JPH0381221A - Antidepressant containing isoxazole compound as active ingredient - Google Patents

Abstract

PURPOSE:To obtain an antidepressant containing an isoxazole compound as an active ingredient and having significant antireserpine action with low toxicity. CONSTITUTION:An antidepressant containing a compound expressed by formula I [R<1> is H, halogen, lower alkyl, lower alkenyl, lower alkynyl, (substituted) benzyl or (substituted) aryl; R<2> is H, lower alkyl, (substituted) aryl or (substituted) heterocyclic group; R<3> and R<4> are H, lower alkyl, (substituted) benzyl, (substituted) aryl or, together with N to which they are bound, form alicyclic amino] or an acid addition salt thereof, e.g. 3-(2-hydroxy-3- morpholinopropoxy)-5-phenylisoxazole.hydrochloride, as an active ingredient. The aforementioned compound is used in an amount of normally 10-100mg at a time for an adult administered one to 3 times a day. The compound expressed by formula I is obtained by condensing 3-hydroxyisoxazole expressed by formula II with an epihalohydrin and then reacting the resultant epoxide expressed by formula III with amines.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an inoxazole compound having an antidepressant effect represented by the general formula (1) below.

[Problem to be solved by the invention]

In recent years, the number of geriatric diseases has been rapidly increasing due to the aging of the population, and the five geriatric diseases are one of them, and the increase in suicides among the elderly has become a social problem. Therefore, there is a strong desire to develop therapeutic agents for these diseases.

In the process of searching for chemical substances for these purposes, the present inventors discovered that inoxazole derivatives having the general formula (1) have strong antidepressant effects, and found that they are useful as antidepressants. After confirming this fact, we have completed the present invention.

[Structure of the invention]

The present invention relates to 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 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 which may have a substituent, or a heterocyclic group which may have a substituent. R3 and R4 represent a hydrogen atom,
represents a lower alkyl group, a benzyl group which may have a substituent, or an aryl group which may have a substituent, or R3
and R4 together represent an alicyclic amino group formed with the nitrogen atom to which they are bonded. ) or its acid addition salt.

Suitable compounds used in the present invention include, in the above general formula (1), R1 is a hydrogen atom; a halogen atom such as fluorine, chlorine, or bromine; methyl, ethyl, D-7
'lopyl, isoflovir, n-butyl, inbutyl, t
Straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as ert-butyl, D-pentyl, isopentyl, n-hexyl: vinyl, allyl, 2-butenyl, 2-methylallyl, etc. linear or branched alkenyl group having 2 to 4 carbon atoms; ethynyl;
Alkynyl group having 2 to 4 carbon atoms such as 2-propynyl: Alkyl group having 1 to 3 carbon atoms in the aromatic ring such as methyl, ethyl, D-propyl, isopropyl, methoxy, ethoxy, n-propoxy , an alkoxy group having 1 to 3 female carbon atoms such as impropoxy;
Halogen atoms such as fluorine, chlorine, and bromine: nitro group,
Benzyl group with or without an amino group or a lower aliphatic acylamino group such as acetylamino or propionylamino: Refers to an aryl group such as phenyl that has or does not have the same substituent as the benzyl group.

R2 is a hydrogen atom; a linear or branched alkyl group having 1 to 4 carbon atoms as exemplified as the alkyl group for R1; phenyl, etc. with or without a substituent of the benzyl group for R1; Aryl group: Or a 5-membered or 6-membered heterocyclic group having an oxygen atom, sulfur atom, or nitrogen atom, such as furyl, thienyl, thiazolyl, and pyridyl.

R5k and R4 are hydrogen atoms: the same linear or branched alkyl group having 1 to 6 carbon atoms as the example of the alkyl group in R1; the same substituent as the benzyl group in R1 above; an aryl group such as a benzyl group or phenyl with or without; a morpholino formed by the housing or R3 and R4 taken together with the nitrogen atom to which they are bonded;
1-piperazinyl, 4-methyl-1-piperazinyl, 1
- May represent a 5- or 6-membered aliphatic amino group such as pyrrolidinyl, piperidino.

Specific examples of the compound represented by the general formula (1) obtained by the present invention include the compounds described below.

Pharmaceutically acceptable acid addition salts of the isoxazole derivative having the general formula (1) include mineral acid salts such as hydrochloride, hydrobromide, sulfate, oxalate, lactate, Mention may be made of organic acid salts such as citrate, tartrate, 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.

First step (II) (m) Second step (1) In the above formula, R1, R2, R5 and R4 have the same meanings as described above.

This production method can be carried out under similar reaction conditions according to the method described in Publication No. 52-31070. At risk, the first step reaction is carried out by condensing 3-hydrodeca diyne oxazole (Ill) with epihalohydrin in the presence of a base, and then the second step reaction is carried out by condensing the 3-hydrodeca diyne oxazole (Ill) with epihalohydrin in the presence of a base, and then the second step reaction amines (IV
) to obtain the target compound (1) of the present invention.

〔Effect of the invention〕

The compound having the general formula (1) of the present invention showed excellent antireserpine activity according to pharmacological tests, and specific data thereof will be explained below.

Method of action: Adult male ddy mice (4 weeks old, weight 22-27 tons) were used, 3 mice per group. Reserpine 2η^ was administered subcutaneously, and 90 minutes later, the degree of ptosis was observed and expressed as a score according to the following criteria. In other words, immediately after taking the mouse out of the cage and placing it on the table, the eye shape is 0 points when it is circular like a normal animal, 1 point is when 1/3 ptosis is observed, and 1 point is when it is abnormal. 2 points were given for the condition, and 3 points were given for the time when the eyelids did not open. The test compound was dissolved in an appropriate solvent (physiological saline, 0
．． The solution was dissolved or suspended in a 5'I CMC solution or a 1-polydimethylsulfoxide solution, and then administered orally immediately before reserpine administration. On the other hand, each solvent was similarly administered to the control group. Symbolize the display on the bottle containing the test drug solution,
The administration was done in random order so that the scorer would not know which drug was administered to which animal. Regarding the above scores, the inhibition rate at each dose was calculated according to the following formula.

Results: The test results are shown in Table 2. Suppression rates of 71 or more were judged as (+), and those from 41 to 70 were judged as (: t13.40 or less were judged as (→).

00 1 0 5 00 1 2, Acute toxicity Manufacturing side Compounds 1, 2 and 3 were suspended in a 0.5% CMC solution and 300η squared was orally administered to 5 mice,
Although observed for 5 days, the gold side survived.

As explained above, the compound ti having the general formula (I) has extremely low toxicity and exhibits a significant anti-reserpine effect, that is, a so-called antidepressant effect. It has been shown that the oral absorption of this compound is very good, and since the hydrochloride salt is soluble in water, intravenous and oral administration is possible clinically.

Among them, the compound having the general formula (Il) has a central muscle relaxing effect (Japanese Patent Application No. 63-12676) and improves brain function (Japanese Patent Application No. 63-287314).
Although it has already been recognized that it is also useful as an antidepressant in the treatment of depression. 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 known adjuvants that are commonly used in the field of pharmaceutical formulation technology, such as excipients, binders, disintegrants, lubricants, and corrigents, to crude drugs according to the purpose according to conventional methods. It can be formulated into a formulation.

The dosage varies depending on symptoms, age, body weight, etc., but in the case of oral administration, it is usually 10 to 10 η per dose for adults.
0 town can be administered 1 to 3 times a day.

Next, a more specific explanation will be given by giving formulation examples, production examples, and reference examples.

Formulation example Capsule lactose 153.
6q Maize If Koshi Starch 100.
0 dust Magnesium stearate 1.419
Total 280.0! After mixing the powder of the above formula and passing it through a 60 mesh sieve, this powder weighs 280g! II was placed in a No. 3 gelatin capsule to prepare a capsule.

Synthesis of Production Example 1 (1-1) 40. of gtoa(+oO111
) Add 17.6f of morpholine to the solution and heat under reflux for 5 hours. The solid substance obtained by concentrating the reaction solution under reduced pressure was recrystallized with ethyl acetate to obtain the title object 50.02 as colorless columnar crystals having a melting point of 123-124°C.

Infrared absorption, X hect/I/ (KBr) tx-'
:3190.1624,1511,1440°Nuclear magnetic resonance spectrum (CDCI) δppm :2.30-2
．． 85 (2Hx3.m), 3.20-3.70 (IH.

b), 3.73 (2HX2.t, J=4.5), 3.9
0-4.55 (IH, m), 4.15-4.50, 2
H, m), 6.18 (IH.

S), 7°35-7.85 (5H, m).

(1-2) 3-(2-hydroxy-3-morpholinopropoxy)-
Synthesis of 5-phenylisoxazole hydrochloride 3-(2-Hydroxy-3-morpholinopropoxy 5-phenylisoxazole S, 4N-MCI/dioxane solution (5,017) in ethyl acetate (2001 Ll) solution of OOl was added and stirred for 10 minutes at room temperature.The reaction solution was concentrated under reduced pressure and the obtained solid was recrystallized with ethyl acetate to obtain 5.21 t of the title object as a colorless powder with a melting point of 149-150C. Obtained.

fF extra-absorption / ) k (KBr) cIL-'
:3215.1625.1513,1461° Nuclear magnetic resonance spectrum (D20) δpyn: 3.66-4.13
(2Hx3.m), 4.50 (2Hx2.t.

J=4.5), 4.69 (2H, d, J=4.5), 4
．． 80-5.20 (IH, m), 6.83 (IH, 8)
, 7.80-8.30 (5H.

m).

In the same manner as in Production Example 1, the following Production Examples 2 to 7 compounds were synthesized.

Reference Example 1 To a solution of 10.00 f of hydroxy-5 phenyl isoxazole in hexamethylphosphoramide (59 m/) were added 10.2 El of anhydrous potassium carbonate and 6.89 F of epichlorohydrin, and the mixture was stirred at room temperature for 24 hours. After removing the insoluble matter from the reaction solution, ethyl acetate (2
0011J) and 101 saline wash (200-X2
)I do. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was removed in an oven and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing agent: cyclohexane/ethyl acetate: 4/1). and melting point 9
11.0O of the title object as colorless needle-like crystals exhibiting a temperature of 8 to 99°C
f (82,0 section) was obtained.

Infrared absorption spectrum (xBr).

1615.1585,1511,1459,1418° Nuclear magnetic resonance spectrum (CDCl2) δppm: 2.
73 (IH, AB-dd, J=4.5, 3.0), 2.
87 (IH.

AB-aa, J = 4.5, 4.5), 3.2
6-3.50 (IH, m), 4.20 (IH, A
B-dd, J=12.0, 6.0), 4.58 (IH.

AB-ad, J = 12.0, 3.0), 6.
20 (IH, s), 7.30-7.90 (5H, 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. R^3 and R^4 represent a hydrogen atom, a lower alkyl group, a benzyl group which may have a substituent, or an aryl group which may have a substituent, Alternatively, R^3 and R^4 may be combined together with the nitrogen atom to which they are bonded to form an alicyclic amino group. agent.