EP0484497A1

EP0484497A1 - Febarbamate for the treatment of cranial nervous disorders and encephalic circulation and metabolism disorders

Info

Publication number: EP0484497A1
Application number: EP91910092A
Authority: EP
Inventors: Akira Awaya; Akira Mizuchi; Tadayuki Sasaki
Original assignee: LABORATOIRES SAUTER SA
Current assignee: LABORATOIRES SAUTER SA
Priority date: 1990-05-30
Filing date: 1991-05-25
Publication date: 1992-05-13
Also published as: AU7899391A; JPH0436236A; HU9200672D0; IE911833A1; CA2063736A1; WO1991018607A1; FI920397A0; HUT60434A

Abstract

L'invention décrit l'utilisation de fébarbamate ou de ses sels acceptables sur le plan pharmaceutique pour apporter une amélioration ou un traitement à des maladies ou des troubles ayant pour origine la défaillance ou la dégénérescence des nerfs crâniens, centraux ou périphériques; des maladies et des troubles relatifs au système nerveux central ou périphérique; des troubles cérébrovasculaires et des troubles dus à la dégénérescence des neurones; et/ou des maladies de la circulation et du métabolisme encéphaliques. L'invention décrit également la préparation de compositions pharmaceutiques appropriées.The invention describes the use of febarbamate or its pharmaceutically acceptable salts for the improvement or treatment of diseases or disorders originating from the failure or degeneration of the cranial, central or peripheral nerves; diseases and disorders relating to the central or peripheral nervous system; cerebrovascular disorders and disorders due to degeneration of neurons; and / or diseases of the circulation and brain metabolism. The invention also describes the preparation of suitable pharmaceutical compositions.

Description

FEBARBAMATE FOR THE TREATMENT OF CRANIAL NERVOUS DISORDERS AND OF ENCEPHALIC CIRCULATION AND METABOLISM DISORDERS

This invention relates to a drug for the improvement and treatment of disorders and diseases originating in the breakdown or degeneration of cranial nerves and disorders in encephalic circulation and metabolism.

Psychoneurotic diseases such as mania, depression, schizophrenia delirium and anxiety neurosis are psychoses to which an abnormality in the action system and metabolic system and the like of various neurotransmitters is considered to have principal relation, and pharmacotherapies using various psychopharmaceuticals are being widely carried out.

However, there have so far been known only a few drugs for use in the improvement and treatment of diseases due to disorders either of central nerves or of peripheral nerves, originating in the organic, physical, chemical and further functional breakdowns and degenerations and the like of cells of

encephalic and nervous systems, and the appearance of such therapeutic drugs for neural diseases is being expected.

Japanese Laid-Open Patent Publication No.

34912/1977 discloses a drug effective for diseases originating in disorders in neurostimulation transmission in the central nervous system and peripheral nervous system, which comprises a dispersion or solution of a ganglioside in a medium.

Japanese Laid-Open Patent Publication No.

222424/1984 discloses that a gangliosides mixture

extracted from a bovine brain and a single component in the gangliosides promotionally act on the growth of primary culture cells and neuroblastoma cells, the formation of neurites and the outgrowth of the neurites, and have the same effects with mechobalamin even in an animal model of a nervous disorder.

This gangliosides mixture is on the market under the name of cronassial^® in Italy. However, gangliosides are natural extracts derived from heterogenous animals and thus it is considered that there are problems of the antigenicity of themselves or impurities, and further it is fairly difficult to prescribe and prepare gangliosides as pharmaceutically uniform and stable substances.

Further, it is known that there are factors in the living body acting on the growth and regeneration of nerves, and the factors are called nerve growth factors (NGF) or neurotrophic factors or the like. These factors are high molecular proteins but there are still many problems to be technically solved before their application to nervous diseases.

On the other hand Japanese Patent Publication No. 28548/1984 discloses 2-isopropylaminopyrimidine orthophosphate and a drug containing it for the treatment of peripheral nervous diseases. Isaxonine

phosphate was clinically studied but at present does not seem to have been placed on the market. As a drug being used in the field of the treatment of disorders in peripheral nerves, there is only mechobalamin, a vitamin, in Japan.

The compound 1-(3-n-butoxy-2-carbamoyloxypropyl)-5 ethyl-5-phenyl-(1H,3H,5H) pyrimidine-2,4,6- trione, known ag|and hereinafter referred to as

febarbamate, and a related malonylurea derivative used as an effective ingredient in the invention are disclosed in Japanese Laid-Open Patent Publication No. 144384/1979 (corresponding to Japanese Patent Publication No. 18553/1986 and British Patent No. 1581834) and Japanese Laid-Open Patent Publication No. 205370/1984. The former Japanese Laid-Open Patent Publication No. 144384/1979 discloses a series of com plexes comprising three kinds of malonylurea derivatives which have an ataractic action, more particularly, a useful action in the treatment of tremors. Further, there is a disclosure in the same publication saying "These

(malonylurea derivatives having abirritant and/or ataractic action(s) generally) constitute a large class of psychopharmaceuticals which have widely uses ciincically for the treatment of many neural disorders, including anxiety states and psychomotor disturbances, whether of emotional, alcoholic, medicinal or mental origin".

In pages (13) and (14) of this patent publication there are only investigated the effects of febarbamate in the behaviour test, the anticonvulsant activity test and the biological test for nonsynergizing action of the effect of an alcohol for the purpose of evaluating the drug actions of the malonylurea derivatives.

Therefore, it is considered that the "neuropathy" referred to in the invention disclosed in this patent publication including the above quoted part is not the same as

disorders and diseases that accompany the breakdown and degeneration of nerves, and disorders caused by degeneration of the blood vessels and neurons of a cerebrum and the like related to disorders in learning, memory and cognitive functions including cerebral aging, cerebrovascular dementia and Alzheimer type senile dementia, and others including so-called psychoses.

Further, the latter Japanese Laid-Open Patent Publication No. 205370/1984 states, "The general class of N-substituted pyrimidinetriones to which febarbamate belongs has good thymoanaleptic properties with no hypnotic or sedative properties and the compound itself enables "the vicious circle of perpetual intoxication and recourse to alcohol to avoid tremor to be broken.

We have further found that in addition to these generally described properties, febarbamate is extremely helpful in the general care of geriatric patients. Such patients are prone to fits of excitation, agitation and aggressivity and frequently become extremely antisocial. In a series of clinical tests, we have found the administration of febarbamate to have a significant improving effect upon the mental well-being of geriatrics. This is not a consequence of any mild sedative action. Indeed febarbamate appears to be superior in its action to the best compounds currently in clinical use for the treat ment of irritable geriatrics.

In contrast to other psychotropic agents, febarbamate does not affect the personality and does not depress the patients' vigilance or other psychic reactions. This is an important quality of the product since elderly people are often quite psychically fragile. We have found febarbamate to produce a gentle and prolonged psychic stimulation which allows the patient to be more social, mentally alert and generally receptive.

Tests have been carried out using geriatric patients which shov; that the action of febarbamate is to be preferred either over the tranquilliser pipamperon

[1-(p-fluorophenyl)-4-(4-piperidino-4-carbamoyl- piperidino)-1-butanone] or the anticholinergic compound biperidene (α-5-norbornen-2-yl-(α-phenyl-1-piperidine- propanol). In general it has been found that at a preferred dosage of three units of 150 mg each per day, numerous dysphoric states have notably improved without being able to detect any secondary effects. The thymism of the patients has, in particular, been improved to the extent that those who have previously been uncooperative have generally become much more amenable. Symptoms of excitability, aggressivity and agitation have been notably improved. The evaluation of such tests is carried out externally.

According to a further aspect of the invention therefore, we provide a method of treating old people to combat irritability and other antisocial behaviour which comprises administering to said people an amount of febarbamate effective to reduce irritability and antisocial behaviour without substantially impairing consciousness and/or resulting in sedation. "

An object of this invention is to provide a drug for the improvement and treatment of disorders and diseases accompanying the breakdown and degeneration of nerves.

A further aspect of the invention is to provide a drug for the improvement and treatment of disorders caused by degeneration of the blood vessels and neurons of a cerebrum and the like related to disorders in learning , memory and cognitive functions including cerebral aging , cerebrovascular dementia and Alzheimer type senile dementia .

Based on a discovery that febarbamate has a novel drug action other than its so far known pharmacological actions , namely an activity to make overgrow the neurites of neurocytes , particularly the neuroblastoma cells of mouse , Homo sapiens , etc . and an antagonistic activity against triethyl-tin-induced brain edema , a yet further feature of this invent ion comprises febarbamate in a form adapted for the treatment of disorders and diseases accompanying the breakdown and degeneration of nerves , and disorders caused by the degeneration of the blood vessels and neurons of a cerebrum and the like related to disorders in learning , memory and cognitive functions including cerebral

aging , cerebrovascular dementia and Alzheimer type senile dementia. Such a form may comprise a pharmaceutically acceptable composition comprising febarbamate in admixture with a pharmaceutically acceptable excipient, diluent or carrier.

Other obj ects and the advantages of the invention will be apparent by the following descripti on .

According to this invention , the above aspects and advantages of the inventicri can be attained by the use of a drug for the improvement and treatment of disorders and diseases accompanying the breakdown and degeneration of nerves or disorders in encephalic circulation and metabolism.

The drug of the invention is

also effective for disorders and diseases accompanying the breakdown and degeneration of any of the central nerves and peripheral nerves.

Disorders and diseases related to the central nervous system include cerebrovascular disorders due to, for example, head injury, brain ischemia, brain infarction, brain bleeding, brain arteriosclerosis, brain venous thrombus and the like; functional breakdowns of the brain due to these cerebrovascular disorders and lowering of the intellectual functions and other symptoms accompanying them; and various mental that follow.

Further, multiple sclerosis, amyotrophic lateral sclerosis, acute sporadic encephalomyelitis, postvaccinal encephalitis, SMON, dementia, Alzheimers syndrome, etc. are also included.

Further, as disorders of the peripheral nervous system, various neuropathies are mentioned representatively. For example, there can be mentioned various peripheral nervous disorders accompanied by kinetic, sensory and/or objective reflex retardation, including nerve root lesions due to traumatic, inflammatory or immunological causes; alcoholic, pharmaceutical, metabolic such as diabetic, and idiopathic peripheral nervous disorders; and the like. More specifically mentioned are facial paralysis, sciatic paralysis, spinal amyotrophy, muscular dystrophy, myasthenia gravis, Guillan-Barre syndrome, rheumatism, etc.

Febarbamate as an effective ingredient of the improvement and treatment agent of the invention may be provided for the treatment as it is, i.e. as a free base, or otherwise as an alkali salt or acid addition salt thereof. Suitable alkali salts thereof include its potassium salt, sodium salt, lithium salt, calcium salt, magnesium salt, zinc salt and aluminum salt and so on. Suitable acid addition salts thereof include its hydrochloride, acetate, tosylate, methanesulfonate, succinate, lactate, benzoate, maleate, tartrate, citrate, fumarate and naphthalenesulfonate salts and so on.

The biological activities and acute toxicity of febarbamate in the invention as a drug for improvement and treatment of cranial nervous disorders and encephalic circulation and metabolism disorders are exhibited in the following examples.

Example 1

The activity of febarbamate on neurocytes was tested in vitro. Used as neurocytes were murine neuroblastoma cells such as a neuro-2a strain (given from the Second Biochemical Classroom, the Medical Department, Tokyo University) and an NS-2OYS strain, human neuroblastoma cells such as a GOTO strain and an NB-1 strain (similarly, given from the Biochemical Classroom, Tokyo University), and so on.

Cells of the murine neuro-2a strain in the logarithmic phase in Dulbecco's modified Eagle's medium (DMEM) containing 10 % bovine fetal serum were scattered on a plate having 48 cells to 1,000 cells/well. The cells in 0.25 ml portions of the culture medium per well were cultured for one day, and thereafter further cultured for 24 hours with substitution of media containing the respective specimens and FCS for the above

medium. Then, the same amount with each medium portions (0.25 ml portions) of a 4 % glutaraldehyde solution were added, and the mixtures were allowed to stand at room temperature for 2 hours to fix the cells. After water washing, a 0.05 % aqueous Methylene Blue solution was added to dye the cells, and the number of cells containing outgrown neurites (cells having at least one neurite with a length at least two times as large as the long diameter of the cell) was counted under a microscope with the naked eye, and the ratio of the number of neurites to the nmuber of total cells was determined. Five fields of view or more (2 % or more of the whole well surface areas) were observed continuously right and left taking as a center the mark put on the bottom of the well center, and thereby 200 or more cells were counted as cell number. Three runs were made per one drug concentration of febarbamate and the values were expressed by average value ± S.D.

The results are shown in Table 1.

Similar results were obtained even in the in vitro test using other neuroblastoma cells.

Further, models with central nerve disorders were prepared using rats, mice, etc. and the drug actions of febarbamate of the invention were tested. Namely, rats, mice, etc. having neuropathies caused by mercury poisoning were prepared and the activity of febarbamate of the invention was tested. As a result, it was revealed that febarbamate has a promoting effect and a therapeutic effect about the improvement of the symptoms and recovery to the normal state.

Further nigral dopamine cells of the rat brain were chemically destroyed by injecting a very small amount of 6-hydroxydopamine to induce motor imbalance. Two weeks later, dopamine cells of fetal brain v/ere transplanted in the caudate nucleus into the lesioned side of the rat brain and an attempt was made to improve the motor trouble. Specifically, beginning on the day of transplantation, febarbamate of the invention was intraperitoneally administered every day over 2 weeks, and the activity of febarbamate on the improvement of the motor imbalance and the growth of the transplanted cells was examined. It was found that febarbamate of the invention has a promoting effect on the improvement, etc. of the motor trouble.

On the other hand, rats whose sciatic nerves were crushed were prepared as a model of peripheral nervous disorder and the effects of febarbamate of the invention were tested. As a result it was revealed that febarbamate has a promoting effect on the recovery to the normal values of parameters of function, such as the distance between the hindlegs of the crush side and twitch tension, and the weight of the musculi extensor digitorum longus of the hindlegs and musculi soleus, and the like.

Further, when the action of febarbamate on triethyl-tin-induced brain edema was investigated,

febarbamate significantly inhibited the formation of brain edema, as is the case with vinpocetine, a brain circulation and metabolism-improving drug. This is

described below by Example 2. Example 2

The action on triethyl-tin-induced brain edema

The action of febarbamate was investigated on brain edema formed by orally administering triethyl-tin (2 mg/kg) to rats every morning (at 9 am) once a day every day over 5 days. Drugs were orally administered twice a day (9 am and 3 pm) every day over 4 days and on the fifth day once a day (9 am). At 3 pm on the fifth day the rats were sacrificed and the water amount of the brains was measured.

Febarbamate (100 and 1000 mg/kg) and vinpocetine (50 mg/kg) exhibited an antagonistic effect against the increase of the brain water amount by triethyl-tin.

The results are shown in Table 2.

Brain edema by triethyl-tin is a cell-impairing brain edema. It is verification of the usefulness of febarbamate as a brain circulation and metabolism- improving drug that febarbamate inhibited this brain edema in comparison with the brain circulation and metabolism-improving drug vinpocetine.

Example 3

When febarbamate was orally administered to animals, LD₅₀ (mg/kg) values were determined and they were 20,000 mg/kg or more for both mice and rats.

Febarbamate of the invention has a promoting effect on the formation and overgrowth of the neurites of neurocytes, and has even on rats, mice, etc. having neuropathies a neurotization effect, a motor function recovery effect, a learing and memory improvement and recovery effect, and an anti-brain edema effect, and thus can suitably be used for the improvement and treatment of central nervous and cerebrovascular disorders, dementia, and nervous system diseases such as peripheric nervous disorders. Further, it is expected that febarbamate can also suitably be used for the recovery, improvement and treatment of nervous system diseases caused by the disorders of nervous tissues and cells related to sensory functions and autonomic functions.

Febarbamate used as an effective ingredient in the invention is used usually in the form of a pharmaceutical composition, and administered through various routes such as oral, subcutaneous, intramuscular, intraveous, intranasal, transcutaneous and rectal routes.

Thus, a yet further feature of this invention is the use of febarbamate or a salt thereof for the preparation of a medicament for the treatment of the diseases and disorders hereinbefore listed.

The composition of the invention can be made into forms such as, for example, tablets, capsules, powders, granules, lozenges, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, sterile injections, molded cataplasmas, tape preparations, soft and hard gelatin capsuls, suppositories and sterilely packaged powders. Examples of pharmaceutically acceptable carriers are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gam arabic, calcium phosphate, alginates, calcium

silicate, finely crystalline cellulose, polyvinylpyrrolidone, tragacanth gum, gelatin, syrup, methylcellulose, carboxymethylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium

stearate, inert polymers, water, mineral oils, etc.

Both solid and liquid compositions can contain fillers, binders, lubricants, wetting agents, disintegrants, emulsifying and suspending agents, preservatives, sweeteners, aromatic agents, etc. as above mentioned. The present composition can be formulated so that, after administration to patients, the active ingredient is released rapidly, lastingly or with delay.

In case of oral administration, febarbamate is mixed with carriers and diluents, and the mixture is made into forms such as tablets and capsules. In parenteral administration, the active ingredient is dissolved in a 10 % aqueous glucose solution, isotonic saline, sterile water or a similar liquid, and sealed into vials or ampules for administration into veins by drip or injection or into muscles by injection. Advantageously, solubilizing agents, local anesthetics, preservatives and buffering agents can also be used. For increasing stability, it is also possible to freeze dry the present composition after injection into vials or ampules. As other forms for parenteral administration there are formulations to be administered transcutaneously such as ointments and cataplasmas. In this connection shaped cataplasmas and tape preparations are advantageous.

The compositions of the invention may contain from 0.1 to 2000 mg, more generally 0.5 to 1000 mg of the active ingredient per unit dose shape. Febarbamate is effective over a wide dose range. For example, its dose per day falls usually within the range of 0.003 to 100 mg/kg. The amount of the compound actually administered is determined by the doctor, actual compound to be administered, the age, weight and response of individual patients, the degree of the symptom of patients, administration routes, etc.

Therefore, the above dose range does not limit the scope of the invention. Proper dosage number can be 1 to 6, usually 1 to 4 per day.

Although febarbamate itself is an effective central nervous and cerebrovascular disorder-improving and treating drug and a peripheral nervous disorder- treating drug, dosage can also be made, if necessary, by combination with one or more other drugs having the same effect.

Preparative Examples of the invention are described below

Preparative Example 1

Tablets containing 200 mg of an active ingredient are prepared as follows.

per tablet

Active ingredient 200 mg

Corn starch 50 mg

Crystalline cellulose 42 mg

Light anhydrous silicic acid 7 mg Magnesium stearate 1 mg

Total 300 mg

The above components were passed through a 80 mesh sieve and then completely mixed. The obtained powder was compression molded to prepare tablets each having a weight of 300 mg.

Preparative Example 2

Capsules containing 100 mg of an active ingredient are prepared as follows. per capsule

Active ingredient 100 mg

Corn starch 40 mg

Lactose 5 mg Magnesium stearate 5 mg

Total 150 mg

The above components are mixed, passed through a 80 mesh sieve and completely mixed. The obtained powder was charged in 150 mg portions into capsules.

Claims

1. A pharmaceutical composition comprissng febarbamate or a pharmaceutically acceptable salt thereof in admixture where necessary withs a

pharmaceutically acceptable excipient, diluent or carrier, for the improvement and treatment of disorders and diseases orginating in the breakdown or the

degeneration of cranial, central or peripheral nerves or disorders and diseases related to the central or peripheral nervous systems.

2. A pharmaceutical composition comprising febarbamate or a pharmaceutically acceptable salt thereof in admixture where necessary with a

pharmaceutically acceptable excipient, diluent or carrier, for the improvement and treatment of

cerebrovascular disorders and neuron degeneration disorders related to learning, memory and cognitive function disorders including cerebral aging,

cerebrovascular dementia and Alzheimer-type senile dementia.

3. A pharmaceutical composition comprising febarbamate or a pharmaceutically acceptable salt thereof in admixture where necessary with a

pharmaceutically acceptable excipient, diluent or carrier, for the improvement and treatment of disorders in encephalic circulation and metabolism.

4. A process for the preparation of a

pharmaceutical composition as claimed in any one of Claims 1 to 3 which comprises admixing febarbamate or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier or diluent.

5. A method of improving or treating disorders and diseases orginating in the breakdown or the degeneration of cranial, central or peripheral nerves or disorders and diseases related to the central or peripheral nervous systems which comprises

administering to a patient an effective amount of febarbamate or a pharmaceutically acceptable salt thereof.

6. A method of improving or treating

cerebrovascular dementia and Alzheimer-type senile dementia which comprises administering to a patient an effective amount of febarbamate or a pharmaceutically acceptable salt thereof.

7. A method of improving or treating disorders in encephalic circulation and metabolism which

comprises administering to a patient an effective amount of febarbamate or a pharmaceutically acceptable salt thereof.

8. The use of febarbamate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the improvement and treatment of

disorders and diseases orginating in the breakdown or the degeneration of cranial, central or peripheral nerves or disorders and diseases related to the central or peripheral nervous systems.

9. The use of febarbamate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the improvement and treatment of cerebrovascular disorders and neuron degeneration disorders related to learning, memory and cognitive function disorders including cerebral aging,

cerebrovascular dementia and Alzheimer-type senile dementia.

10. The use of febarbamate or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the improvement and treatment of disorders in encephalic circulation and metabolism.