JPH051003A - Cinnamic acid amide derivative - Google Patents

Abstract

(57) [Summary] [Purpose] To provide a central muscular relaxant having high potency and long-lasting action. [Structure] Expression (In the formula, X is a fluorine atom or a bromine atom.) A cinnamic acid amide derivative. The compound of the present invention is useful as a therapeutic agent for painful muscular spasticity associated with locomotor disorders such as low back pain and disc herniation, and as a therapeutic agent for spastic paralysis such as cerebrovascular disorder.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cinnamic acid amide derivative, and more particularly to a cinnamic acid amide derivative having a central muscle relaxing action.

[0002]

(E) -N-Cyclopropyl-3- (3)
-Chlorophenyl) -2-butenamide is the journal
Of Medicinal Chemistry (J. Med. Ch
em. ), Vol. 9 (No. 5), pp. 675-681 (19
1966) and reported to exhibit sedative or acclimatizing effects. However, there is no report on the muscle relaxant action of the compound.

Drugs having a sedative action or a habituation action are drugs that lower the psychological activity of the abnormally elevated upper central nervous system or suppress hyperestrousness. On the other hand, the muscle relaxant is a drug that suppresses abnormal hyperactivity of the motor system in the central nervous system, and the pharmacological actions of the two are clearly different. Therefore, conventionally, the muscle relaxant has a different purpose from the sedative.

On the other hand, another cinnamic acid amide derivative having a muscle relaxing action is known (Japanese Patent Publication No. 60-56700). They are trans-3-fluoro-N-cyclopropylcinnamic acid amide (hereinafter referred to as synflumide)
It is described that synflumide is the most preferable compound in terms of efficacy.

[0005]

In view of these facts,
An object of the present invention is to provide a central muscular relaxant having high efficacy and long lasting action.

[0006]

As a result of earnest research, the present inventors have found that a certain cinnamic acid amide derivative achieves the above object, and completed the present invention.

The present invention will be described in detail below. The present invention has the formula

[0008]

[Chemical 2]

(Wherein, X is a fluorine atom or a bromine atom in the chemical formula 2) is a cinnamic acid amide derivative.

The compound of the present invention can be produced, for example, by the following method. That is, first, a known (E) -3- (3-halogenophenyl) -2-butenoic acid and a commonly used halogenating agent (for example, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide, and trisyl chloride). The following formula can be obtained by reacting phosphorus bromide, etc.)

[0011]

[Chemical 3]

(In Chemical Formula 3, X has the same meaning as described above, and X '
Is a halogen atom. ) An acid halide represented by This reaction uses the halogenating agent itself as a solvent, or stirs in an inert solvent (eg, benzene, toluene, tetrahydrofuran, ether, methylene chloride, chloroform) at room temperature to the reflux temperature of the solvent for 30 minutes to 5 hours. Is completed by. A catalyst is not always necessary in this reaction, but the reaction can be promoted by adding a catalytic amount or equimolar amount of pyridine, triethylamine, N, N-dimethylformamide or the like. Then, the compound of Chemical formula 2 can be obtained by dissolving the compound of Chemical formula 3 in the above-mentioned inert solvent and reacting it with cyclopropylamine. In this reaction, it is desirable to use 2-fold or more moles of cyclopropylamine in order to remove hydrogen halide produced, or else tertiary amines such as pyridine and triethylamine may coexist. The reaction is carried out at -30 to 50 ° C and is completed in 1 to 24 hours.

Alternatively, (E) -3- (3-halogenophenyl) -2-butenoic acid can be treated with an alkyl halogenocarbonate (eg, triethylamine, diisopropylethylamine, N-methylmorpholine) in the presence of a base (eg, triethylamine, diisopropylethylamine, N-methylmorpholine). , Methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate, etc.) in the same inert solvent as described above at −30 to 30 ° C. for 0.2 to 3 hours to give the following formula.

[0014]

[Chemical 4]

(Wherein X has the same meaning as above and R is an alkyl group having 1 to 7 carbon atoms), a mixed acid anhydride represented by The compound of formula 2 of the present invention can be obtained by reacting with cyclopropylamine at the same temperature as it is without separating the reaction solution.

In order to use the compound of the present invention as a muscle relaxant, the compound of the present invention is mixed with a carrier of a solid or liquid excipient and prepared into a pharmaceutical preparation suitable for oral or parenteral administration. It Pharmaceutical preparations include tablets, pills, capsules, solids such as granules, injections, syrups, liquids such as emulsions, ointments, external preparations such as suppositories,
They are manufactured according to conventional formulation techniques. Each of the above-mentioned formulations may contain commonly used additives such as auxiliaries, stabilizers, wetting agents and emulsifiers. For example, injectable distilled water for injection, physiological saline, solubilizer such as Ringer's solution, preservative such as methyl paraoxybenzoate, propyl paraoxybenzoate, sorbitol syrup, methylcellulose, glucose in syrups and emulsions,
In addition to sucrose syrup, hydroxyethyl cellulose, edible oil, glycerin, ethanol, water and the like, emulsifiers such as gum arabic and lecithin, and surfactants such as tween and span may be contained. Solid agents include excipients such as lactose, corn starch and mannitol, lubricants such as calcium phosphate, magnesium stearate and talc, binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose, crystalline cellulose and carboxymethyl cellulose calcium. A disintegrating agent, a fluidity-improving agent such as light anhydrous silicic acid, or the like can be used.

The dose of the compound of the present invention to a patient to be treated may vary depending on the patient's age, type of disease and condition, etc.
It can be divided into several doses.

[0018]

The compound represented by Chemical formula 2 according to the present invention is
It has an excellent muscle relaxing action and rigid contraction / relaxation action. Further, the compound represented by Chemical formula 2 according to the present invention has a weak sedative action, and does not show a sedative action at a dose exhibiting a muscle relaxant action. Therefore, the compound represented by Chemical Formula 2 according to the present invention is used as a therapeutic agent for painful muscular spasticity associated with locomotor disorders such as low back pain and disc herniation, and as a therapeutic agent for spastic paralysis such as cerebrovascular disorder. It is useful.

The usefulness of the compounds of the present invention will be shown below in Test Examples. Test Example 1 [Mebrain decerebrate rigidity inhibition test] A rigid specimen was prepared according to the method of Ono et al. [General Pharmacology (Gen. Pharm.), Volume 18,].
57-59 (1987)]. As a test animal,
Four Wistar male rats weighing 250 to 350 g were used in each group.

Under ether anesthesia, the test animal was fixed on a stereotaxic apparatus, and the midbrain was bilateral (AP0, V-3, L ± 1.
It was destroyed in 5). Following the recovery from ether anesthesia, extensible rigidity developed in the hind limbs. The test drug [A: (E) -N-cyclopropyl-3- (3-fluorophenyl) -2-butenamide and B: synflumide] was dissolved in propylene glycol to give 5 mg / kg or 10 mg / kg.
(0.1 ml per 100 g of rat) is intravenously administered or 50 mg / kg (0.1 ml per 100 g of rat) suspended in 0.4% carboxymethylcellulose aqueous solution
Was administered intraduodenally, and the inhibition time of rigidity was measured. The results are shown in Table 1.

[0021]

[Table 1]

*: Numerical value indicates the time of onset (in minutes) of inhibitory action

Test Example 2 [Anemic Decerebral Rigidity Inhibition Test] A rigid specimen was prepared according to the method of Fukuda et al. [Japanese Journal of Pharmacology (Japan.
J. Pharmacol. ), 24, 810-8
Page 13 (1974)]. The test animal weighs 25
Four male Wistar rats weighing 0 to 350 g were used in each group.

Under ether anesthesia, the neck of the test animal was incised and the bilateral carotid arteries were ligated. A circular hole was made in the occipital bone, and the basal artery was cauterized and coagulated using a bipolar electrode coagulator. Following recovery from ether anesthesia, extensor rigidity developed in the forelimbs.
Test drug [A: (E) -N-cyclopropyl-3- (3-
Fluorophenyl) -2-butenamide and B: synflumide] were dissolved in polyethylene glycol 400 to give 5 mg / kg or 10 mg / kg (rat 100 g
0.1 ml) was intravenously administered, and the inhibition time of rigidity was measured. The results are shown in Table 2.

[0025]

[Table 2]

*: Numerical value indicates the time (minute) for the onset of inhibitory action

Test Example 3 [Straup Raising Test] A test was conducted according to the method of Jaju et al. [Journal Experimental Biology (J. Exper. Bio.), Vol. 22, Vol.
427 (1984)]. The test animal weighs 2
Ten ICR male mice of 0 to 30 g were used in each group.

The test drug [A: (E) -N-cyclopropyl-3- (3-fluorophenyl) -2-butenamide and B: synflumide] was suspended in a 0.5% carboxymethylcellulose aqueous solution, and 0 was suspended per 10 g of the mouse. .1
ml was orally administered to each test animal. After 15 minutes, 7 mg / kg of morphine hydrochloride was subcutaneously administered, and 30 minutes after that, the angle of the tail was measured and the inhibition rate of the tail reaction was calculated. Table 3 shows the ED ₅₀ values for inhibition of tailing.

[0029]

[Table 3]

Test Example 4 [Locomotor activity test] As test animals, 6 ICR male mice each weighing 20 to 30 g were used in each group. Test drug [A: (E) -N-cyclopropyl-3- (3-
Fluorophenyl) -2-butenamide was suspended in a 0.4% carboxymethylcellulose aqueous solution to give 50,70.
7 or 100 mg / kg (0.1 per 10 g mouse
ml) was orally administered to each test animal (only 0.4% carboxymethylcellulose aqueous solution was administered to the control group). After 15 minutes, the mouse was placed in an Animix device, and spontaneous locomotion was measured at 5-minute intervals for 30 minutes. Administration 3
The results after 0 minutes are shown in Table 4. As a result of this test, no significant suppressive effect was observed in the test drug administration group as compared with the control group.

[0031]

[Table 4]

Test Example 5 [Acute toxicity test] Ten male ICR mice each weighing 25 to 34 g were used. (E) -N-Cyclopropyl-3- (3-fluorophenyl) -2-butenamide was suspended in a 0.4% carboxymethylcellulose aqueous solution, and 0.1 ml per 10 g of the mouse was orally administered. After the administration, the cells were observed for 7 days and examined for survival. As a result, there was no death even at 1 g / kg, and LD ₅₀ was 1 g / kg p. o. It turned out that it was above.

[0033]

EXAMPLES Next, the production method of the compound of the present invention will be explained in detail with reference to Examples.

Example 1 A solution of 18.0 g of (E) -3- (3-fluorophenyl) -2-butenoic acid in 200 ml of benzene was charged with 1 part of thionyl chloride.
4.5 ml was added, and the mixture was stirred with heating under reflux for 2 hours. Benzene and excess thionyl chloride were distilled off under reduced pressure and dried to obtain 19 g of crude acid chloride. 200 ml of this toluene
Cyclopropylamine 15.2 under ice-cooling stirring.
After a 50 ml solution of 50 ml of toluene was added dropwise, the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water, saturated aqueous sodium hydrogen carbonate, diluted hydrochloric acid, and water in this order, and dried over magnesium sulfate. Toluene was distilled off under reduced pressure, and the residue was recrystallized from n-hexane-acetone to give colorless needle crystals of (E) -N-cyclopropyl-3-.
(3-Fluorophenyl) -2-butenamide 12.9
g was obtained. m. p. 119.0-120.5 ° C

Example 2 (E) -3- (3-fluorophenyl) -under a nitrogen stream.
To a solution of 18.0 g of 2-butenoic acid in 200 ml of toluene,
13.9 ml of triethylamine and then 13.0 ml of isobutyl chlorocarbonate were added with stirring under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled again, 7.6 ml of cyclopropylamine was added dropwise with stirring, and then the mixture was stirred at room temperature for 2 hours. Then, the same treatment as in Example 1 was carried out to obtain 14.0 g of (E) -N-cyclopropyl-3- (3-fluorophenyl) -2-butenamide. m. p. 119.0-12
0.5 ° C

(E) -N-Cyclopropyl-3- (3-bromophenyl) -2-butenamide was obtained in the same manner as in Example 2. m. p. 129.0-131.5 ° C

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazuya Gumi 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd.

Claims (1)

What is claimed is: Claims 1 (In chemical formula 1, X is a fluorine atom or a bromine atom.) A cinnamic acid amide derivative.