JPH0249724A - Encephalon function improving agent containing isooxazole derivative - Google Patents

Abstract

PURPOSE:To obtain a encephalon function improving agent containing isooxazole derivative or acid addition salt thereof as an active ingredient. CONSTITUTION:The aimed encephalon function improving agent containing a compound expressed by the formula (R<1> is H, halogen, lower alkyl, lower alkenyl, lower alkynyl, benzyl, aryl, etc.; R<2> is H, lower alkyl, aryl, heterocyclic group, etc., or R<1> and R<2> may be coupled to form a ring; R<3> and R<4> are H, lower alkyl, benzyl, aryl, etc., or form ring together with N) or acid addition salt thereof as an active ingredient. The compound expressed by the formula exhibits excellent anticerebral ischemic action and antihypoxia action and has low toxicity. Therefore, the above-mentioned compound is effective to remedy for disorder of mental function or nervous function which are aftereffects of cerebral apoplexy or remedy for senile dementia.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an isoxazole derivative represented by the general formula (Il) shown below and having a brain function improving effect.

[Problem to be solved by the invention]

Cerebral circulation disorders such as stroke are the number one cause of death, and -
Even if a person's life is saved, the aftereffects remain, such as impairment in mental or neurological function, and in severe cases, can lead to cerebral circulatory dementia, which is one of today's major social problems as the elderly population increases. It has become. Therefore, the development of therapeutic agents for these disorders is desired.

In the process of searching for chemical substances for these purposes, the present inventors discovered that isoxazole derivatives having the general formula +11 have a strong effect on improving brain function, and found that it is useful as a brain function improving agent. After confirming this fact, we have completed the present invention.

[Structure of the invention]

The novel brain function improving agent of the present invention has the general formula (wherein R1 is 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 R2 represents a hydrogen atom, a lower alkyl group, an aryl group which may have a substituent, or a heterocyclic group which may have a substituent. R2 may form a fused hydrocarbon ring together with the carbon atom to which they are attached.

R3 and R4 represent a hydrogen atom, and lower alkyl represents an alicyclic amino group formed together with the nitrogen atom to which they are bonded. ) or its acid addition salt as an active ingredient.

Suitable compounds used in the present invention include, in the general formula (1), Hl is a hydrogen atom; a halogen atom such as fluorine, chlorine, or bromine; methyl, ethyl, n-
Furovir, 4-sopropyl, n-butyl, inbutyl, t
Straight chain or branched chain alkyl group having 1 to 4 carbon atoms such as art-butyl; vinyl, allyl, 2
- Straight chain or branched alkenyl group having 2 to 4 carbon atoms such as butenyl and 2-methylallyl; Alkynyl group having 2 to 4 carbon atoms such as ethynyl and 2-propynyl; aromatic ring an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isozolobyl; an alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy, n-propoxy, and impropoxy; fluorine; A benzyl group with or without a halogen atom such as chlorine or bromine, a nitro group, an amine group, or a lower aliphatic acylamino group such as acetylamino or propionylamino; Indicates an aryl group such as phenyl that is not present.

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: the benzyl group in R1 has the same substituent as the substituent; or a 5- or 6-membered ring having an oxygen atom, sulfur atom or nitrogen atom such as furyl, thienyl, thiazolyl, pyridyl;
A membered heterocyclic group: or a benzene ring, a cyclohexene ring, which has or does not have the same substituent as the benzyl group of B1, formed together with the carbon atom to which R1 and R2 are bonded, respectively; 6 like cycloheptene ring
to 7-membered fused hydrocarbon ring.

R5 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 above; aryl groups such as benzyl or phenyl with or without; or morpholino, 1-piperazinyl, 4-methyl-1-piperazinyl, which R5 and R4 together form with the nitrogen atom to which they are attached;
It may also represent a 5- or 6-membered alicyclic amino group such as 1-pyrrolidinyl or piperidino.

Specific examples of the compound represented by the general formula (11) of the present invention include the compounds described below.

Pharmaceutically acceptable acid addition salts of the inoxazole derivative having the general formula +11 include mineral acid salts such as hydrochloride, hydrobromide, and sulfate, and oxalate, lactate, and citrate. , tartrate, succinate, maleate,
Examples include organic salts such as fumarate and methanesulfonate.

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

The isoxazole derivative (1) of the present invention is
It can be produced by the following method described in the specification of -9+6S+.

First step: (■) (I[I) Second step: (IV) +11 In the above formula, R1, R2, BS and R4 have the same meanings as described above.

The reaction to obtain the diol compound (III) in the first step is carried out by heating the epoxide compound (Ill) in an aqueous solution of an alkali carbonate or an aqueous alkali metal in the presence of an organic solvent.

The second step, the reaction to obtain the target compound (Il) of the present invention, is carried out through the following steps 1) and 2).

1) Step This reaction is carried out by adding phosgene or a halocarbonate and then a tertiary amine to the diol compound (1[[) in the presence of an organic solvent.

2) Step This reaction is carried out by adding amines (M) to the reaction solution containing the carnate intermediate obtained in the previous step.

The starting compound for the above reaction, 3-
HyP-roxyisoxazole compounds and halohyalin can be produced according to the method described in JP-A-52-31070.

〔Effect of the invention〕

According to pharmacological and toxicity tests, the compound of the present invention having the general formula (I) exhibits excellent cross-layer ischemic effects and anti-hypoxia effects, and is a compound with low toxicity. The results will be explained in detail below.

Improvement method: Male mature (20 weeks old) gerbil (Mongol)
ianGθrbil) was used for 20 animals per group. Bendoparbital (30■749.1.P, ) and halothane (1.5% in a mixed gas of 95% oxygen and 5% carbonic acid)
(included in the ratio of 1)) Under anesthesia, both common carotid arteries were occluded for 30 minutes, and then the occlusion was released and blood flow was resumed. Next, the animals were placed in a dorsal position, and the time from the resumption of blood flow until the onset of convulsion and the survival time were measured. The time to onset of convulsions was observed up to 6 hours after blood flow was resumed, and the survival time was observed up to 7 hours. If no seizures occur within 6 hours, 360 minutes
Also, if you do not die within 7 hours, the survival time is 42
Each time was calculated as 0 minutes. The test compound is 0.51 C
It was suspended in MC solution and administered intraperitoneally at the time of resumption of common carotid artery blood flow. On the other hand, the control group received vehicles 0, 5
'I CMC solution was administered in the same manner, and Mann-
Stochastic analysis was performed using Whitney's U-test.

Results: As shown in Table 2, 3-(3-carbamoyloxy-2-hydroxypropyloxy)-5-(
m-chlorophenyl)inoxazole is 100■/'
The dose of Kt significantly (P<0.05) prolonged both the latency to onset of convulsions caused by cerebral ischemia and the survival time without affecting the righting reflex recovery time.

2. Ligation of both common carotid arteries spontaneously occurs and improves the effect of high blood pressure.
Used for 0 animals. A cerebral ischemia model was created by ligating both common carotid arteries under halothane anesthesia, and the halothane anesthesia was stopped at the same time as ligation. The time and time until death were measured. The test compound was prepared in the same manner as in 1 above and administered intraperitoneally 30 minutes before ligation. A 0.54 CMC solution was similarly administered to the control group. The stochastic analysis was performed in the same way as in 1 above.

Results: As shown in Table 3, 3-(3-carbamoyloxy-2-hydroxypropyloxy)-5-(
m-chlorophenyl)isoxazole is 100 rr
A dose of q/kg significantly (P(0,02)) prolonged the survival time caused by cerebral ischemia, and also significantly increased the survival rate beyond 7 hours.

3. Method of effect on survival time under hypoxia: 1 group of male adult ddy mice (5 withdrawals, 1 body weight approximately 30?)
Used for 1 to 12 animals.

After 2 to 3 animals were placed in a 1.5 liter acrylic damper, a mixed gas of 4% 02 and 96% N2 was aerated at a flow rate of 10 liters/min, and the animals died (cessation of breathing). The time it took was measured. The test compound was prepared in the same manner as in 1 and 2 above, and administered intraperitoneally 30 minutes before the hypoxic challenge.

Results: As shown in Table 4, 3-(3-carbamoyloxy-2-hydroxypropyloxy)-5,-
(m-chlorophenyl)inoxazole is 100■/
'C7 dose significantly reduced survival time under hypoxia (
P<0.01).

Table 4 Significant difference test (t-test) between control 114.9±10.8 versus plate group. City axis: P
(0,01°4, acute toxicity 3-(3-carbamoyloxy-2-hydroxypropyloxy)-5-(m-chlorophenyl)isoxazole suspended in 0.5'I CMC solution, 1000
When wq/kq was orally administered to 3 mice and observed for 5 days, they survived without any notable symptoms.

As explained above, the compound having the general formula (11) has extremely low toxicity and has a so-called brain function improving effect and an antihypoxic effect, which improves neurological symptoms caused by cerebral ischemia. Clinically, it can be administered orally, and is useful as an agent for improving cerebral circulation and metabolism in the acute and chronic stages of stroke, or as a therapeutic agent after brain surgery for brain tumors, head trauma, etc.

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 prepared by adding known adjuvants that can be commonly used in the field of pharmaceutical formulation technology, such as excipients, binders, disintegrants, lubricants, and flavoring agents, to the main drug according to conventional methods. It can be formulated into a formulation. The amount to be used varies depending on the symptoms, age, body weight, etc., but in the case of oral administration, it is usually possible to administer 5 to 50 η once a day to adults, 1 to 3 times a day.

This will be explained in more detail by giving examples of defective formulations and production examples.

Formulation example (capsule) Sol Lactose 15
3.6 Corn starch 100
．． 0 stearin magnesium 1.4
The powder of the above formulation was mixed and passed through a 60 mesh sieve, and 280 square meters of this powder was placed in a No. 3 gelatin capsule to form a capsule.

Production Example 1 Sodium methoxide (28% methanol solution) was added to a solution of 30.0f (0.153 mol) of 5-(m-chlorophenyl)-3-hyP-roxyisoxazole (0.153 mol) in sodium methoxide (28% methanol solution). .62 (0,153m
After stirring at room temperature for 30 minutes, shrimp bromohyde y41.9f (0,306 mol) was added dropwise. After further stirring at room temperature for 3 days, the reaction solution was concentrated under reduced pressure, and ethyl acetate (500ysl) was added to the resulting residue.
Wash with 10% sodium chloride (800%) and dry the ethyl acetate layer over anhydrous magnesium sulfate. The desiccant was removed, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (developing agent: penzene/ethyl acetate = 271
) was recrystallized from inpropyl ether to obtain the desired product 2 as colorless needle-shaped crystals with a mp of 86-87°C.
I got 3.65' (73.5 yen).

0 infrared absorption spectrum k (KBr) crrL-”: 3
120 (Hetro-)1), 1620.1593
(C=N.

Ar).

O nuclear magnetic resonance spectrum k (CDC63) δppm:
2.72 (IH, AB-d, d, J=4.5, 3.0)
,2.88On,An-a,a,J=4.5,4. s)
, 3.26-3.50 (l) 1. m), 4.18 (1
11, AB-d, d, J=12.0.

60), 4.58 (IH,AB-a,a,,y=t2
．． 0,3. o), 6.20 (IH, s), 7.23-7
．． 83 (4H, m).

Production Example 2 Synthesis of 5-(m-chlorophenyl)-3-(2,3-epoxyzolobyloxy)isoxazole (Production Example 1)
Dissolve 15.0fI (59.6mmol) in acetonitrile (50rnl) and add 100ml of 10% potassium carbonate solution.
ml (72.3 mmol) was added and heated under reflux for 3 hours. After cooling, 10 g of brine (400 m4) was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (400 m4).
After drying the ethyl acetate layer over anhydrous magnesium sulfate, the desiccant was removed and the solvent was distilled off under reduced pressure.The resulting residue was subjected to silica gel chromatography (developing agent: penzene/ethyl acetate= 172) and purified with mp92
Colorless/powder object 1.3.2F (8
2.5%) was obtained.

0 infrared absorption spectrum (KBr) cTrt-1:337
0 (OH), 3105 (Hetro-1().

0 nuclear magnetic resonance spectrum k (DMSO-d6) δppm
:3.30~3.70(2)! , m), 3.70-4
．． 10 (1)1.

m), 4.00-4.50 (2H, m), 4.56
(LH,t.

,7=4.5),5.06(IH,d,,7=4.5)
, 6.93 (IH, s), 7.43-8.06 (4H,
m).

Production example 3 5-(m-ri o ruf x 2, 11/) -3-(2,
3-dihydroxypropyloxy)inoxazo-#
10.0? A solution of (37,0 mmol) in dry tetrahydrofuran (3 oomg) was cooled to 5 °C, and 3.969 mmol of trichloromethyl chloroformate (20,0 m
mol) was added dropwise, and after stirring at 5-6°C for 30 minutes, 5-6°C
Torie FK7 Mi 74.04 at 10℃? (40,
After stirring for 1 hour at 3-5°C, 50 ml of 28% 7 mmol water (400,0 mmol) was added dropwise.
The reaction solution was stirred at room temperature for 18 hours, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (400 ml) was added to the resulting residue, and 104 brine (400 ml) was added.
). After drying the ethyl acetate layer over anhydrous magnesium sulfate, the desiccant was removed and the solvent was distilled off under reduced pressure. The solid product obtained was recrystallized with ethyl acetate to obtain mp14.
Colorless, scaly crystal object showing temperature of 9 to 150°C 8.30r
(72,1fi) was obtained.

0 infrared absorption spectrum (KBr) cm-': 3430
．． 3320.3245(NH, On, 3120(Het)
ro-H), 1683 (C=O).

0 nuclear magnetic resonance spectrum (DMSO-d6) δppm
:3°86~4.33 (2H+2H+11(,m)
, 5.32 (LH.

a, J=i, 5), 6.50 (21, b-s), 6.9
3(11(.

S), 7.50-8.00 (48, m).

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a substituent. It represents a benzyl group that may have a benzyl group or an aryl group that may have a substituent. R^2 is a hydrogen atom, a lower alkyl group, an aryl group that may have a substituent, or a substituent. In addition, R^1 and R^2 may form a condensed hydrocarbon ring together with the carbon atom to which they are bonded. R^3 and R^4 are hydrogen atoms, lower Indicates an alkyl group, a benzyl group which may have a substituent, or an aryl group which may have a substituent, or R^3 and R^
4 may be taken together with the nitrogen atom to which they are bonded to form an alicyclic amino group. ) A brain function improving agent containing an isoxazole derivative or an acid addition salt thereof as an active ingredient.