CN114569589A - Natural small molecule and application thereof in medicine preparation - Google Patents
Natural small molecule and application thereof in medicine preparation Download PDFInfo
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Classifications
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Food Science & Technology (AREA)
- Biomedical Technology (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Anesthesiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention relates to a biological activity research of natural chemical small molecules and application thereof in preparation of medicines and foods, in particular to application of 2-hydroxy-2-phenyl-malonamide in medicines, foods and food additives.
Description
Technical Field
The invention belongs to the field of natural medicines, and relates to biological activity of natural small molecules and application of natural active molecules.
Technical Field
Armillariella tabescens (Armillariella tabescens) is the name Armillariella tabescens. Has antiinflammatory, antibacterial and analgesic effects, and has remarkable therapeutic effects on gastritis, cholecystitis, cholangitis, appendicitis, otitis media, etc. It has effects in promoting bile secretion, nourishing liver and mucosa, promoting metabolism, and enhancing liver and kidney functions.
Hydroxy-2-phenyl-malonamide (2-hydroxy-2-phenylmalonamide, PHMA), also known as armillarisin or pseudomellitin, has the chemical structure shown below. Armilaridin is widely present in pseudomellea armillaria sporophore with good medical and edible effects (commonly called Armilaridin), and the content of the Armilaridin in the pseudomellea sporophore is reported to be 0.25 per thousand of dry weight, and researches show that the Armilaridin has strong inhibitory effect on growth of trichoderma hyphae (Shen Jin-Wen, Ma Bing-Ji, LiWen, etc. Activity of armillarisin B in viral acquired plant pathogenic fungal fusion. [ J ]. Z. Naturforsch., C, J. biosci., (11): 2-790). However, the physiological activity of the compound on mammals, especially human bodies, has not been reported yet, and the application value of the compound in clinic is yet to be further researched and developed.
Formula 1.2-hydroxy-2-phenyl-malonamide (2-hydroxy-2-phenylmalonamide, PHMA)
Disclosure of Invention
The invention aims to develop the use value of natural compounds. 2-hydroxy-2-phenyl-malonamide (PHMA) is a secondary metabolite in armillaria tabescens, and the invention further develops the application of the PHMA in the aspects of food, medicine and the like according to the biological activity discovered in the research process. The PHMA and the derivative thereof are applied to all animals, particularly vertebrates, including human beings.
The food of the invention is a finished product and a raw material for various people to eat or drink and is an article which is a food and a medicine according to the tradition. The food includes but is not limited to common food, health food, special functional medical food, beverage, food additive and raw material for making food. The medicine is a substance for preventing, treating and diagnosing human diseases, purposefully regulating the physiological function of human and prescribing indications or functional indications, administration and dosage, and comprises traditional Chinese medicines, chemical medicines, biological products and the like.
When the PHMA is used as food or medicine, the PHMA can be added into a formula as a pure product or a component of other raw materials, and the content can be fixed or in a range.
The PHMA and its derivatives of the present invention can be chemical compounds, biological extracts, biological fermentation products.
In one particular embodiment, the PHMA of the present invention is chemically synthesized in a variety of ways that are well known to those skilled in the art and have been disclosed.
In one embodiment, the PHMA of the present invention is a biological extract, such as Leuconostoc, and various methods of biological extraction are disclosed.
In a particular embodiment, the PHMA of the present invention is a biological fermentation product, the PHMA being active as a component of the fermentation product.
The PHMA and its derivatives can exert bioactivity by injection or oral administration. The injection route comprises intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection and other body cavity injections. For convenient injection, PHMA and its derivatives can be made into preparation forms, including liquid injection and dry powder injection. The oral administration route comprises oral administration, gastrointestinal administration and the like, and for convenient oral administration, the PHMA can be prepared into preparation forms, including common tablets, oral sustained-release tablets, oral controlled-release tablets, capsules, pills, granules, oral powder, oral liquid preparations, oral buccal tablets and the like. The above formulation forms can be further subdivided for better biological activity, and methods for various formulations are well known to those skilled in the art.
PHMA is slightly soluble in water. Solubility can be enhanced by the addition of a co-solvent, which can be ethanol, dimethyl sulfoxide, and the like. The dissolution rate can also be increased by physical means such as heating, stirring, etc.
PHMA natural product and its derivatives can directly generate activity after entering into body; or participate in metabolism to form active new molecules; or the inactive small molecules can participate in metabolism after entering the body to form active new molecules; or the active small molecules can participate in metabolism after entering the body to form new inactive molecules. In particular, the active form of the invention may be PHMA, which is hardly metabolized in the body and is generally secreted in the prototype to the outside, in the form of excreta, such as sweat, urine, feces; or only less than 50%, 40%, 30%, 20%, 10%, 5% of PHMA is involved in human metabolism, and the metabolite can be amidation or esterification or deamination or oxidation or reduction of PHMA to form a new molecule.
The invention discovers that PHMA has the activity of regulating the nervous system for the first time, and particularly shows the application of PHMA in medicines for maintaining the sleep of animals or human beings, promoting the sedation and hypnosis of the animals or the human beings, calming the nerves and nourishing the brain, and treating and/or preventing neurasthenia, anxiety, depression, insomnia, convulsion or epilepsy. The sedation, characterized by a reduction in the frequency and length of activity of the animal. The hypnotic effect is characterized by shortening the time of falling asleep, accelerating the falling asleep or prolonging the sleep time.
The PHMA can regulate the activity of a nervous system, has the function of soothing the nerves and can be used as a medicament for soothing the nerves. Including reducing the amount of activity of the animal in sleep, such as keeping the animal's limbs or head still for a long period of time, or extending the duration of a single sleep, or extending the duration of a deep sleep, etc.
PHMA has activity of regulating nervous system, is natural component with bioactivity acting on nervous system, can be used for preventing or treating nervous system diseases and mental diseases, and can be used for preparing mental medicine or nervous system medicine.
In one embodiment of the invention, PHMA promotes increased sleep and prolonged sleep in mammals, such as mice.
In one embodiment of the invention, PHMA reduces the amount of activity in a mammal, such as a mouse, and promotes sleep in a portion of the mouse, reducing the time to sleep.
In one embodiment of the invention, PHMA can provide a mammal, such as a mouse, with deep sleep. No obvious displacement of limbs and trunk, reduced activity, resting state, prolonged single sleep time, etc. The resting state refers to resting, and the limbs, the head, the tail, the trunk, the eyelid, the mouth and other positions of the animal which are not obviously visible by visual inspection move, so the animal is in a deep sleep state.
In a particular embodiment, PHMA alone is used as the drug; in a particular embodiment as a compound. In the examples, PHMA may be used in a dosage of 500mg/kg body weight, or any dosage of 400mg/kg body weight, 300mg/kg body weight, 200mg/kg body weight, 100mg/kg body weight, 70mg/kg body weight, 50mg/kg body weight, 25mg/kg body weight, or less than 500mg/kg body weight. The final dosage is determined according to actual requirements and safety.
In one embodiment, the PHMA is administered in solution, with the concentration of PHMA in the solution being 7.0%, 5.0%, 1.0%, 0.5%, 0.1%, 0.05%, 0.01%.
In a specific embodiment, the weight of the mice fed with PHMA added to the feed for a long period of 30 days was not significantly different from the weight of the mice in the control group fed without PHMA. In a specific embodiment, the PHMA is added to drinking water of mice for a long period of time of 30 days or more, and the weight of the mice in the group to which the PHMA is added is not significantly different from the weight of the mice in the control group to which the PHMA is not added. The concentration of PHMA in drinking water is 1.0%, 0.5%, 0.1%, 0.05%, 0.01% or less.
In one embodiment, PHMA is added to the water of adult zebra fish, the concentration of PHMA in the water is 0.1 per mill, 0.05 per mill and 0.01 per mill respectively, the zebra fish can normally survive for more than 30 days, and the activity of the zebra fish in the high-dose group is observed to be less than that of the zebra fish in the low-dose and non-PHMA groups.
In a specific embodiment, PHMA is added into the water of adult zebra fish, the concentration of PHMA in the water is 1 per mill, the activity of zebra fish is reduced remarkably, and the zebra fish stops swimming frequently and is in a static state, but in the static state, the pectoral fin is observed to swing or not swing. After 24 hours, the fish is changed into fish water without PHMA, and the zebra fish recovers the normal activity and normally survives for more than 30 days.
PHMA has a solubility in water of about 0.7g/100g at 25 deg.C, and the solubility in aqueous solutions varies greatly at different temperatures. In a specific embodiment, a cosolvent or a solubilizer is added, wherein the cosolvent can be ethanol, dimethyl sulfoxide and the like, and can also be directly dissolved in a solvent such as ethanol, dimethyl sulfoxide and the like.
The PHMA, the coupling compound thereof and the edible or medicinal salt thereof can embody the activity of regulating the nervous system in the mouse, and the person skilled in the art knows that the physiological characteristics of the human and the mouse are similar to each other, which indicates that the PHMA can embody the activity of regulating the nervous system to a certain degree in the human body. Clinical studies have shown that the dosage of a drug administered to a laboratory animal such as a mouse may vary significantly in humans, including being significantly increased or decreased, and in general, the dose of the drug administered per kilogram of body weight in humans will be significantly lower than the dose administered to the laboratory animal, such as 1/2, 1/3, 1/5, 1/10, 1/100, which is decreased to the dose administered to the laboratory animal. Food and health food, functional food development experience has shown that the content of molecules with specific biological activity contained in food is generally significantly lower than that of drugs, and the content may be unstable and distributed over a wide range. The content variation of the above different applications is well known to those skilled in the art and is within the protection scope of the present invention.
One skilled in the art can reasonably speculate the use of PHMA or a pharmaceutically acceptable salt thereof in the preparation of a medicament or food for the mental or neurological system, for example, the use of PHMA in the preparation of a medicament for inducing and maintaining sleep, prolonging sleep time or deep sleep time, promoting sedative hypnosis, tranquilizing mind, nourishing the brain, treating and/or preventing neurasthenia, anxiety, depression, insomnia, convulsion or epilepsy in an animal or a human.
In a particular embodiment, the use of PHMA or an extract or composition comprising PHMA in the manufacture of a medicament for inducing and maintaining sleep, prolonging sleep time or deep sleep time, treating and/or preventing insomnia in an animal or human.
In a particular embodiment, the use of PHMA or an extract or composition comprising PHMA in the manufacture of a medicament for promoting sedation, hypnosis, tranquilization, brain tonic, treatment and/or prevention of neurasthenia, anxiety, depression, convulsions or epilepsy in an animal or human.
In a particular embodiment, the use of PHMA or an extract or composition containing PHMA in a food for soothing the nerves, nourishing the brain, enhancing memory, strengthening the body, promoting sleep, prolonging sleep time or deep sleep time, improving sleep quality.
In a specific embodiment, the PHMA or the extract or the composition containing the PHMA is used in foods or food additives for soothing nerves, nourishing brain, enhancing memory, nourishing and strengthening body, promoting sleep, prolonging sleep time or deep sleep time and improving sleep quality.
The PHMA coupling compound or its edible or medicinal salt can also be used as medicine or food for regulating nervous system.
The PHMA conjugate compound or its edible or medicinal salt can directly generate biological activity in vivo, and also can generate biological activity after metabolism, and the biological activity includes but is not limited to sedation, hypnosis and others. Its metabolism can be in any organ in vivo, or in a simulated environment ex vivo.
When the PHMA coupling compound or the edible or medicinal salt thereof is used as food or medicine, the PHMA coupling compound or the edible or medicinal salt thereof can replace PHMA like PHMA.
Method of implementation
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
Example 1 PHMA direct sleep experiment
The SPF fraction of CD-1 (ICR) mice, approximately 30-35g in weight, was divided into 2 groups of 10 mice each. The control group and the experimental group were injected intraperitoneally with PHMA dissolved in physiological saline at a ratio of 0mg/kg and 70 mg/kg. The mice are placed in independent cage boxes, the video monitoring is started to record the activity condition of the mice, and the number of free activities of the mice within 10 minutes after the administration is counted at 30-40 minutes. Mice turned and walked 90-180 degrees at a time to perform the activity once. The experiment was carried out in a quiet environment at 22 ℃.
The results show that the number of autonomic activities of the mice in the PHMA group is significantly reduced compared to the control group. After 10 minutes of PHMA administration, the mouse activity was significantly less than that of the control group, and the mouse was rarely walking back and forth at both ends of the mouse cage, mostly in a state of lying still, and had a periscopic or sleeping behavior. The outside of the cage box is lightly knocked, and no obvious interference is caused to the mouse. Thus, PHMA has obvious inhibition effect on the independent activity of mice.
In addition, the single time period of sleeping for resting within 1 hour after the administration of the PHMA group mice exceeded 10 minutes to 9, and only one of the mice was in multiple transient resting states. Control mice were relatively active.
After the single time of falling asleep exceeds 10 minutes after the PHMA group mice are administrated, the correction experiment verification is carried out. When the mouse is placed in the back lying position, the mouse can turn over to the right position immediately, if the mouse cannot turn over in more than 1 min, the turning-over reflection is considered to disappear, and the mouse enters a deep sleep state. As a result, 5 PHMA group mice continued to stay asleep for more than 1 minute, and the other 4 mice continued to stay asleep for a while with a turning-over action for 1 minute. And the control group mice are all vigilant and flexible and can turn right immediately.
Example 2 PHMA prolongation of sleep time induced by sodium pentobarbital
Kunming mice, 30-35g in weight, were divided into 2 groups of 10 mice each. The control group and the experimental group were separately gavaged with 7mg/ml PHMA dissolved in physiological saline and physiological saline at 300ul, and after 50 minutes, all mice were intraperitoneally injected with pentobarbital sodium at 36 mg/kg body weight, and the sleep time of each mouse was recorded.
The interval between disappearance of the mouse righting reflex and recovery of the righting reflex was taken as the sleep time. When the mouse is placed in the back lying position, the mouse can turn over to the right position immediately, if the mouse cannot turn over in more than 1 min, the turning over reflection is considered to disappear, the mouse enters sleep, and if the mouse turns over to the right position subsequently, the mouse is considered to be awake. The experiment was carried out in a quiet environment at 22 ℃.
The experimental results show thatPHMA can prolong the time of falling asleep of mice from 17.73 minutes to 38.99 minutes, and the difference between the two groups has statistical significance (p)<0.05), PHMA can prolong the sleep of mice.
| Group of | Animal number (only) | Sleep time (min) |
| Control group | 10 | 17.73±9.86 |
| Experimental group | 10 | 38.99±15.65 |
Example 3 PHMA Effect on sodium pentobarbital subthreshold dose sleep Studies
SPF grade CD-1 (ICR) mice, 30-35g in weight, were divided into 2 groups of 10 mice each. The control group and the experimental group were intraperitoneally injected with 300ul of 5 mg/ml PHMA dissolved in physiological saline and physiological saline (about equivalent to 50mg/kg body weight), and after 20 minutes, pentobarbital sodium was intraperitoneally injected at a dose of 27 mg/kg body weight, and the number of mice that entered sleep during 0.5 hour was recorded.
When the mouse is placed in the back lying position, the mouse can turn over to the right position immediately, and if the mouse cannot turn over in more than 1 min, the turning-over reflection is considered to disappear, and the mouse enters a sleep state. The experiment was carried out in a quiet environment at 22 ℃.
The experiment result shows that PHMA can improve the sleep rate of a mouse from 20% to 90%, can promote the sleep of the mouse, and can increase the sleep rate of animals with subthreshold dose of pentobarbital sodium.
| Group of | Number of animals (only) | Number of sleeping animals | Sleep onset Rate (%) |
| Control group | 10 | 2 | 20 |
| Experimental group | 10 | 9 | 90% |
Claims (10)
- Use of 2-hydroxy-2-phenyl-malonamide or a pharmaceutically acceptable salt thereof in the preparation of a medicament or a food or food additive.
- 2. Use according to claim 1, characterized by the fact that it is used for the preparation of a medicament for the mental or nervous system.
- 3. Use according to claims 1-2, characterized in that it is used for the preparation of a medicament for inducing and maintaining sleep in animals or humans, for promoting sedative-hypnosis, tranquilization and brain-nourishing in animals or humans, for treating and/or preventing neurasthenia, anxiety, depression, insomnia, convulsions or epilepsy.
- 4. Use according to claims 1-3, characterized by having a sedative effect, reducing the frequency or duration of activity in animals.
- 5. Use according to claims 1-3, characterized by having a hypnotic effect, reducing the time to fall asleep and promoting sleep.
- 6. Use according to claims 1-3, characterized by having a sedative effect, reducing the amount of activity in sleep states, or prolonging sleep time, or prolonging deep sleep time.
- 7. Use according to claims 1-6, characterized in that the medicament is a preparation of the compound, or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable adjuvants.
- 8. Use according to claims 1-7, characterized in that the medicament is a tablet, a granule, a capsule, an injection, an oral solution, the tablet can be a common oral tablet, a sustained release preparation, a controlled release preparation.
- Use of 2-hydroxy-2-phenyl-malonamide as a food or food additive, including general foods, health foods, special function medical foods, drinks.
- 10. The use of claims 1-9, characterized by a dose of any dose less than or equal to 500mg/kg body weight, including but not limited to a 500mg/kg body weight dose, 400mg/kg body weight, 300mg/kg body weight, 200mg/kg body weight, 100mg/kg body weight, 70mg/kg body weight, 50mg/kg body weight, 25mg/kg body weight; or the quality concentration in the pharmaceutical preparation or food or beverage is less than or equal to 7.0 per thousand, including but not limited to 1.0 per thousand, 0.5 per thousand, 0.1 per thousand, 0.05 per thousand and 0.01 per thousand.
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