JPH029577B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to fluorophenacyl-amine derivatives as new industrial products. In the description of the specification described below, “fluorophenacyl-amine (fluorophenacyl-amine)
amine) derivative has the formula F―C ₆ H ₄ ―CO―CH ₂
- does not mean only the compound having a fluorophenacyl group represented by the formula F-C ₆ H ₄ -CHOH-CH ₂ - which is derived by reducing the carbonyl group of this compound to an alcohol group. It also means a compound having a β-hydroxy-fluorophenacyl group represented by 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 contains 1-(fluorophenyl), 1-(chlorphenyl), 1-
(bromphenyl) and 1-(iodophenyl)
There is nothing to disclose about derivatives,
It should also be noted that there is no suggestion of its potential action on the CNS. 2-Amino-1-(fluorophenyl)-1-
It is known that fluorophenacyl-amine derivatives belonging to the ethanol family have already been disclosed. In particular, AMLANDS' J.
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 in the paper published in Also, Il Farmaco Ed. of L.VILLA et al.
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, novel fluorophenacyl-amine derivatives acting on the CNS have shown particularly advantageous antiaggressive properties from a therapeutic point of view.
properties). That is, the present invention is based on 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-( 4
-fluorophenyl)-2-t-butylamino-
The present invention is a fluorophenacyl-amine derivative selected from the group consisting of 1-ethanol and addition salts of these compounds. Among these substances, the preferred compound from a therapeutic point of view is N-(4-fluorofenacyl).
-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. Acid 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 and CH ₃ Cl.
can be mentioned. Acid addition salts are suitable salts, of which the hydrochloride is particularly advantageous. The fluorophenacyl-amine derivative according to the present invention can be produced by a method known per se applying a conventional reaction mechanism. Recommended manufacturing methods are as follows: (1) In alcohol, preferably methanol,
under reflux for at least 1 hour, a fluorophenacyl halide of the formula: (However, in the formula, X ₁ is Cl or Br.) An amine represented by the following formula, H ₂ NR () (However, in the formula, R is as defined above.)
to form a “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 sedative agents, antidepressants, and antiaggressive agents;
It is indicated for use in the treatment of depressions. The compounds of the invention are recommended for application in therapeutic compositions, which are 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 only in a pharmaceutically effective amount. Comparative tests have been carried out to clarify these effects on animals, which have made it possible to clearly and effectively distinguish the substances according to the invention from known fluoride analogues. From the above tests,
I decided to outline the tests for anti-aggression.
More specifically, we evaluated the reduction in aggressiveness between groups as follows: A single cage of mice was divided in the center by an opaque partition, and mice were allowed to live on each side for 3 weeks. Thereafter, 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. 30
After 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 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. These results reveal the following: (i) Substances according to the present invention (Examples 1-
3) are their known analogues (CP1 to CP4)
(ii) There is no structure-activity relationship.

[Table] Some production examples are described below, but the present invention is not limited to these. Production example: Obtaining N-(4-fluorofenacyl)-isopropylamine hydrochloride (Example 1; code number: CRL40727) 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-fluorofenacil)-t-butylamine hydrochloride (Example 2; Code number: CRL40828) 50 g (0.362 mol) of orthofluoroacetophenone is dissolved 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 tertiobutyiamine dissolved 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-(4-fluorophenyl)-2-t-butylamino-1-ethanol hydrochloride (Example 3; Code number: CRL40854) 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,
39g 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. After this _and vacuum drying over _P2O5 ,
44 g of CRL40854 is obtained (yield: 61%). melting point
176℃. Tests have been carried out on suitable materials according to the invention, which will be summarized below. (A) Test on CRL40727 (Example 1) 1 Toxicity Maximum non-lethal dose (Example 1)
dose) LD-O is 128 mg/Kg or more and 256 mg/Kg or less when administered intraperitoneally to mice. 2 Effects on the CNS CRL40727 has many sedative effects. - sedation and attenuation of reactivity in mice; - attenuation of locomotion and aggression in mice; - hypothermia and synergistic effect on the hypothermia-inducing effects of apomorphine, oxotremorine, and amphetamine; mild antagonism to the stereotypy induced by this. 3 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)
- A hydrochloride of a ketone, which has a British patent no.
1325192, its code number is LL1656, which is
It is commercially available under the name FONZYLANE. This is administered intravenously at 6 mg/Kg. The flow rate of the femoral artery is, for LL 1656,
It was found that the increase was not as great as when CRL40727 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, a dose of 2.5-5 mg/Kg clearly increases the flow rate of the femoral artery; this effect does not increase with increasing dose, but only slightly. be. A hypotensive effect appears from a dose of 10 mg/Kg. Dose
From 2.5 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 is reduced. Furthermore, it is noteworthy that the bile remains yellow even after the cumulative dose is 38.5 mg/Kg intravenously. (B) Test on CRL40854 (Example 3) A solution of CRL40854 in distilled water was administered to male mice at a volume of 20 ml/Kg.
Each drug was administered intraperitoneally to male rats at a volume of 5 ml/Kg. 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 ptosis. 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. four plate test, towing,
and Effects on Electric Shocks CRL40854, like CRL40827, ensures that the number of incorrect movements that are penalized does not increase, and that no major incapacitation occurs. On the other hand, it does not change the convulsion-inducing effect of electric shock. Effects on spontaneous propriomotility CRL40854 modestly reduces spontaneous locomotion in mice when administered at high doses (64 mg/Kg). Effects on some behaviors impaired by various drugs (a) Activity diminished by habituation to the cage CRL40854 cannot clearly restore motility in mice accustomed to the cage. (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 (curare anesthesia) caused by oxygen deprivation. In conclusion, CRL40854 reduces intergroup aggression in mice and has surprising results as a conventional sedative and antidepressant. In clinical practice, CRL40727 has shown good results as a sedative and antidepressant in the psychiatric field and is administered in the form of tablets or gelatin-coated capsules containing 5 mg of this active ingredient 3 times a day.
When administered to humans as tablets or 3 capsules, each of these showed excellent results as an antidepressant.

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-( 4
-fluorophenyl)-2-t-butylamino-
A fluorophenacyl-amine derivative selected from the group consisting of 1-ethanol and addition salts of these compounds.