阅读说明：本技术 一种用于治疗老年痴呆的药物组合物及其用途 (Medicine composition for treating senile dementia and application thereof ) 是由 徐颖 刘海英 王程圆 李雅楠 王书惠 周洋 白吉祥 于 2020-08-05 设计创作，主要内容包括：本发明公开了一种含有特定质量比的(1R,2R)-N-[5-氟-2-(三氟甲氧基)苯基]-2-(4-氨磺酰基苯基)环丙烷甲酰胺和羟基缬草烯酸的药物组合物。具体而言,该药物组合物以(1R,2R)-N-[5-氟-2-(三氟甲氧基)苯基]-2-(4-氨磺酰基苯基)环丙烷甲酰胺和羟基缬草烯酸作为药物活性成分,且两种药物活性成分之间的质量比为15:3-7。该药物组合物在老年痴呆,特别是阿尔茨海默病的治疗中是特别有用的。(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.)

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 senile dementia.

9. The use according to claim 8, wherein the type of senile dementia is Alzheimer's disease.

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