JPH05186345A - Agent for treating temporomandibular arthrosis - Google Patents

Abstract

PURPOSE:To obtain a new agent effective for the prevention and treatment of temporomandibular arthrosis by using 2-methyl-3-pyrrolidino-1-(4- trifluoromethylphenyl)-1-propane having central muscle relaxing action as an active component. CONSTITUTION:The objective agent for the treatment of temporomandibular arthrosis contains the propiophenone derivative of formula [i.e. 2-methyl-3- pyrrolidino-1-(4-trifluoromethylphenyl)-1-propane] or its pharmacologically allowable salt as an active component. The acid for forming the salt is preferably hydrochloric acid, acetic acid, fumaric acid, maleic acid, tartaric acid, malic acid, etc. The compound is advantageous because it has excellent masseter muscle relaxing action and low toxicity. The action of the compound lasts long.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for temporomandibular disorders.

[0002]

BACKGROUND OF THE INVENTION A propiophenone derivative represented by the following formula [1] [2-methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propane] or its pharmacologically acceptable Salt and its central muscle-relaxing action are already known (JP-A-1-131171). However, it is not known to be effective in preventing or treating temporomandibular disorders. As a substance expected as a prophylactic or therapeutic drug for temporomandibular disorders, for example, eperisone represented by the following formula [2] is known.

[0003]

[Chemical 2]

[0004]

However, eperisone has not yet been put to practical use as a prophylactic or therapeutic drug for temporomandibular disorders, and is currently commercialized as a drug for the purpose of preventing or treating temporomandibular disorders. However, there is a strong desire for the development of new therapeutic agents for temporomandibular disorders.

[0005]

The present invention provides the formula [1].

[0006]

[Chemical 3]

[0007] The present invention relates to a therapeutic agent for temporomandibular disorders, which comprises a propiophenone derivative represented by: or a pharmacologically acceptable salt thereof as an active ingredient. The propiophenone compound represented by the formula [1] forms a salt with an acid, and the acid for forming the salt may be an inorganic acid or an organic acid as long as it is pharmacologically acceptable. .. Examples of the inorganic acid include hydrochloric acid, sulfuric acid,
Nitric acid and phosphoric acid are preferable, and hydrochloric acid is more preferable. As the organic acid, for example, acetic acid, fumaric acid, maleic acid, tartaric acid, malic acid and the like are preferable.

Since the compound of the present invention has one asymmetric carbon in the molecule, there are theoretically two optical isomers. Therefore, the present invention refers to these racemic and optical isomers. It is included. The optically active substance can be obtained from the racemate, for example, by producing an optically active acid and a diastereomeric salt, separating and purifying the product, and isolating an optical isomer from each diastereomeric salt.

When the compound of the formula [1] is used as a therapeutic agent for temporomandibular joint, it can be administered either orally or parenterally. The dose depends on the symptoms of the patient to be administered,
Although it varies depending on age and administration method, it is usually 0.1 to 20.
mg / kg / day. The compound of formula [1] is administered in the form of a preparation prepared by mixing with a suitable pharmaceutical carrier. As the form of the preparation, tablets, granules, fine granules, powders, capsules, injections, suppositories and the like are used.

[0010]

The pharmacological effect of the present invention will be described based on test examples. The test sample of the present invention is (R)-
(−)-2-Methyl-3-pyrrolidino-1- (4-trifluoromethylphenyl) -1-propane · hydrochloride was used.

1. Relaxing action of masticatory muscle (method) Method of Funakoshi et al. Using Wistar male rats (J. D
ent. Res., 53, 598 (1974)).
That is, the animals were intubated in the trachea jugular vein and the cervical esophagus under Nembutal anesthesia (35 mg / kg ip), and then a pair of enamel electrodes were embedded in one masseter muscle. Then, the brain was fixed to a rat stereotaxic apparatus (Summit Medical), and a stimulus of pressure was applied to the maxillary incisor in the lingual labial direction. At this time, the electromyogram induced in the masseter muscle was recorded on a recorder (Nihon Kohden RTA-1200) via a bioelectrical amplifier (Nihon Kohden AB-621G). The EMG firing frequency was also recorded at the same time, and the effect of the drug was examined. A mechanical tooth stimulator consisting of a trapezoidal generator (Diamedical DPS-204) and a vibration generator (Akashi MODEL-101) is used to apply pressure stimulus to the tongue and lip under constant conditions.
A compression stimulus was given for 5 seconds at 5-minute intervals. The drug was dissolved in water using the test sample of the present invention and eperisone of the formula [2] as a control sample, and the administration dose was 100 mg / kg,
A certain amount was intragastrically administered from the cervical esophagus via a cannula. Nembutal was appropriately added until drug administration to maintain anesthesia. The results were expressed as the time-dependent change as a percentage of the electromyographic firing frequency immediately after administration with respect to the electromyographic firing frequency immediately before administration (FIG. 1). In addition, 25, 50, 100, 20 each drug
The dose-response curve of 0 mg / kg was expressed as a percentage of suppression of the EMG firing frequency relative to the EMG firing frequency immediately before administration (FIG. 2). Compared with the 50% inhibition of masseter reflex, it was about 3 times more effective than eperisone. (Results) The results are shown in FIGS. 1 and 2. From these figures, it is understood that the compound of the present invention has a stronger masticatory muscle relaxing action and a longer duration of action as compared with the eperisone of the formula [2].

2. Acute toxicity In mice, the approximate LD ₅₀ value after intragastric administration was determined to be 616 mg / kg (male).

[0013]

The propiophenone derivative represented by the formula [1] or a pharmacologically acceptable salt thereof has an excellent masticatory muscle-relaxing action and low toxicity. Therefore, the therapeutic agent for temporomandibular disorders of the present invention is expected as a prophylactic or therapeutic drug for temporomandibular disorders based on the relaxing action of masticatory muscles.

[0014]

【Example】

Formulation example (R)-(-)-2-methyl-3-pyrrolidino 1-1-
(4-trifluoromethylphenyl) -1-propane
50 parts by weight of hydrochloride, 77 parts by weight of lactose, 19 parts by weight of corn starch and 3 parts by weight of polyvinylpyrrolidone were sufficiently mixed, kneaded with an appropriate amount of distilled water, and then granulated,
dry. To 149 parts by weight of dry granules, 1 part by weight of magnesium stearate is added and mixed well. The mixed granules are tabletted with a tableting punch having a diameter of 7.5 mm at a weight of 150 mg per tablet.

[Brief description of drawings]

FIG. 1 shows the relationship between the time (horizontal axis) after drug administration (100 mg / kg) and the electromyographic firing frequency (vertical axis).

FIG. 2 shows the relationship between the dose of a drug (horizontal axis) and the inhibition rate of masticatory muscle tone (tonic periodontal masseter reflex) (vertical axis). -●-: sample of the present invention (compound of formula [1])-Δ-: control sample (eperisone of formula [2])

Claims (2)

[Claims] 1. A formula [1]: A therapeutic agent for temporomandibular disorders comprising a propiophenone derivative represented by the following formula or a pharmacologically acceptable salt thereof as an active ingredient. 2. The therapeutic agent for the temporomandibular joint according to claim 1, wherein the propiophenone derivative is an R-configuration optical isomer.