WO2023155757A1 - 基于菝契皂苷元结构的衍生物及其药物组合物的用途 - Google Patents
基于菝契皂苷元结构的衍生物及其药物组合物的用途 Download PDFInfo
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to the field of medical technology, in particular to the field of chemical synthesis of medicines, and specifically refers to a novel method for preparing drugs based on smilagenin-like structure derivatives and pharmaceutical compositions thereof for the treatment of associated diseases caused by abnormal mitochondrial function. use.
- Anemarrhena is one of the common Chinese medicines in my country. It is the dry tuber of Anemarrhena asphodeloides Bunge, a plant of the Liliaceae family. Its extract has been shown to have biological activities such as diuretic, antidiabetic, antiplatelet aggregation, antifungal, regulation of metabolism, and also exhibits inhibitory effect on cyclic AMP phosphodiesterase.
- the main chemical components of the extract are steroidal saponins, diphenylpyrone, polysaccharides and lignin.
- steroidal saponins include timosaponins A-I, A-II, A-III, A-IV, B-I, B-II and B-III, and malcogenin 3-O- ⁇ -D-glucopyranose Base (1 ⁇ 2)- ⁇ -D-galactopyranoside B, degalactoside, F-rissasapenoside and smilaxaponin, etc.
- it also contains Anemarrhena polysaccharide A/B/C/D, cis-cypress resinol, monomethyl-cis-cypress resinol, oxidation-cis-cypress resinol, 2,6,4'-trihydroxy-4 -Methoxybenzophenone, p-hydroxyphenyl crotonoleic acid, vinyl behenicate, ⁇ -sitosterol, mangiferin, niacin, niacinamide and pantothenic acid, etc.
- Mitochondrial function and behavior are central to human physiology. Mitochondria perform diverse and interrelated functions, producing ATP and many biosyntheses while also contributing to cellular stress responses such as autophagy and apoptosis. Mitochondria form a dynamic, interconnected network and are tightly bound together with other cellular compartments. Furthermore, mitochondrial function extends beyond cell boundaries and affects the physiology and organization of organisms by regulating intercellular communication.
- the mitochondrial respiratory chain is mainly composed of mitochondrial respiratory chain enzymes, and the defect of the mitochondrial respiratory chain enzyme complex is an important cause of mitochondrial diseases (about 30%-40% of mitochondrial diseases are caused by the defects of mitochondrial respiratory chain enzymes).
- the structure and function of the human respiratory chain super complex, oxidative phosphorylation is completed step by step by five respiratory chain protein complexes located on the inner mitochondrial membrane, and these five protein complexes are complex I (NADH dehydrogenase ), complex II (succinate dehydrogenase), complex III (cytochrome c reductase), complex IV (cytochrome c oxidase), and complex V (ATP synthase).
- complex I NADH dehydrogenase
- complex II succinate dehydrogenase
- complex III cytochrome c reductase
- complex IV cytochrome c oxidase
- complex V ATP synthase
- the action of small molecules on the mitochondria can maintain the complex in an active state, and allosterically regulate the activity and electron transfer efficiency of the complex, and at the same time contribute to the overall structure stability of the complex, thereby reducing the mitochondrial ROS (superoxide free base) generated.
- mitochondrial ROS superoxide free base
- Stroke is commonly known as stroke, including ischemic stroke (cerebral infarction) and hemorrhagic stroke (cerebral parenchymal hemorrhage, ventricular outflow blood, subarachnoid hemorrhage).
- ischemic stroke Cerebral infarction
- hemorrhagic stroke Cerebral parenchymal hemorrhage, ventricular outflow blood, subarachnoid hemorrhage
- multiple causes of stroke lead to cerebrovascular damage, focal (or overall) brain tissue damage, causing clinical symptoms for more than 24 hours or death. It has the characteristics of high morbidity, disability, recurrence and mortality. Stroke is the leading cause of death among Chinese residents.
- Amyotrophic lateral sclerosis also known as motor neuron disease, is a chronic, progressive degenerative disease of upper and lower motor neurons and the trunk, limbs, and head and face muscles they innervate. It often manifests as progressively aggravated muscle weakness, muscle atrophy, and muscle fasciculation caused by combined damage to upper and lower motor neurons.
- the clinical manifestations are progressive skeletal muscle weakness, muscle atrophy, muscle fasciculation, bulbar palsy, and pyramidal tract signs. Early symptoms are mild and easily confused with other diseases. Patients may just feel some weakness, twitching, and easy fatigue. Some symptoms gradually progress to general muscle atrophy and dysphagia, and finally produce respiratory failure.
- Neurodegenerative diseases are divided into acute neurodegenerative diseases and chronic neurodegenerative diseases.
- Acute neurodegenerative diseases mainly include stroke, brain injury (BI) and epilepsy; chronic neurodegenerative diseases mainly include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), muscular atrophy Lateral sclerosis (ALS), different types of spinocerebellar ataxia (SCA) and Pick's disease, etc.
- the causes of neurodegenerative diseases mainly include the following four aspects: 1. Oxidative stress. Oxidative stress is caused by the excessive production of free radicals and (or) the failure to remove them in time, the imbalance of oxidation and anti-oxidation in the body, and the damage of cells and tissues in the body.
- Free radicals are atoms or groups with unpaired electrons, including hydroxyl radicals, superoxide anions, nitric oxide, etc.
- oxidative damage to nerve tissue has been found in neurodegenerative diseases such as AD, PD, and ALS; 2.
- Mitochondrial dysfunction There are mtDNA defects and abnormal oxidative phosphorylation in the brain of AD patients.
- Polymerase chain reaction (PCR) and Western blot hybridization detected mtDNA breaks, base deletions and mistranslation mutations in the brain tissue of sporadic AD patients. Electron microscope observation confirmed that the number of mitochondria increased, the structure was abnormal, and lamellar bodies and crystalline inclusion bodies appeared.
- Novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19), referred to as "new coronary pneumonia", named “2019 coronavirus disease” by the World Health Organization, refers to the acute respiratory infectious disease caused by 2019 new coronavirus infection.
- the clinical manifestations of patients with pneumonia infected by the new coronavirus are: fever, fatigue, and dry cough as the main manifestations, and a state of hypoxia and hypoxia will occur. About half of the patients will have dyspnea after more than a week, and severe cases will rapidly progress to acute respiratory distress syndrome. , septic shock, refractory metabolic acidosis and coagulopathy.
- the treatment drugs include Paxlovid, Azvudine Tablets, Monogravir Capsules, Sanhan Huashi Granules, Qingfei Paidu Decoction, etc.
- the purpose of the present invention is to overcome the defects in the above-mentioned prior art.
- the first aspect of the present invention provides a derivative based on the structure of smilagenin in the preparation of the treatment of related diseases caused by abnormal mitochondrial function.
- the purposes in medicine, its main characteristic is, the structural formula of described derivative is as shown in general formula I,
- the derivative represented by the general formula I is formed by linking the following fragment A and fragment B,
- Z is NR 1 R 2 ;
- R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, and the substituents of C 1 -C 10 alkyl are selected from halogen, hydroxyl, amino , nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl, C 3 -C 14 heterocyclyl, C 3 -C 14 heteroaryl, one or more heteroatoms selected from N, O, S; or R 1 and R 2 together form a three- to eight-membered ring, and the three- to eight-membered ring has one or more selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6
- X is C(O) or S(O) 2 ;
- Y is C(R d )(R e ), C(O) or S(O) 2
- R d and R e are each independently hydrogen or C 1 -C 10 alkyl having at least one substituent, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl, wherein the substituents are selected from halogen, hydroxyl, amino, nitro, cyano, aldehyde, carboxyl, alkoxy group, -CF 3 or -SF 5 , one or more heteroatoms selected from N, O, S, or, R d and Re form together a three to eight-membered ring, and the three to eight-membered ring has one or more selected from C1-C10 alkyl, C3-C10 cycloalkyl, C 6- C 20 aryl, or C 3 -C 14 heteroaryl, halogen, hydroxyl, amino, alkoxy, -CF 3 ,
- X2 is O, S or NH
- R a is independently hydrogen or C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 - having at least one substituent C 14 Heteroaryl, wherein the substituent is selected from halogen, hydroxyl, amino, nitro, cyano, alkoxy, -CF 3 or -SF 5, and the heteroatom is selected from one or more of N, O, S ;
- n is an integer from 0 to 10 and n is not 0, m is 1, or n is 0 and m is 1, or n is an integer from 0 to 10 and n is not 0, m is 0;
- R 3 , R 4a , R 4b , R 5a , R 5b are each independently hydrogen or selected from halogen, substituted alkyl, hydroxyl, amino;
- Each "*" independently represents the racemic, S or R configuration.
- R 6 is hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, and the substituent of C 1 -C 10 alkyl is selected from halogen, hydroxyl, -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, Benzyl, pyridyl, -COalkyl, -COaryl, -SO2alkyl , -SO2aryl , -CO2alkyl, C2 - C4 (CO)alkenyl, -CO2aryl , -SO 3 H;
- L is hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, the substituent of C 1 -C 10 alkyl is selected from halogen, hydroxyl, -NH 2 , nitro, -CN, C 1 -C 4 alkyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl;
- n is an integer from 0 to 10;
- n2 is 0, 1, 2, or 3;
- n, m' are independently an integer from 1 to 4.
- W 1 is C or NH
- V 1 is C or NH
- M is C, S, O or NH
- Y 1 is C(Rd)(Re), C(O) or S(O) 2
- Rd, Re are independently hydrogen or C 1 -C 10 alkyl with at least one substituent, C 3 -C 10 ring Alkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl, wherein the substituent is selected from halogen, hydroxyl, amino, nitro, cyano, aldehyde, carboxyl, alkoxy, -CF 3 or -SF 5 , one or more heteroatoms selected from N, O, and S, or, R d and Re form together a three- to eight-membered ring, and the three- to eight-membered ring has one or more from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 20 aryl, or C 3 -C 14 heteroaryl, halogen, hydroxyl, amino, alkoxy, -CF 3 , -SF 5 or
- L is hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, the substituent of C 1 -C 10 alkyl is selected from halogen, hydroxyl, -NH 2 , nitro, -CN, C 1 -C 4 alkyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl;
- n is an integer from 0 to 10;
- n2 is 0, 1, 2, or 3;
- n3 is an integer from 1 to 10
- n is an integer of 0 to 10.
- R 6 and R 7 are independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, C 1 -C 10 alkyl substituents are selected from halogen, hydroxyl, -NH 2 , nitro, -CN , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkyne Base, phenyl, benzyl, pyridyl, -CO alkyl, -CO aryl, -SO 2 alkyl, -SO 2 aryl, -CO 2 alkyl, C 2 -C 4 (CO) alkenyl , -CO 2 aryl, -SO 3 H;
- L is hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, the substituent of C 1 -C 10 alkyl is selected from halogen, hydroxyl, -NH 2 , nitro, -CN, C 1 -C 4 alkyl , C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl;
- W 2 is C or NH
- V is C, O, S or NH
- n is an integer from 0 to 10;
- n1 is an integer from 1 to 10;
- n2 is 0, 1, 2, or 3.
- Z 1 is hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, the substituent of C 1 -C 10 alkyl is selected from halogen, hydroxyl, -NH 2 , nitro, -CN, C 1 -C 4 alkane C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl , pyridyl, -COalkyl, -COaryl, -SO2alkyl , -SO2aryl, -CO2alkyl , C2- C4 ( CO)alkenyl, -CO2aryl , -SO3H ;
- W 3 is C, S, O or NH
- n is an integer from 0 to 10;
- n4, n5, n6, and n7 are integers from 1 to 4.
- fragment B in the structural formula of the derivative has the following structure:
- the derivative is the following compound, the diastereomeric mixture of the following compound or the following compound One of the enantiomers of
- the derivatives include corresponding deuterated compounds in which any one or more hydrogen atoms are replaced by its stable isotope deuterium.
- compositions which comprises: the above-mentioned compound of general formula I, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug or Its pharmaceutically acceptable carrier.
- additional therapeutic agents are also included, and the additional therapeutic agents include antidepressants, antimanic drugs, drugs for treating Parkinson's disease, drugs for treating Alzheimer's disease or combinations thereof.
- the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, triflate, benzenesulfonate, p-toluene Sulfonate (tosylate), 1-naphthalenesulfonate, 2-naphthalenesulfonate, acetate, trifluoroacetate, malate, tartrate, citrate, lactate, oxalate salt, succinate, fumaric acid Salt, maleate, benzoate, salicylate, phenylacetate, mandelate.
- the additional therapeutic agent is moclobemide, toloxaone, fluoxetine, paroxetine, citalopram, sertraline, venlafaxine, trimipramine, trazodone, Imidamine, desipramine, clomipramine, amitriptyline, nortriptyline, doxepin, maprotiline, loxapine, amoxapine, mirtazapine, buspirone, Clomezadone, tandospirone, lithium carbonate, tacrine, huperzine A, galantamine, donepezil, Lifanstigmine, memantine, pramipexole, tarexol, ropironib, or a combination of them.
- the present invention also provides the application of the pharmaceutical composition in the preparation of medicines for preventing, treating, treating or alleviating diseases, diseases or conditions of patients.
- the associated diseases, disorders or conditions caused by mitochondrial abnormalities are specifically associated diseases, disorders or conditions caused by abnormalities in the respiratory chain, including: metabolic diseases, tumors, inflammation, and central nervous system diseases. kind.
- Metabolic diseases include: hyperglycemia, hyperlipidemia, hypercholesterolemia, high LDL, low HDL, angiogenic disorders, non-alcoholic fatty liver, cerebrovascular accident, myocardial infarction, atherosclerosis , coronary heart disease, anti-aging, urgency and frequent urination, type I diabetes, chronic obstructive pulmonary disease, etc.
- Tumors include: benign prostatic hyperplasia, Wegener's granulomatosis, pulmonary sarcoidosis, leukemia, lymphoma, pancreatic cancer, neurological tumors, etc.
- Inflammation includes: peripheral neuritis, chemotherapy-induced peripheral neuritis, autoimmune diseases, conditions associated with organ transplantation, influenza virus, coronavirus (infection prevention, treatment and resolution of sequelae), acute respiratory distress syndrome, inflammatory Enteropathy, Crohn's disease, ulcerative colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, rheumatoid arthritis, spondyloarthritis, gout, systemic lupus erythematosus, Sjogren's syndrome, provincial scleroderma, antiphospholipid syndrome, vasculitis, osteoarthritis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis, nephritis, chyle Diarrhea, autoimmune ITP, transplant rejection, ischemia-reperfusion injury of solid organs, seps
- Central nervous system disorders include: Pick's disease, spinal cord injury repair, depression, anxiety, Parkinson's disease, Alzheimer's disease, sleep disorders, ischemic stroke, hemorrhagic stroke, amyotrophic lateral Sclerosis, traumatic brain injury, brain atrophy, Huntington's disease, schizophrenia, mania, drug addiction withdrawal, multiple sclerosis, sleep improvement, muscle weakness, etc.
- smilagenin-based compounds Using the smilagenin-based compounds, pharmaceutical compositions and applications of the present invention, through relevant in vivo and in vitro model activity tests on the smilagenin-based compounds, it was unexpectedly found that many derivative compounds have superior cytoprotective activity, especially It has unexpected protective activity on a variety of brain neuron cells, and this type of compound has excellent blood-brain permeability, and has potential wide application and great value for the treatment of diseases caused by a variety of mitochondrial dysfunction, making up for The deficiencies of the prior art in the application of timogenin compounds have important scientific and commercial application value.
- Figure 1 shows the death of neurons under the action of different small molecule compounds.
- Fig. 2 shows the effect of small molecule compounds on hydrogen peroxide (H 2 O 2 )-induced oxidative damage to human SHSY5Y neural tumor cells.
- Figure 3 is the percentage of dead neurons.
- Figure 4 is a phenotype diagram of the effects of each experimental group on zebrafish inflammation.
- Figure 5 is the effect of each experimental group on zebrafish inflammation (number of neutrophils).
- Figure 6 shows the anti-inflammatory effects of each experimental group on inflammatory zebrafish.
- Figure 7 shows changes in cerebral blood flow in mice during the operation.
- Figure 8 shows the body weight changes of mice before and after surgery.
- Figure 9 shows the changes in the grip force of the mouse forelimbs.
- Figure 10 is the score of neurological deficit in mice.
- Figure 11 shows the volume of cerebral infarction in mice.
- Figure 12 is the volume of mouse brain edema.
- Figure 13 is the immobility time of mouse FST.
- Figure 14 is the preference rate of sugar water in mouse SPT.
- Figure 15 is the TST immobility time of mice.
- Figure 16 is the detection of ROS levels in mouse serum.
- Figure 17 is the detection of H2O2 concentration in mouse serum.
- Figure 18 is the detection of NO concentration in mouse serum.
- Figure 19 is the detection of lipid peroxidation level in mouse serum.
- Figure 20 is the detection of ROS levels in the mouse hippocampus.
- Figure 21 is the detection of H 2 O 2 concentration in mouse hippocampus.
- Figure 22 is the detection of NO concentration in mouse hippocampus.
- Figure 23 is the detection of lipid peroxidation level in mouse hippocampus.
- Figure 24 is the detection of IL-1 ⁇ concentration in mouse serum.
- Figure 25 is the detection of IL-6 concentration in mouse serum.
- Figure 26 is the detection of IL-10 concentration in mouse serum.
- Figure 27 is the detection of IL-1 ⁇ concentration in mouse hippocampus.
- Figure 28 is the detection of IL-6 concentration in mouse hippocampus.
- Figure 29 is the detection of IL-10 concentration in mouse serum.
- Figures 30a to 32b show the binding strength of each small molecule to Complex I of the respiratory chain, respectively.
- Figure 33 is a diagram showing the results of the activity of each small molecule on SMP.
- Figure 34 is a schematic diagram of the results of various small molecules on oxygen consumption of cells.
- Figures 35a to 35b are graphs showing the results of small molecules on mitochondrial ROS and mitochondrial transmembrane potential difference, respectively.
- Figures 36a to 36d are graphs showing the effects of small molecules on atherosclerosis in APOE mice, respectively.
- Figures 37a to 37g are graphs showing the water maze results of small molecules on AD rats.
- Fig. 38 is a graph showing the results of small molecules on the T-maze of AD rats.
- Figures 39a and 39b are graphs showing the effect of small molecules on the nesting behavior of AD mice.
- Figures 40a and 40b are graphs showing the water maze results of small molecules on AD mice.
- Figure 41 is a graph showing the light and dark box results of small molecules on AD mice.
- Figures 42a and 42b are graphs of small molecule effects on survival of TDP43 A315T mice.
- Fig. 43 is a graph showing the results of small molecule analysis on the gait of SOD G93A mice.
- Figure 44 is a graph of the open field results of small molecules on SOD G93A mice.
- Figures 45a and 45b are graphs showing the results of small molecules on the DSS mouse enteritis model.
- Figures 46a and 46b are graphs showing the results of small molecules on the TNBS rat enteritis model.
- Figure 47 is a graph showing the effect of small molecules on blood glucose in DB mice.
- Figures 48a to 48d are the result graphs of body weight and body fat percentage of DIO mice.
- Figure 49 is a graph showing the in vivo killing effect of small molecules on hematological tumors.
- Fig. 50 is a result graph showing the protective effect of small molecules on substantia nigra neurons.
- Figure 51 is a graph showing the results of the protective effect of small molecules on virus infection.
- Fig. 52 is a graph showing the results of small molecules on the acute craniocerebral trauma model of rat TBI.
- Fig. 53 is a graph showing the in vitro killing effect of small molecules on pancreatic cancer cells.
- Figure 54 is a graph of the results of small molecule excess urine excretion in DB animals.
- Figures 55a to 55c are graphs of small molecule effects on cardiovascular inflammation in high fat fed APOE mutant mice.
- Figures 56a and 56b are graphs showing the experimental results of the effect of small molecules on the sleep of mice affected by a subthreshold hypnotic dose of pentobarbital sodium.
- alkyl in the present invention refers to a monovalent saturated aliphatic hydrocarbon group with 1 to 10 carbon atoms, including straight chain and branched chain hydrocarbon groups, such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl (( CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), tert-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 —), neopentyl ((CH 3 ) 3 CCH 2 —).
- alkyl includes substituted or unsubstituted alkyl groups.
- substituted or unsubstituted means that the group can be unsubstituted, or the H in the group can be replaced by one or more (preferably 1 to 6, more preferably 1 ⁇ 3) substituents.
- the "substituted" means that the group has one or more (preferably 1-6, more preferably 1-3) substituents selected from the following group: halogen, hydroxyl , -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 alkynyl, phenyl, benzyl, C 2 -C 8 heterocyclyl, C 2 -C 8 heteroaryl, heteroatoms are selected from one or more of N, O and S indivual.
- substituents selected from the following group: halogen, hydroxyl , -NH 2 , nitro, -CN, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalky
- cycloalkyl represents a substituted or unsubstituted C 3 -C 12 cycloalkyl.
- alkoxy refers to an -O-alkyl group, wherein the alkyl group may be saturated or unsaturated, branched, linear, or cyclic.
- the alkoxy group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative examples include, but are not limited to: methoxy, ethoxy, propoxy.
- aryl refers to a monovalent aromatic carbocyclic group of 6 to 20 (preferably 6 to 14) carbon atoms, which has a single ring (such as phenyl) or a condensed ring (such as naphthalene) group or anthracenyl), if the point of attachment is on an aromatic carbon, the fused ring may be non-aromatic (such as 2-benzoxazolone, 2H-1,4-benzoxazin-3(4H)-one- 7-base, etc.).
- Preferred aryl groups include phenyl and naphthyl.
- the term includes substituted or unsubstituted forms wherein the substituents are as defined above.
- alkenyl groups are vinyl, allyl, but-3-enyl.
- cycloalkyl refers to a cyclic alkyl group having 3 to 10 carbon atoms, having a single ring or multiple rings (including fused systems, bridged ring systems and spiro ring systems). In fused ring systems, one or more rings can be cycloalkyl, heterocyclic, aryl, or heteroaryl as long as the point of attachment is through the cycloalkyl ring.
- suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclooctyl.
- halo or halogen refers to fluorine, chlorine, bromine and iodine.
- heteroaryl refers to an aromatic group having 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring, such a heteroaryl group may be monocyclic (such as pyridyl or furyl) or fused ring (such as indolizinyl (indolizinyl) or benzothienyl), wherein the fused ring can be non-aromatic and/or contain a heteroatom, as long as the point of attachment is through an atom of an aromatic heteroaryl.
- the ring atom nitrogen and/or sulfur of the heteroaryl is optionally oxidized to N-oxide (N-O), sulfinyl or sulfonyl.
- N-O N-oxide
- Preferred heteroaryl groups include pyridyl, pyrrolyl, indolyl, thienyl and furyl. The term includes substituted or unsubstituted heteroaryl groups.
- substituted heteroaryl refers to a heteroaryl group substituted by 1 to 5, preferably 1 to 3, more preferably 1 to 2 substituents selected from and The same substituents as defined for substituted aryl.
- heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated, partially saturated or unsaturated group (but not aromatic) , having a single ring or a condensed ring (including a bridged ring system and a spiro ring system), with 1 to 10 carbon atoms and 1 to 4 (such as 3) heteroatoms selected from nitrogen, sulfur or oxygen in the ring, in the fused In a ring system, one or more rings may be cycloalkyl, aryl or heteroaryl as long as the point of attachment is through a non-aromatic ring.
- the nitrogen and/or sulfur atoms of the heterocyclic group are optionally oxidized to provide N-oxide, sulfinyl and sulfonyl moieties.
- substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to a heterocyclic ring substituted by 1 to 5 (eg 1 to 3) substituents group, the substituents are the same as defined for substituted cycloalkyl.
- stereoisomer refers to compounds that differ in chirality at one or more stereocenters.
- Stereotropic Conomers include enantiomers and diastereomers.
- the term "tautomer” refers to alternative forms of compounds that differ in the position of the proton, such as enol-keto and imine-enamine tautomers, or tautomers of heteroaryl groups
- the heteroaryl group contains ring atoms attached to the -NH- part of the ring and the N- part of the ring, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole.
- the invention provides a pharmaceutical composition, which contains active ingredients in a safe and effective dose range, and a pharmaceutically acceptable carrier.
- the "active ingredient" in the present invention refers to the compound of general formula (I) or its pharmaceutically acceptable salt, its stereoisomer or its tautomer, or its prodrug in this invention.
- the "active ingredients" and pharmaceutical compositions described in the present invention can be used as mitochondrial protective agents. In another preferred embodiment, it is used for preparing medicines for preventing and/or treating neurodegenerative diseases. In another preferred embodiment, it is used for preparing medicines for preventing and/or treating metabolic diseases related to mitochondria.
- Safe and effective amount means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose.
- the "one dose” is a tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” here means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.
- the compounds of the preferred embodiments of the present invention may be administered as the sole active agent or in combination with one or more other agents useful in the treatment of cancer.
- the compounds of the preferred embodiments will be administered in a therapeutically effective amount by any of the accepted modes of agents having similar effects.
- the actual amount of the compound (i.e., active ingredient) of the preferred embodiments to be used will depend on a number of factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors. .
- the drug can be administered several times a day, preferably once or twice a day. All of these factors are within the consideration of the attending physician.
- the therapeutically effective dose can generally be a total daily dose administered to the patient once or in divided doses, for example, about 0.001 to about 1000 mg/kg body weight per day, preferably, about 1.0 to about 30 mg/kg body weight.
- Dosage unit compositions may contain dosage factors thereof to yield the daily dose. The choice of dosage form depends on various factors, such as the mode of administration and the bioavailability of the drug substance.
- the compounds of the preferred embodiments may be administered as pharmaceutical compositions by any route appropriate for the condition being treated. Suitable routes include, but are not limited to, oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal), vaginal, intraperitoneal, intrapulmonary and intranasal.
- the preferred route may vary depending on the condition of the patient.
- the preferred mode of administration is oral administration, and the convenient daily dose can be adjusted according to the degree of bitterness. It can be formulated with pharmaceutically acceptable carriers or excipients as tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition wait.
- the compound When the compound is formulated parenterally, it can be formulated with a pharmaceutically acceptable parenteral carrier.
- Another preferred mode of administering the compounds of the preferred embodiments is by inhalation. This is an effective method of delivering therapeutic agents directly to the respiratory tract (see, eg, US Patent No. 5,607,915).
- the present invention can administer the compound in any convenient preparation form, and the "preparation" referred to in the present invention refers to a dosage form containing the compound of general formula I of the present invention that is beneficial to administration (drug delivery), such as: but not limited to, aqueous solution injection, Powder injections, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder sprays, sustained-release and controlled-release preparations, etc.
- drug delivery such as: but not limited to, aqueous solution injection, Powder injections, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder sprays, sustained-release and controlled-release preparations, etc.
- These pharmaceutical excipients can be commonly used in various preparations, such as: but not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrants and lubricants, etc. ; It can also be selected for use in order to be compatible with the substance, such as: emulsifier, solubilizer, bacteriostat, analgesic and antioxidant, etc., this type of adjuvant can effectively improve the stability of the compound contained in the composition and solubility or change the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound of the present invention in vivo, thereby enhancing the administration effect.
- excipients used to achieve specific administration purposes or methods such as sustained-release administration, controlled-release administration, and pulse administration, such as but not limited to, Gelatin, albumin, chitosan, polyether and polyester polymer materials, such as: but not limited to, polyethylene glycol, polyurethane, polycarbonate and its copolymers, etc.
- the main manifestations of the so-called “beneficial” include, but are not limited to, improving the therapeutic effect, increasing bioavailability, reducing toxic and side effects, and improving patient compliance.
- Suitable pharmaceutically acceptable carriers or excipients include, for example, treating agents and drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose , methylcellulose, sodium carboxymethylcellulose, glucose, hydroxypropyl- ⁇ -cyclodextrin, sodium sulfobutyl- ⁇ -cyclodextrin, polyvinylpyrrolidone, low melting point wax, ion exchange resin, etc., and Any combination of two or more thereof.
- treating agents and drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose , methylcellulose, sodium carboxymethylcellulose, glucose, hydroxypropyl- ⁇ -cyclodextrin, sodium sulfobutyl- ⁇ -cyclodextrin, polyvinylpyrrolidone, low melting point
- Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
- Preferred liquid carriers, especially for injectable solutions include water, saline, aqueous dextrose and glycol.
- Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991), incorporated herein by reference.
- the term "pharmaceutically acceptable salt” refers to non-toxic acid or alkaline earth metal salts of compounds of general formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of general formula I, or by reacting suitable organic or inorganic acids or bases with basic or acidic functional groups, respectively.
- Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate , camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, lauryl sulfate, ethanesulfonate, glucose heptanoate, glycerophosphate, hemisulfate, heptanoic acid Salt, Caproate, Fumarate, Hydrochloride, Hydrobromide, Hydroiodide, 2-Hydroxyethanesulfonate, Lactate, Maleate, Methanesulfonate, Nicotinate , 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, Succinate, Sulfate
- nitrogen-containing basic groups can be quaternized with the following reagents: alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups; dialkyl sulfates , such as dimethyl, diethyl, dibutyl, and dipentyl sulfate; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; arane Halides such as benzyl and phenethyl bromide, etc. Water-soluble or oil-soluble or dispersible products are thus obtained.
- alkyl halides such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl groups
- dialkyl sulfates such as dimethyl, diethyl, dibutyl, and dipentyl s
- acids which can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, citric acid.
- Base addition salts can be prepared in situ during the final isolation and purification of the compounds of general formula I, or by separately reacting the carboxylic acid moiety with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate or carbonic acid Hydrogen salt) or ammonia, or organic primary, secondary or tertiary amine reaction.
- Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including , but not limited to: ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc.
- Other representative organic amines for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
- the term "pharmaceutically acceptable prodrug” refers to those prodrugs of the compounds of the preferred embodiments, which are rapidly converted into the parent compound represented by the above general formula in vivo, for example, hydrolyzed in blood.
- pharmaceutically acceptable prodrug refers to those prodrugs of the compounds of the preferred embodiments, which are rapidly converted into the parent compound represented by the above general formula in vivo, for example, hydrolyzed in blood.
- T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems (Pro-drugs as Novel Delivery Systems), Volume 14 of A.C.S.15 Symposium Series” and “Edward B. Roche, eds., Bioreversible Carriers in Drug Design (Bioreversible Carriers in Drug Design), American Pharmaceutical Association and Pergamon Press, 1987", both of which are incorporated herein by reference.
- the present invention provides the preparation method of the compound of general formula (I). Taking timogenin as an example, the preparation method of the key intermediate is as follows:
- the preparation of the compound of general formula (I) is as follows: Take the timosaponin mother nucleus ⁇ configuration as an example (other configurations or certain configurations of other mother nucleus, the preparation method is consistent with the method provided, and the synthetic route is as follows:
- R 1 , R 2 , Y, and n are as above.
- DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene
- DIBAL refers to diisobutylaluminum hydride
- DIAD refers to diisopropyl azodicarboxylate
- DIEA refers to diisopropyl Ethylamine
- DMAP refers to N,N-dimethylaminopyridine
- DME refers to 1,2-dimethoxyethane
- DMF refers to N,N-dimethylformamide
- DMPE refers to 1,2-bis( Dimethylphosphino)ethane
- DMSO means dimethylsulfoxide
- DPPB means 1,4-bis(diphenylphosphino)butane
- DPPE means 1,2-bis(diphenylphosphino)ethane
- DPPF means 1,1'-bis(diphenylphosphino)ferrocene
- DPPM means 1,1'-bis(dipheny
- the preparation process is as follows:
- intermediate 8 was obtained under the same conditions as in the third step in Example 1A, with a yield of 50%.
- intermediate 9 was obtained under the same conditions as in the fourth step in Example 1A, with a yield of 90%.
- Example 1B was obtained, and the yield 65%.
- Example 2 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 3 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 4 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 4A was obtained through the same experimental conditions as described in the fifth step in Example 1A.
- Example 4B was obtained through the same experimental conditions as described in the fifth step in Example 1A.
- Example 5 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 6 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 8 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- Example 9 was obtained through the same experimental conditions as described in the fourth step of Example 1.
- Example 10 was obtained through the same experimental conditions as described in the fourth step in Example 1.
- intermediate 12 In a 500 mL round bottom flask were charged intermediate 12 (5 g, 1 eq), mono-tert-butyl malonate (2 eq), EDC ⁇ HCl (2 eq), DMAP (0.1 eq) and Et3N (5 eq), Dissolve in 100 ml of dry DCM, stir the reaction at room temperature for 2 h, and follow the end of the reaction by TLC (PMA color development). After the reaction was completed, the product was washed twice with saturated NH4Cl aqueous solution, dried, and subjected to silica gel column chromatography to obtain 4.5 g of the product.
- NMR data are as follows: 1HNMR (CDCl3, 400MHz, ppm): ⁇ 0.76 (s, 3H), ⁇ 0.80-2.30 (m, 36H), ⁇ 2.55-3.00 (m, 9H), ⁇ 3.15-4.50 ( m, 14H), ⁇ 5.25 (br s, 1H); mass spectrum: [M+1] 641.5.
- reaction solution After the reaction is completed, slowly drop the reaction solution into water (65L) at 0-10°C, a large amount of solids precipitate out, filter, and rinse the filter cake with 500mL of PE: EA (50:1) mixed solvent, and the obtained solids are vacuum-washed. Dry at low temperature (40-50° C. water bath) for 8 hours to obtain 451 g of solid, namely intermediate 13.
- intermediate 13 25 g, 43.8 mmol
- potassium acetate 8.60 g, 87.6 mmol
- 18-crown-6 23.15 g, 87.6 mmol
- 300 mL of dimethylsulfoxide solvent 300 mL
- the temperature of the reaction system was raised to 55 degrees Celsius, and the temperature was maintained for 16 hours.
- the reaction mixture was poured into 1 L of ice water and stirred for 30 minutes. Filter and wash the filter cake with water to give 7 g of white solid.
- intermediate 14 (2.0 g, 4.36 mmol) was added along with 60 mL THF, 60 mL methanol, 30 mL water and 5.5 mL 4N aqueous LiOH.
- the temperature of the reaction system was raised to 60 degrees Celsius, and the temperature was maintained for 2 hours.
- the organic solvent was spun off, and 50 ml of water was added. Filtration and washing of the filter cake with water yielded 1.7 g of a white solid.
- TMSN 3 (0.12g, 1.1eq, 2eq) and DBU (0.32g, 0.21mmol, 4eq ), N 2 .
- the reaction solution was introduced into water (20 mL) at 0-10°C, stirred at 0-10°C for 5-10 minutes, and then filtered. The filter cake was purified by silica gel column chromatography and eluted with PE:EA to obtain 0.13 g of intermediate 16 as a solid, with a yield of 56%.
- DCM/MeOH 5% ammonia methanol
- Example 14 Using intermediate 18, the same synthesis method as Example 14 can be used to obtain white solid Example 14A.
- Example 14B the white solid Example 14B can be obtained by the same synthesis method as Example 14.
- Example 15 was obtained by the same method as Example 14.
- Example 15A was obtained by the same method as Example 14A.
- Example 15B was obtained by the same method as Example 14A.
- Example 16A was obtained by the same method as Example 13A.
- Example 16B was obtained through the same preparation steps and conditions as Example 13B.
- Example 17A was obtained.
- Example 18A was obtained through the same preparation steps and conditions as described in Example 4A.
- Example 18B was obtained through the same preparation steps and conditions as those described in Example 4B.
- Example 19A Taking heikegenin as a raw material, through the same preparation steps and conditions as intermediate 7, intermediate 24 was obtained; using intermediate 24 as a raw material, through the same preparation method and conditions as described in step 5 of Example 1A, to obtain Example 19A.
- Example 20A was obtained by using hecogenin as a raw material through the same preparation steps and conditions as those described in Example 4A.
- Example 21 was obtained through the same preparation steps and conditions as described in Example 13.
- Example 22 was obtained through the same preparation steps and conditions as described in Example 13.
- Example 24A Example 24B
- Example 24A can be obtained by the same synthesis method as Example 24.
- Example 24B was obtained in the same way.
- the nuclear magnetic data of embodiment 24A is: 1H NMR (400MHz, CDCl3) ⁇ 8.12 (t, 1H), 4.48 (m, 2H), 4.00 (m, 3H), 3.28 (m, 5H), 2.43 (m, 13H) , 1.82 (m, 15H), 1.12 (m, 27H). Mass spectrum: [M+1] 667.5.
- Example 24B nuclear magnetic data is: 1H NMR (400MHz, CDCl3) ⁇ 7.42 (dd, 1H), 4.50 (m, 2H), 3.94 (m, 2H), 3.31 (d, 3H), 3.06 (m, 2H) , 2.56 (m, 11H), 2.31 (s, 3H), 1.40 (m, 42H). Mass Spectrum: [M+1] 667.5.
- Example 25A Example 25B
- Example 25A can be obtained by the same synthesis method as Example 24.
- Example 25B was obtained in the same way.
- the nuclear magnetic data of embodiment 25A is: 1H NMR (400MHz, CDCl3) ⁇ 8.15 (t, 1H), 4.61 (d, 1H), 4.41 (m, 1H), 4.19 (s, 1H), 3.96 (m, 2H) , 3.31 (d, 3H), 3.06 (t, 1H), 2.51 (m, 10H), 1.34 (m, 48H). Mass Spectrum: [M+1] 681.6.
- the nuclear magnetic data of embodiment 25B is: 1H NMR (400MHz, CDCl3) ⁇ 7.38 (d, 1H), 4.42 (q, 1H), 3.96 (dd, 1H), 3.62 (m, 5H), 3.31 (d, 3H) , 2.90 (m, 3H), 2.54 (m, 4H), 2.37 (s, 3H), 1.38 (m, 45H). Mass Spectrum: [M+1] 681.6.
- Example 26A can be obtained by the same synthesis method as Example 24.
- Example 26B was obtained in the same way.
- the nuclear magnetic data of embodiment 26A is: 1H NMR (400MHz, CDCl3) ⁇ 8.09 (d, 1H), 4.40 (q, 1H), 4.16 (d, 1H), 3.95 (dd, 1H), 3.64 (t, 2H) ,3.49(s,5H),3.29(s,2H),2.91(d,2H),2.54(q,4H),2.27(s,3H),1.42(m,44H). Mass spectrum: [M+1] 667.6.
- Embodiment 26B magnetic data is: 1H NMR (400MHz, CDCl3) ⁇ 7.38 (d, 1H), 4.42 (q, 1H), 3.96 (dd, 1H), 3.62 (m, 5H), 3.31 (d, 3H) , 2.90 (m, 3H), 2.54 (m, 4H), 2.37 (s, 3H), 1.38 (m, 45H). Mass Spectrum: [M+1] 667.6.
- Example 27A Example 27B
- Example 27A can be obtained by the same synthesis method as Example 27.
- Example 27B was obtained in the same way as intermediate 21 and N-methyl-2-(1-methylpiperidin-4-yl)ethan-1-amine.
- the nuclear magnetic data of embodiment 27A is: 1H NMR (400MHz, CDCl3) ⁇ 8.45 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.51(t,1H),3.45(t,1H),3.28-3.32(m,3H),3.10(m,3H),2.51(m,10H),2.26(m,3H),1.32-2.10(m, 27H), 1.08 (m, 3H), 0.99 (m, 6H), 0.75 (s, 3H). Mass spectrum: [M+1] 641.6.
- the nuclear magnetic data of embodiment 27B is: 1H NMR (400MHz, CDCl3) ⁇ 8.7.78 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.51(t,1H),3.45(t,1H),3.28-3.32(m,3H),3.10(m,3H),2.51(m,10H),2.26(m,3H),1.32-2.10(m, 27H), 1.08 (m, 3H), 0.99 (m, 6H), 0.75 (s, 3H). Mass spectrum: [M+1] 641.6.
- Example 29A Example 29B
- Example 29A The synthesis process is the same as that of Example 29, and Example 29A can be obtained by using the same synthesis method as Example 29 with Intermediate 18 and 1-(1-ethylpiperidin-4-yl)piperazine. Using intermediate 21 and 1-(1-ethylpiperidin-4-yl)piperazine, Example 29B was obtained in the same way.
- the nuclear magnetic data of embodiment 29A is: 1H NMR (400MHz, CDCl3) ⁇ 8.8.05 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.65(t,2H),3.56(t,2H).3.28-3.32(m,3H),3.15(m,2H),2.51(m,6H),2.30(m,1H),2.10(m,6H) , 1.32-2.10 (m, 27H), 1.08 (m, 3H), 0.99 (m, 9H), 0.75 (s, 3H).. mass spectrum: [M+1] 681.6.
- the nuclear magnetic data of embodiment 29B is: 1H NMR (400MHz, CDCl3) ⁇ 8.7.38 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.65(t,2H),3.56(t,2H).3.28-3.32(m,3H),3.15(m,2H),2.51(m,6H),2.30(m,1H),2.10(m,6H) , 1.32-2.10 (m, 27H), 1.08 (m, 3H), 0.99 (m, 9H), 0.75 (s, 3H).. mass spectrum: [M+1] 681.5.
- Example 32A Example 32B
- Example 32A can be obtained by the same synthesis method as Example 32.
- Example 32B was obtained in the same way.
- the nuclear magnetic data of embodiment 32A is: 1H NMR (400MHz, CDCl3) ⁇ 7.32 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.77 (m, 1H), 3.65(t,2H),3.56(t,2H).,3.28-3.32(m,3H),2.52(m,5H),2.32(m,2H),1.32-2.09(m,27H),1.19(m ,9H), 1.09(dd,3H), 0.99(m,12H), 0.75(s,3H). Mass Spectrum: [M+1] 709.7.
- Example 32B The NMR data of Example 32B are: 1H NMR (400MHz, CDCl3) ⁇ 7.32 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.65(t,2H),3.56(t,2H).,3.28-3.32(m,3H),2.51(m,5H),2.31(m,2H),1.32-2.10(m,27H),1.19(m ,9H), 1.08(dd,3H), 0.99(m,12H), 0.76(s,3H). Mass Spectrum: [M+1] 709.7.
- Example 33A Example 33B
- Example 33A can be obtained by the same synthesis method as Example 33.
- Example 33B was obtained in the same way.
- Example 33B nuclear magnetic data is: 1H NMR (400MHz, CDCl3) ⁇ 7.32 (dd, 1H), 4.52 (m, 1H), 4.48 (m, 1H), 3.94-3.97 (m, 1H) 3.75-3.78 (m ,1H),3.27(m,3H),3.15(t,1H).,2.25-2.75(m,10H),2.2(m,2H),1.32-2.10(m,27H),1.19(m,6H) , 1.09 (m, 9H), 0.75 (s, 3H).. mass spectrum: [M+1] 709.5.
- Example 34A Example 34B
- Example 34A can be obtained by the same synthesis method as Example 34.
- Example 34B was obtained in the same way.
- the nuclear magnetic data of embodiment 34A is: 1H NMR (400MHz, CDCl3) ⁇ 7.33 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.79 (m, 1H), 3.51(m,6H),3.28-3.32(m,3H),2.55(m,8H),1.32-2.11(m,27H),1.19(m,14H),1.08(m,6H),0.99(m, 3H), 0.75(s, 3H).
- Mass spectrum [M+1] 695.7.
- Example 34B The NMR data of Example 34B are: 1H NMR (400MHz, CDCl3) ⁇ 7.32 (dd, 1H), 4.41-4.45 (m, 1H), 3.94-3.98 (m, 1H), 3.75-3.78 (m, 1H), 3.52(m,6H),3.28-3.32(m,3H),2.55(m,8H),1.32-2.11(m,27H),201.19(m,14H),1.08(m,6H),0.99(m, 3H), 0.75(s, 3H). Mass spectrum: [M+1] 695.6.
- Example 35 Using intermediate 11 and 1-(pyridin-4-yl)piperazine as raw materials, the same synthesis method as in Example 28 can be used to obtain Example 35
- Example 35A Example 35B
- Example 35A can be obtained by the same synthesis method as Example 28.
- Example 35B was obtained in the same way.
- the nuclear magnetic data of embodiment 35A is: 1H NMR (400MHz, CDCl3) ⁇ 8.24 (m, 2H), 7.14 (dd, 1H), 6.65 (m, 2H), 4.41-4.44 (m, 1H), 3.94-3.98 ( m,1H),3.75(m,5H),3.25-3.50(m,7H),1.32-2.10(m,27H),1.07(m,6H),0.99(m,3H),0.75(s,3H) .
- Mass spectrum [M+1] 647.6.
- the nuclear magnetic data of embodiment 35B is: 1H NMR (400MHz, CDCl3) ⁇ 8.26 (m, 2H), 7.16 (dd, 1H), 6.66 (m, 2H), 4.41-4.45 (m, 1H), 3.94-3.99 ( m,1H),3.77(m,5H),3.25-3.50(m,7H),1.32-2.11(m,27H),1.08(m,6H),0.99(m,3H),0.75(s,3H) .
- Mass spectrum [M+1] 647.5.
- Example 36 can be obtained by the same synthesis method as Example 31
- Example 41A Example 41B
- Example 41A The synthesis process of Example 41A is as in Example 41, Intermediate 18 is replaced by Intermediate 11, and the nuclear magnetic data is 1H NMR (CDCl3-d6, 400MHz): 7.98 (d, 1H), 4.42 (q, 1H), 4.18 ( s,1H),3.95(dd,1H),3.66(t,2H),3.57(t,2H),3.31(d,1H),3.29(s,2H),2.67-2.82(m,8H),2.47 -2.52(m,4H),1.58-2.10(m,11H),1.15-1.50(m,16H),1.09-1.10(m,6H),1.08(d,3H),0.99(d,3H),0.95 (s,3H), 0.75(s,3H). Mass spectrum: [M+1] 669.7.
- mice 15-day-pregnant rats, dissect fetal mouse brains (E15-16), use 48-well plates for primary culture of cerebral cortex neurons in neuron medium for 14 days (DIV 14), and perform OGD experiment.
- the neuron culture medium was replaced with a sugar-free anaerobic culture medium (95% N 2 /5% CO 2 balance), and the neurons were treated with OGD in the OGD chamber. Then it was replaced with normal neuron culture medium, cultured in 95% Air/5% CO 2 incubator for 24 hours, and then the neuron activity was analyzed.
- Compound treatment Dilute the 13 small molecule compounds from Examples 1 to 20 to 0.5mM mother solution with DMSO, add 1 ⁇ L of the mother solution to 0.5ml culture solution in each well of a 48-well plate to a final concentration of 1 ⁇ M, and 1 ⁇ L of the positive control compound DPQ (mother solution 10mM), negative control 1 ⁇ L DMSO was added to the culture medium 24 hours before the OGD experiment, and the same concentration was added to the sugar-free and anaerobic culture medium and the subsequent normal neuron culture medium.
- Example 2 As shown in Figure 2, Example 2, Example 7, Example 13, and Example 14A significantly protected neurotumor cell damage induced by hydrogen peroxide, wherein, undifferentiated SH-SY5Y cells were pre-protected for 24 hours, and finally The concentration was 1 ⁇ M, and it was detected after 24 hours of hydrogen peroxide treatment.
- the 24-well cell culture plate was pretreated with Poly-D-lysine, and placed in a cell culture incubator at 37°C and 5% CO 2 overnight.
- test compound final concentration 1 ⁇ M
- positive control AP5 [(2R)-amino-5-phosphovaleric acid (ester)] (final concentration 100 ⁇ M)
- L-Cystine 400 ⁇ M
- NaHCO 3 10 mM
- Compound treatment Dilute the 32 small molecule compounds from Examples 1 to 19A to 1 mM mother solution with DMSO, add 1 ⁇ l of the mother solution to 1 ml of the culture solution in each well of the 24-well plate to a final concentration of 1 ⁇ M, and 100 ⁇ l of the positive control compound AP5 ( stock solution 100mM), negative control 1 ⁇ l DMSO.
- Transgenic neutrophil-fluorescing zebrafish were reproduced by natural pair mating. The age is 3 days after fertilization (3dpf), a total of 810 tails, 30 tails in each experimental group. It is used to determine the maximum detection concentration (MTC) of "Example 5" and “Example 6" in the LPS-induced inflammation experiment and the anti-inflammatory effect evaluation of "Example 5" and "Example 6" on LPS-induced inflammation.
- MTC maximum detection concentration
- Zebrafish are kept in 28°C fish farming water (water quality: add 200mg of instant sea salt to every 1L of reverse osmosis water, conductivity is 480-510 ⁇ S/cm; pH is 6.9-7.2; hardness is 53.7-71.6mg/L CaCO 3 ) , provided by the fish breeding center of the company, the license number for the use of experimental animals is: SYXK (Zhejiang) 2012-0171.
- the feeding management complies with the requirements of the international AAALAC certification.
- Example 5 white powder, stored dry at 4°C, received on October 18, 2019, provided by Shenzhen Qingbo Huineng Pharmaceutical Technology Co., Ltd. Prepare 20mM mother solution with DMSO before the experiment and store at -20°C.
- Example 6 white powder, stored dry at 4°C, received on October 18, 2019, provided by Shenzhen Qingbo Huineng Pharmaceutical Technology Co., Ltd. Prepare 20mM mother solution with DMSO before the experiment and store at -20°C.
- Dissecting microscope SZX7, OLYMPUS, Japan
- camera connected to the microscope VertA1
- precision electronic balance CP214, OHAUS, AmericaCP214, OHAUS
- fluorescence microscope AZ100, Nikon, Japan
- methylcellulose Sigma, USA
- Dimethylsulfoxide Sigma, France
- 6-well plate Nest Biotech
- LPS was injected into the yolk sac to treat normal 3dpf transgenic neutrophil fluorescent zebrafish to establish a zebrafish inflammation model.
- zebrafish treated with water for fish farming and model The control group was placed in an incubator at 28°C for 3 hours to observe and record the death of zebrafish, count the number of zebrafish deaths in each experimental group, and determine the maximum detection of zebrafish in "Example 5" and "Example 6" concentration (MTC).
- Inflammation regression effect (%) ((N (model control group)-N (test product group))/N (model control group))*100%
- the maximum solubility of "Example 5" in DMSO is 20mM, and the maximum concentration of DMSO that zebrafish can tolerate is 1%, so the maximum detection concentration of "Example 5" anti-inflammatory effect evaluation is 200 ⁇ M, "Example 5" is in At 200, 100, 50 and 10 ⁇ M concentrations, 30 zebrafish died, and the mortality rate was 100%; at 5 ⁇ M concentration, 3 zebrafish died, and the mortality rate was 10%; Therefore, the maximum detection concentration for the evaluation of the anti-inflammatory effect of "Example 5" was 2.5 ⁇ M.
- Example 6 has a maximum solubility in DMSO of 20 mM, and the maximum concentration of DMSO that zebrafish can tolerate is 1%, so the maximum concentration of "Example 6" anti-inflammatory evaluation is 200 ⁇ M, "Example 6" At the concentration of 200, 100 and 50 ⁇ M, 30 zebrafish died, and the mortality rate was 100%; at the concentration of 10 and 5 ⁇ M, 4 zebrafish died, and the mortality rate was 13.33%; at the concentration of 2.5 ⁇ M, the state of the zebrafish was normal, The drug was not precipitated, so the maximum detection concentration for the evaluation of the anti-inflammatory effect of "Example 6" was 2.5 ⁇ M.
- Figure 4 the dotted line area in Figure 4 is the neutrophils at the site of inflammation.
- the number of neutrophils in the inflammatory site of the model control group (18) was compared with the normal control group (3), p ⁇ 0.001, indicating that the LPS-induced transgenic neutrophil fluorescence zebrafish inflammation model was successfully established.
- the number of neutrophils in the inflammatory site of 80 ⁇ M indomethacin group (6) was less than 0.001, and its anti-inflammatory effect was 67%, indicating that indomethacin has obvious anti-inflammatory effects on inflammatory zebrafish effect.
- Example 5 When the concentration of "Example 5" was 0.28, 0.83, and 2.5 ⁇ M, the number of neutrophils in the zebrafish inflammatory site was 12, 7, and 6, respectively, and the anti-inflammatory effects on zebrafish were 33%, 61%, and 67%; compared with the model control group (18), p ⁇ 0.001 in the 0.28, 0.83 and 2.5 ⁇ M concentration groups, suggesting that "compound 3" has obvious anti-inflammatory effects on inflammatory zebrafish at a concentration of 0.28-2.5 ⁇ M.
- Example 6 when the concentration is 0.28, 0.83, 2.5 ⁇ M, the number of neutrophils in the zebrafish inflammation site is 12, 8 and 7 respectively, and the anti-inflammatory effect on zebrafish is respectively 33%, 56% and 61%; compared with the model control group (18), p ⁇ 0.001 in the 0.28, 0.83 and 2.5 ⁇ M concentration groups, suggesting that "compound 4" has obvious anti-inflammatory effect on inflammatory zebrafish at the concentration of 0.28-2.5 ⁇ M.
- Example 5 Under the concentration conditions of this experiment, both Example 5 and Example 6 have obvious anti-inflammatory effects on inflammatory zebrafish.
- Neurological function scores and cerebral infarct size were used to evaluate the effect of compounds on the mouse cerebral ischemia-reperfusion (MCAO) injury model. The results show that the test compound has the effect of protecting mice from cerebral ischemia-reperfusion (MCAO) injury.
- Physiological saline Name Physiological saline homemade.
- Hydroxypropyl- ⁇ -cyclodextrin Name: Hydroxypropyl- ⁇ -cyclodextrin; Provider: Sarn Chemical Technology (Shanghai) Co., Ltd.; Batch: FG310174; Properties: White solid powder; Quantity: 30g; Storage conditions: room temperature.
- Experimental animals Strain C57BL/6 mice; Week age: 6-8; Sex: male; Order animal weight: 16-20g; Use animal weight: 20-23g; Quantity: 40; Experimental animal provider: Zhejiang Weitongli Hua Experimental Animal Technology Co., Ltd.; production license number: SCKX (Zhejiang) 2019-0001; quality certificate number: No2005130052, No2004280010.
- Quarantine The quarantine period is 7 days. Routine health checks are completed by veterinarians. Animals with abnormal performance are removed before the experiment.
- Animal feeding conditions The experimental animals were kept in an SPF-grade laminar flow clean room with constant temperature and humidity in the Animal Center (AAALAC certification unit), with 3 mice per cage.
- the temperature of the breeding room is 22 ⁇ 3°C, the humidity is 40-70%, and the light is alternated between light and dark for 12 hours.
- Cage Made of polycarbonate.
- Feed and drinking water Clean grade mouse feed was purchased from Beijing Keao Xieli Feed Co., Ltd. Drinking water is autoclaved and food is irradiated with cobalt-60 rays. Animals had free access to sterile food and water.
- Animal number Each cage has a cage label, indicating the number of animals, sex, strain, receiving time, group and the start time of the experiment. Animal number: Each animal is marked with an individual animal number on the tail.
- the specific grouping and treatment are shown in Table 6.
- mice were fasted overnight before surgery, but not water.
- the mice were pre-anesthetized in an induction box of an isoflurane gas anesthesia machine with a concentration of isoflurane of 2.5%. After clamping the unresponsive hind paw of the mouse with dissecting forceps, it was transferred to an anesthesia mask and the concentration of isoflurane was reduced to 1.5%.
- the body temperature of the mice during the operation was maintained at around 37°C by using a body temperature maintenance instrument and a rectal temperature probe.
- the hair on the neck of the mouse in the supine position was shaved, and the skin was disinfected with povidone iodine and alcohol, and an incision was made in the middle of the neck.
- the tissue was bluntly dissected, and the common carotid artery (CCA) was exposed under a stereomicroscope, and its proximal end was ligated with a 6-0 braided suture.
- CCA common carotid artery
- ICA internal carotid artery
- the ECA was fused with a coagulation pen, the external carotid artery ligation was loosened, and the thread plug was inserted into the ICA until the cerebral blood flow stopped at about 10% of the baseline.
- the thread plug blocked the middle cerebral artery (MCA) for 30 minutes. After 30 minutes, the thread plug was pulled out, the stump of the vessel was cauterized, and the CCA ligation was loosened.
- the skin of the neck was sutured, and the mice were placed in an intensive care cage, and the body temperature of the mice was maintained at 37°C until the materials were collected.
- Cerebral blood flow measurement Fix the head of the mouse under the stereotaxic instrument, shave the hair of the head of the mouse, and make a median incision. The periosteum on the skull was removed, and the optical fiber of the laser Doppler flowmeter was fixed with glue at the coordinates of Bregma AP 1.0mm, ML5.0mm, and the blood flow changes during the operation of the middle cerebral artery were recorded. The successful standard of modeling is that the cerebral blood flow drops to 80%-90% of the baseline.
- Preparation of PK samples First, calculate at least the required drug dose m2 per day based on the total weight of each group of mice and the dosage. Weigh an amount of P2 slightly more than m2 into a bottle, and calculate the solvent volume v2 according to the administration volume of 10mL/kg. Add 20% hydroxypropyl- ⁇ -cyclodextrin solution (v2) to the vial, vortex for one minute, sonicate for 15 minutes, and vortex for another minute until dissolved.
- v2 hydroxypropyl- ⁇ -cyclodextrin solution
- Preparation of PK sample Firstly, according to the total weight of each group of mice and the dosage, calculate at least the required dosage m3 per day. Weigh a little more than m3 of P3 into a mortar, and calculate the solvent volume v3 according to the administration volume of 10mL/kg, and measure the solvent of v2 with a syringe. Add 2-3 drops of solvent to the mortar, grind for 5 minutes, after the solvent is dry, add 2-3 drops of solvent, and grind for 5 minutes, repeat three times. Then, wash the compound in the mortar several times with solvent and add it to a suitable sample bottle with a clean glass dropper, sonicate for 15 minutes, and vortex for five minutes until it is uniform and there are no larger particles.
- Body weight Record the body weight of mice on the day before operation and 24 hours after operation.
- Neurological function score Longa behavioral score was performed 2h and 24h after the operation of the mice.
- mice 24 hours before the operation and 24 hours after the operation, the forelimb grip test was performed on the mice respectively.
- the mice were placed on the grip meter, and the mice actively pulled the grip sensor rod, and the peak value of the grip force was recorded, and the average value was obtained by repeating the measurement three times.
- mice 24 hours after the operation, the mice were anesthetized with isoflurane and sacrificed by decapitation.
- the whole brain was peeled off, washed twice with normal saline, placed under the coronal brain mold, the anterior 1mm olfactory bulb and the posterior 4mm cerebellum were removed, and the brain was cut into 2mm pieces, a total of 4 pieces.
- the volume of cerebral infarction and edema were measured by software ImageJ.
- Graghpad Prism 7.0 was used for data statistics in each group, and the experimental results were expressed as "mean ⁇ standard deviation”. Statistical method One-way analysis of variance was used to compare whether there was a statistical difference among the groups, and P ⁇ 0.05 was considered statistically significant.
- the cerebral blood flow of each group dropped to about 10% of the baseline, indicating that the model is successful and can be evaluated for drug efficacy.
- the neurological deficit scores of the 2h MCAO model group after surgery were significantly different from those of the No. 2 administration group and the No. 3 administration group (P ⁇ 0.05); the neurological deficit scores of the 24h MCAO model group after surgery There were significant differences (P ⁇ 0.05) between the score and the positive control drug edaravone group and the No. 3 administration group respectively.
- the results of TTC staining showed that the volume of cerebral infarction in the MCAO model group was significantly different from that of the positive control drug edaravone group (P ⁇ 0.001), No. 2 (P ⁇ 0.001), No. 3 (P ⁇ 0.001), No. 4 (P ⁇ 0.01) and No. 5 drug (P ⁇ 0.01) have significant difference.
- the results of TTC staining showed that the volume of brain edema in the MCAO model group was significantly higher than that of the positive control drug edaravone group (P ⁇ 0.01), No. 2 (P ⁇ 0.001), No. 3 (P ⁇ 0.001), No. 4 (P ⁇ 0.001), No. 5 drug (P ⁇ 0.05) and No. 6 drug (P ⁇ 0.05) had significant difference.
- Example 6 has an antidepressant effect on mice.
- NC Solvent Sodium carboxymethyl cellulose
- Provider Merrill
- Batch 69881020
- Properties white solid powder
- Quantity 200g
- Storage conditions room temperature
- LPS Peripheral and central inflammation inducer
- Experimental animal strain C57BL/6J mice; age: 6-8 weeks; sex: male; animal weight: 18-20g; quantity: 24; experimental animal provider: Guangdong Medical Experimental Animal Center
- Quarantine The quarantine period is 5 days, and animals with abnormal performance are removed before the experiment.
- Animal number each cage has a cage label, indicating the number of animals, sex, strain, receiving time, group and the start time of the experiment.
- Animal number Each animal is marked with an individual animal number on the tail.
- LPS (2mg/kg, ip, QD) was injected on the 1st, 2nd, and 3rd day to induce peripheral and central inflammation in mice.
- the ND drug test group was given pre-protection (ND 30mg/kg, po, QD) 2 hours before LPS injection, and forced swimming, tail suspension and sugar water preference experiments were carried out in experiment D4.
- Solvent (0.5% CMC-Na solution): Take 0.5g CMC-Na white solid powder, add 100ml double distilled water, vortex until dissolved. The prepared solution should be stored in a 4-degree refrigerator and sealed. The solution can be stored for one month, but if it is found to be moldy, it is forbidden to be used in the experiment and needs to be re-prepared.
- mice were placed in a transparent glass cylinder (diameter: 23 cm; height: 31 cm), which was filled with 15 cm of water, and the temperature was maintained at 24 ⁇ 1 °C.
- the FST lasts for 6 minutes, during which a high-definition camera is used to shoot.
- Professional testing software calculates the immobility time of the mouse during the test. After the end of the test, the mouse is immediately put back into the cage, and attention should be paid to keeping warm.
- mice were trained before the test, that is, two bottles of 1% (W/V) sucrose solution were put into each cage, and one of the bottles was replaced with pure water after 24 hours. Test after fasting for 10-24 hours after adaptation. Place 2 pre-weighed water bottles in each cage, one bottle is 1% (W/V) sucrose solution, and the other bottle is pure water. After 12 hours, take the two water bottles and weigh them again, and record the sugar water consumption and pure water consumption of each mouse. .
- Sugar water preference index% sugar water consumption/(sugar water consumption+pure water consumption) ⁇ 100%.
- mice After adapting to the environment, stick the tail of the mouse on the hanging rod, and keep the head of the mouse about 20-25 cm away from the ground for about 6 minutes.
- a high-definition camera shoots a video, and uses behavioral analysis software to identify and count the immobility time of the mice. After the experiment, the mice were returned to their cages.
- Example 20A had obvious anti-inflammatory effect.
- NC Sodium carboxymethyl cellulose
- provider Merrill
- batch 69881020
- properties white solid powder
- quantity 200g
- storage conditions normal temperature.
- LPS Peripheral and central inflammation inducer
- Experimental animal strain C57BL/6J mice; age: 6-8 weeks; gender: male; animal weight: 18-20g; number: 24.
- Laboratory animal provider Guangdong Medical Experimental Animal Center
- the quarantine period is 5 days, and animals with abnormal performance are removed before the experiment.
- Animal number each cage has a cage label, indicating the number of animals, sex, strain, receiving time, group and the start time of the experiment.
- Animal number Each animal is marked with an individual animal number on the tail.
- the animals were randomly divided into 3 groups, and the specific grouping and treatment are shown in Table 11.
- LPS (2mg/kg, i.p., QD) was injected on the 1st, 2nd, and 3rd day to induce peripheral and central inflammation in mice.
- the ND drug test group was administered 2 hours before LPS injection for pre-protection (ND 30mg/kg, p.o., QD).
- plasma and brain tissue of mice were collected for inflammatory factors and peroxidation factors and other indicators.
- Solvent (0.5% CMC-Na solution): Take 0.5g CMC-Na white solid powder, add 100ml double distilled water, vortex until dissolved. The prepared solution should be stored in a 4-degree refrigerator and sealed. The solution can be stored for one month, but if it is found to be moldy, it is forbidden to be used in the experiment and needs to be re-prepared.
- mice After the mice were anesthetized with 1% pentobarbital sodium, the eyeballs were removed and the blood was collected in EP tubes. After standing at 4°C for 1 hour, they were centrifuged at low temperature, and the supernatant was taken, and quickly frozen in liquid nitrogen.
- Hippocampal tissue the mice were anesthetized with 1% pentobarbital sodium, and then the heart was perfused with cold PBS. The brain was taken out, and the tissue was taken on ice and frozen in EP tube with liquid nitrogen.
- the frozen plasma was taken, and various indicators were tested using IL-1 ⁇ , IL-6, and IL-10 kits, and the specific operation procedures were the same as the kit instructions.
- hippocampal supernatant was taken, and various indicators were detected using IL-1 ⁇ , IL-6, and IL-10 kits, and the specific operation procedures were the same as the instructions of each kit.
- Example 20A As shown in Figures 24 to 29, the detection results of important indicators related to serum and hippocampal tissue inflammation in mice in each group showed that Example 20A only affected IL-1 ⁇ in serum and IL-10 in hippocampus, indicating that Example 20A (ND ) has an anti-inflammatory effect. *, P ⁇ 0.05; **, P ⁇ 0.01.
- HEK293 cells were cultured under the condition of 5% CO 2 and the mitochondrial respiratory chain supercomplex I1III2IV1 was purified therefrom.
- the respiratory chain super complex is chemically covalently coupled to the surface of the metal chip, small molecular compound solutions of different concentrations flow through the metal chip, and the change of the reflection coefficient of the metal surface is monitored by the Biacore 8K plus analyzer using SPR technology, and then The corresponding response curves for small molecule binding are plotted.
- the binding strength (KD value) of the small molecule to the human mitochondrial respiratory chain supercomplex I1III2IV1 was calculated by the built-in fitting software of the Biacore 8K plus instrument.
- Compound treatment Dissolve the small molecule shown in ddH 2 O to prepare a 10 mM stock solution.
- 200 ⁇ L of small molecule solutions of various concentrations were taken to flow over the surface of the metal chip.
- HEK293 cells were cultured under the condition of 5% CO 2 and mitochondria were purified therefrom, and mitochondria were sonicated to obtain SMP (submitochondrial particles). After incubating SMP with different concentrations of small molecule compounds or a control drug (Rotenone, 2 ⁇ M) for 10 minutes, 500 ⁇ M NADH was added. The absorbance of NADH was detected by the Enspire multi-mode microplate reader, the enzyme activity curve of the reduction of NADH concentration caused by SMP catalysis was drawn, and the maximum reaction rate of SMP was calculated by linear fitting. Adding 1 mM FeCN to the normal NADH catalytic system of SMP can cause a short circuit of the electronic pathway from NADH to coenzyme Q. In the presence of FeCN and Rotenone, the NADH concentration reduction curve was also determined, and the maximum reaction rate of the SMP flavin site was calculated by linear fitting.
- Compound treatment Dissolve the small molecule shown in ddH 2 O to prepare a 10mM stock solution, and then use 10mM Tris buffer solution to dilute the small molecule gradient to 0.075, 0.1, 0.133, 0.178, 0.237, 0.316, 0.422, 0.563, 0.75, 1 ⁇ M for SMP catalysis experiments.
- HPAEC cells human pulmonary artery endothelial cells
- HPAEC cells human pulmonary artery endothelial cells
- OCR oxygen consumption rate
- HPAEC cells human pulmonary artery endothelial cells
- Spike new coronavirus surface spike protein, 8 ⁇ g/mL
- Example 13B pre-incubated with Example 13B (0.25, 0.5, 1 ⁇ M) for 6 hours and then incubated with Spike (8 ⁇ g/mL) for 24 hours.
- mitochondrial staining was performed using MitoSox Red, PKMDR, and Mitotracker Green mitochondrial fluorescent probes, and fluorescent confocal photos of cells were taken by a Leica stimulated emission depletion super-resolution confocal fluorescence microscope (STED). Subsequently, ImageJ was used to measure the fluorescence intensity of cells in different groups, and the obtained data was used to calculate the standard deviation and standard error, and the T-test analysis was performed to calculate the P value to determine whether there was a significant difference.
- mice After purchasing 6-week-old male APOE-/- mutant B6J mice and WT B6J mice, they first acclimatized in the breeding room for 2 weeks. When the mice were 8 weeks old, except the Vehicle group and the WT group, the other groups began to be given high-fat diet (Research Diets, D12492). When the mice were 9 weeks old, the Control group was given 10% cyclodextrin solution, and the rest of the administration groups Oral gavage of different concentrations of small molecule compounds was started in groups, and the frequency of gavage was once every 2 days. When the drug administration was full for 1 month, blood was collected from the orbital vein of APOE mice, and the blood collection volume was about 500mL.
- the supernatant plasma was drawn and sent for determination of total cholesterol (CHOL), high-density lipoprotein (HDL) and Low-density lipoprotein (LDL) levels.
- CTL total cholesterol
- HDL high-density lipoprotein
- LDL Low-density lipoprotein
- the APOE mice were sacrificed and the aortic arch was dissected. After the mouse aortic arch was fixed with 4% paraformaldehyde, oil red was used to stain the plaque inside the aortic arch, and the stained aortic arch was imaged by a Zeiss stereo microscope.
- the photos taken were analyzed with ImageJ to analyze the overall area of the longitudinal section of the arterial arch and the area of the orange-red plaque, calculate the proportion of the plaque area, and perform T-test analysis on the data to calculate the P value to determine whether there is a significant difference.
- CRISPR Cas9 technology was used to introduce human APP mutant protein into SD rat embryos to obtain a transgenic AD rat model. Rats of this strain had amyloid deposits in the brain at the age of 2 months, and began to show certain behavioral disorders at the age of 5 months.
- the drug was administered from the age of 7 months to the age of 13 months, and a water maze experiment was done to verify the improvement of spatial memory.
- the process of the water maze experiment is divided into three stages: the first stage is 1 day. For the adaptation stage, there is a 15cm diameter escape platform in a large pool with a diameter of 1.8m. There are circles, triangles, The four marks of box and cross are used as hints of spatial position.
- the rats were put into transparent water along the pool wall one by one, and the water surface was 1 cm below the escape platform. Rats will easily find the escape platform and be rescued from the water maze after climbing onto the platform, thereby learning the basic rules of the water maze.
- the second phase of 4 days is the training phase. The setting of the pool remains the same, the water surface is raised to 1cm above the escape platform, and ink is poured in to dye the water black, making the escape platform invisible. Every day, the rats were put into the pool from four directions, southeast, northwest, and rescued after they successfully climbed onto the escape platform. If the platform is not found within 90s, the rats are manually guided to climb up the platform and rescued after standing on the platform for 15s.
- the third stage is 1 day, which is the examination stage.
- the escape platform was taken out, and the rat was put in once along the pool wall. Rats with strong spatial memory will repeatedly shuttle back and forth to the location of the original escape platform. Record the incubation period of the first arrival on the platform, the number of times the platform shuttles, the average distance from the platform, and the residence time in the target quadrant.
- mice in the drug treatment group There are three groups of mice in total, 13 mice in WT group, 7 mice in model group (AD group), 11 mice in drug administration group (group B of Example 13), the latency period of reaching the platform for the first time (as shown in Figure 37a), the number of shuttles on the platform (as shown in Figure 37b), the average distance from the platform (as shown in Figure 37c), and the residence time in the target quadrant (as shown in Figure 37d), the behavioral performance of the rats in the drug treatment group was improved compared with that in the model group .
- Figure 37e to Figure 37g show the heat maps of the movement trajectories of rats in each group in the pool.
- mice Using CRISPR Cas9 technology, the human APP mutant protein was introduced into SD rat embryos to obtain a transgenic AD rat model. Rats of this strain had amyloid deposits in the brain at the age of 2 months, and began to show certain behavioral disorders at the age of 5 months. In order to verify the therapeutic effect, the drug was administered from the age of 7 months to the age of 15 months, and a T-maze experiment was performed to verify the improvement of working memory. The T-maze has four stages: I. Adaptation stage, food is placed in both arms, and the valves of both arms are opened. Each rat was trained twice. Enter the next stage when all the rats have eaten both sides of the food within 5 min for two times. II.
- the forced selection training stage first close the valve on one side, and allow the rats to finish eating the food on the opposite side. Then close the valve on the opposite side, allowing the rats to finish eating the food on the other side.
- Each animal was trained 4 times a day for 3 days. III.
- half the valve on one side is closed first, and the rats are allowed to finish eating the food on the opposite side. Open all the valves again, and if the rat goes to the other side, it can finish the food there. If the rat went to the ipsilateral side, it was given no food and was kept off that side for 30s. This is a training session.
- mice in the WT group There were three groups of mice in total, 3 mice in the WT group, 2 mice in the model group (AD group), and 6 mice in the administration group (Group B of Example 13). As shown in Figure 38, at 1.5 min and 3 min, there was no significant difference between the model group and the administration group, but at 10 min, the working memory of the model group was significantly weakened, while the working memory of the administration group persisted.
- mice introduced with APP/P Example 13B were used, and the background mice were C57BL/6J.
- the phenotype of the model mice was cognitive behavioral changes at the age of 3 months, senile plaques at the age of 5 months, and a large number of senile plaques at the age of 12 months.
- One of the symptoms of AD patients is the inability to take care of themselves, and nesting behavior reflects the level of self-care in mice.
- 10 rectangular pieces of paper were neatly placed in the mouse cage in order. Normal mice shredded pieces of paper to build nests, but mice with severe AD symptoms did not shred paper to build nests. Scores were made according to the degree of shredded paper and the integrity of nest building. The higher the score, the better the nesting behavior of the mice, reflecting the higher level of self-care.
- mice introduced with APP/P Example 13B were used, and the background mice were C57BL/6J.
- the phenotype of the model mice was cognitive behavioral changes at the age of 3 months, senile plaques at the age of 5 months, and a large number of senile plaques at the age of 12 months.
- the process of the water maze experiment is divided into three stages: the first stage is 1 day.
- the adaptation stage there is an escape platform with a diameter of 8 cm in a large pool with a diameter of 1.2 m. There are circles, triangles, The four marks of box and cross are used as hints of spatial position.
- the rats were put into transparent water along the pool wall one by one, and the water surface was 1 cm below the escape platform.
- the mice will easily find the escape platform, climb up the platform and be rescued from the water maze, thereby learning the basic rules of the water maze.
- the second phase of 4 days is the training phase.
- the setting of the pool remains the same, the water surface is raised to 1cm above the escape platform, and ink is poured in to dye the water black, making the escape platform invisible.
- the mice were put into the pool from four directions, southeast, northwest, every day, and were rescued after successfully climbing the escape platform. If the platform is not found within 90s, the rats are manually guided to climb up the platform and rescued after standing on the platform for 15s.
- the third stage is 1 day, which is the examination stage.
- the escape platform was taken out, and the mice were still placed once along the pool wall. Rats with strong spatial memory will repeatedly shuttle back and forth to the location of the original escape platform. Record the number of platform shuttles, dwell time in the target quadrant and other indicators.
- Results In this experiment, the drug was administered from the age of 2 months, and the water maze was used to evaluate the spatial memory 6 months after the drug was administered.
- Four small molecules were tested, Example 23, Example 24, Example 25 and Example 26.
- the results shown in Figures 40a and 40b show that the spatial memory ability of the model group was significantly weakened compared with the WT group, while the improvement of the spatial memory ability of Example 25 was the most obvious from the indicators such as the number of platform shuttles and the dwell time in the target quadrant.
- mice introduced with APP/P Example 13B were used, and the background mice were C57BL/6J.
- the phenotype of the model mice was cognitive behavioral changes at the age of 3 months, senile plaques at the age of 5 months, and a large number of senile plaques at the age of 12 months.
- the principle of the light and dark box experiment is: mice have a natural tendency to be dark. After the mice are placed in the light box, the mice will spontaneously enter the connected dark box. But in this experiment, the dark box is equipped with an electrical stimulation mechanism, and the mice will be shocked by electric shock after entering the dark box.
- mice no longer entered the dark box after being shocked several times, but AD mice did not remember to be shocked after entering the dark box, and would continue to enter the dark box. Therefore, after the mice were put into the light box, the latency period before the mice spontaneously entered the dark box reflected the memory strength of the mouse for the electric shock, and the later the mouse entered the dark box, the stronger the memory for the electric shock was.
- Example 23 Example 24, Example 25 and Example 26.
- Figure 41 compared with the WT group, the memory of electric shock in the model group was significantly weakened, while the two small molecules of Example 23 and Example 25 could effectively enhance the memory of electric shock in model mice.
- mice which can simulate ALS (gradual freezing disease) pathogenesis. Mice of this strain generally begin to die at 90 days and reach a median of 120 days.
- Our experiments were divided into two groups, the model group and the administration group. The model group was not administered, and the administration group was administered from the 60th day, and the small molecule Example 13B was tested at a dose of 40mpk. There were 20 mice in each group. In this experiment, the death date and body weight of each mouse were recorded, and the body weight curve and survival curve were drawn.
- Body weight was an important index reflecting the course of ALS. As shown in Figure 42a, it can be seen that the body weight of the mice in the model group began to drop significantly at 13 weeks, while the mice in the treatment group began to drop significantly at 16 weeks. As shown in the survival curve of Figure 42b, it can be seen that a large number of mice in the model group died from 90 days, the median death was about 120 days, and all died at about 140 days. However, the administration group did not begin to die after 100 days, and a large number of patients began to die after 120 days. The median number of deaths was 135 days, and all died after 150 days. The results show that the small molecule Example 13B can effectively prolong the survival period of TDP43 A315T transgenic mice, indicating that the small molecule may effectively prolong the survival period of ALS patients.
- mice SOD G93A transgenic mice were used.
- the mice of this strain will simulate the pathogenesis of ALS (ALS), and will have obvious motor dysfunction as the age increases.
- Gait analysis is a behavioral analysis method for testing motor dysfunction. Mice with motor impairments had significantly reduced stride length.
- Our experiments were divided into two groups, the model group and the administration group. The model group was not administered, and the administration group was administered from the 60th day, and the small molecule Example 13B was tested at a dose of 40mpk. There were 10 mice in each group, at week 19, the stride length of each mouse was tested.
- mice SOD G93A transgenic mice were used.
- the mice of this strain will simulate the pathogenesis of ALS (ALS), and will have obvious motor dysfunction as the age increases.
- Calculation of mean movement speed in an open field is a behavioral assay for testing motor dysfunction.
- the average movement speed of mice with motor impairment was significantly reduced.
- Our experiment was divided into three groups, WT group, model group and administration group.
- the WT group was normal mice, the model group was not administered, and the administration group was administered from the 60th day to test the small molecule
- Example 13B with a dose of 40mpk There were 10 mice in each group, and the experiment was carried out at the 14th week, and the average movement speed of each mouse in the open field was tested on time every week until the 19th week.
- mice in good health were divided into 6 groups on average according to body weight, 10 in each group: normal control group, model group, positive drug group, different kinds of test substances (embodiment 13B, embodiment 33, embodiment 34 , both are 80mpk) group.
- the other mice except the normal control group were given 3.0% DSS solution to drink water freely to build the model, and the model was built continuously for 8 days; the normal control group was given high-pressure sterilized filtered water to drink freely.
- Administration began on the day of modeling, and the test substance was orally administered according to the designed dose, once a day, for 9 consecutive days. During the administration period, the body weight of the mice was monitored daily, and the shape of the feces and bleeding of the mice were observed. On the day after the last administration, after CO2 deep anesthesia, blood was collected from the heart, plasma was collected, and stored at -80°C; then the abdominal cavity was opened, the liver was removed, and stored at -80°C; finally, the entire colon tissue was removed and measured The length of the colon was photographed, and the contents of the colon were washed with normal saline after dissection along the side of the mesentery and weighed. Part of the lesion tissue was fixed with 10% formalin for HE staining for histopathological observation, and the rest of the colon tissue was frozen at -80°C.
- the anesthesia was continued and the rats were kept in a tilted state for 15 minutes; rats in the normal control group were not stimulated by rectal catheterization. After the animals woke up, they were randomly divided into groups, and then the administration (denoted as D1) was started.
- the blank group and the model group were given the same amount of vehicle, administered by oral gavage, once/day, for 7 consecutive days (D1-D7); daily observation Animal status, feces (loose stools, bloody stools), and body weight monitoring.
- Leptin receptor gene (Obese Gene Receptor, OB-R) is also known as diabetes gene (Diabetes Gene, db), leptin receptor (leptin receptor, Lepr) and obesity, hypertension, diabetes, lipid Metabolic disorders are closely related. The course of the disease is strongly influenced by genetic background. Topical insulin failed to control blood glucose and elevated levels of hepatic gluconeogenesis. Using gene editing technology and embryo injection technology to construct Lepr gene mutant mice. Through blood glucose monitoring of the homozygous strain, it is found that the blood glucose level is significantly different from that of the wild control, and can be used for type II diabetes research.
- the blood sugar of this strain of mice began to soar at the age of 8 weeks, reaching 30mmol/L, while the blood sugar of normal background mice was only about 6mmol/L.
- the small molecules tested were Example 28, Example 29 and Example 30.
- the subjects were all 80mpk, administered by intragastric administration once a day. There were 20 mice in each group. From the age of 8 weeks, blood glucose was monitored every week until they were sacrificed at the age of 20 weeks.
- Example 28 and Example 29 have certain hypoglycemic effects, but Example 30 has the best hypoglycemic effect, which can reach the level of normal background mice.
- DIO model is an obesity model caused by high-fat feeding.
- a body composition analyzer measures body fat percentage.
- Example 34 and Example 35 have the best weight loss effects, and can reduce the weight of obese model mice from more than 50g to the level of normal mice of about 35g.
- Example 33, Example 36, and Example 37 also have a weight loss effect, which can be reduced to about 40g. From the point of view of body fat rate, all small molecules can effectively burn fat in mice and reduce body fat rate, and the fat burning effect of Example 34 and Example 35 is still the best, and Example 33 and Example 36 , embodiment 37 next.
- mice 8-week-old female NOD-Scid immunodeficient mice were used as inoculated mice with Raji-Luc cells. A total of 80 mice were used for in vivo fluorescence imaging on the 9th day after inoculation. According to the fluorescence intensity, the most concentrated fluorescence intensity value in the middle was selected. 60 were used for follow-up experiments. Administration began after the first in vivo imaging, and the dosage was 100mpk once a day for intragastric administration. The small molecules tested were Example 25A, Example 25B, Example 28, Example 38, Example 39, Example 40, each Group 10. Intravital imaging was performed twice weekly after the start of dosing to observe the development of whole blood tumors in mice.
- mice of the C57BL/6 strain were used and divided into 5 groups, including the normal control group (without injection of MPTP), the model group (using MPTP for modeling), and the treatment group of 3 small molecules ( Example 13B, Example 25A, Example 25B).
- Drug administration was started at the same time as modeling. Modeling lasted for 5 days, 30mpk was injected intraperitoneally, administration lasted for 15 days, and 80mpk lasted for 15 days.
- the brain was soaked and fixed in PFA. After the fixation was complete, it was transferred to sucrose dehydration. After the dehydration was complete, the brain was embedded in OCT and sectioned for TH staining.
- the detection index is the number of TH positive cells in the substantia nigra. The more positive cells, the better the protective effect of small molecules on MPTP injury.
- mice in each group statistical results are shown in Figure 50, T-test, **: p ⁇ 0.01, #: p ⁇ 0.05.
- Example 13B group had a statistical difference, indicating that Example 13B had a good effect on protecting the substantia nigra neurons.
- HEK293T cells were used to culture the new coronavirus pseudovirus that only had the ability to infect but not replicate. After the pseudoviruses in the supernatant were collected, normal HEK293T cells with ACE2 receptors on the surface were used as infection objects for pseudovirus infection. After being infected by the virus, the mitochondria in the HEK293T cells will be fragmented, which can be monitored by mitochondrial fluorescent staining (mitotracker red), indicating that the cells are destroyed by the pseudovirus, which is a model group. In the experimental group, 300nM Example 13B was used to incubate the cells for 1 hour in advance and then infected with the pseudovirus to test the protective effect of the small molecule Example 13B on virus infection.
- TBI traumatic brain injury
- the flow cytometry results show that the early apoptotic rate and the total apoptosis rate of the brain of the test substance embodiment 13B (80mpk) and the test substance embodiment 26 (80mpk) group rats are significantly lower than Solvent control group (P ⁇ 0.05).
- Solvent control group P ⁇ 0.05.
- repeated intravenous administration of the test substance Example 13B and Example 26 can significantly improve the neurological damage and apoptosis of brain cells in TBI rats with acute craniocerebral trauma, and promote the recovery of motor ability and neurological function .
- the cell line is a pancreatic cancer cell line, which is widely used in drug sensitivity experiments.
- Cell titer glo was used to detect cell viability, and Graphpad prism was used to draw dose-response curves. The obtained susceptibility curve is shown in the figure below.
- Leptin receptor gene (Obese Gene Receptor, OB-R) is also known as diabetes gene (Diabetes Gene, db), leptin receptor (leptin receptor, Lepr) and obesity, hypertension, diabetes, lipid Metabolic disorders are closely related. The course of the disease is strongly influenced by genetic background. Topical insulin failed to control blood glucose and elevated levels of hepatic gluconeogenesis. Using gene editing technology and embryo injection technology to construct Lepr gene mutant mice. Through blood glucose monitoring of the homozygous strain, it is found that the blood glucose level is significantly different from that of the wild control, and can be used for type II diabetes research.
- mice in this strain is huge, hundreds of times that of normal mice, so it can simulate patients with frequent urination.
- the experiment is divided into three groups, model group (no administration, high urine volume morbidity mice), control group (no administration, normal mice without morbidity), and experimental group (administration embodiment 1A, 80mpk, 2 days gavage once), 2 rats in the control group, and 3 rats in the other two groups.
- the small molecule used was Example 1A.
- Example 1A has the function of suppressing frequent urination.
- mice After purchasing 6-week-old male APOE-/- mutant B6J mice and WT B6J mice, they first acclimatized in the breeding room for 2 weeks. When the mice were 8 weeks old, except the Vehicle group and the WT group, the other groups began to be given high-fat diet (Research Diets, D12492). When the mice were 9 weeks old, the Control group was given 10% cyclodextrin solution, and the rest of the administration groups began to orally gavage different small molecule compounds (Example 13B, Example 33, Example 36 and Example 37) , gavage frequency once every 2 days. After 16 weeks of high-fat feeding, the APOE mice were sacrificed and the aortic arch was dissected. 100 mg/aortic vascular epithelial tissue with a fixed mass was subjected to MSD multifactor detection to determine the expression levels of various inflammatory factors, including IL10, IL-1 ⁇ , and KC/GRO.
- MSD multifactor detection 100 mg/aortic vascular epithelial tissue
- mice By detecting the single oral gavage administration of Example 13B, the time to fall asleep (sleep latency) and sleep duration of the ICR mice induced by a subthreshold hypnotic dose of pentobarbital sodium are affected. Whether the test substance has hypnotic effect, and compare the pharmacodynamics with the positive control drug diazepam. After the mice were adaptively fed, 50 qualified animals were selected according to body weight to enter the experiment, and they were divided into 5 groups using the Excel complete random grouping method: blank control group, positive control group (diazepam), high, medium and low doses of the test substance groups, with 10 animals in each group. Each group of animals should be given medicinal liquid and vehicle.
- the animals of each group were intraperitoneally injected with the maximum subthreshold dose of pentobarbital sodium (at first a preliminary experiment was carried out to determine the maximum subthreshold hypnotic dose of pentobarbital sodium).
- the time to fall asleep (latency to fall asleep) of each animal, the number of animals falling asleep within 30 minutes (the ones whose righting reflex disappeared for more than 1 minute), and the sleep duration of each mouse were recorded.
- the positive drug group was given 1 mg/kg diazepam, which significantly prolongs the sleep of the mice; compared with the blank control group, the small molecule shown in the figure can prolong the sleep time of the mice, but there is no statistical significance In addition, the effect of the small molecule shown in the figure on prolonging the sleep time of mice was significantly weaker than that of 1 mg/kg diazepam.
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Abstract
Description
MCAO模型制作
Claims (15)
- 一种基于菝契皂苷元结构的衍生物在制备治疗线粒体功能异常引起的相关联疾病的药物中的用途,其特征在于,所述的衍生物的结构式如通式(I)所示,
所述的通式(I)所示的衍生物由以下片段A和片段B连接而成,
其中,Z为NR1R2;R1和R2各自独立地为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、氨基、硝基、氰基、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基、C3-C14杂环基、C3-C14杂芳基,杂原子选自N、O、S的一个或多个;或者R1和R2一起形成三至八元环,所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基,杂原子选自N、O、S的一个或多个;X为C(O)或S(O)2;Y为C(Rd)(Re)、C(O)或S(O)2,Rd、Re独立地为氢或具有至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基,其中的取代基选自卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3或-SF5,杂原子选自N、O、S的一个或多个,或者,Rd和Re一起形成三至八元环,所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基,杂原子选自N、O、S的一个或多个;X2为O、S或NH;Ra独立地为氢或具有至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基,其中的取代基选自卤素、羟基、氨基、硝基、氰基、烷氧基、-CF3或-SF5,杂原子选自N、O、S的一个或多个;n为0至10的整数且n不为0,m为1,或者,n为0,m为1,或者,n为0至10的整数且n不为0,m为0;R3、R4a、R4b、R5a、R5b各自独立地为氢或选自卤素、取代的烷基、羟基、氨基;表示单键或者双键;各“*”独立地表示消旋、S或R构型。 - 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式(II)所示,
- 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式III所示,
- 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式IV所示,
- 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式V所示,
其中,R6为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基,吡啶基,-CO烷基,-CO芳香基、-SO2烷基、-SO2芳香基、-CO2烷基、C2-C4(CO)链烯基、-CO2芳香基、-SO3H;L为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基;n为0至10的整数;n2为0,1,2,或3;m,m’独立地为1,2,3,或4;W1为C或NH;V1为C或NH;M为C、S、O或NH。 - 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式VI所示,
Y1为C(Rd)(Re)、C(O)或S(O)2,Rd、Re独立地为氢或具有至少一个取代基的C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基,其中的取代基选自卤素、羟基、氨基、硝基、氰基、醛基、羧基、烷氧基、-CF3或-SF5、杂原子选自N、O、S的一个或多个,或者,Rd和Re一起形成三至八元环,所述的三至八元环具有一个或多个选自C1-C10烷基、C3-C10环烷基、C6-C20芳基、或C3-C14杂芳基、卤素、羟基、氨基、烷氧基、-CF3、-SF5或杂原子为硫、氧、NH或NRa的三至八元杂环的取代基、杂原子选自N、O、S的一个或多个;L为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基;n为0至10的整数;n2为0,1,2,或3;n3为1至10的整数,m为0至10的整数。 - 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式VII所示
其中,R6、R7独立地为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基、吡啶基、-CO烷基、-CO芳香基、-SO2烷基、-SO2芳香基、-CO2烷基、C2-C4(CO)链烯基、-CO2芳香基、-SO3H;L为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基;W2为C或NH;V2为C、O、S或NH;n为0至10的整数;n1为1到10的整数;n2为0,1,2,或3。 - 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式如通式VIII所示
Z1为氢、取代或未取代的C1-C10烷基,C1-C10烷基的取代基选自卤素、羟基、-NH2、硝 基、-CN、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C3-C6环烷基、C2-C4链烯基、C2-C4炔基、苯基、苄基、吡啶基、-CO烷基、-CO芳香基、-SO2烷基、-SO2芳香基、-CO2烷基、C2-C4(CO)链烯基、-CO2芳香基,-SO3H;W3为C、O、S或NH;n为0到10的整数;n4,n5,n6,n7独立地为1至4的整数。 - 根据权利要求1所述的用途,其特征在于,所述的衍生物的结构式中片段B为如下结构:
- 根据权利要求1所述的用途,其特征在于,所述的衍生物为以下化合物、以下化合物的非对映异构体混合物或以下化合物的对映异构体中的一种,
- 根据权利要求1所述的用途,其特征在于,所述的化合物中的一个或多个氢原子为氘原子。
- 一种药物组合物在制备治疗线粒体功能异常引起的相关联疾病的药物中的用途,其特征在于,所述的药物组合物包括第一成分和药学上可接受的载体,或者第一成分、第二成分和药学上可接受的载体的组合,所述的第一成分为根据权利要求1至11任一项所述的用途中化合物、其药学上可接受的盐、立体异构体、互变异构体;所述的第二成分为附加治疗剂,所述的附加治疗剂包括抗抑郁药、抗狂躁药、帕金森病治疗药、阿尔兹默病治疗药或它们的组合。
- 根据权利要求12所述的用途,其特征在于,所述的药学上可接受的盐选自盐酸 盐、氢溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、2-萘磺酸盐、乙酸盐、三氟乙酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、乳酸盐、草酸盐、琥珀酸盐、富马酸盐、马来酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐或扁桃酸盐的一种或多种;所述的附加治疗剂为吗氯贝胺、托洛沙酮、氟西汀、帕罗西汀、西酞普兰、舍曲林、文拉法辛、曲米帕明、曲唑酮、丙咪嗪、地昔帕明、氯米帕明、阿米替林、去甲替林、多塞平、马普替林、洛沙平、阿莫沙平、米氮平、丁螺环酮、氯美扎酮、坦度螺酮、碳酸锂、他克林、石杉碱甲、加兰他敏、多奈哌齐、力帆斯的明、美金刚、普拉克索、他利克索、罗匹罗尼,或它们的组合。
- 根据权利要求1至13中任一项所述的用途,其特征在于,所述的线粒体异常引起的相关联疾病,包括代谢类疾病、肿瘤、炎症、中枢神经系统性疾病。
- 根据权利要求14所述的用途,其特征在于,所述的代谢类疾病包括:高血糖、高血脂、高胆固醇、高低密度脂蛋白、低高密度脂蛋白,血管生成性病症、非酒精性脂肪肝性肝、脑血管意外、心肌梗死、动脉粥样硬化、冠心病、抗衰老、尿急尿频、I型糖尿病、慢性阻塞性肺病;所述的肿瘤包括:前列腺增生、韦格纳肉芽肿、肺结节病、白血病、淋巴瘤、胰腺癌、神经肿瘤;所述的炎症包括:外周神经炎、化疗诱导的外周神经炎、自体免疫疾病、与器官移植相关联的病状、流感病毒、冠状病毒的预防和感染治疗及其后遗症消除、急性呼吸窘迫综合征、炎性肠病、克罗恩氏病、溃疡性结肠炎、银屑病、视网膜脱离、色素性视网膜炎、黄斑变性、胰腺炎、特应性皮炎、类风湿性关节炎、脊椎关节炎、痛风、系统性红斑狼疮、干燥综合症、全省性硬皮病、抗磷脂综合征、血管炎、骨关节炎、自身免疫性肝炎、自身免疫性肝胆疾病、原发性硬发性胆管炎、肾炎、乳糜泻、自身免疫ITP、移植排斥、实体器官的缺血再灌注损伤、败血症、牙周炎、全身性炎症反应综合症、心肌炎、变应性疾病、哮喘、白细胞介素-I转化酶相关的发热综合征、白塞氏病;所述的中枢神经系统性疾病包括:皮克病、脊髓损伤修复、抑郁症、焦虑症、帕金森病、阿尔兹海默病、睡眠障碍、缺血性脑卒中、出血性脑卒中、肌肉萎缩性侧索硬化症、外伤性脑损伤、脑萎缩、亨廷顿病、精神分裂症、躁狂症、毒瘾戒断、多发性硬化症、改善睡眠、肌无力。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5607915A (en) | 1992-09-29 | 1997-03-04 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
WO2015163318A1 (ja) * | 2014-04-25 | 2015-10-29 | レジリオ株式会社 | アルツハイマー病の治療剤を含む、神経細胞の軸索の機能不全が関与する疾患の治療剤 |
CN106905407A (zh) * | 2015-01-27 | 2017-06-30 | 华东理工大学 | 知母皂苷元结构修饰的衍生物、其药物组合物及其应用 |
CN107827949A (zh) * | 2017-11-07 | 2018-03-23 | 西南民族大学 | 一种薯蓣皂苷元抗肿瘤衍生物及其合成方法 |
CN108264535A (zh) * | 2016-12-30 | 2018-07-10 | 中国科学院上海药物研究所 | 一种抗抑郁化合物及其制备方法和应用 |
CN109053854A (zh) * | 2018-09-29 | 2018-12-21 | 莱芜清博汇能医药科技有限公司 | 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 |
CN109206472A (zh) * | 2018-09-27 | 2019-01-15 | 华东理工大学 | 薯蓣皂苷元衍生物、其药物组合物及其应用 |
CN109988218A (zh) * | 2017-12-29 | 2019-07-09 | 中国科学院上海药物研究所 | 一种菝葜皂苷元衍生物及其制备方法和应用 |
-
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5607915A (en) | 1992-09-29 | 1997-03-04 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
WO2015163318A1 (ja) * | 2014-04-25 | 2015-10-29 | レジリオ株式会社 | アルツハイマー病の治療剤を含む、神経細胞の軸索の機能不全が関与する疾患の治療剤 |
CN106905407A (zh) * | 2015-01-27 | 2017-06-30 | 华东理工大学 | 知母皂苷元结构修饰的衍生物、其药物组合物及其应用 |
CN108264535A (zh) * | 2016-12-30 | 2018-07-10 | 中国科学院上海药物研究所 | 一种抗抑郁化合物及其制备方法和应用 |
CN107827949A (zh) * | 2017-11-07 | 2018-03-23 | 西南民族大学 | 一种薯蓣皂苷元抗肿瘤衍生物及其合成方法 |
CN109988218A (zh) * | 2017-12-29 | 2019-07-09 | 中国科学院上海药物研究所 | 一种菝葜皂苷元衍生物及其制备方法和应用 |
CN109206472A (zh) * | 2018-09-27 | 2019-01-15 | 华东理工大学 | 薯蓣皂苷元衍生物、其药物组合物及其应用 |
CN109053854A (zh) * | 2018-09-29 | 2018-12-21 | 莱芜清博汇能医药科技有限公司 | 基于知母菝契皂苷元结构的衍生物、药物组合物及其应用 |
Non-Patent Citations (1)
Title |
---|
T. HIGUCHIV. STELLA: "Bioreversible Carriers in Drug Design", vol. 14, 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS |
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