CN117534617B - 2-amino imidazoline compound, application thereof and pharmaceutical composition containing compound - Google Patents
2-amino imidazoline compound, application thereof and pharmaceutical composition containing compound Download PDFInfo
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- CN117534617B CN117534617B CN202311772718.8A CN202311772718A CN117534617B CN 117534617 B CN117534617 B CN 117534617B CN 202311772718 A CN202311772718 A CN 202311772718A CN 117534617 B CN117534617 B CN 117534617B
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- analgesic
- delta opioid
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- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The invention belongs to the technical field of pharmacy, and particularly relates to a 2-amino imidazoline compound, application thereof and a pharmaceutical composition containing the compound. The structure of the 2-amino imidazoline compound is shown as a formula I. The compound provided by the invention has an agonism effect on delta opioid receptors, can play an analgesic effect in vivo, and remarkably reduces the incidence rate of side effects (such as gastrointestinal tract function inhibition, respiratory depression, addiction and the like) of common opioid drugs. The compound of the invention is used as delta opioid receptor agonist and has wide application prospect in preparing analgesic drugs with low side effects.
Description
Technical Field
The invention belongs to the field of pharmacy, and in particular relates to a 2-amino imidazoline compound, application thereof and a pharmaceutical composition containing the compound.
Background
For a long time, the treatment of clinically moderate to severe pain (such as postoperative pain, cancer late pain, etc.) mainly depends on opioids, and classical opioids are mainly classified into three types of natural type, semisynthetic type and synthetic type, and are represented by morphine, oxycodone and fentanyl respectively. Opioid drugs exert analgesic effects by agonizing opioid receptors, which mainly comprise three subtypes of μ, δ, and κ, wherein the μ subtype mediates the strongest analgesic activity, the δ subtype mediates the second smallest analgesic activity, and the κ subtype mediates the weakest analgesic activity.
Although opioids have strong analgesic effects, serious side effects are accompanied by the use of opioids, including strong respiratory depression (life threatening in severe cases), gastrointestinal dysfunction (e.g. nausea, vomiting, constipation), itching due to histamine release, etc.; in addition, because euphoria can be brought by mediating dopamine channels and the like in the body after administration, opioid medicines can generate high psychological and physiological dependence for long-term use, so that addiction is caused, and huge hidden trouble is brought to society.
In recent years, researchers have proposed various strategies for solving the side effects of opioids, but the incidence of common side effects of drugs designed and developed by the strategies is still high in preclinical and clinical studies. There is a need to develop an opioid receptor agonist with little side effects.
Disclosure of Invention
The invention aims to provide a class of 2-amino imidazoline compounds and application thereof in preparing opioid receptor agonists with small side effects.
The invention provides an application of a compound shown in a formula I, pharmaceutically acceptable salt or stereoisomer thereof in preparing an opioid receptor agonist:
wherein R is selected from hydrogen, halogenPlain, halogenated or non-halogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 An alkoxy group.
Further, the structure of the compound is shown as a formula II:
wherein R is selected from hydrogen, halogen, halogenated or non-halogenated C 1-3 Alkyl, halogenated or non-halogenated C 1-3 An alkoxy group.
Further, the halogen is fluorine, chlorine, bromine or iodine.
Further, the compound is selected from:
further, the pharmaceutically acceptable salt is hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
Further, the opioid receptor agonist is a delta opioid receptor agonist.
Further, the opioid receptor agonist is an analgesic, anxiolytic or antidepressant.
Further, the drug is a drug with little side effects, which are inhibition of gastrointestinal function, respiratory depression or addiction.
Further, the inhibition of gastrointestinal function is inhibition of gastrointestinal motility.
Further, the gastrointestinal motility is inhibited as constipation.
The present invention also provides a compound, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:
the invention also provides a pharmaceutical composition which is a preparation prepared by taking the compound, the pharmaceutically acceptable salt or the stereoisomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a-b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. For example, C 1-3 Alkyl refers to straight or branched chain alkyl groups containing 1 to 3 carbon atoms.
Halogenated C 1-3 Alkyl means C 1-3 One or more hydrogen in the alkyl group is substituted by halogen. For example, CF 3 、CHF 2 、CH 2 F, etc.
By "pharmaceutically acceptable" is meant that the carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising the pharmaceutical dosage form, and physiologically compatible with the recipient.
"salts" are acidic and/or basic salts formed with inorganic and/or organic acids and/or bases of a compound or stereoisomer thereof, and also include zwitterionic salts (inner salts) and also include quaternary ammonium salts, for example alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. Or by mixing the compound, or a stereoisomer thereof, with a suitable amount (e.g., equivalent) of an acid or base. These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium.
The pharmaceutically acceptable salt of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salt of the compound.
The compound provided by the invention has an agonistic effect on opioid receptors, can play an analgesic effect in vivo, and remarkably reduces the incidence rate of common side effects (such as gastrointestinal tract function inhibition, respiratory depression, addiction and the like) of opioid drugs. The compound of the invention is used as an opioid receptor agonist and has wide application prospect in preparing analgesic drugs with low side effects.
Delta opioid receptor agonists have potent analgesic, anxiolytic and antidepressant effects, as is well known to those skilled in the art. Therefore, the compound of the invention has wide application prospect in preparing anxiolytic and antidepressant drugs with low side effects.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a graph of cAMP inhibition caused by activation of delta opioid receptors at various concentrations of each compound.
Figure 2 response curves for G protein dissociation caused by activation of delta opioid receptors at different concentrations of each compound.
FIG. 3 shows analgesic effects of each compound on a mouse CFA pain model, wherein the abscissa B represents a baseline; c represents after molding. * P <0.001 compared to model group; * Represents P <0.01 compared to model group; * Represents P <0.05 compared to the model group.
Figure 4 effect of each compound on gastrointestinal mobility. * P <0.001 compared to the blank solvent group.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The compounds of the present invention were synthesized according to the following general synthetic route:
the following are examples of synthesis of specific compounds of the invention and salts thereof.
Example 1: synthesis of Compounds 1-5 and salts thereof
1. Synthesis of Compound 2 and salt thereof
(1) Preparation of intermediate x-1
Raw material 2-fluorobenzene thiophenol (1.5 g,1 eq) and raw material 2-fluorobenzonitrile (1.42 g,1 eq) were dissolved in an appropriate amount of dimethyl sulfoxide (DMSO), to which potassium carbonate (3.24 g,2 eq) was added at room temperature, followed by raising the reaction solution to 100 ℃ and stirring. After the completion of the reaction was monitored by Thin Layer Chromatography (TLC), the reaction solution was filtered, washed with ethyl acetate, the obtained filtrate was poured into a separating funnel, washed with water, layered, the obtained aqueous layer was extracted twice with ethyl acetate, the organic phases were combined, the obtained organic phase was washed three times with water, and once with saturated brine; adding anhydrous sodium sulfate for drying; using column chromatography, in polar Petroleum Ether (PE): ethyl Acetate (EA) =9: 1 to give intermediate x-1 (1.2 g) in 45% yield.
(2) Preparation of intermediate x-2
Intermediate x-1 (1 g,1 eq) was dissolved in an appropriate amount of anhydrous Tetrahydrofuran (THF), at-10deg.C, N 2 LiAlH was slowly added thereto using a syringe under protection 4 (1M in THF,8.75mL,2eq) after the completion of the addition, the reaction was stirred at room temperature. TLC monitors the reaction to be complete, water and 15% NaOH solution are slowly added into the reaction liquid by using a syringe in sequence under the ice bath condition to quench the reaction, and insoluble matters are filtered out; concentrating the filtrate under reduced pressure, dissolving the residue in a proper amount of ethyl acetate, and washing the organic phase with water; the organic phases were separated and combined and dried over anhydrous sodium sulfate; using column chromatography, in polar PE: ea=15: 1 to give intermediate x-2 as a pale yellow oil in 61.6% yield.
(3) Preparation of target compound 2 and its salt
Intermediate x-2 (0.49 g,2 eq) was dissolved in an appropriate amount of anhydrous 1, 4-dioxane, 2-methylsulfanyl-2-imidazoline hydroiodidate (250 mg,1 eq) was added, and the reaction solution was stirred by heating to 100 ℃. After completion of the reaction by TLC, the reaction solution was dried by spin-drying, toluene (5 mL) was added to the obtained crude product, followed by stirring for 3 hours and filtration to give compound 2 (453 mg) in 61.6% yield. 1 H NMR(400MHz,DMSO-d6)δ8.59(t,J＝6.0Hz,1H),7.43-7.45(m,2H),7.32-7.41(m,3H),7.20-7.27(m,2H),7.13-7.17(m,1H),4.51(d,J＝6.0Hz,1H),3.62(s,4H).
Compound 2 was reacted with hydrochloric acid to obtain a hydrochloride of compound 2. The substitution of hydrochloric acid with other acids gives other soluble salts of compound 2 including sulphate, citrate, besylate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, trifluoroacetate.
2. Synthesis of other Compounds and salts thereof
According to the general formula synthesis route, the compounds 1, 3, 4, 5 and salts thereof according to the present invention are synthesized with reference to the reaction conditions at the time of synthesizing the compound 2 and salts thereof. The structure, mass spectrum and nuclear magnetic characterization data of the compounds are shown in table 1.
TABLE 1 Structure, mass Spectrometry and Nuclear magnetic characterization data for Compounds 1-5
The beneficial effects of the present invention are demonstrated by the test examples below.
Test example one, test of agonistic Activity of Compounds on delta opioid receptors
1. Second messenger level detection
Delta opioid receptors, when activated, cause a decrease in intracellular cyclic adenosine monophosphate (Cyclic Adenosinemonophosphate, cAMP) content. The effect of the compounds of the present invention on cAMP content of CHO cells stably expressing delta opioid receptors was tested by the following in vitro cell experiments to determine the agonistic activity of the compounds on delta opioid receptors.
1.1 Experimental materials
The main equipment is as follows: multifunctional enzyme-labeled instrument (BMG), micro 384 well plate (Greiner).
The main reagent comprises: F12K Medium (Gibco), fetal bovine serum (Corning), bleomycin (Sigma), hygromycin B (Sigma), cAMP detection kit (Cisbio).
Cell line: CHO cells stably expressing delta opioid receptors (Genescript).
1.2 Experimental methods
(1) Cell culture
CHO cells stably expressing delta opioid receptor were cultured in F12K medium containing 10% fetal bovine serum, 200 μg/μl bleomycin, 100 μg/μl hygromycin B and passaged once a day.
(2) Detection of agonistic Activity of Compounds on delta opioid receptors
CHO cells stably expressing delta opioid receptors were digested and centrifuged, plated into a micro 384-well plate, 3000 (5 μl) per well. mu.L of each concentration (final concentration of 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 100pM, 10pM, 1 pM) of test compound solution was added to each well and incubated at 37℃for 45min in the absence of light. mu.L of cAMP Cryptate solution and 5. Mu.L of cAMP d2 antibody were added to each well, and after incubation at room temperature for 1 hour in a dark place, detection was performed on a multifunctional microplate reader (fluorescence emission intensity: 665nm/620 nm). The compounds were fitted to delta opioid receptor agonism relative to standard agonist ADL5859 using GraphPad Software, efficacy to achieve Exposure (EC) corresponding to 50% of maximum effect 50 ) And percent maximum stimulation (Emax), EC 50 The smaller the value of Emax, the greater the concentration required to effect, the stronger the effect and the better the compound effect.
1.3 experimental results
The results of the delta opioid receptor agonistic activity of each compound are shown in fig. 1 and table 2, with ADL-5859 as a positive control.
TABLE 2 EC of individual compounds for delta opioid receptor agonistic activity 50 And Emax
| Compound name/number | EC 50 | Emax |
| ADL5859 | +++ | *** |
| 1 | + | * |
| 2 | +++ | *** |
| 3 | +++ | *** |
| 4 | ++ | * |
| 5 | +++ | * |
Note that: EC (EC) 50 : exposure corresponding to 50% maximum effect was reached; "+": EC of 500nM or less 50 <1500nM；“++”：100nM≤EC 50 ＜500nM；“+++”：EC 50 <100nM。
Emax: the maximum effect percentage refers to the maximum effect of the drug, and mainly reflects the intrinsic activity of the drug; "*": emax is more than or equal to 50% and less than 65%; "**": emax is more than or equal to 65% and less than 80%; "***": emax is 80 percent or less.
The test results above demonstrate that: the compound can be used as a delta opioid receptor agonist, effectively excite the delta opioid receptor and reduce the content of cAMP in cells, wherein the effects of the compounds 2 and 3 are better.
G protein level detection
After delta opioid receptors are agonised, gi/o proteins are recruited. Plasmids for delta opioid receptors as well as Nluc-linked G.alpha.and G.beta.and mVenus-linked G.gamma.plasmids were transiently transfected in HEK293 cells by bioluminescence resonance energy transfer assay (BRET). When delta opioid receptors are not activated, the G protein heterotrimers bind together, and the fluorescence donor NanoLuc luciferase (NLuc) linked to G alpha binds to the gold fluorescent protein (mVenus) linked to G gamma fluorescence receptors to generate BRET signals; after the compound activates the receptor, the heterotrimer dissociates and the BRET signal disappears, and the ability of the compound to activate the delta opioid receptor is characterized by detecting a change in the BRET signal.
2.1 Experimental materials
The main equipment is as follows: multifunctional enzyme-labeled instrument (BMG), 96 well plate (WHB).
The main reagent comprises: DMEM medium (Gibco), fetal bovine serum (Corning), penicillin (Sigma), streptomycin (Sigma), polyimide (PEI), coelenterazine h, hank's balanced salt solution (Hank' sBalanced Salt Solution, HBSS).
Cell line: HEK293 cells (ACTT).
2.2 Experimental methods
(1) Cell culture
HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum, 200. Mu.g/. Mu.L bleomycin, 100. Mu.g/. Mu.L hygromycin B and passaged once every day.
(2) Detection of agonistic Activity of Compounds on delta opioid receptors
Cells were divided into six well plates and transfected at 80% of the area of the dish, delta opioid receptor plasmids and G.alpha. -Nluc and G.beta. -WT, G.gamma. -mVenus plasmids were transiently transfected into HEK293 cells with PEI, after 24 hours of transfection, cells were harvested by digestion and added to a density of 3mL of complete medium per well of six well plates, 100. Mu.L of cells per well were evenly divided into 96 well plates with a row gun, 37℃at 5% CO 2 The incubator continues to incubate for 12 hours.
The supernatant was aspirated and 90. Mu.l HBSS buffer containing 20mM hepes (5. Mu.M coelenterazine h) was added to each well and incubated for 40min. Background (mock) luminescence signal intensity was measured, and test was started after 5min of reaction with addition of test compound solutions with final concentrations of 10. Mu.M, 1. Mu.M, 100nM, 10nM, 1nM, 100pM, 10pM, 1 pM). GraphPad Software 8 was used to fit the data for G protein dissociation caused by delta opioid receptor agonism of each compound. EC (EC) 50 The smaller the value of (c) indicates the lower the concentration required to act, the better the effect of the compound.
2.3 experimental results
Each pair of compoundsEC of delta opioid receptor agonistic activity 50 The results are shown in FIG. 2 and Table 3, and ADL-5859 was used as a positive control.
TABLE 3 EC of G protein dissociation BRET experiments by activation of delta opioid receptors by various compounds 50
Note that: "+": EC of 1000nM or less 50 <1500nM；“++”：300nM≤EC 50 ＜1000nM；“+++”：EC 50 <300nM。
The test results above demonstrate that: the compound can be used as a delta opioid receptor agonist to effectively excite the delta opioid receptor, wherein the compounds 2 and 3 have better effects.
Test example two, evaluation of in vivo analgesic efficacy
1. Experimental method
ICR mice (weighing 20-30 g) were acclimatized to the experimental environment for 3 days. The skin in the middle of the left foot sole of the mouse was stimulated with electronic von frey, and the depsipelas were observed as an index of pain response. First, the basal pain threshold of mechanical stimulation of mice was measured, and mice meeting the criteria of inclusion group (mechanical stimulation pain threshold: 8-12 g) were subcutaneously injected with 0.02mL Freund's complete adjuvant (CFA) to induce pain each at the bottom of the left foot. After about 16 hours, the mechanical stimulus pain threshold of the left foot was measured and mice meeting the conditions (mechanical stimulus pain threshold reduced to 2.5-3.5 g) were randomly divided into model groups, test compound groups of 8-10, male and female halves.
All groups of compounds tested were administered by intraperitoneal injection, with a compound concentration of 60. Mu. Mol/kg and a solvent of DMSO: tween-80: water = 1:1:8, the injection volume is 0.1mL/10g; the model group i.e. the intraperitoneal injection of blank solvent. The mechanical stimulus pain threshold of the left hind foot of the mice at 20min, 40min, 1h, 1.5h, 2h and 3h are recorded after administration. After the experiment was completed, data analysis was performed using GraphPad software. The mechanical stimulus pain threshold is increased, and the statistical difference between the mechanical stimulus pain threshold and the physiological saline group at the corresponding time point represents that the tested compound has analgesic effect.
2. Experimental results
The evaluation results of the analgesic effect of the compound of the present invention on the CFA pain model of the mice are shown in fig. 3. The results show that: the representative compounds 2 and 3 can obviously improve the mechanical stimulation pain threshold of the hind feet of the mice after injection, play an analgesic role in vivo, and have better effects than the control compound ADL-5859.
Test example three, evaluation of in vivo side effects
Opioids often induce side effects, such as constipation, in the course of exerting analgesic effects. The following experiments prove that the side effects of the compounds of the invention are significantly reduced.
1. Experimental method
ICR mice (weighing 20-30 g) were fasted without water withdrawal overnight before the start of the experiment. On the day of the experiment, the animals were randomly divided into a blank solvent (normal) group, a positive compound (fentanyl) group, and a test compound group, 6 animals each, and a male and female half.
Injecting a blank solvent or a tested compound solution into the abdominal cavity 30min in advance, wherein the concentration of the compound is 60 mu mol/kg, and the solvent is DMSO: tween-80: water = 1:1:8, the administration volume was 0.1mL/10g. After 30min, each mouse is irrigated with 0.3mL of gastrointestinal function marker (prepared by repeatedly boiling water solution containing 5% gum arabic and 10% activated carbon powder and cooling; after the gastrointestinal function marker is irrigated for 30min, the mice are killed by cervical dislocation, the celiac separation mesentery is dissected, the pylorus of the mice is sheared to the ileocecum, and the length (S/cm) from the pylorus to the front end of the gastrointestinal function marker and the total length (L/cm) from the pylorus to the ileocecum in the small intestine of the mice are measured by being paved on a table. Gastrointestinal mobility can be found by the following formula:
gastrointestinal mobility (%) =gastrointestinal function marker push rate (%) =s/l×100%
The gastrointestinal mobility was less than 50% and the statistical difference from the blank solvent group suggests that the tested compounds may induce constipation while exerting analgesic effects.
2. Experimental results
The effect of representative compounds 2 and 3 of the present invention on gastrointestinal mobility is shown in figure 4. When the analgesic effect is exerted, the classical opioid (positive control fentanyl) causes strong inhibition of gastrointestinal motility (gastrointestinal mobility < 50%) and induces constipation; while representative compounds 2 and 3 of the present invention did not cause abnormal gastrointestinal motility (gastrointestinal mobility > 50%), no apparent constipation occurred. The experimental results show that the compound can be used as an analgesic with low side effect.
In summary, the invention provides a class of 2-amino imidazoline compounds and application thereof. The compound provided by the invention has an agonizing effect on delta opioid receptors, can play an analgesic effect in vivo, and remarkably reduces the incidence rate of side effects of common opioid medicines. The compound of the invention is used as an opioid receptor agonist and has wide application prospect in preparing analgesic drugs with low side effects.
Claims (4)
1. Use of a compound or a pharmaceutically acceptable salt thereof for the preparation of an opioid agonist, said opioid agonist being an analgesic, said compound being selected from the group consisting of:
2. use according to claim 1, characterized in that: the pharmaceutically acceptable salt is hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
3. A compound having analgesic effect or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
4. a pharmaceutical composition having analgesic effect, characterized in that: a preparation prepared by adding pharmaceutically acceptable auxiliary materials into the compound or pharmaceutically acceptable salt of the compound as an active ingredient in the method of claim 3.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100292A (en) * | 1976-08-14 | 1978-07-11 | Boehringer Ingelheim Gmbh | 2-[N-phenyl-N-(cycloalkyl-methyl)-amino]-2-imidazolines and salts thereof |
| WO2005092836A1 (en) * | 2004-03-15 | 2005-10-06 | Eli Lilly And Company | Opioid receptor antagonists |
| CN1849308A (en) * | 2003-07-09 | 2006-10-18 | 弗·哈夫曼-拉罗切有限公司 | Thiophenylaminoimidazolines |
| WO2011080132A2 (en) * | 2009-12-17 | 2011-07-07 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Compounds, compositions and methods for controlling biofilms |
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- 2023-12-21 CN CN202311772718.8A patent/CN117534617B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4100292A (en) * | 1976-08-14 | 1978-07-11 | Boehringer Ingelheim Gmbh | 2-[N-phenyl-N-(cycloalkyl-methyl)-amino]-2-imidazolines and salts thereof |
| CN1849308A (en) * | 2003-07-09 | 2006-10-18 | 弗·哈夫曼-拉罗切有限公司 | Thiophenylaminoimidazolines |
| WO2005092836A1 (en) * | 2004-03-15 | 2005-10-06 | Eli Lilly And Company | Opioid receptor antagonists |
| WO2011080132A2 (en) * | 2009-12-17 | 2011-07-07 | Katholieke Universiteit Leuven, K.U. Leuven R&D | Compounds, compositions and methods for controlling biofilms |
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| Title |
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| Discovery and SAR development of 2-(phenylamino) imidazolines as prostacyclin receptor antagonists;Robin D. Clark，等;Bioorganic & Medicinal Chemistry Letters;20040223;第14卷(第04期);第1053-1056页 * |
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