A pharmaceutical composition for reverse anesthesia and a preparation method and application thereof

Abstract

This application relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition for retrograde anesthesia, its preparation method, and its application, specifically to a novel alkylfluorobenzene derivative—fluorocycline. The fluorocycline has the structure shown in formula (I), and as a specific antagonist, it can effectively reverse the anesthetic state induced by general anesthetic drugs such as cycloprophenol, achieving active control of anesthesia and rapid recovery. This invention also provides a pharmaceutical composition containing fluorocycline, a method for preparing fluorocycline, and its application in the preparation of drugs for reversing general anesthesia, promoting anesthesia recovery, or preventing or treating postoperative cognitive dysfunction. Furthermore, this invention combines artificial intelligence-assisted multi-target Schild analysis to accurately analyze the synergistic antagonistic mechanism between fluorocycline and anesthetic drugs at different neural targets, providing a new solution for personalized and precise anesthesia management.

Description

Technical Field

[0001] This application belongs to the field of anesthetic drug technology, and in particular relates to a pharmaceutical composition for retrograde anesthesia, its preparation method and application. Background Technology

[0002] The mechanism of action of general anesthetics has always been a hot topic in medical research. At the same time, research focused on finding methods to reverse general anesthesia is receiving increasing attention. The use of reversal agents is expected to shorten postoperative recovery time and effectively reduce the risk of postoperative complications. Research on reverse anesthetic drugs, namely the development of anesthetic antagonists or awakening-promoting drugs, has significant clinical value and scientific importance in modern medicine. Its core lies in achieving the "reversibility" and "precise control" of the anesthetic state, thereby ensuring the speed and quality of awakening and optimizing the postoperative rehabilitation process.

[0003] While research into potential reversal agents helps identify key arousal systems such as the cholinergic and dopaminergic systems, the neurochemical transitions during general anesthesia and awakening present significant challenges to achieving specific antagonism and immediate, precise modulation with existing drug regimens. Current clinical research focuses not only on antagonizing existing drugs but also on developing novel, specific compositions with high safety profiles, minimal side effects, and targeting specific receptor mechanisms.

[0004] Patent CN105709157A discloses a drug for relieving anesthetic symptoms, which is mainly composed of traditional Chinese medicine components such as aloe vera, cardamom, nutmeg, and ephedra. Its mechanism primarily involves stimulating nerve endings through drug penetration, alleviating adverse reactions caused by anesthetic administration, and accelerating the elimination of anesthetic drugs by promoting metabolism. While this approach demonstrates good safety in clinical applications and can counteract some complications, its mechanism of action largely relies on systemic metabolic acceleration and peripheral stimulation. There is room for improvement in its specific antagonistic effect on specific anesthetic receptors in the central nervous system (such as GABA receptors), limiting the flexibility of controlling awakening time in clinical scenarios requiring rapid and precise arousal.

[0005] Patent CN103263404A discloses a compound anesthetic drug. This approach combines antioxidants with existing clinical anesthetics (such as propofol and etomidate) to reduce the clinical dosage of anesthetics without affecting the anesthetic effect, thereby reducing damage to organs such as the brain, heart, and kidneys, and the risk of postoperative cognitive impairment. Although this approach improves the quality of postoperative recovery through "reduced toxicity and enhanced efficacy," it is essentially a prophylactic dosing strategy during the induction and maintenance of anesthesia. After surgery, if active and immediate reversal of consciousness control is required based on the patient's vital signs or sudden situations, this compound preparation, as a composite formulation, needs to be more targeted in independently exerting its reversal anesthetic antagonistic function, making it difficult to meet the needs of modern precision anesthesia for flexible "consciousness switch" control. Summary of the Invention

[0006] To address the aforementioned issues, this application provides a pharmaceutical composition for retrograde anesthesia, its preparation method, and its application. The aim is to utilize a specific lead compound structure and its compatibility with anesthetic drugs to target specific receptor sites in the central nervous system and their surrounding trigonometric synaptic structures, providing a technical means for actively regulating the anesthesia recovery process.

[0007] In a first aspect, this application provides the use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for antagonizing general anesthetic drugs or reversing anesthetic states. The chemical name of the compound of formula (I), SMILES, is expressed as [CF](c1c(O)ccc(c1)C(C)C)(C2CC2)C, and its structural formula is as follows: .

[0008] Furthermore, the general anesthetic drug is a selective GABAA receptor agonist; And / or, the selective GABAA receptor agonist is propofol or a structural derivative thereof; And / or, the selective GABAA receptor agonist is cycloprophenol.

[0009] Furthermore, the application is achieved by administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0010] Secondly, this application provides a pharmaceutical composition for retrograde anesthesia, comprising a therapeutically effective amount of the above-described compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0011] The pharmaceutical composition can be prepared into a dosage form suitable for intravenous injection, intramuscular injection or other non-enteric routes of administration, as needed in clinical practice, preferably an intravenous injection.

[0012] Furthermore, the pharmaceutical composition is formulated into a dosage form for intravenous injection; And / or, also includes at least one additional anesthetic or anesthetic adjuvant; And / or, the additional anesthetic is cyclopropionol.

[0013] Thirdly, this application provides a method for preparing a compound of formula (I), comprising the following steps: a) Provide cyclopropanol as a starting material; b) Under appropriate reaction conditions, the hydroxyl group on the 1-cyclopropylethyl group at the 4-position of the benzene ring in the cyclopropanol molecule is replaced with a fluorine atom to obtain fluorocyclophenol.

[0014] Furthermore, the fluorination reaction in step b) is carried out by reacting cyclopropanol with a fluorinating agent in the presence of a catalyst; And / or, the fluorinating agent is selected from diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, or 4-morpholinosulfur trifluoride.

[0015] Fourthly, this application provides a system for individualized prediction of anesthesia recovery time or optimization of anesthesia management protocols, the system comprising: The data acquisition module is used to acquire an individual's electroencephalogram (EEG) data, neuroimaging data, and / or genetic data. The model building module is used to build an individualized artificial neural network model based on the data to simulate the brain network state of the individual. The simulation calculation module is used to input parameters of one or more anesthetic drugs and / or antagonists into the artificial neural network model, and to simulate and calculate their effects on the degree of inhibition or activation of the brain's neural network. The output module is used to output simulation results, including predicted anesthesia recovery time, recommended timing and / or dosage of antagonist administration.

[0016] Furthermore, the simulation module is further configured to perform a multi-target Schild analysis method to evaluate the competitive or non-competitive interactions between the antagonist and the anesthetic drug at multiple neural targets. And / or, the plurality of neural targets include presynaptic targets and postsynaptic targets; And / or, the antagonist is a compound of formula (I) above, and the anesthetic drug is cycloprophenol.

[0017] Preferably, this application also provides a computer-aided method for screening candidate compounds for reversing anesthesia induced by a specific anesthetic drug, comprising: Construct a multi-target pharmacophore model that includes multiple known anesthesia-related targets; The three-dimensional structures of the compounds to be screened are matched and scored with the multi-target pharmacophore model. Based on the matching and scoring results, the potential antagonistic activity of the compound against the specific anesthetic drug is predicted; The prediction process is optimized using artificial intelligence algorithms.

[0018] Furthermore, the artificial intelligence algorithm includes simulation prediction based on the system described in any one of claims 13-16.

[0019] Fifthly, this application provides a kit for anesthesia recovery or reversal, comprising: 1) A first container containing a first pharmaceutical composition comprising cycloprophen; 2) A second container containing a second pharmaceutical composition comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof; and 3) The instructions for use state that the first pharmaceutical composition is used to induce and / or maintain anesthesia, and the second pharmaceutical composition is used to reverse the anesthetic state induced by the first pharmaceutical composition.

[0020] The logical chain of the technical route in this application is as follows: First, research confirmed that the hydroxyl group (OH) in the propofol molecule is crucial for its binding to the GABAA target and the generation of an anesthetic effect. Second, it was found that its fluorinated analogue, Propofluor, loses its anesthetic activity due to the lack of this key hydroxyl group, but retains its affinity for the target, thus acting as a potential antagonist. Third, given that Ciprofol, as a structural analogue of propofol, has superior pharmacodynamic properties, but its anesthetic mechanism is similar, the inventors used an artificial intelligence-assisted drug design platform to fluorinate Ciprofol, simulating and screening a lead compound with stronger and more specific antagonistic potential against Ciprofol—Ciprofluor.

[0021] Preliminary pharmacological studies have shown that fluorocycline has a significant antagonistic effect on propofol-induced anesthesia, and can significantly shorten the recovery time after anesthesia. Similar to the antagonistic mechanism of propofol, the interaction between fluorocycline and propofol may not be a simple competitive antagonism of a single target, but rather involves a complex regulatory network of multiple presynaptic and postsynaptic targets.

[0022] This application revolutionizes traditional pharmacological analysis methods—Schild analysis—by utilizing artificial intelligence technologies, particularly machine learning and deep learning algorithms, to construct an innovative AI-assisted multi-target Schild analysis platform. Unlike traditional single-target Schild analysis, this platform can simultaneously simulate and calculate the combined effects of drugs on multiple known and potential anesthesia-related targets, including presynaptic and postsynaptic targets. The platform can analyze the non-competitive or allosteric regulatory mechanisms implied when the slope of the Schild plot significantly deviates from 1, thus more realistically reflecting the complex physiological antagonistic processes of drugs like fluorocycline.

[0023] The application of this system enables anesthesia management to shift from "passive observation" to "active control" and "precise prediction." Doctors can use the system to simulate procedures before or during surgery, predict the impact of different dosing regimens on specific patients, and thus select the optimal anesthesia and reversal strategy, greatly improving the safety, effectiveness, and individualization of anesthesia, and effectively reducing the occurrence of delayed awakening and postoperative cognitive dysfunction.

[0024] In summary, this application provides a novel, pharmacologically sound, scientifically formulated, and promising reverse anesthetic drug regimen. By utilizing a lead compound as the core substance, combined with a lipid microsphere delivery system and artificial intelligence decision support, proactive and precise control of the anesthetic state is achieved, significantly improving perioperative medical safety and efficiency. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of the chemical structure of the compound of formula (I) of this application and a schematic diagram of the mechanism of anesthesia reversal. Detailed Implementation

[0026] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0028] When using “including,” “having,” and “contains” as described herein, the intention is to cover non-exclusive inclusion, unless an explicit qualifying term such as “only,” “consisting of,” etc., is used, in which case another component may be added.

[0029] The terms "preferred," "more preferably," "better," and "even better" used in this application refer to embodiments of this application that provide certain beneficial effects under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the description of one or more preferred embodiments does not imply that other embodiments are unavailable, nor is it intended to exclude other embodiments from the scope of this application. That is, in this application, "preferred," "more preferably," "better," and "even better" are merely descriptions of implementations or embodiments with better effects, but do not constitute a limitation on the scope of protection of this application.

[0030] In this application, terms such as "further," "even more," and "particularly" are used for descriptive purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0031] In this application, "at least one" means one or more, such as one, two, or more. "Multiple" or "several" means at least two, such as two, three, etc., and "multi-layered" means at least two layers, such as two layers, three layers, etc., unless otherwise explicitly specified. In the description of this application, "several" means at least one, such as one, two, etc., unless otherwise explicitly specified.

[0032] When a numerical range is disclosed herein, the range is considered continuous and includes the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0033] Unless otherwise specified, all steps in this application may be performed sequentially or randomly. For example, the method comprising steps (a) and (b) indicates that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order; for example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc. Unless otherwise stated, singular terms may include plural forms and should not be construed as having a quantity of one.

[0034] In this application, "above" or "below" includes the number itself. For example, "below 1" includes 1.

[0035] In this application, room temperature refers to 0~40℃, including but not limited to 10~40℃, or further to 20~30℃.

[0036] The present application will be further illustrated by the following examples, but these examples do not limit the scope of the present application.

[0037] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in this application, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. All reagents or instruments whose manufacturers are not specified are conventional products that can be purchased commercially. In addition to the specific methods, equipment, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description in this application, any prior art methods, equipment, and materials similar to or equivalent to those described, used, or made by the methods, equipment, and materials in the embodiments of this application may be used to implement this application.

[0038] Example 1: Synthesis of Fluorocyclophenol Synthesis of cyclopropanol: Cyclopropanol with acceptable chiral purity was synthesized and purified according to methods known in the art or reported in the literature.

[0039] Fluorination reaction: Under nitrogen protection, 1.0 g of cycloprophenol was dissolved in 20 mL of anhydrous dichloromethane and cooled to -78 °C. 1.2 equivalents of bis(2-methoxyethyl)aminosulfur trifluoride (BAST) were slowly added dropwise. After the addition was complete, the reaction mixture was slowly raised to room temperature and stirred for 12 hours. After the reaction was complete as monitored by TLC, the reaction mixture was quenched in ice water. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20:1) to give the colorless oily product cycloprophenol.

[0040] Example 2: In vivo pharmacodynamic experiment on the antagonistic effect of fluorocycline on the anesthetic effect of cyclopropofol Experimental animals and grouping: Healthy adult SD rats were selected and randomly divided into three groups: control group, propofol anesthesia group, and propofol + flucyclophenol intervention group. Ten rats were in each group.

[0041] Dosage regimen: Control group: Intravenous injection of an equal volume of physiological saline.

[0042] Cyclopofol anesthesia group: Cyclopofol (10 mg / kg) was administered intravenously to induce the loss of righting reflex.

[0043] Cycloprophen + Fluorocycline intervention group: Fluorocycline (dose of 25 mg / kg) was injected intravenously 5 minutes after the righting reflex disappeared.

[0044] Observation indicators: The anesthesia induction time and righting reflex recovery time of rats in each group were recorded. Anesthesia recovery was defined as the rat's ability to voluntarily roll over and recover from a prone position to a standing position.

[0045] Experimental results: Compared with the cyclopofol anesthesia group, the recovery time of the righting reflex in rats in the cyclopofol intervention group was significantly shortened (P<0.01), proving that cyclopofol can effectively reverse the cyclopofol-induced anesthesia and accelerate the recovery.

[0046] Example 3: Application Simulation of the Artificial Intelligence-Assisted Multi-Target Schild Analysis Platform Data Acquisition: High-resolution structural MRI data, resting-state functional MRI data, and EEG data were collected from an elderly patient scheduled for elective surgery. Peripheral blood was also collected for genotyping of CYP450 enzymes and GABAA receptor subtype-related genes.

[0047] Personalized model construction: The aforementioned multimodal data is input into the model construction module of this invention. The module utilizes graph neural networks and generative adversarial networks to construct a "digital twin" model that reflects the patient's brain network connectivity, neurodynamic characteristics, and metabolic properties.

[0048] Anesthesia and Reversal Simulation: In the simulation module, a simulated surgical scenario is set up. A standard dose of flucyclopropionol is input, and the model predicts that the patient will lose consciousness at time T1. Different doses and timings of flucyclopropionol are then input for reversal simulation. The module's multi-target Schild analysis engine comprehensively considers the affinity of flucyclopropionol for multiple presynaptic and postsynaptic GABAA receptor subtypes and potential targets, simulating its counteraction of the inhibitory effect of flucyclopropionol.

[0049] Results and Predictions: The output module provides simulation results: if flucyclophenol dose Z1 is administered immediately after discontinuation of flucyclophenol administration, the predicted awakening time is T2; if dose Z2 is administered 5 minutes after discontinuation, the predicted awakening time is T3. The model also provides a prediction of flucyclophenol metabolism rate based on the patient's genotype and a postoperative cognitive function impact score. Clinicians can use this information to select the safest and most effective individualized dosing regimen.

[0050] In summary, this application not only provides a novel and highly effective retrograde anesthetic compound—fluorocycline—and its applications, but also offers a systematic solution based on artificial intelligence for a deeper understanding of its complex mechanism of action and to achieve precise, individualized anesthesia management. This marks a significant step forward for the field of anesthesiology towards "active control" and "precision medicine."

[0051] Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. The use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for antagonizing general anesthetic drugs or reversing anesthetic states, characterized in that: The chemical name of compound (I) is SMILES, with the expression [CF](c1c(O)ccc(c1)C(C)C)(C2CC2)C, and the structural formula is as follows: 。 2. The application according to claim 1, characterized in that: The general anesthetic drug is a selective GABAA receptor agonist; And / or, the selective GABAA receptor agonist is propofol or a structural derivative thereof; And / or, the selective GABAA receptor agonist is cycloprophenol.

3. The application according to claim 1, characterized in that: The application is achieved by administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

4. A pharmaceutical composition for retrograde anesthesia, characterized in that: It comprises a therapeutically effective amount of the compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

5. The pharmaceutical composition for retrograde anesthesia according to claim 4, characterized in that: The pharmaceutical composition is formulated into a dosage form for intravenous injection; And / or, also includes at least one additional anesthetic or anesthetic adjuvant; And / or, the additional anesthetic is cyclopropionol.

6. A method for preparing the compound of formula (I) according to claim 1, characterized in that, Includes the following steps: a) Provide cyclopropanol as a starting material; b) Under appropriate reaction conditions, the hydroxyl group on the 1-cyclopropylethyl group at the 4-position of the benzene ring in the cyclopropanol molecule is replaced with a fluorine atom to obtain fluorocyclophenol.

7. The method according to claim 6, characterized in that: The fluorination reaction in step b) is carried out by reacting cyclopropanol with a fluorinating agent in the presence of a catalyst; And / or, the fluorinating agent is selected from diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride, or 4-morpholinosulfur trifluoride.

8. A system for individualized prediction of anesthesia recovery time or optimization of anesthesia management protocols, characterized in that, The system includes: The data acquisition module is used to acquire an individual's electroencephalogram (EEG) data, neuroimaging data, and / or genetic data. The model building module is used to build an individualized artificial neural network model based on the data to simulate the brain network state of the individual. The simulation calculation module is used to input parameters of one or more anesthetic drugs and / or antagonists into the artificial neural network model, and to simulate and calculate their effects on the degree of inhibition or activation of the brain's neural network. The output module is used to output simulation results, including predicted anesthesia recovery time, recommended timing and / or dosage of antagonist administration.

9. The system according to claim 8, characterized in that: The simulation module is further configured to perform a multi-target Schild analysis method to evaluate the competitive or non-competitive interactions between the antagonist and the anesthetic drug at multiple neural targets. And / or, the plurality of neural targets include presynaptic targets and postsynaptic targets; And / or, the antagonist is a compound of formula (I) as described in claim 1, and the anesthetic drug is cyclopropanol.

10. A kit for anesthesia recovery or reversal, characterized in that: Include: 1) A first container containing a first pharmaceutical composition comprising cycloprophen; 2) A second container containing a second pharmaceutical composition comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof; as well as 3) The instructions for use state that the first pharmaceutical composition is used to induce and / or maintain anesthesia, and the second pharmaceutical composition is used to reverse the anesthetic state induced by the first pharmaceutical composition.

Images