JP2786683B2 - Glycol derivatives and their uses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an isoxazole-substituted glycol derivative having a muscle relaxing action represented by the following general formula (I).

[Problems to be solved by the invention]

Cerebral circulation disorders such as stroke are the number one cause of death,
Even after surviving a life, sequelae or sequelae of head trauma often develop hard muscle or spasticity, making rehabilitation difficult. Therefore, development of a central muscle relaxant without drowsiness that relieves muscular toughness or spasticity as a therapeutic agent for these disorders has been desired.

[Configuration of the invention]

The inventors of the present invention have found that, during the search for substances of the chemical formulas for such purposes, the isoxazole-substituted glycol derivative having the general formula (I) has a strong central muscle relaxing action. The present invention was confirmed to be useful as a muscular relaxant, and the present invention was completed.

The present invention has a general formula (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a benzyl group which may have a substituent or an aryl group which may have a substituent. ² is a hydrogen atom, a lower alkyl group, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent.) .

Preferred compounds used in the present invention include, in the general formula (I), R ¹ is a hydrogen atom; a halogen atom such as fluorine, chlorine and bromine; methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, te
straight or branched chain carbon number 1 such as rt-butyl
An alkyl group having from 2 to 4 linear or branched alkenyl groups having 2 to 4 carbon atoms, such as vinyl, allyl, 2-butenyl, and 2-methylallyl; An alkynyl group having 2 to 4 carbon atoms; an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl and isopropyl on the aromatic ring, and methoxy, ethoxy, n-propoxy and isopropoxy. A benzyl group having or not having an alkoxy group having 1 to 3 carbon atoms, a halogen atom such as fluorine, chlorine and bromine, a nitro group, an amino group or a lower aliphatic acylamino group such as acetylamino and propionylamino; And an aryl group such as phenyl having or not having the same substituent as the substituent of the benzyl group.

R ² is a hydrogen atom; a substituent of the same substituents benzyl group of said R ^1, an alkyl group having 1 to 4 carbon atoms exemplified the same linear or branched chain alkyl group of R ¹ Or a 5-membered ring having an oxygen atom, a sulfur atom or a nitrogen atom such as furyl, thienyl, thiazolyl, pyridyl or 6
A benzene ring having or not having the same substituent as the substituent of the benzyl group of R ¹ , which represents a heterocyclic group of a membered ring; or formed with a carbon atom to which R ¹ and R ² are respectively bonded; And a 6- to 7-membered fused hydrocarbon ring such as a cyclohexene ring and a cycloheptene ring.

Specific compounds represented by the general formula (I) obtained by the present invention include, for example, the following compounds.

In the compound having the general formula (I),
Includes optical isomers due to the presence of asymmetric carbon atoms.

The novel compounds according to the present invention can be prepared by the following methods.

In the above, hal represents a halogen atom, and R ¹ and R ² each have the same meaning as described above.

The reaction for obtaining the epoxide compound (III) in the first step is as follows:
The 3-hydroxyisoxazoles and epihalohydrin can be carried out according to the method described in JP-A-52-31070.

That is, the starting compound, 3-hydroxyisoxazoles (II) is reacted with epihalohydrin in the presence of a base (eg, sodium hydride, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate). (E.g., epibromohydrin, epichlorohydrin). The reaction is
In a suitable solvent (eg, water, methanol, ethanol,
Benzene, toluene, dimethylformamide) at 0 ° C
To about room temperature.

The reaction for obtaining the diol compound (I) in the second step is carried out by heating the epoxide compound (III) in an aqueous solution of an alkali carbonate or an alkali metal hydroxide in the presence of an organic solvent. As the organic solvent used,
Examples thereof include nitriles such as acetonitrile, alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. Potassium carbonate and sodium carbonate as the alkali carbonate of the reaction reagent and potassium hydroxide and sodium hydroxide as the alkali metal hydroxide can be exemplified. The reaction temperature is preferably around the reflux temperature of the reaction solution, and the reaction time is 30 minutes to 5 hours.

After completion of the reaction, the diol compound (I) is collected from the reaction mixture according to a conventional method. For example, if necessary, salt solution is added to the reaction mixture for salting out, extraction is performed with an organic solvent, the organic solvent layer is washed, dried, and the solvent is distilled off. It can be purified by a conventional method, for example, a recrystallization method, chromatography and the like.

〔The invention's effect〕

According to the pharmacological test, the compound having the general formula (I) of the present invention exhibits an excellent central muscle relaxing action.

 Hereinafter, those tests will be specifically illuminated.

1. Decerebrate rigidity and remission (rat)
−5, Narigemo) and fixed on the central reticular body (AP: O, L: ± 1.
5, H: -30), a brain map of Pellegrino et al. [LJ, Pellegrino, ASPellegr]
ino and AJCushman: A Stereotaxic Atlas of the Rat
Brain, Plenum Press, New York and London (1967)]
And inserted bilaterally according to Through this electrode, a high-frequency (1
(00 kHz, 10-20 mA) was applied for 2-3 minutes, and this site was electrically cauterized. At this time, a clip was sandwiched between the scalp intima as an indifferent electrode. Immediately thereafter, the animal was removed from the stereotaxic apparatus, a polyethylene cannula (Fr. 3) was inserted into the duodenum, and the animal was fixed with an adhesive. Immediately after these operations were completed, halothane anesthesia was stopped, and after 1.5 hours the animals were awake from anesthesia before being fixed on a homemade hind limb fixation device. The roots of the ankles of both hind limbs of the animal were fixed, and both footpads were pressed for 6 seconds per minute for a length of 4 mm.
Draw on a polygraph via D-Pick-up (Nihon Kohden).

The test compound was suspended in a 0.5% CMC solution and administered into the duodenum (id) or stomach (po) or intraperitoneally (ip) via a pre-inserted cannula.

Results: The results are listed in Table 3.

As described above, the compound having the general formula (I) does not induce drowsiness and has a central muscle relaxant effect, and is rapidly absorbed by oral administration, intraduodenal or intraperitoneal administration. Thus, the action is manifested. From the animal experiments described above, oral administration is possible clinically, but it is especially useful as a central muscle relaxant for stroke sequelae and head-traumatic sequelae. In addition, spastic spinal palsy, sequelae of cervical spondylomyelitis (including cerebral spinal cord tumor), sequelae of trauma (spinal cord injury, head trauma), amyotrophic lateral sclerosis, cerebral palsy, spinocerebellar degeneration, spinal cord It is also useful for muscular hypertonia such as spastic paralysis due to vascular disorders, SMON, sickness, and other cerebrospinal diseases and systemic swelling and shoulder stiffness. Examples of the administration form include oral administration methods such as tablets, capsules, granules, powders, and syrups, and parenteral administration methods such as injections and suppositories. These various preparations are prepared by using known auxiliaries which can be usually used in the technical field of pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, and flavoring agents according to the purpose according to the purpose according to the conventional method. Can be
The dosage varies depending on the condition, age, body weight, etc., but in the case of oral administration, usually 5 to 50 mg can be administered to an adult once to three times a day.

Next, the present invention will be described specifically with reference to Production Examples, Preparation Examples and Reference Examples.

Production Example 1 Synthesis of 5-chloro-3- (2,3-dihydroxypropyloxy) -1,2-benzisoxazole 5-chloro-3- (2,3-epoxypropyloxy)
A suspension of 21.0 g (92.7 mmol) of acetonitrile (100 ml) in 1,2-benzisoxazole (prepared according to the method described in JP-A-52-31070) was treated with 10% potassium carbonate (256 m
l) and heat to reflux for 3 hours. After cooling, add water (5
The reaction mixture was extracted with ethyl acetate (1000 ml), and the ethyl acetate layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solid residue obtained by evaporating the solvent under reduced pressure was recrystallized with a mixed solvent of ethyl acetate-ethyl ether to obtain 16.7 g of a colorless powdery substance having a mp of 61 to 62 ° C ( 7
4.2%).

Infrared absorption spectrum (KBr) cm ^-1 ; 3410 (OH), 1600, 1539 (C = N, Ar); Nuclear magnetic resonance spectrum (CDCl ₃ ) δ ppm; 2.90 (1H × 2, b-s); 3.60 4.00-4.40 (1H, m); 4.52 (2H, d, J = 4.5); 7.20-7.70 (3H, m).

Production Example 2 Synthesis of 5- (m-chlorophenyl) -3- (2,3-dihydroxypropyloxy) isoxazole 5- (m-chlorophenyl) -3- (2,3-epoxypropyloxy) isoxazole (Reference Example) 1) 15.0g
(59.6 mmol) was dissolved in acetonitrile (50 ml) and 10%
100 ml (72.3 mmol) of potassium carbonate solution is added, and the mixture is heated under reflux for 3 hours. After allowing to cool, 10% saline (400 ml) was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate (400 ml × 2), and the ethyl acetate layer was dried over anhydrous magnesium sulfate.
The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel chromatography (developing agent; benzene / ethyl acetate = 1/2) to give a colorless liquid having an mp of 92 to 93 ° C.
13.2 g (82.5%) of the desired product as a powder crystal was obtained.

Infrared absorption spectrum (KBr) cm ^-1 ; 3370 (OH), 3105 (Hetro-H).

Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ ppm; 3.30 to 3.70 (2H, m), 3.70 to 4.10 (1H, m), 4.00 to 4.50 (2H, m), 4.56 (1H, t, J = 4.5), 5.06 (1H, d, J = 4.5), 6.93 (1H, s), 7.43 to 8.06 (4H, m).

The reaction was carried out in the same manner as in Production Example 2 to produce the following compound.

Production Example Capsule 5- (m-chlorophenyl) -3- (2,3-dihydroxy) isoxazole 25.0 mg (Compound of Production Example 2) Lactose 153.6 mg Corn starch 100.0 mg Magnesium stearate 1.4 mg Total 280 mg After mixing the prescribed powder and passing through a 60-mesh sieve, 280 mg of this powder was placed in a No. 3 gelatin capsule to form a capsule.

Reference Example 1 Synthesis of 5- (m-chlorophenyl) -3- (2,3-epoxypropoxy) isoxazole 30.0 g (0.153 mol) of 5- (m-chlorophenyl) -3-hydroxyisoxazole in dimethylformamide (300 ml) 29.6 g (0.153 mol) of sodium methoxide (28% methanol solution) is added to the solution, and the mixture is stirred at room temperature for 30 minutes, and 41.9 g (0.306 mol) of epibromohydrin is added dropwise. After further stirring at room temperature for 3 days, the reaction solution was concentrated under reduced pressure, and ethyl acetate (500 ml) was added to the resulting residue.
After washing with 0% salt (800 ml), the ethyl acetate layer is dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel chromatography (developing agent; benzene / ethyl acetate = 2/1) to recrystallize a solid obtained with isopropyl ether. mp86 ~
23.6 g (73.5%) of the target substance as colorless and needle-like crystals having a temperature of 87 ° C. was obtained.

Infrared absorption spectrum (KBr) cm ^-1 ; 3120 (Hetro-H), 1620, 1593 (C = N, Ar).

Nuclear magnetic resonance spectrum (CDCl ₃ ) δ ppm; 2.72 (1H, AB-d, d, J = 4.5, 3.0), 2.88 (1H, AB-d, d, J = 4.5, 4.5), 3.26 to 3.50 (1H, m), 4.18 (1H, AB-d, d, J = 12.0, 6.0), 4,58 (1H, AB-d, d, J = 12.0, 3.0), 6.20 (1H, s), 7.23 to 7.83 ( 4H, m).

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 417/04 C07D 417/04 (56) References Patent 2667505 (JP, B2) Patent 2565543 (JP, B2) (58) Searched Field (Int. Cl. ⁶ , DB name) REGISTRY (STN) CA (STN)

Claims (2)

(57) [Claims] (1) General formula (In the formula, R ¹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a benzyl group which may have a substituent or an aryl group which may have a substituent. ² represents a hydrogen atom, a lower alkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ¹ and R ² together with the carbon atom to which they are attached May form a condensed hydrocarbon ring). 2. A central muscle relaxant comprising the isoxazole-substituted glycol derivative according to claim 1 and a salt thereof as an active ingredient.