US-12624004-B2 - Opioid receptor agonist, preparation method therefor and pharmaceutical use thereof

US12624004B2US 12624004 B2US12624004 B2US 12624004B2US-12624004-B2

Abstract

The invention belongs to the field of pharmacy, and relates to a class of opioid receptor agonists, their preparation method and the pharmaceutical use thereof, in particular to 3-(dimethylaminomethyl) cyclohex-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivative or salt thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivative or salt thereof and preparation method thereof, and relate to the use of said compounds in the treatment of opioid receptor-mediated diseases. The use of the compound or pharmaceutically acceptable salt, solvate or hydrate thereof in the preparation of a medicament for treating indications related to opioid receptors. The opioid receptor-related indications are pain, irritable bowel syndrome, pruritus, addiction and depression.

Inventors

Wei Fu

Assignees

FUDAN UNIVERSITY

Dates

Publication Date: 20260512
Application Date: 20201102
Priority Date: 20191106

Claims (5)

1 . A compound or pharmaceutically acceptable salt thereof selected from: 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-(phenylsulfonyl)cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) benzenesulfonamide; 4-((3-chlorophenyl) sulfonamido)-2-((dimethylamino) methyl)-1-(3-methoxyphenyl) cyclohexyl benzoate; 3-chloro-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) benzenesulfonamide; 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-(thiophene-2-sulfonamido) cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) thiophene-2-sulfonamide; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) thiophene-2-sulfonamide; 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-((phenylmethyl) sulfonamido) cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl)-1-benzenesulfonamide hydrochloride; 4-(((3-chlorophenyl)methyl) sulfonamido)-2-((dimethylamino) methyl)-1-(3-methoxyphenyl) cyclohexyl benzoate; 1-(3-chlorophenyl)-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) methanesulfonamide; 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-(N-methylbenzenesulfonamido) cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl)-N-methylbenzenesulfonamide; 4-((3-chloro-N-methylphenyl) sulfonamido)-2-((dimethylamino) methyl)-1-(3-methoxyphenyl) cyclohexyl benzoate; 3-chloro-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(methoxyphenyl) cyclohexyl)-N-methylbenzenesulfonamide; 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-(N-methylthiophene-2-sulfonamido) cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl)-N-methylthiophene-2-sulfonamide; 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-((N-methyl-1-benzyl) sulfonamido) cyclohexyl benzoate; N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl)-N-methyl-1-phenylmethanesulfonamide; 4-((1-(3-chlorophenyl)-N-methyl) sulfonamido)-2-((dimethylamino) methyl)-1-(3-methoxyphenyl) cyclohexyl benzoate; N-benzyl-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) benzenesulfonamide; N-benzyl-3-chloro-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) benzenesulfonamide; N-benzyl-N-(3-((dimethylamino) methyl)-4-hydroxy-4-(3-methoxyphenyl) cyclohexyl) thiophene-2-sulfonamide; 4-(benzylsulfonyl)-2-((dimethylamino) methyl)-1-(3-methoxyphenyl) cyclohexan-1-ol; and 2-((dimethylamino) methyl)-1-(3-methoxyphenyl)-4-((phenylsulfonyl) methyl) cyclohex-1-ol.
2 . A pharmaceutical composition, comprising: the compound or pharmaceutically acceptable salt according to claim 1 , or a solvate or hydrate thereof; and a pharmaceutically acceptable carrier.
3 . A method of treating an opioid receptor-related indication, the method comprising administering a pharmaceutical composition to a subject in need of treating the opioid receptor-related indication, wherein the pharmaceutical composition is a pharmaceutical composition according to claim 2 .
4 . The method of claim 3 , wherein the opioid receptor-related indication is selected from the group consisting of pain, irritable bowel syndrome, pruritus, addiction, depression.
5 . The method of claim 4 , wherein the opioid receptor-related indication is pain, and the pain is selected from the group consisting of pain during surgery, chronic pain, neuropathic pain, and cancer pain.

Description

FIELD OF THE INVENTION The invention belongs to the field of pharmacy, and relates to a class of opioid receptor agonists, their preparation method and pharmaceutical use thereof, in particular to 3-(dimethylaminomethyl) cyclohex-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivatives or salts thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivative or salt thereof and preparation method thereof, 3-(dimethylaminomethyl) piperidin-4-ol derivative or salt thereof and preparation method thereof, and relates to the compound in the opioid receptor agonist and its preparation method and pharmaceutical use. BACKGROUND Pain is a common symptom in the process of many diseases, and it is one of the main problems that plague patients. It has been listed as the fifth vital sign after body temperature, pulse, respiration and blood pressure. At present, opioid analgesics have an irreplaceable role in pain treatment, such as morphine and fentanyl. But their long-term use will cause drug resistance, addiction, withdrawal, respiratory depression and other adverse reactions. Tramadol was a synthetic opioid central system analgesic developed by Grunenthal in 1977, and its trade name was tramal. It was a relatively weak p opioid receptor agonist (Ki=2400 nM at p opioid receptors, EC50>1000 nM) and inhibited serotonin and norepinephrine reuptake. It was mainly metabolized by the liver and is almost completely excreted by the kidneys. As an atypical opioid, tramadol was different from other traditional opioids. It had its unique pharmacological characteristics. It not only had strong analgesic effect, but also had few adverse reactions. It had been widely used in pain treatment. However, clinical application showed that the analgesic effect of tramadol was slightly weaker than that of analgesics such as morphine and fentanyl. In addition, tramadol had side effects such as respiratory depression, addiction, nausea, diarrhea, headache, dizziness, drowsiness, and constipation. Long-term use of the drug could also cause withdrawal symptoms such as sweating, anxiety, poor sleep, pain, and body shaking. In addition, studies have shown that tramadol use was associated with an increased risk of hyponatremia and hypoglycemia requiring hospitalization. Therefore, it is necessary to develop analgesics with stronger analgesic effect and less side effects. SUMMARY OF THE INVENTION Each of the above preferred conditions, on the basis of conforming to the common knowledge in the art, may be arbitrarily combined without going beyond the conception and protection scope of the invention. The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof: Wherein, R0 is selected from formula (1), formula (2), formula (3), formula (4), formula (5), formula (6); the formula (1), formula (2), formula (3)), formula (4), formula (5), formula (6) are as follows: R1 is hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, alkenyl, alkenyl, cycloalkenyl, substituted or unsubstituted aryl C1-6 alkyl;R2 is hydrogen, C1-6 mono- or polysubstituted alkyl, C1-6 mono- or polysubstituted alkylacyl, substituted or unsubstituted arylacyl;R4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;R5 is C1-6 alkyl, cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;R6 is hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, chain alkenyl, cycloalkenyl, aryl C1-6 alkyl;R7 and R8 are independently selected from hydrogen, C1-6 alkyl, cycloalkyl, chain alkenyl, cycloalkenyl, bridged cycloalkyl, bridged cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted substituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl;R9 and R10 are each independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and their substituents can be selected from aryl, halogen, C1-6 alkyl, cyano, alkoxy, amino, nitro, alkanesulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl;R11 is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylcycloalkyl;A is CH2 or NR3, m=0 or 1, wherein R3 is hydrogen, C1-6 alkyl, substituted or unsubstituted arylalkyl;n1=0 or 1; n2=0, 1, 2 or 3; n3=0, 1 or 2. X1 and X2 are independently selected from As a preferred technical solution, the compound represented by formula (I) in the present invention, or a pharmaceutically acceptable salt thereof, is selected from: R1 is hydrogen, C1-6 alkyl, fluoroalkyl, cycloalkyl, alkenyl, alkenyl, cycloalkenyl, substituted or unsubs