CN111728961B - Medicine composition for treating senile dementia and application thereof - Google Patents
Medicine composition for treating senile dementia and application thereof Download PDFInfo
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- CN111728961B CN111728961B CN202010777160.2A CN202010777160A CN111728961B CN 111728961 B CN111728961 B CN 111728961B CN 202010777160 A CN202010777160 A CN 202010777160A CN 111728961 B CN111728961 B CN 111728961B
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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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
- A61K31/18—Sulfonamides
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention discloses a pharmaceutical composition containing (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxy valerenic acid in a specific mass ratio. Specifically, the pharmaceutical composition takes (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid as pharmaceutical active ingredients, and the mass ratio of the two pharmaceutical active ingredients is 15: 3-7. The pharmaceutical composition is particularly useful in the treatment of senile dementia, particularly alzheimer's disease.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition for treating senile dementia and application thereof.
Background
Aging (senescence) is an activity accompanying the development and development of life, and is a process of loss and degeneration of the body from constitutional materials, tissue structures to physiological functions. The physiological changes in the aging process of human body are mainly reflected in the loss of organism tissue cells and constitutional substances, the slowing of organism metabolic rate and the hypofunction of organism and organs. The aging process is continued from the fertilized egg to death, and the aging characteristics are only obviously shown until a certain stage. It is generally considered that the age of a human is pre-aged or pre-aged in the range of 45 to 59 years, aged in the range of 60 to 89 years, and long-lived above 90 years.
Geriatric Diseases (Senile Diseases) refer to Diseases that people suffer from in the elderly, are age-related, and have self-characteristics. The elderly have a disease spectrum different from that of young people, and even if the elderly and young people suffer from the same disease, the clinical manifestations and disease progression of the elderly and young people are different. Generally, the senile diseases are classified into three types, the first type is a disease specific to the elderly, which is a disease accompanied by functional decline and disorder in the process of aging of the elderly, and the disease is only obtained by the elderly and has the characteristics of the elderly, such as senile dementia, senile deafness, senile psychosis and the like; the second is a 'common disease of the elderly', which is related to factors such as pathological aging, decreased immune function, long-term strain of the elderly, and the like, and the disease can occur in the early stage of the elderly and can also occur in the elderly, such as hypertension, coronary heart disease, diabetes, malignant tumor, and the like; the third is "diseases which can occur in all the young, middle-aged and old people", which occur in all age groups, but have the same pathological changes due to the decline of human and machine functions of the old people, and the specificity of the old people, such as peptic ulcer, which can occur in all the young, middle-aged and old people, but the old people are easy to become cancerous or have complications.
Senile dementia, also known as senile dementia and senile dementia, refers to various dementia syndromes occurring in the elderly, including alzheimer disease, vascular dementia, mixed dementia, etc., among which alzheimer disease is the most typical senile dementia. Alzheimer Disease (AD) is a progressive neurodegenerative disease that occurs in older people over the age of 70 and is characterized clinically by global dementia, such as memory impairment, aphasia, disuse, agnosia, impairment of visual spatial skills, impairment of executive function, and personality and behavioral changes. The disease is latent in onset, the etiology is unknown so far, and the disease is generally considered to be related to factors such as family history, head trauma, low education level, thyroid disease, high or low maternal age, virus infection and the like. Vascular dementia refers to a severe cognitive dysfunction syndrome caused by ischemic stroke, hemorrhagic stroke, and cerebrovascular diseases that cause hypoperfusion in brain regions such as memory, cognition, and behavior. Vascular dementia is not characteristic of the elderly, but the elderly are indeed a high-incidence population of vascular dementia. The patient with mixed dementia has the characteristics of the two types of dementia, such as occult disease and gradually declined cognitive function, but the patient has various diseases such as hypertension, hyperlipidemia, diabetes and the like, and has cerebrovascular accidents for many times within a certain period of time, so that the intelligence decline is gradually declined on the basis of slow progress, and focal symptoms and physical signs of a nervous system are presented, and the self-learning ability is gradually lost. With the progress of research, the similarity between these types of senile dementia is more and more emphasized, such as the pathological changes of the characteristics of cerebral beta-amyloid deposition, neuron degeneration and death, neurofibrillary tangles and the like, and the behaviors of the senile dementia are represented by cognitive function impairment, slow action, action disorder and the like.
At present, clinically, symptomatic treatment, intelligence-developing drugs or drugs for improving cognitive functions are mainly adopted as treatment means for senile dementia. Because the pathogenesis of senile dementia is very complicated, although the medical field takes great time and energy to find effective treatment drugs for senile dementia, no specific drugs or methods can reverse and prevent the deterioration and the progress of the senile dementia.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a pharmaceutical composition for treating senile dementia and application thereof.
The inventor of the present invention unexpectedly found through experiments that a pharmaceutical composition comprising (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid in a specific mass ratio has the effect of improving memory dysfunction and spatial cognitive impairment, and thus can be used for treating (including alleviating and improving) senile dementia, in particular alzheimer's disease.
To this end, the present invention provides a pharmaceutical composition comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient is: a) (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide, and b) hydroxyvaleric acid, and the mass ratio between the pharmaceutically active ingredients a) and b) is 15: 3-7.
In one embodiment of the invention, the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 3.
In another embodiment of the present invention, the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 5.
In another embodiment of the present invention, the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 7.
The (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide used in the present invention has the following structural formula:
this compound was previously described in patent document WO2014/019023a1 (intermediate DF) and can be prepared according to the method described on page 95 of the specification of this patent document. Patent document WO2014/019023a1 relates generally to compounds useful for the up-regulation of α 7 nicotinic acetylcholine receptors (α 7 nachrs) and their use in the treatment or prevention of diseases in which up-regulation of α 7 nachrs is beneficial, such as cognitive deficits, inflammatory diseases, neuropathic pain, and the like. However, this document does not disclose any intermediate compounds thereof having any medical use.
Hydroxyvalerenic acid (CAS NO:1619-16-5) can be a chemically synthesized product, isolated from a plant extract such as valerian (valeriana) plant extract, or prepared in other ways. For example, the hydroxyvalerenic acids of the present invention may be isolated from valerian extracts obtained by extracting the roots and/or rhizomes of valerian with petroleum ether, ethyl acetate and/or aqueous alcohols (e.g. aqueous alcohols having an alcohol content of between 40-80 v/v%). At present, valerian is known to be one of the most commonly used herbs for the treatment of insomnia and anxiety, but there are few reports on the biological activity of hydroxyvalerenic acid.
The pharmaceutical composition of the invention also comprises a pharmaceutically acceptable carrier. For the preparation of the pharmaceutical composition, any pharmaceutically acceptable carrier commonly used in the art may be employed.
For example, to prepare solid dosage forms for oral administration, solid carriers known in the art may be used, such as lactose, microcrystalline cellulose, sucrose, cyclodextrin, mannitol, acacia, sodium carboxymethyl starch, corn starch, potato starch, talc, magnesium stearate, gelatin, and the like. In addition, any other carriers generally used for flavoring, coloring, preserving, etc. may be used as long as they are compatible with the active ingredient or ingredients already used.
For another example, to prepare a liquid dosage form for oral administration, liquid carriers known in the art may be used, such as water, ethanol, glycerol, propylene glycol, polyethylene glycol, and vegetable oils such as peanut oil, sesame oil, soybean oil, olive oil, and the like.
For preparing parenteral dosage forms, sterile carriers known in the art may be employed, such as water for injection, oils for injection such as soybean oil, peanut oil, castor oil, other solvents for injection such as ethanol, glycerol, propylene glycol, polyethylene glycol, ethyl oleate, dimethylacetamide and the like. Various additives such as wetting agents, solubilizers, emulsifiers, suspending agents, buffers, antioxidants, bacteriostats, isotonicity adjusting agents, and the like can also be used if desired. For sterile powder for injection, fillers and preservatives such as lactose, trehalose, mannitol, glycine, human serum albumin and the like can also be used.
The pharmaceutical compositions of the present invention may be administered by any suitable route of administration such as oral, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal and parenteral routes. Preferably, the pharmaceutical composition according to the invention is administered by the oral route. It will be appreciated that the preferred route of administration will depend upon factors such as the general condition of the patient to be treated, the age, sex, body weight, severity of the condition to be treated and the like, and will be determined empirically by the attending physician.
The pharmaceutical composition of the present invention can be formulated into specific dosage forms according to the conventional formulation techniques in the art, such as oral administration dosage forms (e.g., tablets, powders, granules, pills, lozenges, capsules, solutions, emulsions, suspensions, syrups or elixirs), parenteral administration dosage forms (e.g., sterile injectable solutions, dispersions, suspensions, emulsions, and sterile powders for injection that are reconstituted into sterile injectable solutions or dispersions prior to use).
The invention also provides application of the pharmaceutical composition in preparing a medicament for treating senile dementia. Preferably, the type of senile dementia is alzheimer's disease.
The pharmaceutical composition containing (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid in a specific ratio is particularly suitable for treating senile dementia, in particular Alzheimer's disease.
In order that the nature and spirit of the present invention may be further understood, preferred embodiments of the present invention and the effects thereof will be described below with reference to specific examples. It is to be understood, however, that such description is merely illustrative of the features and advantages of the present invention, and is not intended to limit the scope of the appended claims in any way.
Detailed Description
Example 1
Pharmaceutical composition 1
150mg of (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and 30mg of hydroxyvaleric acid are weighed and mixed well in a mortar to obtain the pharmaceutical composition 1 of the present invention in the form of powder (powder).
Example 2
Pharmaceutical composition 2
150mg of (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and 50mg of hydroxyvaleric acid are weighed and mixed well in a mortar to obtain the pharmaceutical composition 2 of the present invention in the form of powder (powder).
Example 3
Pharmaceutical composition 3
150mg of (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and 70mg of hydroxyvaleric acid are weighed and mixed well in a mortar, and then the mixture is mixed well in the mortar, so that the pharmaceutical composition 3 of the present invention in the form of powder (powder) is obtained.
Experimental example 1 protective Effect of the pharmaceutical composition of the present invention on in vitro model of amyloid-beta-induced PC12 cell Alzheimer's disease
The purpose of this experiment was to observe the effect of the pharmaceutical composition of the present invention on amyloid beta1-42(A β 42) improvement of rat adrenal pheochromocytoma (PC 12) cell damage induced by the enzyme.
1. Experimental Material
PC12 cell line
2. Test substances
Amyloid beta protein1-42(Abeta.42), 3- (4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl-2-H-tetrazolium bromide (MTT), (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl]-2- (4-sulfamoylphenyl) cyclopropanecarboxamide (hereinafter referred to as Compound A) and hydroxyvalerenic acid (hereinafter referred to as Compound B).
3. Experimental methods
(1) Amyloid beta protein1-42Establishment of (Abeta 42) induced PC12 cell damage model
PC12 cells were incubated at 37 ℃ with 5% CO2In a DMEM medium containing 5% horse serum, 10% fetal bovine serum, 2.0mmol/L glutamine, 100U/mL penicillin and 100. mu.g/mL streptomycin. After 2 days, the cells were seeded at a density of 5000 cells/well in a 96-well culture plate previously coated with polylysine, and then returned to the incubator to continue the culture. After further culturing for 1 day, an A beta 42-induced injury model is established: mu.L of Abeta 42 at a concentration of 500. mu. mol/mL was added to each well of a 96-well plate containing PC12 cells (100. mu.L of culture per well)Nutrient solution) so that the final concentration of a β 42 per well is 10 μmol/mL. A blank control was set and an equal amount of medium without Α β 42 was added.
(2) Method of administration
The 96-well plates were divided into 5 groups of 18 wells each, and then the drugs were administered according to the following dosing schedule:
blank control group: to each well was added 20. mu.L of the above DMEM medium.
Model group: to each well was added 20. mu.L of the above DMEM medium.
Compound group a: to each well was added 20. mu.L of a solution containing 1.5X 10-6mg/mL Compound A in DMEM medium as described above.
Compound group B: to each well was added 20. mu.L of a solution containing 0.5X 10-6mg/mL Compound B in DMEM medium as described above.
Pharmaceutical composition group: to each well was added 20. mu.L of a solution containing 1.5X 10-6mg/mL Compound A and 0.5X 10- 6mol/mL Compound B in DMEM medium as described above.
Then, the 96-well plate was returned to the incubator to continue the incubation for 1 day.
(3) MTT assay
To each well of a 96-well plate, 10. mu.L of MTT (dissolved in PBS at a concentration of 5mg/mL) was added and the mixture was incubated at 37 ℃ with 5% CO2After the purple crystals were completely dissolved, the absorbance value (OD 570) at a wavelength of 570 nm was measured by a microplate reader, and the cell survival rate was reflected by the percentage of the OD value of the administered group to the OD value of the control group. The cell survival (%) of each administration group relative to the blank control group was calculated as follows:
cell survival (%) relative to the blank group [ OD 570 value of other group/OD 570 value of blank group ] × 100%.
4. Results of the experiment
The results of this experiment are shown in table 1 below.
TABLE 1 Effect of the pharmaceutical composition of the present invention on A β 42-induced cell damage model of rat adrenal pheochromocytoma (PC 12)
Note: results are expressed as mean ± standard deviation, p <0.01 compared to model group.
5. Evaluation of the synergistic Effect
The synergistic index of the active ingredients compound a and compound B in the pharmaceutical composition of the present invention with respect to the improvement effect on a β 42-induced rat adrenal pheochromocytoma (PC 12) cell damage model was evaluated with the "treatment rate (%)" parameter as the subject.
Specifically, the synergy index is obtained by a gold positive mean q value method, wherein the q value is calculated by the following formula:
q＝PA+B/(PA+PB-PA×PB)。
in the above formula, PA、PBAnd PA+BThe treatment rates for compound group a, compound group B and the pharmaceutical composition group (i.e., compound a and compound B in combination), respectively. In this experiment, the treatment rate was calculated using the following formula:
the treatment rate is ═ cell survival in the drug group versus the blank group-cell survival in the model group versus the blank group)/cell survival in the model group versus the blank group ] × 100%.
According to the calculated q value, whether the compound A and the compound B generate synergistic effect when used in combination can be judged. When q is less than 1, the antagonism is generated after the two medicines are combined; when q is 1, the two medicines are combined to generate the additive effect; when q is greater than 1, the synergistic effect is generated after the two medicines are combined.
The synergy index (q) for the combination of compound a and compound B was calculated to be 1.88.
The above results indicate that (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid, both alone and in combination, have a direct protective effect on Abeta 42-induced rat adrenal pheochromocytoma (PC 12) cell damage. In particular, when compound a and compound B are used in combination (particularly in a specific weight ratio of 15: 3), this protective effect can be significantly enhanced and a significant synergistic effect results.
Experimental example 2 study of therapeutic Effect of the pharmaceutical composition of the present invention on Experimental Alzheimer's disease rats
The purpose of this experiment was to observe the in vivo therapeutic effect of the pharmaceutical composition of the present invention on experimental alzheimer rats.
1. Laboratory animal
Healthy male SD rats, body weight 200 + -20 g. Animals were acclimated for two days at 22 ℃, 50% relative humidity and 12 hours light-12 hours dark conditions. Animals can eat and drink water freely.
2. Test substances
(1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide (hereinafter referred to as compound A), hydroxyvalerenic acid (hereinafter referred to as compound B), and artemisinic acid (IBO).
3. Experimental methods
Establishing a rat Alzheimer disease model: the rat model of Alzheimer's disease was induced by basal forebrain injection of Armillariella commune. After successful modeling, experimental animals were randomly grouped into 20 animals per group. The dosing schedule for each experimental group is summarized as follows:
normal control group: unmodeled SD rats were selected and given normal food and drinking water for 90 days.
Model group: artemisia anserine-induced Alzheimer disease model SD rats were selected and given normal food and drinking water for 90 days.
Compound group a: rats (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide were also gavaged with a dose of 150 mg/kg/day once daily for 90 days, in addition to normal food and drinking water.
Compound group B: in addition to normal food and drinking water, rats were gavaged with hydroxyvalerenic acid at a dose of 50 mg/kg/day once a day for 90 days.
Pharmaceutical composition group: rats (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide (dose 150 mg/kg/day) and hydroxyvalerenic acid (dose 50 mg/kg/day) were gavaged once daily for 90 days in addition to normal food and drinking water.
After 90 days of administration, each group of experimental animals was placed in the light box of a dark box system. The dark-avoiding box is a device designed by utilizing the habit of darkening and avoiding the light of a rat, wherein one half is a light room, the other half is a dark room, and the light room and the dark room are connected through a small hole, so that the dark-avoiding box has higher sensitivity on the memory process, particularly the memory reproduction. After the rats entered the dark box, electrical stimulation was performed for 1 second, and then the animals were taken out. After 7 days, the above experiment was repeated, and the time and the number of the rats entering the dark box from the light box were recorded.
4. Results of the experiment
The results of this experiment are shown in table 3.
TABLE 3 improving Effect of the pharmaceutical composition of the present invention on memory dysfunction of Alzheimer's disease model SD rats
(n-20, results expressed as mean ± standard deviation within the group,. + -. denotes p <0.01, compared to model group)
In addition, 90 days after administration, each group of experimental animals was also subjected to Morris water maze behavioural experiments. The experiment was continued for 7 days, with rats trained on days 1-6 and behavioural tests on day 7. The results of this experiment are shown in table 4.
TABLE 4 ameliorating Effect of pharmaceutical compositions of the present invention on spatial cognitive impairment of Alzheimer's disease model SD rats
(n-20, results expressed as mean ± standard deviation within the group,. + -. denotes p <0.01, compared to model group)
From the results shown in tables 3 to 4, it was found that (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvalerenic acid, when used alone or in combination, have a certain improving effect on memory dysfunction and spatial cognitive impairment in SD rats in the Alzheimer's disease model. However, the applicants have unexpectedly found that when (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid are used in combination in a specific mass ratio of 15:5, there is a significantly better improvement compared to the two compounds used alone. The above results suggest that the pharmaceutical composition of the present invention comprising (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide and hydroxyvaleric acid in a specific mass ratio has the effect of improving memory dysfunction and spatial cognitive impairment, and thus can be used for the treatment (including alleviation and amelioration) of senile dementia, particularly alzheimer's disease.
The foregoing is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, without departing from the spirit and principle of the present invention, several improvements, modifications, equivalents and the like can be made, and these improvements, modifications, equivalents and the like also should be regarded as falling within the protection scope of the present invention.
Claims (8)
1. A pharmaceutical composition comprising a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, wherein the pharmaceutically active ingredient is: a) (1R,2R) -N- [ 5-fluoro-2- (trifluoromethoxy) phenyl ] -2- (4-sulfamoylphenyl) cyclopropanecarboxamide, and b) hydroxyvaleric acid, and the mass ratio between the pharmaceutically active ingredients a) and b) is 15: 3-7.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 3.
3. The pharmaceutical composition according to claim 1, wherein the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 5.
4. The pharmaceutical composition according to claim 1, wherein the mass ratio between the two pharmaceutically active ingredients a) and b) in the pharmaceutical composition is 15: 7.
5. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition is in a form for oral administration.
6. The pharmaceutical composition of claim 5, wherein said orally administrable dosage form is a solid dosage form or a liquid dosage form.
7. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition is in a form for parenteral administration.
8. Use of a pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of alzheimer's disease.
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