JPH0376287B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to antidepressants containing fluorophenacyl-amine derivatives as new industrial products.

In the description below, "fluorophenacyl-amine" (fluorophenacyl-amine) is used.
amine) derivative has _the formula F- _C6H4 -CO- _CH2-
This does not mean only compounds having a fluorophenacyl group represented by the formula F- _{C6H4 -} CHOH- _CH2- , which is derived by reducing the carbonyl group of this compound to an alcohol group. Also meant are compounds having the β-hydroxy-fluorophenacyl group shown.

[Prior art and problems to be solved by the invention]

Compounds of the 2-amino-1-(halogenophenyl)-1-ethanol type are disclosed in French Patent No. 1503517.
It is included in the formula described in the specification and is indicated as a diuretic inhibitor. However, the French patent does not disclose anything about 1-(fluorophenyl), 1-(chlorphenyl), 1-(bromphenyl) and 1-(iodophenyl) derivatives, and also their potential for CNS. action (potential)
It should be noted that there is no suggestion of action).

Contrary to expectations, novel fluorophenacyl-amine derivatives which act on the CNS have been found to have particularly advantageous antidepressant properties from a therapeutic point of view.

[Means for Solving the Problems] That is, the present invention solves the problem by solving the following equation [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)-2-t-butylamino-1-
Ethanol, 1-(4-fluorophenyl)-2-
The present invention is an antidepressant characterized by containing at least one compound selected from the group consisting of t-butylamino-1-ethanol and addition salts of these compounds.

Among these compounds is N-(4-fluorophenacyl)-isopropylamine and its salts, especially the hydrochloride.

The term "addition salt" refers to an acid addition salt obtained by reacting a free base represented by the formula () with an inorganic acid or an organic acid, and an ammonium salt. Among the acids that can convert the base represented by formula () 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 l and CH ₃ Cl.
can be mentioned. 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: (However, in the formula, X ₁ is Cl or Br.) By reacting an amine represented by the following formula with H ₂ NR () (wherein R is as defined above), “Carbonyl” compound (A=
(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 antidepressants and are indicated for use in the treatment of depressions.

That is, the antidepressant of the present invention contains the above-mentioned fluorophenacyl-amine derivative or a nontoxic addition salt thereof together with a physiologically acceptable excipient. Only a pharmaceutically effective amount should be administered.

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

Production example Obtaining N-(4-fluorophenacyl)-isopropylamine hydrochloride (Code number: CRL 40727) P-fluoroacetophenone 69g (0.5 mol)
is dissolved in 100 ml of acetic acid and cooled in an ice bath, and 25 ml of bromine is added dropwise to this solution. The resulting mixture is stirred for 1 hour and evaporated to dryness. residue
Take up in 100 ml of methanol and pour the solution thus obtained into a solution of 210 ml of isopropylamine in 200 ml of methanol. This is refluxed for 2 hours and evaporated 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 acetone-methanol (1:1) V/V mixture yields 17.2 g of CRL40727 (yield: 14.8%). Melting point 207℃ (decomposition).

Analysis: N% Measured value = 6.01% N% Theoretical value = 6.04% Production example Obtaining N-(2-fluorophenacyl)-t-butylamine hydrochloride (Code number: CRL 40828) Dissolve 50 g (0.362 mol) of orthofluoroacetophenone in 75 ml of acetic acid. The resulting mixture is cooled in an ice bath and 18.1 ml 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 100 ml of methanol. The solution thus obtained is poured into a solution of 132 g of tertiobutylamine 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 the desired hydrochloride salt is precipitated using hydrochloric ethanol. Add this to acetone-ethanol (1:1)
When recrystallized in a V/V mixture, CRL40828 becomes 18
g is obtained (yield=20%). Melting point = 240℃ (decomposition).

Analysis: N% Measured value = 5.74% N% Theoretical value = 5.70% Production example Obtaining 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol hydrochloride (Code number: CRL 40827) 0.04 mol N-(2-fluorophenacyl)-t
-butylamine (free base of CRL 40828),
Dissolve in 120ml of methanol. Cool to −5° C. and add 3 g of sodium borohydride. Leave this in contact for one hour. 5 ml of acetic acid
The excess remaining in the reaction medium is removed using
The NaBH ₄ is destroyed and the mixture is then evaporated to dryness. The evaporation residue is taken up in water, its pH is adjusted to 11 with 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. When this is recrystallized in acetone-ethanol (1:1) V/V mixture, CRL
8 g of 40827 was obtained (yield: 80%). Melting point = 18.5
℃.

Analysis: N% Measured value = 5.60% N% Theoretical value = 5.65% Production example Obtainment of 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol fumarate (Code number: CRL 40827 A ) When 1-(2-fluorophenyl)-2-t-butylamino-1-ethanol (the free base obtained in the production example) and fumaric acid are reacted,
CRL40827A is obtained. Melting point = 195~200℃
(Disassembly).

Production example: Obtaining 1-(4-fluorophenyl)-2-t-butylamino-1-ethanol hydrochloride (Code number: CRL 40854) α-chloro-p-fluoroacetophenone 50g
(0.289 mol) is dissolved in 900 ml of methanol. The resulting mixture was cooled to -5°C and
Add 5.80g of _NaBH4 . This is left in contact for 1 hour and then 10 ml of acetic acid are added. 151 ml of t-butylamine are added and the resulting mixture is refluxed for 12 hours. Evaporate this to dryness,
Take up the evaporation residue in distilled water. If you take the crystallized free base and recrystallize it in hexane,
39 g of 1-(4-fluorophenyl)-2-t-butylamino-1-ethanol is obtained (yield: 63
%). Melting point = 117℃.

When this base is dissolved in diethyl ether and treated with hydrochloric acidic ethanol, the hydrochloride salt precipitates. Take this and vacuum dry it over P ₂ O ₅ .
44 g of CRL40854 is obtained (61% yield). Melting point=
176℃.

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

Tests have been carried out on suitable compounds according to the invention, which are summarized below.

(A) Tests related to CRL40727 1 Toxicity Maximum non-lethal dose
dose) LD-O is 128 mg/Kg or more and 256 mg/Kg or less when administered intraperitoneally to mice.

2. Effects on the cardiovascular system (a) Intravenous administration CRL40727 was given at 0.1 mg/day to two dogs.
Kg, 1mg/Kg, 2.5mg/Kg, 5mg/Kg, 10
Doses of mg/Kg and 20 mg/Kg are perfused intravenously for 6 minutes. Then, these arterial blood pressure, pulse (cardiac frequency), femoral artery flow rate, and rectal temperature are measured.

The following is observed.

CRL40727 increases femoral artery flow rate at doses starting from 1 mg/Kg; this effect increases up to 10 mg/Kg, reaching +140%.

From a dose of 5 mg/Kg, differential arterial blood pressure increases; diastolic and mean arterial blood pressure decreases from 10 and 20 mg/Kg, respectively.

The pulse does not change rapidly.

At doses of 2.5-10 mg/Kg, the skin becomes pink.

Bile remains yellow; rectal temperature does not change.

Tachycardia induced by isoprenaline is reduced, with pulses averaging 182 beats/min at doses above 10 mg/Kg, compared to 215 beats/min in the control group; hypotension The disease does not change.

The following study was conducted as a supplement; when a dog was given an additional dose of 40 mg/Kg of CRL40727 intravenously, hypotension progressed further than with the previous dose. and the bile remains yellow; a second dog receives control drug. It is (2,4,6-trimethoxyphenyl)-3-pyrrolidinopropyl)-
It is a hydrochloride of a ketone and has a British patent no.
1325192, its code number is LL 1656, which is
It is commercially available under the name FONZYLANE. This is administered intravenously at 6 mg/Kg. Femoral artery flow rate is CRL for LL1656
It was found that the increase was not as great as when 40727 was administered at 10 mg/Kg.

(b) Intraduodenal administration CRL40727 was administered at 1 mg/day to three dogs.
Kg, 2.5 mg/Kg, and 10 mg/Kg intraduodenally. Measure the same parameters as described above. The following is observed.

According to CRL40727, there is a clear increase in femoral artery flow rate at a dose of 2.5 mg/Kg; this effect does not increase with increasing dose, but only slightly. . From dosage 10mg/Kg,
A hypotensive effect appears. dosage 2.5
From mg/Kg, the skin becomes very pale pink.

Bile remains yellow. Rectal temperature remains unchanged.

Tachycardia induced by isoprenaline is reduced. Pulse is CRL40727 10mg/Kg
With subsequent doses, the average is 165 beats/min.
On the other hand, in the control area, 220 beats/min (beats/minute)
min) is reached. Hypotension remains unchanged.

The following supplementary test was carried out; one dog was given an additional dose of 20 mg/Kg intraduodenum. Furthermore, a greater hypotensive effect is observed without an accompanying vasodilating effect. Identical results at the end of the test
It was also obtained in another dog that received 5 mg/Kg of CRL40727 intravenously. Furthermore, subsequent intravenous injection of LL1656 at a dose of 6 mg/Kg did not cause additional vasodilation.

Finally, it is difficult to compare the results obtained by intravenous and duodenal routes. If a dog is treated intravenously only, a dose of 20 mg/Kg will cause hypotension, whereas if administered via the duodenum, a dog treated with a dose of 10 mg/Kg will show the same hypotension. It was revealed that the blood pressure was strong.

The vasodilatory effect of CRL40727 is probably due to the β ⁺ ₂ effect; no β ⁺ ₁ effect (no tachycardia) and no bradycardia; in contrast, the tachycardia-inducing effect of isoproterenol descend. Furthermore, it is noteworthy that the bile remains yellow even after the cumulative dose is 38.5 mg/Kg intravenously.

(B) Test on CRL40827 A solution of CRL40827 in distilled water was administered intraperitoneally to male mice at a dose of 20 ml/Kg and to male mice at a dose of 5 ml/Kg, respectively. administered.

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

2 Effects on the CNS Interaction with apomorphine (a) Mus musculus CRL40827 was administered to each batch of 6 mice 30 minutes before subcutaneous injection of apomorphine at a dose of 1 or 16 mg/Kg.
Administer each. When CRL40827 was administered at 0.5 and 2 mg/Kg, especially at 8 and 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 is administered CRL 40827 30 minutes prior to subcutaneous injection of 0.5 mg/Kg apomorphine.
No change in stereotypy induced by apomorphine in rats is observed.

Interaction with amphetamine Each batch of six rats was given CRL
Thirty minutes before administering 40827, amphetamine (2 mg/Kg) is administered intraperitoneally. It was noted that CRL 40827 did not modify amphetamine-induced stereotypy at a dose of 4 mg/Kg, except for the stereotypy index, which was reduced. Ru.

Interaction with reserpine In each batch of six mice,
Four hours after reserpine is administered 2.5 mg/Kg intraperitoneally, CRL40827 is administered, respectively.
CRL40827 clearly inhibited reserpine-induced hypothermia from a dose of 0.5 mg/Kg.
Moreover, it was recognized that there was no change in droop.

Interaction with oxotremorine In each batch of 6 mice,
CRL40827 will be administered 30 minutes before administering 0.5 mg/Kg oxotremorine intraperitoneally. At doses higher than 0.5 mg/Kg, oxotremorine induces hypothermia.
CRL40827 is antagonistic, and this effect is 32
It is observed that there is a high degree of clarity at doses of 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 administration of oxotremorine.

4-Plate Test, Effect on Traction and Electric Shock Tests are performed 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.

Effect on spontaneous activity Thirty minutes after administration of CRL40827, mice (6 treated, 12 control) are placed in an actimeter and their activity is recorded for 30 minutes. It was observed that CRL40827 did not substantially alter spontaneous activity in mice.

Effects on some behaviors that are impaired by various drugs (a) After 18 hours, some active actimeter decreases due to habituation to the cage
Mus musculus (6 treated, 12 control)
administer CRL40827. The rats are immediately replaced in their respective cages and 30 minutes later their motility is recorded over a 30 minute period. CRL40827 administered at high concentrations (34 mg/Kg) appears to modestly restore motility.

(b) Activity reduced by hypoxic challenge Thirty minutes after administration of CRL40827, mice (10 treated, 20 control) were induced into acute anoxia by subjecting them to vacuum [i.e. , 600mmHg over 90 seconds
(i.e., 8×10 ⁴ Pascals),
Return to normal pressure in 45 seconds. ], then
Place the mouse in the actimeter and record its motility for 10 min. The following points were noted. In other words, the decrease in mouse motility caused by being in a depressurized cage, even for a short time,
Even CRL40827 does not recover or improve this at all.

(c) Asphyxial anoxia CRL40827 is administered to each batch of 10 mice 30 minutes prior to 34 mg/Kg intraperitoneal administration of trietoiodide gallamine. At maximum dose (34mg/Kg),
CRL40827 prevented the mice from developing convulsions and inhibited them from aspirating by 40%.

Conclusions regarding effects on the CNS Given the antagonism of hypothermia induced by apomorphine, reserpine, or oxotremorine,
For CRL40827, antidepressant type activity can be expected. These antagonistic effects are observed without anticholinergic effects, making CRL40827 distinct from imipraminic antidepressants.

On the other hand, given the lack of antagonism to the ptosis induced by reserpine and the lack of stimulation of motility as well as stereotypy,
CRL40827 can be distinguished from IMAO and amphetamine-type compounds, respectively.
Briefly, CRL40827 is strongly presumed to behave as a beta-adrenergic stimulant.

(1) Effect on bile secretion In dogs anesthetized with Nembutal, the amount of bile collected in 30 minutes is normally 1.5
ml; after duodenal administration of CRL40827, bile excretion increased;
When the dose of CRL40827 is 2.5mg/Kg,
If the dose is 17.5ml and the dose is 5mg/Kg,
2.25ml and if the dose is 10mg/Kg then 2.5ml. In rats anesthetized with Nembutal, bile excretion was
Increases 1-3 hours after intravenous administration of CRL40827 at doses of 5 mg/Kg and 25 mg/Kg.

(2) Local anesthetic effect Using guinea pigs, 0.1 of CRL40827
0.2 ml of solutions with %, 0.5%, and 1% concentrations,
After subcutaneous injection (using 3 guinea pigs per dose), the anesthetic effect on them was studied. Physiological serum, procaine, and CRL40827 are administered to guinea pigs at designated sites.

5 minutes, 10 minutes, 15 minutes, 20 minutes after injection
The test is carried out by administering a series of 6 injections every 1, 25, and 30 minutes at the site where the injections were made. When CRL40827 was administered at concentrations of 0.5% and 1%,
It was confirmed that it has a local anesthetic effect.

(C) Test on CRL40854 A solution of CRL40854 in distilled water was administered to male mice at a volume of 20ml/Kg.
A dose of 5 ml/Kg was intraperitoneally administered to male rats.

1. Toxicity The maximum non-lethal dose LD-O for mice is 128 mg/Kg or more and 256 mg/Kg or less.

2 Effect on CNS The above method was carried out for CRL40827, and the following was observed.

Interaction with apomorphine CRL40854 moderately inhibited the hypothermia of apomorphine when administered to mice at doses of 16 and 64 mg/Kg, but in this case CRL40854 moderately inhibited the hypothermia effect of apomorphine; There is no change in behavior.

In rats, CRL40854 does not alter apomorphine-induced stereotypy.

Interaction with amphetamine CRL40854 has a
Kg synergistically prolongs the duration of stereotypy induced by amphetamine.

Interaction with reserpine
mg/Kg mildly antagonizes the hypothermia induced by reserpine without altering droop.

Interaction with oxotremorine CRL40854 has a
Kg enhances the hypothermia-inducing effect induced by oxotremorine. this is,
It does not alter tremor, nor does it alter signs of cholinergic peripheral stimulation.

Effects on the four plate test, traction, and electric shocks CRL40854, like CRL40827, ensures that the number of incorrect movements penalized does not increase and that no major incapacitation occurs. do not have. On the other hand, it does not change the convulsion-inducing effect of electric shock.

Effects on spontaneous eigentropy CRL40854 modestly reduces spontaneous activity in mice when administered at high doses (64 mg/Kg).

Effects on some behaviors impaired by various drugs (a) Activity reduced by cage habituation CRL40854 cannot clearly restore motility in cage-accustomed mice.

(b) Activity decreased by hypoxic challenge CRL40854, like CRL40827,
No improvement in motility recovery 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 has surprising results as a conventional antidepressant.

In clinical practice, CRL40727, CRL40827, and
CRL40827A has shown good results as an antidepressant in the psychiatric field. Above all,
CRL40727 and CRL40827A, when administered to humans in the form of tablets or gelatin-coated capsules containing 5 mg of each active ingredient at 3 tablets or 3 capsules per day, each have excellent results as antidepressants. showed that.

Also, to explain the results of a clinical trial conducted on 61 patients with depressive syndromes:
Thirty of the above patients received a placebo, and the remaining 31 received a placebo.
CRL40827 was orally administered at 1 to 4 mg for 40 days. In this case, in the latter case, an administration method was adopted in which the dose was increased by 1 mg every 10 days, such as 1 mg for the first 10 days and 2 mg for the next 10 days.

In terms of medicinal efficacy, the effects include "feeling relaxed,""feelinganxious,""feeling like you want to do something,""feelingtired,""feelingirritable,""feelinghappy,""feeling in good shape (fitness),"
The following items were investigated: ``feeling sad'', ``feeling like to have a conversation'', ``feeling optimistic'', and ``feeling like wanting to sleep''.

As a result, CRL40827 showed 11 more
It was found that it showed excellent antidepressant effects in all of the evaluation items, and particularly remarkable medicinal efficacy in the evaluation items of "happy mood,""goodmood," and "mood like to have a conversation."

Additionally, neither CRL40827 nor the placebo increased drug tolerance in patients.

Furthermore, the optimal ratio of efficacy/tolerance for CRL40827 was obtained at a dosage of 3 mg/day.

Claims (1)

[Claims] 1. [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)-2-t-butylamino-1-
Ethanol, 1-(4-fluorophenyl)-2-
An antidepressant comprising at least one compound selected from the group consisting of t-butylamino-1-ethanol and addition salts of these compounds.