0.02μg/kg、0.03μg/kg、0.04μg/kg、0.06μg/kg、0.08μg/kg、0.1μg/kg、0.5μg/kg、1μg/kg、1.5μg/kg、2μg/kg、2.5μg/kg、3μg/kg、3.5μg/kg、4μg/kg、4.5μg/kg、5μg/kg、6μg/kg、7μg/kg、8μg/kg、9μg/kg、10μg/kg、15μg/kg、20μg/kg、25μg/kg、30μg/kg、40μg/kg、50μg/kg、60μg/kg、70μg/kg或80μg/kg。所述的法尼醇X受体激动剂的用量为1-1000mg，优选1-100mg，更优选5-20mg。
本发明还提供了一种使用选自κ阿片受体激动剂、抗组胺类药物和糖皮质激素的药物联合法尼醇X受体激动剂治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的方法。
优选的，本发明提供了一种法尼醇X受体激动剂联合κ阿片受体激动剂治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的方法。
所述方法的用药种类、给药剂量、给药方式等同前文所述。
再一方面，本发明提供了一种药物组合物，含有选自κ阿片受体激动剂、抗组胺类药物和糖皮质激素中的任意一种或多种药物，以及法尼醇X受体激动剂，以及药学上可接受的载体。其中，抗组胺类药物可以选自氯雷他定和西替利嗪，糖皮质激素可以选自地塞米松。
优选地，所述药物组合物含有κ阿片受体激动剂和法尼醇X受体激动剂，以及药学上可接受的载体。
本发明所述的法尼醇X受体激动剂选自咖啡醇、鹅去氧胆酸、奥贝胆酸、tropifexor、GS-9674、LMB-763、EDP-305、EYP-001、cryptochinone-D、fexaramine、TC-100、BAR-704、M-480、M-450、M-780、M-790、MET-409、RDX-023、INV-33、NTX-023-1、EP-024297、GNF-5120、AKN-083、GSK-8062、GSK-2324、GSK-7230、GSK-7681、GSK-6826、GSK-3088、GSK-4997、GSK-3543、GSK-5327、GSK-3237、GSK-2034、GSK-8359、INT-767、Px-103、AGN-29、AGN-31、SR-45023A、LY-2562175或上述任一化合物的可药用盐。
优选地，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐。
优选地，其中所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐。
Figure PCTCN2017114571-appb-000005
本发明中，所谓“联合用药”或“联用”是一种给药方式，其包括两种药物先后，或同时给药的各种情况，此处所谓“同时”是指在同一给药周期给予法尼醇X受体激动剂与κ阿片受体激动剂，例如在2天内，或1天内给予两种药物。所谓“先后”给药，则包括在不同给药周期内分别给予法尼醇X受体激动剂与κ阿片受体激动剂的情况。这些给药方式，均属于本发明所述的联合给药。优选地，本发明的联用为二者同时给药。
优选地，法尼醇X受体激动剂和κ阿片受体激动剂均为每日给药一次。
本发明所述的的法尼醇X受体激动剂引起的瘙痒包含：(1)患者在使用法尼醇X受体激动剂前已出现瘙痒症状，使用法尼醇X受体激动剂后瘙痒症状加重；(2)患者在使用法尼醇X受体激动剂前未出现瘙痒症状，使用法尼醇X受体激动剂后出现瘙痒症状。此外，本发明的所述κ阿片受体激动剂、抗组胺类药物、糖皮质激素、法尼醇X受体激动剂或其药物组合物可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。所述胃肠外给药方式可为使用注射液、粉针剂等剂型通过静脉内、腹膜内、皮下或肌肉内的途径。
附图说明
图1.式(III)化合物对奥贝胆酸诱导的小鼠瘙痒的抑制作用
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制本发明的范围。
实施例1：式(II)和式(III)化合物的制备
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
式(II)化合物：即如下式1，(R)-N-((R)-6-氨基-1-(4-(3-甲基脲基)哌啶-1-基)-1-氧代己烷-2-基)-2-((R)-2-((R)-2-氨基-3-苯基丙酰胺基)-3-苯基丙酰胺基)-4-甲基戊酰胺
Figure PCTCN2017114571-appb-000006
第一步
4-((苯氧基羰基)氨基)哌啶-1-甲酸叔丁酯1b
将4-氨基哌啶-1-甲酸叔丁酯1a(0.5g，2.5mmol)，吡啶(0.22g，2.75mmol)溶解于15mL四氢呋喃中，0℃下滴加氯甲酸苯酯(0.43g，2.75mmol)，反应液升至室温，搅拌反应2小时。反应液减压浓缩，残余物加入乙酸乙酯溶解，用水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物1b(0.9g，白色固体)，产品不经纯化直接进行下步反应。
第二步
4-(3-甲基脲基)哌啶-1-甲酸叔丁酯1c
将粗品1b(0.9g，2.5mmol)溶解于20mL甲醇中，加入1.3mL 2M甲胺的四氢呋喃溶液，50℃下搅拌反应12小时。反应液冷却至室温，减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1c(0.35g，无色油状物)，产率：55％。
MS m/z(ESI):256.1[M-1]
第三步
1-甲基-3-(哌啶-4-基)脲盐酸盐1d
将1c(0.35g，1.36mmol)溶解于5mL二氯甲烷中，加入1mL 4M氯化氢的1,4-二氧六环溶液，搅拌反应2小时。反应液减压浓缩，得到粗品标题产物1d(0.3g，白色固体)，产品不经纯化直接进行下一步反应。
第四步
(R)-(9H-芴-9-基)甲基叔丁基(6-(4-(3-甲基脲基)哌啶-1-基)-6-氧代己烷-1,5-二基)二氨基甲酸酯1f
将粗品1d(0.3g，1.36mmol)，(R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((叔丁氧基羰基)氨基)己酸1e(637mg，1.36mmol，采用公知的方法“Tetrahedron,2002,58(27),5427-5439”制备而得)溶解于5mL N,N-二甲基甲酰胺中，加入2-(7-偶氮苯丙三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(0.775g，2.04mmol)，三乙胺(0.38mL，2.72mmol)，搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1f(390mg，浅黄色油状物)，产率：47％。
MS m/z(ESI):608.2[M+1]
第五步
(R)-(5-氨基-6-(4-(3-甲基脲基)哌啶-1-基)-6-氧代己基)氨基甲酸叔丁酯1g
将1f(120mg，0.197mmol)溶解于5mL二氯甲烷中，加入1mL六氢吡啶，搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到1g(76mg，白色固体)，产率：100％。
MS m/z(ESI):386.2[M+1]
第六步
N-[(5R)-5-[(2R)-2-[(2R)-2-[(2R)-2-{[(叔丁氧基)羰基]氨基}-3-苯基丙酰胺基]-3-苯基丙酰胺 基]-4-甲基戊酰胺基]-6-{4-[(甲基氨基甲酰基)氨基]哌啶-1-基}-6-氧代己基]氨基甲酸叔丁酯1i
将1g(76mg，0.197mmol)，(6R,9R,12R)-6,9-二苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-3-氧杂-5,8,11-三氮杂十三烷-13-羧1h(104mg，0.197mmol，采用专利申请“US20110212882”公开的方法制备而得)，2-(7-偶氮苯丙三氮唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸酯(112mg，0.296mmol)和三乙胺(0.055mL，0.394mmol)溶解于5mL N,N-二甲基甲酰胺中，搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1i(100mg，白色固体)，产率：57％。
MS m/z(ESI):894.5[M+1]
第七步
(R)-N-((R)-6-氨基-1-(4-(3-甲基脲基)哌啶-1-基)-1-氧代己烷-2-基)-2-((R)-2-((R)-2-氨基-3-苯基丙酰胺基)-3-苯基丙酰胺基)-4-甲基戊酰胺1
将1i(100mg，0.112mmol)溶解于5mL二氯甲烷中，加入0.5mL三氟乙酸，搅拌反应2小时。反应液减压浓缩，用高效液相色谱法纯化所得残余物，得到标题产物1(10mg，白色固体)，产率：14％。
MS m/z(ESI):693.7[M+1]
1H NMR(400MHz,DMSO-d6):δ8.42(d,1H),8.19(d,1H),7.39-7.29(m,10H),7.22(d,1H),6.10(s,1H),5.12(s,4H),4.73(d,1H),4.41-4.37(m,2H),4.09(d,1H),3.74(d,1H),3.27-3.24(m,3H),3.02-2.96(m,4H),2.70(s,3H),2.16-1.90(m,2H),1.85-1.55(m,9H),1.51-1.25(m,6H),1.00(d,3H),0.96(d,3H).
式(III)化合物：即如下式5，4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸5
Figure PCTCN2017114571-appb-000007
Figure PCTCN2017114571-appb-000008
第一步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯5b
将1i(500mg，1.12mmol)和(R)-2-苯基丙-1-胺5a(228mg，1.68mmol，采用公知的方法“Angewandte Chemie,International Edition,2003,42(39),4793-4795”制备而得)溶于10mL N,N-二甲基甲酰胺中，加入碘化钾(372mg，2.24mmol)和碳酸钾(309mg，2.24mmol)，升温至60℃搅拌反应12小时。反应液冷却至室温，加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物5b(600mg，棕黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第二步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-酸苄酯5c
将粗品5b(600mg，1.1mmol)溶于20mL二氯甲烷中，加入二碳酸二叔丁酯(361mg，1.66mmol)和三乙胺(222mg，2.2mmol)，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5c(580mg，浅黄色粘稠状物)，产率：82％。
第三步
(9R,12R)-9-苄基-12-异丁基-2,2-二甲基-4,7,10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11-三氮杂十三-13-甲酸5d
将5c(580mg，0.9mmol)溶于10mL甲醇中，加入钯碳(60mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5d(500mg，浅黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第四步
1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯5e
将粗品5d(365mg，0.66mmol)，1f(393mg，0.66mmol)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(376mg，0.99mmol)和N,N-二异丙基乙胺(0.16mL，0.99mmol)溶于10mL N,N-二甲基甲酰胺中，室温搅拌反应2小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5e(170mg，浅黄色固体)，产率：23％。
第五步
4-氨基-1-((9R,12R,15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2,2-二甲基-4,7,10,13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5,8,11,14-四氮杂十六-16-酰基)哌啶-4-羧酸5f
将5e(80mg，0.0706mmol)溶于10mL甲醇中，加入钯碳(10mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5f(60mg，白色固体)，产品不经纯化直接进行下一步反应。
第六步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸三氟醋酸盐5g
将粗品5f(60mg，0.066mmol)溶于2mL二氯甲烷中，加入1mL 4M氯化氢的1,4-二氧六环溶液，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物5g(30mg，白色固体)。
MS m/z(ESI):708.6[M+1]
第七步
4-氨基-1-((2R,5R,8R,14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4,7,10-三氧代-14-苯基-3,6,9,12-四氮杂十五-1-酰基)哌啶-4-羧酸5
将5g(30mg，0.028mmol)用5mL甲醇/水混合溶剂(V:V＝10:1)溶解，加入碳酸氢钠固体(10mg)搅拌30分钟，调节pH值至7左右，减压浓缩，所得残余物中加入10mL二氯甲烷，搅拌30分钟，过滤，滤饼用10mL二氯甲烷淋洗，滤液减压浓缩，得到标题产物5(17mg，白色固体)。
MS m/z(ESI):708.6[M+1]
1H NMR(400MHz,CD3OD):δ7.33-7.19(m,10H),4.90-4.84(m,2H),4.64-4.61(m,2H),4.42-4.39(m,1H),3.86-3.74(m,5H),3.20-3.12(m,4H),2.94-2.84(m,4H),2.61-2.54(m,2H),2.20-2.15(m,3H),1.79-1.70(m,2H),1.68-1.60(m,8H),1.45-1.40(m,3H),1.30-1.20(m,5H),0.99-0.76(m,6H).
实施例2：κ阿片受体激动剂对奥贝胆酸引起的瘙痒的治疗作用研究
实验仪器：
表1.主要仪器信息
Figure PCTCN2017114571-appb-000009
供试品溶液配制：
(1)20mM醋酸溶液：取1.13mL冰醋酸于适当容器中，加入纯水定容至1000mL。
(2)20mM醋酸钠缓冲液：称取1.64g醋酸钠于适当容器中，加入1000mL纯水，搅拌至完全溶解，用20mM醋酸溶液调pH至4.5～4.6，搅拌均匀。
(3)奥贝胆酸溶液：称取适量奥贝胆酸研磨后，溶于超纯水中配制成浓度为1.0mg/mL的给药液。
(4)式(III)化合物溶液：称取适量式(III)化合物，用20mM醋酸钠缓冲液配制成浓度为0.006、0.06、0.2mg/mL的给药液。
(5)纳呋拉啡溶液：称取适量盐酸纳呋拉啡，用氯化钠注射液配制成0.004mg/mL的给药液。
(6)氯雷他定溶液：称取适量氯雷他定，氯化钠注射液配制成1mg/mL的给药液。
实验动物：
70只SPF级ICR小鼠，雄雌各半，体重为20g-26g，购自上海西普尔-必凯实验动物有限公司，许可证号：SCXK(沪)2013-0016，合格证编号：20130016000547。
实验方法：
动物分组：小鼠根据随机分成阴性对照组，模型对照组(0mg/kg)，氯雷他定(10mg/kg)组，纳呋拉啡(0.04mg/kg)组，式(III)化合物低剂量(0.03mg/kg)组，式(III)化合物中剂量(0.3mg/kg)组，式(III)化合物高剂量(1.0mg/kg)组，每组10只，雌雄各半。氯雷他定于造模前120min小鼠灌胃给予。盐酸纳呋拉啡溶液于造模前20min小鼠皮下注射给予。式(III)化合物各浓度药液于小鼠造模后即刻静脉注射给予。
造模：在小鼠颈部皮下注射奥贝胆酸100μg/只建立瘙痒模型。阴性对照在相同部位皮下注射超纯水。计数给药后30min内小鼠搔抓耳后给药部位的次数(连续不间断挠抓耳后为1次)。
数据采集和分析：
各项指标检查结果按组别经计算机SPSS软件包统计处理，以“均数±标准误差” (“Mean±SE”)表示。
对计量资料，对各剂量组和溶媒对照组间分别作方差齐性检验。若方差齐(P≥0.05)则做单因素方差分析，有显著性差别(P<0.05)，则各剂量组与溶媒对照组间做Dunnett检验；否则检验结束。若方差不齐(P<0.05)，则进行非参数检验(Kruskal-Wallis H检验，即K-W H检验)，如K-W H检验有统计学差异(P<0.05)，则各剂量组与对照组间做Mann-Whitney U检验；否则检验结束。
试验结果：
如表2、图1所示，阴性对照注射等体积的生理盐水后也出现一定的搔抓反应，推测为皮下注射后的应激反应；模型组小鼠颈部皮下注射奥贝胆酸100μg/只后，小鼠出现明显的搔抓耳后给药部位的反应，和阴性对照组相比搔抓次数显著增加(P<0.001)；0.03-1mg/kg外周选择性κ阿片受体激动剂式(III)化合物可剂量依赖性地显著减少搔抓次数(P<0.05-0.001)；0.4mg/kg中枢选择性κ阿片受体激动剂纳呋拉啡组动物未出现搔抓反应；和模型组相比，10mg/kg抗组胺药物氯雷他定组动物的搔抓次数降低(P<0.05)，但搔抓次数显著高于0.1和1mg/kg式(III)化合物组(P<0.05-0.01)及0.4mg/kg纳呋拉啡组(P<0.001)。
表2.式(III)化合物对奥贝胆酸诱导的小鼠瘙痒的抑制作用(Mean±SD，n＝10)
Figure PCTCN2017114571-appb-000010
*P<0.05,**P<0.01,***P<0.001v.s模型组；###P<0.001v.s阴性对照组；§P<0.05,§§§P<0.001v.s氯雷他定组。
结论：
在本试验条件下，奥贝胆酸100μg/只可引起明显的瘙痒；0.03-1mg/kg外周选择性κ阿片受体激动剂式(III)化合物可显著降低小鼠的搔抓次数；0.4mg/kg中枢选择性κ阿片受体激动剂纳呋拉啡同样显著降低小鼠的搔抓次数；10mg/kg抗组胺药物氯雷他定可显著抑制瘙痒，但药效显著弱于0.1mg/kg和1mg/kg式(III)化合物及0.4mg/kg纳呋 拉啡。
总之，κ阿片受体激动剂式(III)化合物和纳呋拉啡对奥贝胆酸引起的瘙痒均有显著的抑制作用，0.1、1mg/kg式(III)化合物0和0.4mg/kg纳呋拉啡的抑制瘙痒药效强于10mg/kg抗组胺药物氯雷他定。

Claims (15)

  1. κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途。
  2. 根据权利要求1所述的用途，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐。
  3. 根据权利要求1所述的用途，其中所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐，
    Figure PCTCN2017114571-appb-100001
  4. 根据权利要求1所述的用途，其中所述的κ阿片受体激动剂的用量为1-1000μg，优选1-100μg。
  5. 根据权利要求1所述的用途，其中所述的κ阿片受体激动剂的用量为0.01-100μg/kg，优选0.1-20μg/kg。
  6. 一种法尼醇X受体激动剂联合κ阿片受体激动剂在制备治疗门静脉高压、胆汁淤积性肝病、原发性胆汁性肝硬化、胆汁酸腹泻或非酒精性脂肪肝的药物中的用途。
  7. 根据权利要求6所述的用途，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐。
  8. 根据权利要求6所述的用途，其中所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐，
    Figure PCTCN2017114571-appb-100002
  9. 根据权利要求6所述的用途，其中所述的κ阿片受体激动剂的用量为1-1000μg，优选1-100μg。
  10. 根据权利要求6所述的用途，其中所述的κ阿片受体激动剂的用量为0.01-100μg/kg，优选0.1-20μg/kg。
  11. 根据权利要求6所述的用途，其中所述的法尼醇X受体激动剂的用量为1-1000mg，优选1-100mg，更优选5-20mg。
  12. 一种药物组合物，含有κ阿片受体激动剂和法尼醇X受体激动剂，以及药学上可接受的载体。
  13. 根据权利要求12所述的组合物，其中所述的法尼醇X受体激动剂为奥贝胆酸或其可药用盐。
  14. 根据权利要求12所述的组合物，其中所述的κ阿片受体激动剂选自纳呋拉啡、式(I)化合物、式(II)化合物和式(III)化合物，或它们的药学上可接受的盐，
    Figure PCTCN2017114571-appb-100003
  15. 根据权利要求12所述的组合物，其中所述的κ阿片受体激动剂和法尼醇X受体激动剂的重量比为1：100000至1：1000，优选1：50000至1：2000，更优选1：12000至1：3000。
PCT/CN2017/114571 2016-12-06 2017-12-05 一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途 WO2018103624A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780016809.5A CN108883185B (zh) 2016-12-06 2017-12-05 一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201611107998.0 2016-12-06
CN201611107998 2016-12-06

Publications (1)

Publication Number Publication Date
WO2018103624A1 true WO2018103624A1 (zh) 2018-06-14

Family

ID=62490694

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/114571 WO2018103624A1 (zh) 2016-12-06 2017-12-05 一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途

Country Status (3)

Country Link
CN (1) CN108883185B (zh)
TW (1) TW201821108A (zh)
WO (1) WO2018103624A1 (zh)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019109937A1 (zh) * 2017-12-06 2019-06-13 江苏恒瑞医药股份有限公司 Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途
EP3795166A4 (en) * 2018-05-16 2021-12-22 Jiangsu Hengrui Medicine Co., Ltd. PHARMACEUTICAL COMPOSITION OF COR-RECEPTOR AGONIST
CN114615976A (zh) * 2019-08-07 2022-06-10 人福医药美国公司 κ阿片受体肽酰胺激动剂
US11492374B2 (en) 2020-06-25 2022-11-08 Humanwell Pharmaceutical US Peptides for treatment of medical disorders
US11820754B2 (en) 2020-08-25 2023-11-21 Eli Lilly And Company Polymorphs of an SSAO inhibitor

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113143950B (zh) * 2021-05-17 2023-04-18 河北医科大学第二医院 一种治疗肝病的药物组合物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1214634A (zh) * 1996-11-25 1999-04-21 东丽株式会社 止痒药物
CN101627049A (zh) * 2006-11-10 2010-01-13 卡拉治疗学股份有限公司 合成酞酰胺
CN107098871A (zh) * 2016-02-23 2017-08-29 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1214634A (zh) * 1996-11-25 1999-04-21 东丽株式会社 止痒药物
CN101627049A (zh) * 2006-11-10 2010-01-13 卡拉治疗学股份有限公司 合成酞酰胺
CN107098871A (zh) * 2016-02-23 2017-08-29 江苏恒瑞医药股份有限公司 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GAO: "Update on pathogenesis and management of pruritus in cholestatic liver disease", CHINESE JOURNAL GASTROENTEROLOGY AND HEPATOLOGY, vol. 22, no. 3, 31 March 2013 (2013-03-31), pages 286 - 290 *
KAORU NAKAO: "Nalfurafine hydrochloride, a selective k opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys", JOURNAL OF PHARMACOLOGICAL SCIENCES, vol. 130, no. 1, 2 December 2015 (2015-12-02), pages 8 - 14, XP055606834, ISSN: 1347-8613 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019109937A1 (zh) * 2017-12-06 2019-06-13 江苏恒瑞医药股份有限公司 Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途
US11471503B2 (en) 2017-12-06 2022-10-18 Jiangsu Hengrui Medicine Co., Ltd. Use of KOR agonist in combination with MOR agonist in preparing drug for treating pain
EP3795166A4 (en) * 2018-05-16 2021-12-22 Jiangsu Hengrui Medicine Co., Ltd. PHARMACEUTICAL COMPOSITION OF COR-RECEPTOR AGONIST
CN114615976A (zh) * 2019-08-07 2022-06-10 人福医药美国公司 κ阿片受体肽酰胺激动剂
US11492374B2 (en) 2020-06-25 2022-11-08 Humanwell Pharmaceutical US Peptides for treatment of medical disorders
US11820754B2 (en) 2020-08-25 2023-11-21 Eli Lilly And Company Polymorphs of an SSAO inhibitor

Also Published As

Publication number Publication date
TW201821108A (zh) 2018-06-16
CN108883185A (zh) 2018-11-23
CN108883185B (zh) 2021-10-08

Similar Documents

Publication Publication Date Title
WO2018103624A1 (zh) 一种κ阿片受体激动剂在制备治疗法尼醇X受体激动剂引起的瘙痒的药物中的用途
CA2344090C (en) Compositions and methods for treating female sexual dysfunction
US20030114440A1 (en) Compositions and methods of treatment for conditions responsive to testosterone elevation
CA2398766A1 (en) Treatments for female sexual dysfunction and methods for identifying compounds useful for treating female sexual dysfunction
CN110638804A (zh) 治疗肥胖
CN1352557A (zh) 提高生育力的组合物
TWI707677B (zh) 肥胖之治療
CN111298120A (zh) 炎性病症的预防和治疗
JP2020517696A5 (zh)
KR20160067118A (ko) (ｓ)-3-(4-((4-(모르폴리노메틸)벤질)옥시)-1-옥소이소인돌린-2-일)피페리딘-2,6-디온의 제제
WO1996009069A1 (fr) Nouvelle utilisation medicale d&#39;un antagoniste de 5ht¿3?
WO2018051230A1 (en) Combination of fxr agonists
JP2023015333A (ja) ステロイド耐性の克服および異常なインターフェロンガンマシグナル伝達に関連する疾患の治療のためのグルタルイミド誘導体の使用
IL280831B2 (en) Combination therapy with C-C antagonists such as cytokine receptor 4 (CCR4) and one or more immune checkpoint inhibitors
WO2011131705A1 (en) Treatment of multiple sclerosis with masitinib
KR20060123183A (ko) 탈리도미드를 포함하는 섬유근육통 치료용 조성물 및 그방법
JP2020536929A (ja) Ｃｃｒ３阻害剤を用いた、そう痒症、乾皮症、及び関連疾患を治療するための方法及び組成物
AU672772B2 (en) Alleviating or prevention of migraine headache onset with mast cell degranulation blocking agents
WO2005030143A2 (en) Chelerythrine, analogs thereof and their use in the treatment of bipolar disorder and other cognitive disorders
WO2016006621A1 (ja) Ｐｇｄ２拮抗剤を含有するアレルギー性疾患に伴う症状の治療用医薬
WO2020135872A1 (zh) 免疫抑制药物组合物及其应用
US20230128304A1 (en) Benzimidazole compound for the treatment of metabolic disorders
CN110891580A (zh) 使用三氧化二砷治疗多发性硬化症的方法
JP4695326B2 (ja) 鼻炎用医薬組成物
JP2006306739A (ja) 神経因性疼痛治療剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17877446

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17877446

Country of ref document: EP

Kind code of ref document: A1