JPH034525B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to muscle relaxants. [Prior Art] Examples of β-aminoketone derivatives having central muscle relaxing effects, such as β-aminopropiofenone derivatives, include 2-methyl-1-(4-methylphenyl)-3-piperidino-1-propanone (generic name: tolperisone). ) is known (Tokuko 1977-
20390). Tolperisone is widely used to treat spastic paralysis and motor paralysis caused by muscle hypertonia. [Problems to be Solved by the Invention] However, tolperisone is not necessarily sufficient in terms of effectiveness and sustainability, and improvements are desired. [Means for solving the problems] The present invention is based on the general formula [In the formula, R ₁ represents a p-trihalogenomethyl group]
The present invention relates to a muscle relaxant containing a novel aminoketone derivative or a salt thereof as an active ingredient. In the above general formula [], examples of the trihalogenomethyl group include a trichloromethyl group and a trifluoromethyl group. The compound of the present invention has the general formula (a) [In the formula, R ₁ is the same as above] It can be obtained by reacting a compound represented by the following with formaldehyde and pyrrolidine. The usage ratio of each raw material compound in the above reaction is
For 1 equivalent of the compound represented by general formula (a), formaldehyde is usually 0.5 equivalent or more, preferably 1 equivalent to 10 equivalents, more preferably 1.5 to 6 equivalents,
The amine of general formula (b) or its acid addition salt is usually 0.5 to
It is about 10 equivalents, preferably about 1 to 3 equivalents. The reaction may be carried out under conventional Mannitz reaction conditions, preferably in the presence of a catalytic amount of acid, more preferably hydrochloric acid. That is, the reaction can be carried out without a solvent, but it is better to use a solvent. Examples of solvents include alcohols such as propanol, isopropanol, butanol, and isobutanol, ketones such as acetone and methyl ethyl ketone, or inert solvents such as ethyl acetate. It will be done. The reaction is preferably carried out at 0°C to 200°C, preferably from 10°C to around the boiling point of the solvent, for about 0.5 to 48 hours, preferably about 3 to 48 hours, to give preferable results. The compound of the present invention represented by the general formula () can be purified and isolated from the reaction solution by a conventional method, and can also be obtained as a free base or an acid addition salt depending on the reaction conditions and treatment method. The free base can be converted into an acid addition salt by conventional methods, if desired. Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, as well as formate, acetate, citrate, maleate, fumarate, tartrate, and lactic acid. It can be made into an organic acid salt such as a salt or methanesulfonate. The compound of the present invention has one asymmetric carbon in the molecule.
Therefore, there are theoretically two optical isomers, and the present invention includes these racemates and optical isomers. The optically active form can be obtained by, for example, producing an optically active acid and a diastereomer salt from the racemate, separating and purifying the same, and isolating the optical isomer from each diastereomer salt. When the compound of the present invention obtained as described above is used as a central muscle relaxant, it can be administered either orally or parenterally. The dosage varies depending on the patient's symptoms, age, and administration method, but is usually 0.1 to 20 mg/Kg/
It is day. The compound of the present invention is administered in the form of a preparation prepared by mixing it with a suitable pharmaceutical carrier. Forms of preparation include tablets, granules, fine granules, powders, capsules,
Injection type, suppository, etc. are used. [Effects] Next, the effects of the compounds of the present invention will be explained. 1 Spinal cord reflex (flexion reflex) suppressive effect Under urethane α-chloralose anesthesia in male Wistar rats, the tibial nerve was dissected and stimulated (0.1 msec, 0.1 Hz) with an electron tube stimulator (Nihon Kohden; MSE-3 type). , supramaximal stimulation) and the evoked electromyogram recorded via an oblique electrode inserted into the ipsilateral anterior tibialis muscle (flexor muscle) was amplified and depicted on a cathode ray tube oscilloscope. The amplitude of this electromyogram was recorded on a pen recorder via a homemade peak holder as an index of flexion reflex. The effect of the drug was expressed as the flexion reflex inhibition rate, taking into account its persistence. That is, the average amplitude of the electromyogram for 10 minutes before administering the test compound is (a), and the test compound is dissolved in physiological saline and 30 minutes after intravenous administration (iv) of 5 mg/Kg.
The flexion reflex suppression rate was calculated using the formula (A), with the average amplitude of the electromyogram per minute as (b). Suppression rate = a-b/a x 100 (%) (A) As a result, the suppression rate was 40.3%. 2 Effect on anemic decerebrate rigidity in rats Method of Fukuda et al. [H.Fukuda, T.Ito, S.
Hashimoto, and Y. Kudo, J. Pharmacol., 24,
810 (1974)], the rigidity-reducing effect of the compounds of the present invention on anemic decerebrate rigidity was investigated. This specimen causes rigidity in the limbs (particularly the forelimbs) due to activation of the α-motor system, and is considered an excellent pathological model for abnormal hypertension of muscle tone such as spasticity in clinical practice.
Compounds that have a relaxing effect on the same specimen are thought to act on the brainstem and spinal cord levels and exhibit central muscle relaxing effects. [Method] Using male Wistar rats (350-500g),
After inserting a tracheal cannula under ether anesthesia according to the method of Fukuda et al., the common carotid arteries on both sides were ligated, and the basal artery was placed with a bipolar coagulator (Mizuho Medical Industries, MICRO-IC).
cauterize to stop blood flow and create a solidified specimen. Recording of rigidity was performed as follows. The rat was fixed in the dorsal position on a fixed stand, and its forelimbs were held on one end of a celluloid plate with strain gauges attached to both sides. The change in resistance that occurred in response to the force pushing up the celluloid plate due to rigidity of the forelimb was recorded as tension through a Pritzge circuit on an automatic balance recorder (Shimadzu R-12M). The inhibition rate of rigidity was calculated using formula [B], setting the tension before administration as 100%. [100 - Average tension (g) for 10 minutes at maximum response/Average tension (g) for 10 minutes before administration x 100
[B] The test compound was dissolved in physiological saline at a concentration of 3.5 mg/Kg.
was administered intravenously. As a result, the suppression rate was 23.6%. 3 Acute toxicity Approximately 50% of intravenous administration using mice
The lethal dose (LD ₅₀ , mg/Kg) was determined to be 61.1 mg/Kg.
It was Kg. As described above, the compound of the present invention has an excellent spinal reflex (flexion reflex) suppressing effect and also has low toxicity.
In addition, the compound of the present invention has a long-lasting effect, has a rigidity-reducing effect in decerebrate rigidity specimens, which is said to be one of the pathological models of spastic paralysis, and also has an anticonvulsant effect, and has a central central effect. As a muscle relaxant, it is expected to have an excellent therapeutic effect in improving spastic paralysis caused by cerebrovascular disease, cerebral palsy, spondylosis, etc., as well as hypertonia in various diseases. Formulation Example 1 50 parts of the active ingredient obtained in Reference Example, 77 parts of lactose, 19 parts of cornstarch, and 3 parts of polyvinylpyrrolidone are thoroughly mixed, kneaded using an appropriate amount of distilled water, and then granulated. Add 1 part of magnesium stearate to 149 parts of dry granules and mix thoroughly. The mixed granules are made into tablets with a weight of 150 mg per tablet using a 7.5 mm diameter tableting punch. Formulation example 2 50 parts of the active ingredient obtained in the reference example, 93.5 parts of lactose,
Thoroughly mix 31 parts of potato starch and 4 parts of HPC-sl, add an appropriate amount of water, knead, and granulate. After drying,
Add 1.5 parts of magnesium stearate to 178.5 parts of the granules, mix thoroughly, and then tablet with a φ8 mm punch at a weight of 180 mg per tablet. Reference example 1-(4-trifluoromethylphenyl)-2-
Methyl-3-pyrrolidino-1-propanone (compound No. 4-1) hydrochloride 1-(4-α,α,α-trifluoromethylphenyl)-1-propanone 2.50g, paraformaldehyde 1.11g, pyrrolidine hydrochloride Concentrated hydrochloric acid in a mixture of 1.60 g of salt and 20 ml of isopropyl alcohol.
Add 0.1 ml and heat under reflux for 16 hours. After the reaction is complete,
The reaction solution was concentrated under reduced pressure to remove isopropyl alcohol. Water is added to the resulting residue and washed with ethyl acetate. The aqueous layer is made alkaline with aqueous ammonia and extracted with ethyl acetate. This ethyl acetate layer is dried over anhydrous magnesium sulfate. The desiccant is removed and the liquid is concentrated under reduced pressure. As an oil, 1-(4-α,α,α-trifluoromethylphenyl)-2-methyl-3-pyrrolidino-1-
1.58 g (44.8%) of propanone is obtained. IR ν ^neat _nax cm ^-1 : 1690 NMR δ (CDCl ₃ , TMS): 1.25 (d, 3H, J
=7.0Hz, -COCH( _CH3 ) _CH2- ), 1.4~2.1
(m, 4H,

[Formula]), 2.3 to 3.2 (m, 6H,

[Formula]), 3.65 (1H,

【formula】). 7.70 (2H, d, J = 8.0Hz, aromaticH), 8.05 (2H, d, J = 8.0Hz, aromaticH), Mass m/z (relative intensity): 285 (2.21,
M ⁺ ), 214 (100), 173 (100), 145 (100), 95
(29.7), 84 (100) Dissolving this oil in ethyl ether and introducing dry hydrogen chloride gas gives the hydrochloride. mp.154-156℃ (acetone-ethyl acetate)

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a p-trihalogenomethyl group]
A muscle relaxant containing a novel aminoketone derivative or a salt thereof as an active ingredient.