JPH08119858A - Autism therapeutic agent - Google Patents

Abstract

PURPOSE: To obtain a medicine containing 2-(4-methylaminobutoxy) diphenylmethane as an active ingredient reduced in side effects, and useful for the therapy of infant autism. CONSTITUTION: The autism therapeutic agent contains a compound of the formula, and its hydrate, or their salts as active ingredients. The compound of the formula can be administered as such, but is preferably mixed with conventional additives and subsequently prepared into an oral, percutaneous or transmucosal administration form. The active ingredient is orally administered at a dose of 5-300mg (as the amount of the active ingredient), especially 150mg, per a day for an adult, and the oral administration dose for a child is converted from the oral administration for the adult. The application target for the therapeutic agent is the autism of children, e.g. 4-12 year old children. The autism therapeutic agent is useful for the therapy of diffuse development disorders comprising a group of disorders characterized by qualitative disorders in the patterns of mutual social relations and communications and by the widths of circumscribed, stereotyped and repeated interests and actions, and is further useful for the reduction in the disease states.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent useful for treating autism in children.

2. Description of the Related Art Childhood autism has 3
The presence of developmental abnormalities and / or disorders that appear in pre-aged children, as well as characteristic types of functional abnormalities in all three areas of inter-social relationships, communication, and limited repetitive behavior Pervasive Developmental Disorders: a qualitative disorder in patterns of intersocial social relationships and communication, and a group of disorders characterized by localized stereotyped, repetitive interest and breadth of activity is there.

[0002] Children with autism have 15 epileptic seizures.
It is known that it appears in ~ 30%, and EEG abnormalities are present in 30-70%. The incidence of these is significantly higher than that of ordinary children, suggesting that the cause of autism in children may be brain damage. However, since it is extremely rare to be able to specify the site of brain damage, it is generally considered to be a disorder of central nervous system function as a system.

Conventionally, a medical treatment method has been mainly used for the treatment of pediatric autism, and psychotherapy, behavior therapy,
It is practiced to perform sensory integration therapy and to train them to live a proper society. As for drug therapy, pimozide (“Olap”: Fujisawa Pharmaceutical Co., Ltd.) has acquired indications for symptoms such as movement, emotions, motivation, and interpersonal relationships associated with autistic disorders in children. , Tetrahydrobiopterin is in clinical trials. However, since pimozide has strong side effects, it is problematic to administer it to children, and the usefulness of tetrahydrobiopterin has not yet been established. In addition, other than the above-mentioned drugs, there are no known drugs useful for pediatric autism, and doctors empirically or experimentally treat them with drugs that have not acquired indications for autism. Stays in.

[0004]

Therefore, the present invention aims to provide a therapeutic agent that enables effective drug therapy for autism in children. Another object of the present invention is to provide a therapeutic agent for pediatric autism with reduced side effects.

[Means for Solving the Problems] The present inventor has found that 2- (4-methylaminobutoxy) diphenylmethane (Japanese Patent Publication No. 60-6349).
It was found that the present invention is useful for treating pediatric autism, and completed the present invention. That is, according to the present invention, the following formula (I):

Embedded image There is provided a therapeutic agent for autism, which comprises 2- (4-methylaminobutoxy) diphenylmethane, a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient.

The active ingredient of the therapeutic agent for autism of the present invention 2
-(4-Methylaminobutoxy) diphenylmethane has been reported to have antidepressant activity (Japanese Patent Publication No. 60-
6349), and it is known to be useful as an agent for improving / treating mental functional symptoms caused by organic disorders in the brain such as stroke (Japanese Patent Publication No. 2-33689). A drug containing 2- (4-methylaminobutoxy) diphenylmethane hydrochloride as an active ingredient (generic name "bifemelane hydrochloride") has been clinically used to improve cranial nerve function (effect / effect: cerebral infarction sequelae,
It is used for treatment aimed at lowering motivation and improving emotional disorders associated with sequelae of cerebral hemorrhage.

[0006] The therapeutic agent of the present invention is applied to children with autism (childhood autism), and for example, children autism aged 4 to 12 can be treated. Autism is a group of pervasive developmental disorders that are characterized by qualitative impairments in patterns of mutual social relationships and communication, and by localized stereotyped and recurrent interest and breadth of activity. , Meets the following diagnostic criteria:

[Diagnostic criteria] There are at least eight of the following 16 items, of which at least 2 items from A and 1 items from B
Item, including 1 item from C. A. It is a qualitative obstacle in interpersonal interaction and is seen as follows. Significant deficiency in recognizing the presence or feeling of others Lack of seeking comfort in abnormal times, or abnormal seeking Lack of imitation, or lack Lack of social play or abnormal peer relationships Insufficient ability

B. Qualitative obstacles in verbal and non-verbal communication and imaginary activities, as seen below. There is no mode of communication, such as speech, facial expressions, gestures, imitations, or spoken words that convey the will, non-verbal will communication, such as eye contact, facial expressions, gestures, etc., to initiate interpersonal interactions. Significant abnormalities of coordinating Lack of imaginary activity, such as adult roles, playing as a fancy person or animal, not interested in talking about imaginary events Volume, height, emphasis, speed, rhythm , Marked abnormalities in the way of speaking, including intonation, abnormalities in the form or content of the conversation, including the use of stereotypic or repetitive language, to initiate or continue a conversation with another person, despite having sufficient language skills Significant disability

C. The repertoire of activities, interests, etc. is remarkably limited, which can be seen as follows. Stereotyped physical movements, clapping hands, twisting hands, whirling, hitting the head, complex whole-body movements Persisted and sustained by parts of the object Marked pain for changing subtle aspects of the environment Unreasonable insistence on following details in an accurate and consistent manner Consistent and localized patterns of interest D. Onset is in infancy or childhood.

The compound of the above formula (I) contained in the therapeutic agent for autism of the present invention is the compound of Example 1 of JP-B-60-6349 or columns 4-5 of JP-B-2-33689. It can be easily produced by the method described in. As the active ingredient of the therapeutic agent for autism of the present invention, the above compound in a free form may be used, but any hydrate thereof, or a physiologically acceptable compound or any hydrate thereof. Acid addition salts can also be used.

The pharmaceutically acceptable acid addition salts include
For example, mineral salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate, or acetate,
Maleate, fumarate, citrate, oxalate,
Organic acid salts such as succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate and 10-camphorsulfonate can be mentioned. Of these, it is preferable to use the hydrochloride of the above compound. In addition, hydrochloride is a general name "Bifemelane hydrochloride"
Is a clinically used substance.

The administration form of the therapeutic agent for autism of the present invention is not particularly limited, and it can be administered orally or parenterally.
Preferably, it may be administered orally. The compound of formula (I), which is the active ingredient of the present invention for treating autism, may be used as it is, but usually, if necessary, pharmacologically, the compound of formula (I) which is the active ingredient may be used. It should be provided as a formulation in a form well known to those skilled in the art, with addition of pharmaceutically acceptable additives. The pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes,
Diluent, base, solubilizer or solubilizer, isotonicity agent, pH
A regulator, a stabilizer, a propellant, an adhesive and the like can be used.

Examples of preparations suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids,
Or syrups and the like can be mentioned. Formulations suitable for parenteral administration include, for example, injections, drops, suppositories,
Examples thereof include inhalants and patches.

The preparations suitable for oral administration, transdermal or transmucosal administration include pharmacologically and pharmaceutically acceptable additives such as glucose, lactose, D-mannitol,
Excipients such as starch or crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, starch or carboxymethylcellulose calcium; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or gelatin; magnesium stearate Or a lubricant such as talc; a coating agent such as hydroxypropylmethyl cellulose, sucrose, polyethylene glycol or titanium oxide; a base such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, or hard fat be able to. In addition, propellants such as CFCs, diethyl ether, or compressed gas; adhesives such as sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene, polybutene; additives for formulations such as cotton cloth or plastic cloth base cloth. It may be used to produce a formulation.

Formulations suitable for injection or drip include solubilizers or solubilizers such as distilled water for injection, physiological saline, propylene glycol and the like, which can constitute aqueous or injectable injections; glucose, sodium chloride, Tonicity agents such as D-mannitol and glycerin; pharmaceutical additives such as pH adjusting agents such as inorganic acids, organic acids, inorganic bases or organic bases may be added.

A cranial nerve function-improving agent containing the compound of the above formula (I) as an active ingredient has already been clinically used (generic name "bifemelane hydrochloride": drug names "alnato" and "celote", respectively). Are sold by Fujisawa Pharmaceutical Co., Ltd. and Eisai Co., Ltd.), and thus the above-mentioned commercially available formulation may be used as it is as an agent for treating autism of the present invention.

The dose of the therapeutic agent for autism of the present invention is not particularly limited and may be appropriately selected depending on the administration form, the age and weight of the patient, the symptoms and the like. For example, the oral dose per day for adults (the amount of active ingredient) is about 5 to 300 mg, preferably about 50 to
The pediatric oral dosage can be converted to 200 mg, particularly preferably 150 mg. The therapeutic agent for autism of the present invention may be administered once or in several divided doses per day, and the administration period can be arbitrarily determined according to the age of the child, the degree of improvement of symptoms, and the like. In addition, 2- (4-methylaminobutoxy) diphenylmethane, which is an active ingredient of the therapeutic agent for autism of the present invention, is a highly safe substance, and its acute toxicity value is shown in Table 1 of Japanese Patent Publication No. 2-33689. It is described in. As the therapeutic agent for autism of the present invention is intended for application to children, it will be easily understood by those skilled in the art that the high safety of the therapeutic agent for autism of the present invention is a very advantageous property. .

[0018]

【Example】

Formulation Examples Formulation examples of the therapeutic agent for autism of the present invention are shown below, but the dosage form of the therapeutic agent of the present invention is not limited to these examples. Formulation Example 1 2- (4-Methylaminobutoxy) diphenylmethane hydrochloride 100 g Mannitol 300 g Corn starch 450 g Lactose 300 g Hydroxypropyl cellulose 38 g Calcium stearate 12 g The above ingredients are mixed according to a conventional method, and 1 piece 120 Produces mg capsules.

Formulation Example 2 2- (4-methylaminobutoxy) diphenylmethane hydrochloride 100 g Corn starch 200 g Lactose 500 g Carboxymethylcellulose calcium 150 g Polyvinylpyrrolidone 75 g Talc 75 g Microcrystalline cellulose 250 g Ingredients according to the conventional method Are mixed to form granules and compression molded to produce 120 mg tablets.

Formulation Example 3 2- (4-Methylaminobutoxy) diphenylmethane hydrochloride 50 mg Hydroxypropylcellulose 4 mg Hydroxypropylmethylcellulose 50 mg Sodium citrate 50 mg Sodium saccharin 3 mg White sugar Suitable amount Corn starch 29 mg D-mannitol 67 mg Mono Glycerin stearate 200 mg Eudragit L-30D55 71 mg Macrogol 6000 7 mg Talc 21 mg Sodium lauryl sulphate Trace fragrance Trace 1000 mg The above ingredients are mixed according to a conventional method to produce a dry syrup preparation.

Production Example 4 2- (4-Methylaminobutoxy) diphenylmethane hydrochloride 50 mg Hydroxypropyl cellulose 70 mg Corn starch 50 mg D-mannitol A suitable amount Aminoalkyl methacrylate copolymer E 85 mg Talc 60 mg Calcium stearate 5 mg 1000 mg The above ingredients are mixed according to a conventional method to produce granules.

Example of clinical test Bifemelane hydrochloride was administered to 3 patients diagnosed with autism by a doctor for 12 weeks. The dosage was set to 3 mg / kg as a guide, and the dose was increased depending on the symptoms. Example 1 A boy who is 5 years and 3 months old. The main complaints were motivation, interpersonal relationships, and language problems. As for the history of childbirth, there was a wrapping cord at the time of delivery. Severity was verbal and interstitial “severe”, cognitive behavior was “moderate”, and general severity was “severe”. Improvement began to appear 4 weeks after the administration, and at the end of the 12th administration, the language improved to “moderate” and the interpersonal social and cognitive behaviors improved to “mild”.

Example 2 A boy, 3 years and 3 months old. Aspiration was given at birth. Language problems were “moderate”, interpersonal sociality, and cognitive behavior were “severe”. Improvement was seen from around the 8th week of dosing, and at the end of the 12th week of dosing, all symptoms had improved to "mild". Example 3 A 6 year old boy. For delivery, a Caesarean section was performed for prevention. Although the interstitiality was "moderate", the child was "mild" in terms of language problems and cognitive behavior. Improvement was observed from 8 weeks after the administration, and it was generally improved at 12 weeks, but the linguistic problems had disappeared.

[0024]

INDUSTRIAL APPLICABILITY The therapeutic agent of the present invention is highly effective in treating pediatric autism and alleviating its pathological condition, and is also highly safe.

Claims (1)

[Claims] 1. The following formula: An agent for treating autism, comprising 2- (4-methylaminobutoxy) diphenylmethane, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.