JPH01249759A - Isoxazolin-3-one derivative and use thereof - Google Patents

Abstract

NEW MATERIAL:An isoxazolin-3-one derivative shown by formula I [R<1> is lower alkyl, lower alkenyl, lower alkynyl, (substituted) benzyl, (substituted)aryl; R<2> is H, lower alkyl, (substituted)aryl or (substituted)heterocyclic group; R<3> and R<4> are the same or different, H, lower alkyl, (substituted)aryl, (substituted) benzyl or R<3> and R<4> together with adjacent N form alicyclic amino)] and a salt thereof. EXAMPLE:2-(2-Hydroxy-3-morpholinopropyl)-4-methyl-5-phenyl-4-isoxazoli n-3-one. USE:Useful as a central muscle relaxant and a cerebral function improver having low toxicity, capable of being orally administered. PREPARATION:Iso-oxazolin-3-one shown by formula II is condensed with an amine shown by formula III in the presence of an amine to give a compound shown by formula I.

Description

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

[Conventional technology]

Cerebral circulation disorders such as stroke are the number one cause of death, and -
Even if the patient survives, he develops muscular stiffness or spasticity as an aftereffect of head trauma, making rehabilitation difficult. For this reason, it is desired to develop a therapeutic agent (brain function improving agent) for these disorders and a central muscle relaxant that relieves muscle rigidity or spasticity and does not cause drowsiness.

[Problem that the invention seeks to solve]

In the process of searching for chemical substances for these purposes, the present inventors discovered that isoxazolin-3-one derivatives having general formula (1) have strong central muscle relaxant and anti-cerebral ischemic effects. The present invention was completed by discovering that the compound has the following properties and confirming that it is useful as a central muscle relaxant and a brain function improving agent.

[Structure of the Invention] - The present invention is based on the general formula (wherein R1 is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a benzyl group that may have a substituent, or a benzyl group that may have a substituent) represents an aryl group, R2 represents a hydrogen atom, a lower alkyl group, an aryl group, or a heterocyclic group, and R3 and R4 are the same or different and may have a hydrogen atom, a lower alkyl group, or a benzyl group which may have a substituent. group, an optionally substituted group, or R3 and R4
together indicate an alicyclic amine group that they form with the adjacent nitrogen atom. ) and its acid addition salts.

In the general formula (t), R1 is preferably a linear or branched chain having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. an alkyl group having one carbon number; for example, a linear or branched alkenyl group having one carbon number of 2 to 4 such as vinyl, allyl, 2-butenyl, 2-methylallyl; for example, ethynyl, 2-propynyl, Alkynyl group having 2 to 4 carbon atoms such as: For example, an alkyl group having 1 to 3 carbon atoms in the aromatic ring such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, impropoxy an alkoxy group having 1 to 3 carbon atoms, such as
Benzyl group with or without a halogen atom such as fluorine, chlorine, or bromine, or a nitro group: Refers to an aryl group such as phenyl that has or does not have the same substituent as the above-mentioned benzyl group.

R2 is a hydrogen atom; the same linear or branched alkyl group having 1 to 4 carbon atoms as the example of the alkyl group in R1; or the same substituent as the benzyl group in R1 Does not have an aryl group such as phenyl or furyl, thienyl.

Represents a 5- or 6-membered heterocyclic group having an oxygen atom, sulfur atom, or nitrogen atom, such as thiazolyl and pyridyl.

R3 and R4 are hydrogen atoms; the same linear or branched alkyl group having 1 to 4 carbon atoms as the example of the alkyl group in R1; the same substituent as the benzyl group in R1; aryl groups such as benzyl or phenyl with or without: or R3 and R4 taken together to form them with the adjacent nitrogen atoms, e.g. morpholino, 1-piperazinyl, 4-methyl-1-piperazinyl, 1 - May represent a 5- or 6-membered alicyclic amino group such as pyrrolidinyl or piperidino.

Specific examples of the compound represented by the general formula e obtained by the present invention include the compounds described below. Examples of the acid addition salt of the isoxazolin-3-one derivative having the general formula (1) include mineral acid salts such as hydrochloride, hydrobromide, and sulfate, or e.g. oxalate and lactic acid salts. salt, citrate, tartrate,
Mention may be made of organic acid salts such as succinate, maleate, fumarate, methanesulfonate.

Note that the compound having the general formula (11) includes optical isomers due to the presence of an asymmetric carbon atom.

The novel compound according to the present invention can be produced by the method shown below.

H (1)
(Seal) J1-1 In the above formula, R1, 'R2, R3 and R4 have the same meanings as described above, and 2 represents a halogen atom such as chlorine, bromine, or iodine.

In carrying out this production method, the reaction is carried out by condensing an isoxazolin-3-one derivative represented by general formula (1) with an amine represented by general formula (2) in the presence of a base.

The amines used include ammonia, aliphatic or secondary amines, or cyclic amines as described above.

Bases used in the reaction include, for example, alkali metal hydrides such as sodium hydride, sodium hydroxide,
Preferred are alkali metal hydroxides such as potassium hydroxide, alkali metal alkoxides such as potassium methoxide and sodium ethoxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. The solvent used is not particularly limited, but methanol, ethanol, n-propanol, isopropyl alcohol, n-
Alcohols such as butanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ketones such as acetone, methyl butyl ketone, and methyl amyl ketone, and halogens such as tetrachloroethane, chlorobenzene, and dichlorobenzene. Hydrocarbons are used. There is no particular limitation on the reaction temperature, but a range of 0°C to 150°C,
Preferably it is 20°C to 130°C. The reaction time varies depending on the type of raw material compound and the reaction temperature, but is usually 1 to 4 hours. After the reaction is complete, the target compound is collected from the reaction mixture according to a conventional method.For example, if the target compound precipitates out of the reaction system, it can be removed by removing P, or if it is in solution, the solvent can be distilled off. The residue can be obtained by dissolving the residue in a solvent that is difficult to mix with water, washing with acid and water, and then distilling off the solvent, and if necessary, using conventional methods such as recrystallization, vacuum distillation, etc. It can be purified by chromatography or the like.

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

In addition, the isoxazolin-3-one derivative having the above-mentioned formula (1), which is a raw material compound of the present invention, is disclosed in JP-A-55-
It can be synthesized according to the method described in Japanese Patent No. 83766.

〔Effect of the invention〕

According to pharmacological and toxicological tests, the compound of the present invention having the above-mentioned formula (rl) shows excellent central muscle relaxant action and cross-layer ischemic action, and is a compound with low toxicity. The test will be explained in detail.

1. Method of decerebrate rigidity-relaxing action: Rats were placed under halothane anesthesia using a stereotaxic apparatus (SR).
-5, Narishige) and the mesencephalic reticular formation (AP: 0.
L: main 1°5, H: -3,0), diameter 0711
Jl with an insulated electrode other than the tip 11IjI and Pelle
Grino et al.'s brain map (L, J, Pelleg
-rino, A, S, Pellegrino a
nd A, J, Cushman: A 5tere.
otaxic At1as of the Rat B
rain, PlenumPress, New Yo
rk and London (1967”)]
It was inserted bilaterally according to the instructions. A high frequency (100 KHz, 10 to 20 mA) current was applied from a region generator (LM4A, manufactured by Glass) for 2 to 3 minutes through this electrode to electrically cauterize this site. In addition,
At this time, a clip was used as an indifferent electrode placed on the lining of the scalp. Thereafter, the animal was immediately removed from the stereotaxic apparatus and a polyethylene cannula (Ft", 3
) was inserted and fixed with adhesive. After these surgeries were completed, the Yaguchisen anesthesia was immediately stopped, and after 1.5 hours had elapsed, the animals were allowed to wake up from the anesthesia, and then fixed on a homemade hindlimb fixation device. The base of the front ankles of both hind legs of the animal was fixed, and the heels of both feet were held at 4 tm for 6 seconds per minute.
The repulsive force of the insect repellent was drawn on a polygraph using an FD pick φ-up (Nihon Kohden).

The test compound was suspended in Q, 5% CMC solution and injected into the duodenum (i, d,
) or intragastric (p, o,) or intraperitoneal (t, pe
) was administered.

Results: Results are listed in Table 1.

Table 1 Suppressive effect on rat decerebrate rigidity 2, Male mature (20 weeks old) gerbil (Mongolian) for use as a brain function improving agent
GerbH) was used for 20 animals per group. Bendoparbital (31 v/b, 1.P) and halothane (1.5 g mixed in a gas mixture of 95 g oxygen and 5% carbon dioxide) were used to occlude both common carotid arteries for 3 minutes under anesthesia, and then The blockage was removed and blood flow resumed. Next, the animals were placed in a dorsal position, and the time from when blood flow resumed to the onset of convulsions and the survival time were measured. The onset time of convulsions was observed up to 6 hours after resumption of blood flow, and the survival time was observed up to the same time T. The survival time was calculated as 360 minutes if convulsions did not occur within 6 hours, and 420 minutes if death did not occur within 7 hours. The test compound was suspended in a 0.51 CMC solution and administered intraperitoneally at the time of resumption of striate artery blood flow.

On the other hand, in the control group, the vehicle Q,s% CM
C solution was administered in the same manner, and the Mann-Whitney
A stochastic analysis using the U-test of y revealed that 2-(2-hydroxy-3-morpholinopropyl)-
4-Methyl-5-phenyl-4-isoxazoline-3-
At a dose of 1oow9/kg, Ono hydrochloride significantly reduced both the onset latency and survival time of convulsions caused by cerebral ischemia (P
<o, ol) Extended.

λ Acutely toxic compound 13 hydrochloride was dissolved in a 0.5*CMC solution, and soow/kg and 1000IIf/- were orally administered to 3 mice and observed for 5 days. As a result, most of the mice survived.

As explained above, the compound having the formula (11) is
It does not induce drowsiness, has extremely low toxicity, has a central muscle relaxing effect and protects the brain from ischemia, and is rapidly absorbed and exerts its effects when administered orally, intraduodenumally, or intraperitoneally. This is what leads to its manifestation.

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), trauma sequelae (spinal cord injury, head trauma), amyotrophic lateral sclerosis, cerebral palsy, and medullocerebellar degeneration. It is also useful for spastic paralysis and generalized cramps caused by spinal cord vascular disorders, SMON (5M0N), diver's disease, and other spinal cord diseases, as well as muscular tension problems such as stiff shoulders.

Further, as a brain function improving agent, it is useful in the treatment of acute and chronic strokes, and in the treatment of brain tumors, head trauma, etc. after neurosurgery.

Examples of the administration form include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration using injections, suppositories, etc. These various preparations are made by adding excipients and excipients to the main drug according to the purpose according to conventional methods.
It can be formulated using known adjuvants commonly used in the field of pharmaceutical formulation technology, such as binders, disintegrants, lubricants, and flavoring agents. The dosage varies depending on symptoms, age, body weight, etc., but when administered orally, it is usually given to adults.
A single dose of 5wI to SOWg can be administered 1 to 3 times a day.

Next, the present invention will be explained in more detail with reference to production examples, formulation examples, and reference examples.

Production Example 1 Ethanol (50 l) solution of 2-(3-chloro-2-hydroxypropyl)-4-methyl-5-phenyl-4-isoxazolin-3-one 4.00 fl (14,9 rrmoJ) , morpholine 1.551 (17
, 9mrnol) and anhydrous potassium carbonate powder 2.4
611 (17.9 mmol) was added, and the mixture was heated under reflux for 4 hours. After cooling, insoluble materials were removed from P, and the P solution was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (
Purified with developer: 5-thimethanol/ethyl acetate),
Colorless candy-like object 2 showing nFJ' 1.5740
-(2-hydroxy-3-morpholinopropyl)-4-
4.21'l (83,5'1) of methyl-5-phenyl-4-isoxazolin-3-one were obtained.

・Infrared absorption spectrum (CHCl5)cIR-';
340G (OR), 1660 (sh)s 164
5 (C=O): Nuclear magnetic resonance spectrum (CDCl3
) δppm ; 2.10 (3H, @') ; 2.2
3 to 2.83 (2H x 3. m); 3.70 (21 (
X2. t, J=4.5); 3.93(IH,b
-5); 4.10 C2H, d, J=lO); 3
．． 80-4.30 (IH, m); 7.26-7.8
3 (5H, m): Production Example 2 2-(2-hydroxy-3-morpholinopropyl)-4
-Methyl-5-phenyl-4-isoxazoline-3-
On 2.50 g (7.4 mmol).

Add 2.00 g of 4N -HCI/dioxane solution to the ethanol (25 g/) solution and stir at room temperature for 3 hours. The precipitated crystals were collected with F, washed with isopropanol (10 m), and recrystallized with ethanol. te, mp130-13
The target product 2-(2-hydroxy-
3-morpholinopropyl)-4-methyl-5-phenyl-4-isoxazolin-3-one hydrochloride 2.309
I got (87,7 arrogance).

・Infrared absorption spectrum (KBr) cll-1;3
700-3100 (-OH), 1646 (C=0):・
Nuclear magnetic resonance spectrum (D20) δppm; 2.4
0(3H,s)+ 3.60~4.10 (2HX 3
), 4.44 (2H.

d, J=4.5), 4.53(2HX2.t,
J=4.5).

4.83-5.23 (IH, m), 7.86-8.
26 (5H, m) (Compound 13 hydrochloride) Lactose 15
&6 Corn Starch 100.0 Magnesium Stearate 1.
A total of 280 μg of the powder of the above formulation 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.

Reference Example 3-H) 6.339 (68.4 mmol) of epichlorohydrin was added to 6.00 f (34.2 mmol) of cuxi 4-methyl-5-phenylisoosazole, and the mixture was heated and stirred at 75°C for 5 hours. Excess epichlorohydrin was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing agent: Schiff).

Purification with lohexane:ethyl acetate=2:1) gave 6.51f (71
, 1ch) were obtained.

0 infrared absorption spectrum (KBr) ax-1; 326
5(OH), 1651.1637(C=O) Nuclear magnetic resonance spectrum CCDC15) δppm; 2.10 (
3H,S), 3.40-3.83 (2H,m),
4.23 (2H.

d, J=3.0), 3.90-4.50 (IH
, m), 4.63 (IH.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a lower alkyl group, a lower alkenyl group,
It represents a lower alkynyl group, a benzyl group which may have a substituent, or an aryl group which may have a substituent, and 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, 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 substituent,
Aryl group which may have a substituent, or R^3 and R^
4 taken together indicate an alicyclic amino group which they form with the adjacent nitrogen atom. ) isoxazolin-3-one derivatives and salts thereof. 2. A central muscle relaxant comprising the isoxazolin-3-one derivative and its salt according to claim 1 as an active ingredient. 3. A brain function improving agent containing the isoxazolin-3-one derivative and its salt according to claim 1 as an active ingredient.