JPS63264417A - Central muscle relaxant - Google Patents

Abstract

PURPOSE:To obtain a central muscle relaxant having extremely low toxicity and applicable without inducing drowsiness, by using an isoxazolin-3-one derivative as an active component. CONSTITUTION:The objective agent contains, as an active component, a com pound of formula (R<1> is H or halogen; R<2> is lower alkyl, aryl or heterocyclic group; R<1> and R<2> may together with adjacent C form a hydrocarbon ring; R<3> is H or lower alkyl; R<4> is lower alkyl; R<3> and R<4> may together with adjacent N form an alicyclic amino group) or its acid addition salt, e.g. 2-(2-hydroxy-3- morpholinopropyl)-5-phenyl-4-isoxazolin-3-one. The compound is useful for the treatment of sequela of cerebral apoplexy and cranial trauma. It is administered usually at a rate of 5-50mg/dose and 1-3 doses a day for adult in the case of oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a central muscle relaxant containing an inoxazolin-3-one derivative represented by the general formula fll below as an active ingredient.

[Conventional technology]

Muscle rigidity or spasticity often develops as a sequela of cerebral circulation disorders such as stroke or head trauma, making rehabilitation difficult. There is a great desire in this world to develop a central muscle relaxant that relieves these muscle rigidities or spasticity and does not cause drowsiness.

[Problem that the invention seeks to solve]

In the process of searching for chemical substances in line with these objectives, the present inventors discovered isoxasilicate/
The inventors discovered that -3-one derivatives have a strong central muscle relaxant effect, confirmed that they are useful as central muscle relaxants, and completed the present invention.

[Structure of the invention]

The novel central muscle relaxant of the present invention has the general formula (wherein R1 represents a hydrogen atom or a halogen atom, R
2 represents a lower alkyl group, aryl group or heterocyclic group, B1 and R2 may each form a hydrocarbon ring together with adjacent carbon atoms, R3 represents a hydrogen atom or a lower alkyl group, and R1 represents a lower alkyl group. Further, R3 and R4 may be taken together to form an alicyclic amine group with the respective adjacent nitrogen atoms. ) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

Suitable compounds for use in the present invention include the above general formula (11), where R1 preferably represents a hydrogen atom, for example a halogen atom such as fluorine, chlorine, or bromine, and B2 represents, for example, methyl, ethyl, D -Propyl, isopropyl, n-butyl, inbutyl s'je r
Straight chain or branched chain with 1 carbon number such as t-butyl
to 4 alkyl groups, such as methyl in the aromatic ring,
Alkyl groups having 1 to 4 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, and 1-carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-cytoxy, and imbutoxy. an alkoxy group having 1 to 4 carbon atoms, a halogen atom such as fluorine, chlorine, or bromine, a hydroxyl group, a trifluoromethyl group, or an alkyl group having 1 to 4 carbon atoms such as niprovil, isopropyl, n-butyl, isobutyl, methoxy , ethoxy, n-propoxy, isopropoxy, n-butoxy, alkoxy having 1 to 4 carbon atoms such as imbutoxy, silyl group, halogen atom such as fluorine, chlorine, bromine, hydroxyl group, trifluoromethyl group, or It represents a 5- and 6-membered heterocyclic group having an oxygen atom, sulfur atom or nitrogen atom such as furyl, chenyl, thiazolyl, pyridyl with or without a nitro group, or R1 and R2 are each adjacent to each other. A 6- to 7-membered hydrocarbon ring such as a benzene ring, a cyclohexene ring, or a cycloheptene ring formed with a carbon atom. R3 represents a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; R4 is, for example, methyl, ethyl,
Represents a linear or branched alkyl group having 1 to 4 carbon atoms such as n-propyl, isozolobyl, n-butyl, isobutyl, tert-butyl, or B3 and R4 taken together For example, morpholino, thiomorpholino, 1-
It may also represent a 5- to 6-membered aliphatic amino group such as 4-lower alkyl-1-piperazinyl, 1-pyrrolidinyl, piperidino, etc., such as piperazinyl, 4-methyl-1-piperazinyl, 4-isopropyl-1-piperazinyl. .

A more preferable compound having the general formula (II) is a compound in which R1 represents a hydrogen atom or a halogen atom, and R2 has the above-mentioned substituent on an alkyl group having 1 to 4 carbon atoms or an aromatic ring. R1 and R2 each represent a benzene ring formed with adjacent carbon atoms, and R6 is a hydrogen atom or has 1 carbon atom.
represents an alkyl group having 1 to 4 carbon atoms, R4 represents an alkyl group having 1 to 4 carbon atoms, or R6 and R4
can be used to form the above-mentioned 5- to 6-membered fatty amino group.

The theoretically acceptable acid addition salts of the inoxasily/-3-one derivatives having the general formula Ell include mineral acid salts such as hydrochloride, hydrobromide, sulfate, or mineral acid salts such as oxalate, lactic acid salt, etc. Mention may be made of organic acid salts such as salts, citrates, tartrates, succinates, maleate salts, fumarates, methanesulfonates.

Note that the compound having the above general formula (RI) includes optical isomers due to the presence of an asymmetric carbon atom.

The inoxazolin-3-one derivative having the general formula (II), which is the active ingredient of the present invention, is disclosed in JP-A-56-34FI7
It is manufactured according to the method described in the specification of Publication No. 4.

〔Effect of the invention〕

The compound having the general formula (11) of the present invention has an excellent central muscle relaxing effect and low toxicity according to pharmacological tests and durability tests. Explain.

1. Decerebrate rigidity-relaxing effect (rats) Method: Rats were placed under halothane anesthesia using a stereotaxic apparatus (SR).
-5, Narishige) and the mesencephalic reticular formation (AP: 0.
L: ±1.5, H: -3,0), a Pellegrin electrode with a diameter of 0.7 mm and insulated except for the tip 1 u was used.

brain map (L, J, Pellegrino,
A.S. Pellegrii.

and A, J, Cushman: A 5te.
reotaxic At1as of theRa
t Brain, Plenum Press,
New York and London (1
[967]] was inserted bilaterally. A Region Noenerator (manufactured by Glass Co., Ltd., LA4A
) for 2 to 3 minutes to electrically cauterize this site.

Note that a clip was used as an indifferent electrode at this time by inserting it into the scalp lining. Immediately thereafter, the animal was removed from the brain paw fixation device and a polyethylene cannula (Fr) was inserted into the duodenum.
, 3) was inserted and fixed with adhesive. After these surgeries were completed, the halothane anesthesia was immediately stopped, and after 1.5 hours had passed when the animal woke up from the anesthesia, it was fixed on a hindlimb fixation device made by Zero Jaku. The animal was immobilized at the base of the front ankles of both hind legs, and the ankles on both sides were held at the ankles for 6 seconds per minute.
Push only the length of the dragon and use the repellent force to remove insects with the FD pick.
It was drawn on a polygraph via Up (Nihon Kohden).

The test compound was suspended in 0.51 CMC solution and introduced into the duodenum (i, d,) through a cannula that had been inserted in advance.
or intravenously (p-o-) or intraperitoneally (<1-p).

That is, all of Compounds 1 to 7 alleviate decerebrate rigidity in rats, but especially Compounds 1 and 2 are central muscle relaxants, such as Eperisone, which is already used clinically as a treatment for sequelae such as cerebral circulation disorders. It has been shown that -HCl salt (Compound 8) and Afloqualone (Compound 9) alleviate decerebrate rigidity in rats, which is said to be a model of human spasticity, to the same extent or better.

Method: Adult cats (body weight 3.0-4.5 kg) were used. A tracheal cannula was attached under ether anesthesia, and both carotid arteries were ligated, the scalp was incised, a hole was made in the skull, and the brain was decerebrated by suction at the anterior end of the body. Immediately thereafter, ether anesthesia was stopped, and a pair of needle electrodes was inserted into the cervical splendid muscle to record myocardial discharge. Recordings were started at least 2 hours after cessation of anesthesia. That is, the myoelectric discharge was amplified with a preamplifier and then recorded on a pen recorder. At the same time, the integrated waveform of myocardial discharge was similarly drawn via an integrator. In addition, blood pressure was induced from the femoral artery and was constantly recorded and monitored along with body temperature and heart rate.

In addition, the test compound suspended in 0.5% C1vLC solution,
After confirming that stable muscle discharge was obtained, the drug was administered into the duodenum via a cannula inserted in advance. The effect of the test compound was expressed as a ratio to the integrated myoelectric discharge value before administration.

Results: Compounds 1 and 2 were both administered intraduodenally at a dose of 1001 HIACy.
The decerebrate rigidity started to be relaxed in 3 minutes, and at about 3 minutes after administration
) Also, in 1 hour, about 65% of cells were suppressed, and this state persisted for the 2 hours observed. In addition, the control drug Eperisone HCl salt (compound 8) 50η/
When kq was administered in the same manner, the animals vomited immediately after administration, and blood pressure and heart rate also fluctuated, and decerebrate rigidity was suppressed, but recovered within 30 minutes after administration, and the duration of the effect was longer than that in rats. The effect on decerebrate rigidity was similarly short-lived.

Compounds 1 and 2 also alleviated decerebrate rigidity, known as muscle stiffness, which is a sequela of stroke, in cats; currently, there are no clinically available drugs to treat this type of disease. Eperisone-HCl used as a salt (
It was found to have weaker side effects than compound 8) and to be effective for a long time.

Methods: Adult cats (body i 3.0-4.5 to 7) were used. After ether induction anesthesia, α-chloralose (50η/
After anesthetizing the animal with l
4-S3), the pith was exposed. After incising the dura mater, the right L
6-S, the ventral root was cut, and the stump was ligated with cotton thread soaked in Ringer's solution. The exposed pith was covered with liquid paraffin pre-warmed to 37°C, and the pool temperature was maintained at 37°C with a thermistor and heater. L7 or S1 ventral roots were fixed on a pair of bipolar platinum electrodes. Separately, a pair of collar molds were attached to the tibial nerve and saphenous nerve of the right hind limb. After all surgeries were completed, the animals were treated with nonancuronium bromide (0
, 5η7'ky, iy, ) and maintained by artificial respiration (407 min). Recordings were started at least 2 hours after cessation of the ether anesthesia used for induction. frost, duration 0.01-01 ms, ultra-maximum (5
A square wave pulse of 0 V) was applied to the peripheral nerve at a frequency of 0.3 Hz, and the medullary monosynaptic reflex, polysynaptic reflex, and medullary-bulbar motor reflex induced from the pre-amplifier were applied to the peripheral nerve. After amplification, insert it onto an oscilloscope (VC-10, Nihon Kohden) and output its output to a signal processor (7T).
-07A, NEC-Sanei) and averaged 10 times. The blood pressure, heart rate, and body temperature of the animals were monitored and recorded in the same manner as in the cat decerebrate rigidity experiment. In addition, the test compound was also administered in the same manner.

Results: Compounds 1 and 2.HCl salts at a dose of 100 A7 hardly suppressed monosynaptic reflexes, markedly inhibited polysynaptic reflexes, and almost completely abolished medullary-aminopathic reflexes. This effect began to be seen 5 minutes after administration, reached a maximum in 30 minutes, and then continued for about 2 hours. Chlorphene is currently used clinically as a central muscle relaxant.
sin carbamatal 00111/? A similar effect was shown by the same administration of . ! 1", the compounds 1 and 2 are Chlorphenesin Carb
It was found to be an intervening double blocker similar to amate.

Method = Group of 5-7 DDY male adult mice (body weight 2
0-30v) was used. Test compound (0,5
% CMC solution) was orally administered.
Thiobental (30 Tv'Kg) was administered through the tail vein.
m, and the time until the righting reflex of the mouse recovered was measured.

Table 2 Effect of thiobental on anesthesia time 0
7 254.7±19.51 50
p, o, 8 288.5±20.110
0 7 237.3±25.50
10 206±13.1100
5 247±34.90 1
0 206± 13.19 10 p, Os
5 242± 10.030
5 4657±636.6°”, i.e. compounds 1 and 2
E is already used clinically as a central muscle relaxant.
Similar to perisone-HCl salt (compound 8), thiobental did not significantly prolong the anesthesia time, but Afloqualope (compound 9), which is used for the same purpose, significantly prolonged the anesthesia time at a medicinal dose (30tyyAcy). . This means that compound 1 is Afloqua
1 (Compound 9) means that it does not cause drowsiness, which is a side effect.

5. Suspend the acutely toxic compound l in 0.5% CMC solution and add 10100O
/kf to 5 DDY male adult mice (body weight 20-2
The drug was orally administered to patients (52) and observed for 5 days, and although a decrease in body tone due to drug efficacy was observed approximately 3 hours after administration, all patients survived. Also, compound 2 and its 1-IC1
When salt was administered in the same manner at a rate of 500 η/ni, all cases survived for 81 days for 5 days, although a decrease in body tone due to the drug's efficacy was observed for up to 3 hours after administration.

As explained above, the compound having the general formula (1+) does not induce drowsiness, has extremely low toxicity, has a central muscle relaxing effect, and can be administered orally, intraduodenally, or intraperitoneally. It is absorbed by the body and exerts its effects.The above animal experiments show that clinically, it can be administered orally, but it is particularly effective as a central relaxant for the after-effects of stroke and head trauma. It is also useful for treating spasticity with spinal cord palsy, cervical spondylosis after-effects (including spinal cord tumors), trauma sequelae (spinal cord injury, head trauma), amyotrophic lateral sclerosis, and cerebral spinal cord disease. Infantile paralysis, medullocerebellar degeneration, medullary vascular disorder, SMON (5M0N), diving disease, spastic paralysis due to other cerebral medullary disorders, and oral administration method using pills, granules, powders, syrups, etc. Parenteral administration methods include injections, halved drugs, etc.These various preparations are prepared by adding pharmaceutical ingredients such as excipients, binders, disintegrants, lubricants, and flavoring agents to the main drug according to the purpose according to conventional methods. The formulation can be formulated using known adjuvants that can be commonly used in the field of formulation technology.The amount used depends on the symptoms,
Although it varies depending on age, body weight, etc., in the case of oral administration, usually 5 to 50 doses can be administered to adults 161 to 3 times.

It was put into Latin capsules and used as capsules.

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

Formulation Example 1 (Tablet) Sacilin-3-one Corn Starch 25.0 Milk
sugar 83,
3HPC (Nippon Soda Manufacturing Co., Ltd.) 1.2 total 12011v One tablet 120
■Tablets were prepared.

Formulation example 2 (capsule) Lactose 15
3.6 Corn starch 100
．． 0 total 280■

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a halogen atom,
R^2 represents a lower alkyl group, an aryl group, or a heterocyclic group; R^1 and R^2 may each form a hydrocarbon ring together with adjacent carbon atoms; and R^3 is a hydrogen atom. or represents a lower alkyl group, and R^4 represents a lower alkyl group. Further, R^3 and R^4 may be taken together to form an alicyclic amino group with each adjacent nitrogen atom. ) A central muscle relaxant containing as an active ingredient an isoxazolin-3-one derivative or a pharmacologically acceptable acid addition salt thereof.