JPH029818A - Central muscle relaxant containing piperazine derivative - Google Patents

Abstract

PURPOSE:To obtain a central muscle relaxant having low toxicity and excellent central muscle relaxing action by using a piperazine derivative or its salt as an active component. CONSTITUTION:The objective drug can be prepared by using a piperazine derivative of formula [R<1> is H, lower alkyl or (substituted) aryl or benzyl; R<2> is (substituted) benzyl, carboxymethyl, lower alkoxycarbonylmethyl, etc.], or its salt as an active component, properly compounding with an excipient, binder, disintegrant, lubricant, flavor, etc., as necessary, and forming to a drug preparation by conventional method. It can be used in the form of tablet, capsule, granule, powder, syrup, injection, suppository, etc., and administered at a rate of 5-50mg daily for adult in 1-3 divided doses in the case of oral administration. It is effective to sequela of cerebral apoplexy, sequela of head lesion, contusion rachioplegia, sequela of lesion, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a central muscle relaxant containing a Vipera, Syn derivative represented by the general formula (1) 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. For this reason, it is desired to develop a central muscle relaxant that relieves these muscle rigidities or spasticity and does not cause drowsiness.

[Problem to be solved by the invention]

In the process of searching for chemical substances for these purposes, the present inventors discovered that a piperazine derivative having the general formula (11) has a strong central muscle relaxant effect, and it has been used as a central muscle relaxant. The present invention was completed after confirming its usefulness.

[Structure of the invention]

The novel central muscle relaxant of the present invention has the general formula (wherein R1 represents a hydrogen atom, a lower alkyl group, an aryl group which may have a substituent, or a benzyl group which may have a substituent, R2 represents a benzyl group which may have a substituent, a carboxymethyl group, a lower alkoxycarbonylmethyl group, a substituted, a carbamoylmethyl group which may have a substituent) or a pharmacologically acceptable piperazine derivative thereof. The active ingredient is salt.

In the compound having the general formula (R) used in the present invention, R1 is preferably a hydrogen atom; Branched alkyl group having 1 to 4 carbon atoms: alkyl group having 1 to 3 carbon atoms in the aromatic ring such as methyl, ethyl, n-propyl, isozorobyl, methoxy, ethoxy, n-propoxy, Alkoxy group having 1 to 3 carbon atoms such as impropoxy; fluorine, chlorine, bromine, etc.), rogene atom: having a nitro group, an amino group, or a lower aliphatic acylamino group such as acetylamino or propionylamino An aryl group such as phenyl, which has or does not have a substituent; a benzyl group which has or does not have the same substituent as the substituent of the aryl group.

R2 is a pennor group which has or does not have the same substituent as the substituent of the aryl group of R1: Cal? Oxymethyl group: methoxymergonylmethyl, ethoxycarbonylmethyl,
Having a linear or branched chain alkoxy moiety having 1 to 4 carbon atoms such as n-propoxycarbonylmethyl, impropoxycarbonylmethyl, n-butoxycarbonylmethyl, isozotoxyrudenylmethyl, and tart-butoxycarbonylmethyl. Alkoxylgenylmethyl group, carbamoylmethyl group; methylcarbamoylmethyl, ethylcarbamoylmethyl% n-furobylcarbamoylmethyl, isopropylcarbamoylmethyl, n-butylcarbamoylmethyl, inbutylcarbamoylmethyl, dimethylcarbamoylmethyl, diethylcarbamoylmethyl, dipropylcarbamoylmethyl ,・
It represents a carbamoylmethyl group substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, such as isopropylcarbamoylmethyl, butylcarbamoylmethyl, and noisobutylcarbamoylmethyl.

The following compounds can be exemplified as suitable compounds for piperazine derivatives having the general formula (11).

(113,5-dioxopiperazine-1-acetic acid (2)
3.5-Dioxobiperason-1-acetamide (3) l-benzyl-3,5-nooxobiperazine The pharmacologically acceptable salt of the piperazine derivative represented by the above general formula (1) is , salts of alkali metals and alkaline earth metals, such as sodium, potassium, magnesium, and calcium salts, such as cargenate metal salts;
Examples include aluminum salts, mineral acid salts such as hydrochloride, hydrobromide, sulfate, oxalate, lactate, citrate, methanesulfonate, and benzenesulfone, which are amine salts. It can open organic acid salts such as acid salts.

The piperazine derivatives having the general formula +11, which are the active ingredients of the present invention, are produced according to methods described in the literature. For example, compound (1) can be synthesized by the reaction of nitrilotriacetic acid and carbamate ester, as described in Reference Examples, and compound (2) can be synthesized by Chem, Abst,
14, 3664 (1920).

〔Effect of the invention〕

According to pharmacological and toxicological tests, the compound having the general formula +11 of the present invention exhibits excellent central muscle relaxant action and is a compound with low toxicity.The following describes these tests in detail. do.

Method: Rats were placed under stereotaxic anesthesia using a stereotaxic apparatus (S
R-5, Narishige) and the mesencephalic reticular formation (AP:O).
, L: ±1.5, H: -3,0), diameter 0.7
In the city, Pellegrin electrodes are insulated except for one tip.
.

brain maps (L, J, Pellegrino, A,
S, Pellegtrin.

and A, J, CuS111LINan: A
5tereotaxic At1as of theR
at Brain, Plenum Press, N
ew York and London (1967)
It was inserted bilaterally according to :). A high frequency (100 kHz, 10-20 mA) current was applied from a region generator (LM4A, manufactured by Glass Co., Ltd.) through this electrode.
The site was electrocauterized for ~3 minutes.

Note that a clip was used as an indifferent electrode at this time by inserting it into the scalp lining. Thereafter, the animal was immediately removed from the stereotaxic apparatus, 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 1.5
After waiting for the animal to emerge from anesthesia over time, it was fixed on a homemade hindlimb fixation device. After fixing the bases of the front ankles of both hind legs of the animal, the animal's ankles were pressed by a distance of 4 mm for 6 seconds per minute, and the repulsive force of the insect removal was transmitted through an FD pickup (Nihon Kohden). Drawn on a polygraph.

The test compound was suspended in a 0.510 MC solution and administered intragastrically (p, o) or intravenously (i, v, ) via a cannula inserted in advance.

A: The results are summarized in Table 1.

Table 1: Relaxation effect on rat decerebrate rigidity (control compound) Ebilicin hydrochloride 50 p, o, 50 30 minutes. It is clear that Shiwake Compound (3) alleviates decerebrate rigidity in rats, which is said to be a human spasticity model, to the same or better extent than epilysine hydrochloride, which is already used clinically as a therapeutic agent for after-effects such as cerebral circulation disorders. was made into

2. Acutely toxic compounds (1) and (3) were suspended in a 0.5% CMC solution, and 300 q/ni were intraperitoneally administered to 5 DDY male adult mice (body weight 20-252). We observed it for several days, but the goldfish survived.

Furthermore, when compound (1) was injected at 50 η/kg and 30 minutes later, thiobental sodium was injected 9 times intravenously at 30 η/kg, and the duration of anesthesia was not significantly prolonged. On the other hand, the duration of anesthesia with thiobental sodium, which was measured 5-15 minutes after administration of epilysine hydrochloride (100μ, p, o,), was significantly prolonged,
g, p, o, ) After administration, the same anesthesia duration studied at 1 hour was also significantly prolonged.

As explained above, the compound having the general formula fil does not induce drowsiness, has extremely low toxicity, has a central muscle relaxing effect, and is rapidly absorbed by oral or intraperitoneal administration. , which leads to the manifestation of the effect. 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.

Furthermore, spasticity can be treated as spinal cord palsy, cervical spondylosis after-effects (including spinal cord tumors), and trauma sequelae (spinal cord injury, head trauma).
, amyotrophic lateral sclerosis, cerebral palsy, medullocerebellar degeneration, medullary vascular disease, SMON (5IJON), diving disease,
It is also useful for spastic paralysis and generalized cramps caused by other brain disorders, as well as muscle hypertonia caused by stiffness. 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 prepared using known adjuvants commonly used in the field of pharmaceutical formulation technology, such as excipients, binders, disintegrants, lubricants, and flavoring agents, in addition to crude drugs according to conventional methods. The dosage varies depending on the symptoms, age, body weight, etc., but when administered orally, it is usually administered to adults at 5 times a day.
11 #y to 50 #y can be administered 181 to 3 times.

Next, a more specific explanation will be given with reference examples and formulation examples.

Add ethyl carbamate 1oo,or (1,12 mol) to nitrilotriacetic acid so,or (o2s mol),
After stirring at 155-165°C for 6 hours, it was allowed to cool, and water was added to
00N was added and left in the refrigerator (5°C) for 2 days. The precipitated crystals were collected, washed with water, and recrystallized from a dioxane-ethanol mixture to obtain the desired product 20.11 (44.9 cm) as a colorless powder having a melting point of 168 to 170°C.

Infrared absorption spectrum & (KBr)Cm-”: 3700
~2200(-C02H), 3200.3150, 31
00 (NH), 1742.1702 (Doo-○--8-N
) Nuclear magnetic resonance spectrum (DMSO-d6) δppm=3
．． 47 (2HX2, s), 3.36 (2H, s
), 10.83-11.50 (IH, b) Formulation Example 1 Tablet 3.5-dioxobiberanone-1-acetic acid 1
0.0 ■ Corn starch
25.0 lactose
83.3RPC (manufactured by Nippon Soda) 12 Magnesium stearate 0.5 total 120 ■ One tablet of the above formulation is 120
■Tablets were prepared.

Formulation Example 2 Capsule 1-benzyl-3,5-dioxohyheracin 1
0.0η lactose
168.6 corn starch
1000 Magnesium Stearate
1.4 A total of 280 μg of the above-mentioned powder was mixed and passed through a 60-mesh sieve, and 280 μg of this powder was placed in a No. 3 gelatin capsule to form a capsule.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is a hydrogen atom, a lower alkyl group, an aryl group that may have a substituent, or a substituent. R^2 represents a benzyl group that may have a substituent, a carboxymethyl group, a lower alkoxycarbonylmethyl group, or a carbamoylmethyl group that may have a substituent. A central muscle relaxant containing a piperazine derivative or a pharmacologically acceptable salt thereof.