Method of producing n-/2-(4-fluorophenyl)-1-methyl/ethyl-n-methyl-n-propynylamine as racemate or its

专利摘要:
New N-[2-(4-fluoro-phenyl)-1-methyl]-ethyl-N-methyl-N-propynyl amine of the general formula (I), and isomers and salts thereof. The compound of the formula (I) is useful as medicine. The compound of the formula (I), may be prepared by methods known per se.
公开号:SU1549477A3
申请号:SU864027666
申请日:1986-06-16
公开日:1990-03-07
发明作者:Эчери Золтан；Кнолл Йожеф；Шомфаи Ева；Терек Золтан；Синньеи Ева；Можолич Карой
申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of a novel compound (4-fluorophenyl) -1-methyl-ethyl-M-methyl-N-propinylamine () and its salts, which are obtained in the form of a racemate or an optically active isomer, have an antidepressant effect, this inhibitor of the absorption of biogenic amines, and by virtue of the indicated properties, can be used in medicine.
The purpose of the invention is the discovery in the series of N-phenylisopropylalkylamines of new compounds with a higher antidepressant activity in combination with a selective MAO-B effect.
Example 1 1.72 g of 1- (4-fluorophenyl) -2-chloropropane and 1.4 g of N-methyl propargylamine are heated in a sealed tube for 5 hours. The reaction mixture is dissolved in 30% aqueous ethanol containing hydrochloric acid and evaporated. From the residue, 0.35 g of hydrochloride (i:) - N-Meran-N- (2-propynyl) -2- (4-fluorophenyl) -1-metshG ethylamine is obtained. Mp. 130-132 ° C.
Example p20 8.6 g (0.05 mol)
3 mm Hg
  1.5072) is dissolved in 16 ml of acetone, to which 2.65 g of methyl iodide is added. The mixture is heated under reflux for 2 hours, then filtered and evaporated. The residue is dissolved in a 10% hydrochloric acid solution, clarified and filtered. The filtrate is alkalinized and extracted with loluol. After drying, the toluene solution is acidified with an ethanolic solution, hydrochloric acid. The precipitated product is filtered and dried. Thus obtained 2.1 g
J5 hydrochloric (i) -N-MeTHn-N-propynyl-J2- (4-fluorophenyl) -1-methyl-ethylamine, t, pl0 131 133 ° C.
PRI me R 4. 16,72 g (0.1 mol) of (Ј) -N-methyl-2- (4-fluorophenyl) -1-me1- (4-fluorophenyl) -2-chloropropane and 25 ml Type 20-ethylamine, prepared according to the method described in Example 2, is reacted with 7.5 g (0.05 mol) of D-tartaric acid dissolved in 1.4 ml of water and 5 g (0 S05 mol) 37 % hydrochloric acid for 5 h at 0-5 ° C. The salt that separated was filtered out and washed with water.
10 g (0.028 mol) of 13.9 g of the (Ј) -I-methyl-2- (4-fluorophenyl) -1-methyl-di-hydramide-citrate dehydrate thus obtained (t.pl 88-91 ° C) solution the solution is alkalified and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is dissolved with 60 ml of acetone, then up to 25% methylamine is reacted in a sealed tube for 5 hours at 70-800СТС. The mixture is cooled, basified and extracted with benzene. The combined organic 25 phase is dried, filtered and evaporated. The residue is distilled in vacuum,
4.6 g of (th) -N-methyl-2- (4-hfluorophen, l) -1-methyl-ethylamine thus obtained (mp, 87-90 ° C, 10
mm
Hg, 1.4920) is dissolved in 48 ml of acetone, to which 25.28 g (0.19 mol) of potassium carbonate is added, then 4s0 g (0.034 mol) of distilled propargyl bromide is added dropwise with stirring. The reaction mixture is stirred for 3.5 hours at 55 ° C, then cooled and filtered, washed with acetone and -1 the filtrate is evaporated. The residue is distilled in vacuo.
Thus, (±) - N-methyl-III-propynyl-2-(4-fluorophenyl) -1-methyl-ethylamine is obtained. Bp 120 - 122 ° С, 10 mm of mercury “st., P ™ 1,5050,
Example 8.34 g (0.03 mol) of 1- (4-fluorophenyl) -2-propyl p-tol urol sulfonate and 8.26 g of W-propargylamine are reacted in a sealed tube for 5 hours at 110 ° C. The mixture is dissolved in benzene, then extracted with aqueous hydrochloric acid. The aqueous layer is alkalinized, extracted with benzene, dried, filtered and evaporated. The residue is distilled in a vacuum.
2.65 g of the thus obtained (±) -N-propinyl 2- (4-fluorophenyl) -1 - metshG-ethyl amine (so kip. 117-126 C.
thirty
35
40
45
50
55
22E5 g (0816 mol) of potassium carbonate was added, and then a 60% toluene solution of 5.96 g of propargyl bromide was added dropwise with stirring. The reaction mixture was stirred for 3 hours, then filtered and evaporated. The residue was dissolved in toluene and extracted with 0% hydrochloric acid solution. The aqueous extract is basified and extracted with toluene. After drying, the toluene solution is acidified to pH b with a 31% ethanolic solution of hydrochloric acid. The product is filtered, washed with acetone and dried.
In this way, 2.0 g of hydrochloric (±) -M-methyl-I-propinyl-2- (4-fluorophenyl) -1-methyl-ethylamine is obtained. Heat, 1 68-1 70 ° С, 10.89 ° - (water, с 2.5),
PRI me R 5 „16.77 g (0.05 mol) of 1-4-nitrophenyl-2-propyl-p-toluene 3 mm Hg,
  1.5072) is dissolved in 16 ml of acetone, to which 2.65 g of methyl iodide is added. The mixture is heated under reflux for 2 hours, then filtered and evaporated. The residue is dissolved in a 10% hydrochloric acid solution, clarified and filtered. The filtrate is alkalinized and extracted with toluene. After drying, the toluene solution is acidified with an ethanolic solution, hydrochloric acid. The precipitated product is filtered and dried. Thus obtained 2.1 g
5 hydrochloric (i) -N-MeTHn-N-propynyl-J2- (4-fluorophenyl) -1-methyl-ethylamine, t, pl0 131 133 ° C.
EXAMPLE 4 16.72 g (0.1 mol) of (Ј) -No-methyl-2- (4-fluorophenyl) -1-me0 type of ethylamine, prepared according to the method described in Example 2, reacted with 7.5 g (0.05 mol) of D-tartaric acid dissolved in 1.4 ml of water and 5 g (0 S05 mol) of 37% hydrochloric acid for 5 hours at 0-5 ° s The salt that separated was filtered out and washed with water.
thirty
35
0
five
0
five
22E5 g (0816 mol) of potassium carbonate was added, and then a 60% toluene solution of 5.96 g of propargyl bromide was added dropwise with stirring. The reaction mixture was stirred for 3 hours, then filtered and evaporated. The residue was dissolved in toluene and extracted with 0% hydrochloric acid solution. The aqueous extract is basified and extracted with toluene. After drying, the toluene solution is acidified to pH b with a 31% ethanolic solution of hydrochloric acid. The product is filtered, washed with acetone and dried.
In this way, 2.0 g of hydrochloric (±) -M-methyl-I-propinyl-2- (4-fluorophenyl) -1-methyl-ethylamine is obtained. Heat, 1 68-1 70 ° С, 10.89 ° - (water, с 2.5),
PRI me R 5 „16.77 g (0.05 mol) of 1-4-nitrophenyl-2-propyl-p-toluene-methyl-1U-propynyl-2- (4-fluorophenyl) - 1-methyl | - ethylamine. Bp 120-122 ° C, 12 mmHg, g4 ° 1.5054.
Example 6: 8.28 g (0.0495 mol) () -G} -methyl- 2- (4-fluorophenyl) -1-methyl-M-ethylamine is dissolved in 45 ml of toluene. To the resulting solution, 0.078 g of benzyltriethylammonium chloride was added and 6.48 g (0.0545 mol) of propargyl bromide were added in parallel and a solution of 2.17 g (0.0543 mol) of sodium hydroxide was added dropwise with stirring over 5 minutes. 7.5 ml of water. The temperature of the reaction mixture rises from 23 to 2 ° C, the reaction mixture is stirred at 26-28 ° C for 20 hours, after which the phases are separated, and the toluene layer is dried over anhydrous sodium sulfate and evaporated. The residue is distilled at 80-82 ° C, 0.1 mm Hg. The result of 5.05 g (±) -M-methyl-G1
515
the sulfonate is reacted with 7 g (0, mol) of N-methylpropylamine in a sealed tube for 5 hours at 70-80 ° C. After cooling, the reaction mixture was dissolved in a 30% ethanolic hydrochloric acid solution and evaporated. The residue is repeatedly crystallized from ethanol.
5 g (0.018 mol) of 6.7 g of N-methyl-M-propinyl-2- (4-p-aminophenyl) -1-methyl-ethylamine hydrochloride thus obtained (mp, 164-167 ° C) is dissolved in a mixture of 10 ml of water and 3 ml of concentrated hydrochloric acid, after which 4.7 g of zinc dust is added. The reaction mixture is stirred for 2 hours at 75 ° Co. Then the solution is alkalinized and extracted with benzol. The organic layer is dried and filtered, then evaporated. In this way, 5 g of crude (g) -H-methyl-M-propynyl-2- (4-aminophenyl) -1-me-ethylamine type are obtained, which are diazotized in a fluorine-boric acid medium. The diazonium fluoroborate thus obtained is decomposed with copper chlorine () at 80 C. A (Ј) - K-methyl-HT-propynyl | 2- (4-fluorophenyl) -1-methyl ethylamine. The mixture is alkalized and extracted with benzene. The organic layer is dried, filtered and evaporated. The residue is distilled under vacuum.
Thus, 1.7 g (±) are obtained.



N
propinyl-2- (4-fluorophenyl) 1-methyl-ethylamine, 1, 5050.
The hydrochloride of this substance has so pl. 132-133 ° C (from ethanol and ether)
Calculated,%: C 65.59; H 7.09;
5.79; C1 14.66; F 7.85,
N
C H17 NC1F
Found,%: C 65.00; H 6.97; 5.95; C1 4.90; F 8.01,
EXAMPLE 7, 3.38 g (0.022 mol) (±) -N-methyl- 2- (4-fluorophenyl) -1-methyl-ethylamine was dissolved in 35 ml of acetone, after which 19 g (0.14 mol) of potassium carbonate and with stirring, over 10 minutes, 2.95 g (0.025 mol) of distilled propargyl bromide are added dropwise. The temperature of the mixture is raised from 22 to 25 ° C. The reaction mixture is heated for 3.5 hours at 55 ° C and under stirring. Then the reaction mixture was incubated overnight, filtered, washed three times with 25 ml portions of acetone and the acetone filtrate was evaporated. The residue is distilled at a pressure of 2 mm Hg. 2.28 g of (±) -M-methyl-N-propinyl-2- (4-fluorophenyl} -methyl-ethylamine are obtained as a result. Yield 51.7%. Bp, 12 mmt, art.
1le
 1.5050 „
Synthesized in the implementation of the proposed method, the compound was tested for pharmacological activity.,
0
0
five
The following notation is used: 1A-hydrochloride of (i) -N-MeTnn-N-L (2-propynyl) -2- (4-fluorophenyl) -1-methyl) ethylamine (PPP); (B) -N-methyl-N- (2-propynyl) -2- (4-fluorophenyl) -1-methyl-ethyl amine 1B-hydrochloride; pC1P hydrochloride (+) -L-methyl-N- Ј (2-g pininyl) -2- (4-chlorophenyl) 1-metagG | -ethyl-amine; pBrP (+) - and-methyl- W (2-propinyl) -2- (4-bromophenyl) -1-methylJ-ethylamine hydrochloride.
1, Monoamine oxidase (MAO) inhibitory activity.
1.1, In Vitro Testing ,,
1.1.1. Measurement in the brain homogenizate and rat liver freed from the cell core. Substrates: MAO-B: 4C-PEA-: 0.2 mM, special “activity 0.5 | KC1 / ml MAO-Ag 14C-5NT-: 5, 0 mM, spec. activity (0.25 (UCi / ml
The results are shown in table 1.
715
1.1.2 Measured by rat brain mitochondria,
Method: From the brain of male rats of the CFy species weighing 200-250 g, mitochondria were obtained as follows.
After decapitation, tissue homogenization was obtained in 0.25 M sucrose, It was centrifuged for 15 min at 9000 rpm. and the precipitate was applied to 0.25 M sucrose.
Substrates: MAO-A: 6x10 M 5NT, MAO-B: PEA0 Results: Values (M) of Compound 1A: MAO-A: 5 x, MAO-B: 3 x.
1.2, In vivo testing, evaluated in brain homogenizate and ne
cheni rats freed from the cell core. Method: The rats were treated subcutaneously with different doses of the substances and 4 hours after the substance was injected the organs were removed and the MAO activity was determined as described in 1.1.1.
The results are shown in table 2. After treatment, which lasted for 21 days / daily dose of 0.25 mg / kg, sc, compound 1A) MAO-B inhibition was 92–94%, expressed as a percentage of control, and MAO-A inhibition was 0% .
2o Inhibitory activity of tyramine absorption in the pulmonary arteries of rabbits.
Rabbits of both sexes and weighing 2-4 kg were used for the experiments. The faces were euthanized by a blow to the neck and the heart was immediately removed and placed in an oxygen-blown Krebs solution. The composition of the Krebs solution, mmol / l: NaCl 111; KC1 4.7; CaCl2.52 MgS04 1.64; NaHC03 25; KH4POq 1.2; glucose 11. The blood vessel was cleared of connective tissue and a 1.5 mm wide helix was cut out of the tissue. The blood vessel segment obtained in this way was placed in an organ bath containing Krebs solution through which a gas mixture consisting of 95% 02 + 5% COj was passed and which was thermostatic at 37 ° C. Mechanical activity
was registered on a semi-isometric compensator, using 1 g of a predetermined load.
Tyramine absorption was inhibited on the above preparation.
eight
0
five
five
0
Q
five
0
five
0
five
compound 1B depending on the dose IDSO 4, 5x1 Mo
The results are shown in table 3.
3, Inhibition of the absorption of biogenic amines,
4 o Activities that stimulate the activity of external phenethylamine (PEA) (in vivo MAO-B).
4.10 Stimulating blink membrane of anesthetized cats
The flashing membrane shrinks when an intravenous dose of PEA is administered. Compression activity curves from PEA are doses that are dependently shifted to the left upon intravenous administration of compound 1A at a dose of 0.1 or 0.25 mg / kg.
4.2. Increasing the dose of PEA inducing stereotypical behavior.
The results are shown in table 4.
The activity induced by PEA at a dose of 50 mg / kg is potentiated by compound 1A at doses of 0.5-0.25 mg / kg subcutaneously, depending on the dose.
5. Tests of the central nervous system
5.1, Modified Shudder Test.
Compound 1A does not inhibit the avoidance reflex in rats at a dose of 15 mg / kg (method: Knoll, 1963).
5.2. Metabolic rate, Compound 1A at a dose of 5 kg / kg
does not increase metabolism (metabolism) in rats,
5.3, Activity testing on food consumption.
Tests were carried out after 96 h of starvation of rats (p. 10-13).
When Compound 1A was administered subcutaneously at a dose of 5 mg / kg, mainly one-hour food intake was significantly reduced, and when higher doses were used (10-15 mg / kg, subcutaneously), the five-hour food intake was significantly reduced.
5.4. Effect on catalepsy, Catatoni, inducible tetrabenes
otherwise, at a dose of 3 mg / kg, it inhibits, depending on the dose of both compounds 1A and IB. LD50-1A 2.6 mg / kg; LDgp-lB 2.9 mg / kg.
6. Testing sexual activity of male rats.
Inert male rats, compound 1A exerts a strong, long-lasting
continuing stimulating effect. Lust-stimulating activity from a single dose of 0.1 mg / kg and 0.25 mg / kg, respectively, significantly increases the number of eoculations 24 hours and 2-3 weeks and 4 weeks, respectively, after administration of compound 1A relative to the control.
7. Toxicity.
Tests were carried out on male albino rats of the CFy species weighing 100-120 g. Compounds were administered intravenously and the animals were observed for 48 hours,
As a result, for the test substance IA, the LDSO toxicity was 60 mg / kg, for 1B - 64 mg / kg, for pC1P - 35 mg / kg,
Conducted in vitro tests on rat brain homogenates and on rat brain liver and mitochondria showed that the proposed compounds are more active and selective inhibitors of MAO-type, B, than pC1P and pBrP. Tests in vivo in rats showed that 1A (PPP) is a selective MAO-B inhibitor and is more active than pBrH
At the same time, 1A does not inhibit the absorption of tyramine in the terminal of the noradrenergic nerve in the rabbit pulmonary strip.
The biological activity of the proposed compounds is determined by three different biological actions: selective inhibition of the MAO-B type (monoamine oxidase enzyme); inhibiting the absorption of catecholamines and indirectly acting monoamines, for example tyramine; protection of the neuron against endogenous (6-OHDA) and exogenous (MRTP) selectively acting toxins.
The combination of these biological actions is extremely important for obtaining a selective and potent MAO-B inhibitor without a cheese effect.
Due to the high specific spectrum of pharmacological activity, the proposed compounds can

49477
to be used as an antidepressant by counteracting the age-related weakening of the function of a black-striped pre-reminder neuron, to improve the quality of life of old people.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining GG-Ј2- (4-fluorophenyl) -1-methyl-ethyl-M-methylpropylamine formula
-.
J5xH2-CH-tf-CH2 - C: CH
SNA SNCh
ten
in the form of a racemate or its L-isomer, or its salts, characterized in that the phenylisopropyl derivative of the formula
; H2-Shh
CH3
where X is halogen, tosylate;
Y - Fluorine, 1GO29
enter into interaction with the amine of the general formula
35
Sh
 RI
/
Where
Rr-CH2-C H
CH, H;
Kg - H, -CH ,, in the case of R - - CH2C CE, RZ - Ne, the resulting product is methylated and, in case, R2 - - CHa, s, the resulting product is then reacted with HC C-CH4Br and, in the case that J - Sh2, the product is reduced, then the resulting amino derivative is diazotized in fluoroboric acid, followed by decomposition of the diazonium fluoroborate with copper chloride and the target product is isolated as a racemate, L-isomer or its salts.
eleven
154947712
Table I
R
one
1B
1A
4.57 x 10
.-eight
4.17 x 10
1.98 x 10
238.38
r in
1, 19 x 10
580.68
with in
Selectivity index
ID so MAO-A lD5 ™ MAO-B
Table 2 IB I 1A
Li -. LiiJ
Organ
0.104 0.0765.61
0.772 0.2928.85
148.8 168,613,33
„ID so MAO-A
Selectivity index s nrx-r-.
UJyo MAu-B
3
NA: N-Norepinephrine.
5HT: 3H-5-hydroxy-tryptamine.
V "jla
DA: H-Dopamine.
IPC1R
rVgR
with in
1.48 x 3.98 x 1 x 1.64 x
43.47
51.28
Table 2 IB I 1ArVgR
i - LiiJ
Table3
13
0.25
0.1
0.05
154947714
Table
1.1 7 + 0.54 8.17 ± 0.87 5,; 49 2.83 ± 1.01

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU842124A|HU207282B|1984-05-31|1984-05-31|Process for producing phenyl-alkyl-amine derivatives and pharmaceutical compositions containing them|MD94-0136A| MD87C2|1984-05-31|1985-05-31|The process for obtaining the N-[2--1 methyl]-ethyl-N-propynylamine in kind of racemate or his L-isomer, and his salts.|

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LV930488A| LV5227A3|1984-05-31|1993-06-08|R-racemate or l-isomer form of N-U2--1-methyl--ethyl-n-methyl-n-propynylamine or its yield|

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LTRP649A| LT2175B|1984-05-31|1993-06-12|N--1-METHYL) -ETHYL-N-METHYL-N-PROPINILAMIN RECEIVING RACEMATO OR ITS L-ISOMER OR ITS SALTS|