IE83506B1 - Use of N-(2,6-dimethylphenyl)-2-(2-oxo-1- pyrrolidinyl)acetamide for the treatment of dementia - Google Patents

Description

ACETAMIDE FOR THE TREATMENT OF DEMENTIA FIELD OF TFE INVENTION This invention relates to Hwxmcor N—(2,6-dimethylphenyl)—2—(2~oxo~1— pyrrolidinyl) acetamide (hereinafter, referred to as compound A) represented by the following formula (I): CH3 (iEu—cu2coNH~%’3 (I) CH3 QACKGROUND OF THE INVENTION or a salt thereof In developed countries including Japan. United States and European countries, the number of patients with dementia has been rapidly increasing with the sudden increase in aged population. Since there is no effective therapeutics for’ this disease, it is a serious social problem to treat and attend on these patients- Under these circumstances, a number of drugs have been examined in order to develop an effective remedy for »dementia' However, no drug which is clinically usable therefor has been found out hitherto. on the other hand. it is known that compound A is effective in prolonging the survival time upon a decrease in blood oxygen level and in relieving failure of memory due to cerebropathy, as described in JP-B5404 (the term "JP«B" as used herein means an "examined Japanese patent publication) (corresponding to GB-A—2053909).

Further animal studies relating to compound A are reported in Kojima et al., Advances in Behavioral Biology, vol 38B:367—37O (1990) and pages 371-374.

However, there has been never report that the compound A is clinically usable for improving the symptoms of dementia.

SUMMARY OF THE INVENTION The present inventors have found out that the administration of the compound A to patients with dementia such as Alzheimer type dementia or cerebrovascular dementia causes excellent effects of improving the symptoms of these types of diseases, which had never been expected from the conventional therapeutics, thus completing the present invention.

The present invention relates to zthe use of compound A for preparing a pharmaceutical composition for improving the symptoms of Alzheimer type dementia or cerebrovascular dementia.

DETAILED DESCRIPTION F THE INVENTION Demetia relating to the present invention can be into Alzheimer type dementia and mainly classified cerebrovascular demetia. Alzheimer type dementia may be classified into senile dementia and Alzheimer type diSea5e« It is expected that compound A exerts excellent effects On these diseases.

The compound A may be administered either orally or parenterally (for example, intravenously) in a dose of frmn 60 to 900 mg/day per adult (in the case of oral administration). Examples of preparations containing compound A include tablets, capsules, pills, emulsions, suspensions, fine subtilaes and injection. These prepara- tions may be formulated by a known pharmaceutical tech- niques with the use of common additives (for example, fillers, binders (hydroxypropylcellulose, etc.), ingredient (lactose, cornstarch, etci). ‘ The compound A has a high safety. When orally administered to Hale and female mice, it showed acute toxicities (Lnw) of 2,005 mg/kg and 1,940 mg/kg, respecti- vely. Thus it has been clinically confirmed that compound A is highly safe.

The compound A is highly effective in improving a decline in mental functions such as disorientation (place, time), which are the major symptoms of dementia, as well as general side symptoms such as decreased spontaneity, emotional disturbances, contact disturbances, abnormal behaviors, disturbances in activity of daily living and motivation. Accordingly, the compound A is a very excellent agent for improving dementia.

The present invention is further explained in detail hereinafter by the following Examples, but the present invention is not limited to these examples.

EXAMPLE 1 mg/day of compound A was orally administered f0‘: 8 to 12 weeks to 5 patients (excepting cerebrovascular dementia based cnx Hachinski cerebro—ischemic score) who showed encephalatrophy or ventricular enlargement in CT (computed tomography) or MRI (magnetic resonance image) and thus were diagnosed as Alzheimer type dementia based on clinical symptoms specified in DSM—III-R (Handbook for the Diagnosis of Mental Diseases prepared by U.S. Society of Psychopathy). Before the administration and 44 weeks, 8 weeks and 12 neeks thereafter, the dementia conditions of these patients were clinically evaluated by typical methods for evaluating dementia, namely; classification of severity by fast staging (hereinafter, referred to simply as Fast), criteria for evaluating cognitive functions (modified GBS), udni-mental state examination (hereinafter, referred to simply as HHS), Hasegawa's simplified dementia scale (hereinafter, referred to simply as HD5) and Crichton's Criteria for evaluating behaviors. Based on the data thus obtained, the final global improvement rate (hereinafter, referred to simply as FGIR) and the overall safety rate (hereinafter, referred to simply as OSR) of each case were evaluated.

Table 1 shows the results of FGIR and DSR, while Table 2 shows the number of improved or worsened patients for each symptmu. Tables 3 and 4 show each a patient showing improvement in FGIR.

Table 1 Evaluation No. of Case 1 1; _LL 1! X, Z; FGIR 5 2 2 1 08R 5 5 [FGIR] I: remarkably improved.

II: improved.

III: slightly impioved.

Ivt unchanged.

V: Slightly aggravated.

VI: aggravated.

[DSR] I: no safety problems.

II: negligible safety problems existed.

III: safety problems existed.

IV: significant safety problems existed.

Table 2 Improved or worsened Item (symgtom) Decreased spontaneity Emotional disturbance Contact disturbance Decline in mental function Abnormal behaviors No. of Case Improved worsened S 2 D 2 1 2 O 2 0 l 1 1 1 1 Disturbance in activity of daily living As the above Tables clearly show, compound A is effective in improving mental symptoms (for example, decreased spontaneity, emotional disturbances, Contact mental functions, abnormal disturbances, decline in behaviors) of patients with Alzheimer type dementia.

Evaluating the improvement effect on these symptoms, the compound A is 40% (2 overall improvement rate of (improvement case) per 5 all tried case). Also, as apparently from the Table 1, the mental symptoms of 2 cases per 5 cases were not worsened. Furthermore, any side effect was not observed for all tried patients.

Generally, a main characteristic points of patients with Adzheimer type dementia is just that the symptoms of this disease become worse and worse, and any medicines have never showed clinical effects to this disease.

Therefore, these clinical effect of compound A to Alzheimer type dementia, that is, the improvement effect on the symptoms, the suppresing effect on getting worse relating to the symptoms_and the effect relating to the safety have never been expected from the clinical effect of convertional medicines for this disease.

EXAMPLE 2 150 to 450 mg/day of compound A was orally administered for 8 weeks to 145 patients with cerebra- -13..’ **: safety rate = vascular dementia who showed infarction or hemorrhagic lesions in CT (computed tomography) and scored less than 22 points in Hasegawa's simplified dementia scale (HDS) frequently employed in the simplified diagnosis for dementia. The clinical conditions of each patient were evaluated with HDS, which is frequently used for evaluating the effects of nootropic agents, before the initiation of the administration and 4 weeks and 8 weeks thereafter.

Based on these data, the final global improvement rate (FGIR) and the overall safety rate (OSR) were determined.

Table 1 shows the results of FGIR and OSR, while Table 2 shows the improvement rate (%) for each symptom.

Table 1 No. of Case I II III IV V gg FGIR 145 7 37 57 33 5 5 72.? [improvement mm(%V] OSR 145 134 B 3 0 — O 97.9 [safety rate (%)**l *: improvement rate = (I + II + III)/139 x 100 (I + II)/145 x 100 II: moderately improved.

[FGIR] I: remarkably improved.

III: slightly improved. IV: unchanged- V: aggravated. DP: dropped out.

[OSR] I: no safety problem.

II: negligible safety problems existed. ~14; III: doubtful in safety.

IV: safety problems existed.

Table 2 Svmptom No. of Case Improved worsened (*3) (‘H Decreased spontaneity 138 59.4 0.0 Emotional disturbance 135 54.1 1.5 Contact disturbance 122 38.5 0.8 Decline in mental function 139 46.0 2.2 Abnormal behaviors 49 49.0 10.2 As the above Tables clearly show, compound A is effective in improving mental symptoms (for example, decreased spontaneity, emotional disturbances, Contact disturbances, decline in mental functions, abnormal behaviors) of patients with cerebrovascular dementia. The overall improvement rate determined by generally evaluating these results in 72.7%, showing excellent effects.

In general, it is considered that the effects of medicinal treatments on cerebrovascular dementia are inferior to those on sequela of cerebrovascular disorders, namely, the preceding stage of the former. However, compound A achieves a high overall improvement rate (72.7%) for cerebrovascular dementia which is comparable to, or even exceeds, the overall improvement rate {about 70%) of for the sequela conventional nootropic agent oerebrovascular disorders. -15.; Further, it is doubtful whether or not medicinal treatments are effective on the decline in mental function, i.e., the major symptom of dementia. The overall improvement rate of compound A.on this symptom is 46% which is higher than those of pracebo (25%) and other nootropic agent (about 35%).

On the other hand, it has been confirmed that compound A is highly safe (OSR = 97.9%) and only fugitive side effects were observed in 4 cases (3%).

These results indicate that compound A is highly superior in the effects of improving cerebrovascular dementia to drugs conventionally employed therefor.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can he made therein without departing from the spirit and scope thereof.

Claims (6)

Claims

1.I. The use of N-(2, 6-dimethylphenyl)(2-oxopyrrolidinyliacetamide represented by the formula (I): 0 CH3 étt-CHZCONH or a salt thereof for preparing a phamraceutical composition for improving the symptoms CH3 of Alzheimer type dementia or cerebrovascular dementia.

2. The use according to claim 1, wherein the symptoms are a decline in mental functions.

3. The use according to claim 2, wherein decline in mental functions is a disorientation.

4. The use according to anyone of claims 1 to 3, wherein symptoms are selected from the group of decreased spontaneity, emotional disturbances, contact disturbances, abnormal behaviours, and disturbances in activity of daily living and motivation.

5. The use according to any one of the preceding claims, wherein an oral dose of 60 to 900 mg/day per adult is administered.

6. Use according to any preceding claim, substantially as hereinbefore described and/or exemplified. TOMKINS S5 C0. 17