WO2022127050A1 - 具有抗氧化作用2-(3,6-二甲基-5-羟甲基-吡嗪-2)-5-甲基-吡唑-3酮化合物 - Google Patents
具有抗氧化作用2-(3,6-二甲基-5-羟甲基-吡嗪-2)-5-甲基-吡唑-3酮化合物 Download PDFInfo
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Definitions
- the present invention relates to the field of pharmaceutical chemistry, in particular to a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof.
- Free radicals are atoms, molecules, ions, or groups of atoms that have one or more unpaired electrons and are highly reactive. Free radicals are mainly formed in the process of electron transfer in the body and are the products of normal cellular aerobic metabolism. Aerobic organisms will continuously generate free radicals containing oxygen and/or nitrogen with metabolism, mainly superoxide anion free radicals ( ⁇ O2), hydroxyl free radicals ( ⁇ OH), carboxyl free radicals (ROO ⁇ ), and lipid oxygen free radicals. radicals, nitric oxide radicals (NO ⁇ ), nitro radicals ( ⁇ ONOO-), etc. Oxygen free radicals are the most important type, accounting for more than 95% of the total free radicals in the human body. Oxygen free radicals and molecules such as H 2 O 2 , singlet oxygen (1O 2 ) and ozone that can be converted into free radicals are collectively referred to as reactive oxygen species (ROS).
- ROS reactive oxygen species
- Free radicals are chemically highly reactive and can react with biomolecules (proteins, lipids, sugars, DNA) to change their structure and function. Under normal circumstances, organisms have a complete antioxidant system that can maintain the metabolic balance of free radicals. However, under pathological conditions, excessive production of free radicals or elimination of obstacles can lead to lipid peroxidative damage to biofilms and macromolecules, triggering pathological oxidative stress in the body.
- oxidative stress-induced damage to cellular components such as proteins, lipids, and DNA is the causative factor for a variety of chronic diseases, such as stroke, atherosclerosis, myocardial infarction and other cardiovascular and cerebrovascular diseases, neurodegenerative diseases, and diabetes. , kidney disease, retinal disease, cancer, inflammatory disease, immune disease, etc. (Yun-Zhong F, et al. Free radiicals, antioxidants, and nutrition. Nutrition. 2002; 18:872–879.). The relationship between the body's impaired antioxidant status, indicators of oxidative damage, and disease is well established.
- the brain is one of the organs with the highest oxygen load and the most active metabolism in the body. Compared with other organs, brain tissue is more likely to produce free radicals and lipid peroxides, and is more susceptible to oxidative stress. Free radical attack on nerve cells can lead to degenerative changes and trigger neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), etc.
- PD Parkinson's disease
- AD Alzheimer's disease
- MS multiple sclerosis
- ALS amyotrophic lateral sclerosis
- oxidative stress, mitochondrial dysfunction, excitotoxicity, immune inflammation and apoptosis are the main pathogenesis of neurodegenerative diseases.
- Oxidative stress and free radical generation catalyzed by redox transition metals are thought to play a key role (Mark PM.Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative Disorders.Ann.N.Y.Acad.Sci.2004 ; 1012:37–50).
- Antioxidant drugs can scavenge or reduce free radicals, protect nerve cells from free radical damage, delay and prevent neurodegeneration, and play a therapeutic role.
- Oxidative stress is also an obvious and important pathological phenomenon in ischemic cerebrovascular disease, and it plays a different role in each stage.
- the stimulation of various risk factors such as hypertension, hyperglycemia, hyperlipidemia, infection, and overwork can cause damage to vascular endothelial function, oxidative stress and inflammatory response, induce the secretion of various inflammatory factors, and initiate atherosclerosis pathological process.
- Oxidative stress and inflammatory responses promote each other, which in turn further aggravates the damage of endothelial function.
- LDL low-density lipoprotein
- ox-LDL oxidized low-density lipoprotein
- Oxidative stress not only plays an important role in plaque formation, but is also a key factor in inducing plaque rupture, which is a trigger for acute cerebrovascular events. Cerebral vascular thrombosis and embolism, resulting in reduced blood flow or interruption of blood supply to the brain, ischemia and hypoxia in cerebral tissue, triggering a cascade of cerebral ischemia damage,
- Oxidative stress can also induce neuronal cell necrosis through lipid peroxidation, protein denaturation, and/or DNA modification, and can also initiate neuronal apoptosis through mitochondria, endoplasmic reticulum, or death receptors. Therefore, oxidative stress plays a key role in the cascade of cerebral ischemia and reperfusion injury. In conclusion, oxidative stress is involved in the whole process of ischemic cerebrovascular disease from pathological initiation to prognosis recovery.
- Inhibiting oxidative stress and scavenging free radicals are important therapeutic strategies throughout the course of ischemic cerebrovascular disease.
- the use of antioxidants in various stages of ischemic cerebrovascular disease can bring different benefits to patients and play an important role in preventing and treating the occurrence and development of cerebrovascular disease. (Wang Yongjun, Oxidative Stress and Ischemic Cerebrovascular Disease, Chinese Journal of Stroke 2008;3(3):163-165)
- Oxidative stress is also considered to be closely related to cardiovascular disease, because atherosclerosis is the most important pathological basis of cardiovascular disease, and oxidative stress runs through atherosclerosis. Oxidative stress plays an important role in the pathological process of atherosclerosis, myocardial ischemia and reperfusion injury, myocardial infarction, coronary heart disease, heart failure and other cardiovascular diseases.
- Oxidative stress can also damage cell membranes, forming one of the mechanisms of intracellular calcium overload, and cardiac systolic dysfunction may exist in damaged myocardium.
- Oxidative stress also plays an important role in the aging process, free radicals contribute to aging and various geriatric diseases. Free radicals attack genes that are being replicated, causing genetic mutations that can lead to cancer. In addition, free radicals are also associated with diabetes and diabetic vascular system complications, inflammatory bowel disease, macular degeneration and cataracts, macular degeneration and cataracts, rheumatoid arthritis, etc. Free radical damage caused by oxidative stress is involved in diseases pathological process.
- oxidative stress damage caused by accumulation of free radicals is closely related to the occurrence and development of various diseases.
- Antioxidants can prevent or treat related diseases by scavenging free radicals.
- Edaravone is the first marketed free radical scavenger that scavenges free radicals and inhibits lipid peroxidation, thereby inhibiting oxidative damage to brain cells, vascular endothelial cells and nerve cells.
- Approved as a brain protectant in Japan in 2001 Improve neurological symptoms, activities of daily living and functional impairment caused by acute cerebral infarction. It was approved by the FDA in 2017 for the treatment of amyotrophic lateral sclerosis (ALS).
- edaravone also has the potential to be used for the prevention and treatment of oxidative damage to various extra-brain organs and chronic diseases related to free radical damage.
- Edaravone belongs to the pyrazolone class of compounds. Under physiological conditions, it can form tautomeric forms from keto-enol tautomerism, including amine, keto and enol forms. Edaravone is in vivo. Basis of antioxidant activity (Kazutoshi Watanabe, et al. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr. 2018;62(1):20–38). Preclinical and clinical studies have shown that edaravone has good free radical scavenging and antioxidant activities, and can protect brain cells, nerve cells and vascular endothelial cells from oxygen free radical damage. Although the treatment effect is positive, there are also obvious shortcomings.
- Fan Lingling et al. recently published (patent application CN201810292836.1) a new pyrazolol compound, which has the dual effects of anti-platelet aggregation and protection of nerve cells.
- compound 1 (Y1502) is the most similar in structure to edaravone, and its antiplatelet aggregation activity is similar to that of edaravone, but its neuroprotective activity is weaker than that of edaravone. Also, no oral bioavailability data were provided, and no other comparative advantage with edaravone was seen.
- the object of the present invention is to provide a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof for solving the problems in the prior art The problem.
- one aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, the chemical structural formula of the compound is such as formula I shown:
- Another aspect of the present invention provides a method for preparing the above-mentioned compound, comprising: hydrolyzing the compound of formula III to provide the compound of formula I, and the reaction equation is as follows:
- Another aspect of the present invention provides the use of the above compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof in the manufacture of a medicament.
- Another aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof.
- Figure 1 is a schematic diagram showing the average blood concentration-time curve of X1901 in male SD rats after intragastric administration or intravenous administration of X1901 in Example 7 of the present invention.
- Fig. 2 is a schematic diagram showing the average blood concentration-time curve of Y1502 after intragastric administration or intravenous administration of Y1502 to male SD rats in Example 7 of the present invention.
- the inventor of the present invention unexpectedly found a more advantageous pyrazolone compound, the pyrazolone compound has stronger free radical scavenging and antioxidant activities, and has better nerve cells
- the invention has been completed on the basis of protective activity and anti-platelet aggregation activity, as well as good oral absorption characteristics, which can be used for preparing medicines.
- a first aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and the chemical structural formula of the compound is shown in formula I:
- Keto-Enol Tautomerism usually refers to the chemical equilibrium between ketones or aldehydes and enols, that is, carbonyl compounds such as ketones and aldehydes have acidic ⁇ -protons, which are in different The transfer of protons is carried out at pH value to form keto and enol forms, thus forming tautomers.
- isomers may include compounds of formula Ia and/or formula II.
- Isomers respectively ketone form, enol form and amine form, the specific forms are as follows:
- salt should be understood as any form of active compound used by the present invention, wherein the compound may be in ionic form or charged or coupled to a counterion (cation or anion) or in solution.
- This definition may also include quaternary ammonium salts and complexes of active molecules with other molecules and ions, especially complexes through ionic interactions.
- This definition especially includes physiologically acceptable salts, the term being understood to be equivalent to "pharmacologically acceptable salts".
- the term "pharmaceutically acceptable salt” generally refers to any salt ( Generally speaking, this means that it is nontoxic, especially as a result of the counterion).
- physiologically acceptable salts may be formed with cations or bases, and in the context of the present invention, especially when administered in humans and/or mammals, are to be understood as being provided by the present invention at least A compound, usually an acid (deprotonated), such as a salt of an anion and at least one physiologically tolerated cation, preferably an inorganic cation.
- salts with alkali metals and alkaline earth metals may be included, in particular, but not limited to, with (mono) or (di) sodium , (mono) or (di) potassium, magnesium or calcium salts.
- physiologically acceptable salts may also be formed with anions or acids, and in the context of the present invention, in particular when administered in humans and/or mammals, should be understood as provided by the present invention
- salts formed from physiologically tolerable acids may specifically include, but are not limited to Salts formed with hydrochloric, hydrobromic, sulfuric, methanesulfonic, formic, acetic, oxalic, succinic, malic, tartaric, mandelic, fumaric, lactic or citric acids.
- prodrug in the present invention is used in its broadest sense and includes those derivatives that can be converted into the compounds of the present invention in vivo. Methods of preparing prodrugs of a given active compound should be known to those skilled in the art, see, for example, Krogsgaard-Larsen et al., "Textbook of Drug design and Discovery” Related content published in Taylor & Francis (April 2002).
- solvate generally refers to any form of the active compound according to the present invention combined with another molecule (usually a polar solvent) through a non-covalent bond, and the obtained substance may specifically include but not Limited to hydrates and alcoholates such as methanolates.
- the second aspect of the present invention provides the preparation method of the compound provided by the first aspect of the present invention, comprising: hydrolyzing the compound of formula III (X1901-6) to provide the compound of formula I, and the reaction equation is as follows:
- the hydrolysis reaction can usually be carried out in the presence of a base.
- a base can be an alkali metal hydroxide, etc., more specifically, lithium hydroxide, etc.
- the amount used is usually substantially equal or excess relative to the compound of formula III.
- the molar ratio of the compound of formula III to the base can be 1:1-5, 1:1-1.2, 1:1.2-1.5, 1:1.5- 2. 1: 2-2.5, 1: 2.5-3, 1: 3-4, or 1: 4-5.
- the reaction can usually be carried out at room temperature to the boiling point of the reaction solvent, preferably at room temperature.
- Those skilled in the art can appropriately adjust the reaction time of the hydrolysis reaction according to the reaction progress. Methods for monitoring the reaction progress should be known to those skilled in the art, such as analytical methods such as chromatography and nuclear magnetic resonance.
- the time may be 1-24 hours, 1-2 hours, 2-4 hours, 4-8 hours, 8-12 hours, or 12-24 hours.
- the reaction is usually carried out in the presence of a solvent, and the solvent can usually be a good solvent for the reaction raw materials, and usually needs to include water, so that the reaction raw materials can be fully dispersed and the smooth progress of the reaction can be ensured.
- the reaction solvent may include water, and may also include alcohol solvents, etc., specifically methanol and the like.
- post-treatment of the hydrolysis reaction may include: removal of solvent.
- the reaction system can be desolvated to provide compounds of formula I and formula II.
- the resulting product after removal of the solvent can also be further purified (eg, by column chromatography, etc.) to provide compounds of formula I and II in higher purity.
- the third aspect of the present invention provides the use of the compound provided in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof in the preparation of a medicament.
- the compounds provided by the present invention have stronger free radical scavenging and antioxidant activities.
- the compound has been shown to have a protective effect against neuronal cell (eg, PC12 cell) damage (eg, glutamate-induced cell damage) in cellular experiments, and the neuronal cell survival rate was significant in the presence of the test compound
- the generation of ROS in nerve cells was significantly inhibited in a dose-dependent manner.
- the compound has been shown to have a significant inhibitory effect on platelet aggregation (eg, ADP-induced platelet aggregation), and can effectively reduce the size of cerebral infarction (eg, in rats with focal cerebral ischemia-reperfusion). model) in a dose-dependent manner.
- platelet aggregation eg, ADP-induced platelet aggregation
- cerebral infarction eg, in rats with focal cerebral ischemia-reperfusion. model
- the compound also has good pharmacokinetic properties and drug distribution trends, has a longer elimination half-life, and can pass through the blood-brain barrier to achieve higher exposure levels in the brain. It can be seen that the above compounds or their pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates can be used in the preparation of medicaments.
- the above-mentioned drugs can generally be used to treat diseases caused by oxidative stress (eg, acute oxidative stress, chronic oxidative stress, etc.) and/or thrombosis caused by free radicals.
- diseases can be cardiovascular and cerebrovascular diseases (eg, arteriosclerosis, heart failure, heart disease, cerebral stroke, myocardial ischemia and ischemia-reperfusion injury, myocardial infarction, coronary heart disease, or heart failure, etc.), neurodegenerative diseases (eg, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), or amyotrophic lateral sclerosis (ALS), etc.), senile/aging diseases (eg, arthritis) , diabetes and complications (for example, diabetic cardiomyopathy, diabetic nephropathy, diabetic cerebrovascular disease, diabetic retinopathy, etc.), osteoarthritis, cataract, macular degeneration, prostate disease, etc. ), cancer, liver disease, lung disease, digestive organ damage, etc. ,
- the fourth aspect of the present invention provides a pharmaceutical composition, comprising the compound provided in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, the pharmaceutical combination
- the substance may also include at least one pharmaceutically acceptable carrier.
- the composition may include one or more pharmaceutically acceptable carriers, generally referred to as carriers used for the administration of therapeutic agents, which themselves do not induce the production of antibodies detrimental to the individual receiving the composition, And there is no excessive toxicity after administration.
- carriers are well known to those skilled in the art, for example, relevant information on pharmaceutically acceptable carriers is disclosed in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991).
- the carrier can be a combination including, but not limited to, one or more of saline, buffer, dextrose, water, glycerol, ethanol, adjuvants, and the like.
- the above-mentioned compounds or their pharmaceutically acceptable salts, isomers, prodrugs, polymorphs or solvates can be a single active ingredient, or can be combined with other active ingredients , constitute a combined preparation.
- Other active ingredients may be various other drugs that may be used to treat diseases caused by oxidative stress and/or blood clots caused by free radicals.
- the content of the active ingredient in the composition is usually a safe and effective amount, which should be adjustable by those skilled in the art.
- the administration amount of the above-mentioned compound as an active ingredient or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof, and the active ingredient of the pharmaceutical composition generally depends on the patient's body weight, application type, condition and severity of the disease.
- the administration amount of the above-mentioned compound as an active ingredient or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvate thereof can usually be 0.1-1000 mg/kg/day, 0.1-0.5 mg /kg/day, 0.5 ⁇ 1mg/kg/day, 1 ⁇ 2mg/kg/day, 2 ⁇ 3mg/kg/day, 3 ⁇ 4mg/kg/day, 4 ⁇ 5mg/kg/day, 5 ⁇ 6mg/kg /day, 6 ⁇ 8mg/kg/day, 8 ⁇ 10mg/kg/day, 10 ⁇ 20mg/kg/day, 20 ⁇ 30mg/kg/day, 30 ⁇ 40mg/kg/day, 40 ⁇ 60mg/kg/day , 60 ⁇ 80mg/kg/day, 80 ⁇ 100mg/kg/day, 100 ⁇ 150mg/kg/day, 150 ⁇ 200mg/kg/day, 200 ⁇ 300mg/kg/day, 300 ⁇ 400mg/kg/day, 400 ⁇ 600m
- the compounds provided by the present invention can be adapted to any form of administration, which can be oral or parenteral, for example, can be pulmonary, nasal, rectal and/or intravenous, more specifically, intradermally , subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, buccal, sublingual, nasal, transdermal, vaginal, oral or parenteral administration.
- pulmonary, nasal, rectal and/or intravenous more specifically, intradermally , subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, buccal, sublingual, nasal, transdermal, vaginal, oral or parenteral administration.
- pulmonary, nasal, rectal and/or intravenous more specifically, intradermally , subcutaneous, intramuscular, intraarticular, intraperitoneal, pulmonary, buccal, sublingual, nasal, transdermal, vaginal, oral or parenteral administration.
- Those skilled in the art can select a suitable formulation according to the mode of administration.
- formulations suitable for oral administration may include, but are not limited to, pills, tablets, chews, capsules, granules, drops or syrups etc.
- formulation forms suitable for parenteral administration may include, but are not limited to, solutions, suspensions, rehydratable dry formulations or sprays, etc.
- those suitable for rectal administration may usually be suppositories .
- a fifth aspect of the present invention provides a method of treatment comprising: administering to an individual a therapeutically effective amount of a compound provided in the first aspect of the present invention or a pharmaceutically acceptable salt, isomer, prodrug, polymorph or solvent thereof compound, or the pharmaceutical composition provided by the fourth aspect of the present invention.
- “individual” generally includes humans, non-human primates, such as mammals, dogs, cats, horses, sheep, pigs, cattle, etc., which can be treated by using the formulation, kit or combination formulation and benefit.
- therapeutically effective amount generally refers to an amount that, after an appropriate period of administration, can achieve the effect of treating the diseases listed above.
- the compounds provided by the present invention have greater performance advantages, better anti-oxidation, neuroprotective and anti-platelet aggregation activities, easy to pass through the blood-brain barrier, and good oral administration Bioavailability can greatly improve patient compliance and clinical convenience. It can be developed as a drug for the treatment and prevention of cardiovascular and cerebrovascular diseases, neurodegenerative diseases and other oxidative stress-related diseases, and can also be used for thromboembolic diseases. It has a good industrialization prospect.
- aqueous phase was adjusted to pH 9-10 with Na2CO3 solid, extracted 10 times with DCM, all organic phases were combined, washed once with saturated NaCl aqueous solution, and the organic phase was spin-dried under reduced pressure. 106 g of oily liquid X1901-1 was obtained with a yield of 94%.
- X1901-1 (106 g, 0.767 mol) was dissolved in toluene, cooled to 0° C., POCl 3 (400 ml) was added dropwise, the temperature was raised to 90° C. and reacted for 9 hours.
- the Antioxidant Capacity Index is a standard method for evaluating antioxidant activity. It uses the azo compound AAPH as the source of peroxy radicals, sodium fluorescein as the fluorescent indicator, and the water-soluble vitamin E analogue Trolox as the quantitative standard.
- the fluorescence microplate analyzer tests the reduction of fluorescence intensity by free radicals and the protective effect of antioxidants. In the experiment, Trolox or test samples, sodium fluorescein and potassium phosphate buffer were placed in microwells of 96-well plate, pre-set at 37°C for 5 minutes, and AAPH was quickly added to start the reaction, and the fluorescence decay curve was tested.
- the fluorescence decay curves of sodium fluorescein-AAPH and sodium fluorescein+AAPH were measured as controls.
- ORAC was calculated from the area under the fluorescence decay curve under the action of antioxidants and the area under the fluorescence decay curve under the action of free radicals in the absence of antioxidants.
- ORAC value [(AUC sample -AUC +AAPH )/(AUC Trolox -AUC +AAPH )]*(Trolox molarity/sample molarity)
- PCI2 cells are rat adrenal chromaffin cells that originate from the ectoderm of the generative nervous system and share many similar characteristics with dopaminergic neurons. It is often used to replace dopaminergic neurons in experiments to study the function and biological characteristics of some nerve cells. It is one of the most widely used cell lines to study nerve cell damage and protection in vitro. (Shafer WJ, Atchison WD. Transmitter, ion channel and receptor properties of pheochromocytoma (PC12) cells: a model for neurotoxicological studies. Neurotoxicology 1991.12(3):473-492)
- Glutamate is one of the main neurotransmitters of excitatory synapses in the brain and plays an important role in maintaining normal physiological functions.
- glutamate is a potential neurotoxic substance that can produce "excitotoxicity" on nerve cells in the central nervous system, and oxidative stress injury is a key pathological mechanism (Sztakowski M, Atwell D. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci, 1994, 17(9):359-365).
- ROS reactive oxygen species
- PC12 cells After the PC12 cells were recovered, they were resuspended in DMEM complete medium and cultured in a 37°C, 5% CO2 constant temperature cell incubator. PC12 cells in logarithmic growth phase were seeded in a 96-well plate, 5 ⁇ 10 3 cells/well, and cultured with DMEM medium overnight (37° C.). After adding different concentrations of test compounds and incubating for 1 h, sodium glutamate (10 mM) was injured for 24 h.
- Cell viability was detected by MTT colorimetry. Cells were treated with MTT (a tetramethylazolium salt) solution for 4 h at 37°C. Finally, the formazan crystals were dissolved in 120 ⁇ L DMSO, and the OD value was measured at 570 nm. Cell viability is the percentage of the OD value of the normal control group.
- MTT a tetramethylazolium salt
- PC12 cells were resuspended in DMEM complete medium after recovery, and cultured in a 37°C, 5% CO2 constant temperature cell incubator. After the cells were cultured to logarithmic phase, they were digested with 0.25% trypsin to prepare a single cell suspension, adjusted to a cell density of 1.5 ⁇ 10 5 /mL, and seeded in a six-well plate with 2 mL per well. Incubate for 24h in a 5% CO2, 37°C incubator.
- the medium containing 10 mM sodium glutamate was added, the test compound (as the administration group), or its blank vehicle (0.1% DMSO, as the model control group) was added, and a normal control group was set separately.
- 2 mL of DMEM complete medium (containing 0.1% DMSO) was added.
- three replicate wells were set in each group, and were cultured in an incubator at 37° C., 5% CO 2 for 24 hours. After 24 h, cells were harvested. Resuspend the cells with 0.1 mL of 10 ⁇ M H2DCFDA solution and incubate in a 37°C water bath for 30 min in the dark.
- Experiment 1 To investigate the in vitro efficacy of the test compound X1901 on the glutamate-induced PC12 oxidative stress injury model, and to conduct a parallel comparative study with edaravone at a concentration of 100 ⁇ M. The results are shown in Table 2. It can be seen from Table 2 that compared with the normal control group, the addition of sodium glutamate can induce a significant increase in the ROS level of PC12 cells, and the MFI value increased from 2144 ⁇ 202 in the normal control group to 3537 ⁇ 32.3 in the model control group; Both Feng and X1901 can significantly reduce the MFI value, the ROS generation is close to the normal value, and the activity of X1901 is better. Experiments show that X1901 can inhibit the oxidative stress injury of PC12 cells caused by glutamate, and play a protective effect on nerve cells.
- MFI mean fluorescence intensity; compared with normal control group, ⁇ : P ⁇ 0.001; compared with model control group, ***: P ⁇ 0.001, ****: P ⁇ 0.0001.
- MCAO model After rats were anesthetized with chloral hydrate, a pretreated special suture was inserted into the right common carotid artery (CCA) and into the internal carotid artery (ICA) until it blocked the origin of the middle cerebral artery (MCA). . After 2 hours of occlusion of the artery, the filament was carefully removed to restore blood perfusion to achieve tissue blood reperfusion for 24 hours. In the sham-operated group, the carotid artery was exposed but no suture was inserted.
- 12 male SD rats were divided into 4 groups, 3 rats/group, the first-2 groups were given Y1502 by oral gavage and tail vein injection, respectively, the doses were 10 mg/kg and 5 mg/kg, respectively, the third-4 groups X1901 was administered by oral gavage and tail vein injection at doses of 13.4 mg/kg and 5 mg/kg, respectively.
- 0.2 mL of blood was collected at 5min, 10min, 15min, 30min, 45min, 1.0h, 1.5h, 2.0h, 3.0h, 5.0h, 7.0h, and 24.0h after administration; in the tail vein administration group At 2min, 5min, 10min, 15min, 30min, 45min, 1.0h, 1.5h, 2.0h, 5.0h, 7.0h, 24.0h after administration, 0.2mL of blood was collected (the anticoagulant was sodium metabisulfite containing 16.7mg/mL sodium metabisulfite). heparin sodium solution). The plasma was separated by centrifugation, the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by DAS 3.2.7 software.
- Brain tissue sample processing Take the left hemisphere of the rat and put it into a tube with grinding beads, and add 5 mg/mL sodium metabisulfite physiological saline solution at a mass-to-volume ratio of 1:3. In the grinder, centrifuge at 6000 rpm for 30 s for 1 cycle, and grind for 4 cycles, waiting 20 s for each cycle. The homogenate was placed in a freezer at -20°C until processing.
- the present invention effectively overcomes various shortcomings in the prior art and has high industrial utilization value.
Abstract
式(I)化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,其制备方法、制药用途及其药物组合物。该化合物具有良好抗氧化、神经细胞保护及抗血小板聚集活性,可开发为治疗和预防心脑血管疾病、神经退行性疾病等氧化应激相关疾病的药物,也可用于血栓栓塞性疾病的治疗;易于通过血脑屏障,并具有良好口服生物利用度,可提高患者的依从性和临床的便利性。
Description
本发明涉及药化领域,特别是涉及一种化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物。
自由基是具有一个或多个未配对电子并具有高度反应性的原子、分子、离子或原子团。自由基主要在机体内电子传递过程中形成,是正常细胞有氧代谢的产物。需氧有机体会随着新陈代谢不断产生含有氧和/或氮的自由基,主要有超氧阴离子自由基(·O2)、羟自由基(·OH)、羧自由基(ROO·)、脂氧自由基、一氧化氮自由基(NO·)、硝基自由基(·ONOO-)等。氧自由基是其中最重要的类型,占人体总自由基的95%以上。氧自由基和能转化成为自由基的H
2O
2、单线态氧(1O
2)和臭氧等分子又被统称为活性氧(reactive oxygen species,ROS)。
自由基化学性质高度活泼,可以和生物分子(蛋白质、脂质、糖、DNA)反应,改变其结构和功能。正常情况下,生物体内有一套完整的抗氧化体系,可以维持自由基的代谢平衡。但是,在病理情况下,自由基过量产生或消除障碍,可导致生物膜和大分子物质发生脂质过氧化损伤,引发机体病理性的氧化应激反应。
研究表明氧化应激所致蛋白质、脂质和DNA等细胞组分损伤是多种慢性疾病的致病因素,如中风、动脉粥样硬化、心肌梗塞等心脑血管疾病、神经退行性疾病、糖尿病、肾脏疾病、视网膜疾病、癌症、炎症性疾病、免疫性疾病等(Yun-Zhong F,et al.Free radicals,antioxidants,and nutrition.Nutrition.2002;18:872–879.)。现已很好地建立了机体受损的抗氧化剂状况、氧化损伤的指标和疾病之间的关系。
大脑是体内氧负荷最高、代谢最活跃的器官之一,与其他器官相比,脑组织更易产生自由基和脂质过氧化物,较易受到氧化应激影响。神经细胞受到自由基攻击可导致退行性改变,引发神经退行性疾病,如帕金森病(PD)、阿尔茨海默病(AD)、多发性硬化症(MS)和肌萎缩侧索硬化症(ALS)等。根据研究,氧化应激、线粒体机能障碍、兴奋性毒性、免疫炎症及细胞凋亡等是神经退行性疾病主要发病机制。氧化还原过渡金属催化的氧化应激和自由基生成被认为在其中发挥着关键作用(Mark PM.Metal-catalyzed disruption of membrane protein and lipid signaling in the pathogenesis of neurodegenerative Disorders.Ann.N.Y.Acad.Sci.2004;1012:37–50)。抗氧化药物可清除或减少自由基,保护神经细胞免受自由基的损伤,延缓和阻止神经退行性病变,发挥治疗作用。
氧化应激在缺血性脑血管疾病中也是一个明显、重要的病理现象,在各个阶段都起着不同程度的作用。高血压、高血糖、高血脂、感染、过劳等多种危险因素的刺激可造成血管内皮功能的受损,发生氧化应激和炎症反应,诱发各种炎性因子分泌,启动动脉粥样硬化的病理过程。而氧化应激和炎症反应相互促进,反过来又会进一步加剧内皮功能的损伤。血管内皮功能受损,使低密度脂蛋白(LDL)进入内皮下,被氧自由基攻击修饰,形成氧化低密度脂蛋白(ox-LDL),ox-LDL可进一步诱发动脉粥样硬化斑块形成。而不稳定斑块破裂并发血栓则导致缺血性脑血管病。氧化应激不但在斑块形成中发挥重要作用,也是诱发斑块破裂的关键因素,而动脉粥样硬化斑块的破裂是导致急性脑血管事件的触发因素。脑血管血栓形成、栓塞,导致脑局部血流减少或供血中断,脑组织缺血缺氧,引发脑缺血损伤级联反应,
而缺血及再灌注又使局部自由基暴增,脂质过氧化,加重血管内皮细胞的损伤,使内皮细胞水肿,通透性增加,加重脑组织损伤。氧化应激还可以通过脂质过氧化、蛋白质变性和/或DNA修饰等途径促使神经细胞坏死,也可以通过线粒体、内质网或死亡受体等途径启动神经细胞凋 亡。因此,在脑缺血及再灌注损伤级联反应过程,氧化应激起着关键作用。总之,氧化应激参与了缺血性脑血管病由病理始动直到预后恢复的整个过程。抑制氧化应激及清除自由基是贯穿缺血性脑血管病病程的重要治疗策略。缺血性脑血管病各阶段使用抗氧化剂,可为患者带来不同的获益,对于防治脑血管病的发生、发展起到重要的作用。(王拥军,氧化应激与缺血性脑血管病,中国卒中杂志2008;3(3):163-165)
氧化应激也被认为与心血管疾病密切相关,因为动脉粥样硬化是心血管病最主要的病理基础,而氧化应激贯穿动脉粥样硬化始终。在动脉粥样硬化、心肌缺血及再灌注损伤、心肌梗塞、冠心病、心脏衰竭等的心血管疾病的病理过程中,氧化应激均发挥着重要作用。
如在局部缺血后的心肌内,氧自由基可加速形成,对局部缺血损伤部位造成的损伤。氧化应激反应还能损伤细胞膜,形成细胞内钙负荷超量现象的机制之一,在受损的心肌中可存在心脏收缩机能障碍。
氧化应激在老化过程中也扮演着重要的角色,自由基导致老化以及各种老年病。自由基攻击正在复制中的基因,可造成基因突变,诱发癌症发生。此外,自由基与糖尿病和糖尿病血管系统并发症、炎症性肠道病、黄斑变性和白内障、黄斑变性和白内障、类风湿性关节炎等也有相关性,氧化应激反应所致自由基损伤参与疾病病理过程。
综上,自由基累积引起的氧化应激损伤与多种疾病的发生、发展密切相关。抗氧化剂通过清除自由基能够对相关疾病治疗起到预防或治疗作用。
依达拉奉(Edaravone)是首个上市的自由基清除剂,可清除自由基,抑制脂质过氧化,从而抑制脑细胞、血管内皮细胞和神经细胞的氧化损伤。(K.Toyoda,et al.Free radical scavenger,edaravone,in stroke with internal carotid artery occlusion.J Neurol Sci,2004;221(1–2):11-17)2001年在日本批准作为脑保护剂用于改善急性脑梗塞所致的神经症状、日常生活活动能力和功能障碍。2017年FDA批准 用于治疗肌萎缩性脊髓侧索硬化(ALS)。此外,依达拉奉还有潜力用于预防和治疗各种脑外器官的氧化损伤,自由基损伤相关的慢性疾病。
依达拉奉属于吡唑啉酮类化合物,生理条件下,可由酮-烯醇互变异构形成互变异构形式,包括胺形、酮形和烯醇形,是依达拉奉在体内抗氧化活性的基础(Kazutoshi Watanabe,et al.How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?J Clin Biochem Nutr.2018;62(1):20–38)。临床前及临床研究显示,依达拉奉具有良好的自由基清除和抗氧化活性,可保护脑细胞、神经细胞及血管内皮细胞免受氧自由基损伤。虽然治疗效果肯定,但也存在明显不足。主要体现在水溶性差,口服生物利用度低,临床只能采用静脉注射给药,不方便临床使用。此外,依达拉奉虽然能够一定程度进入脑,但血脑屏障的渗透性有限。大鼠静脉注射
14C依达拉奉后5分钟,在脑脊液(CSF)中仅发现6%的血浆放射性水平(https://www.accessdata.fda.gov/),影响其药效发挥。开发更易透过血脑屏障的口服有效的自由基清除剂是临床未满足迫切需求,有望提高疗效,而且更适于因氧化应激所致慢性疾病的长期用药。
樊玲玲等最近公开(专利申请CN201810292836.1)了新的吡唑醇类化合物,兼具抗血小板聚集和保护神经细胞的双重作用。其中,化合物1(Y1502)与依达拉奉结构最为相近,其抗血小板聚集活性与依达拉奉相近,但神经细胞保护活性弱于依达拉奉。而且未提供口服生物利用度数据,也未见其它与依达拉奉的比较优势。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供一种化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,用于解决现有技术中的问题。
为实现上述目的及其他相关目的,本发明一方面提供一种化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,所述化合物的化学结构式如式I所示:
本发明另一方面提供上述化合物的制备方法,包括:将式III化合物水解,以提供式I化合物,反应方程式如下:
本发明另一方面提供上述的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物在制备药物中的用途。
本发明另一方面提供一种药物组合物,包括上述的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物。
图1显示为本发明实施例7中雄性SD大鼠灌胃或静脉给予X1901后的平均血药浓度-时间曲线示意图。
图2显示为本发明实施例7中雄性SD大鼠灌胃或静脉给予Y1502后的平均血药浓度-时间曲线示意图。
为了使本发明的发明目的、技术方案和有益技术效果更加清晰,以下结合实施例对本发明进行进一步详细说明,熟悉此技术的人士可由本说明书所揭露的内容容易地了解本申请发明的其他优点及功效。
本发明发明人经过大量实践研究,意外发现一种更具优势的吡唑啉酮类化合物,该吡唑啉酮类化合物具有更强的自由基清除和抗氧化活性,且具有更好的神经细胞保护活性和抗血小板聚集活性、以及良好的口服吸收特性,从而可以被用于制备药物,在此基础上完成了本发明。
本发明第一方面提供一种化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,所述化合物的化学结构式如式I所示:
上述所提供的式I化合物,通常可以形成互变异构体,具体可以形成一组烯醇式-酮式互变异构体。烯醇式-酮式互变异构体(Keto-Enol Tautomerism)通常是指因酮或醛和烯醇之间的化学平衡,即酮和醛等羰基化合物具有酸性的α-质子,在不同的pH值下进行质子的转移,形成酮式和烯醇式,从而构成的互变异构体。例如,异构体可以包括化学结构式如式Ia和/或式II所示的化合物。具体来说,上述所提供的式I化合物在一定条件下(例如,pH=6~8、或中性的水溶液中),可以与式Ia化合物和/或式II化合物之间形成一组互变异构体,分别为酮形、烯醇形和胺形, 具体形式如下:
本发明中,术语“盐”应当被理解为由本发明使用的任何形式的活性化合物,其中所述化合物可以为离子形式或带电荷或被偶联到反离子(阳离子或阴离子)或在溶液中。这个定义还可以包括活性分子与其它分子和离子的季铵盐和络合物,特别是通过离子相互作用的络合物。该定义尤其包括生理上可接受的盐,该术语可以被理解为与“药理学上可接受的盐”等同。
本发明中,术语“药学上可接受的盐”通常指当以适当的方式用于治疗时(特别是在人类和/或哺乳动物中应用或使用时)在生理学上可耐受的任何盐(通常来说,这意味着它是无毒的,特别是作为抗衡离子的结果是无毒的)。这些生理上可接受的盐可以是与阳离子或碱形成的,并且在本发明的上下文中,尤其是在人类和/或哺乳动物中施用时,它们应该被理解为由按照本发明所提供的至少一种化合物,通常为酸(去质子化的),如阴离子和至少一种生理学上耐受的阳离子(优选无机阳离子)形成的盐。在本发明的上下文中,具体地可以包括与碱金属和碱土金属形成的盐、以及与铵阳离子(NH
4
+)形成的盐,具体可以是包括但不限于与(单)或(二)钠、(单)或(二)钾、镁或钙形成的盐。这些生理上可接受的盐也可以是与阴离子或酸形成的,并且在本发明的上下文中,特别是在人类和/或哺乳动物中施用时,它们应该被理解为由按照本发明所提供的至少一种化合物,通常质子化的(例如在氮上),如阳离子和至少一种生理上可耐受的阴离子形成的盐。在本发明的上下文中,具体地可以包括由生理上可耐受的酸形成的盐,即特定的活性化合物与生理上可耐受的有 机或无机酸形成的盐,具体可以是包括但不限于与盐酸、氢溴酸、硫酸、甲磺酸、甲酸、乙酸、草酸、琥珀酸、苹果酸、酒石酸、扁桃酸、富马酸、乳酸或柠檬酸形成的盐。
本发明中术语“前药”以其最广泛的意义使用,并且包括在体内可以转化为本发明的化合物的那些衍生物。制备指定的起作用化合物的前药的方法对于本领域技术人员来说应该是已知的,例如,可以参阅如Krogsgaard-Larsen等人,“药物设计和发现教科书”(Textbook of Drug design and Discovery)泰勒弗朗西斯出版社Taylor&Francis(2002年4月)中所公开的相关内容。
本发明中,术语“溶剂化物”通常指任何形式的根据本发明的活性化合物通过非共价键与另一分子(通常为极性溶剂)相结合,所获得的物质,具体可以是包括但不限于水化物和醇化物,例如甲醇化物。
本发明第二方面提供本发明第一方面所提供的化合物的制备方法,包括:将式III化合物(X1901-6)水解,以提供式I化合物,反应方程式如下:
本发明所提供的制备方法中,所述水解反应通常可以在碱存在的条件下进行。本领域技术人员可选用合适种类和用量的碱,用于上述水解反应,例如,所述碱可以是碱金属的氢氧化物等,更具体可以是氢氧化锂等,再例如,所述碱的用量相对于式III化合物通常是基本等量或者过量的,具体的,式III化合物与碱的摩尔比可以为1:1~5、1:1~1.2、1:1.2~1.5、1:1.5~2、1:2~2.5、1:2.5~3、1:3~4、或1:4~5。
本发明所提供的制备方法中,反应通常可以在室温至反应溶剂沸点 的条件下进行,优选可以在室温下进行。本领域技术人员可根据反应进程适当调整水解反应的反应时间,监测反应进程的方法对于本领域技术人员来说应该是已知的,例如可以是色谱法、核磁共振法等分析方法,具体的反应时间可以是1~24小时、1~2小时、2~4小时、4~8小时、8~12小时、或12~24小时。
本发明所提供的制备方法中,反应通常在溶剂存在的条件下进行,所述溶剂通常可以是反应原料的良溶剂、且通常需要包括水,从而可以充分分散反应原料并保证反应的顺利进行。合适的反应溶剂的种类和用量对于本领域技术人员来说应该是已知的,例如,反应溶剂可以包括水,还可以包括醇类溶剂等,具体可以是甲醇等。
本发明所提供的制备方法中,本领域技术人员可选择合适的方法对反应产物进行后处理。例如,水解反应的后处理可以包括:脱除溶剂。反应结束后,可以将反应体系脱除溶剂,以提供式I化合物和式II化合物。脱除溶剂以后的所得产物还可以进一步纯化(例如,柱层析纯化等),以提供纯度更高的式I化合物和式II化合物。
本发明第三方面提供本发明第一方面所提供的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物在制备药物中的用途。本发明所提供的化合物具有更强的自由基清除、抗氧化活性。此外,在细胞实验中证实该化合物对神经细胞(例如,PC12细胞)的损伤(例如,谷氨酸诱导的细胞损伤)具有保护作用,在受试化合物存在的条件下,神经细胞的存活率显著升高、而神经细胞ROS的生成则明显地被抑制,并具有一定的剂量依赖性。进一步在动物实验中,该化合物被证实对血小板聚集(例如,ADP诱导的血小板聚集)有明显的抑制作用、且能够有效减少脑梗死范围(例如,在大鼠局灶性脑缺血-再灌注模型中),并具有一定的剂量依赖性。而在药代动力学方面,该化合物也具有良好的药代动力学性能和药物分布趋势,具有更长的消除半衰期,并可透过血脑屏障,在脑中实现更高的暴露水平。可见,上述化合物或其药学上可接受的盐、 异构体、前药、多晶型物或溶剂化物可以被用于制备药物。
本发明所提供的用途中,上述药物通常可以用于治疗由自由基引起的氧化应激(例如,急性氧化应激、慢性氧化应激等)和/或血栓所导致的疾病。这些疾病可以是心脑血管病(例如,动脉硬化症、心衰、心脏病、脑中风、心肌缺血及缺血再灌注损伤、心肌梗塞、冠心病、或心脏衰竭等)、神经退行性疾病(例如,老年痴呆症(AD)、帕金森氏病(PD)、多发性硬化症(MS)、或肌萎缩侧索硬化症(ALS)等)、老年性/衰老性疾病(例如,关节炎、糖尿病及并发症(例如,糖尿病高糖氧化应激导致的糖尿病性心肌病、糖尿病性肾病、糖尿病性脑血管病、糖尿病性视网膜病等)、骨关节炎、白内障、黄斑变性、前列腺病等)、癌症、肝病、肺病、消化道疾病、肾病、感染性疾病和免疫病等。
本发明第四方面提供一种药物组合物,包括本发明第一方面所提供的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,所述药物组合物还可以包括至少一种药学上可接受的载体。
本发明中,所述组合物可以包括一种或多种药学上可接受的载体,其通常指用于治疗剂给药的载体,它们本身不诱导产生对接受该组合物的个体有害的抗体,且给药后没有过分的毒性。这些载体是本领域技术人员所熟知的,例如,在Remington’s Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中公开了关于药学上可接受的载体的相关内容。具体来说,所述载体可以是包括但不限于盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂等中的一种或多种的组合。
本发明所提供的药物组合物中,上述化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物可以是单一有效成分,也可以与其他活性组分进行组合,构成联合制剂。其他活性组分可以是其他各种可以用于治疗由自由基引起的氧化应激和/或血栓所导致的疾病的药物。组合物中活性组分的含量通常为安全有效量,所述安全有效量对于本领域技术人员来说应该是可以调整的。例如,作为活性成分的上述化合物或 其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物、和药物组合物的活性成分的施用量通常依赖于患者的体重、应用的类型、疾病的病情和严重程度。再例如,作为活性成分的上述化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物的施用量通常可以为0.1~1000mg/kg/day、0.1~0.5mg/kg/day、0.5~1mg/kg/day、1~2mg/kg/day、2~3mg/kg/day、3~4mg/kg/day、4~5mg/kg/day、5~6mg/kg/day、6~8mg/kg/day、8~10mg/kg/day、10~20mg/kg/day、20~30mg/kg/day、30~40mg/kg/day、40~60mg/kg/day、60~80mg/kg/day、80~100mg/kg/day、100~150mg/kg/day、150~200mg/kg/day、200~300mg/kg/day、300~400mg/kg/day、400~600mg/kg/day、600~800mg/kg/day、800~1000mg/kg/day,更优为0.1~20mg/kg/day。
本发明所提供的化合物可以适应于任何形式的给药方式,可以是口服或胃肠外给药,例如,可以是经肺、经鼻、经直肠和/或静脉注射,更具体可以是真皮内、皮下、肌内、关节内、腹膜内、肺部、口腔、舌下含服、经鼻、经皮、阴道、口服或胃肠外给药。本领域技术人员可根据给药方式,选择合适的制剂形式,例如,适合于口服给药的制剂形式可以是包括但不限于丸剂、片剂、咀嚼剂、胶囊剂、颗粒剂、滴剂或糖浆等,再例如,适合于胃肠外给药的制剂形式可以是包括但不限于溶液、悬浮液、可复水的干制剂或喷雾剂等,再例如,适合于直肠给药的通常可以是栓剂。
本发明第五方面提供一种治疗方法包括:向个体施用治疗有效量的本发明第一方面所提供的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物、或本发明第四方面所提供的药物组合物。
本发明中,“个体”通常包括人类、非人类的灵长类,如哺乳动物、狗、猫、马、羊、猪、牛等,其可因利用所述制剂、试剂盒或联合制剂进行治疗而获益。
本发明中,“治疗有效量”通常指一用量在经过适当的给药期间后, 能够达到治疗如上所列出的疾病的效果。
本发明所提供的化合物相对于现有技术中类似的化合物具有更大的性能上的优势,具有更好的抗氧化、神经细胞保护及抗血小板聚集活性,易于通过血脑屏障,并具有良好口服生物利用度,可以极大地提高了患者的依从性和临床的便利性,可开发为治疗和预防心脑血管疾病、神经退行性疾病等氧化应激相关疾病的药物,也可用于血栓栓塞性疾病的治疗,具有良好的产业化前景。
下面通过实施例对本申请的发明予以进一步说明,但并不因此而限制本申请的范围。
实施例1
化合物X1901的合成:
1、X1901-1的合成
用二氯甲烷溶解X1901-SM(100g,0.819mol),降温至0℃,向溶液中分批加入间氯过氧苯甲酸m-CPBA(155g,0.898mol),加毕,升温至45℃回流反应4h。TLC监控至反应完毕,将反应液冷却至室温,过滤,滤饼为反应副产物间氯苯甲酸,滤饼用二氯甲烷淋洗至无色。滤液用Na2SO3水溶液猝灭m-CPBA,分液,水相在用Na2CO3固体调pH9-10,用DCM萃取10遍,合并所有有机相,用饱和NaCl水溶液洗1遍,有机相减压旋干后得到106g的油状液体X1901-1,收率94%。
2、X1901-2的合成
将X1901-1(106g,0.767mol)溶于甲苯,降温至0℃,逐滴滴加POCl
3(400ml),滴毕,升温至90℃反应9小时。TLC监控至反应完毕,将反应液冷却至室温,减压浓缩除尽POCl
3得到油状物,用二氯甲烷溶解油状物,利用NaHCO
3调水溶液pH8-9,分液,水相用DCM萃取4遍,合并所有有机相,依次经饱和食盐水、无水MgSO
4干燥,减压旋干得到60g油状液体X1901-2,收率45%。
3、X1901-3的合成
将60g的X1901-2(0.383mol)溶于DCM中,0℃下逐滴分多批加入m-CPBA(73g,0.423mol),加毕,室温搅拌过夜反应。TLC监控至反应完毕,将反应液冷却至10℃,过滤,滤饼为反应副产物间氯苯甲酸,滤饼用二氯甲烷淋洗至无色。滤液用Na2SO3水溶液猝灭m-CPBA,分液,有机相在用饱和NaHCO3水溶液洗2遍,分液,水相合并,用DCM萃取4遍,合并有机相,用饱和NaCl水溶液洗1遍,蒸干后得油状液体X1901-3,利用正庚烷:EA(1:0-50:1)柱层析纯化得到21g的X1901-3,收率32%。
4、X1901-4的合成
将21g的X1901-4(0.122mol)分散于水合肼中,升温至120℃反应4小时。TLC监控至反应完毕,将反应液冷却至10℃,过滤,滤饼蒸干后得15g的白色固体X1901-4,收率73%。
5、X1901-5的合成
利用300ml水溶解15g的X1901-4(0.089mol),搅拌下滴加乙酰乙酸乙酯(29g,0.22mol),滴毕,升温至50℃反应1小时。TLC监控至原料全部转化为中间体,加入2eq的碳酸钠(18.9g,0.178mol),升温至100℃,TLC监控至反应完毕。加入甲苯,将水溶液减压旋干,滤饼用甲醇分散,抽滤,除去不溶解的无机盐,有机相用水反洗3次,分液,有机相弃去,产物主要集中于水相,水相减压旋干得到X1901-5粗品,利用DCM-甲醇柱层析纯化得到6g的X1901-5,收率29%。
6、X1901-6的合成
用60ml的乙酸酐分散溶解6g的X1901-5(0.026mol),搅拌下升温至140℃反应10h。TLC监控反应至原料反应完毕,将反应液降至室温,减压浓缩,残余物用100mL的DCM溶解,饱和碳酸氢钠调节pH至7.0,减压浓缩得到粗品。利用DCM-甲醇柱层析纯化得到4.2g的X1901-6,收率59%。
7、X1901的合成
C
11H
14N
4O
2 Mol.Wt 234.25
42ml的甲醇溶解4.2g的X1901-6,10ml的水溶解一水合氢氧化锂,搅拌下,将碱溶液滴加到甲醇溶液中,室温搅拌3小时。TLC监控反应至原料反应完毕,减压浓缩得到粗品。利用DCM-甲醇柱层析纯化得到2g的泡沫状固体X1901,收率56%。X1901分子式C
11H
14N
4O
2,分子量:234.25,1H-NMR(400MHz,CDCl3):2.76-2.73(m,2H),4.12(t,1H),3.44(s,2H),2.55-2.45(m,6H),2.24(s,3H),LC-MS:m/z=235(M+1)
实施例2
ORAC方法测定抗氧化活性:
抗氧化能力指数(ORAC)是评价抗氧化活性的标准方法,是以偶氮类化合物AAPH作为过氧自由基来源,荧光素钠为荧光指示剂,维生素E水溶性类似物Trolox为定量标准,使用荧光微孔板分析仪测试自由基对荧光强度的消减,以及抗氧化剂的保护效果。实验取Trolox或受试样品、 荧光素钠及磷酸钾缓冲液于96孔板微孔中,37℃预置5min,迅速加入AAPH启动反应,测试荧光衰减曲线。并测定荧光素钠-AAPH和荧光素钠+AAPH的荧光衰减曲线作为对照。根据抗氧化剂作用下的荧光衰减曲线下面积和无抗氧化剂存在时自由基作用的荧光衰减曲线下面积,计算ORAC。
ORAC值=[(AUC
sample-AUC
+AAPH)/(AUC
Trolox-AUC
+AAPH)]*(Trolox摩尔浓度/样品摩尔浓度)
结果显示:X1901具有明显抗氧化活性,ORAC为20.3μmol Trolox,抗氧化能力强于依达拉奉和Y1502(4.17和11.5μmol Trolox)。
实施例3
对谷氨酸诱导的PC12细胞损伤的保护作用:
PCI2细胞是大鼠肾上腺嗜铬细胞,发源于生成神经系统的外胚层,与多巴胺能神经元有许多相似特征。常被用来代替多巴胺能神经元进行部分神经细胞功能和生物特性研究的实验,是研究体外神经细胞损伤及保护作用最为广泛的细胞系之一。(Shafer WJ,Atchison WD.Transmitter,ion channel and receptor properties of pheochromocytoma(PC12)cells:a model for neurotoxicological studies.Neurotoxicology 1991.12(3):473-492)
谷氨酸是脑内兴奋性突触的主要神经递质之一,对维持正常的生理功能发挥重要作用。然而,谷氨酸却是潜在的神经毒性物质,对中枢神经系统的神经细胞可产生“兴奋毒性”(excitotoxicity),而氧化应激损伤是其中的关键病理机制(Sztakowski M,Atwell D.Triggering and execution of neuronal death in brain ischaemia:two phases of glutamate release by different mechanisms.Trends Neurosci,1994,17(9):359-365)。采用流式细胞荧光分选技术(FACS)使用荧光探针H2DCFDA,检测谷氨酸诱发的PC12细胞活性氧(Reactive oxygen species, ROS)水平。
PC12细胞复苏后,用DMEM完全培养基重悬,置于37℃、5%CO2恒温细胞培养箱内培养。将对数生长期的PC12细胞接种在96孔板中,5×10
3个细胞/孔,用DMEM培养液培养过夜(37℃)。加入不同浓度受试化合物孵育1h后,谷氨酸钠(10mM)损伤24h。每个浓度设3个复孔,设正常对照和模型对照(正常对照不加谷氨酸钠及受试化合物,模型对照加谷氨酸钠,但不加受试化合物(以空白溶媒替代),对照与实验孔平行操作),培养48h后观察细胞的存活率。
细胞的存活率采用MTT比色法检测。细胞用MTT(一种四甲基偶氮唑盐)溶液在37℃中处理4h。最后甲瓒晶体溶解于120μL DMSO中,在570nm测量OD值。细胞存活率为正常对照组的OD值的百分比。
实验结果详见表1。由表1可知,与正常对照组细胞生存率100%相比,用谷氨酸钠可诱发PC12细胞氧化应激损伤,平均细胞生存率降低到58.4%。X1901对谷氨酸诱发致伤的PC12细胞具有显著的保护作用,1μM以上浓度细胞存活率显著升高,并具有剂量依赖性,且同样浓度(10μM)下保护效果明显优于Y1502。
表1对谷氨酸诱发PC12细胞的生存率的影响
注:与正常对照相比,###:P<0.01;与模型对照相比,**:P<0.01,***:P<0.001;与Y1502相比,&:P<0.05,&&&:P<0.001
实施例4
对谷氨酸诱导的PC12细胞ROS生成的抑制作用:
PC12细胞复苏后用DMEM完全培养基重悬,置于37℃、5%CO2恒温细胞培养箱内培养。待细胞培养至对数期后,用0.25%胰酶消化,制成单细胞悬液,调整细胞密度为1.5×10
5/mL,接种在六孔板中,每孔2mL。5%CO2、37℃培养箱中培养24h。24h后吸弃上清,加入含10mM谷氨酸钠的培养基,加入受试化合物(作为给药组),或其空白溶媒(0.1%DMSO,作为模型对照组),另设正常对照组,加入2mL DMEM完全培养基(含0.1%DMSO)代替谷氨酸钠溶液。上述各组,每组设三个复孔,于37℃,5%CO
2,培养箱内培养24h。24h后,收集细胞。用0.1mL 10μM H2DCFDA溶液重悬细胞,在37℃水浴锅内,避光孵育30min。孵育后,1500r/min离心5min,用500μL不含血清的培养基重悬细胞,使用流式细胞仪检测平均荧光强度(MFI),以评估活性氧自由基(ROS)的生成。按以上方法分别进行了两次实验。
实验一:考察受试化合物X1901在谷氨酸诱导的PC12氧化应激损伤模型上的体外药效,并与依达拉奉进行平行对比研究,浓度均为100μM,结果如表2所示。由表2可知,与正常对照组相比,加入谷氨酸钠可诱导PC12细胞ROS水平明显升高,MFI值由正常对照组的2144±202增加到模型对照组的3537±32.3;依达拉奉和X1901均可使MFI值显著降低,ROS生成接近正常值,X1901活性更优。试验表明X1901可抑制谷氨酸导致的PC12细胞氧化应激损伤,发挥神经细胞保护作用。
表2对谷氨酸诱发PC12细胞ROS生成的抑制作用(均值±标准误,n=3)
注:MFI:平均荧光强度(mean fluorescence intensity);与正常对照组相比,ΔΔΔ:P<0.001;与模型对照组相比,***:P<0.001,****:P<0.0001。
实验二:进一步考察了X1901抑制ROS生成效应的剂量关系,并与Y1502进行平行比较。X1901设低、中、高三个浓度剂量,结果如表3所示。由表3可知,模型对照组MFI与正常对照组相比显著升高(P<0.001),表明存在明显氧化应激损伤。与模型对照组相比,X1901各剂量组均可显著降低MFI(P<0.01或P<0.001),并具有剂量依赖性。在同样剂量下(10μM)X1901的药效显著优于Y1502(P<0.05)(表3)。
表3对谷氨酸诱发PC12细胞ROS生成的抑制作用(均值±标准差,n=3)
注:与正常对照组比较,###:p<0.001,与模型组比较,**:p<0.01,***:p<0.001。与Y1502比较,&:p<0.05。
实施例5
对ADP诱导的血小板聚集的抑制作用
雄性SD大鼠10只,采用枸橼酸抗凝负压管收集大鼠动脉血液,即刻颠倒混匀,800r/min离心10min,制备富血小板血浆(PRP),吸取所需PRP,集中混匀备用,再将剩余血以3000r/min离心20min,制备贫血小板血浆(PPP)。取490μl的PRP加入含磁棒的反应杯,再加入10μl不同浓度的受试样品,空白对照组加入10μl生理盐水,每个浓度重复3次,37℃孵育5min,取500μl的PPP加入不含磁棒的反应杯,均预温5min,向PRP中加入1mol/ml的二磷酸腺苷(ADP)5μl进行诱导刺激,记录血小板聚集率曲线。
具体结果如表4所示,由表4可知,X1901各剂量组均显著抑制ADP诱导的体外血小板聚集(P<0.05,P<0.01或P<0.001),且具有剂量依赖性。同等剂量下抑制效应优于Y1502(P<0.001)。
表4体外对ADP诱导的血小板聚集的抑制作用
注:与模型对照组比较,*:p<0.05,**:p<0.01,***:p<0.001。与Y1502比较,
&&&:p<0.001。
实施例6
对局灶性脑缺血-再灌注大鼠脑梗塞范围的影响:
雄性SD大鼠(购于北京维通利华实验动物技术有限公司,许可证号:SCXK(京)2016-0006)70只,体重250-280g,分为6组:假手术组、模型组、Y1502 12.5mg/kg、X1901 6.7mg/kg、X1901 13.4mg/kg、X190126.8mg/kg。实验检疫期结束后,随机分组,采用线栓法分批平行进行局灶性脑缺血-再灌注(MCAO)模型制备。(E Z Longa,P R Weinstein,S Carlson,R Cummins,Reversible middle cerebral artery occlusion without craniectomy in rats.Stroke.1989;20(1):84-91)造模前30min单次灌胃给药,模型组给予空白溶媒。
MCAO模型:大鼠用水合氯醛麻醉后,将预处理的特制栓线插入右侧颈总动脉(CCA),并进入颈内动脉(ICA)直至其阻塞大脑中动脉(MCA)的起始处。在闭塞动脉2h后,小心取出细丝恢复血流灌注实现组织血液再灌注24h。假手术组暴露颈动脉但不插入栓线。
脑梗死范围评价:实验动物于脑缺血再灌注24h后剖检取脑,在冰箱 中速冻15min,取出后行冠状切4刀分为5片。迅速将脑片置于1.2%的TTC染液中(0.02M K
2HPO
4配制),37℃避光温孵20min,取出后置于组织固定液中避光保存。正常组织经染色后呈玫瑰红色,梗塞组织呈白色。将每个脑平面按序摆放在滤纸上,小心挖下白色组织并称重,以梗塞组织重量占全脑重量及手术侧半脑重量的百分比作为梗塞范围(%)。计算抑制率:(模型对照组梗死范围-给药组梗死范围)/模型对照组梗死范围=梗死抑制率。
具体结果如表5所示,由表5可知,X1901能显著减小MCAO模型大鼠术侧和全脑的梗死范围(P<0.05,P<0.01或P<0.001),并呈现剂量相关性。X1901效果优于Y1502(表5)。
注:与模型对照组比较,*:p<0.05,**:p<0.01,***:p<0.001。与Y1502比较,&:p<0.05,&&:p<0.01。
实施例7
大鼠药代动力学:
雄性SD大鼠12只,分为4组,3只/组,第1-2组分别经口灌胃和尾 静脉注射给予Y1502,剂量分别为10mg/kg和5mg/kg,第3-4组分别经口灌胃和尾静脉注射给予X1901,剂量分别为13.4mg/kg和5mg/kg。口服灌胃给药组于给药后5min、10min、15min、30min、45min、1.0h、1.5h、2.0h、3.0h、5.0h、7.0h、24.0h取血0.2mL;尾静脉给药组于给药后2min、5min、10min、15min、30min、45min、1.0h、1.5h、2.0h、5.0h、7.0h、24.0h取血0.2mL(抗凝剂为含16.7mg/mL焦亚硫酸钠的肝素钠溶液)。离心分离血浆,LC-MS/MS方法分析药物浓度,DAS 3.2.7软件计算药代动力学参数。
结果:药时曲线见图1-2,药代动力学参数参见表6-7。由表6和表7可知:
1)口服灌胃给药,X1901在大鼠体内迅速吸收,Tmax为0.25h,平均t1/2为10.12h,口服绝对生物利用度为88%,远高于依达拉奉(5.23%)(Rong,W.T.,et al.Hydroxypropylsulfobutyl-beta-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes.Journal of Pharmaceutical Sciences,2014;103(2):730-742)。与Y1502相比,半衰期更长、口服生物利用度更高。
2)尾静脉注射给药,X1901在大鼠的平均t
1/2为20.28h,平均CLz为0.34L/h/kg,表观分布容积(Vz)均值为9.81L/kg。相较Y1502,具有更长的消除半衰期,更高的组织分布特性。有利于在效应器官或组织维持更高、更持久的药物暴露水平。
表6大鼠灌胃给药的药代动力学参数
单位 | Y1502 | X1901 | |
剂量 | mg/kg | 10 | 13.4 |
AUC 0-24h | h*ng/mL | 7791±488 | 30338±6727 |
AUC 0-∞ | h*ng/mL | 7883±367 | 31730±7339 |
C max | ng/mL | 7168±2335 | 13136±3199 |
t 1/2 | h | 3.14±2.49 | 10.12±2.98 |
T max | h | 0.14±0.048 | 0.25±0 |
F | % | 64 | 88 |
表7大鼠静脉注射给药的药代动力学参数
单位 | Y1502 | X1901 | |
剂量 | mg/kg | 5 | 5 |
AUC 0-24h | h*ng/mL | 6164±5 | 12911±977 |
AUC 0-∞ | h*ng/mL | 6165±4 | 14835±1459 |
t 1/2 | h | 1.82±0.57 | 20.28±5.22 |
MRT 0-∞ | h | 2.70±0.47 | 11.74±3.16 |
Vz | L/kg | 2.13±0.66 | 9.81±2.08 |
CLz | L/h/kg | 0.81±0.001 | 0.34±0.034 |
实施例8
大鼠口服给药在脑中的分布
取雄性SD大鼠6只,分为2组,分别灌胃给予等摩尔剂量的X1901 或依达拉奉(57.4μmol/kg),于给药后10min、1.0h大鼠腹腔取血后处死,取脑组织。脑组织样品处理:取大鼠左半脑放入放有研磨珠的管中,按1:3的质量体积比,加入5mg/mL焦亚硫酸钠生理盐水溶液。在研磨器中,以6000rpm离心30s为1个循环,研磨4个循环,每个循环等待20s。匀浆液置于-20℃的冰箱中冷冻待处理。取50μL的血浆/脑组织匀浆样品于1.5mL离心管中,加入200μL的内标工作液(100ng/mL依达拉奉甲醇溶液),涡旋5min后,于高速离心机12000rpm下离心10min。取上清液,UPLC/MS/MS方法分析组织匀浆上清液药物浓度。
具体结果如表8所示。由表8可知,大鼠口服X1901后,药物可快速分布于脑组织,脑中药物暴露水平明显高于依达拉奉,而且持续时间更长。
表8大鼠单次灌胃给药后脑组织中原型药物的浓度(ng/g)
综上所述,本发明有效克服了现有技术中的种种缺点而具高度产业利用价值。
上述实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (10)
- 如权利要求1所述的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,其特征在于,所述异构体为互变异构体。
- 如权利要求1所述的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物,其特征在于,所述异构体为酮-烯醇互变异构形成的互变异构体。
- 如权利要求1~4任一权利要求所述的化合物或其药学上可接受的盐、 异构体、前药、多晶型物或溶剂化物在制备药物中的用途。
- 如权利要求6所述的用途,其特征在于,所述药物用于治疗由自由基引起的氧化应激和/或血栓所导致的疾病。
- 如权利要求7所述的用途,其特征在于,所述由自由基引起的氧化应激和/或血栓所导致的疾病包括心脑血管病、神经退行性疾病、老年性/衰老性疾病、癌症、肝病、肺病、消化道疾病、肾病、感染性疾病、或免疫病。
- 如权利要求8所述的用途,其特征在于,所述心脑血管病包括动脉硬化症、心衰、心脏病、脑中风、心肌缺血及缺血再灌注损伤、心肌梗塞、冠心病、或心脏衰竭;和/或,所述神经退行性疾病包括老年痴呆症、帕金森氏病、多发性硬化症、或肌萎缩侧索硬化症;和/或,所述老年性/衰老性疾病包括关节炎、糖尿病及并发症、骨关节炎、白内障、黄斑变性、前列腺病。
- 一种药物组合物,包括如权利要求1-4任一权利要求所述的化合物或其药学上可接受的盐、异构体、前药、多晶型物或溶剂化物。
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CN108558833A (zh) * | 2018-03-30 | 2018-09-21 | 贵州医科大学 | 吡唑醇类化合物、其药物组合物及其在药物中的应用 |
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