JPH01301621A - Central muscle relaxant containing glycol derivative - Google Patents

Abstract

PURPOSE:To obtain a central muscle relaxant, containing a specific glycol derivative as an active ingredient, having powerful central muscle relaxing action with low toxicity, rapidly absorbable by oral administration and useful for sequelae of cerebral apoplexy, etc., without inducing sleepiness. CONSTITUTION:A central muscle relaxant containing a glycol derivative expressed by the formula (R<1> is H, lower alkyl or halogen; R<2> is lower alkyl, etc.; R<3> and R<4> are H or lower alkyl), e.g. 2-(2,3-dihydroxypropyl)-5-(p- chlorophenyl)-4-isoxazolin-3-o-ne as an active ingredient. The compound expressed by the formula is administered by oral administration with a tablet, capsule, granule, etc., or parenteral administration with an injection, suppository, etc. In the case of the oral administration, 5-50mg is normally administered to an adult 1-3 times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a central muscle relaxant containing a glycol derivative represented by general formula (1) below as an active ingredient.

[Problem to be solved by the invention]

Muscle rigidity or spasticity often develops as a sequela of cerebral circulation disorders such as stroke or head trauma, making rehabilitation difficult. For this purpose, these muscle rigidities or spasticity are relaxed. It is desired to develop a central muscle relaxant that does not cause drowsiness.

In the process of searching for chemical substances for these purposes, the present inventors discovered that a glycol derivative having the general formula (1) k has a strong central muscle relaxant effect, and found that it is a central muscle relaxant. The present invention was completed after realizing that the present invention is useful as a method.

[Structure of the invention]

The novel central muscle relaxant of the present invention has the general formula (wherein Rj represents a hydrogen atom, a lower alkyl group, or a halogen atom, and R2 represents a lower alkyl group.

Indicates an aryl group which may have a substituent or a heterocyclic group which may have a substituent, and the one-length R1 and R2 may form a fused hydrocarbon ring together with the carbon atom to which they are bonded. , R3 and R4 represent a hydrogen atom or a lower alkyl group. ) is used as an active ingredient.

Suitable compounds used in the present invention include, in the general formula (1), R1 is a hydrogen atom; methyl;
A linear or branched alkyl group having 1 to 4 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, or fluorine and chlorine.

Indicates a halogen atom such as bromine.

R2 is a linear or branched alkyl group having 1 to 4 carbon atoms as exemplified as the alkyl group in R1, or a carbon group such as methyl, ethyl, n-propyl, or isopropyl as a substituent on the aromatic ring. Alkyl group having number 1 to 3, methoxy.

an alkoxy group having 1 to 3 carbon atoms such as ethoxy, n-propoxy, and isopropoxy;

An aryl group such as phenyl with or without a halogen atom such as fluorine, chlorine, or bromine or a nitro group; or furyl, thienyl, or thiazolyl with or without the same substituent as that of the aryl group in the heterocyclic ring. , represents a 5- and 6-membered heterocyclic group having an oxygen atom, sulfur atom or nitrogen atom such as pyridyl; or R1
and R2 represent a 6- to T-membered hydrocarbon ring such as a benzene ring, cyclohexane ring, or cycloheptene ring formed together with the carbon atom to which they are bonded.

R3 and R4 represent a hydrogen atom; or a linear or branched alkyl group having 1 to 4 carbon atoms as exemplified as the alkyl group for R1 above.

(In addition, the above-mentioned general compound having 2(11) contains optical isomers due to the presence of an asymmetric carbon atom.

The glycol derivative having the general formula (1), which is the active ingredient of the present invention, is produced according to the method described in 1% Japanese Patent Publication No. 83788/1983.

〔Effect of the invention〕

According to pharmacological and toxicological tests, the compound of the present invention having the general formula (1) has an excellent central muscle relaxing effect and is a compound with low toxicity. Explain.

1. Decerebrate rigidity-relaxation effect (rats) Method: Rats were placed under ether anesthesia using a stereotaxic device (S
R-5, Narishige] and the mesencephalic reticular formation (Ap:o
, L: ±1.5. H knee s, o), diameter 0.7m, tip +ff1ll! An electrode with other parts insulated (i-Pell-
Brain map of egrino Sゝ [I, , , T, Pel
legrino, A., S.

Pellegrino ana A, J, Cu8h, m
an: A5tereotaxic Atlas o
f th, e R4t Braln, Plenum-P
ress, New York ancl London (
, 1967)] was inserted bilaterally. A high frequency (+00KH2,251
A current of nA) was applied for 3 minutes.

This area was electrically cauterized. Note that a clip was used as an indifferent electrode at this time by inserting it into the scalp lining. The animals were allowed to emerge from anesthesia and were immobilized on a homemade hindlimb immobilization device. The roots of the front ankles of both hind legs of the animal were fixed, and the toes of both hind legs were pushed four times in one direction for 6 seconds in a total of 1 minute, and the tension of the stretch reflex of the extensor muscles of the hind legs was measured.
It was drawn on a polygraph via Up (Nihon Kohden).

After the experiment is over, kill the rat with a runny chill and measure the tension at that time (
pae81vθtθn5ion) f Subtracted from the tension (tothl tenexon) obtained during the experiment,
The true reflex tension (active tension) f was determined.

05% CMOf the test compound! Suspended in i solution and administered orally via a pre-inserted cannula (p, o,)
did.

(vinegar Results: The results are summarized in Table 1.

That is, it was revealed that all of the above-mentioned compounds 1 to 6 caused decerebrate rigidity in rats to relax with extremely short onset latency.

1 Thiobental anesthesia enhancement (mouse) Method: 1 group 7~
Eight adult DDY male mice (body weight 20-301) were used. One hour after orally administering 1 test compound (suspended in 0.05% OMO solution) to the mice, thiobencool (
30 μ/U] was injected through the tail vein, and the time until the righting reflex of the mouse recovered was measured.

Results: The results are summarized in Table 2.

That is, Compound 4 did not significantly prolong thiobental anesthesia time. This means that Compound 4 is less likely to cause drowsiness, which is a side effect.

3 Suspend acutely toxic compound 1.4 or 6 in 0.5% cyam solution,
9 was orally administered to three DDY male adult mice (body weight 20 to 25 f) at 300 μ/kg and observed for 5 days.
All cases survived although it was observed for some time.

As explained above, the compound having the general formula m* is
It does not cause drowsiness, has extremely low toxicity, and has a central muscle relaxing effect, and upon oral administration, it is quickly absorbed and exerts its effects. From the above animal experiments, it has been shown that oral administration is clinically possible, and it is particularly useful as a central muscle relaxant for the aftereffects of stroke and head trauma. In addition, spasticity can be treated as spinal cord paralysis, cervical spondylosis after-effects (including spinal cord tumors in the brain), trauma sequelae (spastic spinal cord injury, 1 head injury), amyotrophic lateral sclerosis, cerebral palsy,
medullocerebellar disease, medullary vascular disease, SMON, diving disease,
It is also useful for spastic paralysis caused by other spinal cord diseases of the brain, generalized cramps, and muscular tension such as stiff shoulders. Examples of the form include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration using injections, suppositories, etc. These various preparations are formulated according to the conventional method according to the purpose using known adjuvants that are commonly used in the field of pharmaceutical formulation technology, such as crude drugs, excipients, binders, disintegrants, lubricants, and flavoring agents. can be converted into The amount used varies depending on the symptoms, age, weight, etc.

For oral administration: 1. Usually for adults, 5 to 50 mg/dose.
qi can be administered 1 to 3 times a day.

Next, a more specific explanation will be given using formulation examples.

(1η Formulation Example 1 (Tablet 9) 4-chloro-2-(2,3-dihydroxy-3■-monomethylbutyl)-5-phenyl-4-iso 10.
0 Xazolin-3-one (Compound 4) Corn starch 250 Lactose
83.3HP
O (Nippon Soda Manufacturing) 1.2 Magnesium stearate 0.5 Total 120
■ Use the above formulation according to normal formulation procedures).

Each tablet weighed 120 cm.

Formulation Example 2 (Capsule) 2-(λ3-dihydroxyglobil)-5-■ (p-chlorenyl)-4-inoxazo 25
0 phosphorus-3-one (compound 1) lactose
1536 Corn starch 100.
0 total 280~ The powders of the above formulation were mixed and passed through a 60 mesh sieve, and then placed in gelatin capsules of 280q'i No. 3 to form capsules.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 represents a hydrogen atom, a lower alkyl group or a halogen atom, and R^2 represents a lower alkyl group or a substituent. represents an aryl group that may have a substituent or a heterocyclic group that may have a substituent, and R^1 and R^2 may form a fused hydrocarbon ring together with the carbon atom to which they are bonded, R^
3 and R^4 represent a hydrogen atom or a lower alkyl group. ) A central muscle relaxant whose active ingredient is a glycol derivative represented by