JP2582402B2 - Isoxazolin-3-one derivatives and uses thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an isoxazolin-3-one derivative represented by the following general formula (I), which has a muscle relaxing action and a brain function improving action.

[Conventional technology]

Cerebral circulation disorders such as stroke are the number one cause of death,
Even after a lifetime, sequelae or sequelae of head trauma often develop hard muscle or spasticity, making rehabilitation difficult. For this reason, there is a demand for the development of therapeutic agents (cerebral function improving agents) for these disorders and central muscle relaxants without sleepiness that relieve muscle hardening or spasticity.

[Problems to be solved by the invention]

The present inventors have found that the isoxazolin-3-one derivative having the general formula (I) exerts a strong central muscle relaxing action and an anti-cerebral ischemic action in the course of searching for a chemical substance meeting such a purpose. The present invention has been found to be useful as a central muscle relaxant and a brain function improving agent, and the present invention has been completed.

[Configuration of the invention]

The present invention has the general formula (Wherein, R ¹ represents 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, R ² represents a hydrogen atom, A lower alkyl group, an aryl group, or a heterocyclic group, wherein R ³ and R ⁴ are the same or different and each have a hydrogen atom, a lower alkyl group, a benzyl group which may have a substituent, Or a cycloaliphatic amino group formed by R ³ and R ^{4 taken} together with the adjacent nitrogen atom.)
On derivatives and acid addition salts thereof.

In the general formula (I), preferably, R ¹ is a straight-chain or branched-chain carbon number 1 to 1 such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. An alkyl group having 4; a linear or branched alkenyl group having 2 to 4 carbon atoms such as vinyl, allyl, 2-butenyl, and 2-methylallyl; such as ethynyl and 2-propynyl; An alkynyl group having 2 to 4 carbon atoms; for example, an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl and isopropyl on an aromatic ring, methoxy, ethoxy, n-propoxy and isopropoxy. An alkoxy group having 1 to 3 carbon atoms, a halogen atom such as fluorine, chlorine or bromine, or a benzyl group having or not having a nitro group 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 An aryl group such as phenyl with or without a phenyl or a 5- or 6-membered heterocyclic group having an oxygen atom, a sulfur atom or a nitrogen atom such as furyl, thienyl, thiazolyl and pyridyl.

R ³ and R ⁴ are hydrogen atoms; the same linear or branched alkyl group having 1 to 4 carbon atoms as exemplified for the alkyl group for R ¹ ; the same as the substituent for the benzyl group for R ¹ above Aryl groups such as benzyl or phenyl, with or without substituents of the formula: or R ³ and R ^{4 taken} together to form together with adjacent nitrogen atoms, for example morpholino, 1-
It may represent a 5- or 6-membered alicyclic amino group such as piperazinyl, 4-methyl-1-piperazinyl, 1-pyrrolidinyl, piperidino.

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

Examples of the acid addition salt of the isoxazolin-3-one derivative having the general formula (I) include mineral salts such as hydrochloride, hydrobromide and sulfate, or oxalate and lactate, for example. Organic salts such as citrate, tartrate, succinate, maleate, fumarate, methanesulfonate can be mentioned.

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 formula, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, and Z represents a halogen atom such as chlorine, bromine and iodine.

In carrying out the present production method, the reaction is represented by the general formula (II)
By condensing the isoxazolin-3-one derivative represented by the formula with an amine represented by the formula (III) in the presence of a base. The amines used include ammonia, aliphatic primary or secondary amines, and cyclic amines as described above.

Examples of the base used in the reaction include alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as potassium methoxide and sodium ethoxide. And alkali metal carbonates such as sodium carbonate and potassium carbonate. Also,
Although the solvent used is not particularly limited, methanol, ethanol, n-propanol, isopropyl alcohol,
alcohols such as n-butanol, benzene, toluene, aromatic hydrocarbons such as xylene, acetone,
Ketones such as methyl butyl ketone and methyl amyl ketone, and halogenated hydrocarbons such as tetrachloroethane, chlorobenzene and dichlorobenzene are used.
The reaction temperature is not particularly limited, but is in the range of 0 ° C to 150 ° C, preferably 20 ° C to 130 ° C. The reaction time varies depending on the type of the starting compound and the reaction temperature, but is usually 1 to 4 hours. After completion of the reaction, the target compound (I) is collected from the reaction mixture according to a conventional method. For example, if the target compound precipitates from the reaction system, take it off.If it is in the form of a solution, distill off the solvent, dissolve the residue in a solvent that is difficult to mix with water, wash with acid and water, and evaporate the solvent. The compound can be purified by a conventional method, for example, a recrystallization method, a vacuum distillation method, or chromatography if necessary.

The obtained target compound of the present invention can be converted into an acid addition salt according to a conventional method, if necessary.

The isoxazolin-3-one derivative having the above general formula (II), which is a starting compound of the present invention, is disclosed in
It can be synthesized according to the method described in JP 83766.

〔The invention's effect〕

According to the pharmacological test and the toxicity test, the compound having the general formula (I) of the present invention exhibits excellent central muscle relaxant action and anti-cerebral ischemic action and has low toxicity. These tests will be described specifically.

1. Decerebrate rigidity relieving action Method: Brain stereotaxic device (SR)
−5, Narigemo) and fixed on the mesencephalic reticulum (AP: 0, L: ± 1.
5, H: -3.0) and a brain map of Pellegrino et al. [LJPelleg-rino, ASPel
legrino and AJCushman: A Stereotaxic Atlas of the
Rat Brain. Plenum Press, New York and London (196
7)] and inserted bilaterally. A high-frequency (100 KHz, 10 to 20 mA) current was passed from a region generator (JM4A, manufactured by Glass Co., Ltd.) through this electrode for 2 to 3 minutes, and the site was electrically cauterized. In this case, 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 fixed with an adhesive. Immediately after these operations were completed, halothane anesthesia was stopped and the animals were awake from anesthesia after 1.5 hours and 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 4 seconds for 6 seconds per minute, and the repulsive force generated at that time was polygraphed via ED pick-up (Nihon Kohden). Pictured above.

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 previously inserted cannula.

 Results: The results are listed in Table 1.

2. Brain function improving effect Male gerbil (20 weeks old) Mongolian gerbil (Mongolian Cerbil)
Was used for 20 animals per group. Pentobarbital (30mg / kg,
ip) and halothane (1.5% mixed in a gas mixture of 95% oxygen and 5% carbon dioxide).
The occlusion was released for a minute, after which the occlusion was released and blood flow resumed.
Next, the animal was left standing in a dorsal position, and the time from the resumption of blood flow until the occurrence of convulsions and the survival time were measured. The time of onset of convulsions was observed up to 6 hours after resumption of blood flow, and the survival time was observed up to 7 hours after resumption. If no convulsions occurred within 6 hours, it was calculated as 360 minutes, and if it did not die within 7 hours, the survival time was calculated as 420 minutes. The test compound was suspended in a 0.5% CMC solution and administered intraperitoneally when the common carotid artery blood flow was resumed.
On the other hand, a 0.5% CMC solution as a vehicle was similarly administered to the control group. Statistical analysis was performed using the Mann-Whitney U-test between the control group and the test compound administration group for each of the above times, and it was found that 2- (2-hydroxy-
3-morpholinopropyl) -4-methyl-5-phenyl-4-isoxazolin-3-one hydrochloride at a dose of 100 mg / kg significantly increased both the onset of convulsion and the survival time caused by cerebral ischemia ( P <0.01).

3.Acute toxicity Compound 13 hydrochloride is dissolved in 0.5% CMC solution and 500mg / kg
And 1000 mg / kg were orally administered to three mice and observed for 5 days. As a result, all the animals survived.

As described above, the compound having the formula (I) has extremely low toxicity and has a central muscle relaxing action and an action of protecting the brain from ischemia without inducing drowsiness,
It is absorbed promptly by oral administration or by intraduodenal or intraperitoneal administration, resulting in the onset of action. From the animal experiments described above, oral administration is possible clinically, but it is particularly useful as a central muscle relaxant for sequelae in brain fraction and head-traumatic sequelae. Also, spastic spinal palsy, sequelae of spastic spondylosis (including cerebrospinal tumors), sequelae of trauma (spinal cord injury, head trauma), amyotrophic lateral sclerosis,
It is also useful for hypertonia such as cerebral palsy, spinocerebellar degeneration, spinal vascular disorders, spontaneous paralysis due to SMON (smon), diving sickness, other cerebrospinal diseases, and systemic cramping disease and stiff shoulders.

Further, it is also useful as a brain function improving agent in the treatment of acute and chronic stroke, or in the treatment after brain surgery due to brain tumor, head injury and the like.

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 may contain known auxiliaries which can be usually used in the technical field of pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, and flavoring agents, depending on the purpose, according to the purpose. Can be used to formulate. The amount used depends on the condition, age, body weight, etc., but in the case of oral administration, usually 5 to 50 mg per day can be administered to an adult once to three times a day.

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

Production Example 1. 2- (2-hydroxy-3-morpholinopropyl) -4
-Methyl-5-phenyl-4-isoxazoline-3-
Synthesis of ON 2- (3-chloro-2-hydroxypropyl) -4-
In a solution of 4.00 g (14.9 mmol) of methyl-5-phenyl-4-isoxazolin-3-one in 50 ml of ethanol, 1.55 g (17.9 mmol) of morpholine and anhydrous potassium carbonate powder
2.46 g (17.9 mmol) is added, and the mixture is refluxed for 4 hours. After cooling, insoluble materials were removed, and the residue obtained by concentrating the solution under reduced pressure was subjected to silica gel column chromatography (developing agent; 5%
Purification with methanol / ethyl acetate) yielded ▲ n ²⁴ ₀ ▼ 1.57
Colorless candy-like target compound showing 40 2- (2-hydroxy-
4.21 g (83.5%) of 3-morpholinopropyl) -4-methyl-5-phenyl-4-isoxazolin-3-one were obtained.

Infrared absorption spectrum (CHCl ₃ ) cm ^-1 ; 3400 (OH), 1660
(Sh), 1645 (C = O): nuclear magnetic resonance spectrum (CDCl ₃ ) δ ppm; 2.10 (3H, s);
2.23 to 2.83 (2H x 3, m); 3.70 (2H x 2, t, J = 4.5); 3.93
(1H, b-s); 4.10 (2H, d, J = 3.0); 3.80-4.30 (1H,
m); 7.26 to 7.83 (5H, m): Production Example 2. 2- (2-hydroxy-3-morpholinopropyl)-
4-methyl-5-phenyl-4-isoxazoline-3
-One hydrochloride 2- (2-hydroxy-3-morpholinopropyl)-
4-methyl-5-phenyl-4-isoxazoline-3
4N in a solution of 2.50 g (7.4 mmol) of -one in ethanol (25 ml)
After adding 2.00 ml of a HCl / dioxane solution and stirring at room temperature for 3 hours, the precipitated crystal was collected, washed with isopropanol (10 ml), recrystallized with ethanol, and obtained as a colorless powder having a mp of 130 to 133 ° C. 2.30 g (87.7%) of 2- (2-hydroxy-3-morpholinopropyl) -4-methyl-5-phenyl-4-isoxazolin-3-one hydrochloride were obtained.

Infrared absorption spectrum (KBr) cm ^-1 ; 3700 to 3100 (-O
H), 1646 (C = 0): nuclear magnetic resonance spectrum (D ₂ O) δ ppm; 2.40 (3H, s), 3.
60 to 4.10 (2H x 3), 4.44 (2H, d, J = 4.5), 4.53 (2H x
2, t, J = 4.5), 4.83-5.23 (1H, m), 7.86-8.26 (5H, m) In the same manner as Production Examples 1 and 2, the following Production Examples 3-9
Was obtained.

Formulation Example Capsule 2- (2-hydroxy-3-morpholinopropyl)-
4-methyl-5-phenyl-4-isoxazoline-3
-One hydrochloride (Compound 13 hydrochloride) 25.0 mg Lactose 153.6 Maize starch 100.0 Magnesium stearate 1.4 Total 280 mg Mix the powder of the above formulation, pass through a 60 mesh sieve, and 280 mg of this powder into No. 3 gelatin capsule Into a capsule.

Reference Example 2- (3-chloro-2-hydroxypropyl) -4-
Synthesis of methyl-5-phenyl-4-isoxazolin-3-one 3-hydroxy-4-methyl-5-phenyl-isoosasol 6.00 g (34.2 mmol) and epichlorohydrin 6.33 g
(68.4 mmol), and the mixture is heated and stirred at 75 ° C. for 5 hours. The residue obtained by evaporating excess epichlorohydrin under reduced pressure is purified by silica gel column chromatography (developing agent; cyclohexane: ethyl acetate = 2: 1) to obtain mp82-8.
6.51 g (71.1 g) of colorless powdery crystals having a temperature of 3 ° C. were obtained.

Infrared absorption spectrum (KBr) cm ^-1 ; 3265 (OH), 1651, 16
37 (C = 0) Nuclear magnetic resonance spectrum (CDCl ₃ ) δ ppm; 2.10 (3H, S),
3.40 to 3.83 (2H, m), 4.23 (2H, d, J = 3.0), 3.90 to 4.50
(1H, m), 4.63 (1H, bs), 7.30-7.83 (5H, m)

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07D 413/04 213 C07D 413/04 213 333 333

Claims (2)

(57) [Claims] (1) General formula (Wherein, R ¹ represents 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, R 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, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a lower alkyl group, A benzyl group which may have a group, an aryl group which may have a substituent, or an alicyclic amino group formed by R ³ and R ⁴ together with an adjacent nitrogen atom.) The isoxazoline-3-represented
On derivatives and salts thereof. 2. The isoxazoline-3 according to claim 1,
A central muscle relaxant containing an -one derivative and a salt thereof as an active ingredient;