JPH0228110A - Treatment composition - Google Patents

Abstract

PURPOSE: To obtain a composition which contains a specific fluorophenacyl- amine derivative and is useful for treatment of depressive illness. CONSTITUTION: This preparation contains a compound selected from the group consisting of N-(4-fluorophenacyl)-isopropylamine, N-(2-fluorophenacyl)-t- butylamine, 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol and their addition salts among compounds of the formula [A is CO, CHOH; R is CH(CH3 )2 or C(CH3 )3 ] and together with a physiological excipient. These compounds are all active to CNS and has an interesting effect on cardiovascular vessels, particularly these compounds act on CNS as a sedative, antidepressant and antiaggresive.

Description

DETAILED DESCRIPTION OF THE INVENTION Industrial Application The present invention relates to the therapeutic application of fluorophenacyl-amine derivatives as new industrial products.

In the following specification description, "fluorophenacyl-amine" (fluorophenacyl-a
mine) derivative is 2F-CJ*-Co-CHz-
This does not mean only the compound having a fluorophenacyl group shown in
J*-CHOH-CI (also means a compound having a β-hydroxy-fluorophenacyl group represented by z-).

[Prior art and problems to be solved by the invention] 2-
Compounds of the amino-1-(halogenophenyl)-1 ethanol type are included in the formula described in French Patent No. 1,503,517 and are indicated as anti-diuretic agents. However, in the above French patent, ■-(fluorophenyl), 1-(chlorphenyl)
.

Nothing is disclosed about the 1-(bromphenyl) and 1-(iodophenyl) derivatives, nor are their potential effects on the CNS.
It should be noted that there is no suggestion of an action.

It is known that fluorophenacylamine derivatives belonging to the 2-amino-1-(fluorophenyl)-1-ethanol family have already been disclosed. Especially A! 1. J from LANDS.

Pharmacol, Exptl, Therap,
106, 440-443 (1952), 1-(3-fluorophenyl)-2-
Isopropylamino-1-ethanol and 1-(3-fluorophenyl)-2-t-butylamino-1-ethanol are disclosed and also L, VILLA et
al's II Farn+aco Ed.

5cientifica, 24 (tk3), 3
29-340 (1969) includes 1-(
4-Fluorophenyl)-2-isopropylamino-1
-ethanol and 1-(2-fluorophenyl)-2-
Isopropylamino-1-ethanol is disclosed. Although these known fluorides act on the CNS, they do not reduce aggression.
ng) The effect is 1 either not at all or only to a small extent.

Contrary to expectations, novel fluorophenacyl-amine derivatives that act on the CNS show particularly advantageous antiaggressive properties from a therapeutic point of view.
It was found that the company had the following properties:

[Means to solve the problem]

That is, the present invention provides a fluorophenacyl-amine derivative represented by the following formula [wherein A is CO or CHOH, and R is C1 ((C1l*)x or C(CHs)i]. Among the compounds in system i, N-(4-fluorophenacyl)-isopropylamine, N-(2-fluorophenacyl)-1
-butylamine, 1-(2-fluorophenyl)-2-
Pharmaceutical composition of at least one compound selected from the group consisting of t-butylamino-1-ethanol, 1-(4-fluorophenyl)2-t-butylamino-1-ethanol, and addition salts of these compounds. A therapeutic composition comprising an effective amount of a physiological excipient.

Among these substances, a preferred compound from a therapeutic point of view is N-(4-fluorophenacyl)isopropylamine and its salts, especially the hydrochloride.

The term "addition salt" referred to in the table refers to an acid addition salt obtained by reacting a free base represented by formula (1) with an inorganic acid or an organic acid, and an ammonium salt. Among the acids that can be formed, 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 compounds capable of providing the desired ammonium salt, CH31 and C,)13(J) are particularly preferred.Acid addition salts are preferred. salts, of which the hydrochloride is particularly preferred.

The fluorophenacyl-amine derivative according to the present invention can be produced by a method known per se applying a conventional reaction mechanism. The following manufacturing methods are recommended.

1) In an alcohol, preferably methanol, under reflux for at least 1 hour, a fluorophenacyl halide represented by the following formula: (wherein X is C1 or Br) a fluorophenacyl halide represented by the following formula: amine, 1(, NR(I[I) in which R is as defined above) to obtain a "carbonyl" compound (A=CO), 2) if necessary , the corresponding carbonyl derivative is particularly preferably reduced with NaBIl to obtain the "alcohol' compound (A=CIIO old).

All compounds according to the invention are active on the CNS and also have interesting effects on the cardiovascular system.

In particular, these compounds are sedative agents.
agents), antidepressants (anttdepres
sanL), and antiaggressive agents (antiaggressi
It acts on the CNS as a vehicle agent and is indicated for use in the treatment of depression.

According to the present invention, a therapeutic composition is proposed, which is particularly useful for the treatment of depression. This therapeutic composition is characterized in that it contains at least one fluorophenacyl-amine derivative or a non-toxic addition salt thereof according to the invention together with a physiologically acceptable excipient, The active ingredient will, of course, be administered in only a pharmaceutically effective amount.

Comparative tests have been carried out to demonstrate these effects on animals, which have resulted in a clear effective differentiation of the substances according to the invention against known fluoride analogues. Among the above tests, we decided to outline the tests regarding anti-aggressive properties.

More specifically, intergroup aggression (aggression) is determined as follows.
The reduction in graciousness was evaluated.

That is, one cage of Mus musculus was divided in the center by an opaque septum, and on each side there were 3A mints.
After a period of residence, a solution of the substance to be tested in distilled water was administered intraperitoneally to a group of three female mice, each weighing approximately 20 g. Control animals received only distilled water intraperitoneally. After 30 minutes, the fusion wall was pulled out, the two groups in the same cage were brought together, and the struggles occurring 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 without the substance to be tested.

The results in Table 1 below show a reduction in aggression among the population compared to the control batch. The substance to be tested is
All via peritoneal route (1,P, route) dose 8*
/kg. The following can be seen from these results.

(1) The substances according to the invention (Examples 1 to 5) have a clearly higher anti-attack effect than their known analogues (CPI to CP4), and (ii) there is no structure-activity relationship.

Some production examples will be described below, but the present invention is not limited to these.

Obtainment of Kakezari ■-Sat N-(4-fluorophenacyl)-isopropylamine hydrochloride (Example 1; code number: CRL 40727) P
- 10 g of fluoroacetophenone (<0.5 mol)
25 mff1 of bromine are added dropwise to the solution in 0 mA acetic acid, which has been cooled in a water bath. 1 of the obtained mixture
Stir for an hour and evaporate to dryness.

100mj of residue! of methanol, and the solution thus obtained is poured into a solution of 210 l of isopropylamine dissolved in 200 m# of methanol.
Reflux for an hour and evaporate to dryness.

The residue is taken up in water and the free base of the substance of interest is extracted with ethyl acetate, the solvent is dried and the hydrochloride salt is precipitated using hydrochloric ethanol. Recrystallization from an acetone-methanol (1:1) V/V mixture gives 17.2 g of CRL40727 (yield: 14.8%), melting point 207° C. (decomposition).

Analysis: N% Measured value = 6.01% N% Theoretical value = 6.04% Obtainment of N-(2-fluorophenacyl)-1-butylamine hydrochloride (Example 2; code number : CRL 40828) Dissolve 50 g (0,362 mol) of orthofluoroacetophenone in acetic acid 75-1. The mixture obtained is cooled in a water bath and 18.1*J of bromine are added dropwise to it. This is left in contact for 1 hour and evaporated to dryness, then the residue is taken up in lOml methanol. The solution thus obtained was mixed with t-butylamine (te
132 g of M. rtiobutylas + ine) in 100 ml of methanol, this is refluxed for 1 hour and evaporated to dryness, then the residue is taken up in water, extracted with ether and purified with hydrochloric ethanol. Precipitate the hydrochloride. Add this to acetone-
Recrystallization in ethanol (1:1) V/V mixture gives 18 g of CRL40828 (-20% yield)
, melting point -240°C (decomposition).

Analysis = N% Measured value = 5.74% N% Theoretical value = 5.70% Example 3; Code number: CRL 40827) 0.04 mol of N (2-fluorophenacyl) t-butylamine (free base of CRL 40828) is dissolved in 120 μl of methanol, cooled to -5°C,
Add 3 g of sodium borohydride to this. This is 1
The excess NaBHa remaining in the reaction medium is destroyed using acetic acid 5-1, which is left in contact for an hour, and the mixture is then evaporated to dryness. The evaporation residue is taken up in water, its pi adjusted to 11 with NaOH, extracted with ether, the ether phase is washed with water and the ether phase is dried over -gsO4. After treatment, the free base is collected and the desired hydrochloride salt is precipitated using hydrochloric ethanol. Add this to acetone-ethanol (
1:1) when recrystallized in a V/V mixture, CRL 40
8 g of 727 is obtained (yield: 80%), melting point -180
,5℃.

Analysis 2 N% Measured value = 5.60% N% Theoretical value = 5.65% Acquisition of 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol fumarate (Example 4; Code number: CRL40B27 A) When 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol (TfM base obtained in Production Example ①) and fumaric acid are reacted , CRL40827A is obtained. Melting point = 195-200'C (decomposed).

Preparation plate - Obtaining (4-fluorophenyl)-2-1-butylamino-1-ethanol hydrochloride (Example 5; code number: CRL 40854) α-chloro-p-fluoroacetophenone 50 g (0,289 mo/I/)/-/I/900 ml (,M). The resulting mixture was cooled to -5°C and 5.80 g of NaBHs
Add. This is left in contact for 1 hour and then 10 m/l of acetic acid are added. t-butylamine 1
51 mN is added and the resulting mixture is refluxed for 12 hours. This is evaporated to dryness and the evaporated residue is taken up in distilled water. The crystallized free base is collected and recrystallized in hexane to obtain 39 g of 1-(4-fluorophenyl)-2-t-butylamino-1-ethanol (yield 6).
3%). Melting point -117°C.

When this base is dissolved in diethyl ether and treated with hydrochloric acidic ethanol, the hydrochloride salt precipitates. When this was taken out in a furnace and vacuum dried on PxOs, CRL40854 was obtained.
44g of is obtained (yield: 61%). Melting point = 176°C.

CRL40854 is N-(2-fluorophenacyl)
It can also be produced by repeating the method described in Production Example (2) using N-(4fluorophenacyl)-1-butylamine instead of -1-butylamine.

The preferred materials according to the invention have been tested and are summarized below.

A) CRL40727 (1) 11J.

Maximum non-lethal! (maximum non-1ethal
dose) LD-0 is 128q/kg or more and 256aw/kg or less when administered intraperitoneally to mice.

2 CRL40727 in the CNS has many sedative effects. Namely, sedation in mice, and reduction in locomotion and aggression in mice, hypothermia, and apomorphine, oxotremorine,
Synergistic effect on the hypothermia-inducing effects of amphetamines, mild antagonism on the hyperthermia induced by amphetamines.

3 Heart and Blood 7. a) By intravenous administration CRL40727 was administered to two dogs at 0.1 kg/kg sequentially.
, 1■/kg, 2.5■/kg, 5■/kg, 10w/
kg and a dose of 20 μg/kg, perfused intravenously for 6 minutes. And these arterial blood pressure, pulse rate (cardi
ac frequency), femoral artery flow rate, and rectal temperature.

The following is observed.

CRL40727 increases femoral artery flow rate at doses as low as 1/kg;
The effect will increase to +140%.

Administration! From 5 ■/kg, differential arterial blood pressure increases; diastolic and mean arterial blood pressure decreases from 10 and 20 ■/kg, respectively.

The pulse does not change appreciably.

At doses of 2.5 to 10 μ/kg, the skin becomes pink.

Bile remains yellow; rectal temperature does not change.

Tachycardia induced by isobrenaline is reduced, with pulse rates averaging 182 beats/kg at doses of 10 at/kg and above.
However, in the control group, the rate was 215 beats/min;
Hypotension remains unchanged.

The following supplementary tests were conducted: - CRL4
With an additional intravenous dose of 40*/kg of 0727, a further progression of hypotension than with the previous dose was observed, and the bile remained yellow;
A second dog receives control drug. it is,(
2,4,6-Dorimethoxyphenyl)-3-pyrrolidinopropyl) ketone hydrochloride, which is disclosed in British Patent No. 132
It is described in the specification of No. 5192, and its code number is LL 1656, which means FONZYLAN [!
It is marketed under the name. This is 6vIl/kir
Administer intravenously.

The flow rate of the femoral artery is CRL in the case of LL1656.
It was found that when 10 μ/kg of 40727 was administered, there was no increase in phlegm.

b) By intraduodenal administration CRL40727 was administered to three dogs at 1 kg/kg and 2
．． It is administered intraduodenally at a dose of 5 ■/kg and 10 ■/kg. A zero order is observed measuring the same parameters as mentioned above.

According to CRL40727, the flow rate of the femoral artery is clearly increased at a dose of 2.5-5 kg/kg; this effect does not increase with increasing dose, but slightly increases. It is something to do. A hypotensive effect appears from a dose of 10/k+r.

From a dose of 2.5 ■/kg, the skin becomes very pale pink.

Bile remains yellow. Rectal temperature remains unchanged.

Tachycardia induced by isobrenaline is reduced. Pulse rate was on average 165 nights/min after administration of CRL40727 10*/kir, whereas in the control group, pulse rate was 22/min.
Reach 0 beats/min (beats/5hin). Hypotension remains unchanged.

The following supplementary test was carried out; - 20at/
A further dose of kg is administered intraduodenally. Furthermore, a greater hypotensive effect is observed without an accompanying vasodilating effect. The same result was obtained with CRL407 at the end of the test.
It was also obtained in another dog injected intravenously with 5*/kg of 27. Furthermore, subsequent intravenous injection of LL1656 at a dose of 6 μg/kg did not cause additional vasodilation.

Finally, it is difficult to compare the results obtained by intravenous and duodenal routes. When dogs were treated intravenously only, hypotension occurred at a dose of 20 ■/pupil, whereas when administered via the duodenum, dogs treated at a dose of 10 ■/kg showed no symptoms. It was revealed that they had the same hypotension intensity.

The vasodilator effect of CRL40727 is unlikely (no tachycardia) and no bradycardia; in contrast, the tachycardia-inducing effect of isoproterenol is reduced. Furthermore, even after the cumulative dose was 38.5 μ/kg by intravenous administration,
It should also be noted that the bile remains yellow.

B) CRL40827 (3) CRL40
A solution of 827 in distilled water was administered intraperitoneally to male myna mice at a dose of 20 ml/kg and to male mice at a dose of 5 ml/kg.

1 The maximum non-defeat death ILD-0 for male myna rats is
64*/kg or more and 128+w/kg or less 2C
a) Mus musculus in NS Each batch of 6 mice is each administered CRL 40827 30 minutes before subcutaneous injection of apomorphine at a dose of 1 or 16 μ/pupil. CRL
When 40827 was administered at doses of 0.5 and 2 ■/pupil, particularly at 8 and 32 ■/kg, the hypothermia caused by large doses of apomorphine was clearly prevented; It is recognized that there is no

b) Rats Each batch of 6 rats received 0 apomorphine.
．． 5 ■/ktr 30 minutes before subcutaneous injection, CRL408
27 respectively. It is observed that there is no change in stereotypy induced by apomorphine in rats.

CRL 40827 for each batch of 6 rats with amphetamine.
Amphetamine (2/-) is administered intraperitoneally 30 minutes before administration. CRL 40827 is 4■/k, except for the permanent index, which has decreased.
It is noted that doses of g do not alter amphetamine-induced hyperstasis (modHy).

Each batch of 6 mice with reserpine received 2.5 W/kg i.p. of reserpine and 4 h after CR.
L40827 is administered respectively. It was observed that CRL40827 clearly inhibited reserpine-induced hypothermia starting from a dose of 0.65 kg/kg, without altering ptosis.

Each batch of 6 minnows with oxotremorine receives CRL 40827 30 minutes before administering oxotremorine 0.5 μ/dose intraperitoneally.

It is observed that at doses of 0.5 IIIr/kir or higher, CRL40827 antagonizes the hypothermia-inducing effect of oxotremorine, and this effect is very pronounced at a dose of 32 ■/kg. Also, CRL4
0827 does not alter the tremor strength induced by oxotremorine. Finally, CRL4082
7 does not alter the signs of cholinergic peripheral irritation that appear after oxotremorine administration.

In each batch of 10 mice, CR
CRL, tested 30 minutes after administering L40827
40B27 does not increase the number of incorrect movements that are punished, it does not cause any major incapacitation, and in large doses it reduces the convulsive effects of electric shock.

Thirty minutes after administration of CRL40827, mice (6 treated, 12 vs. Wl) were placed on an actimeter (ac).
tiseter) to raise the rat's activity level to 30.
Record for minutes. It was observed that CRL40827 did not substantially alter spontaneous activity in mice.

a) Mice (6 treated, 12 control) are administered CRL40827 after 18 hours in an active actimeter that is reduced by habituation to the cage. The rats are immediately replaced in their respective cages and 30 minutes later their motility is recorded over a 30 minute period. When CRL40827 is administered at high concentrations (34
coughing/klr) and appears to gently restore motility.

b) Active C, RL40 diminished by oxygen pressure-lowering attack
Thirty minutes after administration of 827, mice (10 treated, 20 control) were subjected to acute anoxia by applying vacuum [i.e., 600 mice over 90 seconds].
Reduce pressure to flHg (i.e. 8 x 10' Pascals),
Return to normal pressure in 45 seconds. ], then the eighth step was noted, in which the myna mouse was placed in an actimeter and its motility was recorded for 10 minutes. In other words, CRL40827 does not at all restore or improve the decreased motility of rats caused by being in a depressurized cage even for a short period of time.

C) Asphyxial anoxia Each batch of 10 myna rats is given 3411Ir/kf 3411Ir/kf intraperitoneally.
minutes before administration of CRL40827. At the highest dose (34/kg), CRL 40827 prevented the development of convulsions and mortality in mice by 40%.

Antidepressant-type activity could be expected for CRL 40827, given its antagonism to the hypothermia induced by apomorphine, reserpine, or oxotremorine, which affect the CNS. . These antagonistic effects are observed without anticholinergic effects, so CRL
40827 is an imipramine antidepressant (1mipr
asjnic antidepressants).

On the other hand, CRL 40827 can be distinguished from IMAO and amphetamine-type compounds, respectively, due to the lack of antagonism to reserpine-induced ptosis and the lack of stimulation of locomotion as well as cyclothymia. Briefly, CRL40827 is strongly designated 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) The following things that affect the heart and blood are observed. That is, CRL40827 acts as a hypotensive and tachycardia inducing agent in anesthetized dogs and awake but genetically hypotensive rats, and the drug acts as a hypotensive and tachycardia inducing agent in anesthetized dogs and awake but genetically hypotensive rats; This drug reduces the resistance of the blood vessels in the thighs and kidneys, lowers all peripheral resistance, reduces the function of the left hand ventricle, eliminates diastole, stimulates respiration,
In dogs, noradrenaline-induced hypertension is lowered at doses starting from 1/kg (approx.
The maximum effect is achieved at a dose of ■ / kg).

Although the local blood flow rate does not increase, the resistance decreases; this phenomenon may imply that
That is, CRL40827 appears to imply that venous drainage increases while simultaneously inducing arterial peripheral vasodilation, as cardiac blood output remains the same.

4) In dogs anesthetized with bonneptal, usually 30
The amount of bile collected per minute is 1.5 ml; CRL49
After duodenal administration of 827, bile excretion increased;
The amount is 17.5 ml when the dose of CRL40827 is 2.5 curvature/-, and when the dose is 5 ■/pupil,
2.25 so 1, and if the dose is 10 ■/- then 2.5 ml. In rats anesthetized with Nemptal, bile excretion increased by 5 w/w/CRL40827.
kg and 1-3 hours after intravenous administration at a dose of 25 kg/kg.

0, 1%, 0 of CRL40827 using guinea pigs
．． The anesthetic effect on 0.2 ml of 5% and 1% solutions was studied after subcutaneous injection (3 guinea pigs were used per 1 dose).

Each guinea pig is given physiological serum,
Administer Protin, and CRL40827.

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. CRL
40827 was confirmed to have local anesthetic effects when administered at concentrations of 0.5% and 1%.

CCRL 854
A solution of 5CRL4G854 in distilled water was used at 20sj for male mice! /− and for male rats, 5 mff1/kHz, respectively.

1 Ko-1 The maximum non-lethal dose LD-0 is 128 for myna mice.
It is more than day/pupil and less than 256cm/kg.

After implementing the method described above for CRL40827 in 2 CNS, the following was observed.

CRL40854 with apomorphine has been tested against mice by 16
When administered at a dose of 64 µ/-, the hypothermia caused by apomorphine was mildly inhibited, but there was no change in the behavior of hemorrhagic movements or cyclothymia.

In rats, CRL40854 has no effect on apomorphine-induced myelopathy.

CRL40854 with amphetamines, whose dosage is 8 and 32 ■/k
g synergistically prolongs the duration of amphetamine-induced diapause.

CRL40854 with reserpine has a dosage of 4.16 and 64
/kg mildly antagonizes the hypothermia induced by reserpine without altering ptosis.

CRL40854 with oxotremorine has a dosage of 16 and 64 μ/k.
If g, the body aS induced by oxotremorine
SSS lower pestle attack use length. This does not alter agitation, nor does it alter the signs of cholinergic peripheral stimulation.

CRL 40854, like CRL 40827, ensures that the number of penalized incorrect movements does not increase and that no major incapacitation occurs;
It does not change the convulsion-inducing effect of electric shock.

CRL40854 modestly reduces spontaneous activity in mytina when administered at high doses (64af/!r).

a) Active CRL4 decreases due to habituation to the cage
0854 cannot clearly restore motility in cage-habituated myna rats.

b) Active CRL408 diminished by hypoxic challenge
54, like CRL40827, does not improve hyperthermia in recovery of motility in mice.

C) Asphyxial anoxia CRL40854 does not improve the occurrence of convulsions, nor does it improve the occurrence of death associated with anoxia caused by oxygen deprivation (curare anesthesia).

In conclusion, CRL40854 reduces intergroup aggression in mystic mice and has surprising results as a conventional sedative and antidepressant.

In clinical practice, CRL 40727. CRL 4082
7, and CRL 40827A have shown good results as sedatives and antidepressants in the psychiatric field.

Among others, CRL 40727 and CRL 40827
A. When administered to humans in the form of tablets or gelatin-coated capsules containing 5 μg of each active ingredient, 3 tablets or 3 capsules per day, each of these has shown excellent results as an antidepressant. Indicated.

Claims (1)

[Claims] (1) The following formula▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [However, in the formula, A is CO or CHOH, and R is CH(CH_3)_2 or C(CH_3)_3. ] Among the compounds belonging to the fluorophenacyl-amine derivative system represented by N-(4-fluorophenacyl)-
Isopropylamine, N-(2-fluorophenacyl)
-t-butylamine, 1-(2-fluorophenyl)-
At least one compound selected from the group consisting of 2-t-butylamino-1-ethanol, 1-(4-fluorophenyl)-2-t-butylamino-1-ethanol, and addition salts of these compounds. A therapeutic composition comprising, together with a physiological excipient, a pharmaceutically effective amount of.