JPH0552822B2 - - Google Patents

Description

[Detailed description of the invention]

[0002]

FIELD OF INDUSTRIAL APPLICATION The present invention relates to fluorophenacyl-amine derivatives as new industrial products.

【0003】

[Prior art and problems to be solved by the invention] 2-amino-1-(halogenophenyl)-1
- Ethanol type compounds are covered by French patent no.
It is included in the formula described in No. 1503517 and is indicated as a diuretic inhibitor. However, the above French patent does not disclose anything about 1-(fluorophenyl), 1-(chlorphenyl), 1-(bromphenyl) and 1-(iodophenyl) derivatives, and also their potential for CNS. It should be noted that there is no suggestion of potential action. It is known that fluorophenacyl-amine derivatives belonging to the 2-amino-1-(fluorophenyl)-1-ethanol family have already been disclosed. In particular, AMLANDS' J.
Pharmacol.Exptl.Therap. 106 , 440−443 (1952)
The paper published in 1-(3-fluorophenyl)
-2-isopropylamino-1-ethanol and 1-(3-fluorophenyl)-2-t-butylamino-1-ethanol are disclosed and also in L. VILLA et al., Il Farmaco Ed.
Scientifica, 24 (No. 3), 329-340 (1969), 1-(4-fluorophenyl)-2-
Isopropylamino-1-ethanol and 1-
(2-Fluorphenyl)-2-isopropylamino-1-ethanol is disclosed. Although these known fluorides act on the CNS,
Aggression-reducing effects have either no or only a slight effect. Contrary to expectations, new fluorophenacyl-amine derivatives which act on the CNS have been found to have particularly advantageous antiaggressive properties from a therapeutic point of view.

[0004]

[Means for Solving the Problems] The present invention provides the following formula

【0005】

[Case 2]

[In the formula, A is CHOH, and R is C
( _CH3 ) ₃ . ] Among the compounds belonging to the fluorophenacyl-amine derivative system shown in This is a fluorophenacyl-amine derivative characterized by the following. The term "addition salt" refers to an acid addition salt obtained by reacting a free base represented by Chemical Formula 2 with an inorganic acid or an organic acid, and an ammonium salt. Among the acids that can convert the base represented by Chemical Formula 2 into a salt form, particularly preferred are the following. Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, benzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, lactic acid, tartaric acid, P- Toluenesulfonic acid, and methanesulfonic acid. Among the compounds capable of providing the desired ammonium salt, particularly preferred are CH ₃ I and CH ₃ Cl. Acid addition salts are suitable salts, of which the hydrochloride is particularly advantageous. The fluorophenacyl-amine derivatives according to the invention can be produced by methods known per se, applying conventional reaction mechanisms. The following manufacturing methods are recommended. (1) in alcohol, preferably methanol,
Under reflux for at least 1 hour, a fluorophenacyl halide represented by the formula:

[0006]

[Chemical formula 3]

[In the formula, X ₁ is C1 or Br. ] React with an amine of the formula H ₂ NR, where R is as defined above, to obtain a “carbonyl” compound (A=CO), (2) if necessary, The corresponding carbonyl derivative,
Particular preference is given to reduction with NaBH ₄ to obtain the "alcohol" compound (A=CHOH). All compounds according to the invention are active on the CNS and also have interesting effects on the cardiovascular system. In particular, these compounds act on the CNS as sedative agents, antidepressants, and antiaggressive agents;
It is indicated for use in the treatment of depressions. According to the present invention, a therapeutic composition is recommended, which is particularly useful for the treatment of depression. This therapeutic composition is characterized in that it contains the fluorophenacyl-amine derivative or its non-toxic addition salt according to the present invention together with a physiologically acceptable excipient. The ingredients are, of course, administered only in pharmaceutically effective amounts.

[0007]

[Action] The compound of the present invention acts on the CNS as a sedative, an antidepressant, and an antiaggressive agent, and has low toxicity.

[0008]

[Example] Comparative tests were carried out to clarify these effects on animals, and as a result, it was possible to clearly and effectively distinguish the substances according to the present invention from known fluoride analogues. . Among the above tests, we decided to outline the tests regarding anti-aggressive properties. More specifically, the reduction in intergroup aggressiveness was evaluated as follows. That is, one cage of mice was divided in the center by an opaque septum, and after housing mice on each side for three weeks, each cage weighed approximately
A solution of the substance to be tested in distilled water was administered intraperitoneally to a group of three female mice weighing 20 g. Control animals received only distilled water intraperitoneally. After 30 minutes, the retaining wall was pulled out, the two groups in the same cage were brought together, and the struggles that occurred during the 10 minute period were noted. Three cages were each used for the substance to be tested and six cages were used for control batches not administered the substance to be tested. The results in Table 1 below demonstrate a reduction in aggression among the groups compared to the control batch. All substances to be tested are administered intraperitoneally (IProute).
The dose was 8 mg/Kg. The following can be seen from these results. (i) Substances according to the present invention (Example 1,
2) are their known analogues (CP1 to CP4)
(ii) There is no structure-activity relationship.

[0009]

[Table 1] ■■■ Tortoise Shell [0073] ■■■ Some production examples are described below, but the present invention is not limited to these.

[0010] Production example: Obtaining 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol hydrochloride

[0011]

[C4]

[Chemical Example 1; Code number: CRL 40827] 0.04 mol of N-(2-fluorophenacyl)-t
- Dissolve the butylamine in 120 ml of methanol.
Cool to −5° C. and add 3 g of sodium borohydride. Leave this in contact for one hour. The excess NaBH ₄ remaining in the reaction medium is destroyed using 5 ml of acetic acid and the mixture is then evaporated to dryness. Take the evaporation residue in water,
The pH is adjusted to 11 using NaOH, extracted with ether, the ether phase is washed with water and the ether phase is dried over MgSO ₄ . After filtration, the free base is collected and the desired hydrochloride salt is precipitated using hydrochloric ethanol. This is recrystallized in an acetone-ethanol (1:1) V/V mixture to obtain 8 g of CRL 40827 (yield: 80%). Melting point = 180.5℃. Analysis: N% Measured value = 5.60% N% Theoretical value = 5.65%

[0012] Production example 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol fumarate salt acquisition (Example 2; code number: CRL 40827 A) 1-(2-fluorophenyl) )-2-t-butylamino-1-ethanol (free base obtained in the production example) and fumaric acid are reacted,
CRL40827A is obtained. Melting point = 195~200℃
(Disassembly).

[0013] Tests have been carried out on suitable materials according to the present invention, which will be summarized below. (A) Test on CRL40827 (Example 1) A solution of CRL40827 in distilled water was administered at a dose of 20 ml/Kg for male mice and at a dose of 5 ml/Kg for male mice. Each was administered intraperitoneally.

1. Toxicity The maximum non-lethal dose LD-O is 64 mg/Kg or more and 128 mg/Kg or less for male mice.

2 Effects on the CNS Interaction with apomorphine (a) Mus musculus Each batch of 6 mice was administered CRL 40827 30 minutes before subcutaneous injection of apomorphine at a dose of 1 or 16 mg/Kg. do.
CRL40827 at 0.5 and 2 mg/Kg, especially 8 and
When administered at 32 mg/Kg, the hypothermia effect caused by large doses of apomorphine was clearly prevented;
No change in stereotypy or verticalization was observed. (b) Rats Each batch of 6 rats received CRL 30 min before subcutaneous injection of 0.5 mg/Kg apomorphine.
40827 respectively. No change in stereotypy induced by apomorphine in rats is observed.

Interaction with amphetamine In each batch of 6 rats, CRL
Thirty minutes before administering 40827, administer amphetamine (2
mg/Kg) intraperitoneally. Taking only the stereotypy index and excluding the fact that this decreased, the CRL
It is noted that 40827 does not modify stereotypy induced by amphetamine at a dose of 4 mg/Kg.

Interaction with Reserpine 4 hours after administering 2.5 mg/Kg of reserpine intraperitoneally to each batch of 6 mice,
Administer CRL40827, respectively. CRL 40827 is
It was observed that from a dose of 0.5 mg/Kg, the hypothermia caused by reserpine was clearly suppressed, and at the same time, there was no change in drooping.

Interaction with Oxotremorine Each batch of 6 mice receives CRL40827 30 minutes before administering 0.5 mg/Kg oxotremorine intraperitoneally. 0.5mg/Kg
It was observed that at the above doses, CRL40827 antagonized the hypothermia-inducing effect of oxotremorine, and this effect was very clear at a dose of 32 mg/Kg. Also, CRL40827 does not alter the tremor intensity induced by oxotremorine. Finally, CRL40827 does not alter the signs of cholinergic peripheral irritation that appear after oxotremorine administration.

Effect on 4-plate test, traction and electric shock Tests are carried out 30 minutes after administration of CRL40827 in each batch of 10 mice.
CRL40827 does not increase the number of incorrect movements penalized, does not result in any major incapacitation, and, in large doses, reduces the convulsive effects of electric shock.

[0020] Effect on spontaneous activity Thirty minutes after administration of CRL 40827, mice (6 mice treated, 12 controls) were placed in an actimeter (actimeter), and the activity of the mice was reduced to 30 minutes after administration of CRL 40827.
Record for minutes. It was observed that CRL40827 did not substantially alter spontaneous activity in mice.

[0021] Effects on some behaviors that are impaired by various drugs (a) Decreased activity due to habituation to the cage After being placed in the actimeter for 18 hours, mice (6 mice were treated, 12 mice were control mice) ) to CRL 40827
administer. The rats are immediately replaced in their respective cages and 30 minutes later their motility is recorded over a 30 minute period. CRL 40827 administered at high concentrations (34 mg/Kg) appears to mildly restore motility.

(b) Activity reduced by hypoxic challenge Thirty minutes after administering CRL40827, mice (10 treated, 20 control) were made to suffer from acute anoxia by subjecting them to reduced pressure. 〔In other words,
The pressure was reduced to 600 mmHg (i.e., 8 x 10 ⁴ Pascals) over 90 seconds, and returned to normal pressure over 45 seconds. ],
The mouse was then placed in the actimeter,
Record its motility for 10 minutes. The following points were noted. In other words, even CRL40827 does not improve the decline in mouse motility caused by being in a depressurized cage, even for a short period of time.

(c) Asphyxial anoxia Each batch of 10 mice was given 34 mg/Kg of triethiodide gallamine intraperitoneally.
minutes before administering CRL40827. At the highest dose (34 mg/Kg), CRL 40827 prevented the development of convulsions and mortality in mice by 40%.

Conclusions regarding effects on the CNS Given its antagonistic effects on hypothermia induced by apomorphine, reserpine, or oxotremorine, antidepressant-type activity is expected for CRL 40827. can do. These antagonistic effects are observed without anticholinergic effects, so CRL 40827 is considered an imipraminic antidepressant.
It is different from. On the other hand, given the lack of antagonism to reserpine-induced ptosis and lack of stimulation of locomotion along with stereotypy, CRL 40827
can be distinguished from IMAO and amphetamine-type compounds, respectively. Simply put,
CRL40827 is strongly presumed to behave as a beta-adrenergic stimulant. Furthermore, CRL40827 alone exhibits anticonvulsant effects when used in high concentrations. Finally, it reduces intergroup aggression in mice.

(3) Effects on cardiovascular and respiratory systems The following are observed. i.e. CRL40827
acts as a hypotensive and tachycardia inducing agent in anesthetized dogs and awake but genetically hypotensive rats; , and kidneys), lowering all peripheral resistance,
This drug reduces left hand ventricular function, eliminates diastole, stimulates respiration, and reduces noradrenaline-induced hypertension in dogs at doses starting from 1 mg/Kg (approximately 10 mg/Kg). maximum effect is achieved at a dose of Although the local blood flow rate does not increase,
The resistance decreases; this phenomenon may imply the following. That is, CRL40827 appears to imply that venous drainage increases while simultaneously inducing arterial peripheral vasodilatory properties, as cardiac blood output remains the same.

(4) Effect on bile secretion In dogs anesthetized with Nembutal, the amount of bile collected in 30 minutes is usually 1.5 ml;
After duodenal administration of CRL40827, bile excretion increased and the amount increased by 2.5 doses of CRL40827.
If mg/Kg, it will be 17.5ml and the dose will be 5mg/Kg.
, the dose is 2.25ml and the dose is 10mg/Kg.
In this case, it will be 2.5ml. In rats anesthetized with Nembutal, bile excretion was significantly lower than CRL40827.
is administered intravenously at doses of 5 mg/Kg and 25 mg/Kg, increasing 1 to 3 hours later.

[0027] (5) Local anesthetic effect Using guinea pigs, 0.1% and 0.5 of CRL40827
%, and 1% solutions were studied for their anesthetic effect after subcutaneous injection (3 guinea pigs were used per dose). Physiological serum, procaine, and CRL40827 are administered to guinea pigs at designated sites. 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes after injection
The test is performed by administering a series of 6 injections every 30 minutes and 30 minutes at the site where the injections were made. CRL40827 was confirmed to have local anesthetic effects when administered at concentrations of 0.5% and 1%. In addition, in clinical practice, CRL 40827 and CRL 40827A
have shown good results as sedatives and antidepressants in the field of psychiatry and are administered to humans in the form of tablets or gelatin-coated capsules containing 5 mg of each active ingredient, 3 tablets or 3 capsules per day. All of these showed excellent results as antidepressants.

【0028】

[Effect of the invention] Fluorofenacil of the present invention
Amine derivatives are useful as sedatives and as treatments for depression.

Claims (1)

[Claims] [Claim 1] The following formula [0001] [Formula 1] [In the formula, A is CHOH, and R is C
( _CH3 ) ₃ . ] Among the compounds belonging to the fluorophenacyl-amine derivative system shown in A fluorophenacyl-amine derivative characterized by: